George A. Fisher Jr.
Colleen Haas Chair in the School of Medicine
Medicine - Oncology
Bio
I conduct clinical research on a variety of gastrointestinal cancers and provide care for patients with those cancers. We have trials of combined modality therapy (surgery +/- radiation +/- chemotherapy) on gastric, esophageal, pancreas and rectal cancers. We also perform phase I and II trials of biologically targeted agents as well as newer immunotherapeutics. In collaboration with a number of colleagues, we conduct translational studies analyzing novel imaging (e.g. contrast enhanced ultrasound and perfusion scans) and molecular biomarkers (e.g. CDX2 as a prognostic and predictive factor in colon cancer and matrix metalloproteinases as prognostic factors in pancreas cancer). Neuroendocrine tumors, pancreas, colorectal and gastro-esophageal cancers have been areas of particular research focus with multiple therapeutic and translational studies devote to each. Examples of recently completed trials include a randomized phase III trial of a vaccine (algenpantucel) for resected pancreas cancer, phase Ib trial of anti-PD-L1 and separate phase II trials using PD-1 antibody for tumors with micro satellite instability and chemotherapy with angiogenesis inhibitors for advanced neuroendocrine tumors and gastro-esophageal adenocarcinomas. Currently active areas of study include combining immunomodulating antibodies in combination therapy and randomized phase II colon cancer trials of an antibody to interleukin 1 or a first in class agent known as RadioRx. Participation and leadership in NCI cooperative group protocols gives our patients access to the randomized trials that hope to establish new standards of care for a variety of GI cancers.
Clinical Focus
- Cancer > GI Oncology
- Medical Oncology
- Oncology
- Cancer of the Pancreas
- Colorectal Neoplasms
- Neuroendocrine Tumors
- gastro esophageal cancer
- gastric cancer
- stomach cancer
- pancreatic neoplasms
- small intestinal cancer
- cholangiocarcinoma
- bile duct cancer
- gall bladder cancer
- carcinoid tumor
- appendiceal cancer
- anal cancer
Academic Appointments
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Professor - University Medical Line, Medicine - Oncology
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Member, Stanford Cancer Institute
Administrative Appointments
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Director, Cancer Clinical Trials Office (2004 - 2013)
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Vice Chair GI Committee, ECOG-ACRIN (2015 - Present)
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Physician Leader, GI Clinical Research Group (2010 - 2015)
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Physician Leader, GI Oncology Disease Management Group (2011 - 2015)
Boards, Advisory Committees, Professional Organizations
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Chair, 2020 GI Symposium Steering Committee (2019 - Present)
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Co-Chair Scientific Advisory Board, Neuroendocrine Tumor Research Foundation (2011 - Present)
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member, NCI GI Steering Committee, National Cancer Institute (2017 - Present)
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Member, Scientific and Medical Advisory Board, Pancreatic Cancer Action Network (2012 - Present)
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Vice Chair; GI Committee, ECOG/ACRIN (2015 - Present)
Professional Education
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Board Certification: American Board of Internal Medicine, Medical Oncology (2024)
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Medical Education: Stanford University School of Medicine (1987) CA
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Fellowship: Stanford University Hematology and Oncology Fellowship (1993) CA
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Residency: Stanford University Internal Medicine Residency (1989) CA
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Internship: Stanford University Internal Medicine Residency (1988) CA
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BS, Stanford University, Biology (1976)
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PhD, Stanford University, Cancer Biology (1987)
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MD, Stanford University, Medicine (1987)
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Residency, Stanford University, Internal Medicine (1989)
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Fellowship, Stanford University, Medical Oncology (1993)
Current Research and Scholarly Interests
Clinical expertise in GI cancers with research which emphasizes Phase I and II clinical trials of novel therapies but also includes translational studies including biomarkers, molecular imaging, tumor immunology and development of immunotherapeutic trials.
Clinical Trials
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A Study to Evaluate PEEL-224 in Patients With Advanced Solid Tumors
Recruiting
This is a first-in-human, dose escalation, repeat-dose, multi-center, open-label study evaluating safety, tolerability, PK, and preliminary antitumor activity of PEEL-224 in patients with advanced solid tumors.
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A Study Using [18F]F AraG PET to Evaluate Response to Checkpoint Inhibitor Therapy(CkIT) in Patients With Solid Tumors
Recruiting
In this study, patients with advanced solid tumors will undergo \[18F\]F AraG PET/CT imaging to assess for changes in tracer uptake following treatment with CkIT.
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Fluorescent Probe VGT-309 to ID Cancerous Colorectal Lesions During Augmented Colonoscopy
Recruiting
The purpose of this study is to determine the safety and feasibility of VGT-309 for the visualization of colorectal tumors in real-time using near-infrared (NIR) fluorescence endoscopy. In addition, signatures of 50+ biomarkers will be evaluated in biopsies using CODEX multi-plexing.
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A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Solid Tumors
Not Recruiting
This is a Phase 1b/2, multi-center study to assess the safety and efficacy of ibrutinib in combination with durvalumab (MEDI4736) in participants with relapsed or refractory solid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Phase 1 Study of Safety and Bioactivity With FG-3019 in Combination With Gemcitabine and Erlotinib for Subjects With Locally Advanced or Metastatic Pancreatic Cancer
Not Recruiting
Objectives * Primary: To evaluate the safety and tolerability of FG-3019 in combination with gemcitabine and erlotinib * Secondary: To evaluate the efficacy and pharmacokinetics of FG-3019 in combination with gemcitabine and erlotinib
Stanford is currently not accepting patients for this trial. For more information, please contact Donna Williams, (650) 498 - 6608.
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A Phase 1-2 Trial of Cetuximab in Combination With Oxaliplatin, Capecitabine, and Radiation Therapy Followed by Surgery for Locally-advanced Rectal Cancer
Not Recruiting
The objectives of this study are to: 1. To assess dose-limiting toxicities (DLTs) of capecitabine +/- oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1) 2. To determine the maximum-tolerated dose (MTD) when capecitabine * oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1) 3. To determine the pathologic response rate of cetuximab +/- oxaliplatin in combination with capecitabine and radiotherapy (Phase 2)
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
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A Phase 1/2 Study of HKI-272 (Neratinib) in Combination With Paclitaxel (Taxol) in Subjects With Solid Tumors and Breast Cancer
Not Recruiting
The purpose of this study is to learn whether it is safe and effective to administer HKI-272 (neratinib) in combination with paclitaxel in patients with breast cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Mary Chen, (650) 723 - 8686.
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A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer
Not Recruiting
This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study. Patients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib. On progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab. Whether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.
Stanford is currently not accepting patients for this trial. For more information, please contact Rachel Kasson, 650-723-0168.
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A Phase 2 Study of Pertuzumab and Erlotinib for Refractory Pancreatic Adenocarcinoma
Not Recruiting
A phase 2 study combining pertuzumab with erlotinib for patients with gemcitabine refractory pancreatic adenocarcinoma
Stanford is currently not accepting patients for this trial. For more information, please contact Donna Collins Williams, (650) 498 - 6608.
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A Phase Ib Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Cibisatamab in Combination With Atezolizumab After Pretreatment With Obinutuzumab in Participants With Previously Treated Metastatic Colorectal Adenocarcinoma
Not Recruiting
CO40939 is a Phase Ib, open-label, multicenter, single-arm study designed to evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of cibisatamab in combination with atezolizumab administered after pretreatment with obinutuzumab in patients with Stage IV microsatellite stable (MSS) metastatic colorectal cancer (mCRC) whose tumors have high carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression and who have progressed on two or more chemotherapy regimens. The study is composed of a safety run-in and an exploratory part.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Phase II Study of Pertuzumab and Erlotinib for Metastatic or Unresectable Neuroendocrine Tumors
Not Recruiting
To determine objective response rates (RR) by RECIST guideline version 1.1 for all patients treated with this strategy consisting of initial therapy with pertuzumab as a single agent and then addition of erlotinib for those who have stable disease or progressive disease at three months (Simon design).
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
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A Phase III Study of Xilonix in Patients With Advanced Colorectal Cancer
Not Recruiting
The purpose of this study is to determine if the True Human Monoclonal antibody Xilonix (MABp1) can prolong the life of colorectal carcinoma patients that are refractory to standard therapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Flordeliza Mendoza, 650-724-2056.
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A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours
Not Recruiting
This was a multicenter, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with Lutathera plus best supportive care (30 mg Octreotide LAR) to treatment with high dose (60 mg) Octreotide LAR in participants with metastasized or locally advanced, inoperable, somatostatin receptor positive, histologically proven midgut carcinoid tumours with progression despite LAR treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Flordeliza Mendoza, 650-724-2056.
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A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC)
Not Recruiting
This open-label, exploratory study is designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or combinations, in participants with metastatic colorectal cancer (mCRC) whose tumors are biomarker positive as per treatment arm-specific definition. Eligible participants with mCRC will be enrolled into specific treatment arms based on their biomarker assay results.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Study of Aflibercept Administered in Combination With Pemetrexed and Cisplatin in Participants With Advanced Carcinoma
Not Recruiting
The purpose of the study was to determine whether the combination of aflibercept, pemetrexed and cisplatin is safe and effective in treating non-small cell lung cancer (NSCLC).
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
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A Study of ASA404 or Placebo in Combination With Docetaxel in Second-line Treatment for (Stage IIIb/IV) Non-small Cell Lung Cancer
Not Recruiting
The purpose of this study is to determine if adding ASA404 to docetaxel chemotherapy makes the cancer treatment more effective in patients with locally advanced or metastatic non-small cell lung cancer
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
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A Study of Atezolizumab (an Engineered Anti-Programmed Death-Ligand 1 [PDL1] Antibody) to Evaluate Safety, Tolerability and Pharmacokinetics in Participants With Locally Advanced or Metastatic Solid Tumors
Not Recruiting
This Phase I, multicenter, first-in-human, open-label, dose-escalation study will evaluate the safety, tolerability, and pharmacokinetics of atezolizumab (MPDL3280A) administered as single agent to participants with locally advanced or metastatic solid malignancies or hematologic malignancies. The study will be conducted in two cohorts: Dose-escalation cohort and Expansion cohort.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.
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A Study of Autogene Cevumeran (RO7198457) as a Single Agent and in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Tumors
Not Recruiting
This is a Phase 1a/1b, open-label, multicenter, global, dose-escalation study designed to evaluate the safety, tolerability, immune response, and pharmacokinetics of autogene cevumeran (RO7198457) as a single agent and in combination with atezolizumab (MPDL3280A, an engineered anti-programmed death-ligand 1 \[anti-PD-L1\] antibody).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Study of CDX-1127 (Varlilumab) in Patients With Select Solid Tumor Types or Hematologic Cancers
Not Recruiting
This is a study of CDX-1127, a therapy that targets the immune system and may act to promote anti-cancer effects. The study enrolls patients with hematologic cancers (certain leukemias and lymphomas), as well as patients with select types of solid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Vargas, 650-723-0371.
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A Study of EZN-2208 Administered With or Without Cetuximab in Patients With Metastatic Colorectal Carcinoma
Not Recruiting
This is a Phase 2, multicenter, multiple-arm, open-label study to evaluate the efficacy, safety, and tolerability of EZN-2208. EZN-2208 will be administered as a single agent in patients with K-RAS mutations in the tumors. Patients with wild type K-RAS in tumors will be randomized to EZN-2208 + cetuximab or to standard of care (Camptosar® + cetuximab), patients must have failed regimens containing irinotecan (Camptosar®, CPT-11), oxaliplatin (Eloxatin®), and fluoropyrimidine. After discontinuation of study treatment, patients will receive care as considered appropriate by the investigator. Patients will continue to be followed for disease progression, subsequent anticancer therapy, and survival.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, (650) 721 - 3114.
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A Study of HGS1029 (AEG40826-2HCl) in Subjects With Advanced Solid Tumors
Not Recruiting
The purpose of this study is to evaluate the safety and tolerability of HGS1029 in subjects with advanced solid tumors and to determine a phase 2 dose.
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
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A Study of HGS1036 in Combination With Chemotherapy in Subjects With Advanced Solid Malignancies
Not Recruiting
The primary purpose of this study is to determine the maximally tolerated dose (MTD) of HGS1036 when used in combination with the standard chemotherapeutic regimens paclitaxel plus carboplatin, cisplatin plus etoposide, or docetaxel.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Vargas, 650-723-0371 .
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A Study of Nilotinib Versus Imatinib in GIST Patients
Not Recruiting
This study will evaluate efficacy and safety of nilotinib versus imatinib in adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST).
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
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A Study of Pharmacokinetic Drug Interaction Study of the Hedgehog Pathway Inhibitor GDC-0449 in Combination With Rosiglitazone or Combined Oral Contraceptive in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or for Whom No Standard Therapy Exists
Not Recruiting
This is a single-arm, multicenter, Phase Ib study designed to describe the effect of GDC-0449 on the pharmacokinetics of rosiglitazone and oral contraceptives in patients with advanced solid tumors who are refractory to treatment or for whom no standard therapy exists.
Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.
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A Study of RO6958688 in Participants With Locally Advanced and/or Metastatic Carcinoembryonic Antigen Positive Solid Tumors
Not Recruiting
Study BP29541 is a first-in-human, open-label, multi-center, dose-escalation Phase I clinical study of single-agent RO6958688 in participants with locally advanced and/or metastatic carcinoembryonic antigen (CEA) positive solid tumors who have progressed on standard treatment, are intolerant to standard of care (SOC), and/or are non-amenable to SOC. The study will be conducted in two parts. Part I of the study will investigate the safety and pharmacokinetics of a single dose of RO6958688 in single participant cohorts with dosing starting from a minimal anticipated biological effect level dose of 0.05 milligrams (mg) and up to a maximum dose of 2.5 mg. Part II will establish the appropriate therapeutic dose based on safety, pharmacokinetics, and the maximum tolerated dose (MTD) of RO6958688 for the once per week (QW) regimen, every three weeks (Q3W) regimen, and for the step up dosing regimen.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Study of the Safety and Efficacy of Atezolizumab Administered in Combination With Bevacizumab and/or Other Treatments in Participants With Solid Tumors
Not Recruiting
This study will evaluate the safety, efficacy, and pharmacokinetics of atezolizumab in combination with bevacizumab, bevacizumab + oxaliplatin, leucovorin and 5-fluorouracil (5-FU) (FOLFOX), vanucizumab, nab-paclitaxel + gemcitabine, FOLFOX, or 5-FU + cisplatin, in participants with solid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Study of the Safety, Pharmacokinetics, and Therapeutic Activity of RO6958688 in Combination With Atezolizumab in Participants With Locally Advanced and/or Metastatic Carcinoembryonic Antigen (CEA)-Positive Solid Tumors
Not Recruiting
This is an open-label, multicenter, dose-escalation and expansion Phase Ib clinical study of RO6958688 in combination with atezolizumab. Part I of the study is subdivided into parts IA and IB. Part IA is dose escalation with a starting dose of 5 mg of RO6958688 given QW (once a week) and a fixed, flat dose of 1200 mg given Q3W (every 3 weeks) of atezolizumab, to evaluate the safety and determine the MTD of RO6958688 in combination with atezolizumab. Part IB is a dose/schedule finding part that will explore different administration schedules of RO6958688 in combination with atezolizumab (1200 mg Q3W) to establish the appropriate dose/schedule of RO6958688 in combination with atezolizumab.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Study of XL184 (Cabozantinib) With or Without Erlotinib in Adults With Non-Small Cell Lung Cancer
Not Recruiting
In Phase 1 of this study, the purpose is to evaluate the safety, tolerability, and highest safe dose of the multiple receptor tyrosine kinase inhibitor (including VEGFR2, MET, and RET) XL184 in combination with the EGFR inhibitor erlotinib administered to adults with Non-Small-Cell Lung Cancer (NSCLC). In Phase 2 of this study, the purpose is to evaluate the objective response rate of daily oral administration of XL184 with or without erlotinib in subjects with NSCLC who have progressed after responding to treatment with erlotinib.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
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A Study of XmAb®18087 in Subjects With NET and GIST
Not Recruiting
This is a Phase 1, multiple dose, ascending dose escalation study; to define a MTD/RD and regimen consisting of a first "priming" dose and escalated subsequent doses of XmAb18087; to describe safety and tolerability; to assess PK and immunogenicity; and to preliminarily assess anti-tumor activity of XmAb18087 in subjects with advanced NET or GIST. The study will enroll dosing cohorts to establish a MTD/RD and regimen in subjects with advanced NET or GIST, then enroll additional subjects into separate NET and GIST expansion cohorts to collect additional data on safety and potential efficacy of XmAb18087.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Study to Evaluate the Efficacy and Safety of Simtuzumab Combined With Gemcitabine for Metastatic Pancreatic Adenocarcinoma
Not Recruiting
This study will compare the efficacy of simtuzumab (GS-6624) versus placebo in combination with gemcitabine in adults with pancreatic cancer. The treatment phase of this study will be comprised of 2 sequential parts: an open label treatment phase and a double-blinded treatment phase.
Stanford is currently not accepting patients for this trial. For more information, please contact Donna Collins Williams, (650) 498 - 6608.
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An Efficacy and Safety Study of Somatuline Depot (Lanreotide) Injection to Treat Carcinoid Syndrome
Not Recruiting
The purpose of this study was to determine whether monthly deep subcutaneous (s.c.) injections of lanreotide Autogel (Somatuline Depot) were effective and safe in controlling diarrhoea and flushing by reducing the usage of s.c. short-acting octreotide as a rescue medication to control symptoms in subjects with carcinoid syndrome.
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
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An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene
Not Recruiting
This is a Phase 3 trial comparing the safety and anti-tumor activity of PF-02341066 versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer with specific gene profile involving the ALK gene after failure of one previous chemotherapy regimen that included one platinum drug.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
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An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene
Not Recruiting
This is a Phase 2 trial that will evaluate the safety and efficacy of PF-02341066 in patients with advanced non-small cell lung cancer with a specific gene profile involving the ALK gene. This trial will also allow patients from a Phase 3 trial who received standard of care chemotherapy (Study A8081007) to receive PF-02341066.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
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An Observational Study of the Ethnic Impact of Patients Undergoing Second (2nd) Line Treatment for Non-Small Cell Lung Cancer Using Pemetrexed
Not Recruiting
This large, non-randomized observational study is being conducted to provide data about the impact of ethnic origin on outcomes and resource utilization during the 2nd line treatment of non-small cell lung cancer (NSCLC) in a routine medical care setting.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
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Assessment of Health Related Quality of Life in Patients Treated for Rectal Cancer
Not Recruiting
Treatment of rectal cancer often consists of surgical resection of the tumor. Chemotherapy and/or radiotherapy are frequently given before or after surgery. In this study, we wish to learn if there are differences in the treatment effectiveness or in the quality of life of patients based on their type of treatment (e.g. Radiotherapy and chemotherapy before or after surgery). Information from this questionnaire collected from you and other patients may help improve the quality of life of rectal cancer patients in the future. Medical information on your tumor, treatment received, and side effects will be compiled and maintained in a database to learn more about outcomes of treatment for rectal cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Moe Jalali, (650) 724 - 4023.
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Avastin/[18-F]-5-fluorouracil PET/CT Imaging Feasibility Project
Not Recruiting
To determine whether using a radiolabelled analog of 5-FU, \[18F\]-5-fluorouracil, for PET/CT imaging can visually demonstrate differential chemotherapy delivery to known tumor sites before and after administration of bevacizumab and determine the optimal timing of bevacizumab administration to maximize the chemotherapy delivery into the tumor for improved cancer treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Maurice Zissen, (650) 736 - 1365.
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Bemarituzumab Plus Chemotherapy and Nivolumab Versus Chemotherapy and Nivolumab for FGFR2b Overexpressed Untreated Advanced Gastric and Gastroesophageal Junction Cancer.
Not Recruiting
The main objective of Part 1 is to evaluate the safety and tolerability of bemarituzumab plus 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) and nivolumab. The main objective Part 2 is to compare efficacy of bemarituzumab plus chemotherapy (mFOLFOX6 or capecitabine combined with oxaliplatin (CAPOX)) and nivolumab to placebo plus chemotherapy (mFOLFOX6 or CAPOX) and nivolumab as assessed by overall survival.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Capecitabine, Temozolomide, and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors
Not Recruiting
The purpose of this research is to evaluate the effectiveness and safety of a combination of capecitabine, temozolomide and bevacizumab in the treatment of advanced pancreatic neuroendocrine tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Ben Priestley, 650-723-2990.
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Clinical and Pathologic Studies of Patients Undergoing Treatment With EGFR Inhibitors
Not Recruiting
Cetuximab, erlotinib, and panitumumab are all recently FDA approved epidermal growth factor receptor (EGFR) inhibitors that treat a wide variety of tumor types, such as colon, lung, and head and neck. Blockade of the EGFR results in inhibition of multiple downstream pathways, leading to slowed tumor growth. In addition, these inhibitors may enhance anti-tumor immune responses through uncharacterized mechanisms. While producing significant responses in many settings, EGFR inhibitors also result in significant skin toxicity (rash) in a high percentage of patients. Multiple studies have correlated the presence and severity of rash with clinical response. Unfortunately, severe rash can often lead to dose delays, reductions, or even discontinuation of EGFR inhibitors, thus limiting their efficacy. The mechanism of both the rash and its correlation with tumor response is poorly understood. Skin biopsies display a robust leukocyte infiltrate, but a systematic analysis of the type of infiltrating leukocytes, activation state, or homing receptor expression has not been performed. Chemokines and chemokine receptors control leukocyte trafficking to the skin and other tissue sites, and defined receptor profiles for skin-, gut-, and lung-homing leukocytes are well established. In this study, the investigators propose to evaluate the homing phenotype of leukocytes from peripheral blood and skin biopsies of patients receiving EGFR inhibitors. The investigators will use RNA microarrays to evaluate the expression of chemokines and other key genes regulated in skin during treatment. The investigators will utilize in vitro methods to investigate effects of EGFR inhibitors on imprinting of T cell tissue-specific homing receptors. The investigators will examine correlations among the pathologic data, clinical findings, and tumor response. If validated, peripheral blood evaluation could potentially be used as a predictive indicator for patients receiving EGFR inhibitors. This study may also identify novel targets for limiting skin toxicity while receiving EGFR inhibitors, thus allowing maximal dosing and clinical response from these agents.
Stanford is currently not accepting patients for this trial. For more information, please contact Russell Pachynski, (650) 906 - 6530.
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Clinical Study of BYM338 for the Treatment of Unintentional Weight Loss in Patients With Cancer of the Lung or the Pancreas
Not Recruiting
A safety \& efficacy clinical study of the investigational medicinal product BYM338 for the treatment of unintentional weight loss in patients with cancer of the lung or the pancreas
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
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Collection of Biospecimen & Clinical Information in Patients w/ Gastrointestinal Cancers
Not Recruiting
We have an active research program in gastrointestinal cancers including clinical trials, epidemiologic, and translational studies. We would like to establish a biospecimen bank linked to useful clinical information in order to learn more about diagnostic, predictive and prognostic markers for gastrointestinal cancers. PRIMARY OBJECTIVES: 1. To collect and store tumor and normal tissue (previously collected paraffin embedded or frozen specimen) and blood in patients with gastrointestinal (GI) cancers. SECONDARY OBJECTIVES: 1. Collect detailed clinical information via a patient questionnaire that includes demographic, socioeconomic, lifestyle, family, past medical, medication and cancer histories 2. Collect details about the tumor specimen extracted from patient charts.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, (650) 498 - 6000.
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Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair
Not Recruiting
This phase III trial studies combination chemotherapy and atezolizumab to see how well it works compared with combination chemotherapy alone in treating patients with stage III colon cancer and deficient deoxyribonucleic acid (DNA) mismatch repair. Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy with atezolizumab may work better than combination chemotherapy alone in treating patients with colon cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Sigurdis Haraldsdottir, 650-498-7061.
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Combination SBRT With TACE for Unresectable Hepatocellular Carcinoma
Not Recruiting
To determine the efficacy and toxicity of TACE combined with SBRT
Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Ann Columbo, 650-736-0792.
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Combination Study of Urelumab and Cetuximab in Patients With Advanced/Metastatic Colorectal Cancer or Advanced/Metastatic Head and Neck Cancer
Not Recruiting
The purpose of the study is to determine the safety, tolerability and maximum tolerated dose of Urelumab in combination with Cetuximab in patients with Advanced/Metastatic Colorectal Cancer or Advanced/Metastatic Squamous Cell Carcinoma of the Head and Neck.
Stanford is currently not accepting patients for this trial. For more information, please contact Risa Jiron, 650-736-1598.
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Comparing Two Treatment Combinations, Gemcitabine and Nab-Paclitaxel With 5-Fluorouracil, Leucovorin, and Liposomal Irinotecan for Older Patients With Pancreatic Cancer That Has Spread
Not Recruiting
This phase II trial compares two treatment combinations: gemcitabine hydrochloride and nab-paclitaxel, or fluorouracil, leucovorin calcium, and liposomal irinotecan in older patients with pancreatic cancer that has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as gemcitabine hydrochloride, nab-paclitaxel, fluorouracil, leucovorin calcium, and liposomal irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This study may help doctors find out which treatment combination is better at prolonging life in older patients with metastatic pancreatic cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Cyberknife Radiosurgery for Locally Advanced Pancreatic Cancer
Not Recruiting
The purpose of the trial is to test the efficacy of combining conventional chemoradiotherapy with radiosurgery for locally advanced pancreas cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Stanford Cancer Clinical Trials Office, (650) 498 - 7061.
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EAP 177Lu-DOTA0-Tyr3-Octreotate for Inoperable, SSR+, NETs, Progressive Under SSA Tx
Not Recruiting
Advanced Accelerator Applications is currently pursuing marketing approval for 177Lu-DOTA0-Tyr3-Octreotate (Lutathera). This expanded access therapeutic protocol aims to allow patients suffering from inoperable, somatostatin receptor positive, neuroendocrine tumors, progressive under somatostatin analogue therapy to access the investigational product, 177Lu-DOTA0-Tyr3-Octreotate (Lutathera), prior to its commercial availability.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Efficacy and Safety of Lanreotide Autogel/ Depot 120 mg vs. Placebo in Subjects With Lung Neuroendocrine Tumours
Not Recruiting
This is a Phase 3, prospective, multi-center, randomized, double-blind, study evaluating the efficacy and safety of LAN plus BSC versus placebo plus BSC for the treatment of well-differentiated, metastatic and/or unresectable, typical or atypical bronchopulmonary NETs. This study contains two phases: the Double-Blind (DB) Phase, and the Open Label (OL) Phase. The DB Phase includes: Screening, Baseline and Treatment period. The OL Phase will consist of two periods: Treatment Period and Follow-Up Period. The primary objective will be to describe the antitumour efficacy of Lanreotide Autogel/Depot 120 mg (LAN) plus Best Supportive Care (BSC) every 28 days, in terms of progression-free survival (PFS), measured by central review using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria, every 12 weeks, in subjects randomized to LAN with unresectable and/or metastatic well differentiated, typical or atypical bronchopulmonary neuroendocrine tumours. Recent updates of National Cancer Institute Cancer Network (NCCN) \& European Neuroendocrine Tumor Society (ENETS) guidelines recommend SSA in first line for the treatment of locoregional unresectable or metastatic bronchopulmonary NETs as an option beyond 'observation' leading to slow and difficult recruitment in SPINET study. Consequently, it was decided to prematurely stop the recruitment in the SPINET study and to transition all subjects still treated in the double-blind phase to the open label (OL) treatment and follow-up phases following respective country approvals of Amendment #5. The new aim of this Phase 3, multicenter, prospective, randomized placebo-controlled clinical study is to describe the antitumor efficacy and safety of Lanreotide Autogel/Depot 120 mg (LAN) plus Best Supportive Care (BSC) in subjects with well-differentiated, metastatic and/or unresectable, typical or atypical, bronchopulmonary NETs.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Efficacy and Safety of Simtuzumab (SIM) With FOLFIRI as Second Line Treatment in Colorectal Adenocarcinoma
Not Recruiting
The primary objective of this study is to compare the additive efficacy of SIM versus placebo in combination with leucovorin (folinic acid), irinotecan, and fluorouracil (FOLFIRI) as measured by improvement in progression-free survival (PFS) in participants with metastatic KRAS mutant colorectal adenocarcinoma who have progressed following a first-line oxaliplatin- and fluoropyrimidine-containing regimen.
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
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Evaluation of Stereotactic Radiosurgery For Liver Malignancies
Not Recruiting
This study is intended to establish the practicality of treating cancer in the liver with precisely administered single fractions of high-energy radiation using a radiosurgical (cross-firing) technique. A second purpose is to establish a safe dose for such therapy. Finally, the efficacy of radiosurgical ablation of liver tumors, in terms of radiographic response, will be measured.
Stanford is currently not accepting patients for this trial. For more information, please contact Jeff Kim, (650) 498 - 7703.
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Exploratory Platform Trial to Evaluate Immunotherapy Combinations With Chemotherapy for the Treatment of Patients With Previously Untreated Metastatic Pancreatic Adenocarcinoma
Not Recruiting
This trial is designed to evaluate multiple clinical hypotheses and mechanistically-defined combinations to evaluate the safety and efficacy of first-line chemo-immunotherapy combinations in participants with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Stanford is currently not accepting patients for this trial. For more information, please contact Gino Pineda, 650-725-8474.
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Fluorouracil, Leucovorin, and Oxaliplatin With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II or Stage III Colon Cancer
Not Recruiting
This randomized phase III trial is studying giving oxaliplatin, leucovorin, and fluorouracil together with bevacizumab to see how well it works compared to oxaliplatin, leucovorin, and fluorouracil alone in treating patients who have undergone surgery for stage II or stage III colon cancer. Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as bevacizumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Bevacizumab may also stop the growth of tumor cells by stopping blood flow to the tumor. Giving chemotherapy together with bevacizumab may kill more tumor cells. It is not yet known whether treatment with oxaliplatin, leucovorin, and fluorouracil is more effective with or without bevacizumab in treating patients who have undergone surgery for colon cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Marilyn Florero, 650-724-1953.
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GVAX Pancreas Vaccine (With CY) and CRS-207 With or Without Nivolumab
Not Recruiting
The primary objective of this study is to compare the overall survival (OS) of subjects with previously treated metastatic pancreatic cancer treated with cyclophosphamide (CY)/nivolumab/GVAX pancreas vaccine followed by nivolumab/CRS-207 (Arm A) to subjects treated with CY/GVAX pancreas vaccine followed by CRS-207 (Arm B).
Stanford is currently not accepting patients for this trial. For more information, please contact Melissa Worman, 650-725-0379.
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High-Dose Interferon Alfa in Treating Patients With Stage II or Stage III Melanoma
Not Recruiting
RATIONALE: Interferon alfa may interfere with the growth of cancer cells. It is not yet known whether treatment with interferon alfa is more effective than observation alone for stage II or stage III melanoma that has been completely removed surgically. PURPOSE: This randomized phase III trial is studying high dose interferon alfa to see how well it works compared to observation only in treating patients with stage II or stage III melanoma that has been completely removed by surgery.
Stanford is currently not accepting patients for this trial. For more information, please contact Sunil Arani Reddy, (650) 736 - 1234.
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Immunotherapy Study for Surgically Resected Pancreatic Cancer
Not Recruiting
The purpose of this study is to assess overall survival after treatment with a regimen of adjuvant therapy (Gemcitabine alone or with 5-FU chemoradiation) with or without HyperAcute®-Pancreas (algenpantucel-L) immunotherapy in subjects who have undergone surgical resection.
Stanford is currently not accepting patients for this trial. For more information, please contact Donna Williams, (650) 498 - 6608.
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Ipilimumab and Local Radiation for Selected Solid Tumors
Not Recruiting
This pilot phase 1-2 trial studies the side effects and best of dose ipilimumab when given together with local radiation therapy and to see how well it works in treating patients with recurrent melanoma, non-Hodgkin lymphoma, colon, or rectal cancer. Monoclonal antibodies, such as ipilimumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiation therapy uses high energy x rays to kill cancer cells. Giving monoclonal antibody therapy together with radiation therapy may be an effective treatment for melanoma, non-Hodgkin lymphoma, colon, or rectal cancer. * The phase 1 component ("safety") of this study is ipilimumab 25 mg monotherapy. * The phase 2 component ("treatment-escalation") of this study is ipilimumab 25 mg plus radiation combination therapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Erin Waller, 650-725-0379.
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Long Term Follow-Up Study for Subjects Previously Treated With Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy
Not Recruiting
This protocol (NLG0705) provides a mechanism for the 15-year follow-up period that the FDA requires for all participants in gene transfer protocols and assures that adequate follow-up can be maintained for subjects who have received at least one dose of algenpantucel-L.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Nivolumab After Combined Modality Therapy in Treating Patients With High Risk Stage II-IIIB Anal Cancer
Not Recruiting
This phase III trial investigates how well nivolumab after combined modality therapy works in treating patients with high risk stage II-IIIB anal cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Stanford is currently not accepting patients for this trial. For more information, please contact Site Public Contact, 650-498-7061.
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Octreotide Acetate and Recombinant Interferon Alfa-2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor
Not Recruiting
This randomized phase III trial studies octreotide acetate and recombinant interferon alfa-2b to see how well it works compared to octreotide acetate and bevacizumab in treating patients with high-risk neuroendocrine tumors that have spread to other places in the body (metastatic) or spread from where it started to nearby tissue or lymph nodes (locally advanced). Octreotide acetate and recombinant interferon alfa-2b may interfere with the growth of tumor cells and slow the growth of cancer. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving octreotide acetate together with recombinant interferon alfa-2b is more effective than giving octreotide acetate together with bevacizumab in treating patients with neuroendocrine tumor.
Stanford is currently not accepting patients for this trial. For more information, please contact Deryn Warner, (650) 723 - 2876.
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Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II Colon Cancer
Not Recruiting
This randomized phase III trial studies oxaliplatin, leucovorin calcium, fluorouracil, and bevacizumab to see how well they work compared to oxaliplatin, leucovorin calcium, and fluorouracil in treating patients who have undergone surgery for stage II colon cancer. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving combination chemotherapy together with bevacizumab is more effective than combination chemotherapy alone in treating colon cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Nancy Mori, (650) 724 - 0201.
