Bio
Dr. Das specializes in the treatment of thoracic malignancies. She sees and treats patients both at the Stanford Cancer Center and at the Palo Alto VA Hospital. She is Chief of Oncology at the Palo Alto VA and is an active member of the VA national Lung Cancer Working Group and Lung Cancer Precision Oncology Program. In 2023, she was elected President the Association of Northern California Oncologists (ANCO), where she displays her passion for patient advocacy and also for clinician education by helping to organize Bay Area focused continuing medical education programs. She is the VA site director for the Stanford fellowship program and leads the VA thoracic tumor board on a biweekly basis. She has a strong interest in clinical research, serving as a principal investigator for multiple clinical and translational studies at the Palo Alto VA, and also as a co-investigator on all of the lung cancer trials at Stanford. In her free time, she enjoys spending time with her family, traveling, and running.
Clinical Focus
- Thoracic Oncology
- Medical Oncology
Administrative Appointments
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Chief, Oncology, VA Palo Alto Health Care System (2015 - Present)
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Associate Program Director, Oncology Fellowship, Stanford University (2015 - Present)
Boards, Advisory Committees, Professional Organizations
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Member, International Association for the Study of Lung Cancer (IASLC) (2009 - Present)
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Member, American Society of Clinical Oncology (ASCO) (2008 - Present)
Professional Education
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Fellowship, Stanford University Hematology and Oncology Fellowship, CA (2011)
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Board Certification: American Board of Internal Medicine, Medical Oncology (2011)
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Residency: Stanford University Hospital -Clinical Excellence Research Center (2007) CA
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Internship: Stanford University Hospital -Clinical Excellence Research Center (2005) CA
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Medical Education: University of Massachusetts Medical Center (2004) MA
Clinical Trials
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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 1/2 Study to Evaluate MEDI4736
Not Recruiting
This is a multicenter, open-label, first-time-in-human study with a standard 3+3 dose-escalation phase in participants with advanced solid tumors followed by an expansion phase in participants with advanced solid tumors. An exploration cohort has been added to determine the safety using every 4 weeks (Q4W) dosing.
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 Phase II Study to Evaluate the Efficacy and Safety of Oral Ceritinib in Patients With ALK-positive NSCLC Metastatic to the Brain and/or to Leptomeninges
Not Recruiting
This was a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of oral ceritinib treatment was assessed in patients with NSCLC metastatic to the brain and/or to leptomeninges harboring a confirmed ALK rearrangement, using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). If documentation of ALK rearrangement as described above was not locally available, a test to confirm ALK rearrangement was performed by a Novartis designated central laboratory. Patients waited for the central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib.
Stanford is currently not accepting patients for this trial. For more information, please contact Richard A Quick, 650-724-1388.
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A Study of Atezolizumab in Participants With Programmed Death - Ligand 1 (PD-L1) Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Not Recruiting
This multicenter, single-arm study will evaluate the efficacy and safety of Atezolizumab in participants with PD-L1-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). Participants will receive Atezolizumab 1200 milligrams (mg) intravenously every 3 weeks as long as participants are experiencing clinical benefit as assessed by the investigator, that is , in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease progression.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, 650-736-4112.
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An Open-Label, Randomized, Phase 3 Trial of Nivolumab Versus Investigator's Choice Chemotherapy as First-Line Therapy for Stage IV or Recurrent PD-L1+ Non-Small Cell Lung Cancer (CheckMate 026)
Not Recruiting
The purpose of this study is to show that Nivolumab will improve progression free survival in subjects with strongly Stage IV or Recurrent PD-L1+ non-small cell lung cancer when compared to chemotherapy
Stanford is currently not accepting patients for this trial. For more information, please contact Smriti Rai, 650-723-0270.
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Cisplatin and Etoposide With or Without Veliparib in Treating Patients With Extensive Stage Small Cell Lung Cancer
Not Recruiting
This randomized phase I/II trial studies the side effects and best dose of veliparib when given together with or without cisplatin and etoposide and to see how well they work in treating patients with extensive stage small cell lung cancer or large cell neuroendocrine non-small cell lung cancer that has spread to other parts of the body. Drugs used in chemotherapy, such as cisplatin and etoposide, 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. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cisplatin and etoposide with or without veliparib may work better in treating patients with extensive stage small cell lung cancer or metastatic large cell neuroendocrine non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.
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Erlotinib Hydrochloride or Crizotinib and Chemoradiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer
Not Recruiting
This randomized phase II trial studies how well erlotinib hydrochloride or crizotinib with chemoradiation therapy works in treating patients with stage III non-small cell lung cancer. 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. Drugs used in chemotherapy, such as cisplatin, etoposide, 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. It is not yet known whether giving erlotinib hydrochloride is more effective than crizotinib with chemoradiation therapy in treating patients with non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Katie Brown, 650-723-1423.
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Expanded Treatment Protocol With LDK378 in ALK(+) NSCLC
Not Recruiting
Novartis-sponsored, open-label, multi-center, interventional ETP to provide LDK378 to patients with ALK (+)NSCLC, who have been pre-treated with an ALK inhibitor; except in countries where ALK inhibitors are not approved or available. The protocol will further evaluate the safety of LDK378 in patients with ALK(+) 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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Liquid Biopsy With PET/CT Versus PET/CT Alone in Diagnosis of Small Lung Nodules
Not Recruiting
The purpose of this study is to determine if a liquid biopsy, a method of detecting cancer from a blood draw, combined with a PET/CT scan, a type of radiological scan, is better at determining whether a lung nodule is cancerous when compared to a PET/CT scan alone. A PET/CT scan is already used for diagnosis of lung nodules, but its efficacy is uncertain in nodules 6-20 mm in size. Therefore, the PET/CT will be evaluated for its diagnostic ability in lesions this size alone and in combination with a liquid biopsy. Secondarily, a machine learning model will be created to see if the combination of the PET/CT imaging data and the liquid biopsy data can predict the presence of cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Rajesh Shah, MD, 650-493-5000 Ext. 65925.