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Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Celecoxib in Treating Patients With Stage III Colon Cancer Previously Treated With Surgery
Not Recruiting
PURPOSE: This randomized phase III trial is studying giving oxaliplatin, leucovorin calcium, and fluorouracil together to compare how well they work when given together with or without celecoxib in treating patients with stage III colon cancer previously treated with surgery. RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving oxaliplatin, leucovorin calcium, and fluorouracil is more effective with or without celecoxib in treating colon cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Ben Priestley, 650-723-2990 (Palo Alto and South Bay locations).
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Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors
Not Recruiting
This randomized phase II trial studies how well pazopanib hydrochloride works in treating patients with carcinoid tumors that are growing, spreading, or getting worse. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Ben Priestley, 650-723-2990.
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Perfusion CT as a Predictor of Treatment Response in Patients With Hepatic Malignancies
Not Recruiting
A research study of liver perfusion (how blood flows to the liver over time). We hope to learn whether perfusion characteristics of liver masses may be predictive of response to treatment and whether liver perfusion characteristics can be used to follow response to treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Elizabeth Chitouras, 650-498-0623.
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Perfusion CT as a Predictor of Treatment Response in Patients With Rectal Cancer
Not Recruiting
A research study of rectal cancer perfusion (how blood flows to the rectum over time). We hope to learn whether perfusion characteristics of rectal masses may be predictive of response to treatment and whether rectal perfusion characteristics can be used to follow response to treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, 650-736-0798.
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Permission to Collect Blood Over Time for Research
Not Recruiting
To determine whether biomarkers assessed in blood samples can be used to detect individuals at risk for developing blood clots or worsening of their underlying disease. The ultimate goal of the study is to identify key biomarkers derived from blood that are most characteristic and informative of individuals who will go on to develop a clotting complication.
Stanford is currently not accepting patients for this trial. For more information, please contact Fizaa Ahmed, 650-725-6409.
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Ph 3 ADI-PEG 20 Versus Placebo in Subjects With Advanced Hepatocellular Carcinoma Who Have Failed Prior Systemic Therapy
Not Recruiting
This is a study of ADI-PEG 20 (pegylated arginine deiminase), an arginine degrading enzyme versus placebo in patients with hepatocellular carcinoma who have failed prior systemic treatment (chemotherapy). Hepatocellular carcinomas have been found to require arginine, an amino acid. Thus the hypothesis is that by restricting arginine with ADI-PEG 20, the hepatocellular carcinoma cells will starve and die.
Stanford is currently not accepting patients for this trial. For more information, please contact Flordeliza Mendoza, 650-724-2056.
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Ph II of Capecitabine, Carboplatin & Bevacizumab for Gastroesophageal Junction & Gastric Carcinoma
Not Recruiting
To investigate bevacizumab in combination with carboplatin and capecitabine for patients with unresectable or metastatic GEJ or gastric cancers. We hope that by adding bevacizumab to standard chemotherapy for this patient population we will improve Progression Free Survival by 90% over historical controls.
Stanford is currently not accepting patients for this trial. For more information, please contact Prachi Nandoskar, (650) 725 - 0438.
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Pharmacokinetic and Safety Study of SPARC1023 Alone and in Carboplatin Combination
Not Recruiting
Phase I study of SPARC1023 alone and in combination with carboplatin
Stanford is currently not accepting patients for this trial. For more information, please contact Flordeliza Mendoza, 650-724-2056.
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Phase 1 Trial of Oral Ixabepilone
Not Recruiting
This Phase 1 study of oral ixabepilone given every 6 hours for 3 doses on Day 1, every 21 days, was a dose-finding study designed to determine the maximum tolerated dose (MTD) and safety of this dosing schedule in participants with advanced cancer
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
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Phase 1-2 Vatalanib and Gemcitabine in Advanced Pancreatic Cancer
Not Recruiting
The purpose of the study is to determine the optimal safe and tolerable dose of gemcitabine in combination with once daily or twice daily dose of PTK/ZK in patients with unresectable pancreatic cancer. The Phase II part of this study planned to determine the antitumor activity of this regimen and its effectiveness of preventing tumor growth and spread.
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
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Phase 2 Neoadjuvant Doxorubicin and Cyclophosphamide -> Docetaxel With Lapatinib in Stage II/III Her2Neu+ Breast Cancer
Not Recruiting
This trial combines dose dense chemotherapy with doxorubicin and cyclophosphamide (AC) followed by standard, every 3 week docetaxel and GW572016 (lapatinib) for neoadjuvant treatment of Her2neu positive stage II/III breast cancer. The purpose of the study was to determine whether lapatinib combined with chemotherapy was safe and resulted in an increase in pathologic complete response rates.
Stanford is currently not accepting patients for this trial. For more information, please contact Mary Chen, (650) 723 - 8686.
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Phase 2 Study of Gemzar, Taxol & Avastin Combination as 1st Line Treatment for Metastatic Breast Cancer
Not Recruiting
Single-institution phase 2 trial investigating the efficacy of capecitabine, oxaliplatin and bevacizumab for patients with metastatic neuroendocrine tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Mary Chen, (650) 723 - 8686.
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Phase I Dose Escalation of Stereotactic Radiosurgical Boost for Locally Advanced Esophageal Cancer
Not Recruiting
To study the safety and feasibility of stereotactic radiation dose escalation following neoadjuvant chemotherapy with concurrent conventionally fractionated radiation, by evaluating the acute and late toxicity of treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Ann Columbo, (650) 736 - 0792.
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Phase I Intratumoral Dendritic Cell Immunotherapy in Thermally Ablated Liver Metastases
Not Recruiting
Up to twenty-two patients will be enrolled in this study to receive autologous dendritic cells (DCs) administered intratumorally into liver metastases following radiofrequency thermal ablation of those lesions. Patients will receive two vaccinations of DCs at monthly intervals. A dose escalation study of DCs will be included in this study in an attempt to define the maximum tolerated dose of administered DCs.
Stanford is currently not accepting patients for this trial. For more information, please contact Jenna Rogers, (650) 723 - 4467.
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Phase I Oral mTOR Inhibitor RAD001 in Combo w/ Capecitabine for Metastatic Breast
Not Recruiting
In order to improve the survival of metastatic breast patients, it is important to investigate the use of novel therapeutic agents combined with known active agents in the treatment of breast cancer. This is a phase I study evaluating the maximum tolerated doses and toxicities of RAD001 in combination with capecitabine for the treatment of metastatic breast cancer. RAD001 (INN: everolimus) is a novel macrolide, which is being developed as an antiproliferative drug with applications as an immunosuppressant and anticancer agent. Phase I trials in patients with solid tumors have shown that treatment with RAD001 is well-tolerated with a minimal side effect profile. Capecitabine (Xeloda, Roche) is an oral fluoropyrimidine that was approved in 1998 for the treatment of patients with metastatic breast cancer. The all-oral regimen of RAD001 with capecitabine is an attractive approach as the treatment of metastatic breast cancer has not yet proven to be curative. We also want to find out what possible benefit this combination of drugs might have on treating your cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Mary Chen, (650) 723 - 8686.
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Phase I Vandetanib Plus Capecitabine, Oxaliplatin and Bevacizumab for Metastatic Colorectal Cancer
Not Recruiting
To determine the maximum tolerated dose of Vandetanib with a current standard first-line chemotherapy regimen, capecitabine and oxaliplatin without and then with bevacizumab for the first line treatment of metastatic colorectal cancer (CRC) and to define the dose limiting toxicities associated with the combination.
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
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Phase I/II Intratumoral DC Immunotherapy With Gemcitabine & XRT in Unresectable Pancreatic Cancer
Not Recruiting
To determine the safety, feasibility and appropriate dendritic cell dose to vaccinate patients with pancreas cancer
Stanford is currently not accepting patients for this trial. For more information, please contact Jenna Rogers, (650) 723 - 4467.
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Phase II Capecitabine, Oxaliplatin & Bevacizumab for Metastatic / Unresectable Neuroendocrine Tumors
Not Recruiting
Given the lack of other viable treatment options for metastatic neuroendocrine tumors, contrasted with our positive anecdotal experience, and the relative tolerability of the treatment regimen for colorectal cancer patients, we propose a single-institution phase II trial investigating the efficacy of capecitabine, oxaliplatin and bevacizumab for patients with metastatic neuroendocrine tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
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Phase II Gemcitabine + Fractionated Stereotactic Radiotherapy for Unresectable Pancreatic Adenocarcinoma
Not Recruiting
This multi-institutional trial aims to evaluate the potential benefit and side effects of adding fractionated stereotactic body radiotherapy/surgery (SBRT) before and after chemotherapy with gemcitabine for locally advanced pancreatic cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Ann Columbo, 650-736-0792.
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Phase II SBRT & Chemo for Unresectable Cholangiocarcinoma Followed by Liver Transplantation
Not Recruiting
The purpose of this study is to determine progression-free survival at 12 months for stereotactic body radiotherapy (SBRT) and chemotherapy for unresectable hilar cholangiocarcinoma (CCA).
Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Ann Columbo, (650) 736 - 0792.
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Phase III Trans-Arterial Chemo-Embolization (TACE) Adjuvant HCC
Not Recruiting
The purpose of this study is to compare the Overall Survival (OS) of HCC patients who receive brivanib as adjuvant treatments to TACE therapy, with the OS of HCC patients who receive matched placebo with TACE therapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Rebecca Bristol, (650) 721 - 3114.
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Pilot 3D Contrast-Enhanced Ultrasound Imaging to Predict Treatment Response in Liver Metastases
Not Recruiting
Patients are invited to participate in a research study of liver perfusion (how blood flows to the liver over time). Researchers hope to learn whether perfusion characteristics of liver metastases may be predictive of response to treatment and whether liver perfusion characteristics can be used to follow response to treatment. Patients were selected as a possible participant in this study because they are identified as having liver metastases
Stanford is currently not accepting patients for this trial. For more information, please contact Risa Jiron, 650-736-1598.
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Pilot Study of 89-Zr Panitumumab in Pancreas Cancer
Not Recruiting
The main purpose of the study is to assess the safety of 89Zr-panitumumab as a molecular imaging agent in patients with (metastatic) pancreas cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Alexander A Valencia, 650-498-5185.
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Prognostic Value of Baseline Computed Tomography (CT) Perfusion Parameters of Pancreatic Cancer for Patients Undergoing Stereotactic Body Radiotherapy or Surgical Resection
Not Recruiting
The purpose of this study is first, to determine whether baseline perfusion characteristics of pancreatic cancer, as characterized by CT perfusion studies, can predict tumor response to treatment by stereotactic body radiotherapy (SBRT). The second goal of this study is to determine whether baseline perfusion characteristics in those patients with resectable pancreatic cancer correlate with immunohistologic markers of angiogenesis such as microvessel density and vascular endothelial growth factor (VEGF) expression.
Stanford is currently not accepting patients for this trial. For more information, please contact Lindee Burton, (650) 725 - 4712.
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PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery
Not Recruiting
The standard treatment for locally advanced rectal cancer involves chemotherapy and radiation, known as 5FUCMT, (the chemotherapy drugs 5-fluorouracil/capecitabine and radiation therapy) prior to surgery. Although radiation therapy to the pelvis has been a standard and important part of treatment for rectal cancer and has been shown to decrease the risk of the cancer coming back in the same area in the pelvis, some patients experience undesirable side effects from the radiation and there have been important advances in chemotherapy, surgery, and radiation which may be of benefit. The purpose of this study is to compare the effects, both good and bad, of the standard treatment of chemotherapy and radiation to chemotherapy using a combination regimen known as FOLFOX, (the drugs 5-fluorouracil (5-FU), oxaliplatin and leucovorin) and selective use of the standard treatment, depending on response to the FOLFOX. The drugs in the FOLFOX regimen are all FDA (Food and Drug Administration) approved and have been used routinely to treat patients with advanced colorectal cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Ben Priestley, 650-723-2990.
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QUILT-3.026: AMG 655 in Combination With AMG 479 in Advanced, Refractory Solid Tumors
Not Recruiting
This is a multi-center, 2-part phase 1b/2 study of AMG 655 in combination with AMG 479 to be conducted in the United States and Spain. Part 1 is a dose escalation segment to identify a dose of AMG 655 in combination with AMG 479 that is safe and tolerable. Part 2 will evaluate the safety and estimate the efficacy of AMG 655 at the dose selected in Part 1 in combination with AMG 479 for the treatment of patients with advanced NSCLC (non-squamous histology; squamous histology), CRC, pancreatic cancer, ovarian cancer, and sarcoma.
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
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Radiation Therapy, Paclitaxel, and Carboplatin With or Without Trastuzumab in Treating Patients With Esophageal Cancer
Not Recruiting
This randomized phase III trial studies how well radiation therapy, paclitaxel, and carboplatin with or without trastuzumab work in treating patients with esophageal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving radiation therapy and combination chemotherapy together with or without trastuzumab is more effective in treating esophageal cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Polly Young, 650-497-7499.
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S0809: Capecitabine, Gemcitabine, and RT in Patients w/Cholangiocarcinoma of the Gallbladder or Bile Duct
Not Recruiting
RATIONALE: Drugs used in chemotherapy, such as capecitabine and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving more than one drug (combination chemotherapy) together with radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving capecitabine together with gemcitabine followed by capecitabine and radiation therapy works in treating patients with cholangiocarcinoma of the gallbladder or bile duct.
Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, (650) 736 - 0798.
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Safety and Efficacy of APX005M With Gemcitabine and Nab-Paclitaxel With or Without Nivolumab in Patients With Previously Untreated Metastatic Pancreatic Adenocarcinoma
Not Recruiting
The main purposes of this study are to learn how effective the study drug combinations are in treating patients with metastatic pancreatic adenocarcinoma. The drug combinations are APX005M+Nivolumab+Gemcitabine+nab-Paclitaxel, or APX005M+Gemcitabine+nab-Paclitaxel.
Stanford is currently not accepting patients for this trial. For more information, please contact Stanford Cancer Clinical Trials Office, Outreach, 650-498-7061.
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Safety and Pharmacology of SNX-5422 Plus Everolimus in Subjects With Neuroendocrine Tumors
Not Recruiting
Study is designed to determine the maximum tolerated dose (MTD) of SNX-5422 when given in combination with everolimus.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Dauriac, 650-736-0697.
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Study of Atezolizumab in Combination With Cobimetinib in Participants With Locally Advanced or Metastatic Solid Tumors
Not Recruiting
This is a Phase Ib, open-label, multicenter study designed to assess the safety, tolerability, and pharmacokinetics of coadministration of intravenous (IV) dosing of atezolizumab (an engineered anti-programmed death-ligand 1 \[anti-PD-L1\] antibody) and oral dosing of cobimetinib in participants with metastatic or locally advanced cancer for which no standard therapy exists.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, 650-736-4112.
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Study of Cabozantinib (XL184) in Adults With Advanced Malignancies
Not Recruiting
This is a Phase 2 study to evaluate the efficacy and safety of cabozantinib (XL184) in subjects with selected advanced tumor types.
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
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Study of Cobimetinib in Participants With Solid Tumors
Not Recruiting
This non-randomized, open-label, study will determine the highest safe dose of cobimetinib, how often it should be taken, how well participants with cancer tolerate cobimetinib and will assess the pharmacokinetic effect of midazolam and dextromethorphan on the study drug.
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
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Study of GSK1363089 in Metastatic Gastric Cancer
Not Recruiting
This clinical study is being conducted at multiple sites to determine the best confirmed response rate, safety, and tolerability of GSK1363089 treatment in metastatic gastric carcinoma.
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
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Study of IDO Inhibitor in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer
Not Recruiting
This phase I/II trial is designed to efficiently identify the regimen limiting toxicity (RLT) and recommended phase 2 dose (RP2D) for the combination of the immunotherapeutic agent indoximod when administered in combination with standard of care chemotherapy gemcitabine plus nab-paclitaxel in subjects with metastatic adenocarcinoma of the pancreas. All subjects will receive the same standard gemcitabine plus nab-paclitaxel regimen, plus indoximod in doses increasing from 600 mg twice daily to, potentially, 1200 mg twice daily.
Stanford is currently not accepting patients for this trial. For more information, please contact Melissa Worman, 650-725-0379.
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Study of Magrolimab (Hu5F9-G4) in Combination With Cetuximab in Participants With Solid Tumors and Advanced Colorectal Cancer
Not Recruiting
The primary objectives of this study are: (Phase 1b) to investigate the safety and tolerability and to determine the recommended Phase 2 dose (RP2D) for magrolimab in combination with cetuximab; and (Phase 2) to evaluate overall response rate (ORR) of magrolimab in combination with cetuximab in participants with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutant and KRAS wild-type colorectal cancer (CRC).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Study of Magrolimab Given Together With FOLFIRI/BEV in Patients With Previously Treated Advanced Inoperable Metastatic Colorectal Cancer (mCRC)
Not Recruiting
The goals of this clinical study are to learn more about the safety, tolerability and effectiveness of magrolimab in combination with bevacizumab and 5-fluorouracil, irinotecan, and leucovorin (FOLFIRI) in previously treated participants with advanced inoperable metastatic colorectal cancer (mCRC). The primary objectives of this study are: (safety run-in cohort) to evaluate safety and tolerability, and the recommended Phase 2 dose (RP2D) and (randomized cohort) to evaluate the efficacy of magrolimab in combination with bevacizumab and 5-fluorouracil, irinotecan, and leucovorin (FOLFIRI) in previously treated participants with advanced inoperable metastatic colorectal cancer (mCRC).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Previously-Treated Locally Advanced Unresectable or Metastatic Colorectal Cancer (MK-3475-164/KEYNOTE-164)
Not Recruiting
In this study, participants with previously-treated locally-advanced unresectable or metastatic mismatched repair (MMR) deficient or microsatellite instability-high (MSI-H) colorectal carcinoma (CRC) will be treated with pembrolizumab (MK-3475, KEYTRUDA®) monotherapy. There will be two cohorts in this study: Cohort A and Cohort B. For Cohort A, participants are required to have been previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan. Enrollment into Cohort A has been completed. For Cohort B, participants are required to have been previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti-vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. The primary hypothesis is that Objective Response Rate (ORR) based on Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST 1.1) assessed by central imaging vendor in participants with locally advanced unresectable or metastatic MMR deficient or MSI high CRC is greater than 15%.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177)
Not Recruiting
In this study, participants with stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) colorectal carcinoma (CRC) will be randomly assigned to receive either pembrolizumab or the Investigator's choice of 1 of 6 standard of care (SOC) chemotherapy regimens for the treatment of advanced colorectal carcinoma. The primary study hypothesis is that pembrolizumab will prolong progression-free survival (PFS) or overall survival (OS) compared to current SOC chemotherapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Study of Personalized Immunotherapy in Adults With Metastatic Colorectal Cancer
Not Recruiting
This study will evaluate the safety and tolerability of a personalized live, attenuated, double-deleted Listeria monocytogenes (pLADD) treatment in adults with metastatic colorectal cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Flordeliza Mendoza, CCRC, 650-724-2056.
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Study of XL647 Administered Orally Daily to Patients With Solid Tumors
Not Recruiting
The purpose of this study is to assess the safety and tolerability of the multiple receptor tyrosine kinase (RTK) inhibitor (including EGFR, VEGFR2, ErbB2, and EphB4) XL647 when given orally daily to adults with advanced solid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Joanne Fehling, (650) 736 - 1694.
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Study of XL647 in Subjects With NSCLC Who Have Progressed After Responding to Treatment With Gefitinib or Erlotinib
Not Recruiting
The purpose of this study is to determine the best confirmed response rate of daily administration of the multiple receptor tyrosine kinase (RTK) inhibitor (including EGFR and VEGFR2) XL647 in subjects with NSCLC who have progressed after responding to treatment with either erlotinib or gefitinib.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
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TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome)
Not Recruiting
The primary objective of the study is to confirm that at least 1 or more doses of telotristat etiprate compared to placebo is effective in reducing the number of daily bowel movements (BMs) from baseline averaged over the 12-week double-blind portion (Treatment Period) of the trial in patients not adequately controlled by current SSA therapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Hemamalini Vairamuthu, 650-723-0186.
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Telotristat Etiprate - Expanded Treatment for Patients With Carcinoid Syndrome Symptoms
Not Recruiting
The primary objective of this study is to evaluate the long-term safety and tolerability of orally administered telotristat etiprate.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Dauriac, 650-736-0697.
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Telotristat Etiprate for Carcinoid Syndrome Therapy
Not Recruiting
The purpose of the study is to evaluate the effect of telotristat etiprate versus placebo on the incidence of treatment-emergent adverse events and on 5-hydroxyindoleacetic acid (5-HIAA) levels.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Dauriac, 650-736-0697.
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Temozolomide With or Without Capecitabine in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors
Not Recruiting
This randomized phase II trial studies how well giving temozolomide with or without capecitabine works in treating patients with advanced pancreatic neuroendocrine tumors. Drugs used in chemotherapy, such as temozolomide and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether temozolomide is more effective with or without capecitabine in treating patients with advanced pancreatic neuroendocrine tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Benjamin Priestley, 650-723-2990.
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Transarterial Chemoembolization vs CyberKnife for Recurrent Hepatocellular Carcinoma
Not Recruiting
Primary Objective: To compare the efficacy of TACE vs. CyberKnife SBRT in the treatment of locally recurrent HCC after initial TACE. Secondary Objectives: 1. To determine the progression-free survival of TACE vs. CyberKnife SBRT 2. To determine the overall survival of TACE vs. CyberKnife SBRT for locally recurrent HCC 3. To determine the toxicities associated with TACE or CyberKnife SBRT for the treatment of recurrent HCC.
Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Ann Columbo, (650) 736 - 0792.
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Trilogy Stereotactic Body Radiotherapy for Pancreatic Cancer
Not Recruiting
This study will assess the efficacy of treating locally advanced pancreatic cancer using Stereotactic Body Radiotherapy (using Trilogy) and Gemcitabine
Stanford is currently not accepting patients for this trial. For more information, please contact Jeff Kim, (650) 498 - 7703.
2024-25 Courses
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Independent Studies (5)
- Directed Reading in Medicine
MED 299 (Aut, Win, Spr, Sum) - Early Clinical Experience in Medicine
MED 280 (Aut, Win, Spr, Sum) - Graduate Research
MED 399 (Aut, Win, Spr, Sum) - Medical Scholars Research
MED 370 (Aut, Win, Spr, Sum) - Undergraduate Research
MED 199 (Aut, Win, Spr, Sum)
- Directed Reading in Medicine
All Publications
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Circulating KRAS G12D but not G12V is associated with survival in metastatic pancreatic ductal adenocarcinoma.
Nature communications
2024; 15 (1): 5763
Abstract
While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.
View details for DOI 10.1038/s41467-024-49915-5
View details for PubMedID 38982051
View details for PubMedCentralID 8034833
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Advancing Clinical Trial Equity through Integration of Telehealth and Decentralized Treatment.
JNCI cancer spectrum
2024
Abstract
Innovative strategies to increase clinical trial accessibility and equity are needed. We conducted a retrospective review of a phase II investigator-initiated trial to determine whether the modification of clinical trial design to decentralize study treatment can improve trial accessibility among underrepresented groups. Sociodemographic characteristics including area deprivation indices as well as study site travel distance, time, and costs were compared between those enrolled participants who received chemotherapy locally and those who did not. Participants who received chemotherapy locally lived significantly farther from the study site (median 95.90 vs 25.20 miles, p = .004), faced a greater time burden traveling to the study site (median 115.00 vs 34.00 minutes, p = .002), and had higher travel-related costs for a single trip to the study site (median 62.81 vs 16.51 dollars, p = .004). This study highlights opportunities for alleviating financial and time toxicities associated with clinical trial participation, promoting equity in clinical research.
View details for DOI 10.1093/jncics/pkae050
View details for PubMedID 38902952
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Phase II trial of organ preservation program using short-course radiation and FOLFOXIRI for rectal cancer (SHORT-FOX).
LIPPINCOTT WILLIAMS & WILKINS. 2024
View details for Web of Science ID 001275557400852
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Clinical and translational results from REVOLUTION cohorts A (nivolumab plus ipilimumab plus chemotherapy) and B (hydroxychloroquine plus ipilimumab plus chemotherapy) in patients with previously untreated metastatic pancreatic adenocarcinoma.
LIPPINCOTT WILLIAMS & WILKINS. 2024
View details for Web of Science ID 001275557401107
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Inflamed immune phenotype predicts favorable clinical outcomes of immune checkpoint inhibitor therapy across multiple cancer types.
Journal for immunotherapy of cancer
2024; 12 (2)
Abstract
The inflamed immune phenotype (IIP), defined by enrichment of tumor-infiltrating lymphocytes (TILs) within intratumoral areas, is a promising tumor-agnostic biomarker of response to immune checkpoint inhibitor (ICI) therapy. However, it is challenging to define the IIP in an objective and reproducible manner during manual histopathologic examination. Here, we investigate artificial intelligence (AI)-based immune phenotypes capable of predicting ICI clinical outcomes in multiple solid tumor types.Lunit SCOPE IO is a deep learning model which determines the immune phenotype of the tumor microenvironment based on TIL analysis. We evaluated the correlation between the IIP and ICI treatment outcomes in terms of objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) in a cohort of 1,806 ICI-treated patients representing over 27 solid tumor types retrospectively collected from multiple institutions.We observed an overall IIP prevalence of 35.2% and significantly more favorable ORRs (26.3% vs 15.8%), PFS (median 5.3 vs 3.1 months, HR 0.68, 95% CI 0.61 to 0.76), and OS (median 25.3 vs 13.6 months, HR 0.66, 95% CI 0.57 to 0.75) after ICI therapy in IIP compared with non-IIP patients, respectively (p<0.001 for all comparisons). On subgroup analysis, the IIP was generally prognostic of favorable PFS across major patient subgroups, with the exception of the microsatellite unstable/mismatch repair deficient subgroup.The AI-based IIP may represent a practical, affordable, clinically actionable, and tumor-agnostic biomarker prognostic of ICI therapy response across diverse tumor types.
View details for DOI 10.1136/jitc-2023-008339
View details for PubMedID 38355279
View details for PubMedCentralID PMC10868175
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Predicting rapid progression and overall survival in stage II-III pancreatic cancer using a CT-based radiomic signature.
LIPPINCOTT WILLIAMS & WILKINS. 2024: 706
View details for DOI 10.1200/JCO.2024.42.3_suppl.706
View details for Web of Science ID 001266680500362
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Clinicopathological features and clinical outcomes in individuals with Krukenberg tumors of colorectal origin.
LIPPINCOTT WILLIAMS & WILKINS. 2024: 191
View details for DOI 10.1200/JCO.2024.42.3_suppl.191
View details for Web of Science ID 001266680500518
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Early results of a pancreas cancer learning health network: Canopy Cancer Collective.
LIPPINCOTT WILLIAMS & WILKINS. 2024: 645
View details for DOI 10.1200/JCO.2024.42.3_suppl.645
View details for Web of Science ID 001266680500642
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KRAS Sequence Variation as Prognostic Marker in Patients With Young- vs Late-Onset Colorectal Cancer.
JAMA network open
2023; 6 (11): e2345801
Abstract
The understanding of the association between KRAS sequence variation status and clinical outcomes in colorectal cancer (CRC) has evolved over time.To characterize the association of age at onset, tumor sidedness, and KRAS sequence variation with survival among patients diagnosed with CRC.This cross-sectional study used data extracted from the Surveillance, Epidemiology, and End Results database. Patients diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2015 were included and were classified as having young-onset (YO) cancer if diagnosed between ages 20 to 49 years and late-onset (LO) cancer if diagnosed at age 50 years or older. Data were analyzed from April 2021 through August 2023.CRC cause-specific survival (CSS) was summarized using Fine and Gray cumulative incidence and Kaplan-Meier curves. Estimation of subdistribution hazard ratios (sHRs) for the association of KRAS status, age at onset, and tumor location with CRC CSS was conducted using the Fine and Gray competing risk model. Cox proportional hazards regression was used to estimate and compare HRs.Among 21 661 patients with KRAS sequence variation status (mean [SD] age at diagnosis, 62.50 [13.78] years; 9784 females [45.2%]), 3842 patients had YO CRC, including 1546 patients with KRAS variants, and 17 819 patients had LO CRC, including 7311 patients with KRAS variants. There was a significant difference in median CSS time between patients with variant vs wild-type KRAS (YO: 3.0 years [95% CI, 2.8-3.3 years] vs 3.5 years [95% CI, 3.3-3.9 years]; P = .02; LO: 2.5 years [95% CI, 2.4-2.7 years] vs 3.4 years [95% CI, 3.3-3.6 years]; P < .001). Tumors with variant compared with wild-type KRAS were associated with higher risk of CRC-related death (YO: sHR, 1.09 [95% CI, 1.01-1.18]; P = .03; LO: sHR, 1.06 [95% CI, 1.02-1.09]; P = .002). Among patients with YO cancer, mortality hazards increased by location, from right (sHR, 1.02 [95% CI, 0.88-1.17) to left (sHR, 1.15 [95% CI, 1.02-1.29) and rectum (sHR, 1.16 [95% CI, 0.99-1.36), but no trend by tumor location was seen for LO cancer.In this study of patients diagnosed with CRC, KRAS sequence variation was associated with increased mortality among patients with YO and LO tumors. In YO cancer, variant KRAS-associated mortality risk was higher in distal tumors than proximal tumors.
View details for DOI 10.1001/jamanetworkopen.2023.45801
View details for PubMedID 38032636
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ASO Visual Abstract: Patterns of Recurrence after Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation.
Annals of surgical oncology
2023
View details for DOI 10.1245/s10434-023-14475-3
View details for PubMedID 37875741
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Patterns of Recurrence After Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation.
Annals of surgical oncology
2023
Abstract
BACKGROUND: Improved treatment strategies are needed for patients with locally advanced gastric cancer with poor response to neoadjuvant chemotherapy. We aimed to describe patterns of failure for patients with no or partial response (NR, PR) to preoperative chemotherapy.PATIENTS AND METHODS: We analyzed patients with locally advanced gastric cancer treated from 2008 to 2022 with preoperative chemotherapy followed by surgery with D2 resection. We excluded patients who received radiation. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated. For patients with recurrent abdominal disease, hypothetical radiation clinical treatment volumes (CTV) were contoured on postoperative scans and compared with patterns of recurrence.RESULTS: A total of 60 patients were identified. The most used preoperative chemotherapy was FLOT (38.6%), followed by FOLFOX (30%) and ECF/ECX/EOX (23.3%). Four (6.7%), 40 (66.7%), and 9 patients (15%) had a complete pathologic response (CR), PR, and NR to neoadjuvant therapy, respectively. Among patients without a CR, 3-year overall and progression-free survival rates were 62.3% (95% CI 48-76.6%) and 51.3% (95% CI 36.9-65.7%), respectively. Three-year cumulative incidence of LRF and DM were 8.4% (95% CI 0.4-16.4%) and 41.0% (95% CI 26.3-55.4%), respectively. Absolute rates of patients having the first site of recurrence encompassed by a postoperative radiation CTV was 2.0% for patients without a CR and 0% for patients with NR.CONCLUSIONS: Patients with locally advanced gastric cancer with less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival.
View details for DOI 10.1245/s10434-023-14350-1
View details for PubMedID 37755563
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Definitive Treatment of Brain Metastases From a Neuroendocrine Tumor With Peptide Receptor Radionuclide Therapy With 177Lutetium DOTATATE: A Case Report.
Cureus
2023; 15 (9): e45327
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare malignancies that arise from secretory endocrine cells of the gastroenteropancreatic system. Clinical outcomes have improved for patients with GEP-NETs due to the development and recent FDA approval of 177Lutetium DOTATATE. However, the response of brain metastases from GEP-NETs from 177Lutetium DOTATATE is unreported. We present the case of an 81-year-old man with low-grade small bowel GEP-NET with liver and brain metastases treated with a total of six cycles of 177Lutetium DOTATATE. With over three years of follow-up from his initial treatment, his brain metastases have had complete or partial responses, with no need for brain radiotherapy or radiosurgery.
View details for DOI 10.7759/cureus.45327
View details for PubMedID 37849592
View details for PubMedCentralID PMC10577096
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A Phase I Trial of the ABCB1 Inhibitor, Oral Valspodar, in Combination With Paclitaxel in Patients With Advanced Solid Tumors.
American journal of clinical oncology
2023
Abstract
OBJECTIVES: Multidrug resistance mediated by P-glycoprotein is a potential obstacle to cancer treatment. This phase 1 trial determined the safety of paclitaxel with valspodar, a P-glycoprotein inhibitor, in patients with advanced solid tumors.PATIENTS AND METHODS: Patients were treated with single-agent paclitaxel Q3W 175mg/m2 (or 135mg/m2 if heavily pretreated) as a 3-hour infusion. If their disease was stable (SD) or progressive (PD), paclitaxel at 30% (52.5mg/m2), 40% (70mg/m2), or 50% (87.5mg/m2) of 175mg/m2 (full dose) was administered with valspodar 5mg/kg orally 4 times daily for 12 doses. Pharmacokinetic sampling (PK) for paclitaxel and valspodar was performed during single-agent and combination therapy.RESULTS: Sixteen patients had SD/PD after one cycle of paclitaxel and then received paclitaxel at 30% (n=3), 40% (n=3), and 50% (n=10) with valspodar. Hematologic adverse events (AEs) including myelosuppression at paclitaxel 40% were comparable to those of full-dose paclitaxel. Non-hematologic AEs consisted of reversible hepatic (hyperbilirubinemia and transaminitis) and neurologic AEs (ataxia and paresthesias). Eleven patients experienced SD with a median of 12.7 weeks (range, 5.4 to 36.0), 4 patients progressed, and 1 was inevaluable. Reduced dose paclitaxel with valspodar resulted in lower plasma peak concentrations of paclitaxel; otherwise, concentrations were similar to single-agent paclitaxel.CONCLUSION: Paclitaxel at 70mg/m2 was administered safely with valspodar. Limited efficacy in hematologic and solid tumors resulted in discontinuation of its clinical development and other transporter inhibitors. Recently, the development of ATP-binding cassette transporter inhibitors has been reconsidered to mitigate resistance to antibody-drug conjugates.