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MAGE A10ᶜ⁷⁹⁶T for Advanced NSCLC
Not Recruiting
This first time in human study is intended for men and women at least 18 years of age who have advanced lung cancer which has grown or returned after being treated. In particular, it is a study for subjects who have a blood test positive for HLA-A\*02:01 and/or HLA-A\*02:06 and a tumor test positive for MAGE A10 protein expression (protein or gene). This trial is a dose escalation trial that will evaluate 3 doses of transduced cells administered after a lymphodepleting chemotherapy regimen using a 3+3 dose escalation design .The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells. When the MAGE A10ᶜ⁷⁹⁶T cells are available, subjects will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine, followed by the T cell infusion. The purpose of this study is to test the safety of genetically changed T cells and find out what effects, if any, they have in subjects with lung cancer. The study will evaluate three different cell dose levels in order to find out the target cell dose. Once the target cell dose is determined, additional subjects will be enrolled to further test the safety and effects at this cell dose. Subjects will be seen frequently by the Study Physician right after receiving their T cells back and up to first 6 months. After that, subjects will be seen every three months. Subjects will be seen every 6 months by their Study Physician for the first 5 years after the T cell infusion. If the T cells are found in the blood at five years, then the subjects will continue to be seen once a year until the T cells are no longer found in the blood for a maximum of 15 years. If the T cells are no longer found in the blood at 5 years, then the subject will be contacted by the Study Physician for the next 10 years. Subjects who have a confirmed response or clinical benefit ≥4 weeks after the first T-cell infusion and whose tumor continues to express the appropriate antigen target may be eligible for a second infusion. All subjects, completing or withdrawing from the Interventional Phase of the study, will enter a 15-year long-term follow-up phase for observation of delayed adverse events. All subjects will continue to be followed for overall survival during the long-term follow-up phase.
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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Osimertinib and Necitumumab in Treating Patients With EGFR-Mutant Stage IV or Recurrent Non-small Cell Lung Cancer Who Have Progressed on a Previous EGFR Tyrosine Kinase Inhibitor
Not Recruiting
This phase I trial studies the safety, side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back after a period of improvement (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be safe, tolerable in treating patients with EGFR-mutant non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Sukhmani K. Padda, 650-498-7061.
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PDR001 in Combination With Platinum-doublet Chemotherapy and Other Immunology Agents in PD-L1 Unselected, Metastatic NSCLC Patients
Not Recruiting
The primary purpose of this study is to establish the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of PDR001 when administered in combination with platinum-doublet chemotherapy and other immunooncology agent(s) in treatment naive patients with PD-L1 unselected, advanced NSCLC, and to estimate the preliminary anti-tumor activity in this patient population.
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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Pembrolizumab in Patients With Metastatic Non-squamous Non-small Cell Lung Cancer
Not Recruiting
This phase II trial studies how well pembrolizumab works in treating patients with non-squamous non-small cell lung cancer which has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, 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 Richard Quick, 650-723-2983.
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Phase 1/2 Study of X-396, an Oral ALK Inhibitor, in Patients With ALK-positive Non-Small Cell Lung Cancer
Not Recruiting
This is the first human study to use X-396 (ensartinib), a drug being developed for treatment of advanced cancers. The initial purpose of the study is to determine the largest amount of X-396 that can be safely given to humans (the maximum tolerated dose). Once the recommended Phase 2 dose has been determined, an expansion phase will assess the preliminary anti-tumor activity of X-396 in ALK-positive non-small cell lung cancer. The study will also provide early information on how the body handles the drug (pharmacokinetics) and on the efficacy of X-396.
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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Phase 2 Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer
Not Recruiting
This phase 2 trial evaluates how well pegylated irinotecan (NKTR-102) works in treating patients with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or breast cancer (mBC) that has spread to the brain and does not respond to treatment. Pegylated irinotecan 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 Sophie Bertrand, 650-723-4467.
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Safety and Efficacy Study of Abraxane as Maintenance Treatment After Abraxane Plus Carboplatin in 1st Line Stage IIIB / IV Squamous Cell Non-small Cell Lung Cancer
Not Recruiting
Maintenance treatment of advanced stage squamous cell NSCLC. Phase III, randomized, open-label, multi-center study of nab-paclitaxel with best supportive care (BSC) or BSC alone as maintenance treatment after response or stable disease (SD) with nab-paclitaxel plus carboplatin as induction in subjects with stage IIIB/IV squamous cell NSCLC. Subjects who discontinued treatment from the maintenance part for any reason other than withdrawal of consent, lost to follow-up, or death, were entered into a Follow-up period that had a visit 28 days after progression or discontinuation. Those who entered Follow-up without progression continued with follow-up scans according to standard of care (SOC) until documentation of progression of disease. Additionally, subjects were followed for OS by phone approximately every 90 days for a minimum of 18 months, for up to approximately 5 years after the last subject was randomized.
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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Safety, Pharmacokinetic and Preliminary Efficacy Study of AC0010MA in Advanced Non Small Cell Lung Cancer
Not Recruiting
AC0010MA is a new, irreversible, Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor. Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. The molecular mechanism: by irreversible combining the EGFR-RTKs ATP binding site of cell, selectively suppress the activities of EGFR tyrosine kinase phosphorylation, block the signal transduction pathway of EGFR and inhibit the function of ras/raf/MAPK downstream, thus block the tumor cell growth by EGFR induction, and promotes apoptosis. AC0010MA Maleate Capsules has three characters: 1. Irreversible binding to EGFR; 2. Effectively suppresses the tumor cell with EGFR mutant while has no suppression to EGFR wild-type cell; 3. Efficient suppress the tumor cell with EGFR T790M drug-resistant mutation.