View details for DOI 10.1097/COC.0000000000001014
View details for PubMedID 37264515
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Paclitaxel With or Without Cixutumumab as Second-Line Treatment of Metastatic Esophageal or Gastroesophageal Junction Cancer: A Randomized Phase II ECOG-ACRIN Trial.
The oncologist
2023
Abstract
Patients with advanced esophageal cancer carry poor prognoses; limited data exist to guide second-line therapy in the metastatic setting. Paclitaxel has been used yet is associated with limited efficacy. There is preclinical evidence of synergy between paclitaxel and cixutumumab, a monoclonal antibody targeting insulin-like growth factor-1 receptor. We conducted a randomized phase II trial of paclitaxel (arm A) versus paclitaxel plus cixutumumab (arm B) in the second-line for patients with metastatic esophageal or gastroesophageal junction (GEJ) cancers.The primary endpoint was progression-free survival (PFS); 87 patients (43 in arm A, 44 in arm B) were treated.Median PFS was 2.6 months in arm A [90% CL 1.8-3.5] and 2.3 months in arm B [90% 2.0-3.5], P = .86. Stable disease was observed in 29 (33%) patients. Objective response rates for Arms A and B were 12% [90% CI, 5-23%] and 14% [90% CI, 6-25%]. Median overall survival was 6.7 months [90% CL 4.9-9.5] in arm A and 7.2 months [90% CL 4.9-8.1] in arm B, P = 56.The addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GEJ cancer was well tolerated but did not improve clinical outcomes relative to standard of care (ClinicalTrials.gov Identifier: NCT01142388).
View details for DOI 10.1093/oncolo/oyad096
View details for PubMedID 37104870
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Complete Remission of Widely Metastatic Human Epidermal Growth Factor Receptor 2-Amplified Pancreatic Adenocarcinoma After Precision Immune and Targeted Therapy With Description of Sequencing and Organoid Correlates.
JCO precision oncology
2023; 7: e2100489
View details for DOI 10.1200/PO.21.00489
View details for PubMedID 37079860
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Validation of a Resectability Scoring System for Prediction of Pancreatic Adenocarcinoma Surgical Outcomes.
Annals of surgical oncology
2023
Abstract
BACKGROUND: The most used pancreatic cancer (PC) resectability criteria are descriptive in nature or based solely on dichotomous degree of involvement (<180° or >180°) of vessels, which allows for a high degree of subjectivity and inconsistency.METHODS: Radiographic measurements of the circumferential degree and length of tumor contact with major peripancreatic vessels were retrospectively obtained from pre-treatment multi-detector computed tomography (MDCT) images from PC patients treated between 2001 and 2015 at two large academic institutions. Arterial and venous scores were calculated for each patient, then tested for a correlation with tumor resection and R0 resection.RESULTS: The analysis included 466 patients. Arterial and venous scores were highly predictive of resection and R0 resection in both the training (n=294) and validation (n=172) cohorts. A recursive partitioning tree based on arterial and venous score cutoffs developed with the training cohort was able to stratify patients of the validation cohort into discrete groups with distinct resectability probabilities. A refined recursive partitioning tree composed of three resectability groups was generated, with probabilities of resection and R0 resection of respectively 94 and 73% for group A, 61 and 35% for group B, and 4 and 2% for group C. This resectability scoring system (RSS) was highly prognostic, predicting median overall survival times of 27, 18.9, and 13.5 months respectively for patients in RSS groups A, B, and C (p<0.001).CONCLUSIONS: The proposed RSS was highly predictive of resection, R0 resection, and prognosis for patients with PC when tested against an external dataset.
View details for DOI 10.1245/s10434-023-13120-3
View details for PubMedID 36792768
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Clinical benefit of granulocyte-colony stimulating factor (GCSF) use during chemoimmunotherapy treatment for metastatic pancreatic adenocarcinoma (mPDAC).
LIPPINCOTT WILLIAMS & WILKINS. 2023: 757
View details for Web of Science ID 001093994600772
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Therapeutic Implications of Oncogenic Missense HER2 (ERBB2) Mutations in Gastric Adenocarcinoma.
JCO precision oncology
2023; 7: e2200093
View details for DOI 10.1200/PO.22.00093
View details for PubMedID 36787506
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Phase 2 randomized, active-controlled, multicenter trial to assess the safety and efficacy of RRx-001+irinotecan vs. regorafenib plus irinotecan in third/fourth-line colorectal cancer.
LIPPINCOTT WILLIAMS & WILKINS. 2023: 97
View details for Web of Science ID 001093994600203
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ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer.
Clinical colorectal cancer
2022
Abstract
INTRODUCTION: RRx-001 is a novel cysteine-targeted alkylating agent that releases nitric oxide (NO). The primary biological activities of this hybrid molecule include macrophage repolarizing and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001+irinotecan vs. regorafenib in third/fourth line colorectal cancer that previously received treatment with irinotecan.PATIENTS AND METHODS: A total of 34 patients were randomized (24 to RRx-001+irinotecan (RxI) and 10 to single-agent regorafenib (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month "primer" followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the (ITT) efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months, at which point RRx-001 was discontinued, followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. There were 3 patients (3/24=12.5%) with prior single agent irinotecan on the RRx-001 randomized arm and 2 (2/10=20%) on the regorafenib randomized arm. Numerous patients had irinotecan combination therapies prior to randomized treatment. There were 15 patients on RRx-001 arm that received irinotecan post-RRx-001 in the randomized trial. There were 5 PRs on RRx-001 plus irinotecan leading to an overall response of 20.8% (5/24). There were 37.5% (9/24) of RRx-001 randomized patients with KRAS mutant type while 60% (6/10) regorafenib randomized patients were of KRAS type mutant. There were only 4 patients with available QOL and Edmonton Symptom Assessment System, an insufficient sample size to allow for any meaningful analysis.RESULTS: Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, 2-sided log-rank test, P=.0030). The toxicity profile of RxI was substantially improved compared with RegI.CONCLUSION: The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed "signal" accompanied by a sufficient safety profile.
View details for DOI 10.1016/j.clcc.2022.11.003
View details for PubMedID 36529613
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Late-Onset Immunotherapy-Induced Myocarditis 2 Years After Checkpoint Inhibitor Initiation.
JACC. CardioOncology
2022; 4 (5): 727-730
View details for DOI 10.1016/j.jaccao.2022.04.007
View details for PubMedID 36636432
View details for PubMedCentralID PMC9830192
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EXPLORATORY PLATFORM TRIAL TO EVALUATE IMMUNOTHERAPY COMBINATIONS WITH CHEMOTHERAPY FOR THE TREATMENT OF PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC PANCREATIC ADENOCARCINOMA (REVOLUTION)
BMJ PUBLISHING GROUP. 2022: A687
View details for DOI 10.1136/jitc-2022-SITC2022.0656
View details for Web of Science ID 000919423400616
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A phase II study of sapanisertib (TAK-228) a mTORC1/2 inhibitor in rapalog-resistant advanced pancreatic neuroendocrine tumors (PNET): ECOG-ACRIN EA2161.
Investigational new drugs
2022
Abstract
This was a two-stage phase II trial of a mTORC1/2 inhibitor (mTORC: mammalian target of rapamycin complex) Sapanisertib (TAK228) in patients with rapalog-resistant pancreatic neuroendocrine tumors (PNETs) (NCT02893930). Approved rapalogs such as everolimus inhibit mTORC1 and have limited clinical activity, possibly due to compensatory feedback loops. Sapanisertib addresses the potential for incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2, and thus to reverse resistance to earlier rapamycin analogues. In stage 1, patients received sapanisertib 3mg by mouth once daily on a continuous dosing schedule in 28-day cycle. This trial adopted a two-stage design with the primary objective of evaluating objective tumor response. The first stage would recruit 13 patients in order to accrue 12 eligible and treated patients. If among the 12 eligible patients at least 1 patient had an objective response to therapy, the study would move to the second stage of accrual where 25 eligible and treated patients would be enrolled. This study activated on February 1, 2017, the required pre-determined number of patients (n=13) had entered by November 5, 2018 for the first stage response evaluation. The accrual of this trial was formally terminated on December 27, 2019 as no response had been observed after the first stage accrual. Treatment-related grade 3 adverse events were reported in eight (61%) patients with hyperglycemia being the most frequent, in three patients (23%). Other toxicities noted in the trial included fatigue, rash diarrhea, nausea, and vomiting. The median PFS was 5.19months (95% CI [3.84, 9.30]) and the median OS was 20.44months (95% CI [5.65, 22.54]). Due to the lack of responses in Stage 1 of the study, the study did not proceed to stage 2. Thus the potential to reverse resistance was not evident.
View details for DOI 10.1007/s10637-022-01311-w
View details for PubMedID 36264382
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A Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients with Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211).
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2022: 101200JCO2201013
Abstract
Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies suggest that capecitabine and temozolomide are associated with high response rates (RR) and long progression-free survival (PFS).E2211 was a multicenter, randomized, phase II trial comparing temozolomide vs. capecitabine/temozolomide in patients with advanced low or intermediate grade pancreatic NETs. Key eligibility criteria included: progression within the preceding 12 months and no prior temozolomide, DTIC, capecitabine or 5-fluorouracil. The primary endpoint was PFS; secondary endpoints were overall survival (OS), RR, safety, and MGMT by immunohistochemistry (IHC) and promoter methylation.144 patients were enrolled between 4/2013 to 3/2016 to temozolomide (n = 72) or capecitabine and temozolomide (n = 72); the primary analysis population included 133 eligible patients. At the scheduled interim analysis in 1/2018, median PFS was 14.4 months for temozolomide vs. 22.7 months for capecitabine/temozolomide (HR = 0.58), which was sufficient to reject the null hypothesis for the primary endpoint (stratified log rank p = 0.022). In the final analysis (5/2021), median OS was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (HR = 0.82, p = 0.42). MGMT deficiency was associated with response.The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared to temozolomide alone in patients with advanced pancreatic NETs. The median PFS and RR observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic NETs. MGMT deficiency was associated with response and, although, routine MGMT testing is not recommended, it can be considered for select patients in need of objective response. NCT01824875.
View details for DOI 10.1200/JCO.22.01013
View details for PubMedID 36260828
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Building a learning network to accelerate improvement in pancreas cancer care and outcomes: Canopy Cancer Collective
LIPPINCOTT WILLIAMS & WILKINS. 2022: 368
View details for Web of Science ID 000891944700364
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Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial.
Nature medicine
2022
Abstract
Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P=0.006 compared to historical 1-year OS of 35%, n=34) but was not met for sotiga/chemo (48.1%, P=0.062, n=36) or sotiga/nivo/chemo (41.3%, P=0.223, n=35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.
View details for DOI 10.1038/s41591-022-01829-9
View details for PubMedID 35662283
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EA2183: A phase III study of consolidative radiotherapy in patients with oligometastatic HER2-negative esophageal and gastric adenocarcinoma
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680304916
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A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: Final analysis of efficacy and evaluation of MGMT as a predictive biomarker (ECOG-ACRIN E2211).
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680301172
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Circulating KRAS variant-specific shedding and association with survival in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) receiving chemoimmunotherapy
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680300771
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The inflamed immune phenotype (IIP): A clinically actionable artificial intelligence (AI)-based biomarker predictive of immune checkpoint inhibitor (ICI) outcomes across > 16 primary tumor types
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680300844
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Distinct biosignatures associate with survival after chemoimmunotherapy in a randomized, three-arm phase II study in patients with metastatic pancreatic cancer.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680301178
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Randomized phase II study of platinum and etoposide (EP) versus temozolomide and capecitabine (CAPTEM) in patients (pts) with advanced G3 non-small cell gastroenteropancreatic neuroendocrine neoplasms (GEPNENs): ECOG-ACRIN EA2142.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680301186
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Radiographic, Biochemical, or Pathologic Response to Neoadjuvant Chemotherapy in Resected Pancreatic Cancer: Which Is Best?
SPRINGER. 2022: 351
View details for Web of Science ID 000789811800041
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Evaluation of Liver and Renal Toxicity in Peptide Receptor Radionuclide Therapy for Somatostatin Receptor Expressing Tumors: A 2-Year Follow-Up.
The oncologist
2022
Abstract
Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin receptor (SSR) analogs is now an established systemic treatment for neuroendocrine tumors (NET). However, more short- and long-term data about renal and hepatotoxicity is needed. Here we present our experience in this clinical scenario.Eighty-six patients with progressive SSR-expressing malignancies underwent PRRT with Lu-177 Dotatate and were followed up for up to 2 years. Laboratory tests were done 1 week before each cycle and every 2 months at follow-up. Hepatic and renal toxicity was determined based on NCI CTCAE V5.0.55/86 (64%) patients completed all 4 cycles of PRRT; 18/86 (20.9%) are currently being treated; 13/86 (15.1%) had to discontinue PRRT: 4/13 (31%) due to hematologic toxicity, 9/13 (69%) due to non-PRRT-related comorbidities. Out of the patients who finished treatment, only transient grade 2 toxicities were observed during PRRT: hypoalbuminemia in 5.5% (3/55), and renal toxicity (serum creatinine and estimated glomerular filtration rate) in 1.8% (1/55). No grade 3 or 4 liver and renal toxicity occurred. Patients presenting with impaired liver or renal function prior to PRRT, either improved or had stable findings. No deterioration was observed.Peptide receptor radionuclide therapy does not have a negative impact on liver and renal function, even in patients with pre-existing impaired parameters. No grade 3 or 4 hepatic or renal toxicity was identified. Only transient grade 2 hypoalbuminemia in 5.5% and nephrotoxicity in 1.8% of patients were seen during PRRT.
View details for DOI 10.1093/oncolo/oyab072
View details for PubMedID 35641196
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Peptide Receptor Radionuclide Therapy (PRRT) in Advanced Pheochromocytoma and Paraganglioma From a Single Institution Experience
LIPPINCOTT WILLIAMS & WILKINS. 2022: E42-E43
View details for Web of Science ID 000819123700057
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Safety, Pharmacodynamic, and Antitumor Activity of Tidutamab, an SSTR2 x CD3 Bispecific Antibody, in Subjects With Advanced Neuroendocrine Tumors
LIPPINCOTT WILLIAMS & WILKINS. 2022: E58
View details for Web of Science ID 000819123700109
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MULTIOMIC BIOMARKER SIGNATURES IDENTIFY SUBSETS OF PATIENTS WHO MAY BENEFIT FROM EITHER NIVOLUMAB OR SOTIGALIMAB IN COMBINATION WITH CHEMOTHERAPY IN METASTATIC PANCREATIC CANCER
BMJ PUBLISHING GROUP. 2021: A370
View details for DOI 10.1136/jitc-2021-SITC2021.343
View details for Web of Science ID 000774877500332
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Durable response after immune checkpoint inhibitor-related diabetes in mismatch repair deficient pancreatic cancer.
Immunotherapy
2021
Abstract
Mismatch repair protein deficiency occurs in 0.8-2% of pancreatic ductal adenocarcinomas and confers susceptibility to immunotherapy. Herein, we report the case of a patient with Lynch syndrome-associated, locally advanced mismatch repair protein deficiency pancreatic ductal adenocarcinomas who demonstrated a sustained response to second-line treatment with pembrolizumab, but eventually developed immune-related diabetic ketoacidosis requiring discontinuation of treatment. He has since remained in remission, off treatment, over the following 3years, with regular surveillance showing no clinical or radiographic evidence of disease progression. The patient's unusual disease course raises the question of whether this serious immune-related adverse event affecting the organ of malignant involvement may have predicted his remarkable and durable response.
View details for DOI 10.2217/imt-2021-0008
View details for PubMedID 34338034
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Baseline level and early on-treatment clearance of circulating mutant KRAS in metastatic pancreatic ductal adenocarcinoma treated with chemotherapy with or without immunotherapy.
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for DOI 10.1200/JCO.2021.39.15_suppl.4122
View details for Web of Science ID 000708120602222
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A phase II/III study of perioperative nivolumab and ipilimumab in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: Results of a safety run-in-A trial of the ECOG-ACRIN Cancer Research Group (EA2174).
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for DOI 10.1200/JCO.2021.39.15_suppl.4064
View details for Web of Science ID 000708120602164
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A phase I pharmacokinetic and safety study of Paclitaxel Injection Concentrate for Nano-dispersion (PICN) alone and in combination with carboplatin in patients with advanced solid malignancies and biliary tract cancers.
Cancer chemotherapy and pharmacology
2021
Abstract
PURPOSE: Paclitaxel injection concentrate for nano-dispersion (PICN) is a Cremophor-free, nanotechnology-driven paclitaxel formulation. This phase I study examined the safety, tolerability, pharmacokinetics and maximum tolerated dose (MTD) of PICN alone and in combination with carboplatin. Its early efficacy in unresectable biliary tract cancers (BTCs) was also evaluated.METHODS: This multi-center study comprised two parts. Part A contained a dose-escalation cohort following "3+3" design using PICN monotherapy in advanced solid tumors (Part A1); Part A2 dose-expansion cohort was then conducted in advanced BTCs due to observed efficacy in Part A1. Part B1 and B2 evaluated escalating dose of PICN with carboplatin in advanced solid tumors. PICN was administered as a 30min-infusion every 3weeks without pre-medications for hypersensitivity reactions.RESULTS: Thirty-six patients received PICN monotherapy in Part A and 21 received PICN plus carboplatin in Part B. The MTD of PICN was determined to be 295mg/m2 both as a monotherapy and in combination with carboplatin at AUC 5. Dose-proportional exposure in paclitaxel Cmax and AUC was observed overdose range from 175 to 325mg/m2 for PICN monotherapy and its combination with carboplatin. Carboplatin did not alter PICN exposure. Clinically significant toxicities mainly include neutropenia and peripheral neuropathy. PICN monotherapy yielded a response rate of 20% in unresectable BTCs.CONCLUSION: This study demonstrated the safety and stable pharmacokinetics of PICN as a monotherapy and in combination with carboplatin. Single-agent PICN showed promising antitumor activity in advanced BTCs, warranting further studies to investigate its role in gastrointestinal cancers.
View details for DOI 10.1007/s00280-021-04235-z
View details for PubMedID 33634324
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CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study.
The Lancet. Oncology
2021; 22 (1): 118–31
Abstract
Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.
View details for DOI 10.1016/S1470-2045(20)30532-5
View details for PubMedID 33387490
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Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes predicts survival after immune checkpoint inhibitor therapy across multiple cancer types.
Journal of Clinical Oncology
2021; 39
View details for DOI 10.1200/JCO.2021.39.15_suppl.2607
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CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study
LANCET ONCOLOGY
2021; 22 (1): 118–31
View details for Web of Science ID 000610553800054
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Universal Screening of Gastrointestinal Malignancies for Mismatch Repair Deficiency at Stanford.
JNCI cancer spectrum
2020; 4 (5): pkaa054
Abstract
Background: In light of recent Food and Drug Administration (FDA) approval of immune checkpoint inhibitors for mismatch repair deficient (dMMR) malignancies, identifying patients with dMMR malignancies has become increasingly important. Although screening for dMMR in colorectal cancer (CRC) is recommended, it is less common for extracolonic gastrointestinal (GI) malignancies. At Stanford Comprehensive Cancer Institute (SCCI), all GI malignancies have been screened for dMMR via immunohistochemistry since January 2016.Methods: In this study, we conducted a retrospective review of all patients with GI malignancies screened for dMMR between January 2016 and December 2017. Tumor sequencing was performed on cases negative for germline pathogenic variants where tumor material was available.Results: A total of 1425 consecutive GI malignancies were screened for dMMR at SCCI during the study period, and 1374 were included for analysis. dMMR was detected in 7.2% of all GI malignancies. We detected the highest prevalence of dMMR in gastric (15 of 150, 10.0%) followed by colorectal (63 of 694, 9.1%), pancreatic (13 of 244, 5.3%), and gastroesophageal malignancy (6 of 132, 4.5%) patients. Lynch syndrome was the most common etiology for dMMR in colorectal cancer (41.5%), double somatic (confirmed or possible) pathogenic variants the most common etiology in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation the most common etiology in gastric (73.3%) and gastroesophageal cancer (83.3%).Conclusions: Given the relatively high incidence of dMMR in GI malignancies, we recommend screening all GI malignancies. Our results suggest that although a rare occurrence, double somatic pathogenic variants may be a biologically significant pathway causing dMMR in pancreatic cancer.
View details for DOI 10.1093/jncics/pkaa054
View details for PubMedID 33225206
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A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7445.AM2020-CT301
View details for Web of Science ID 000590059302192
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Tumour-specific fluorescence-guided surgery for pancreatic cancer using panitumumab-IRDye800CW: a phase 1 single-centre, open-label, single-arm, dose-escalation study.
The lancet. Gastroenterology & hepatology
2020
Abstract
BACKGROUND: Complete surgical resection remains the primary curative option for pancreatic ductal adenocarcinoma, with positive margins in 30-70% of patients. In this study, we aimed to evaluate the use of intraoperative tumour-specific imaging to enhance a surgeon's ability to detect visually occult cancer in real time.METHODS: In this single-centre, open-label, single-arm study, done in the USA, we enrolled patients who had clinically suspicious or biopsy-confirmed pancreatic ductal adenocarcinomas and were scheduled for curative surgery. Eligible patients were 19 years of age or older with a life expectancy of more than 12 weeks and a Karnofsky performance status of at least 70% or an Eastern Cooperative Oncology Group or Zubrod level of one or lower, who were scheduled to undergo curative surgery. Patients were sequentially enrolled into each dosing group and 2-5 days before surgery, patients were intravenously infused with 100 mg of unlabelled panitumumab followed by 25 mg, 50 mg, or 75 mg of the near-infrared fluorescently labelled antibody (panitumumab-IRDye800CW). The primary endpoint was to determine the optimal dose of panitumumab-IRDye800CW in identifying pancreatic ductal adenocarcinomas as measured by tumour-to-background ratio in all patients. The tumour-to-background ratio was defined as the fluorescence signal of the tumour divided by the fluorescence signal of the surrounding healthy tissue. The dose-finding part of this study has been completed. This study is registered with ClinicalTrials.gov, NCT03384238.FINDINGS: Between April, 2018, and July, 2019, 16 patients were screened for enrolment onto the study. Of the 16 screened patients, two (12%) patients withdrew from the study and three (19%) were not eligible; 11 (69%) patients completed the trial, all of whom were clinically diagnosed with pancreatic ductal adenocarcinoma. The mean tumour-to-background ratio of primary tumours was 3·0 (SD 0·5) in the 25 mg group, 4·0 (SD 0·6) in the 50 mg group, and 3·7 (SD 0·4) in the 75 mg group; the optimal dose was identified as 50 mg. Intraoperatively, near-infrared fluorescence imaging provided enhanced visualisation of the primary tumours, metastatic lymph nodes, and small (<2 mm) peritoneal metastasis. Intravenous administration of panitumumab-IRDye800CW at the doses of 25 mg, 50 mg, and 75 mg did not result in any grade 3 or higher adverse events. There were no serious adverse events attributed to panitumumab-IRDye800CW, although four possibly related adverse events (grade 1 and 2) were reported in four patients.INTERPRETATION: To our knowledge, this study presents the first clinical use of panitumumab-IRDye800CW for detecting pancreatic ductal adenocarcinomas and shows that panitumumab-IRDye800CW is safe and feasible to use during pancreatic cancer surgery. Tumour-specific intraoperative imaging might have added value for treatment of patients with pancreatic ductal adenocarcinomas through improved patient selection and enhanced visualisation of surgical margins, metastatic lymph nodes, and distant metastasis.FUNDING: National Institutes of Health and the Netherlands Organization for Scientific Research.
View details for DOI 10.1016/S2468-1253(20)30088-1
View details for PubMedID 32416764
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Extrahepatic Ga-68-DOTATATE-Avid Tumor Volume and serum Chromogranin A Predict Short-Term Outcome of Lu-177-DOTATATE in Late-Stage Metastatic Gastroenteropancreatic Neuroendocrine Tumors
SOC NUCLEAR MEDICINE INC. 2020
View details for Web of Science ID 000568290500275
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Toxicity identification and evaluation of peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs)
SOC NUCLEAR MEDICINE INC. 2020
View details for Web of Science ID 000568290501378
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Peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NET): A two-year single institution experience
SOC NUCLEAR MEDICINE INC. 2020
View details for Web of Science ID 000568290501374
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Natural killer cell and stroma abundance are independently prognostic and predict gastric cancer chemotherapy benefit.
JCI insight
2020
Abstract
BACKGROUND: Specific features of the tumor microenvironment (TME) may provide useful prognostic information. We conducted a systematic investigation of the cellular composition and prognostic landscape of TME in gastric cancer.METHODS: We evaluated the prognostic significance of major stromal and immune cells within TME. We proposed a composite TME-based risk score and tested it in six independent cohorts of 1,678 patients with gene expression or immunohistochemistry measurements. Further, we devised a new patient classification system based on TME characteristics.RESULTS: We identified natural killer cells, fibroblasts, and endothelial cells as the most robust prognostic markers. The TME risk score combining these cell types was an independent prognostic factor when adjusted for clinicopathologic variables (gene expression: HR [95% CI]: 1.42 [1.22-1.66]; immunohistochemistry: 1.34 [1.24-1.45], P<0.0001). Higher TME risk scores consistently associated with worse survival within every pathologic stage (HR range: 2.18-3.11, P<0.02) and among patients who received surgery only. The TME risk score provided additional prognostic value beyond stage, and combination of the two improved prognostication accuracy (likelihood-ratio test chi2 = 235.4 vs. 187.6, P<0.0001; net reclassification index: 23%). The TME risk score can predict the survival benefit of adjuvant chemotherapy in non-metastatic patients (stage I-III) (interaction test P<0.02). Patients were divided into four TME subtypes that demonstrated distinct genetic and molecular patterns and complemented established genomic and molecular subtypes.CONCLUSION: We developed and validated a TME-based risk score as an independent prognostic and predictive factor, which has the potential to guide personalized management of gastric cancer.
View details for DOI 10.1172/jci.insight.136570
View details for PubMedID 32229725
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A phase Ib/II study of the anti-CD47 antibody magrolimab with cetuximab in solid tumor and colorectal cancer patients
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000530922700108
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Immune-Related Adverse Events and Immune Checkpoint Inhibitor Efficacy in Patients with Gastrointestinal Cancer with Food and Drug Administration-Approved Indications for Immunotherapy.
The oncologist
2020
Abstract
Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy.The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes.Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset.Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response.Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.
View details for DOI 10.1634/theoncologist.2019-0637
View details for PubMedID 31943525
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Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-mesothelin (CRS-207) With or Without Nivolumab in Patients with Pancreatic Cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research
2020
Abstract
Two studies in previously-treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B).Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses and immunologic correlates.Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 (95% CI, 4.7, 8.6) and 6.1 (95% CI, 3.5, 7.0) months, respectively, with a hazard ratio 0.86 (95% CI, 0.55, 1.34). Objective responses were seen in three patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The
grade 3 related adverse event rate while higher in Arm A (35.3% vs 11.9%) was manageable. Changes in the microenvironment, including increase in CD8+ T cells and a decrease in CD68+ myeloid cells, were observed in long-term survivors in Arm A only.While the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable to standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident. View details for DOI 10.1158/1078-0432.CCR-19-3978
View details for PubMedID 32273276
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Outcomes and Tolerability of Definitive and Preoperative Chemoradiation in Elderly Patients With Esophageal Cancer: A Retrospective Institutional Review.
Advances in radiation oncology
2020; 5 (6): 1188–96
Abstract
Our purpose was to report outcomes of elderly patients who underwent definitive treatment involving radiation therapy for esophageal cancer at our institution.We performed a retrospective review of patients aged ≥75 years with esophageal cancer treated with definitive radiation therapy (≥45 Gy) at our institution from 1997 to 2019. Acute and late Radiation Therapy Oncology Group grade 3+ toxicities were recorded. Survival was estimated using the Kaplan-Meier method.Of the 89 patients included, median age was 80 and 78% were male. Median adjusted Charlson Comorbidity Index and Karnofsky Performance Status were 5 (3-12) and 80 (50-100), respectively. The majority of cancers were adenocarcinoma (58%), distal (67%), and stage III (62%). Fifty-eight percent underwent definitive chemoradiotherapy, and one-third underwent preoperative intent chemoradiotherapy. Median prescribed dose was 50 Gy (45-66 Gy), and intensity modulated radiation therapy was used in 76%. Eighty-five percent completed the radiation therapy course. Among these, 20% had radiation therapy breaks. For those receiving concurrent chemotherapy, 37% had a dose reduction and 39.5% had a break/cycle reduction. Acute grade 3+ toxicity was 22%, with 2% grade 5 toxicity. Twenty-one of the 29 patients (72%) treated with preoperative intent underwent surgery. There were no deaths 90 days postoperatively. For patients who underwent surgery, 1- and 2-year overall survival were 95% and 84%. For those who did not undergo surgery, 1- and 2-year overall survival were 70% and 52%.There is a role for aggressive radiation therapy in well-selected elderly patients with esophageal cancer. However, optimization of supportive care, chemotherapy regimens, radiation therapy dose/fractionation, and surgical indications are needed to reduce toxicity.
View details for DOI 10.1016/j.adro.2020.05.001
View details for PubMedID 33305080
View details for PubMedCentralID PMC7718494
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Complete Response and Immune-Mediated Adverse Effects With Checkpoint Blockade: Treatment of Mismatch Repair-Deficient Colorectal Neuroendocrine Carcinoma.
JCO precision oncology
2019; 3: 1-7
View details for DOI 10.1200/PO.19.00098
View details for PubMedID 35100735
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Feasibility and design of a cloud-based digital platform in patients with advanced cancer.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.27_suppl.211
View details for Web of Science ID 000518223100208
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Comparison of definitive chemoradiation with 5-fluorouracil versus capecitabine in anal cancer
JOURNAL OF GASTROINTESTINAL ONCOLOGY
2019; 10 (4): 605–15
View details for DOI 10.21037/jgo.2019.02.17
View details for Web of Science ID 000474645400002
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Comparison of definitive chemoradiation with 5-fluorouracil versus capecitabine in anal cancer.
Journal of gastrointestinal oncology
2019; 10 (4): 605-615
Abstract
Capecitabine (Cap) is an established treatment alternative to 5-fluorouracil (5-FU) for chemoradiation in rectal cancer. Few studies have compared the two agents in anal cancer. We compared outcomes and toxicities using Cap versus 5-FU in non-metastatic anal cancer patients at Stanford.All non-metastatic anal cancer patients treated with definitive chemoradiation at Stanford from 1997-2016 were included. Fisher's exact and Mann-Whitney U tests were used to compare nominal and continuous variables. Gray's test was used to compare incidence of recurrence and colostomy, and Log-rank test was used to compare survival.Sixty-eight patients were included. Thirty-six patients received Cap and 32 received 5-FU (12 received standard 5-FU and 20 received low-dose continuous 5-FU). Patient characteristics were similar between the two groups. There was no difference in the 3-year overall and disease-specific survival between Cap and 5-FU (94% vs. 80%, P=0.197; 100% vs. 86%, P=0.051). Overall incidence of recurrence was equivalent between Cap and 5-FU (11% vs. 13%, P=0.703), but incidence of locoregional recurrence was higher in the 5-FU group (0% vs. 13%, P=0.042); patients treated with Cap had longer recurrence-free intervals (18 vs. 6 months, P=0.400), and all recurrences were distant. More colostomies were needed with 5-FU (3% vs. 13%, P=0.133). Toxicities were similar between the two groups. The most common grade ≥2 toxicities were dermatitis (77%), anal pain (78%), and diarrhea (56%).Overall survival (OS), cancer-specific survival and incidence of recurrence were equivalent between Cap and 5-FU in anal cancer. Patients treated with Cap had statistically significant lower incidence of loco-regional relapses.
View details for DOI 10.21037/jgo.2019.02.17
View details for PubMedID 31392040
View details for PubMedCentralID PMC6657317
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Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial.
JAMA oncology
2019
Abstract
Importance: New therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC.Objective: To evaluate the safety and efficacy of the anti-PD-L1 (programmed death-ligand 1) antibody using either durvalumab monotherapy or in combination with the anticytotoxic T-lymphocyte antigen 4 antibody using durvalumab plus tremelimumab therapy in patients with mPDAC.Design, Setting, and Participants: Part A of this multicenter, 2-part, phase 2 randomized clinical trial was a lead-in safety, open-label study with planned expansion to part B pending an efficacy signal from part A. Between November 26, 2015, and March 23, 2017, 65 patients with mPDAC who had previously received only 1 first-line fluorouracil-based or gemcitabine-based treatment were enrolled at 21 sites in 6 countries. Efficacy analysis included the intent-to-treat population; safety analysis included patients who received at least 1 dose of study treatment and for whom any postdose data were available.Interventions: Patients received durvalumab (1500 mg every 4 weeks) plus tremelimumab (75 mg every 4 weeks) combination therapy for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until the onset of progressive disease or unacceptable toxic effects.Main Outcomes and Measures: Safety and efficacy were measured by objective response rate, which was used to determine study expansion to part B. The threshold for expansion was an objective response rate of 10% for either treatment arm.Results: Among 65 randomized patients, 34 (52%) were men and median age was 61 (95% CI, 37-81) years. Grade 3 or higher treatment-related adverse events occurred in 7 of 32 patients (22%) receiving combination therapy and in 2 of 32 patients (6%) receiving monotherapy; 1 patient randomized to the monotherapy arm did not receive treatment owing to worsened disease. Fatigue, diarrhea, and pruritus were the most common adverse events in both arms. Overall, 4 of 64 patients (6%) discontinued treatment owing to treatment-related adverse events. Objective response rate was 3.1% (95% CI, 0.08-16.22) for patients receiving combination therapy and 0% (95% CI, 0.00-10.58) for patients receiving monotherapy. Low patient numbers limited observation of the associations between treatment response and PD-L1 expression or microsatellite instability status.Conclusion and Relevance: Treatment was well tolerated, and the efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease. Patients were not enrolled in part B because the threshold for efficacy was not met in part A.Trial Registration: ClinicalTrials.gov identifier: NCT02558894.