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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Screening Protocol for Tumor Antigen Expression Profiling and HLA Typing for Eligibility Determination
Not Recruiting
This screening study is intended for men and women ≥ 18 to ≤ 75 years of age who have advanced solid or hematologic malignancy. The study will assess a subject's human leukocyte antigen (HLA) subtype and tumor antigen expression profile. Based on the results, it will be determined if a subject is eligible to be considered for Adaptimmune sponsored clinical trials testing the safety and efficacy of genetically changed T cells targeting specific tumor antigens. No treatment intervention will occur as part of this screening study. Upon enrollment, subjects will be required to provide a blood sample for HLA subtype analysis. If the results of the analysis match the HLA-A subtypes noted in the inclusion criteria and do not express the HLA subtypes that are exclusionary for the available interventional clinical trial(s), then the subject will be required to provide either an archival tumor specimen or fresh tumor tissue biopsy. The tumor specimen will be screened at a central laboratory for the expression (protein or gene) of multiple antigens which may include, but are not limited to MAGE-A4. Based upon the results of these diagnostic analyses, if eligible, subjects will be referred to an appropriate available interventional clinical trial(s) at the discretion of the Investigator. Following screening, tumor samples will be retained by Adaptimmune for the purpose of developing and validating in vitro diagnostic (IVD) assay(s) for antigen expression profiling which is required for regulatory approval of a new therapeutic product indication.
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 to Assess Safety and Efficacy of Atezolizumab (MPDL3280A) Compared to Best Supportive Care Following Chemotherapy in Patients With Lung Cancer [IMpower010]
Not Recruiting
This is a Phase III, global, multicenter, open-label, randomized study to compare the efficacy and safety of 16 cycles (1 cycle duration=21 days) of atezolizumab (MPDL3280A) treatment compared with best supportive care (BSC) in participants with Stage IB-Stage IIIA non-small cell lung cancer (NSCLC) following resection and adjuvant chemotherapy, as measured by disease-free survival (DFS) as assessed by the investigator and overall survival (OS). Participants, after completing up to 4 cycles of adjuvant cisplatin-based chemotherapy, will be randomized in a 1:1 ratio to receive atezolizumab for 16 cycles or BSC.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
All Publications
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A phase 2 single-arm trial of high-dose precision targeted radiotherapy added to immunotherapy for patients with metastatic non-small cell lung cancer.
International journal of radiation oncology, biology, physics
2024
Abstract
For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS).In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%.Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis.The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease.
View details for DOI 10.1016/j.ijrobp.2024.09.038
View details for PubMedID 39357790
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ROS1-rearranged non-small cell lung cancer: Understanding biology and optimizing management in the era of new approvals.
Current problems in cancer
2024; 53: 101133
Abstract
Rearrangements involving the ROS1 gene are infrequent in non-small cell lung cancer (NSCLC) but represent an important targetable driver alteration. Occurring most commonly in patients with adenocarcinoma who have a light or never smoking history, ROS1 rearrangements can be identified by either fluorescence in-situ hybridization (FISH) or next-generation sequencing techniques. Multiple tyrosine kinase inhibitors (TKIs) are now available for the effective treatment of ROS1-rearranged NSCLC in the metastatic setting including crizotinib, entrectinib, and repotrectinib as first-line therapy options. In addition, newer targeted therapies with increased selectivity for ROS1 over other targets are also emerging. As treatment of the disease continues to evolve, understanding the clinical course of patients with ROS1-rearranged NSCLC as well as the data supporting the latest therapy options is key to timely, effective, and longitudinal care.
View details for DOI 10.1016/j.currproblcancer.2024.101133
View details for PubMedID 39260124
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The performance status gap in immunotherapy for frail patients with advanced non-small cell lung cancer.
Cancer immunology, immunotherapy : CII
2024; 73 (9): 172
Abstract
In advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitor (ICI) monotherapy is often preferred over intensive ICI treatment for frail patients and those with poor performance status (PS). Among those with poor PS, the additional effect of frailty on treatment selection and mortality is unknown.Patients in the veterans affairs national precision oncology program from 1/2019-12/2021 who received first-line ICI for advanced NSCLC were followed until death or study end 6/2022. Association of an electronic frailty index with treatment selection was examined using logistic regression stratified by PS. We also examined overall survival (OS) on intensive treatment using Cox regression stratified by PS. Intensive treatment was defined as concurrent use of platinum-doublet chemotherapy and/or dual checkpoint blockade and non-intensive as ICI monotherapy.Of 1547 patients receiving any ICI, 66.2% were frail, 33.8% had poor PS (≥ 2), and 25.8% were both. Frail patients received less intensive treatment than non-frail patients in both PS subgroups (Good PS: odds ratio [OR] 0.67, 95% confidence interval [CI] 0.51 - 0.88; Poor PS: OR 0.69, 95% CI 0.44 - 1.10). Among 731 patients receiving intensive treatment, frailty was associated with lower OS for those with good PS (hazard ratio [HR] 1.53, 95% CI 1.2 - 1.96), but no association was observed with poor PS (HR 1.03, 95% CI 0.67 - 1.58).Frail patients with both good and poor PS received less intensive treatment. However, frailty has a limited effect on survival among those with poor PS. These findings suggest that PS, not frailty, drives survival on intensive treatment.
View details for DOI 10.1007/s00262-024-03763-w
View details for PubMedID 38954019
View details for PubMedCentralID 9359868
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Teleoncology in the Veterans Health Administration: Models of Care and the Veteran Experience.
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
2024; 44 (3): e100042
Abstract
The Veterans Health Administration (VHA) has pioneered teleoncology to address access challenges faced by Veterans requiring cancer care. This ASCO Educational Book highlights the development of teleoncology programs within the VHA: the local VA Pittsburgh Healthcare System (VAPHS) Virtual Cancer Care Center, the National TeleOncology Program (NTO), and the regional Clinical Resource Hub (CRH) Oncology Program. These initiatives provide oncology care using a hub-and-spoke model, which centralizes expertise at hub sites and reaches Veterans at distant spoke sites through synchronous and asynchronous care. The deployment of these teleoncology programs has resulted in significant benefits, such as decreased travel for Veterans, high levels of patient satisfaction, and improved access to specialized treatments. Despite these advancements, disparities in teleoncology utilization and access to clinical trials persist. This educational manuscript highlights the successes and challenges of tele-oncology within the VHA, underscoring the critical role of telehealth in overcoming access barriers.