View details for DOI 10.1001/jamaoncol.2019.1588
View details for PubMedID 31318392
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Detection of visually occult metastatic lymph nodes using molecularly targeted fluorescent imaging during surgical resection of pancreatic cancer
HPB
2019; 21 (7): 883–90
View details for DOI 10.1016/j.hpb.2018.11.008
View details for Web of Science ID 000475487400014
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A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients
AMER ASSOC CANCER RESEARCH. 2019
View details for DOI 10.1158/1538-7445.AM2019-CT004
View details for Web of Science ID 000488129900004
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Access to diagnostics and treatment of neuroendocrine tumors (NETs): The difference between patient perception and reality.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.15_suppl.e13524
View details for Web of Science ID 000487345800347
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ROCKET: A randomized, multicenter phase 2 study of RRx-001+irinotecan versus regorafenib in 3rd/4th line colorectal cancer.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.15_suppl.3526
View details for Web of Science ID 000487345805104
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Predicting Pancreatic Cancer Resectability and Outcomes Based on an Objective Quantitative Scoring System
LIPPINCOTT WILLIAMS & WILKINS. 2019: 622–28
View details for DOI 10.1097/MPA.0000000000001314
View details for Web of Science ID 000480685300015
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First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers
JOURNAL OF CLINICAL ONCOLOGY
2019; 37 (12): 946-+
View details for DOI 10.1200/JCO.18.02018
View details for Web of Science ID 000466717700002
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Effect of Lanreotide Depot/Autogel on Urinary 5-Hydroxyindoleacetic Acid and Plasma Chromogranin A Biomarkers in Nonfunctional Metastatic Enteropancreatic Neuroendocrine Tumors
ONCOLOGIST
2019; 24 (4): 463–74
View details for DOI 10.1634/theoncologist.2018-0217
View details for Web of Science ID 000468006600015
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Lanreotide for the Prolonged Control of Carcinoid Syndrome (CS) in Somatostatin Analog (SSA)-Naive or -Experienced Patients
LIPPINCOTT WILLIAMS & WILKINS. 2019: 455–56
View details for Web of Science ID 000462541800125
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Pancreatic Adenocarcinoma, Version 1.2019
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK
2019; 17 (3): 203–10
Abstract
The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.
View details for PubMedID 30865919
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Unmet Needs in the Global NETs Patient Community From the Perspectives of Patients, Patient Advocates, and NET Health Professionals
LIPPINCOTT WILLIAMS & WILKINS. 2019: 442
View details for Web of Science ID 000462541800079
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A Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors: ATrial of the ECOG-ACRIN Cancer Research Group (E2211)
LIPPINCOTT WILLIAMS & WILKINS. 2019: 443
View details for Web of Science ID 000462541800082
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First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2019: JCO1802018
Abstract
PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis.PATIENTS AND METHODS: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort.RESULTS: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months.CONCLUSION: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.
View details for PubMedID 30811285
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Detection of visually occult metastatic lymph nodes using molecularly targeted fluorescent imaging during surgical resection of pancreatic cancer.
HPB : the official journal of the International Hepato Pancreato Biliary Association
2019
Abstract
BACKGROUND: Although most patients with PDAC experience distant failure after resection, a significant portion still present with local recurrence. Intraoperative fluorescent imaging can potentially facilitate the visualization of involved peritumoral LNs and guide the locoregional extent of nodal dissection. Here, the efficacy of targeted intraoperative fluorescent imaging was examined in the detection of metastatic lymph nodes (LNs) during resection of pancreatic ductal adenocarcinoma (PDAC).METHODS: A dose-escalation prospective study was performed to assess feasibility of tumor detection within peripancreatic LNs using cetuximab-IRDye800 in PDAC patients. Fluorescent imaging of dissected LNs was analyzed exvivo macroscopically and microscopically and fluorescence was correlated with histopathology.RESULTS: A total of 144 LNs (72 in the low-dose and 72 in the high-dose cohort) were evaluated. Detection of metastatic LNs by fluorescence was better in the low-dose (50mg) cohort, where sensitivity and specificity was 100% and 78% macroscopically, and 91% and 66% microscopically. More importantly, this method was able to detect occult foci of tumor (measuring<5mm) with a sensitivity of 88% (15/17 LNs).CONCLUSION: This study provides proof of concept that intraoperative fluorescent imaging with cetuximab-IRDye800 can facilitate the detection of peripancreatic lymph nodes often containing subclinical foci of disease.
View details for PubMedID 30723062
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Prevalence and molecular etiology of mismatch repair deficiency among gastrointestinal cancers.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.4_suppl.215
View details for Web of Science ID 000489107600248
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The eye of the beholder: orbital metastases from midgut neuroendocrine tumors, a two institution experience.
Cancer imaging : the official publication of the International Cancer Imaging Society
2018; 18 (1): 47
Abstract
BACKGROUND: Metastases to the orbit occur rarely in midgut neuroendocrine tumor (NET) patients with only 20 cases reported to date. Patients typically present with bilateral involvement of the recti muscles and experience symptoms such as diplopia, proptosis, and decreased vision. Although orbital MRI remains the gold standard for imaging orbital disease, many orbital lesions are now detected on somatostatin-receptor (SSTR) based imaging such as 68Ga-DOTATATE PET-CT.CASE PRESENTATIONS: Patient 1 is a 72year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with orbital metastases during a hospitalization for pre-septal cellulitis in 2018. Her disease has been controlled with capecitabine rather than local therapy. Patient 2 is a 68year-old male with a G2 ileal NET who was diagnosed with orbital involvement after developing left peri-orbital swelling in 2017. He was found to have bilateral rectus muscle involvement and was treated with image-guided radiation therapy (IGRT) to both orbits and achieved disease control. Patient 3 is a 63year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with bilateral orbital masses in her recti after undergoing a 68Ga-DOTATATE PET-CT in 2015. She was asymptomatic initially however has now developed diplopia. She will be starting 177Lu-DOTATATE peptide radionuclide receptor therapy (PRRT) shortly. Patient 4 is a 72year-old male with a grade 2 ileal NET who was incidentally diagnosed with a left lateral rectus metastasis in 2007. This was monitored via surveillance MRI until it began to grow and became symptomatic in 2015. The patient received stereotactic radiation to the site and has been asymptomatic since. Patient 5 is a 61year-old female with a grade 2 ileal NET who developed progressive diplopia in 2016. Bilateral orbital metastases were noted on orbital MRI and she completed IGRT to the sites shortly thereafter. In the setting of continued growth of the masses she was switched to chemotherapy with capecitabine which has controlled her orbital disease.CONCLUSIONS: NETs can metastasize to the orbits. Orbital disease now often is detected on SSTR-based imaging rather than orbital MRI; when found, it changes treatment approach and surveillance for patients.
View details for PubMedID 30522522
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Effect of Lanreotide Depot/Autogel on Urinary 5-Hydroxyindoleacetic Acid and Plasma Chromogranin A Biomarkers in Nonfunctional Metastatic Enteropancreatic Neuroendocrine Tumors.
The oncologist
2018
Abstract
BACKGROUND: Urinary 5-hydroxyindoleacetic acid (5-HIAA) is an established biomarker in neuroendocrine tumors and carcinoid syndrome; however, its role in nonfunctional neuroendocrine tumors is not defined. We present post hoc data on urinary 5-HIAA and plasma chromogranin A (CgA) from the CLARINET study.METHODS: Patients with well- or moderately differentiated, nonfunctioning, locally advanced or metastatic enteropancreatic neuroendocrine tumors were randomized to deep subcutaneous lanreotide depot/autogel 120 mg or placebo once every 28 days for 96 weeks. Tumor response, evaluated centrally (RECIST 1.0), and progression-free survival (PFS) were assessed by treatment and biochemical response, defined as (a) baseline >upper limit of normal (ULN, 41.6 mumol per day 5-HIAA; 98.1 mug/L CgA) and (b) ≥50% decrease from baseline and to ≤ULN value on study.RESULTS: Forty-eight percent (82 of 171; lanreotide, n = 45; placebo, n = 37) and 66% (129 of 195; lanreotide, n = 65; placebo, n = 64) of randomized patients had 5-HIAA and CgA > ULN at baseline. Among patients with >ULN baseline values who did not progress after 96 weeks of treatment, significantly greater reductions in 5-HIAA and CgA were observed in lanreotide-treated versus placebo-treated patients throughout the study (all p < .05). PFS was significantly prolonged among 5-HIAA responders versus nonresponders (median not reached vs. 16.2 months, p < .0001; hazard ratio [HR] = 0.21, 95% confidence interval [CI], 0.09-0.48) and CgA responders versus nonresponders (median not reached vs. 16.2 months, p = .0070; HR = 0.30, 95% CI, 0.12-0.76), regardless of treatment arm. PFS was also significantly prolonged among lanreotide-treated 5-HIAA responders versus nonresponders (p = .0071) but was not significantly different among placebo-treated 5-HIAA responders versus nonresponders. There were no significant differences in PFS between lanreotide-treated CgA responders versus nonresponders or between placebo-treated CgA responders versus nonresponders.CONCLUSIONS: The 5-HIAA findings are noteworthy because they occurred in patients with nonfunctioning enteropancreatic neuroendocrine tumors. Monitoring 5-HIAA and CgA may be useful when treating patients with nonfunctional neuroendocrine tumors.IMPLICATIONS FOR PRACTICE: Current guidelines focus only on the monitoring of 5-hydroxyindoleacetic acid (5-HIAA) in the diagnosis and management of functional neuroendocrine tumors with carcinoid syndrome. The current post hoc analysis of patients with nonfunctional enteropancreatic neuroendocrine tumors in the CLARINET study demonstrated that measuring and following both 5-HIAA and chromogranin A as biomarkers of disease progression may be useful in the management of patients with nonfunctional neuroendocrine tumors.
View details for PubMedID 30355775
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Long-Term Survivors of Pancreatic Cancer: A California Population-Based Study.
Pancreas
2018; 47 (8): 958–66
Abstract
OBJECTIVES: Pancreatic cancer continues to carry a poor prognosis with survival rates that have had minimal improvement over the past 4 decades. We report a population-based, comprehensive analysis of long-term survivors of pancreatic adenocarcinoma diagnosed in the diverse population of California.METHODS: Data from the California Cancer Registry were used to evaluate long-term survival. A total of 70,442 patients diagnosed with pancreatic adenocarcinoma between 1988 and 2009 were identified. Logistic regression was used to identify factors associated with achieving 5-year survival.RESULTS: The overall 5-year survival was 2.5%, with minimal incremental improvements throughout the 3 decades. Age, stage, degree of differentiation, and surgical resection were associated with 5-year survival. Furthermore, younger age and receiving care at a National Cancer Institute-designated cancer center were similarly correlated with 5-year survival regardless of surgical intervention. In addition, we identified stage, differentiation, and adjuvant chemotherapy as significant factors for long-term survival in surgically resected patients. In the unresectable patients, Asian/Pacific islanders and Hispanics were significantly more likely to reach the 5-year milestone than non-Hispanic whites.CONCLUSIONS: Although pancreatic cancer mortality remains high, our study highlights baseline characteristics, treatment, biological factors, and ethnicity that are associated with long-term survival. These findings may serve as a springboard for further investigation.
View details for PubMedID 30074526
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Intraoperative Pancreatic Cancer Detection using Tumor-Specific Multimodality Molecular Imaging.
Annals of surgical oncology
2018; 25 (7): 1880–88
Abstract
BACKGROUND: Operative management of pancreatic ductal adenocarcinoma (PDAC) is complicated by several key decisions during the procedure. Identification of metastatic disease at the outset and, when none is found, complete (R0) resection of primary tumor are key to optimizing clinical outcomes. The use of tumor-targeted molecular imaging, based on photoacoustic and fluorescence optical imaging, can provide crucial information to the surgeon. The first-in-human use of multimodality molecular imaging for intraoperative detection of pancreatic cancer is reported using cetuximab-IRDye800, a near-infrared fluorescent agent that binds to epidermal growth factor receptor.METHODS: A dose-escalation study was performed to assess safety and feasibility of targeting and identifying PDAC in a tumor-specific manner using cetuximab-IRDye800 in patients undergoing surgical resection for pancreatic cancer. Patients received a loading dose of 100mg of unlabeled cetuximab before infusion of cetuximab-IRDye800 (50mg or 100mg). Multi-instrument fluorescence imaging was performed throughout the surgery in addition to fluorescence and photoacoustic imaging ex vivo.RESULTS: Seven patients with resectable pancreatic masses suspected to be PDAC were enrolled in this study. Fluorescence imaging successfully identified tumor with a significantly higher mean fluorescence intensity in the tumor (0.09±0.06) versus surrounding normal pancreatic tissue (0.02±0.01), and pancreatitis (0.04±0.01; p<0.001), with a sensitivity of 96.1% and specificity of 67.0%. The mean photoacoustic signal in the tumor site was 3.7-fold higher than surrounding tissue.CONCLUSIONS: The safety and feasibilty of intraoperative, tumor-specific detection of PDAC using cetuximab-IRDye800 with multimodal molecular imaging of the primary tumor and metastases was demonstrated.
View details for PubMedID 29667116
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Change in Patient-Reported Symptom Control in Patients With Neuroendocrine Tumors Treated With Lanreotide Depot
LIPPINCOTT WILLIAMS & WILKINS. 2018: 358
View details for Web of Science ID 000426086300113
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5-Hydroxyindoleacetic Acid (5-HIAA) and Chromogranin A (CgA) as Biomarkers Secreted by Neuroendocrine Tumors (NETs): A Pooled Analysis of the ELECT and CLARINET Studies
LIPPINCOTT WILLIAMS & WILKINS. 2018: 339
View details for Web of Science ID 000426086300043
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LANREOTIDE THERAPY IN CARCINOID SYNDROME: PROSPECTIVE ANALYSIS OF PATIENT-REPORTED SYMPTOMS IN PATIENTS RESPONSIVE TO PRIOR OCTREOTIDE THERAPY AND PATIENTS NAIVE TO SOMATOSTATIN ANALOGUE THERAPY IN THE ELECT PHASE 3 STUDY
ENDOCRINE PRACTICE
2018; 24 (3): 243–55
Abstract
This ELECT prospective analysis examined lanreotide depot/autogel for carcinoid syndrome (CS) symptom control in patients with neuroendocrine tumors (NETs) who were responsive to prior octreotide (prior octreotide group) compared with patients who were naïve to prior somatostatin analogue treatment (de novo group).Adults with histopathologically confirmed NET and stable CS (diarrhea and/or flushing) were randomized to subcutaneous (SC) lanreotide 120 mg or placebo every 4 weeks for 16 weeks. Patients reported diarrhea and/or flushing symptom severity and frequency and short-acting SC octreotide rescue therapy daily using an Interactive Voice/Web Response System. To evaluate the efficacy of lanreotide compared with placebo, the novel primary endpoint of patient-determined use of SC octreotide rescue therapy for breakthrough symptoms was used as a surrogate for symptom control. Clinically meaningful patient-reported treatment benefit was examined using daily patient-reported symptoms of diarrhea and flushing.Of the 115 randomized patients, 51 (n = 26 lanreotide, n = 25 placebo) were octreotide-naïve (de novo) and 64 (n = 33 lanreotide; n = 31 placebo) received prior octreotide. Lanreotide versus placebo patients had a lower mean percentage of days of SC octreotide rescue therapy in de novo and prior octreotide groups (least squares [LS] mean difference -19.1, P = .0477 and -6.9, P = .4332, respectively). The mean percentage of days with moderate/severe diarrhea and/or flushing was lower in lanreotide versus placebo patients in de novo and prior octreotide groups (LS mean difference -14.6, P = .0140 and -10.9, P = .0746, respectively). The transition from octreotide to lanreotide was generally well-tolerated.Improvement in CS symptoms occurred with lanreotide treatment, regardless of prior octreotide use.CI = confidence interval CS = carcinoid syndrome DB = double blind ELECT = Evaluation of Lanreotide depot/autogel Efficacy and safety as a Carcinoid-syndrome Treatment IOL = initial open-label IVRS/IWRS = interactive voice/web response system LS = least square NET = neuroendocrine tumor OR = odds ratio SC = subcutaneous SSA = somatostatin analogue SSTR = somatostatin receptor TEAE = treatment-emergent adverse event.
View details for DOI 10.4158/EP172000.OR
View details for Web of Science ID 000429649500001
View details for PubMedID 29547049
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Elevated Levels of 5-HIAA and CgA in Patients With Pancreatic Neuroendocrine Tumors (PanNETs): Analyses From the CLARINET Study
LIPPINCOTT WILLIAMS & WILKINS. 2018: 350–51
View details for Web of Science ID 000426086300086
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Lanreotide Depot/Autogel for Symptomatic Control of Carcinoid Syndrome (CS) in Patients With Neuroendocrine Tumors (NETs) Previously Responsive to Octreotide: Subanalysis of Patient-Reported Symptoms From the Phase 3 ELECT Study
LIPPINCOTT WILLIAMS & WILKINS. 2018: 352
View details for Web of Science ID 000426086300089
- A first-in-class, first-in-human Phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study of Hu5F9-G4, an anti-CD47 monoclonal antibody (mAb), in patients with advanced solid tumors. American Society of Clinical Oncology. 2018 ASCO Annual Meeting (June 1-5, 2018). 2018
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Hidden Figures: Occult Intra-Cardiac Metastases in Asymptomatic Neuroendocrine Tumor Patients.
Journal of oncology and cancer research
2018; 2: 23–27
Abstract
Carcinoid heart disease is a devastating paraneoplastic consequence of unchecked hormone production from neuroendocrine tumors (NET) and often results in right-sided heart failure. While it occurs frequently in NET patients with carcinoid syndrome, cardiac metastases occur much less often and are usually only incidentally found. Gallium-68 dotatate (ga-68) is an imaging tracer which binds to somatostatin receptor 2 with greater avidity than Indium-111, the tracer used commonly in octreotide scans. Ga-68 PET/CT is the most sensitive study for detecting occult NET metastases and has emerged as the current imaging gold standard. We describe two cases from Vanderbilt University Medical Center and Stanford University Medical Center where asymptomatic patients with well-differentiated midgut NET were diagnosed with intra-cardiac metastases using ga-68 PET/CT. Management of these patients was altered based on the findings as they underwent extensive cardiac evaluation and initiation of therapy with octreotide. Fortunately, they have not suffered life-threatening cardiac complications seen in some NET patients, from other published series, such as bradycardia, heart block, syncope and arrhythmias. These possibilities suggest early cardiology evaluation and consideration of other therapies beyond octreotide, such as surgery or PRRT, may be essential for all NET patients found to have intra-cardiac metastases.
View details for DOI 10.28967/jocr.2018.02.18005
View details for PubMedID 31388651
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Patient-Reported Symptom Control of Diarrhea and Flushing in Patients with Neuroendocrine Tumors Treated with Lanreotide Depot/Autogel: Results from a Randomized, Placebo-Controlled, Double-Blind and 32-Week Open-Label Study
ONCOLOGIST
2018; 23 (1): 16–24
Abstract
In the double-blind (DB) ELECT study, lanreotide depot/autogel significantly reduced versus placebo the need for short-acting octreotide for symptomatic carcinoid syndrome (CS) control in neuroendocrine tumor (NET) patients. Here we present patient-reported symptom data during DB and initial open-label (IOL) treatment.Adults with NETs and CS history, with/without prior somatostatin analog use, were randomized to 16 weeks' DB lanreotide 120 mg subcutaneous or placebo every 4 weeks, followed by 32 weeks' IOL lanreotide. Patients recorded diarrhea and/or flushing frequency and severity daily by Interactive Voice (Web) Response System for 1 month prior to randomization and throughout the study.Of 115 patients randomized (n = 59 lanreotide, n = 56 placebo), 56 lanreotide and 45 placebo patients enrolled in the IOL phase. During DB treatment, least square (LS) mean percentages of days with moderate/severe diarrhea and/or flushing were significantly lower for lanreotide (23.4%) versus placebo (35.8%; LS mean difference [95% confidence interval]: -12.4 [-20.73 to -4.07]; p = .004). For DB lanreotide patients, average daily composite (frequency × severity) diarrhea scores improved significantly between DB and IOL treatment (mean difference: -0.71 [-1.20 to -0.22]; p = .005), and remained stable for diarrhea and/or flushing. For DB placebo patients, composite scores for diarrhea, flushing, and diarrhea and/or flushing improved significantly between DB and IOL treatment (mean differences: -1.07 [-1.65 to -0.49]; -1.06 [-1.93 to -0.19]; and -2.13 [-3.35 to -0.91]; all p ≤ .018).Improved diarrhea and flushing control in CS patients during 16-week lanreotide treatment was sustained during maintenance of lanreotide treatment for the 32-week IOL phase (48 weeks total).This study prospectively collected daily patient-reported data on diarrhea and flushing from the ELECT trial to evaluate the direct impact of lanreotide depot on patients' relief of carcinoid syndrome symptoms. Treatment with lanreotide depot was associated with significant reductions in the percentages of days patients reported symptoms of diarrhea and flushing, as well as reductions in the frequency and severity of daily symptoms compared with placebo during 16 weeks of double-blind treatment. These improvements were sustained for 32 additional weeks of open-label lanreotide treatment (i.e., through week 48 of treatment), resulting in clinically meaningful, long-term symptom reduction.
View details for PubMedID 29038234
View details for PubMedCentralID PMC5759819
- A Phase 1b/2 Study of CD40 Agonistic Monoclonal Antibody (APX005M) Together with Gemcitabine and nab-Paclitaxel with or without Nivolumab in Untreated Metastatic Pancreatic Adenocarcinoma Patients. American Society of Clinical Oncology. 2018 ASCO Annual Meeting (June 1-5, 2018). 2018
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Change in Patient-Reported Symptom Control in Patients With Neuroendocrine Tumors Treated With Lanreotide Depot
NATURE PUBLISHING GROUP. 2017: S652–S653
View details for Web of Science ID 000439259002411
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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade
SCIENCE
2017; 357 (6349): 409–13
Abstract
The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.
View details for PubMedID 28596308
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Reduced dose CT with model-based iterative reconstruction compared to standard dose CT of the chest, abdomen, and pelvis in oncology patients: intra-individual comparison study on image quality and lesion conspicuity.
Abdominal radiology
2017
Abstract
To compare image quality and lesion conspicuity of reduced dose (RD) CT with model-based iterative reconstruction (MBIR) compared to standard dose (SD) CT in patients undergoing oncological follow-up imaging.Forty-four cancer patients who had a staging SD CT within 12 months were prospectively included to undergo a weight-based RD CT with MBIR. Radiation dose was recorded and tissue attenuation and image noise of four tissue types were measured. Reproducibility of target lesion size measurements of up to 5 target lesions per patient were analyzed. Subjective image quality was evaluated for three readers independently utilizing 4- or 5-point Likert scales.Median radiation dose reduction was 46% using RD CT (P < 0.01). Median image noise across all measured tissue types was lower (P < 0.01) in RD CT. Subjective image quality for RD CT was higher (P < 0.01) in regard to image noise and overall image quality; however, there was no statistically significant difference regarding image sharpness (P = 0.59). There were subjectively more artifacts on RD CT (P < 0.01). Lesion conspicuity was subjectively better in RD CT (P < 0.01). Repeated target lesion size measurements were highly reproducible both on SD CT (ICC = 0.987) and RD CT (ICC = 0.97).RD CT imaging with MBIR provides diagnostic imaging quality and comparable lesion conspicuity on follow-up exams while allowing dose reduction by a median of 46% compared to SD CT imaging.
View details for DOI 10.1007/s00261-017-1140-5
View details for PubMedID 28417170
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Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.
Journal for immunotherapy of cancer
2017; 5: 22-?
Abstract
T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.Patients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 10(10) total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.Fourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had (111)Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.These findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity.
View details for DOI 10.1186/s40425-017-0222-9
View details for PubMedID 28344808
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Quantitative Three-Dimensional Dynamic Contrast-Enhanced Ultrasound Imaging: First-In-Human Pilot Study in Patients with Liver Metastases
THERANOSTICS
2017; 7 (15): 3745–58
Abstract
Purpose: To perform a clinical assessment of quantitative three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) feasibility and repeatability in patients with liver metastasis, and to evaluate the extent of quantitative perfusion parameter sampling errors in 2D compared to 3D DCE-US imaging. Materials and Methods: Twenty consecutive 3D DCE-US scans of liver metastases were performed in 11 patients (45% women; mean age, 54.5 years; range, 48-60 years; 55% men; mean age, 57.6 years; range, 47-68 years). Pairs of repeated disruption-replenishment and bolus DCE-US images were acquired to determine repeatability of parameters. Disruption-replenishment was carried out by infusing 0.9 mL of microbubbles (Definity; Latheus Medical Imaging) diluted in 35.1 mL of saline over 8 min. Bolus consisted of intravenous injection of 0.2 mL microbubbles. Volumes-of-interest (VOI) and regions-or-interest (ROI) were segmented by two different readers in images to extract 3D and 2D perfusion parameters, respectively. Disruption-replenishment parameters were: relative blood volume (rBV), relative blood flow (rBF). Bolus parameters included: time-to-peak (TP), peak enhancement (PE), area-under-the-curve (AUC), and mean-transit-time (MTT). Results: Clinical feasibility and repeatability of 3D DCE-US using both the destruction-replenishment and bolus technique was demonstrated. The repeatability of 3D measurements between pairs of repeated acquisitions was assessed with the concordance correlation coefficient (CCC), and found to be excellent for all parameters (CCC > 0.80), except for the TP (0.74) and MTT (0.30) parameters. The CCC between readers was found to be excellent (CCC > 0.80) for all parameters except for TP (0.71) and MTT (0.52). There was a large Coefficient of Variation (COV) in intra-tumor measurements for 2D parameters (0.18-0.52). Same-tumor measurements made in 3D were significantly different (P = 0.001) than measurements made in 2D; a percent difference of up to 86% was observed between measurements made in 2D compared to 3D in the same tumor. Conclusions: 3D DCE-US imaging of liver metastases with a matrix array transducer is feasible and repeatable in the clinic. Results support 3D instead of 2D DCE US imaging to minimize sampling errors due to tumor heterogeneity.
View details for PubMedID 29109773
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Patient-reported outcomes of a multicenter phase 2 study investigating gemcitabine and stereotactic body radiation therapy in locally advanced pancreatic cancer.
Practical radiation oncology
2016; 6 (6): 417-424
Abstract
We previously reported clinical outcomes and physician-reported toxicity of gemcitabine and hypofractionated stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (LAPC). Here we prospectively investigate the impact of gemcitabine and SBRT on patient-reported quality of life (QoL).Forty-nine LAPC patients received 33 Gy SBRT (6.6 Gy daily fractions) upfront or after ≤3 doses of gemcitabine (1000 mg/m(2)) followed by gemcitabine until progression. European Organization for Research and Treatment of Cancer QoL core cancer (QLQ-C30) and pancreatic cancer-specific (European Organization for Research and Treatment of Cancer QLQ-PAN26) questionnaires were administered to patients pre-SBRT and at 4 to 6 weeks (first follow-up [1FUP]) and 4 months (2FUP) post-SBRT. Changes in QoL scores were deemed clinically relevant if median changes were at least 5 points in magnitude.Forty-three (88%) patients completed pre-SBRT questionnaires. Of these, 88% and 51% completed questionnaires at 1FUP and 2FUP, respectively. There was no change in global QoL from pre-SBRT to 1FUP (P = .17) or 2FUP (P > .99). Statistical and clinical improvements in pancreatic pain (P = .001) and body image (P = .007) were observed from pre-SBRT to 1FUP. Patients with 1FUP and 2FUP questionnaires reported statistically and clinically improved body image (P = .016) by 4 months. Although pancreatic pain initially demonstrated statistical and clinical improvement (P = .020), scores returned to enrollment levels by 2FUP (P = .486). A statistical and clinical decline in role functioning (P = .002) was observed in patients at 2FUP.Global QoL scores are not reduced with gemcitabine and SBRT. In this exploratory analysis, patients experience clinically relevant short-term improvements in pancreatic cancer-specific symptoms. Previously demonstrated acceptable clinical outcomes combined with these favorable QoL data indicate that SBRT can be easily integrated with other systemic therapies and may be a potential standard of care option in patients with LAPC.
View details for DOI 10.1016/j.prro.2016.05.005
View details for PubMedID 27552809
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Oxaliplatin-Fluoropyrimidine Chemotherapy Plus Bevacizumab in Advanced Neuroendocrine Tumors: An Analysis of 2 Phase II Trials.
Pancreas
2016; 45 (10): 1394-1400
Abstract
This study aimed to determine the safety and effectiveness of bevacizumab (B) plus FOLFOX or CAPOX in advanced neuroendocrine tumors (NETs) by performing a combined analysis of 2 separate prospective phase II studies.In the FOLFOX/B study, patients received chemotherapy without scheduled breaks in 3 cohorts: carcinoid, pancreatic NET, and poorly differentiated neuroendocrine carcinomas. In the CAPOX/B study, NET subtypes were pooled, and patients were treated with 4 cycles of CAPOX/B followed by optional maintenance therapy. Primary end points were radiographic response rate (RR) after 12 cycles (FOLFOX/B), progression-free survival (PFS) (CAPOX/B), and toxicity (both).Seventy-six patients (FOLFOX/B, n = 36; CAPOX/B, n = 40) were included. In FOLFOX/B, RR for carcinoid at 12 cycles 3/22 (13.6%), median PFS 19.3 months; RR for pancreatic NET at 12 cycles 4/12 (41.7%), median PFS 21 months; RR 1/2 (50%) in poorly differentiated neuroendocrine carcinoma; pooled RR 25% and median PFS 21 months (1-year PFS 68%). In CAPOX/B (pooled NET), RR 18% and median PFS 16.7 months (1-year PFS 65%). Predictable toxicity was observed.Neither study met its primary end point, but radiographic responses and prolonged disease stability in previously progressing patients suggest that selected patients with NET may benefit from oxaliplatin-fluoropyrimidine chemotherapy plus bevacizumab and that the combination may warrant further study.
View details for PubMedID 27171514
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Neuroendocrine tumors of the pancreas: Degree of cystic component predicts prognosis.
Surgery
2016; 160 (3): 708-713
Abstract
Although most pancreatic neuroendocrine tumors are solid, approximately 10% are cystic. Some studies have suggested that cystic pancreatic neuroendocrine tumors are associated with a more favorable prognosis.A retrospective review of all patients with pancreatic neuroendocrine tumors who underwent operative resection between 1999 and 2014 at a single academic medical center was performed. Based on cross-sectional imaging performed before operation, pancreatic neuroendocrine tumors were classified according to the size of the cystic component relative to the total tumor size: purely cystic (100%), mostly cystic (≥50%), mostly solid (<50%), and purely solid (0%). Clinicopathologic characteristics and recurrence-free survival were assessed between groups.In the study, 214 patients met inclusion criteria: 8 with purely cystic tumors, 7 with mostly cystic tumors, 15 with mostly solid tumors, and 184 with purely solid tumors. The groups differed in terms of tumor size (1.5 ± 0.5, 3.0 ± 1.7, 3.7 ± 2.6, and 4.0 ± 3.5 cm), lymph node positivity (0%, 0%, 26.7%, and 34.2%), intermediate or high grade (0%, 16.7%, 20.0%, and 31.0%), synchronous liver metastases (0%, 14.3%, 20.0%, and 26.6%) and need for pancreaticoduodenectomy (0%, 0%, 6.7%, and 25.0%), respectively. No cases of purely cystic pancreatic neuroendocrine tumors were associated with synchronous liver or lymph node metastasis, intermediate/high grade, recurrence, or death due to disease. Among patients presenting without metastatic disease, 10-year recurrence-free survival was 100% in patients with purely and mostly cystic tumors versus 53.0% in patients with purely and mostly solid tumors; however, this difference did not reach statistical significance.Pancreatic neuroendocrine tumors demonstrate a spectrum of biologic behavior with an increasing cystic component being associated with more favorable clinicopathologic features and prognosis. Purely cystic pancreatic neuroendocrine tumors may represent 1 subset that can be safely observed without immediate resection.
View details for DOI 10.1016/j.surg.2016.04.005
View details for PubMedID 27216830
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EVALUATION OF LANREOTIDE DEPOT/AUTOGEL EFFICACY AND SAFETY AS A CARCINOID SYNDROME TREATMENT (ELECT): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL.
Endocrine practice
2016; 22 (9): 1068-1080
Abstract
To evaluate the efficacy and safety of lanreotide depot/autogel 120 mg for the control of carcinoid syndrome (CS) symptoms in patients with neuroendocrine tumors (NETs).This was a 16-week, randomized, double-blind, phase 3 trial (Clinicaltrials.gov: NCT00774930). Patients with/without prior somatostatin analog (SSA) use were randomized to lanreotide depot/autogel 120 mg or placebo every 4 weeks, with access to short-acting octreotide as rescue medication. The primary endpoint was the percentage of days in which short-acting octreotide was used, which was assessed from daily diaries using an analysis of covariance including the stratification variables baseline short-acting octreotide use and frequency of diarrhea/flushing. The proportions of patients experiencing treatment success was a supportive analysis. Adverse events were recorded at all visits.A total of 115 patients were enrolled (lanreotide, n = 59; placebo, n = 56). The adjusted mean (95% confidence interval [CI]) percentage of days with rescue octreotide use (primary endpoint) was significantly lower in the lanreotide (33.7%; 95% CI, 25.0%-42.4%) versus the placebo group (48.5%; 95% CI, 39.6%-57.4%), representing an absolute difference of -14.8% (95% CI, -26.8% to -2.8%; P = .017). The odds ratio of full/partial treatment success (≤3 days short-acting octreotide use weeks 12 to 15) was significantly greater with lanreotide than placebo (2.4; 95% CI, 1.1-5.3; P = .036). No new safety concerns were identified, and lanreotide was well tolerated.Lanreotide depot/autogel is effective for the control of CS symptoms in patients (SSA-naïve or experienced) with NETs.AE = adverse event BMI = body mass index CS = carcinoid syndrome ELECT = Evaluating Lanreotide Efficacy and safety as a Carcinoid-syndrome Treatment HRQoL = health-related quality of life LTOLE = long-term open-label extension NET = neuroendocrine tumor OL = open label SSA = somatostatin analog.
View details for DOI 10.4158/EP151172.OR
View details for PubMedID 27214300
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CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer
NEW ENGLAND JOURNAL OF MEDICINE
2016; 374 (3): 211-222
Abstract
Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.).
View details for DOI 10.1056/NEJMoa1506597
View details for Web of Science ID 000368404800006
View details for PubMedCentralID PMC4784450
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CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer.
The New England journal of medicine
2016; 374 (3): 211-22
Abstract
Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.).
View details for DOI 10.1056/NEJMoa1506597
View details for PubMedID 26789870
View details for PubMedCentralID PMC4784450
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The Development Of RRx-001, A Novel Nitric-Oxide-Mediated Epigenetically Active Anticancer Agent.
Redox biology
2015; 5: 422-?
Abstract
RRx-001 is a novel NO and hypoxia mediated anticancer agent with epigenetic activity. In the first-in-human, Phase I trial, 5/5 patients who progressed on RRx-001 treatment were resensitized to previously refractory therapy, hinting at a generalized resensitization effect.A randomized open-label multi-part, multi-center phase II trial of RRx-001 versus regorafenib (ROCKET) has commenced to explore the resensitization and/or 'episensitization' potential in irinotecan refractory tumors and its impact on overall survival.Patients with irinotecan-refractory metastatic colorectal cancer with an ECOG PS 0-1 who progressed on oxaliplatin-, and irinotecan-based regimens with or without bevacizumab, cetuximab or panitumumab are randomized 2:1 to receive RRx-001 16.5mg/m(2) IV 1x/week or regorafenib 160mg orally 21 of 28 days until progression or unacceptable toxicity followed by treatment with refractory irinotecan-based therapies.To date, 26 patients have been randomized with 18 patients evaluable for resensitization. Post RRx-001 patients demonstrated marked decreases in CEA in 12/13 patients as compared to 5 patients receiving regorafenib who were too systemically unwell to proceed to subsequent treatment. Progression free survival (ongoing) for RRx-001+irinotecan is 4.9 months compared 1.8 months on Regorafenib+irinotecan.Early results in the ROCKET study suggest that RRx-001-mediated resensitization to previously refractory therapies may have a generalized effect, independent of KRAS or p53 status. These early results are intriguing, suggesting improved QOL and overall survival over currently approved therapy in the chemotherapy refractory colorectal cancer.
View details for DOI 10.1016/j.redox.2015.09.035
View details for PubMedID 28162292
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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
NEW ENGLAND JOURNAL OF MEDICINE
2015; 372 (26): 2509-2520
Abstract
Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02).This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).
View details for DOI 10.1056/NEJMoa1500596
View details for PubMedID 26028255
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A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN Cancer Research Group (E2211).
Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) / Clinical Science Symposium on Predicting and Improving Adverse Outcomes in Older Adults with Cancer
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036904753
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Phase 2 Multi-institutional Trial Evaluating Gemcitabine and Stereotactic Body Radiotherapy for Patients With Locally Advanced Unresectable Pancreatic Adenocarcinoma
CANCER
2015; 121 (7): 1128-1137
Abstract
This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC).A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m(2) ) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT.The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections.Fractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy. Cancer 2015;121:1128-1137. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
View details for DOI 10.1002/cncr.29161
View details for Web of Science ID 000351615800022
View details for PubMedID 25538019
View details for PubMedCentralID PMC4368473
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Perspectives on clinical trials for gastrointestinal malignancies.
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting
2015: 40-43
View details for DOI 10.14694/EdBook_AM.2015.35.40
View details for PubMedID 25993140
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Appropriate customization of radiation therapy for stage II and III rectal cancer: Executive summary of an ASTRO Clinical Practice Statement using the RAND/UCLA Appropriateness Method.
Practical radiation oncology
2015; 6 (3): 166–75
Abstract
To summarize results of a Clinical Practice Statement on radiation therapy for stage II-III rectal cancer, which addressed appropriate customization of (neo)adjuvant radiation therapy and use of non-surgical therapy for patients who are inoperable or refuse abdominoperineal resection.The RAND/University of California, Los Angeles, Appropriateness Method was applied to combine current evidence with multidisciplinary expert opinion. A systematic literature review was conducted and used by the expert panel to rate appropriateness of radiation therapy options for different clinical scenarios. Treatments were categorized by median rating as Appropriate, May Be Appropriate, or Rarely Appropriate.In the neoadjuvant setting, chemoradiation was rated Appropriate and the ratings indicated short-course radiation therapy, chemotherapy alone, and no neoadjuvant therapy are potential options in selected patients. However, neoadjuvant endorectal brachytherapy was rated Rarely Appropriate. For adjuvant therapy, chemoradiation (plus ≥4 months of chemotherapy) was rated Appropriate and chemotherapy alone May Be Appropriate for most scenarios. For medically inoperable patients, definitive external beam radiation therapy and chemotherapy alone were rated May Be Appropriate, whereas endorectal brachytherapy and chemoradiation plus endorectal brachytherapy were possible approaches for some scenarios. The last option, definitive chemoradiation, was rated Appropriate to May Be Appropriate based on performance status. Finally, for patients with low-lying tumors refusing abdominoperineal resection, definitive chemoradiation alone, chemoradiation plus endorectal brachytherapy, and chemoradiation plus external beam radiation therapy were all rated Appropriate.This Clinical Practice Statement demonstrated the central role of radiation therapy in stage II-III rectal cancer management and evaluated ways to better individualize its use in the neoadjuvant, adjuvant, and definitive settings. Ongoing trials may clarify areas of continuing uncertainty and allow further customization.
View details for PubMedID 26922700
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Single-versus Multifraction Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma: Outcomes and Toxicity
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2014; 90 (4): 918-925
Abstract
We report updated outcomes of single- versus multifraction stereotactic body radiation therapy (SBRT) for unresectable pancreatic adenocarcinoma.We included 167 patients with unresectable pancreatic adenocarcinoma treated at our institution from 2002 to 2013, with 1-fraction (45.5% of patient) or 5-fraction (54.5% of patients) SBRT. The majority of patients (87.5%) received chemotherapy.Median follow-up was 7.9 months (range: 0.1-63.6). The 6- and 12-month cumulative incidence rates (CIR) of local recurrence for patients treated with single-fraction SBRT were 5.3% (95% confidence interval [CI], 0.2%-10.4%) and 9.5% (95% CI, 2.7%-16.2%), respectively. The 6- and 12-month CIR with multifraction SBRT were 3.4% (95% CI, 0.0-7.2%) and 11.7% (95% CI, 4.8%-18.6%), respectively. Median survival from diagnosis for all patients was 13.6 months (95% CI, 12.2-15.0 months). The 6- and 12- month survival rates from SBRT for the single-fraction group were 67.0% (95% CI, 57.2%-78.5%) and 30.8% (95% CI, 21.9%-43.6%), respectively. The 6- and 12- month survival rates for the multifraction group were 75.7% (95% CI, 67.2%-85.3%) and 34.9% (95% CI, 26.1%-46.8%), respectively. There were no differences in CIR or survival rates between the single- and multifraction groups. The 6- and 12-month cumulative incidence rates of gastrointestinal toxicity grade ≥3 were 8.1% (95% CI, 1.8%-14.4%) and 12.3% (95% CI, 4.7%-20.0%), respectively, in the single-fraction group, and both were 5.6% (95% CI, 0.8%-10.5%) in the multifraction group. There were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT (P=.005). Local recurrence and toxicity grade ≥2 were independent predictors of worse survival.Multifraction SBRT for pancreatic cancer significantly reduces gastrointestinal toxicity without compromising local control.
View details for DOI 10.1016/j.ijrobp.2014.06.066
View details for Web of Science ID 000344734300029
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Single- versus multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma: outcomes and toxicity.
International journal of radiation oncology, biology, physics
2014; 90 (4): 918-925
Abstract
We report updated outcomes of single- versus multifraction stereotactic body radiation therapy (SBRT) for unresectable pancreatic adenocarcinoma.We included 167 patients with unresectable pancreatic adenocarcinoma treated at our institution from 2002 to 2013, with 1-fraction (45.5% of patient) or 5-fraction (54.5% of patients) SBRT. The majority of patients (87.5%) received chemotherapy.Median follow-up was 7.9 months (range: 0.1-63.6). The 6- and 12-month cumulative incidence rates (CIR) of local recurrence for patients treated with single-fraction SBRT were 5.3% (95% confidence interval [CI], 0.2%-10.4%) and 9.5% (95% CI, 2.7%-16.2%), respectively. The 6- and 12-month CIR with multifraction SBRT were 3.4% (95% CI, 0.0-7.2%) and 11.7% (95% CI, 4.8%-18.6%), respectively. Median survival from diagnosis for all patients was 13.6 months (95% CI, 12.2-15.0 months). The 6- and 12- month survival rates from SBRT for the single-fraction group were 67.0% (95% CI, 57.2%-78.5%) and 30.8% (95% CI, 21.9%-43.6%), respectively. The 6- and 12- month survival rates for the multifraction group were 75.7% (95% CI, 67.2%-85.3%) and 34.9% (95% CI, 26.1%-46.8%), respectively. There were no differences in CIR or survival rates between the single- and multifraction groups. The 6- and 12-month cumulative incidence rates of gastrointestinal toxicity grade ≥3 were 8.1% (95% CI, 1.8%-14.4%) and 12.3% (95% CI, 4.7%-20.0%), respectively, in the single-fraction group, and both were 5.6% (95% CI, 0.8%-10.5%) in the multifraction group. There were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT (P=.005). Local recurrence and toxicity grade ≥2 were independent predictors of worse survival.Multifraction SBRT for pancreatic cancer significantly reduces gastrointestinal toxicity without compromising local control.
View details for DOI 10.1016/j.ijrobp.2014.06.066
View details for PubMedID 25585785
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Limitations of Body Surface Area-Based Activity Calculation for Radioembolization of Hepatic Metastases in Colorectal Cancer
JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
2014; 25 (7): 1085-1093
Abstract
To calculate absorbed radiation doses in patients treated with resin microspheres prescribed by the body surface area (BSA) method and to analyze dose-response and toxicity relationships.A retrospective review was performed of 45 patients with colorectal carcinoma metastases who received single-session whole-liver resin microsphere radioembolization. Prescribed treatment activity was calculated using the BSA method. Liver volumes and whole-liver absorbed doses (D(WL)) were calculated. D(WL) was correlated with toxicity and radiographic and biochemical response.The standard BSA-based administered activity (range, 0.85-2.58 GBq) did not correlate with D(WL) (mean, 50.4 Gy; range, 29.8-74.7 Gy; r = -0.037; P = .809) because liver weight was highly variable (mean, 1.89 kg; range, 0.94-3.42 kg) and strongly correlated with D(WL) (r = -0.724; P < .001) but was not accounted for in the BSA method. Patients with larger livers were relatively underdosed, and patients with smaller livers were relatively overdosed. Patients who received D(WL) > 50 Gy experienced more toxicity and adverse events (> grade 2 liver toxicity, 46% vs 17%; P < .05) but also responded better to the treatment than patients who received D(WL)< 50 Gy (disease control, 88% vs 24%; P < .01).Using the standard BSA formula, the administered activity did not correlate with D(WL). Based on this short-term follow-up after salvage therapy in patients with late stage metastatic colorectal carcinoma, dose-response and dose-toxicity relationships support using a protocol based on liver volume rather than BSA to prescribe the administered activity.
View details for DOI 10.1016/j.jvir.2013.11.018
View details for Web of Science ID 000338174200016
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Limitations of body surface area-based activity calculation for radioembolization of hepatic metastases in colorectal cancer.
Journal of vascular and interventional radiology
2014; 25 (7): 1085-1093
Abstract
To calculate absorbed radiation doses in patients treated with resin microspheres prescribed by the body surface area (BSA) method and to analyze dose-response and toxicity relationships.A retrospective review was performed of 45 patients with colorectal carcinoma metastases who received single-session whole-liver resin microsphere radioembolization. Prescribed treatment activity was calculated using the BSA method. Liver volumes and whole-liver absorbed doses (D(WL)) were calculated. D(WL) was correlated with toxicity and radiographic and biochemical response.The standard BSA-based administered activity (range, 0.85-2.58 GBq) did not correlate with D(WL) (mean, 50.4 Gy; range, 29.8-74.7 Gy; r = -0.037; P = .809) because liver weight was highly variable (mean, 1.89 kg; range, 0.94-3.42 kg) and strongly correlated with D(WL) (r = -0.724; P < .001) but was not accounted for in the BSA method. Patients with larger livers were relatively underdosed, and patients with smaller livers were relatively overdosed. Patients who received D(WL) > 50 Gy experienced more toxicity and adverse events (> grade 2 liver toxicity, 46% vs 17%; P < .05) but also responded better to the treatment than patients who received D(WL)< 50 Gy (disease control, 88% vs 24%; P < .01).Using the standard BSA formula, the administered activity did not correlate with D(WL). Based on this short-term follow-up after salvage therapy in patients with late stage metastatic colorectal carcinoma, dose-response and dose-toxicity relationships support using a protocol based on liver volume rather than BSA to prescribe the administered activity.
View details for DOI 10.1016/j.jvir.2013.11.018
View details for PubMedID 24457263
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Symptoms and palliative care needs of pancreatic adenocarcinoma patients.
Journal of palliative medicine
2014; 17 (6): 640-641
View details for DOI 10.1089/jpm.2014.0056
View details for PubMedID 24875242
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Pancreatic neuroendocrine tumours: hypoenhancement on arterial phase computed tomography predicts biological aggressiveness.
HPB
2014; 16 (4): 304-311
Abstract
Contrary to pancreatic adenocarcinoma, pancreatic neuroendocrine tumours (PNET) are commonly hyperenhancing on arterial phase computed tomography (APCT). However, a subset of these tumours can be hypoenhancing. The prognostic significance of the CT appearance of these tumors remains unclear.From 2001 to 2012, 146 patients with well-differentiated PNET underwent surgical resection. The degree of tumour enhancement on APCT was recorded and correlated with clinicopathological variables and overall survival.APCT images were available for re-review in 118 patients (81%). The majority had hyperenhancing tumours (n = 80, 68%), 12 (10%) were isoenhancing (including cases where no mass was visualized) and 26 (22%) were hypoenhancing. Hypoenhancing PNET were larger, more commonly intermediate grade, and had higher rates of lymph node and synchronous liver metastases. Hypoenhancing PNET were also associated with significantly worse overall survival after a resection as opposed to isoenhancing and hyperenhancing tumours (5-year, 54% versus 89% versus 93%). On multivariate analysis of factors available pre-operatively, only hypoenhancement (HR 2.32, P = 0.02) was independently associated with survival.Hypoenhancement on APCT was noted in 22% of well-differentiated PNET and was an independent predictor of poor outcome. This information can inform pre-operative decisions in the multidisciplinary treatment of these neoplasms.
View details for DOI 10.1111/hpb.12139
View details for PubMedID 23991643
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Reassessment of the Current American Joint Committee on Cancer Staging System for Pancreatic Neuroendocrine Tumors
JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS
2014; 218 (2): 188-195
Abstract
Adopting a unified staging system for pancreatic neuroendocrine tumors (PNETs) has been challenging. Currently, the American Joint Committee on Cancer (AJCC) recommends use of the pancreatic adenocarcinoma staging system for PNETs. We sought to explore the prognostic usefulness of the pancreatic adenocarcinoma staging system for PNETs.The Surveillance, Epidemiology, and End Results program data were used to identify patients with PNETs who underwent curative-intent surgical resection from 1983 to 2008. The discriminatory ability of the AJCC system was examined and a new TNM system was devised using extent of disease variables.In 1,202 patients identified, lymph node metastasis was associated with worse 10-year overall survival after resection (51% vs 63%; p < 0.0001), as was the presence of distant metastatic disease (35% vs 62%; p < 0.0001). The current AJCC system (recorded by the Surveillance, Epidemiology, and End Results program in 412 patients since 2004) distinguished 5-year overall survival only between stages I and II (p = 0.01), but not between stages II and III (p = 0.97), or stages III and IV (p = 0.36). By modifying the T stage to be based on size alone (0.1 to 1.0 cm, 1.1 to 2.0 cm, 2.1 to 4.0 cm, and >4.0 cm) and revising the TNM subgroups, we propose a novel TNM system with improved discriminatory ability between disease stages (stages I vs II; p = 0.16; II vs III; p < 0.0001; and III vs IV; p = 0.008).In this study evaluating the current AJCC staging system for PNETs, there were no significant differences detected between stages II and III or stages III and IV. We propose a novel TNM system that might better discriminate between outcomes after surgical resection of PNETs.
View details for DOI 10.1016/j.jamcollsurg.2013.11.001
View details for PubMedID 24321190
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Randomized Phase 2 Study of Pegylated SN-38 (EZN-2208) or Irinotecan Plus Cetuximab in Patients With Advanced Colorectal Cancer
CANCER
2013; 119 (24): 4223-4230
Abstract
Irinotecan is cytotoxic in patients with advanced colorectal cancer (CRC). SN-38 (10-hydroxy-7-ethyl-camptothecin) is the active metabolite of irinotecan. Attachment of polyethylene glycol (PEG) polymer chains (pegylation) to SN-38 (EZN-2208) increases the solubility, exposure, and half-life of SN-38. Preclinical studies demonstrated superior in vitro efficacy of EZN-2208 when it was tested in irinotecan-refractory human CRC cell lines.Patients with metastatic or locally recurrent CRC who had previously received 5-flurouracil (5-FU), oxaliplatin, and irinotecan were assigned to receive EZN-2208 monotherapy (9 mg/m(2) on days 1, 8, and 15 every 28 days for patients with KRAS-mutant tumors only [arm A]), and patients with KRAS wild-type tumors were randomized (2:1) to receive either EZN-2208 plus cetuximab (400 mg/m(2) loading dose on day 1 followed by 250 mg/m(2) weekly starting on day 8 [arm B]) or irinotecan 125 mg/m(2) on days 1 and 8 every 21 days plus cetuximab at the same doses indicated above (arm C).The overall response rate and progression-free survival were 0% and 1.8 months, respectively, in arm A; 10.7% and 4.9 months (95% confidence interval [CI], 3.2-5.8 months), respectively, in arm B; and 14.3% and 3.7 months (95% CI, 2.1-5.8 months), respectively, in arm C. EZN-2208 was well tolerated in combination with cetuximab. No statistically significant difference in survival was observed between arm B (9.8 months; 95% CI, 7.2-11.2 months) and arm C (9.1 months; 95% CI, 6.0-13.0 months).EZN-2208, either as monotherapy or in combination with cetuximab, was well tolerated in patients with refractory CRC. Overall survival and progression-free survival were similar in the cetuximab plus irinotecan arm and the EZN-2208 arm.
View details for DOI 10.1002/cncr.28358
View details for Web of Science ID 000330091900005
View details for PubMedID 24105075
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Seventh Edition (2010) of the AJCC/UICC Staging System for Gastric Adenocarcinoma: Is there Room for Improvement?
ANNALS OF SURGICAL ONCOLOGY
2013; 20 (5): 1631-1638
Abstract
The gastric cancer AJCC/UICC staging system recently underwent significant revisions, but studies on Asian patients have reported a lack of adequate discrimination between various consecutive stages. We sought to validate the new system on a U.S. population database.California Cancer Registry data linked to the Office of Statewide Health Planning and Development discharge abstracts were used to identify patients with gastric adenocarcinoma (esophagogastric junction and gastric cardia tumors excluded) who underwent curative-intent surgical resection in California from 2002 to 2006. AJCC/UICC stage was recalculated based on the latest seventh edition. Overall survival probabilities were calculated using the Kaplan-Meier method.Of 1905 patients analyzed, 54 % were males with a median age of 70 years. Median number of pathologically examined lymph nodes was 12 (range, 1-90); 40 % of patients received adjuvant chemotherapy, and 31 % received adjuvant radiotherapy. The seventh edition AJCC/UICC system did not distinguish outcome adequately between stages IB and IIA (P = 0.40), or IIB and IIIA (P = 0.34). By merging stage II into 1 category and moving T2N1 to stage IB and T2N2, T1N3 to stage IIIA, we propose a new grouping system with improved discriminatory abilityIn this first study validating the new seventh edition AJCC/UICC staging system for gastric cancer on a U.S. population with a relatively limited number of lymph nodes examined, we found stages IB and IIA, as well as IIB and IIIA to perform similarly. We propose a revised stage grouping for the AJCC/UICC staging system that better discriminates between outcomes.
View details for DOI 10.1245/s10434-012-2724-5
View details for PubMedID 23149854
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Systemic Treatment in Unresectable Metastatic Well-Differentiated Carcinoid Tumors Consensus Results From a Modified Delphi Process
PANCREAS
2013; 42 (3): 397-404
Abstract
This study aimed to develop expert consensus for the use of systemic treatments for unresectable metastatic well-differentiated (grade 1-2) carcinoid tumors using the RAND/UCLA modified Delphi process.After a comprehensive literature review, 404 patient scenarios addressing the use of systemic treatments for carcinoid tumors were constructed. A multidisciplinary panel of 10 physicians assessed the scenarios as appropriate, inappropriate, or uncertain (on a 1-9 scale) or as an area of disagreement before and after an extended discussion of the evidence.Experts were medical and surgical oncologists, interventional radiologists, and gastroenterologists. Among rated scenarios, disagreement decreased from 14% before the meeting to 4% after. Consensus statements about midgut carcinoids included the following: (1) Somatostatin analogs are appropriate as first-line therapy for all patients; (2) In patients with uncontrolled secretory symptoms, it is appropriate to increase the dose/frequency of octreotide long-acting repeatable up to 60 mg every 4 weeks or up to 40 mg every 3 weeks as second-line therapy for refractory carcinoid syndrome. Other options may also be appropriate. Consensus was similar for non-midgut carcinoids.The Delphi process provided a structured methodological approach to assist clinician experts in reaching consensus on the appropriateness of specific medical therapies for the treatment of advanced carcinoid tumors.
View details for DOI 10.1097/MPA.0b013e31826d3a17
View details for Web of Science ID 000316201700003
View details for PubMedID 23211372
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Capecitabine-Induced Chest Pain Relieved by Diltiazem
AMERICAN JOURNAL OF CARDIOLOGY
2012; 110 (11): 1623-1626
Abstract
Five patients with primary colorectal adenocarcinoma or anal squamous cell carcinoma were started on a 2-weeks-on, 1-week-off capecitabine dosing regimen in addition to other chemotherapeutic agents and/or radiation. Within the first few doses, patients experienced chest pain and/or dyspnea at rest or with exertion. Acute electrocardiographic findings suggestive of ischemia were found in some cases at initial presentation, and 1 patient had troponin elevation consistent with an acute ST-segment elevation myocardial infarction. Subsequent ischemia evaluations were not suggestive of clinically significant coronary artery disease. All patients experienced immediate and sustained relief from chest pain after discontinuation of capecitabine and were able to successfully tolerate retreatment using a novel management strategy based on secondary prophylaxis with diltiazem. In conclusion, guidelines for the evaluation of and therapy for capecitabine-induced chest pain are proposed.
View details for DOI 10.1016/j.amjcard.2012.07.026
View details for PubMedID 22939579
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Long-Term Survivors of Gastric Cancer: A California Population-Based Study
JOURNAL OF CLINICAL ONCOLOGY
2012; 30 (28): 3507-3515
Abstract
In the United States, gastric cancer is rapidly fatal with a 25% 5-year survival. Of the few patients who survive, little is known about their demographic, clinical, and tumor characteristics.Data regarding all cases of gastric and gastroesophageal junction (GEJ) adenocarcinoma diagnosed in California between 1988 and 2005 were obtained from the California Cancer Registry, a member of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. A Cox proportional hazards model was constructed to understand the independent relationships of patient demographic, disease, and treatment factors with survival.We identified 47,647 patients diagnosed with gastric or GEJ cancer. Of those, only 9,325 (20%) survived at least 3 years. Variables associated with longer survival were localized stage (hazard ratio [HR], 0.20), surgery with diagnosis in 2002 or later (HR, 0.34), surgery with diagnosis in 2001 or before (0.37), regional stage (HR, 0.53), chemotherapy (HR, 0.56), intestinal histology (HR, 0.74), well- or moderately differentiated tumors (HR, 0.76), radiation (HR, 0.80), Asian/Pacific Islander race (HR, 0.81), treatment at an academic hospital (HR, 0.85), fundus/body/antrum location (HR, 0.90), highest socioeconomic status quintile (HR, 0.91), female sex (HR, 0.92), Hispanic race (HR, 0.92), and hospital size more than 150 beds (HR, 0.94). Kaplan-Meier curves showed longer median disease-specific survival (DSS) in patients with tumors originating in the fundus/body/antrum compared with esophagus/cardia (13.4 v 10.8 months). Intestinal histology had significantly longer median DSS (28.9 months) compared with other (11.0 months) or diffuse (10.1 months) histology.Patients who survive gastric and GEJ cancer more than 3 years after diagnosis have demographic and pathologic characteristics distinct from those who do not survive.
View details for DOI 10.1200/JCO.2011.35.8028
View details for PubMedID 22949151
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Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features
MODERN PATHOLOGY
2012; 25 (8): 1128-1139
Abstract
Recent literature suggests an increasing incidence of colorectal carcinoma in young patients. We performed a histologic, molecular, and immunophenotypic analysis of patients with sporadic early-onset (≤40 years of age) colorectal carcinoma seen at our institution from the years 2000-2010 and compared these tumors to a cohort of consecutively resected colorectal carcinomas seen in patients >40 years of age. A total of 1160 primary colorectal adenocarcinomas were surgically resected for the years 2000 through 2010. Of these, 75 (6%) were diagnoses in patients ≤40 years of age of which 13 (17%) demonstrated abnormalities in DNA mismatch repair, 4 (5%) were in patients with known germline genetic disorders (two patients with familial adenomatous polyposis, one patient with juvenile polyposis, and one patient with Li-Fraumeni syndrome), and three patients (4%) had long-standing chronic inflammatory bowel disease. The sporadic early-onset colorectal carcinoma group comprised a total of 55 patients (55/1160, 5%) and were compared with a control group comprising 73 consecutively resected colorectal carcinomas with proficient DNA mismatch repair in patients >40 years of age. For the early-onset colorectal carcinoma group, most cases (33/55, 60%) were diagnosed between the age of 35 and 40 years of age. Compared with the control group, the early-onset colorectal carcinoma group was significantly different with respect to tumor location (P<0.007) with 80% (44/55 cases) identified in either the sigmoid colon (24/55, 44%) or rectum (20/55, 36%). Morphologically, early-onset colorectal carcinomas more frequently displayed adverse histologic features compared with the control colorectal carcinoma group such as signet ring cell differentiation (7/55, 13% vs 1/73, 1%, P=0.021), perineural invasion (16/55, 29% vs 8/73, 11%, P=0.009) and venous invasion (12/55, 22% vs 4/73, 6%, P=0.006). A precursor adenomatous lesion was less frequently identified in the early-onset colorectal carcinoma group compared with the control group (19/55, 35% vs 39/73, 53%, P=0.034). Of the early-onset colorectal carcinomas, only 2/45 cases (4%) demonstrated KRAS mutations compared with 11/73 (15%) of the control group colorectal adenocarcinomas harboring KRAS mutations, although this difference did not reach statistical significance (P=0.13). BRAF V600E mutations were not identified in the early-onset colorectal carcinoma group. No difference was identified between the two groups with regard to tumor stage, tumor size, number of lymph node metastases, lymphatic invasion, tumor budding, mucinous histology, or tumor-infiltrating lymphocytes. Both groups had similar recurrence-free (P=0.28) and overall survival (P=0.73). However, patients in the early-onset colorectal carcinoma group more frequently either presented with or developed metastatic disease during their disease course compared with the control colorectal carcinoma group (25/55, 45% vs 18/73, 25%, P=0.014). In addition, 8/55 patients (15%) in the early-onset colorectal carcinoma group developed local recurrence of their tumor while no patients in the control colorectal carcinoma group developed local recurrence (P<0.001), likely due to the increased incidence of rectal carcinoma in the patients with early-onset colorectal carcinoma. Our study demonstrates that colorectal carcinoma is not infrequently diagnosed in patients ≤40 years of age and is not frequently the result of underlying Lynch syndrome or associated with other cancer-predisposing genetic conditions or chronic inflammatory conditions. These tumors have a striking predilection for the distal colon, particularly the sigmoid colon and rectum and are much more likely to demonstrate adverse histologic factors, including signet ring cell differentiation, venous invasion, and perineural invasion.
View details for DOI 10.1038/modpathol.2012.61
View details for PubMedID 22481281
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Pancreatic Neuroendocrine Tumors: Radiographic Calcifications Correlate with Grade and Metastasis
ANNALS OF SURGICAL ONCOLOGY
2012; 19 (7): 2295-2303
Abstract
Studies to identify preoperative prognostic variables for pancreatic neuroendocrine tumor (PNET) have been inconclusive. Specifically, the prevalence and prognostic significance of radiographic calcifications in these tumors remains unclear.From 1998 to 2009, a total of 110 patients with well-differentiated PNET underwent surgical resection at our institution. Synchronous liver metastases present in 31 patients (28%) were addressed surgically with curative intent. Patients with high-grade PNET were excluded. The presence of calcifications in the primary tumor on preoperative computed tomography was recorded and correlated with clinicopathologic variables and overall survival.Calcifications were present in 16% of patients and were more common in gastrinomas and glucagonomas (50%), but never encountered in insulinomas. Calcified tumors were larger (median size 4.5 vs. 2.3 cm, P=0.04) and more commonly associated with lymph node metastasis (75 vs. 35%, P=0.01), synchronous liver metastasis (62 vs. 21%, P<0.01), and intermediate tumor grade (80 vs. 31%, P<0.01). On multivariate analysis of factors available preoperatively, calcifications (P=0.01) and size (P<0.01) remained independent predictors of lymph node metastasis. Overall survival after resection was significantly worse in the presence of synchronous liver metastasis (5-year, 64 vs. 86%, P=0.04), but not in the presence of radiographic calcifications.Calcifications on preoperative computed tomography correlate with intermediate grade and lymph node metastasis in well-differentiated PNET. This information is available preoperatively and supports the routine dissection of regional lymph nodes through formal pancreatectomy rather than enucleation in calcified PNET.
View details for DOI 10.1245/s10434-012-2305-7
View details for PubMedID 22396008
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A phase I trial of vandetanib combined with capecitabine, oxaliplatin and bevacizumab for the first-line treatment of metastatic colorectal cancer
INVESTIGATIONAL NEW DRUGS
2012; 30 (3): 1082-1087
Abstract
Vandetanib is a tyrosine kinase inhibitor of both the vascular endothelial growth factor (VEGFR) and epidermal growth factor (EGFR) receptors. The primary objectives of this study were to determine the maximum tolerated dose of vandetanib with capecitabine and oxaliplatin, without and with bevacizumab, for the first line treatment of metastatic colorectal cancer (mCRC), and to define the dose limiting toxicities.Three cohorts of patients were studied, with capecitabine at 1,000 mg/m(2) twice daily p.o. on days 1-14 of a 3 week cycle, with oxaliplatin i.v. at 130 mg/m(2) on day 1. Vandetanib dosing was 100 mg/day in cohort 1 and 300 mg/day in cohorts 2 and 3. Bevacizumab was added in cohort 3 at 7.5 mg/kg i.v. on day 1 every 3 weeks.Thirteen patients were enrolled and received from one to eight cycles per patient. Grade 4 dermatitis developed in one patient in the first cohort, and the cohort was expanded to six patients with no further dose limiting toxicities (DLT). The second cohort of 3 patients was well tolerated. The third cohort resulted in grade 3 diarrhea, requiring several days of hospitalization and i.v. hydration, in 3 of the 4 patients. Given the severity and duration of diarrhea, each of these was considered a DLT, and therefore cohort 3 was considered to be above the maximum tolerated dose. Six of the 13 patients achieved a partial or complete remission (46%). The time to progression ranged from 2 to 14 months.Vandetanib at doses of 100 mg and 300 mg daily in combination with capecitabine and oxaliplatin was well tolerated. However, the addition of bevacizumab resulted in severe diarrhea in three out of four patients. Bevacizumab was not well tolerated with vandetanib and XELOX in combination.
View details for DOI 10.1007/s10637-011-9656-y
View details for Web of Science ID 000303878700023
View details for PubMedID 21404105
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Medical treatment consensus in unresectable midgut gastrointestinal neuroendocrine tumors.
48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO)
AMER SOC CLINICAL ONCOLOGY. 2012
View details for Web of Science ID 000318009801399
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A phase I dose-escalation and pharmacokinetic study of enzastaurin and erlotinib in patients with advanced solid tumors
CANCER CHEMOTHERAPY AND PHARMACOLOGY
2012; 69 (4): 1013-1020
Abstract
Enzastaurin, an oral serine/threonine kinase inhibitor, targets the protein kinase C and AKT pathways with anti-tumor and anti-angiogenic effects. Erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has activity in solid tumors. Based on the promising combination of EGFR inhibitors and anti-angiogenic agents, this phase I trial was initiated.This single-institution, open-label, non-randomized trial used a standard 3 + 3 dose-escalation model in patients with advanced solid malignancies including non-small-cell lung cancer (NSCLC). Two dose levels of enzastaurin (with loading doses) were explored: 250 mg daily and 500 mg daily. Erlotinib was given at 150 mg daily.Sixteen patients were enrolled in this study (median age, 64 years). Most patients were heavily pre-treated, female, and Caucasian and had NSCLC. The highest dose of enzastaurin, 500 mg daily, was tolerated with no unexpected adverse events and no alteration in the pharmacokinetics of either drug at this dose level. The mean clearance was 5.75 L/h for erlotinib and 53.8 L/h for enzastaurin. The most common possibly drug-related grade 3-4 adverse events included diarrhea (25.0%), neurologic symptoms (18.8%), and vomiting (18.8%). Activity was noted, with a partial response in one patient and prolonged disease stability for >12 cycles in three patients.The combination of enzastaurin 500 mg daily and erlotinib 150 mg daily is well tolerated and does not alter the pharmacokinetics of the individual drugs, with clinical activity seen. A phase II trial of this combination has been initiated in patients with advanced-stage NSCLC.