View details for DOI 10.1200/EDBK_100042
View details for PubMedID 38870449
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Ensuring precision medicine for veterans with lung cancer: A randomized clinical trial
LIPPINCOTT WILLIAMS & WILKINS. 2024
View details for Web of Science ID 001275557400229
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Novel immunotherapy combinations in neoadjuvant non-small cell lung cancer (NSCLC): a better chance at cure?
Translational lung cancer research
2024; 13 (3): 673-677
View details for DOI 10.21037/tlcr-23-735
View details for PubMedID 38601451
View details for PubMedCentralID PMC11002516
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Randomized Trial of a Volunteer-Led Symptom Assessment Intervention on Documentation, Patient-Reported Outcomes, and Health Care Use Among Veterans With Lung Cancer.
JCO oncology practice
2024: OP2300557
Abstract
PURPOSE: Identification and documentation of Veterans' symptoms are crucial for optimal lung cancer care delivery. The objective of this study was to determine whether a volunteer-led proactive telephone symptom assessment intervention could improve comprehensive symptom documentation.METHODS: Veterans with lung cancer were randomly assigned to usual care (control group) or usual care with proactive symptom assessment in which a peer volunteer made weekly phone calls to assess patient symptoms under nurse practitioner supervision. The primary outcome was oncologist documentation of symptoms in the electronic health record at all clinical visits within 6 months after enrollment. Secondary outcomes included patient satisfaction with decision, patient activation, health-related quality of life (HRQOL), and symptom burden, measured at baseline, and 3, 6, and 9 months after enrollment, and acute care use within 9 months after enrollment.RESULTS: Among 60 Veterans randomly assigned, median (range) age was 70.2 (50-86) years; 57 (95.0%) were male. More intervention participants had oncologist documentation of symptoms than control group participants (24 [77.4%] v seven [24.1%], respectively; odds ratio, 16.46 [95% CI, 4.58 to 59.16]). Intervention group participants had greater improvements over time in HRQOL (expected mean difference, 25.3 [95% CI, 15.00 to 35.70]) and patient activation (expected mean difference, 13.6 [95% CI, 3.79 to 23.39]), lower symptom burden (expected mean difference, -6.39 [95% CI, -15.21 to -2.46]), lower rates of emergency room visits (incidence rate ratio, 0.48 [95% CI, 0.30 to 0.75]), and hospitalizations (incidence rate ratio, 0.47 [95% CI, 0.28 to 0.77]) than control group participants.CONCLUSION: This symptom assessment intervention is an effective strategy for Veterans with lung cancer.
View details for DOI 10.1200/OP.23.00557
View details for PubMedID 38207246
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UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.
Cell reports. Medicine
2024: 101381
Abstract
Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.
View details for DOI 10.1016/j.xcrm.2023.101381
View details for PubMedID 38244540
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Patient Selection and Outcomes for Hypofractionated Accelerated Radiation and Concurrent Chemotherapy for Non-Small-Cell Lung Cancer.
Clinical lung cancer
2023
Abstract
Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection.We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts.Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation CONCLUSION: In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients.
View details for DOI 10.1016/j.cllc.2023.11.008
View details for PubMedID 38065707
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Personalized Accelerated ChEmoRadiation (PACER) for Lung Cancer: Protocol for a Bayesian Optimal Phase I/II Trial.
Clinical lung cancer
2023
Abstract
Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs).Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint.PACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer.
View details for DOI 10.1016/j.cllc.2023.11.004
View details for PubMedID 38040540
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Molecular Distribution of Patients with Non-Small Cell Lung Cancer Eligible for Lung Cancer Screening
ELSEVIER SCIENCE INC. 2023: S102-S103
View details for Web of Science ID 001098831600116
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Systemic Therapy for Small-Cell Lung Cancer: ASCO-Ontario Health (Cancer Care Ontario) Guideline.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2023: JCO2301435
Abstract
To provide evidence-based recommendations to practicing clinicians on the management of patients with small-cell lung cancer.An Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened to conduct a literature search, which included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2022. Outcomes of interest included response rates, overall survival, disease-free survival or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.The literature search identified 95 relevant studies to inform the evidence base for this guideline.Evidence-based recommendations were developed to address systemic therapy options, timing of therapy, treatment in patients who are older or with poor performance status, role of biomarkers, and use of myeloid-supporting agents in patients with small-cell lung cancer.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
View details for DOI 10.1200/JCO.23.01435
View details for PubMedID 37820295
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Crosstalk between small-cell lung cancer cells and astrocytes mimics brain development to promote brain metastasis.
Nature cell biology
2023
Abstract
Brain metastases represent an important clinical problem for patients with small-cell lung cancer (SCLC). However, the mechanisms underlying SCLC growth in the brain remain poorly understood. Here, using intracranial injections in mice and assembloids between SCLC aggregates and human cortical organoids in culture, we found that SCLC cells recruit reactive astrocytes to the tumour microenvironment. This crosstalk between SCLC cells and astrocytes drives the induction of gene expression programmes that are similar to those found during early brain development in neurons and astrocytes. Mechanistically, the brain development factor Reelin, secreted by SCLC cells, recruits astrocytes to brain metastases. These astrocytes in turn promote SCLC growth by secreting neuronal pro-survival factors such as SERPINE1. Thus, SCLC brain metastases grow by co-opting mechanisms involved in reciprocal neuron-astrocyte interactions during brain development. Targeting such developmental programmes activated in this cancer ecosystem may help prevent and treat brain metastases.
View details for DOI 10.1038/s41556-023-01241-6
View details for PubMedID 37783795
View details for PubMedCentralID 6602095
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CNS Control after First-Line Osimertinib in Patients with Metastatic EGFR-Mutant NSCLC.