View details for DOI 10.1007/s00280-011-1792-8
View details for PubMedID 22160298
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Intensity-Modulated Radiotherapy for Pancreatic Adenocarcinoma
51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO)
ELSEVIER SCIENCE INC. 2012: E595–E601
Abstract
To report the outcomes and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for pancreatic adenocarcinoma.Forty-seven patients with pancreatic adenocarcinoma were treated with IMRT between 2003 and 2008. Of these 47 patients, 29 were treated adjuvantly and 18 definitively. All received concurrent 5-fluorouracil chemotherapy. The treatment plans were optimized such that 95% of the planning target volume received the prescription dose. The median delivered dose for the adjuvant and definitive patients was 50.4 and 54.0 Gy, respectively.The median age at diagnosis was 63.9 years. For adjuvant patients, the 1- and 2-year overall survival rate was 79% and 40%, respectively. The 1- and 2-year recurrence-free survival rate was 58% and 17%, respectively. The local-regional control rate at 1 and 2 years was 92% and 80%, respectively. For definitive patients, the 1-year overall survival, recurrence-free survival, and local-regional control rate was 24%, 16%, and 64%, respectively. Four patients developed Grade 3 or greater acute toxicity (9%) and four developed Grade 3 late toxicity (9%).Survival for patients with pancreatic cancer remains poor. A small percentage of adjuvant patients have durable disease control, and with improved therapies, this proportion will increase. Systemic therapy offers the greatest opportunity. The present results have demonstrated that IMRT is well tolerated. Compared with those who received three-dimensional conformal radiotherapy in previously reported prospective clinical trials, patients with pancreatic adenocarcinoma treated with IMRT in our series had improved acute toxicity.
View details for DOI 10.1016/j.ijrobp.2011.09.035
View details for PubMedID 22197234
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HER2 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma in a US Population: Clinicopathologic Analysis With Proposed Approach to HER2 Assessment
APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
2012; 20 (1): 13-24
Abstract
Recent evidence suggests that trastuzumab, a monoclonal antibody which targets HER2, in combination with chemotherapy is a therapeutic option in patients with HER2-positive gastric or gastroesophageal junction cancer. Widely accepted guidelines for HER2 testing in gastric and gastroesophageal junction cancer have not been established. The purpose of this study was to analyze the incidence and patterns of HER2 expression in gastric and gastroesophageal junction cancer using a tissue microarray approach, which closely simulates small biopsies routinely tested for HER2. One hundred sixty-nine patients, including 99 primary gastric adenocarcinomas and 70 primary gastroesophageal junction carcinomas were analyzed for HER2 overexpression by immunohistochemistry and HER2 gene amplification by fluorescence in situ hybridization using scoring schemes proposed by both American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) and the results of the recently published Trastuzumab for Gastric Cancer (ToGA) trial. In our analysis, 19 adenocarcinomas were HER2 positive, defined as either a HER2/CEP17 ratio >2.2 and/or a 3+ HER2 immunohistochemistry score with either the ASCO/CAP or ToGA scoring schemes. Of the 19 HER2-positive adenocarcinomas, 8 (42%) exhibited a characteristic strongly intense basolateral membranous staining pattern which would be interpreted as negative (1+) using the accepted ASCO/CAP scoring scheme for HER2 assessment in breast carcinoma, but were correctly labeled as 3+ positive using the proposed ToGA scoring scheme. Of the 19 HER2-positive adenocarcinomas, 8 (42%) demonstrated heterogeneous HER2 protein expression by immunohistochemistry. Twelve of 99 (12%) gastric carcinomas were positive for HER2. Of these, HER2 was more often identified in intestinal-type adenocarcinomas (10 of 52, 19%) compared with diffuse (2 of 34, 6%) adenocarcinoma. Seven of 70 (10%) gastroesophageal junction carcinomas were positive for HER2 of which all were intestinal type (7 of 58, 12%). HER2 status or primary tumor site did not correlate with patient survival. Gastric and gastroesophageal junction adenocarcinomas typically display a characteristic basolateral membranous pattern of HER2 expression which is often heterogeneous rendering routine evaluation of HER2 status on small tissue samples challenging.
View details for DOI 10.1097/PAI.0b013e31821c821c
View details for PubMedID 21617522
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Phase I trial of oblimersen (GenasenseA (R)) and gemcitabine in refractory and advanced malignancies
INVESTIGATIONAL NEW DRUGS
2011; 29 (5): 971-977
Abstract
Overexpression of Bcl-2 is associated with worse prognosis for a number of cancer types. The present study was designed to determine the maximum tolerated dose (MTD) of oblimersen (antisense Bcl-2) and gemcitabine when administered to patients with refractory malignancies.Sixteen patients with advanced solid tumors refractory to standard therapies were treated with escalating doses of oblimersen continuous, 120-h intravenous infusion given every 14 days, with a fixed-dose-rate intravenous infusion of gemcitabine administered on day 5 of each cycle. Serial plasma samples were collected to calculate the pharmacokinetics of oblimersen and gemcitabine, and also to measure the effect of oblimersen on Bcl-2 expression.7 women and 9 men, median age 55 years (range 35-74 years), received a 5-day infusion of oblimersen at dose levels of 5 mg/kg/day (n = 4) or 7 mg/kg/day (n = 12). On the 5th day of the infusion, gemcitabine was given at 10 mg/m(2)/h for a total dose of 1,000 mg/m(2) (n = 7; cohorts I and II), 1,200 mg/m(2) (n = 3; cohort III), or 1,500 mg/m(2) (n = 6; cohort IV). Edema was the dose-limiting toxicity (DLT), necessitating expansion of cohort IV. No subsequent DLTs were noted. Thus, the maximum planned doses were well tolerated, and a formal MTD was not determined. Most hematologic toxicities were grade 1 or 2. There was low-grade fatigue, nausea/vomiting, and myalgias/arthralgias. Oblimersen C(ss) and AUC increased in relation to the dose escalation, but gemcitabine triphosphate levels did not correlate well with dose. There were no objective responses, though 5 patients had stable disease. A >75% reduction in Bcl-2 expression in peripheral blood mononuclear leucocytes was seen more frequently in patients who achieved stable disease than in progressing patients.The maximal planned dose levels of oblimersen and gemcitabine in combination were well tolerated. Only one DLT (edema) occurred. There was a correlation between Bcl-2 reduction and stable disease. The recommended doses of the drugs for future studies are 7 mg/kg/day of oblimersen on days 1-5, and gemcitabine 1,500 mg/m(2) on day 5, every two weeks.
View details for DOI 10.1007/s10637-010-9416-4
View details for PubMedID 20349264
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Intensity-Modulated Radiation Therapy Versus Conventional Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal
CANCER
2011; 117 (15): 3342-3351
Abstract
The purpose of this study was to compare outcomes in patients with anal canal squamous cell carcinoma (SCCA) who were treated with definitive chemoradiotherapy by either intensity-modulated radiation therapy (IMRT) or conventional radiotherapy (CRT).Forty-six patients who received definitive chemoradiotherapy from January 1993 to August 2009 were included. Forty-five patients received 5-fluorouracil with mitomycin C (n = 39) or cisplatin (n = 6). Seventeen (37%) were treated with CRT and 29 (63%) with IMRT. The median dose was 54 Gy in both groups. Median follow-up was 26 months (CRT) and 32 months (IMRT). T3-T4 stage (P = .18) and lymph node-positive disease (P = .6) were similar between groups.The CRT group required longer treatment duration (57 days vs 40 days, P < .0001), more treatment breaks (88% vs 34.5%, P = .001), and longer breaks (12 days vs 1.5 days, P < .0001) than patients treated with IMRT. Eleven (65%) patients in the CRT group experienced grade >2 nonhematologic toxicity compared with 6 (21%) patients in the IMRT group (P = .003). The 3-year overall survival (OS), locoregional control (LRC), and progression-free survival were 87.8%, 91.9%, and 84.2%, respectively, for the IMRT groups and 51.8%, 56.7%, and 56.7%, respectively, for the CRT group (all P < .01). On multivariate analysis, T stage, use of IMRT, and treatment duration were associated with OS, and T stage and use of IMRT were associated with LRC.The use of IMRT was associated with less toxicity, reduced need for treatment breaks, and excellent LRC and OS compared with CRT in patients with SCCA of the anal canal.
View details for DOI 10.1002/cncr.25901
View details for PubMedID 21287530
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Pancreatic Endocrine Tumors With Major Vascular Abutment, Involvement, or Encasement and Indication for Resection
ARCHIVES OF SURGERY
2011; 146 (6): 724-732
Abstract
Surgery for pancreatic endocrine tumors (PETs) with blood vessel involvement is controversial.Resection of PETs with major blood vessel involvement can be beneficial.The combined databases of the National Institutes of Health and Stanford University hospitals were queried.Operation, pathologic condition, complications, and disease-free and overall survival.Of 273 patients with PETs, 46 (17%) had preoperative computed tomography evidence of major vascular involvement. The mean size for the primary PET was 5.0 cm. The involved major vessel was as follows: portal vein (n = 20), superior mesenteric vein or superior mesenteric artery (n = 16), inferior vena cava (n = 4), splenic vein (n = 4), and heart (n = 2). Forty-two of 46 patients had a PET removed: 12 (27%) primary only, 30 (68%) with lymph nodes, and 18 (41%) with liver metastases. PETs were removed by either enucleation (n = 7) or resection (n = 35). Resections included distal or subtotal pancreatectomy in 23, Whipple in 10, and total in 2. Eighteen patients had concomitant liver resection: 10 wedge resection and 8 anatomic resections. Nine patients had vascular reconstruction: each had reconstruction of the superior mesenteric vein and portal vein, and 1 had concomitant reconstruction of the superior mesenteric artery. There were no deaths, but 12 patients had complications. Eighteen patients (41%) were immediately disease free, and 5 recurred with follow-up, leaving 13 (30%) disease-free long term. The 10-year overall survival was 60%. Functional tumors were associated with a better overall survival (P < .001), and liver metastases decreased overall survival (P < .001).These findings suggest that surgical resection of PETs with vascular abutment/invasion and nodal or distant metastases is indicated.
View details for PubMedID 21690450
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F-18-5-fluorouracil dynamic positron emission tomography/computed tomography shows decreased tracer activity after bevacizumab in colorectal metastases
NUCLEAR MEDICINE COMMUNICATIONS
2011; 32 (5): 343-347
Abstract
The aim of this study was to evaluate the potential of fluorine-18 (F)-5-fluorouracil (F-5-FU) positron emission tomography/computed tomography (PET/CT) to show differences in 5-FU activity in metastatic colorectal cancer before and after treatment with bevacizumab.This was a pilot study of five patients with newly diagnosed and untreated metastatic colorectal adenocarcinoma. The presence of cancer was confirmed by histopathological analysis before enrollment. Patients underwent F-5-FU PET/CT scanning before treatment and at approximately 24 h postbevacizumab. PET/CT scanning consisted of a dynamic acquisition of images taken 0-20 min after injection of radiotracer. The degree of F-5-FU activity at the metastatic sites was assessed using visual interpretation and semiquantitative standardized uptake value analyses.The sizes of the metastatic lesions ranged from the smallest lesion measuring 3.04 × 1.50 cm to the largest measuring 4.19 × 2.76 cm. By drawing regions of interest, time-activity curves were generated at each tumor site and area under the curve (AUC) analyses were carried out. At baseline, during the first 5 min after F-5-FU injection the mean AUCtumor/AUCaorta ratio was 1.24 ± 0.30 (range, 0.424-2.14). Less than 24 h after the administration of bevacizumab, the AUCtumor/AUCaorta ratio decreased to 1.06 ± 0.32 (range, 0.23-2.13, P=0.04), which represented an average decline of 20.2% (range, 0.4-45%). Radiotracer uptake on the 5, 10, 15, and 20-min images did not show any significant change between baseline and posttreatment. Follow-up CT imaging showed stable tumor size in one patient and a decrease in metastasis size in the remaining four patients.In this pilot study of five patients with metastatic colorectal carcinoma, F-5-FU PET/CT scanning showed a significant perfusion-related decrease in tracer activity 24 h postbevacizumab.
View details for DOI 10.1097/MNM.0b013e328344894b
View details for PubMedID 21412178
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Future Directions in the Treatment of Neuroendocrine Tumors: Consensus Report of the National Cancer Institute Neuroendocrine Tumor Clinical Trials Planning Meeting
JOURNAL OF CLINICAL ONCOLOGY
2011; 29 (7): 934-943
Abstract
Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. The recent completion of several phase III studies, including those evaluating octreotide, sunitinib, and everolimus, has demonstrated that rigorous evaluation of novel agents in this disease is both feasible and can lead to practice-changing outcomes. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future NET studies for the US cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Studies evaluating novel agents for the control of hormonal syndromes should avoid somatostatin analog washout periods when possible and should include quality-of-life end points. Because of the observed long survival after progression of many patients, progression-free survival is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies where a delay in progression is expected in the absence of radiologic responses.
View details for DOI 10.1200/JCO.2010.33.2056
View details for Web of Science ID 000287729900037
View details for PubMedID 21263089
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Expression of p16(INK4A) But Not Hypoxia Markers or Poly Adenosine Diphosphate-Ribose Polymerase Is Associated With Improved Survival in Patients With Pancreatic Adenocarcinoma
51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO)
WILEY-BLACKWELL. 2010: 5179–87
Abstract
Pancreatic cancer is associated with mutations in the tumor suppressor gene cyclin-dependent kinase inhibitor 2A (p16(INK4A) ), a regulator of the cell cycle and apoptosis. This study investigates whether immunohistochemical expression of p16(INK4A) as well as hypoxia markers and poly adenosine diphosphate-ribose polymerase (PARP) correlates with survival in patients with resected pancreatic adenocarcinoma.Seventy-three patients with pancreatic adenocarcinoma who underwent curative resection at Stanford University were included. From the surgical specimens, a tissue microarray was constructed using triplicate tissue cores from the primary tumor and used for immunohistochemical staining for the following markers: carbonic anhydrase IX, dihydrofolate reductase, p16(INK4A) , and PARP1/2. Staining was scored as either positive or negative and percentage positive staining. Staining score was correlated with overall survival (OS) and progression-free survival (PFS).Of the markers tested, only immunohistochemical expression of p16(INK4A) correlated with clinical outcome. On univariate analysis, p16(INK4A) expression in the tumor was associated with improved OS (P = .038) but not PFS (P = .28). The median survival for patients with positive versus negative p16(INK4A) staining was 28.8 months versus 18 months. On multivariate analysis, p16(INK4A) expression was associated with improved OS (P = .026) but not PFS (P = .25). Age (P = .0019) and number of nodes involved (P = .025) were also significant for OS. Adjuvant chemotherapy and margin status did not correlate with OS or PFS.Expression of p16(INK4A) is associated with improved OS in patients with resected pancreatic adenocarcinoma. Further investigation is needed for validation, given conflicting data in the published literature. .
View details for DOI 10.1002/cncr.25481
View details for PubMedID 20665497
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Comparison of Intensity-Modulated Radiotherapy and 3-Dimensional Conformal Radiotherapy as Adjuvant Therapy for Gastric Cancer
51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO)
JOHN WILEY & SONS INC. 2010: 3943–52
Abstract
The current study was performed to compare the clinical outcomes and toxicity in patients treated with postoperative chemoradiotherapy for gastric cancer using intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3D CRT).Fifty-seven patients with gastric or gastroesophageal junction cancer were treated postoperatively: 26 with 3D CRT and 31 with IMRT. Concurrent chemotherapy was capecitabine (n=31), 5-fluorouracil (5-FU) (n=25), or none (n=1). The median radiation dose was 45 Gy. Dose volume histogram parameters for kidney and liver were compared between treatment groups.The 2-year overall survival rates for 3D CRT versus IMRT were 51% and 65%, respectively (P=.5). Four locoregional failures occurred each in the 3D CRT (15%) and the IMRT (13%) patients. Grade>or=2 acute gastrointestinal toxicity was found to be similar between the 3D CRT and IMRT patients (61.5% vs 61.2%, respectively) but more treatment breaks were needed (3 vs 0, respectively). The median serum creatinine from before radiotherapy to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but increased in the 3D CRT group from 0.80 mg/dL to 1.0 mg/dL (P=.02). The median kidney mean dose was higher in the IMRT versus the 3D CRT group (13.9 Gy vs 11.1 Gy; P=.05). The median kidney V20 was lower for the IMRT versus the 3D CRT group (17.5% vs 22%; P=.17). The median liver mean dose for IMRT and 3D CRT was 13.6 Gy and 18.6 Gy, respectively (P=.19). The median liver V30 was 16.1% and 28%, respectively (P<.001).Adjuvant chemoradiotherapy was well tolerated. IMRT was found to provide sparing to the liver and possibly renal function.
View details for DOI 10.1002/cncr.25246
View details for PubMedID 20564136
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(18)FLUORODEOXYGLUCOSE PET IS PROGNOSTIC OF PROGRESSION-FREE AND OVERALL SURVIVAL IN LOCALLY ADVANCED PANCREAS CANCER TREATED WITH STEREOTACTIC RADIOTHERAPY
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2010; 77 (5): 1420-1425
Abstract
This study analyzed the prognostic value of positron emission tomography (PET) for locally advanced pancreas cancer patients undergoing stereotactic body radiotherapy (SBRT).Fifty-five previously untreated, unresectable pancreas cancer patients received a single fraction of 25-Gy SBRT sequentially with gemcitabine-based chemotherapy. On the preradiation PET-CT, the tumor was contoured and the maximum standardized uptake value (SUVmax) and metabolic tumor burden (MTB) were calculated using an in-house software application. High-SUVmax and low-SUVmax subgroups were created by categorizing patients above or below the median SUVmax. The analysis was repeated to form high-MTB and low-MTB subgroups as well as clinically relevant subgroups with SUVmax values of <5, 5-10, or >10. Multivariate analysis analyzing SUVmax, MTB, age, chemotherapy cycles, and pretreatment carbohydrate antigen (CA)19-9 was performed.For the entire population, median survival was 12.7 months. Median survival was 9.8 vs.15.3 months for the high- and low- SUVmax subgroups (p <0.01). Similarly, median survival was 10.1 vs. 18.0 months for the high MTB and low MTB subgroups (p <0.01). When clinical SUVmax cutoffs were used, median survival was 6.4 months in those with SUVmax >10, 9.5 months with SUVmax 5.0-10.0, and 17.7 months in those with SUVmax <5 (p <0.01). On multivariate analysis, clinical SUVmax was an independent predictor for overall survival (p = 0.03) and progression-free survival (p = 0.03).PET scan parameters can predict for length of survival in locally advanced pancreas cancer patients.
View details for DOI 10.1016/j.ijrobp.2009.06.049
View details for Web of Science ID 000280459700020
View details for PubMedID 20056345
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Pathological response after chemoradiation for T3 rectal cancer.
Colorectal disease
2010; 12 (7 Online): e24-30
Abstract
The aim of this study was to investigate the effect of preoperative chemoradiotherapy (CRT) on nodal disease in locally advanced rectal adenocarcinoma.Thirty-two patients staged uT3N0 and 27 patients staged uT3N1 rectal adenocarcinoma who underwent pre-CRT staging using endoscopic ultrasound or rectal protocol CT were included. The median radiation dose was 50.4 Gy (range: 45-50.4 Gy) at 1.8 Gy per fraction and all patients received concurrent 5-FU or capecitabine-based chemotherapy. Low anterior resection or abdomino-perineal resection occurred at a median of 46 days (range: 27-112 days) after CRT.Eleven of 32 uT3N0 patients (34.4%) and 13 of 26 uT3N1 patients (50.0%) had ypN+ (P = 0.29). For patients with uT3N0, 10 of 20 (50.0%) with ypT2-3 and 1 of 12 (8.3%) with ypT0-1 were ypN+ (P = 0.02). For patients with uT3N1, 12 of 20 (60.0%) with ypT2-3 and 1 of 6 (16.7%) with ypT0-1 were ypN+ (P = 0.16). Overall, the ypN+ rate was 11.1% in the ypT0-yT1 group compared with 55.0% in the ypT2-yT3 group (P = 003). Among patients with uT3N0 disease, the ypN+ rate in patients who had surgery > 46 days vs
46 days vs 46 days vs View details for DOI 10.1111/j.1463-1318.2009.02013.x
View details for PubMedID 19614668
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Pathological response after chemoradiation for T3 rectal cancer
COLORECTAL DISEASE
2010; 12 (7): E24-E30
Abstract
The aim of this study was to investigate the effect of preoperative chemoradiotherapy (CRT) on nodal disease in locally advanced rectal adenocarcinoma.Thirty-two patients staged uT3N0 and 27 patients staged uT3N1 rectal adenocarcinoma who underwent pre-CRT staging using endoscopic ultrasound or rectal protocol CT were included. The median radiation dose was 50.4 Gy (range: 45-50.4 Gy) at 1.8 Gy per fraction and all patients received concurrent 5-FU or capecitabine-based chemotherapy. Low anterior resection or abdomino-perineal resection occurred at a median of 46 days (range: 27-112 days) after CRT.Eleven of 32 uT3N0 patients (34.4%) and 13 of 26 uT3N1 patients (50.0%) had ypN+ (P = 0.29). For patients with uT3N0, 10 of 20 (50.0%) with ypT2-3 and 1 of 12 (8.3%) with ypT0-1 were ypN+ (P = 0.02). For patients with uT3N1, 12 of 20 (60.0%) with ypT2-3 and 1 of 6 (16.7%) with ypT0-1 were ypN+ (P = 0.16). Overall, the ypN+ rate was 11.1% in the ypT0-yT1 group compared with 55.0% in the ypT2-yT3 group (P = 003). Among patients with uT3N0 disease, the ypN+ rate in patients who had surgery > 46 days vs
46 days vs 46 days vs View details for DOI 10.1111/j.1463-1318.2009.02013.x
View details for Web of Science ID 000208355900003
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Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors
ANNALS OF ONCOLOGY
2010; 21 (2): 376-381
Abstract
Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity. Materials and methods: This phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors.Thirty-one patients received lexatumumab over five dose levels (0.1-10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (+/-standard deviation) t(1/2b) was 13.67 +/- 4.07 days, clearance was 4.95 +/- 1.93 ml/day/kg, V(1) was 45.55 ml/kg and V(ss) was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected.Lexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.
View details for DOI 10.1093/annonc/mdp292
View details for PubMedID 19633048
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Advances in the treatment of gastroenteropancreatic neuroendocrine tumors.
Clinical and experimental gastroenterology
2010; 3: 79-86
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and heterogeneous class of neoplasms. While surgical resection is the mainstay of treatment, non-surgical therapies play a role in the setting of unresectable and metastatic disease. The goals of medical therapy are directed both at alleviating symptoms of peptide release and shrinking tumor mass. Biotherapies such as somatostatin analogs and interferon can decrease the secretion of peptides and inhibit their end-organ effects. A second objective for treatment of unresectable GEP-NETs is limiting tumor growth. Options for limiting tumor growth include somatostatin analogs, systemic chemotherapy, locoregional therapies, ionizing radiation, external beam radiation, and newer targeted agents. In particular, angiogenesis inhibitors, tyrosine kinase inhibitors, and mTOR inhibitors have shown early promising results. The rarity of these tumors, their resistance to standard chemotherapy, and the excellent performance status of most of these patients, make a strong argument for consideration of novel therapeutic trials.
View details for PubMedID 21694850
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Multimodality treatment with intensity modulated radiation therapy for esophageal cancer
DISEASES OF THE ESOPHAGUS
2010; 23 (4): 300-308
Abstract
The objective of this study is to determine the feasibility and report the outcome of patients with locally advanced esophageal cancer treated with preoperative or definitive chemoradiotherapy (CRT) using intensity-modulated radiation therapy (IMRT). Between 2003 and 2007, 30 patients with non-cervical esophageal cancer received concurrent chemotherapy and IMRT at Stanford University. Eighteen patients were planned for definitive CRT and 12 were planned for preoperative CRT. All patients had computed tomography-based treatment planning and received IMRT. The median dose delivered was 50.4 Gy. Patients planned for preoperative CRT underwent surgery 4-13 weeks (median 8.3 weeks) following completion of CRT. Median follow-up of surviving patients from start of RT was 24.2 months (range 8.2-38.3 months). The majority of tumors were adenocarcinomas (67%) and poorly differentiated (57%). Tumor location was 7% upper, 20% mid, 47% lower, and 27% gastroesophageal junction. Actuarial 2-year local-regional control (LRC) was 64%. High tumor grade was an adverse prognostic factor for LRC and overall survival (OS) (P= 0.015 and 0.012, respectively). The 2-year LRC was 83% vs. 51% for patients treated preoperatively vs. definitively (P= 0.32). The 2-year disease-free and OS were 38% and 56%, respectively. Twelve patients (40%) required feeding tube placement, and the average weight loss from baseline was 4.8%. Twelve (40%) patients experienced grade 3+ acute complications and one patient died of complications following feeding tube placement. Three patients (10%) required a treatment break. Eight patients (27%) experienced grade 3 late complications. No grade 4 complications were seen. IMRT was effective and well tolerated. Disease recurrence remains a challenge and further investigation with dose escalation to improve LRC and OS is warranted.
View details for DOI 10.1111/j.1442-2050.2009.01004.x
View details for PubMedID 19732129
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Identification of a biomarker panel using a multiplex proximity ligation assay improves accuracy of pancreatic cancer diagnosis
JOURNAL OF TRANSLATIONAL MEDICINE
2009; 7
Abstract
Pancreatic cancer continues to prove difficult to clinically diagnose. Multiple simultaneous measurements of plasma biomarkers can increase sensitivity and selectivity of diagnosis. Proximity ligation assay (PLA) is a highly sensitive technique for multiplex detection of biomarkers in plasma with little or no interfering background signal.We examined the plasma levels of 21 biomarkers in a clinically defined cohort of 52 locally advanced (Stage II/III) pancreatic ductal adenocarcinoma cases and 43 age-matched controls using a multiplex proximity ligation assay. The optimal biomarker panel for diagnosis was computed using a combination of the PAM algorithm and logistic regression modeling. Biomarkers that were significantly prognostic for survival in combination were determined using univariate and multivariate Cox survival models.Three markers, CA19-9, OPN and CHI3L1, measured in multiplex were found to have superior sensitivity for pancreatic cancer vs. CA19-9 alone (93% vs. 80%). In addition, we identified two markers, CEA and CA125, that when measured simultaneously have prognostic significance for survival for this clinical stage of pancreatic cancer (p < 0.003).A multiplex panel assaying CA19-9, OPN and CHI3L1 in plasma improves accuracy of pancreatic cancer diagnosis. A panel assaying CEA and CA125 in plasma can predict survival for this clinical cohort of pancreatic cancer patients.
View details for DOI 10.1186/1479-5876-7-105
View details for PubMedID 20003342
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Impaired interferon signaling is a common immune defect in human cancer
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2009; 106 (22): 9010-9015
Abstract
Immune dysfunction develops in patients with many cancer types and may contribute to tumor progression and failure of immunotherapy. Mechanisms underlying cancer-associated immune dysfunction are not fully understood. Efficient IFN signaling is critical to lymphocyte function; animals rendered deficient in IFN signaling develop cancer at higher rates. We hypothesized that altered IFN signaling may be a key mechanism of immune dysfunction common to cancer. To address this, we assessed the functional responses to IFN in peripheral blood lymphocytes from patients with 3 major cancers: breast cancer, melanoma, and gastrointestinal cancer. Type-I IFN (IFN-alpha)-induced signaling was reduced in T cells and B cells from all 3 cancer-patient groups compared to healthy controls. Type-II IFN (IFN-gamma)-induced signaling was reduced in B cells from all 3 cancer patient groups, but not in T cells or natural killer cells. Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction.
View details for DOI 10.1073/pnas.0901329106
View details for PubMedID 19451644
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Stereotactic Radiotherapy for Unresectable Adenocarcinoma of the Pancreas
CANCER
2009; 115 (3): 665-672
Abstract
The authors report on the local control and toxicity of stereotactic body radiotherapy (SBRT) for patients with unresectable pancreatic adenocarcinoma.Seventy-seven patients with unresectable adenocarcinoma of the pancreas received 25 gray (Gy) in 1 fraction. Forty-five patients (58%) had locally advanced disease, 11 patients (14%) had medically inoperable disease, 15 patients (19%) had metastatic disease, and 6 patients (8%) had locally recurrent disease. Nine patients (12%) had received prior chemoradiotherapy. Sixteen patients (21%) received between 45 to 54 Gy of fractionated radiotherapy and SBRT. Various gemcitabine-based chemotherapy regimens were received by 74 patients (96%), but 3 patients (4%) did not receive chemotherapy until they had distant failure.The median follow-up was 6 months (range, 3-31 months) and, among surviving patients, it was 12 months (range, 3-31 months). The overall rates of freedom from local progression (FFLP) at 6 months and 12 months were 91% and 84%, respectively. The 6- and 12-month isolated local recurrence rates were 5% and 5%, respectively. There was no difference in the 12-month FFLP rate based on tumor location (head/uncinate, 91% vs body/tail, 86%; P = .52). The progression-free survival (PFS) rates at 6 months and 12 months were 26% and 9%, respectively. The PFS rate at 6 months was superior for patients who had nonmetastatic disease versus patients who had metastatic disease (28% vs 15%; P = .05). The overall survival (OS) rates at 6 months and 12 months from SBRT were 56% and 21%, respectively. Four patients (5%) experienced grade > or = 2 acute toxicity. Three patients (4%) experienced grade 2 late toxicity, and 7 patients (9%) experienced grade > or = 3 late toxicity. At 6 months and 12 months, the rates of grade > or = 2 late toxicity were 11% and 25%, respectively.SBRT for pancreatic adenocarcinoma was effective for local control with associated risk of toxicity and should be used with rigorous attention to quality assurance. Efforts to reduce complications are warranted. Distant metastases account for the vast majority of disease-related mortality.
View details for DOI 10.1002/cncr.24059
View details for PubMedID 19117351
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Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2008; 72 (3): 678-686
Abstract
Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy.A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT.All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13).SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.
View details for DOI 10.1016/j.ijrobp.2008.01.051
View details for PubMedID 18395362
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A Phase II Study of Gefitinib, 5-Fluorouracil, Leucovorin, and Oxaliplatin in Previously Untreated Patients with Metastatic Colorectal Cancer
CLINICAL CANCER RESEARCH
2008; 14 (21): 7074-7079
Abstract
We investigated the gefitinib, 5-fluorouracil (5-FU), leucovorin and oxaliplatin (IFOX) regimen as first-line therapy in patients with metastatic colorectal cancer.Eligible patients had stage IV colorectal adenocarcinoma, and had not received prior chemotherapy for metastatic disease. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin, leucovorin, and 5-FU (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg orally daily throughout the 14-day cycle.Forty-five patients were enrolled and were assessable for toxicity. Forty-three patients were assessable for response. Thirty-one of the 43 patients (72%) had either a complete or partial response by the Response Evaluation Criteria in Solid Tumors. Median overall survival was 20.5 months. Median time to progression was 9.3 months. Commonly encountered grade 3 or 4 toxicities included diarrhea in 67% of patients and neutropenia in 60%. Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients.IFOX is an active first-line regimen in patients with metastatic colorectal adenocarcinoma, showing higher response rates but also increased toxicities compared with FOLFOX-4 alone in a similar patient population.
View details for DOI 10.1158/1078-0432.CCR-08-1014
View details for Web of Science ID 000260732200044
View details for PubMedID 18981005
View details for PubMedCentralID PMC2583341
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Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate
ANNALS OF ONCOLOGY
2008; 19 (9): 1613-1618
Abstract
In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiotoxicity was reported to be reversible and without clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a high incidence of symptomatic heart failure.Patients receiving sunitinib at Stanford University from 1 July 2004 to 1 July 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic grade 3/4 left ventricular systolic dysfunction were identified. Potential cardiac risk factors were analyzed.Forty-eight patients treated with sunitinib were assessable. Seven patients experienced symptomatic grade 3/4 left ventricular dysfunction 22-435 days after initiation of sunitinib. Three patients had persistent cardiac dysfunction after discontinuation of sunitinib and initiation of heart failure therapy. A history of congestive heart failure, coronary artery disease and lower body mass index were factors associated with increased risk.Among patients treated with sunitinib at our institution, 15% developed symptomatic grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand.
View details for DOI 10.1093/annonc/mdn168
View details for Web of Science ID 000259505400015
View details for PubMedID 18436521
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Tissue effects after stereotactic body radiotherapy using cyberknife for patients with abdominal malignancies
CLINICAL ONCOLOGY
2008; 20 (1): 69-75
Abstract
To report the tissue effects of treatment with single fraction stereotactic body radiotherapy (SBRT) using Cyberknife on malignant tumours of the abdomen and adjacent normal organs.The data from four autopsies with unresectable pancreatic carcinoma and one lymph node excision from a case of recurrent neuroblastoma were reviewed for radiation-related tissue effects within the primary cancer and the normal organs within the radiation field.Cases of unresectable pancreatic carcinoma consistently showed radiation-induced changes in both the primary tumour and the adjacent, non-malignant colorectal tissue. An additional case of lymph nodes exposed to stereotactic radiation showed typical radiation-related changes, including lymphocyte depletion and capsular fibrosis.A myriad of radiation-related tissue effects are seen after SBRT with Cyberknife. The changes parallel those reported after conventionally fractionated radiotherapy and suggest that the pathophysiological mechanisms of radiation-induced normal tissue damage are similar for biologically equivalent single and fractionated doses of radiotherapy.
View details for DOI 10.1016/j.clon.2007.08.009
View details for Web of Science ID 000253281700013
View details for PubMedID 17900882
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Phase H study of imatinib in unresectable hepatocellular carcinoma
AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS
2008; 31 (1): 84-88
Abstract
The expression of platelet-derived growth factor, a potent mitogen, and its receptor both in tissue and serum correlate with the severity of liver cirrhosis. Over-expression of platelet-derived growth factor has been demonstrated in human hepatocellular carcinoma (HCC) tumors and cell lines. Imatinib, a potent inhibitor of BCR-ABL and c-kit, also inhibits the platelet-derived growth factor receptor tyrosine kinase. The trial was designed to assess the efficacy and safety of imatinib in patients with unresectable HCC.Eligibility criteria consisted of HCC patient over the age of 18 with reasonable organ function, unresectable but measurable disease, not candidates for chemoinfusion, and a performance status of 0 to 2. Imatinib was started at 300 mg/d orally with 100 mg/wk dose escalation up to 800 mg/d if toxicity permitted.Fifteen patients, median age 58 years, were enrolled and treated with imatinib. Most, or 7, patients had hepatitis B virus as a risk factor for HCC, followed by hepatitis C virus in 3 patients. Metastatic disease (American Joint Committee on Cancer stage IV) was noted in 13 patients and locally advanced (stage III) in the remainder. The median dose-level of imatinib was 500 mg/d. Two patients had stable disease lasting more than 2 months. The remainder progressed within 2 months of initiation of imatinib. No grade 3 or 4 hematologic toxicity was observed. Two patients had grade 3 elevated liver function tests during treatment; otherwise, there was no other grade 3 or 4 nonhematologic toxicity noted.Although toxicities were tolerable, imatinib as a monotherapy for the treatment of unresectable HCC has little, if any, significant efficacy.
View details for DOI 10.1097/COC.0b013e3181131db9
View details for Web of Science ID 000253102700014
View details for PubMedID 18376233
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NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines.
Journal of the National Comprehensive Cancer Network
2007; 5: S1-29
Abstract
The NCCN Soft Tissue Sarcoma Guidelines include a subsection about treatment recommendations for gastrointestinal stromal tumors (GISTs). The standard of practice rapidly changed after the introduction of effective molecularly targeted therapy (such as imatinib and sunitinib) for GIST. Because of these changes, NCCN organized a multidisciplinary panel composed of experts in the fields of medical oncology, molecular diagnostics, pathology, radiation oncology, and surgery to discuss the optimal approach for the care of patients with GIST at all stages of the disease. The GIST Task Force is composed of NCCN faculty and other key experts from the United States, Europe, and Australia. The Task Force met for the first time in October 2003 and again in December 2006 with the purpose of expanding on the existing NCCN guidelines for gastrointestinal sarcomas and identifying areas of future research to optimize our understanding and treatment of GIST.
View details for PubMedID 17624289
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Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer
EXPERT OPINION ON INVESTIGATIONAL DRUGS
2007; 16 (4): 467-476
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related deaths in Western countries and is among the deadliest diseases in humans. At present, gemcitabine is the standard chemotherapy for advanced pancreatic cancer, although (despite its use) prognosis continues to be dismal with a median survival of < 6 months. While targeting tumor vasculature has provided improved outcomes in colon, lung, breast and renal cell cancers, trials of angiogenesis inhibitors have lagged behind in pancreatic cancer. This review provides the rationale for exploring antiangiogenic therapies in the treatment of pancreatic cancer as well as summarizes present clinical development of VEGF receptor tyrosine kinase inhibitors and their application to pancreatic cancer.
View details for DOI 10.1517/13543784.16.4.467
View details for Web of Science ID 000245307500007
View details for PubMedID 17371195
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Phase I study of I-131-chimeric(ch) TNT-1/B monoclonal antibody for the treatment of advanced colon cancer
CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS
2006; 21 (3): 243-256
Abstract
The primary aim of this study was to evaluate the biodistribution and toxicity of 131I-chimeric(ch) TNT-1/B monoclonal antibody (MAB), which binds to intracellular antigens of necrotic regions within tumors, in patients with advanced colon or colorectal cancer. The rationale for targeting areas of tumor necrosis is the observation that necrotic lesions are more abundant in cancer lesions than in surrounding tissues.Cohorts of patients with advanced colon or colorectal cancer were administered a one-time 30-60-minute intravenous (i.v.) infusion of 131I-chTNT-1/B at doses ranging from 12.95 to 66.23 MBq/kg (0.35-1.79 mCi/kg).The dose-limiting toxicity, experienced at 66.23 MBq/kg (1.79 mCi/kg) 131I-chTNT-1/B MAB, was myelosuppression. Two (2) patients at the 66.23-MBq/kg (1.79 mCi/kg) dose level had both grade 3 thrombocytopenia and grade 3 neutropenia that persisted for at least 2 weeks but were reversible. The maximum tolerated dose was 58.09 MBq/kg (1.57 mCi/kg) 131I-chTNT-1/B MAB. Of the 21 patients, one developed a moderate human antichimeric antibody (HACA) response and 6 developed low HACA responses.The infusion of 131I-chTNT-1/B MAB was well tolerated, without significant nonhematological toxicity. No patient obtained a complete or partial response, based on tumor cross-product response criteria. Tumor localization was seen in patients with dose levels at, and exceeding, 50.23 MBq/kg (1.36 mCi/kg) 131I-chTNT-1/B MAB.
View details for Web of Science ID 000239162600010
View details for PubMedID 16918301
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Phase I study of gefitinib, oxaliplatin, 5-fluorouracil, and leucovorin (IFOX) in patients with advanced solid malignancies
INVESTIGATIONAL NEW DRUGS
2006; 24 (2): 117-123
Abstract
Aphase 1 study of gefitinib in combination with oxaliplatin, 5-fluorouracil and leucovorin (IFOX)was conducted to evaluate the safety and feasibility of this regimen.Patients with advanced solid malignancies were treated with escalating doses of gefitinib (250 mg or 500 mg once daily) in combination with FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin). The initial dose of oxaliplatin was 70 mg/m2 with sequential dose escalation to 85 mg/m2.Sixteen patients received a total of 138 14-day courses of daily gefitinib in combination with FOLFOX. Escalation of gefitinib from 250 mg/d to 500 mg/d with FOLFOX was well-tolerated. In addition, no severe toxicities precluded subsequent dose escalation of oxaliplatin from 70 mg/m2 to 85 mg/m2 at which no dose-limiting toxicity was seen. No further dose escalation was performed as this represented the oxaliplatin dose administered in the standard FOLFOX-4 regimen. The most predominant toxicity was diarrhea, which was well controlled with oral antidiarrheal agents. Four partial remissions occurred in patients with metastatic colorectal cancer.Gefitinib as a 500 mg daily continuous dose was well tolerated in combination with full doses of FOLFOX-4.
View details for DOI 10.1007/s10637-006-2032-7
View details for Web of Science ID 000236793800003
View details for PubMedID 16683204
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A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance
ANNALS OF ONCOLOGY
2005; 16 (12): 1968-1973
Abstract
The aim of this study was to determine (i) the maximum tolerated dose (MTD) of liposomal doxorubicin (L-DOX) and paclitaxel (DP), (ii) the MTD of DP plus valspodar (DPV) and (iii) pharmacokinetic (PK) interactions of valspodar with L-DOX and paclitaxel.Twenty-three patients with metastatic cancers received DP, followed 4 weeks later by DPV. Dose levels of DP were (mg/m2 for L-DOX/paclitaxel): 30/135 (n = 7), 30/150 (n = 4), 35/150 (n = 8) and 40/150 (n = 4). Dose levels of DPV were 15/70 (n = 10) and 15/60 (n = 10). Serial, paired PK studies were performed.The MTD of DP was 40/150. For DPV at 15/70, five of 10 patients experienced grade 4 neutropenia. In the next cohort, a reduced dose of 15/60 was well tolerated. Valspodar produced reversible grade 3 ataxia in seven patients, requiring dose reduction from 5 to 4 mg/kg. Paired PK studies indicated no interaction between L-DOX and valspodar, and a 49% increase in the median half-life of paclitaxel. Two partial and one minor remissions were noted.The use of valspodar necessitated dose reductions of DP, with neutropenia being dose limiting. Valspodar PK interactions were observed with paclitaxel but not L-DOX.
View details for DOI 10.1093/annonc/mdi396
View details for PubMedID 16126736
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Current status of small-molecule tyrosine kinase inhibitors targeting epidermal growth factor receptor in colorectal cancer.
Clinical colorectal cancer
2005; 5: S62-70
Abstract
The epidermal growth factor receptor (EGFR) is expressed in the majority of colorectal cancers (CRCs) and is associated with poor clinical outcome. Ample evidence suggests that inhibition of this pathway by monoclonal antibodies directed against EGFR leads to antitumor activity in CRC. Small-molecule tyrosine kinase inhibitors (TKIs) provide distinct advantages over monoclonal antibodies by virtue of lower production costs, ease of oral administration, and ability to target multiple cellular survival pathways. Despite theoretical advantages, multiple early-phase trials of EGFR TKIs fail to demonstrate single-agent activity in CRC. However, the unusually high response rates observed when gefitinib, an EGFR TKI, is combined with chemotherapy for patients with metastatic CRC suggest a possible synergistic effect. This effect is not seen in non-small-cell lung cancer (NSCLC), for which larger phase III trials have been conducted. The differences between NSCLC and CRC with respect to EGFR expression and mutation status do not completely explain this dichotomy, and further investigation into the pharmacogenomics of EGFR tyrosine kinase inhibition in CRC is under way. Significant effort is directed toward newer strategies targeted at the EGFR in CRC. A new generation of small-molecule TKIs is emerging in which multiple receptor pathways, including ErbB2 and vascular endothelial growth factor receptor, can be simultaneously targeted with EGFR. These agents are still in early-phase clinical trials, and specific data for patients with CRC are forthcoming.
View details for PubMedID 16336751
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A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-alpha administered as a 24-hour weekly infusion schedule in patients with advanced cancer
36th Annual Meeting of the American-Society-of-Clinical-Oncology
SPRINGER. 2005: 467–77
Abstract
A phase I study was performed to determine the maximum tolerated dose (MTD), safety profile and pharmacology of aprinocarsen (ISIS 3521), an antisense oligonucleotide to protein kinase C-alpha, in patients with refractory solid tumors.Fourteen patients were treated in sequential cohorts of aprinocarsen by 24-hour continuous infusion (CIV), weekly, at doses of 6, 12, 18 and 24 mg/kg.One grade 4 toxicity was observed, transient grade 4 neutropenia at 18 mg/kg. Grade 3 toxicities included neutropenia at 12 mg/kg, fever and hemorrhage at 18 mg/kg, and neutropenia, nausea, and chills at 24 mg/kg. Grade 2 toxicities included thrombocytopenia myalgias, chills, headache, fatigue, fever and nausea/vomiting. Mean prothrombin times and activated partial thromboplastin times (aPTT) increased by 10% and 29% from baseline (p = 0.006 and 0.005). Mean complement split products (Bb and C3a) increased 1.6-fold and 3.6-fold (from p = 0.014 and 0.004, respectively). These changes correlated with dose and were transient with recovery to baseline by day 7. Steady state plasma concentrations (Css) of aprinocarsen were achieved within four hours. Css better described changes in aPTT than dose. Clinical evidence of complement activation was not observed.In contrast to 21-day protracted infusion schedules, delivery of aprinocarsen over a 24-hour infusion schedule showed concentration-dependent effects on coagulation and complement, which are consistent with nonclinical toxicology studies performed in the phosphorothioate DNA antisense drug class. These coagulation and complement changes resulted in a maximum tolerated dose 24 mg/kg.
View details for DOI 10.1007/s10637-005-2906-0
View details for PubMedID 16133798
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Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2005; 63 (2): 320-323
Abstract
To determine the efficacy of concurrent 5-fluorouracil (5-FU) and intensity-modulated radiotherapy (IMRT) followed by body stereotactic radiosurgery (SRS) in patients with locally advanced pancreatic cancer.In this prospective study, all patients (19) had pathologically confirmed adenocarcinoma and were uniformly staged. Our treatment protocol consisted of 45 Gy IMRT with concurrent 5-FU followed by a 25 Gy SRS boost to the primary tumor.Sixteen patients completed the planned therapy. Two patients experienced Grade 3 toxicity (none had more than Grade 3 toxicity). Fifteen of these 16 patients were free from local progression until death. Median overall survival was 33 weeks.Concurrent IMRT and 5-FU followed by SRS in patients with locally advanced pancreatic cancer results in excellent local control, but does not improve overall survival and is associated with more toxicity than SRS, alone.
View details for DOI 10.1016/j.ijrobp.2005.07.002
View details for PubMedID 16168826
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Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer
40th Annual Meeting of the American-Society-of-Clinical-Oncology
AMER SOC CLINICAL ONCOLOGY. 2005: 5613–19
Abstract
To investigate the gefitinib, fluorouracil (FU), leucovorin, and oxaliplatin regimen (IFOX) in previously treated patients with metastatic colorectal cancer.Eligible patients had stage IV colorectal adenocarcinoma and had demonstrated progression or intolerance to a prior chemotherapy regimen not including oxaliplatin. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin 85 mg/m2 intravenously (IV) during 2 hours on day 1, hours 0 to 2; leucovorin 200 mg/m2 IV on days 1 and 2, hours 0 to 2; FU 400 mg/m2 IV push on days 1 and 2; and FU 600 mg/m2 IV on days 1 and 2, hours 2 to 24 (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg/d administered orally throughout the 14-day cycle.Twenty-seven patients were enrolled onto the study. The median number of prior chemotherapy regimens was two, and 74% of all patients received prior irinotecan. Nine of the 27 patients (33%) and six of the 20 patients (30%) who had prior FU and irinotecan had a partial response by Response Evaluation Criteria in Solid Tumors Group criteria. Median overall survival was 12.0 months. Median event-free survival was 5.4 months. Grade 3 to 4 toxicities included neutropenia (48%), diarrhea (48%), nausea (22%), and vomiting (15%).IFOX is an active regimen in patients with previously treated metastatic colorectal adenocarcinoma, demonstrating higher response rates than those reported with FOLFOX-4 alone in a similar patient population.
View details for DOI 10.1200/JCO.2005.08.359
View details for PubMedID 16110021
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A phase I trial of irinotecan (CPT-11) with amifostine in patients with metastatic colorectal cancer
INVESTIGATIONAL NEW DRUGS
2005; 23 (3): 241-242
View details for DOI 10.1007/s10637-005-6732-1
View details for Web of Science ID 000228876800006
View details for PubMedID 15868380
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Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma
CANCER
2005; 103 (1): 119-125
Abstract
The hypervascular nature of hepatocellular carcinoma (HCC) is well characterized. Recent data have suggested that thalidomide possesses antiangiogenic and immunomodulatory activity. Therefore, the authors initiated a study to assess the efficacy and toxicity of thalidomide in patients with advanced HCC as primary and secondary endpoints, respectively.Inclusion criteria were unresectable HCC with bidimentionally measurable disease, age > or = 18 years, Eastern Cooperative Oncology Group performance status < or = 2, and adequate organ function. Thalidomide was administered at a starting dose of 200 mg per day in a 100-mg-per-week dose escalation regimen, up to the maximum tolerated dose or to 800 mg per day. Toxicity was monitored according to the National Cancer Institute Common Toxicity Criteria.Twenty-six of 27 patients were eligible and assessable for toxicity and response. A median daily dose of 300 mg was achieved. One patient experienced near-complete recovery of alpha-fetoprotein levels and a partial radiographic response on computed tomography. Two patients had stable disease during the 16-week study period. The median duration of progression-free survival was 42 days. The overall median survival was 123 days. Fatigue and somnolence were the most common side effects, occurring in 81% and 62% of patients, respectively. No Grade 4 hematologic toxicity was observed. Three patients experienced Grade 4 hepatic toxicity (namely, hyperbilirubinemia).With gradual dose escalation, thalidomide was tolerated in most patients with advanced HCC. However, treatment with thalidomide alone was associated with only a modest response in the treatment of HCC.
View details for DOI 10.1002/cncr.20732
View details for Web of Science ID 000226237000015
View details for PubMedID 15565573
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Phase I study of I-131-chimeric(ch) TNT-1/B antibody for the treatment of advanced colorectal cancer
10th Conference on Cancer Therapy with Antibodies and Immunoconjugates
MARY ANN LIEBERT INC. 2004: 528–28
View details for Web of Science ID 000224115300050
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Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2004; 58 (4): 1017-1021
Abstract
To determine the feasibility and toxicity of delivering stereotactic radiosurgery to patients with locally advanced pancreatic cancer.Patients with Eastern Cooperative Oncology Group performance status < or=2 and locally advanced pancreatic cancer were enrolled on this Phase I dose escalation study. Patients received a single fraction of radiosurgery consisting of either 15 Gy, 20 Gy, or 25 Gy to the primary tumor. Acute gastrointestinal toxicity was scored according to the Radiation Therapy Oncology Group criteria. Response to treatment was determined by serial high-resolution computed tomography scanning.Fifteen patients were treated at 3 dose levels (3 patients received 15 Gy, 5 patients received 20 Gy, and 7 patients received 25 Gy). At these doses, no Grade 3 or higher acute gastrointestinal toxicity was observed. This trial was stopped before any dose-limiting toxicity was reached, because the clinical objective of local control was achieved in all 6 evaluable patients treated at 25 Gy.It is feasible to deliver stereotactic radiosurgery to patients with locally advanced pancreatic cancer. The recommended dose to achieve local control without significant acute gastrointestinal toxicity is 25 Gy.
View details for DOI 10.1016/j.ijrobp.2003.11.004
View details for PubMedID 15001240
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A phase II trial of aprinocarsen, an antisense oligonucleotide inhibitor of protein kinase C alpha, administered as a 21-day infusion to patients with advanced ovarian carcinoma
36th Annual Meeting of the American-Society-of-Clinical-Oncology
JOHN WILEY & SONS INC. 2004: 321–26
Abstract
It has been postulated that protein kinase C alpha (PKC-alpha) plays a pivotal role in signal transduction in tumor cancer cells. Aprinocarsen, a 20-base antisense oligonucleotide, has shown ability to inhibit PKC-alpha protein expression and inhibit tumor growth in human xenograft models. In a previous Phase I trial, the authors demonstrated the safety and some evidence of activity in ovarian carcinoma of aprinocarsen administered as a 21-day, continuous, intravenous infusion.In this Phase II trial, 36 patients with advanced ovarian carcinoma were treated with aprinocarsen at a dose of 2 mg/kg per day delivered as a 21-day, continuous, intravenous infusion. The primary objective was to determine the antitumor response, and the secondary objectives were to evaluate toxicity and to evaluate effects on quality of life (QOL).Between September 1997 and December 1999, 36 patients (median age, 58 years) were enrolled in this trial. Patients were stratified into 2 groups: a platinum-sensitive group (n = 12 patients) and a platinum-resistant group (n = 24 patients). All 36 patients were evaluable for toxicity, and 27 patients were fully assessable for antitumor response after 2 cycles of therapy. All patients had received prior treatments. No objective responses were noted in the platinum-sensitive group. In the platinum-resistant group, 1 patient had some evidence of antitumor activity indicated by a decrease in serum CA 125 and stable disease on imaging studies for 8 months. No changes were noted in overall patient ratings for any of the five QOL domains.When it was administered as a single agent, aprinocarsen did not have significant clinical activity in patients with advanced ovarian carcinoma. Further study may be warranted in combination with platinum-based regimens.
View details for DOI 10.1002/cncr.11909
View details for PubMedID 14716767
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The Stanford experience with preoperative chemoradiation using CPT-11 and 5-FU in locally advanced rectal cancer: Toxicities and outcomes
46th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology
ELSEVIER SCIENCE INC. 2004: S417–S418
View details for Web of Science ID 000223854700483
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A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer.
AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
AMER ASSOC CANCER RESEARCH. 2003: 6103S–6103S
View details for Web of Science ID 000187467300140
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Phase I and pharmacokinetic study of BMS-188797, a new taxane analog, administered on a weekly schedule in patients with advanced malignancies
CLINICAL CANCER RESEARCH
2003; 9 (14): 5187-5194
Abstract
The purpose of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary activity of BMS-188797 administered weekly.Patients with advanced malignancies were treated with escalating doses of BMS-188797 on a weekly schedule as a 1-h i.v. infusion. Plasma sampling was performed to characterize the pharmacokinetics of BMS-188797.Eighteen patients with advanced malignancies were enrolled at three dose levels ranging from 35 to 65 mg/m(2). The number of patients evaluated at each dose level was as follows: 35 mg/m(2) (n = 3); 50 mg/m(2) (n = 9); and 65 mg/m(2) (n = 6). At 65 mg/m(2), three of six patients had a DLT (one had grade 4 neutropenia lasting >7 days, and two had grade 3 diarrhea). Expansion of the 50-mg/m(2) dose cohort to nine patients established this dose as the MTD, with one patient experiencing a DLT (grade 4 neutropenia with fever). Two partial responses were observed (lung cancer, 7+ months; ovarian cancer, 6+ months durations), as well as two minor responses (esophageal cancer, 5 months; ovarian cancer, 5 months). Both patients with partial responses had been clinically resistant to paclitaxel. Plasma pharmacokinetic mean values of maximum concentration (C(max)) and area under the curve (AUC(0-48)) increased in a dose-dependent manner within the range of doses used in this study, and in three of four patients, the DLTs correlated with AUC.The MTD and the recommended Phase II dose of weekly BMS-188797 is 50 mg/m(2). The drug demonstrates antitumor activity in taxane-refractory solid tumors and is now being evaluated in combination with carboplatin.
View details for PubMedID 14613998
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Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2003; 55 (1): 132-137
Abstract
CPT-11 sensitizes tumor cells to radiation and in combination therapy with 5-fluorouracil (5-FU) results in enhanced cytotoxicity to metastatic colorectal cancer. We report the results from a Phase II trial of preoperative radiotherapy (RT), CPT-11, and 5-FU for patients with ultrasound-staged T3 rectal cancer.Between April 1999 and August 2001, 32 patients (21 men, 11 women; median age 52 years, range 40-74) with biopsy-proven adenocarcinoma of the rectum were enrolled in the study. All patients underwent endorectal ultrasonography for staging (uT3N0 = 19; uT3N1 = 13; uT2N1 = 1). RT was prescribed to the draining lymph nodes (45 Gy in 1.8-Gy daily fractions) and tumor (50.4 Gy in 1.8-Gy daily fractions). Patients also received concurrent CPT-11 (50 mg/m(2), Days 1, 8, 15, and 22) and 5-FU (200 mg/m(2) daily, 7 d/wk, Days 1-33). Surgical resection was performed 6-10 weeks after completing chemoradiotherapy.Acute toxicity was frequently observed, and 18 patients (56%) required either a chemotherapy dose reduction or RT interruption of >3 days. One patient withdrew because of diarrhea and abdominal cramping (Grade III) after 10 days of treatment. Although no Grade IV toxicity was observed, Grade III diarrhea (n = 9, 28%), mucositis (n = 7, 21%), rectal sores (n = 7, 21%), abdominal cramping (n = 3, 9%) were noted. Of the 32 patients who underwent surgery, 12 had a complete pathologic response. Of the 32 patients, the disease of 23 (71%) was downstaged. The average length of hospitalization was between 5 and 12 days, with 1 patient staying 33 days. All patients were followed for disease-free survival.Although associated with frequent acute toxicity, the regimen is associated with significant tumor "downstaging." Additional patients and longer follow-up are necessary to define the role of this regimen fully.
View details for PubMedID 12504045
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A phase I study of ZD 1839 (Iressa) in combination with oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) in advanced solid malignancies
14th EORTC/NCI/AACR Symposium on Molecular Targets and Cancer Therapeutics
ELSEVIER SCI LTD. 2002: S63–S63
View details for Web of Science ID 000179895700204
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The effect of oral valspodar (psc 833), a modulator of multidrug resistance, on the pharmacokinetics of liposomal doxorubicin.
NATURE PUBLISHING GROUP. 2002: P48–P48
View details for Web of Science ID 000174178600176
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Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound staged T3 rectal cancer
LIPPINCOTT WILLIAMS & WILKINS. 2001: 539–39
View details for Web of Science ID 000172773300063
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Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2001; 98 (15): 8809-8814
Abstract
Most tumor-associated antigens represent self-proteins and as a result are poorly immunogenic due to immune tolerance. Here we show that tolerance to carcinoembryonic antigen (CEA), which is overexpressed by the majority of lethal malignancies, can be reversed by immunization with a CEA-derived peptide. This peptide was altered to make it a more potent T cell antigen and loaded onto dendritic cells (DCs) for delivery as a cellular vaccine. Although DCs are rare in the blood, we found that treatment of advanced cancer patients with Flt3 ligand, a hematopoietic growth factor, expanded DCs 20-fold in vivo. Immunization with these antigen-loaded DCs induced CD8 cytotoxic T lymphocytes that recognized tumor cells expressing endogenous CEA. Staining with peptide-MHC tetramers demonstrated the expansion of CD8 T cells that recognize both the native and altered epitopes and possess an effector cytotoxic T lymphocyte phenotype (CD45RA(+)CD27(-)CCR7(-)). After vaccination, two of 12 patients experienced dramatic tumor regression, one patient had a mixed response, and two had stable disease. Clinical response correlated with the expansion of CD8 tetramer(+) T cells, confirming the role of CD8 T cells in this treatment strategy.
View details for Web of Science ID 000169967000107
View details for PubMedID 11427731
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A phase I trial of doxorubicin, paclitaxel, and valspodar (PSC 833), a modulator of multidrug resistance
34th Annual Meeting of the American-Society-of-Clinical-Oncology
AMER ASSOC CANCER RESEARCH. 2001: 1221–29
Abstract
P-glycoprotein is an efflux pump for many drugs including doxorubicin and paclitaxel. This study evaluated the coadministration of these drugs with the P-glycoprotein inhibitor valspodar (PSC 833) with the aim of determining: (a) maximum tolerated doses (MTDs) of doxorubicin followed by paclitaxel (DP); (b) the MTD of DP combined with PSC 833 (DPV), without and with filgrastim (G-CSF); and (c) the pharmacokinetic interactions of PSC 833 with doxorubicin and paclitaxel.For the first cycle, patients received doxorubicin as a 15-min infusion followed by paclitaxel as a 1-h infusion. For the second cycle, patients received reduced doses of DP with PSC 833 at 5 mg/kg p.o., four times a day for 12 doses.Thirty-three patients with various refractory malignancies were enrolled and assessable. The MTD of DP without PSC 833 was 35 mg/m(2) doxorubicin and 150 mg/m(2) paclitaxel. The MTD of DPV without G-CSF was 12.5 mg/m(2) doxorubicin and 70 mg/m(2) paclitaxel. The dose-limiting toxicity for both DP and DPV was neutropenia without thrombocytopenia. With G-CSF, the MTD for DPV was 20 mg/m(2) doxorubicin and 90 mg/m(2) paclitaxel. No grade 4 nonhematological toxicities were observed. Five partial and two minor tumor remissions were observed. Paired pharmacokinetics with and without PSC 833 revealed substantial drug interactions with both doxorubicin and paclitaxel.PSC 833 can be administered safely with doxorubicin and paclitaxel. The pharmacokinetic profiles of these drugs are significantly affected by PSC 833, requiring approximately 60% dose reductions for equivalent degrees of myelosuppression.
View details for PubMedID 11350887
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Protracted venous infusion 5-fluorouracil with concomitant radiotherapy compared with bolus 5-fluorouracil for unresectable pancreatic cancer
AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS
2001; 24 (2): 155-159
Abstract
Radiation therapy (RT) with concurrent 5-fluorouracil (5-FU) administered by protracted venous infusion (PVI) replaced our prior institutional protocol of RT with bolus administration of 5-FU as standard therapy for unresectable pancreatic cancer in 1994. In this article, we compare the treatment intensity, toxicity, and outcome for patients with unresectable pancreatic cancer treated on these sequential protocols. Fifty-four patients, 27 on each protocol, with biopsy-confirmed pancreatic cancer received chemoradiotherapy. The radiotherapy field included the gross tumor volume and regional lymph nodes to a dose of 45 Gy, followed by "boost" to the gross tumor volume to 54 Gy to 60 Gy. From 1987 to 1994, patients received concurrent 5-FU administered by bolus injection, at a dose of 500 mg/m2 on days 1 to 3 and days 29 to 31 of RT. After December 1994, 5-FU was administered by PVI (200-250 mg/m2) beginning on day 1 and continuing until the completion of RT. The chemotherapy treatment intensity was increased in the group receiving 5-FU by PVI, as evidenced by an increased average weekly and cumulative dose of 5-FU (p < 0.01). The radiotherapy treatment intensity was equivalent between the two groups. The incidence of objectively quantified toxicity was not statistically different between treatment groups. Overall survival remained poor in both treatment groups. With a median follow-up of 18 months (range: 3-30 months) for surviving patients, the 6-month, 1-year, and 2-year survivals for the PVI 5-FU-treated group versus the bolus 5-FU-treated group were 56% versus 52%, 34% versus 18%, and 22% versus 13%, respectively (p = 0.9). Radiotherapy with concomitant 5-FU by PVI results in a greater weekly and total dose of chemotherapy. The method of 5-FU administration (bolus versus PVI) did not change the RT treatment intensity, experienced toxicity, or overall survival.
View details for Web of Science ID 000168186300012
View details for PubMedID 11319291
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Center experience in liver transplantation for hepatocellular carcinoma associated with cirrhosis
18th World Congress of the Transplantation-Society
ELSEVIER SCIENCE INC. 2001: 1490–91
View details for Web of Science ID 000167629900694
View details for PubMedID 11267387
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Preoperative chemoradiation for marginally resectable adenocarcinoma of the pancreas
82nd Annual Meeting of the American-Radium-Society
SPRINGER. 2001: 27–35
Abstract
Only 10% to 20% of patients with pancreatic cancer are considered candidates for curative resection at the time of diagnosis. We postulated that preoperative chemoradiation therapy might promote tumor regression, eradicate nodal metastases, and allow for definitive surgical resection in marginally resectable patients. The objective of this study was to evaluate the effect of a preoperative chemoradiation therapy regimen on tumor response, resectability, and local control among patients with marginally resectable adenocarcinoma of the pancreas and to report potential treatment-related toxicity. Patients with marginally resectable adenocarcinoma of the pancreas (defined as portal vein, superior mesenteric vein, or artery involvement) were eligible for this protocol. Patients received 50.4 to 56 Gy in 1.8 to 2.0 Gy/day fractions with concurrent protracted venous infusion of 5-fluorouracil (250 mg/m2/day). Reevaluation for surgical resection occurred 4 to 6 weeks after therapy. Fifteen patients (9 men and 6 women) completed preoperative chemoradiation without interruption. One patient required a reduction in the dosage of 5-fluorouracil because of stomatitis. Acute toxicity from chemoradiation consisted of grade 1 or 2 nausea, vomiting, diarrhea, stomatitis, palmar and plantar erythrodysesthesia, and hematologic suppression. CA 19-9 levels declined in all nine of the patients with elevated pretreatment levels. Nine of the 15 patients underwent a pancreaticoduodenectomy, and all had uninvolved surgical margins. Two of these patients had a complete pathologic response, and two had microscopic involvement of a single lymph node. With a median follow-up of 30 months, the median survival for resected patients was 30 months, whereas in the unresected group median survival was 8 months. Six of the nine patients who underwent resection remain alive and disease free with follow-up of 12, 30, 30, 34, 39, and 72 months, respectively. Preoperative chemoradiation therapy is well tolerated. It may downstage tumors, sterilize regional lymph nodes, and improve resectability in patients with marginally resectable pancreatic cancer. Greater patient accrual and longer follow-up are needed to more accurately assess its future role in therapy.
View details for Web of Science ID 000167919800010
View details for PubMedID 11309645
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Radiotherapy, concomitant protracted-venous-infusion 5-fluorouracil, and surgery for ultrasound-staged T3 or T4 rectal cancer
36th Annual Meeting of the American-Society-of-Clinical-Oncology
SPRINGER. 2001: 52–58
Abstract
A prospective study was undertaken to evaluate the response and toxicity of neoadjuvant chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer.Since 1995, 30 patients (18 males; median age, 56 (range, 25-83) years) have received preoperative chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer. All patients underwent an endorectal ultrasound, CT scan, and review in our multidisciplinary Gastrointestinal Tumor Board before treatment. All patients had pathology-demonstrated invasive adenocarcinoma of the rectum. Eleven patients were Stage T3N0, 14 were T3N1, and five were T4N1. Patients received radiotherapy to the primary tumor and draining lymph nodes (45 Gy) followed by a tumor boost (50.4-54 Gy). Protracted-venous-infusion 5-fluorouracil (225 mg/m2 per day, seven days per week) was administered throughout treatment. Surgical resection was performed six to ten weeks after completing chemoradiotherapy. Using endorectal ultrasound measurements, the primary tumor was a median of 4 (range, 0-12) cm from the anal verge, encompassed 50 (range, 20-90) percent of the rectal circumference, and was 6 (range, 3-12) cm in diameter.No Grade 4 toxicity was observed during chemoradiotherapy. Three patients experienced Grade 3 toxicity (diarrhea), and four patients required a treatment interruption of greater than three days. All patients completed at least 90 percent of the prescribed radiotherapy dose. All patients underwent surgical resection. Ninety-four percent had clear surgical margins. All pathologic specimens had significant evidence of necrosis, hyalinization, and fibrosis. Thirty-three percent of the specimens had a complete pathologic response (defined as no evidence of viable tumor cells). Of the 19 patients with ultrasound-staged N1 disease, only five had pathologic evidence of nodal involvement after chemoradiotherapy. Of the 25 patients with ultrasound-staged T3 disease, pathologic staging revealed eight with T0, two with T1, five with T2, and ten with T3 disease. Of the five patients with ultrasound-staged T4 disease, pathologic staging revealed two with T0, one with T2, and two with T3 disease. No patient developed progressive disease while on treatment. Two patients have experienced local failure at 6 and 20 months, and one patient failed in the liver at seven months. Twenty-seven patients remain free of disease with a median follow-up of 20 (range, 3-53) months.Our experience suggests that preoperative chemoradiotherapy is well tolerated, down-stages tumors, and sterilizes regional lymph nodes.