International journal of radiation oncology, biology, physics
2023; 117 (2S): e110
Abstract
Although osimertinib (osi) has excellent intracranial activity in EGFR-mutant metastatic non-small cell lung cancer (NSCLC), there is no consensus regarding whether to continue osi for central nervous system (CNS) control with second-line chemotherapy (chemo) at the time of systemic progression. We aimed to compare CNS outcomes after first-line osi in patients receiving second-line chemo with or without continuation of osi.We retrospectively reviewed patients with EGFR-mutant NSCLC with brain metastases (BrM) at the time of initiating first-line osi who experienced progression and started second-line chemo. Cumulative incidence of local and distant CNS progression, and extracranial (EC) progression was calculated from time of second-line chemo initiation with death as a competing risk. Overall survival (OS) was analyzed using Kaplan-Meier.We included 52 patients with a median follow up of 9.6 months (range 0.4-36.4). Median OS and CNS progression-free survival (PFS) from the time of starting second-line chemo was 12.5 months (95% CI 8.1-16.9), and 5.3 months (95% CI 3.35-7.26), respectively. The 1-year cumulative incidence of local, distant CNS progression, any CNS progression, and EC progression was 14.4% (95% CI 4.5-24.2), 42.8% (95% CI 22.8-56.8), 42.8% (95% CI 22.8-56.8) and 66.8% (95% CI 53.5-80.2), respectively. After progression on first-line osi, 25 (48.1%) and 27 patients (51.9%) continued and discontinued osi, respectively. Patients who continued osi had significantly higher BrM burden than those who did not, with 17 (68%), 3 (12%), and 5 (20%) versus 26 (96%), 0, and 1 (3.7%) patient having <10 or >11 parenchymal brain lesions, or leptomeningeal disease (LMD) at the time of second line therapy, respectively (p<0.01). In those who continued osi vs those who did not, median OS (10.8 vs 12.5 months; p = 0.37), median intracranial PFS (5.3 vs 4.8 months; p = 0.99), 1-year cumulative incidence of local (8.4% versus 20 % p = 0.26), and 1-year distant CNS progression (24.8% vs 60%; p = 0.08) was not significantly different. CNS complications such as symptomatic, hospitalizations, and steroid initiation for CNS disease, and progression of LMD were not significantly different between the two groups. Eventually, 10 patients underwent salvage RT post first-line osi and median time to salvage RT was 7.8 months (range 2-9.4). Of patients who underwent salvage RT, 2 patients (20%) had continued osi with second-line chemo. Twelve patients (44.4%) who did not continue osi eventually re-started osi for progressive disease.Patients who continued osi had significantly higher BrM tumor burden. Despite these patients being at higher risk for CNS progression, time to CNS progression and incidence of CNS complications were not significantly different in the two cohorts. Patients who discontinued osi were more likely to undergo salvage RT. Continuation of osi may allow patients to defer salvage RT.
View details for DOI 10.1016/j.ijrobp.2023.06.888
View details for PubMedID 37784648
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Understanding Barriers and Facilitators to High-Quality Cancer Care Among Veterans With Lung Cancer: A Qualitative Study.
JCO oncology practice
2023: OP2300228
Abstract
Veteran populations have higher lung cancer incidence and worse overall survival compared with non-Veteran populations. Although recent clinical advancements have reduced lung cancer death rates, these advances are not routinely received among Veteran populations because of multilevel factors, including Veterans' complex comorbidities, limited health literacy, and other economic and social disadvantages. This study aimed to assess Veterans' perspectives regarding their lung cancer care with a specific focus on identifying modifiable barriers to evidence-based care delivery.We conducted 1:1 semistructured interviews with 24 Veterans diagnosed with lung cancer at the Veterans Affairs Palo Alto Health Care System. All interviews were recorded, transcribed, and analyzed using the constant comparative method of qualitative analysis.Four themes emerged. These included (1) social and economic disadvantages can prevent routine delivery of evidence-based cancer care; (2) fragmented care contributes to worsening patient mental and emotional well-being; (3) lack of health system interventions to address limited health literacy inhibits patient engagement in shared decision making regarding diagnosis, genomic and molecular testing, targeted and other treatments, and end-of-life care; and (4) deep appreciation for care and VA trustworthiness facilitates adherence to cancer care recommendations.This study revealed critical gaps in lung cancer care delivery and the role of institution-engendered trust in overcoming barriers in the VA system. Targeted solutions should address the identified barriers to routine, evidence-based lung cancer care delivery among Veterans.
View details for DOI 10.1200/OP.23.00228
View details for PubMedID 37774255
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Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial.
JAMA oncology
2023
Abstract
Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy.To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control.This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3).Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3.Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up.In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects).The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials.ClinicalTrials.gov Identifier: NCT01463423.
View details for DOI 10.1001/jamaoncol.2023.3495
View details for PubMedID 37707820
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Small Cell Lung Cancer: Emerging Targets and Strategies for Precision Therapy.
Cancers
2023; 15 (16)
Abstract
Small cell lung cancer is an aggressive subtype of lung cancer with limited treatment options. Precision medicine has revolutionized cancer treatment for many tumor types but progress in SCLC has been slower due to the lack of targetable biomarkers. This review article provides an overview of emerging strategies for precision therapy in SCLC. Targeted therapies include targeted kinase inhibitors, monoclonal antibodies, angiogenesis inhibitors, antibody-drug conjugates, PARP inhibitors, and epigenetic modulators. Angiogenesis inhibitors and DNA-damaging agents, such as PARP and ATR inhibitors, have been explored in SCLC with limited success to date although trials are ongoing. The potential of targeting DLL3, a NOTCH ligand, through antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapy, has opened up new therapeutic options moving forward. Additionally, new research in epigenetic therapeutics in reversing transcriptional repression, modulating anti-tumor immunity, and utilizing antibody-drug conjugates to target cell surface-specific targets in SCLC are also being investigated. While progress in precision therapy for SCLC has been challenging, recent advancements provide optimism for improved treatment outcomes. However, several challenges remain and will need to be addressed, including drug resistance and tumor heterogeneity. Further research and biomarker-selected clinical trials are necessary to develop effective precision therapies for SCLC patients.
View details for DOI 10.3390/cancers15164016
View details for PubMedID 37627044
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Amivantamab vs Mobocertinib in Exon 20 NSCLC
ONCOLOGY-NEW YORK
2023; 37 (8): 340-342
View details for Web of Science ID 001096527200005
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Are We Getting Closer to the Promise of Cure? New Progress and Future Directions in the Treatment of Early-Stage Non-Small-Cell Lung Cancer.
JCO oncology practice
2023: OP2300170
View details for DOI 10.1200/OP.23.00170
View details for PubMedID 37116106
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Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2023
Abstract
Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFi). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone.We evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any grade and grade-three-plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR + VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone.Treatment with VEGFi + SABR was associated with higher rates of G3+ pulmonary hemorrhage compared to those treated with SABR alone for the overall cohort (3-year incidence: 7.9% vs 0.6%, p<0.01) and those with central tumors (19.1% vs 3.3%, p=0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% vs 45.0%, p = 0.044), but not central non-abutting tumors (0.0% vs 1.3% p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi + SABR compared to VEGFi alone (9.6 vs 1.3%, p=0.04).The combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.
View details for DOI 10.1016/j.jtho.2023.04.007
View details for PubMedID 37085030
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Cost-effectiveness of adjuvant atezolizumab for patients with stage II-IIIA PD-L1+ non-small-cell lung cancer.
Immunotherapy
2023
Abstract
Aim: Atezolizumab improved disease-free survival (DFS) versus best supportive care (BSC) as adjuvant treatment following resection and platinum-based chemotherapy for stage II-IIIA PD-L1+ NSCLC in IMpower010. Materials & methods: This cost-effectiveness study evaluated atezolizumab versus BSC (US commercial payer perspective) using a Markov model with DFS, locoregional recurrence, first- and second-line metastatic recurrence and death health states, and a lifetime time horizon with 3% annual discounting. Results: Atezolizumab provided 1.045 additional quality-adjusted life-years (QALY) at an incremental cost of $48,956, yielding an incremental cost-effectiveness ratio of $46,859/QALY. Scenario analysis showed similar findings in a Medicare population ($48,512/QALY). Conclusion: At a willingness-to-pay threshold of $150,000/QALY and an incremental cost-effectiveness ratio of $46,859/QALY, atezolizumab is cost-effective versus BSC for adjuvant NSCLC treatment.
View details for DOI 10.2217/imt-2022-0311
View details for PubMedID 37021770
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Impact of PD-L1 Status on Survival on Immunotherapy Monotherapy in Real-World Patients with Poor Performance Status: A US Nationwide Veterans Affairs Study
ELSEVIER SCIENCE INC. 2023: E11-E12
View details for Web of Science ID 000989330100021
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Use of Machine Learning and Lay Care Coaches to Increase Advance Care Planning Conversations for Patients With Metastatic Cancer.
JCO oncology practice
2022: OP2200128
Abstract
Patients with metastatic cancer benefit from advance care planning (ACP) conversations. We aimed to improve ACP using a computer model to select high-risk patients, with shorter predicted survival, for conversations with providers and lay care coaches. Outcomes included ACP documentation frequency and end-of-life quality measures.In this study of a quality improvement initiative, providers in four medical oncology clinics received Serious Illness Care Program training. Two clinics (thoracic/genitourinary) participated in an intervention, and two (cutaneous/sarcoma) served as controls. ACP conversations were documented in a centralized form in the electronic medical record. In the intervention, providers and care coaches received weekly e-mails highlighting upcoming clinic patients with < 2 year computer-predicted survival and no prior prognosis documentation. Care coaches contacted these patients for an ACP conversation (excluding prognosis). Providers were asked to discuss and document prognosis.In the four clinics, 4,968 clinic visits by 1,251 patients met inclusion criteria (metastatic cancer with no prognosis previously documented). In their first visit, 28% of patients were high-risk (< 2 year predicted survival). Preintervention, 3% of both intervention and control clinic patients had ACP documentation during a visit. By intervention end (February 2021), 35% of intervention clinic patients had ACP documentation compared with 3% of control clinic patients. Providers' prognosis documentation rate also increased in intervention clinics after the intervention (2%-27% in intervention clinics, P < .0001; 0%-1% in control clinics). End-of-life care intensity was similar in intervention versus control clinics, but patients with ≥ 1 provider ACP edit met fewer high-intensity care measures (P = .04).Combining a computer prognosis model with care coaches increased ACP documentation.
View details for DOI 10.1200/OP.22.00128
View details for PubMedID 36395436
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Characterizing Metastatic Non-Small Cell Lung Cancer Presenting to an Academic Medical Center in an Era of Changing Treatment Paradigms
ELSEVIER SCIENCE INC. 2022: E407
View details for Web of Science ID 000892639301234
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Local Control of Brain Metastases with Osimertinib Alone in Patients with EGFR-Mutant Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2022: E54-E55
View details for Web of Science ID 000892639300120
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Regression of Malignant Pleural Mesothelioma in Absence of Chemotherapy or Surgery: A Case Series.
Clinical lung cancer
2022
View details for DOI 10.1016/j.cllc.2022.10.002
View details for PubMedID 36323592
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Local control of brain metastases with osimertinib alone in patients with EGFR-mutant non-small cell lung cancer.