View details for Web of Science ID 000166587400015
View details for PubMedID 11805563
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Adjuvant chemoradiotherapy for "unfavorable" carcinoma of the ampulla of vater - Preliminary report
ARCHIVES OF SURGERY
2001; 136 (1): 65-69
Abstract
Adjuvant chemoradiotherapy decreases the risk of local recurrence in patients with adenocarcinoma of the ampulla of Vater and high-risk features. Adjuvant chemoradiotherapy for this population can be administered safely and without much morbidity.Controlled, prospective, single-arm study.Tertiary care referral hospital.From June 1995 to March 1999, 12 patients (7 men and 5 women; median age, 66 years; age range, 38-78 years) with "unfavorable" ampullary carcinoma were treated with adjuvant chemoradiotherapy. All patients underwent pancreaticoduodenectomy, and all pathologic findings were confirmed at Stanford University Medical Center, Stanford, Calif. Unfavorable features were defined as involved lymph nodes (n = 10), involved surgical margins (n = 1), poorly differentiated histological features (n = 3), tumor size greater than 2 cm (n = 6), or the presence of neurovascular invasion (n = 4).Four to 6 weeks after undergoing pylorus-preserving pancreaticoduodenectomy with regional lymphadenectomy, patients began adjuvant chemoradiotherapy consisting of concurrent radiotherapy (45 Gy) and fluorouracil by protracted venous infusion (225-250 mg/m(2) per day, 7 days per week) for 5 weeks.Local recurrence, distant recurrence, overall survival rate, and treatment-related toxic effects.All patients completed the prescribed treatment course. Toxic effects were assessed twice a week during treatment and graded according to the National Cancer Institute Common Toxicity Criteria Scale. One patient required a treatment interruption of 1 week for grade III nausea/vomiting. No grade IV or V toxic effects were observed. At median follow-up of 24 months (range, 13-50 months), 8 of 12 patients were alive and disease free. One patient was alive but had disease recurrence. Three patients died of this disease (liver metastases). Actuarial overall survival at 2 years was 89%, and median survival was 34 months. One surviving patient developed a local recurrence and a lung lesion. Actuarial overall survival and median survival were better than in a parallel cohort with resected high-risk pancreatic cancer (n = 26) treated with the same adjuvant chemoradiotherapy regimen (median survival, 34 vs 14 months; P<.004).Adjuvant chemoradiotherapy for carcinoma of the ampulla of Vater is well tolerated and might improve control of this disease in patients with unfavorable features.
View details for Web of Science ID 000166307500014
View details for PubMedID 11146780
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Adjuvant radiotherapy and concomitant 5-fluorouracil by protracted venous infusion for resected pancreatic cancer
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2000; 48 (5): 1483-1487
Abstract
To assess the toxicity and clinical benefit from adjuvant chemoradiotherapy consisting of protracted venous infusion 5-fluorouracil (5-FU) and concomitant radiotherapy in patients with resected pancreatic cancer.Between 1994 and 1999, 52 patients who underwent pancreaticoduodenectomy received adjuvant chemoradiotherapy. The tumor bed and regional nodes received a dose of 45 Gy in fractions of 1.8 Gy followed by boost to the tumor bed if the surgical margins were involved (total dose, 54 Gy). The patients also received concomitant 5-FU by protracted venous infusion (200-250 mg/m(2)/day, 7 days/week) during the entire radiotherapy course.Fifty-two patients (30 men, 22 women) were enrolled and treated on this protocol. The median age was 63 years (range, 38-78 years), and the median Karnofsky Performance Status was 80 (range, 70-100). Thirty-five percent had involved surgical margins and 59% had involved lymph nodes. All patients completed therapy, and there were no Grade IV/V toxicities observed. With median follow-up of 24 months (range, 3-52 months) for surviving patients, the median survival is 32 months, and 2-year and 3-year survivals are 62%, and 39%, respectively.Radiotherapy with concomitant 5-FU by protracted venous infusion as adjuvant treatment for resected pancreatic cancer is well tolerated. This approach allows for greater dose intensity with reduced toxicity. The median survival of this cohort of patients compares favorably with our earlier experience and other published series.
View details for Web of Science ID 000165604600030
View details for PubMedID 11121652
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Pancreatic tumors show high levels of hypoxia
36th Annual Meeting of the American-Society-of-Clinical-Oncology
ELSEVIER SCIENCE INC. 2000: 919–22
Abstract
Because of the dismal outcomes of conventional therapies for pancreatic carcinomas, we postulated that hypoxia may exist within these tumors.Seven sequential patients with adenocarcinomas of the pancreas consented to intraoperative measurements of tumor oxygenation using the Eppendorf (Hamburg, Germany) polargraphic electrode.All 7 tumors demonstrated significant tumor hypoxia. In contrast, adjacent normal pancreas showed normal oxygenation.Tumor hypoxia exists within pancreatic cancers.
View details for Web of Science ID 000165238800002
View details for PubMedID 11072146
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Liver transplantation for hepatocellular carcinoma and the role of preoperative chemoembolization.
LIPPINCOTT WILLIAMS & WILKINS. 2000: S215–S215
View details for Web of Science ID 000086911800392
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Effect of high-dose cyclosporine on etoposide pharmacodynamics in a trial to reverse P-glycoprotein (MDR1 gene) mediated drug resistance
CANCER CHEMOTHERAPY AND PHARMACOLOGY
2000; 45 (4): 305-311
Abstract
The consequences of using cyclosporine (CsA) therapy to modulate P-glycoprotein-mediated multidrug resistance include increased myelosuppression, hyperbilirubinemia, and altered disposition of the cytotoxin. The purpose of this study was to analyze further the relationship between the degree of leukopenia, and etoposide pharmacokinetic factors.Each patient initially received intravenously-administered etoposide alone (150-200 mg/m2/d x 3). Later it was given in combination with CsA administered at escalating loading doses (range 2-7 mg/kg) as a 2 hour intravenous (IV) infusion followed by a 3 day continuous infusion, at doses ranging from 5 to 21 mg/ kg/day. Serial plasma etoposide concentration-time samples were assayed by high-performance liquid chromatography (HPLC). The area under the curve (AUC) of unbound etoposide was calculated from the total plasma etoposide AUC using a previous published equation [22] where % unbound etoposide = (1.4 x total bilirubin) - (6.8 x serum albumin) + 34.4. The percent decrease in white blood cell (WBC) count and the total or unbound etoposide AUC relationship was fitted to a sigmoid Emax model adapted for paired observations, where: % Decrease in WBC count =E(max) x PDRV(H+Z x delta)/(PDRV50 + Z x beta) + PDRVH + Z x delta In this equation, Z was the variable describing the two treatment groups (0 = no CsA and 1 = CsA). The fitted parameters were PDRV50, the pharmacodynamic response variable (PDRV) producing 50% of the maximal response; parameter beta, which describes the effect of the treatment group on the PDRV50; parameter H (Hill constant), which defines the slope of the response curve and parameter delta, which describes the effect of the treatment group on parameter H.CsA at a median concentration of 1,938 microg/ml resulted in a median increase in the total plasma etoposide AUC by 103% and the calculated unbound plasma etoposide AUC by 104%. This paralleled a 12% greater median percent decrease in WBC count during etoposide + CsA treatment (72% vs. 84%, P = 0.03). The percent decrease in WBC count and total or unbound etoposide AUC relationship was fitted to the sigmoid Emax model. The model using the unbound etoposide AUC described the data adequately (r = 0.790) and was precise, with a mean absolute error of 6.4% (95% confidence interval: -4.9, 7.8). The fitted parameter-estimates suggested that at equivalent unbound etoposide AUC values above 10 microg x h/ml, the sigmoid Emax model predicted a 5% greater WBC count suppression when CsA was added to the treatment regimen.These findings suggest that a small degree of the enhanced myelosuppression observed with CsA combined with etoposide might be attributable to inhibition of P-glycoprotein in bone marrow precursor cells. However, the majority of the effect observed appears to be due to pharmacokinetic interactions, which result in increases in unbound etoposide.
View details for Web of Science ID 000086159200007
View details for PubMedID 10755319
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Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer
CLINICAL CANCER RESEARCH
1999; 5 (11): 3357-3363
Abstract
Protein kinase C (PKC) is an attractive target in cancer therapy. It is overexpressed in a variety of cancers, and nonspecific inhibitors of PKC have demonstrated antitumor activity. Antisense oligonucleotides targeted against PKC-alpha, which have high specificity, can inhibit mRNA and protein expression as well as the growth of tumors in vitro and in vivo. This Phase I study sought to characterize the safety profile and to determine the maximum tolerated dose of antisense to PKC-alpha when administered by continuous infusion in patients. Patients with incurable malignancies received ISIS 3521, a 20-length phosphorothioate oligodeoxynucleotide specific for PKC-alpha. Treatment was delivered over a period of 21 days by continuous i.v. infusion followed by a 7-day rest period. Doses were increased from 0.5 to 3.0 mg/kg/day. Patients continued on the study until evidence of disease progression or unacceptable toxicity was detected. Between August 1996 and September 1997, 21 patients were treated in five patient cohorts. The maximum tolerated dose was 2.0 mg/kg/day. The dose-limiting toxicities were thrombocytopenia and fatigue at a dose of 3.0 mg/kg/day. Pharmacokinetic measurements showed rapid plasma clearance and dose-dependent steady-state concentrations of ISIS 3521. Evidence of tumor response lasting up to 11 months was observed in three of four patients with ovarian cancer. The recommended dose of ISIS 3521 for Phase II studies is 2.0 mg/kg/day when given over a period of 21 days. Side effects are modest and consist of thrombocytopenia and fatigue. Evidence of antitumor activity provides the rationale for Phase II studies in ovarian cancer and other malignancies.
View details for Web of Science ID 000083853200005
View details for PubMedID 10589745
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Chemo-radiotherapy for localized pancreatic cancer: Increased dose intensity and reduced acute toxicity with concomitant radiotherapy and protracted venous infusion 5-fluorouracil
Conference on Overcoming Bad Blood in Cancer Clinical Trials - Tuskegee Trial Revisited
ELSEVIER SCIENCE INC. 1998: 93–99
Abstract
Although concomitant radiation therapy (RT) and bolus 5-Fluorouracil (5-FU) have been shown to improve survival in locally confined pancreatic cancer, most patients will eventually succumb to their disease. Since 1994, we have attempted to improve efficacy by administering 5-FU as a protracted venous infusion (PVI). This study compares treatment intensity and acute toxicity of consecutive protocols of concurrent RT and 5-FU by bolus injection or PVI.Since 1986, 74 patients with resected or locally advanced pancreatic cancer were treated with continuous course RT and concurrent 5-FU by bolus injection (n = 44) or PVI throughout the course of RT (n = 30). Dose intensity was assessed for both 5-FU and radiotherapy. Toxicity endpoints which could be reliably and objectively quantified (e.g., neutropenia, weight loss, treatment interruption) were evaluated.Cumulative 5-FU dose (mean = 7.2 vs. 2.5 gm/m2, p < 0.001) and weekly 5-FU dose (mean = 1.3 vs. 0.5 gm/m2/wk, p < 0.001) were significantly higher for patients receiving PVI 5-FU. Following pancreaticoduodenectomy, 95% of PVI patients maintained a RT dose intensity of > or = 900 cGy/wk, compared with 63% of those receiving bolus 5-FU (p = 0.02). No difference was seen for patients with locally advanced disease (72% vs. 76%, p = n.s.). Grade II-III neutropenia was less common for patients treated with PVI (13% vs. 34%, p = 0.05). Grade II-III thrombocytopenia was uncommon (< or = 3%) in both treatment groups. Mean percent weight loss (3.8% vs. 4.1%, p = n.s.) and weight loss > or = 5% of pre-treatment weight (21% vs. 31%, p = n.s.) were similar for PVI and bolus treatment groups, respectively. Treatment interruptions for hematologic, gastrointestinal or other acute toxicities were less common for patients receiving PVI 5-FU (10% vs. 25%, p = 0.11).Concurrent RT and 5-FU by PVI was well tolerated and permitted greater chemotherapy and radiotherapy dose intensity with reduced hematologic toxicity and fewer treatment interruptions compared with RT and bolus 5-FU. Longer follow-up will be needed to assess late effects and the impact on overall survival.
View details for Web of Science ID 000071164200015
View details for PubMedID 9422563
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Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein
12th Bristol-Myers-Squibb Nagoya International Cancer Treatment Symposium
SPRINGER. 1997: S13–S19
Abstract
Intrinsic and acquired multidrug resistance (MDR) in many human cancers may be due to expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. There is substantial evidence that Pgp is expressed both as an acquired mechanism (e.g., in leukemias, lymphomas, myeloma, and breast and ovarian carcinomas) and constitutively (e.g., in colorectal and renal cancers) and that its expression is of prognostic significance in many types of cancer. Clinical trials of MDR modulation are complicated by the presence of multiple-drug-resistance mechanisms in human cancers, the pharmacokinetic interactions that result from the inhibition of Pgp in normal tissues, and, until recently, the lack of potent and specific inhibitors of Pgp. A large number of clinical trials of reversal of MDR have been undertaken with drugs that are relatively weak inhibitors and produce limiting toxicities at doses below those necessary to inhibit Pgp significantly. The advent of newer drugs such as the cyclosporin PSC 833 (PSC) provides clinicians with more potent and specific inhibitors for MDR modulation trials. Understanding how modulators of Pgp such as PSC 833 affect the toxicity and pharmacokinetics of cytotoxic agents is fundamental for the design of therapeutic trials of MDR modulation. Our studies of combinations of high-dose cyclosporin (CsA) or PSC 833 with etoposide, doxorubicin, or paclitaxel have produced data regarding the role of Pgp in the clinical pharmacology of these agents. Major pharmacokinetic interactions result from the coadministration of CsA or PSC 833 with MDR-related anticancer agents (e.g., doxorubicin, daunorubicin, etoposide, paclitaxel, and vinblastine). These include increases in the plasma area under the curve and half-life and decreases in the clearance of these cytotoxic drugs, consistent with Pgp modulation at the biliary lumen and renal tubule, blocking excretion of drugs into the bile and urine. The biological and medical implications of our studies include the following. First, Pgp is a major organic cation transporter in tissues responsible for the excretion of xenobiotics (both drugs and toxins) by the biliary tract and proximal tubule of the kidney. Our clinical data are supported by recent studies in mdr-gene-knockout mice. Second, modulation of Pgp in tumors is likely to be accompanied by altered Pgp function in normal tissues, with pharmacokinetic interactions manifesting as inhibition of the disposition of MDR-related cytotoxins (which are transport substrates for Pgp). Third, these pharmacokinetic interactions of Pgp modulation are predictable if one defines the pharmacology of the modulating agent and the combination. The interactions lead to increased toxicities such as myelosuppression unless doses are modified to compensate for the altered disposition of MDR-related cytotoxins. Fourth, in serial studies where patients are their own controls and clinical resistance is established, remissions are observed when CsA or PSC 833 is added to therapy, even when doses of the cytotoxin are reduced by as much as 3-fold. This reversal of clinical drug resistance occurs particularly when the tumor cells express the mdr1 gene. Thus, tumor regression can be obtained without apparent increases in normal tissue toxicities. In parallel with these trials, we have recently demonstrated in the laboratory that PSC 833 decreases the mutation rate for resistance to doxorubicin and suppresses activation of mdr1 and the appearance of MDR mutants. These findings suggest that MDR modulation may delay the emergence of clinical drug resistance and support the concept of prevention of drug resistance in the earlier stages of disease and the utilization of time to progression as an important endpoint in clinical trials. Pivotal phase III trials to test these concepts with PSC 833 as an MDR modulator are under way or planned for patients with acute myeloid leukemias, multiple myeloma, and ovarian carcinoma.
View details for Web of Science ID A1997XR32900004
View details for PubMedID 9272128
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Clinical decision making based on radionuclide determined ejection fraction in oncology patients
JOURNAL OF NUCLEAR MEDICINE
1997; 38 (5): 702-705
Abstract
Decreased left ventricular ejection fraction (LVEF) is a relative contraindication for the use of potentially cardiotoxic chemotherapy. A resting LVEF of 50% is usually used as the lower limit of normal values. The decision to change chemotherapy, however, is complex and is affected by many factors, including ejection fraction.To determine how LVEF data were used by clinical oncologists in clinical decision making, we performed a retrospective analysis of patients referred for ejection fraction measurements from the hematology/oncology divisionS of Stanford University from March 1992 through March 1995. The records of 565 patients treated with potentially cardiotoxic chemotherapy were evaluated.LVEFs < 50% were found in 153 patients. The charts of patients with reduced ejection fractions were reviewed to determine if the radionuclide measurement resulted in either discontinuation of the cardiotoxic agent or substitution of a less cardiotoxic drug or mode of administration. These specific changes in therapy occurred in only 43 of the 153 (28%) patients with ejection fractions below 50%; 24 of the 43 (57%) had ejection fractions < or = 40%. Patients with lower ejection fraction values were more likely to have their therapy changed than those with LVEFs close to normal. Patients with ejection fractions < or = 30 generally had cardiotoxic agents discontinued. Of patients who had a resting LVEF < 50% and whose therapy was not changed, 81% had a normal increase in LVEF with exercise.In clinical practice at our institution, ejection fraction < 50% is not used as an absolute contraindication to cardiotoxic chemotherapy. When the LVEF is less than 40%, potentially cardiotoxic therapy is most often discontinued or omitted. Radionuclide evidence of cardiac reserve may account for decisions to continue cardiotoxic agents despite ejection fractions < 50% in the majority of patients. Further study will be needed to establish standard criteria. Reserve function, as measured by the change in ejection fraction from rest to stress may be an important parameter used by oncologists to help select patients for continued therapy in spite of a reduced ejection fraction. Our results argue that use of fixed criteria may be too restrictive.
View details for Web of Science ID A1997WX89600017
View details for PubMedID 9170431
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Pharmacological considerations in the modulation of multidrug resistance
EUROPEAN JOURNAL OF CANCER
1996; 32A (6): 1082-1088
View details for Web of Science ID A1996UT29600020
View details for PubMedID 8763350
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Drug resistance in clinical oncology and hematology. Introduction.
Hematology/oncology clinics of North America
1995; 9 (2): xi-xii
View details for PubMedID 7642462
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CLINICAL-STUDIES WITH MODULATORS OF MULTIDRUG-RESISTANCE
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
1995; 9 (2): 363-382
Abstract
Improved understanding of the mechanisms underlying chemotherapeutic failure has led to new strategies to circumvent drug resistance. Expression of the multidrug transporter, P-glycoprotein (P-gp), is likely to be a significant mechanism contributing to the clinical resistance of some cancers to chemotherapy. Phase I trials of currently available MDR modulators have yielded important pharmacologic principles pertaining to normal tissue P-gp function and its influence on the disposition of MDR-related anticancer drugs. Currently available P-glycoprotein inhibitors lack the potency to completely reverse the MDR phenotype at clinically achievable concentrations. Despite this, encouraging clinical results have been obtained in the hematolymphoid malignancies. As these more potent modulators become available, careful characterization of pharmacologic interactions with MDR-related cytotoxins will be critical to the rational design of Phase II and III studies that will ultimately test the efficacy of MDR modulation.
View details for Web of Science ID A1995QT66400007
View details for PubMedID 7642468
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The reversal of multidrug resistance.
Cancer treatment and research
1995; 78: 45-70
View details for PubMedID 8595147
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MAMMALIAN-CELL SURVIVAL STUDIES CHARACTERIZING MULTIPORT NEGATIVE PI-MESON IRRADIATION WITH THE STANFORD MEDICAL PION GENERATOR (SMPG)
INTERNATIONAL JOURNAL OF HYPERTHERMIA
1994; 10 (3): 361-370
Abstract
Radiobiological measurements have been made under various conditions of muliport pion irradiation using the Stanford Medical Pion Generator (SMPG). Chinese hamster cells (HA-1) were suspended in a tissue-equivalent 25% gelatin/medium solution. Hypoxic and aerobic HA-1 cells were irradiated simultaneously in a cylindrical water tank at either 4 or 16 degrees C. Irradiation at the focus of 60 converging pion beams, at a peak dose rate of 6 rads/min, gave relative biological effectiveness (RBEs) of 2.8, 1.8 and 1.4 at 50, 20 and 5% survival, respectively, and an oxygen enhancement ratio (OER) of 1.7. Plateau irradiation with crossing pion beams, at a peak dose-rate of 3 rads/min, resulted in survival values very close to those obtained with similar doses of 85 kV X-rays. Preliminary studies with large irradiation volumes in broadened pion stopping regions indicate RBEs significantly > 1 for survival > 50%. Supporting microdosimetric data with the SMPG are consistent with the radiobiological results.
View details for Web of Science ID A1994NP47600008
View details for PubMedID 7930802
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PHASE-I TRIAL OF DOXORUBICIN WITH CYCLOSPORINE AS A MODULATOR OF MULTIDRUG-RESISTANCE
JOURNAL OF CLINICAL ONCOLOGY
1994; 12 (4): 835-842
Abstract
To study the effects of cyclosporine (CsA), a modulator of multidrug resistance (MDR), on the pharmacokinetics and toxicities of doxorubicin.Nineteen patients with incurable malignancies entered this phase I trial. Initially patients received doxorubicin alone (60 or 75 mg/m2) as a 48-hour continuous intravenous (i.v.) infusion. Patients whose tumors did not respond received CsA as a 2-hour loading dose of 6 mg/kg and a 48-hour continuous infusion of 18 mg/kg/d with doxorubicin. Target CsA levels were 3,000 to 4,800 ng/mL (2.5 to 4.0 mumol/L). Doxorubicin doses were reduced to 40% of the prior dose without CsA, and then escalated until myelosuppression equivalent to that resulting from doxorubicin alone was observed. Doxorubicin pharmacokinetics were analyzed with and without CsA.Thirteen patients received both doxorubicin alone and the combination of doxorubicin and CsA. Mean CsA levels were more than 2,000 ng/mL for all cycles and more than 3,000 ng/mL for 68% of cycles. Dose escalation of doxorubicin with CsA was stopped at 60% of the doxorubicin alone dose, as four of five patients at this dose level had WBC nadirs equivalent to those seen with doxorubicin alone. Nonhematologic toxicities were mild. Reversible hyperbilirubinemia occurred in 68% of doxorubicin/CsA courses. The addition of CsA to doxorubicin increased grade 1 and 2 nausea (87% v 47%) and vomiting (50% v 10%) compared with doxorubicin alone. There was no significant nephrotoxicity. Paired pharmacokinetics were studied in 12 patients. The addition of CsA increased the dose-adjusted area under the curve (AUC) of doxorubicin by 55%, and of its metabolite doxorubicinol by 350%.CsA inhibits the clearance of both doxorubicin and doxorubicinol. Equivalent myelosuppression was observed when the dose of doxorubicin with CsA was 60% of the dose of doxorubicin without CsA. Understanding these pharmacokinetic interactions is essential for the design and interpretation of clinical trials of MDR modulation, and should be studied with more potent MDR modulators.
View details for Web of Science ID A1994NG39500028
View details for PubMedID 8151326
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Clinical reversal of multidrug resistance.
Cancer treatment and research
1994; 73: 149-165
View details for PubMedID 7710904
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CLINICAL-TRIALS OF MODULATION OF MULTIDRUG-RESISTANCE - PHARMACOKINETIC AND PHARMACODYNAMIC CONSIDERATIONS
2nd national conference on new oncologic agents : Practical applications
WILEY-LISS. 1993: 3502–14
Abstract
A growing body of evidence indicates that expression of the mdr1 gene, which encodes the multidrug transporter, P-glycoprotein, contributes to chemotherapeutic resistance of human cancers. Expression of this protein in normal tissues such as the biliary tract, intestines, and renal tubules suggests a role in the excretion of toxins. Modulation of P-glycoprotein function in normal tissues may lead to decreased excretion of drugs and enhanced toxicities. A clinical trial of etoposide with escalating doses of cyclosporine (CsA) as a modulator of multidrug resistance was performed. CsA was delivered as a 2-hour loading dose followed by a 60-hour intravenous infusion, together with etoposide administered as a short infusion daily for 3 days. Patients received one or more courses of etoposide alone before the combined therapy to establish their clinical resistance to etoposide and to study etoposide pharmacokinetics without and then with CsA. Plasma and urinary etoposide was measured by high-performance liquid chromatography and plasma CsA by a nonspecific immunoassay. Conclusions from the initial phase I trial with the use of CsA as a modulator of etoposide are: (1) Serum CsA steady-state levels of up to 4800 ng/ml (4 microM) could be achieved with acceptable toxicity. (2) Toxicities caused by the combined treatment included increased nausea and vomiting, increased myelosuppression, and hyperbilirubinemia, consistent with modulation of P-glycoprotein function in the blood-brain barrier, hematopoietic stem cell, and biliary tract. Renal toxicity was uncommon, but severe in two patients with steady-state plasma CsA levels above 6000 ng/ml. (3) CsA administration had a marked effect on the pharmacokinetics of etoposide, with a doubling of the area under the concentration-time curve as a result of both decreased renal and nonrenal clearance, necessitating a 50% dose reduction in patients with normal renal function and hepatic function. (4) The recommended dose of CsA is a 6-7 mg/kg loading dose administered as a 2-hour intravenous infusion followed by a continuous infusion of 18-21 mg/kg/day for 60 hours with adjustments in the infusion rate to maintain steady-state serum levels of 3000-4800 ng/ml (2.5-4.0 M). We are performing additional phase I trials combining CsA with single-agent doxorubicin and taxol, and the CsA analog PSC-833 with various multidrug-resistant-related cytotoxins.
View details for Web of Science ID A1993ML14300016
View details for PubMedID 7902206
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REVERSAL OF MULTIDRUG-RESISTANCE TO CANCER-CHEMOTHERAPY
2nd national conference on new oncologic agents : Practical applications
WILEY-LISS. 1993: 3484–88
Abstract
In the past few years, the role of membrane-bound transport genes in human disease has been increasingly recognized and understood. Of these genes, the p170 membrane glycoprotein may function as an outward transport pump for many cancer chemotherapeutic drugs associated with the multidrug resistance phenotype. This article reviews the different classes of the current major modulators of multidrug resistance.
View details for Web of Science ID A1993ML14300013
View details for PubMedID 8242580
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THE MODULATION OF MULTIDRUG-RESISTANCE - CLINICAL-STUDIES AT STANFORD
INTERNATIONAL SYMP ON THE MECHANISM AND NEW APPROACH ON DRUG RESISTANCE OF CANCER CELLS
ELSEVIER SCIENCE PUBL B V. 1993: 255–266
View details for Web of Science ID A1993BZ12G00034
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PHASE-I TRIAL OF ETOPOSIDE WITH CYCLOSPORINE AS A MODULATOR OF MULTIDRUG RESISTANCE
JOURNAL OF CLINICAL ONCOLOGY
1992; 10 (10): 1624-1634
Abstract
To determine the maximum-tolerated dose (MTD) of cyclosporine (CsA) infusion administered with etoposide for 3 days in patients with cancer.Of the 72 registered patients, 26 were treated initially with CsA and etoposide. Forty-six received etoposide alone until disease progression, and 31 of these proceeded to CsA and etoposide. CsA was administered as a 2-hour loading dose (LD) and as a 3-day continuous infusion (CI); doses were escalated from 2 to 8 mg/kg LD and 5 to 24 mg/kg/d CI.Fifty-seven patients were treated with 113 cycles of CsA with etoposide. Steady-state serum CsA levels (nonspecific immunoassay) more than 2,000 ng/mL were achieved in 91% of the cycles at CsA doses > or = 5 mg/kg LD and > or = 15 mg/kg/d CI. The major dose-related toxicity of CsA was reversible hyperbilirubinemia, which occurred in 78% of the courses with CsA levels > 2,000 ng/mL. Myelosuppression and nausea were more severe with CsA and etoposide. Other CsA toxicities included hypomagnesemia, 60%; hypertension, 29%; and headache, 21%. Nephrotoxicity was mild in 12% and severe in 2% of the cycles. Tumor regressions occurred in four patients after the addition of CsA (one non-Hodgkin's lymphoma, one Hodgkin's disease, and two ovarian carcinomas). Biopsy procedures for tumors from three of the four patients who responded were performed, and the results were positive for mdr1 expression.Serum CsA levels of up to 4 mumol/L (4,800 ng/mL) are achievable during a short-term administration with acceptable toxicities when administered in combination with etoposide. The CsA dose that is recommended in adults is a LD of 5 to 6 mg/kg, followed by a CI of 15 to 18 mg/kg/d for 60 hours. CsA blood levels should be monitored and the doses should be adjusted to achieve CsA levels of 2.5 to 4 mumol/L (3,000 to 4,800 ng/mL). Reversible hyperbilirubinemia may be a useful marker of inhibition by CsA of P-glycoprotein function. When used with high-dose CsA, etoposide doses should be reduced by approximately 50% to compensate for the pharmacokinetic effects of CsA on etoposide (Lum et al, J Clin Oncol, 10:1635-1642, 1992).
View details for Web of Science ID A1992JQ71900018
View details for PubMedID 1403040
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DNA DAMAGE DOES NOT APPEAR TO BE A TRIGGER FOR THERMOTOLERANCE IN MAMMALIAN-CELLS
INTERNATIONAL JOURNAL OF RADIATION BIOLOGY
1988; 54 (2): 285-298
Abstract
The hypothesis that DNA damage is the trigger for thermotolerance in mammalian cells was tested in Chinese hamster ovary cells by looking for evidence of thermotolerance after ionizing radiation or ultraviolet light exposure. As previous studies have demonstrated that relatively non-toxic radiation exposures do not induce thermotolerance in mammalian cells (Li et al. 1976), higher doses, comparable to those used in yeast to induce thermotolerance (Mitchel and Morrison 1984), were tested in this study. Doses of this magnitude are lethal to mammalian cells, thereby precluding the use of clonogenic survival as an endpoint. We therefore used three alternative assays which are indicators of the subsequent development of thermotolerance. These were; (a) heat-induced inhibition of total protein synthesis, (b) heat-induced uptake of dansyl lysine, and (c) synthesis of heat shock proteins. Only total protein synthesis revealed evidence of a small degree of thermotolerance which occurred immediately after ionizing radiation exposure. By 4 h postirradiation the tolerance, as measured by this assay, was no longer evident. No evidence of thermotolerance was seen following UV exposure. In addition, when a large radiation dose was given either immediately before or after a heat treatment used to induce thermotolerance, there was no alteration in the level of heat-induced tolerance, despite the extensive number of DNA stand breaks caused by the radiation. Our data therefore suggest that, in mammalian cells, the type of DNA damage caused by ionizing radiation is not the trigger for the induction of thermotolerance.
View details for Web of Science ID A1988P584100013
View details for PubMedID 2900284
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CORRELATION OF MAMMALIAN-CELL KILLING BY HEAT-SHOCK TO INTRAMEMBRANOUS PARTICLE AGGREGATION AND LATERAL PHASE-SEPARATION USING FLUORESCENCE-ACTIVATED CELL SORTING
RADIATION RESEARCH
1987; 112 (2): 351-364
Abstract
Heat shock induces a dose-dependent increase in the fraction of Chinese hamster ovary cells that stain the fluorescent membrane probe N-epsilon-dansyl-L-lysine (DL). Dansyl lysine has previously been shown to select for cholesterol-free membrane domains in phospholipid liposomes. We found that the fraction of cells excluding DL could be closely correlated to cell survival as assayed by 37 degrees C incubation following heat treatment. Fluorescence-activated cell sorting indicated that essentially all of the DL-staining cells were nonviable. Freeze fracture electron microscopy of sorted cells showed that all the cells that stained with DL also had highly suggested intramembranous particle (IMP) aggregation while DL-excluding cells did not. Furthermore, IMP aggregation was shown to occur immediately after heat shock and to precede DL staining. Treatment with other membrane-active agents such as ethanol, amphotericin B, filipin, procaine, and lidocaine (i) induced DL staining that was closely correlated to survival, (ii) induced dramatic cytotoxic sensitization when combined with heat, and (iii) induced aggregated IMPs at relevant cytotoxic concentrations. Several nonmembrane-active agents were examined; none induced DL staining, dramatic cytotoxic sensitization, or IMP aggregation. These results raise the possibility that heat shock inactivates mammalian cells primarily via nonspecific aggregation and denaturation of membrane proteins resulting in a lateral phase separation of membrane components, including the generation of phospholipid domains.
View details for Web of Science ID A1987L131300011
View details for PubMedID 3120236
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INDUCTION OF THERMOTOLERANCE AND EVIDENCE FOR A WELL-DEFINED, THERMOTROPIC COOPERATIVE PROCESS
RADIATION RESEARCH
1982; 89 (2): 361-368
View details for Web of Science ID A1982NA43900014
View details for PubMedID 7063618
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MODIFICATION OF THE THERMAL RESPONSE BY D2O .1. CELL-SURVIVAL AND THE TEMPERATURE SHIFT
RADIATION RESEARCH
1982; 92 (3): 530-540
View details for Web of Science ID A1982PT13800012
View details for PubMedID 7178418
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MODIFICATION OF THE THERMAL RESPONSE BY D2O .2. THERMOTOLERANCE AND THE SPECIFIC-INHIBITION OF DEVELOPMENT
RADIATION RESEARCH
1982; 92 (3): 541-551
View details for Web of Science ID A1982PT13800013
View details for PubMedID 7178419
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Predicting Pancreatic Cancer Resectability and Outcomes Based on an Objective Quantitative Scoring System.
Pancreas
; 48 (5): 622–28
Abstract
To quantitatively assess the probability of tumor resection based on measurements of tumor contact with the major peripancreatic vessels.This is a retrospective cohort study of pancreatic cancer patients treated between January 2001 and December 2015 in a single academic comprehensive cancer center. Radiographic measurements of the circumferential degree and length of solid tumor contact with major peripancreatic vessels were obtained from diagnostic pancreatic protocol computed tomography images and tested for correlation with tumor resection and margin status.Of 294 patients analyzed, 113 (38%) were resected, with 71 (63%) with negative margins. Based on the individual measurements of vascular involvement, a resectability scoring system (RSS) was created. The RSS correlated strongly with resection (P < 0.0001) and R0 resection (P < 0.0001) probabilities. Moreover, the RSS correlated with overall survival (P < 0.0001) and metastasis-free survival (P < 0.0001), being able to substratify resectable (P = 0.022) and unresectable patients (P = 0.014) into subgroups with different prognosis based on RSS scores.Based on a comprehensive and systematic quantitative approach, we developed a scoring system that demonstrated excellent accuracy to predict tumor resection, surgical margin status, and prognosis.
View details for PubMedID 31091207