Journal of neuro-oncology
2022
Abstract
Although osimertinib has excellent intracranial activity in metastatic non-small cell lung cancer (NSCLC) with exon 19 deletion or L858R EGFR alterations, measures of local control of brain metastases are less well-reported. We describe lesion-level outcomes of brain metastases treated with osimertinib alone.We retrospectively reviewed patients with EGFR-mutant NSCLC with untreated brain metastasis measuring ≥ 5 mm at the time of initiating osimertinib. Cumulative incidence of local recurrence in brain (LRiB) was calculated with death as a competing risk, and univariable and multivariable analyses were conducted to identify factors associated with LRiB.We included 284 brain metastases from 37 patients. Median follow-up was 20.1 months. On initial MRI after starting osimertinib, patient-level response was complete response (CR) in 11 (15%), partial response (PR) in 33 (45%), stable disease (SD) in 18 (25%) and progressive disease (PD) in 11 (15%). The 1-year cumulative incidence of LRiB was 14% (95% CI 9.9-17.9) and was significantly different in patients with a CR (0%), PR (4%), and SD (11%; p = 0.02). Uncontrolled primary tumor (adjusted hazard ratio [aHR] 3.78, 95% CI 1.87-7.66; p < 0.001), increasing number of prior systemic therapies (aHR 2.12, 95% CI 1.49-3.04; p < 0.001), and higher ECOG score (aHR 7.8, 95% CI 1.99-31.81; p = 0.003) were associated with LRiB.Although 1-year cumulative incidence of LRiB is < 4% with a CR or PR, 1-year cumulative incidence of LRiB is over 10% for patients with less than a PR to osimertinib on initial MRI. These patients should be followed closely for need for additional treatment such as stereotactic radiosurgery.
View details for DOI 10.1007/s11060-022-04145-x
View details for PubMedID 36227422
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Understanding the barriers and experiences of veterans with lung cancer
LIPPINCOTT WILLIAMS & WILKINS. 2022: 160
View details for Web of Science ID 000891944700160
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Early Outcomes and Toxicity with Concurrent Chemotherapy and Hypofractionated Radiation Therapy in Patients with Non-Small Cell Lung Cancer
LIPPINCOTT WILLIAMS & WILKINS. 2022: S44
View details for Web of Science ID 000847787800093
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The Impact of Current Smoking Status at Initiation of Immune Checkpoint Inhibitor Therapy on Tumor Mutation Burden and Survival
ELSEVIER SCIENCE INC. 2022: S359-S360
View details for Web of Science ID 000858678101363
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Cost-Effectiveness of Atezolizumab for Adjuvant Treatment of Patients with Stage II-IIIA PD-L1+Non-small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2022: S253
View details for Web of Science ID 000858678100415
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Improving Supportive Care for Patients with Thoracic Cancer
ELSEVIER SCIENCE INC. 2022: S261
View details for Web of Science ID 000858678100429
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Improving supportive care for patients with Thoracic Malignancies - A randomized controlled trial.
Contemporary clinical trials communications
2022; 28: 100929
Abstract
Veterans have higher lung cancer incidence and mortality rates than civilians. Frequently, Veterans with lung cancer suffer from undertreated symptoms due to complex comorbidities, limited social support, and reluctance in discussing symptoms with their oncologists. Evidence supports proactive symptom screening among civilians with cancer; however, no studies to date have evaluated whether Veteran volunteer-led proactive symptom screening is feasible and effective among Veterans with lung cancer. The "Improving Supportive Care for Patients with Thoracic Malignancies" study was co-developed by a pre-established Veteran and Family Advisory Board. Veterans with lung cancer are randomized in a 1:1 allocation to either a 9-month intervention combined with usual oncology care (intervention group) or usual oncology care alone (control group). A Veteran volunteer is assigned to all Veterans in the intervention group and conducts weekly symptom assessments using validated symptom surveys and reviews all symptom scores with an oncology nurse practitioner. The primary outcome is to evaluate whether the intervention improves documentation of symptoms at 6 months post-enrollment among Veterans in the intervention group as compared with the control group. Secondary outcomes include changes in patient-reported outcomes (i.e., symptom burden, patient activation, patient satisfaction with decision, health-related quality of life) and differences in acute care use (i.e., emergency department visits, hospitalizations) from baseline (time of enrollment in the study) to 3-, 6-, and 9-months post enrollment. This study addresses a significant concern expressed by Veterans and their caregivers. Findings can advance our understanding of how to improve symptom-burden among Veterans with lung cancer. ClinicalTrials.gov Registration #NCT03216109.
View details for DOI 10.1016/j.conctc.2022.100929
View details for PubMedID 35669484
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Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer.
Practical radiation oncology
2022
Abstract
Stereotactic ablative radiotherapy (SABR) results in high rates of primary tumor control for early-stage non-small cell lung cancer (NSCLC). For patients with isolated hilar or mediastinal nodal recurrences (INR) after SABR, the optimal salvage treatment strategy is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and to describe patterns of care and treatment outcomes after salvage therapy.This retrospective cohort study included 342 patients with Stage T1-3N0M0 NSCLC treated with definitive SABR from 2003-2018. We evaluated the incidence of INR and baseline factors between patients who did and did not experience INR. Among patients who experienced INR, we described treatment patterns and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method.With a median follow-up of 3.3 years, the 3-year INR rate was 10.6% (6.6% -13.4%). Among the 34 patients experiencing INR, the 3-year rates of OS and PFS were 39.3% (24.4 - 63.3%) and 26.7% (14.1 - 50.3%), respectively. The 34 patients with INR were treated with RT alone (26.7 %), concurrent chemoradiotherapy (CRT) (43.3 %), chemotherapy alone (13.3%), or observation (16.7%). CRT had the best survival outcomes with a 3-year OS and PFS of 81.5% (61.1 - 100.0%) and 63.9% (40.7 - 100.0%), respectively. Of the patients treated with salvage RT or CRT, 14.3% experienced grade 3 toxicity with no patients having grade 4+ toxicity.INR occurred in approximately 10% of patients treated with SABR for early-stage NSCLC. The highest rates of OS an PFS among patients with INR were observed in those treated with salvage chemoradiotherapy.
View details for DOI 10.1016/j.prro.2022.06.013
View details for PubMedID 35858658
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Characterization of ERBB2 (HER2) Alterations in Metastatic Non-small Cell Lung Cancer and Comparison of Outcomes of Different Trastuzumab-based Regimens.
Clinical lung cancer
2022
Abstract
About 3%-5% of mNSCLC have ERBB2 (HER2) alterations, but currently, there are no FDA-approved targeted therapies for this indication. We compared treatment response between trastuzumab-based and non-targeted regimens in ERBB2-mutant mNSCLC.This retrospective, single-institution study included patients with mNSCLC with ERBB2 alterations identified by next-generation sequencing. Best overall response was determined using Response Evaluation Criteria in Solid Tumors 1.1.We identified 3 groups of patients: ERBB2-mutant/EGFR-wildtype mNSCLC (n = 33), ERBB2-amplified/EGFR-wildtype mNSCLC without concurrent ERBB2 mutations (n = 6), and ERBB2-altered/EGFR-mutant mNSCLC (n = 8). Observed mutations included A775_G776insYVMA (n = 23), Gly778_Pro780dup (n = 4), Ser310Phe (n = 3), and others (n = 5). Among the 33 with ERBB2-mutant/EGFR-wildtype mNSCLC, those with and without A775_G776insYVMA had significantly different median overall survival (OS) of 17.7 and 52.9 months, respectively (Cox regression multivariable HR: 5.03, 95% CI: 1.37-18.51, P = .02). In those with mNSCLC with A775_G776insYVMA, trastuzumab-based therapies were associated with greater OS (20.3 vs. 9.8 months; multivariable HR: 0.19, 95% CI: 0.04-0.87, P = .032). Objective response and disease control rates (median tumor size change) in the 33 patients with ERBB2-mutant/EGFR-wildtype mNSCLC were 40.0% and 80.0% (-35.8%), respectively, for patients treated with trastuzumab deruxtecan; 0% and 30.0% (-5.2%) for trastuzumab emtansine; and 7.1% and 50.0% (-13.0%) for trastuzumab/chemotherapy combinations.In ERBB2-mutant/EGFR-wildtype mNSCLC, while most trastuzumab-based regimens had modest activity in this real-world analysis, trastuzumab deruxtecan had highest response rates and best tumor size reduction. Receipt of any trastuzumab-based regimen was associated with greater OS with A775_G776insYVMA. There remains an unmet need for approved targeted therapies for ERBB2-mutant/EGFR-wildtype NSCLC.
View details for DOI 10.1016/j.cllc.2022.05.015
View details for PubMedID 35753988
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Improving supportive care for patients with thoracic cancer.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680300576
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Characterization of Metastatic Non-Small Cell Lung Cancer and Oligometastatic Incidence in an Era of Changing Treatment Paradigms.
International journal of radiation oncology, biology, physics
2022
Abstract
Due to the limitations of current staging systems and evolving definitions, there are limited data on oligometastatic non-small cell lung cancer (NSCLC) epidemiology. The purpose of this study is to evaluate metastatic disease burden and the incidence of oligometastatic disease using recent clinical trial edibility criteria.A cohort of patients with metastatic NSCLC, diagnosed from 2016 to 2019, were randomly sampled from a curated tumor registry. Definitions for oligometastatic disease were obtained from relevant clinical trials. The Stanford Cancer Institute Research Database (SCIRDB) was used to identify baseline patient factors, systemic and local therapy, extent and location of metastatic lesions, and survival outcomes.Among 120 patients presenting with metastatic NSCLC, the majority had de novo metastatic disease (75%) with a median of 4 metastatic lesions involving 3 organ systems. 37.5% would have been eligible for at least one oligometastatic trial with 28.3% meeting criteria for MDACC, 20.0% for NRG-LU002, 6.7% for SINDAS and 16.7% for SABR-COMET. By adding malignant pleural effusions (MPE) and early progression as exclusionary criteria, only 54.1% of patients with ≤3 synchronous metastases were eligible for consideration of local therapy. Early progression on systemic therapy was associated with worse survival (10.0 vs. 42.4 months, p < 0.001), whereas presence of MPE was not. Of those tumors identified as oligometastatic, 44.4% received local therapy and 28.9% underwent ablative therapy to all sites. There was a trend towards greater overall survival (44.4 vs 24.9 months, p=0.055) and progression free survival (8.0 vs. 5.4 months, p=0.06) in patients meeting eligibility for at least one oligometastatic trial.Around 48% of patients with metastatic NSCLC had ≤3 metastases at presentation and 28% met clinical trial criteria for oligometastatic disease. Future research is needed to better define the oligometastatic state and identify patients most likely to benefit from local therapy.
View details for DOI 10.1016/j.ijrobp.2022.04.050
View details for PubMedID 35654305
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Biological and clinical correlates of the patient health questionnaire-9: exploratory cross-sectional analyses of the baseline health study.
BMJ open
2022; 12 (1): e054741
Abstract
We assessed the relationship between the Patient Health Questionnaire-9 (PHQ-9) at intake and other measurements intended to assess biological factors, markers of disease and health status.We performed a cross-sectional analysis of 2365 participants from the Baseline Health Study, a prospective cohort of adults selected to represent major demographic groups in the USA. Participants underwent deep phenotyping on demographic, clinical, laboratory, functional and imaging findings.Despite extensive research on the clinical implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and other measures of health and disease; we sought to better understand this relationship.None.Cross-sectional measures of medical illnesses, gait, balance strength, activities of daily living, imaging and laboratory tests.Compared with lower PHQ-9 scores, higher scores were associated with female sex (46.9%-66.7%), younger participants (53.6-42.4 years) and compromised physical status (higher resting heart rates (65 vs 75 bpm), larger body mass index (26.5-30 kg/m2), greater waist circumference (91-96.5 cm)) and chronic conditions, including gastro-oesophageal reflux disease (13.2%-24.7%) and asthma (9.5%-20.4%) (p<0.0001). Increasing PHQ-9 score was associated with a higher frequency of comorbidities (migraines (6%-20.4%)) and active symptoms (leg cramps (6.4%-24.7%), mood change (1.2%-47.3%), lack of energy (1.2%-57%)) (p<0.0001). After adjustment for relevant demographic, socioeconomic, behavioural and medical characteristics, we found that memory change, tension, shortness of breath and indicators of musculoskeletal symptoms (backache and neck pain) are related to higher PHQ-9 scores (p<0.0001).Our study highlights how: (1) even subthreshold depressive symptoms (measured by PHQ-9) may be indicative of several individual- and population-level concerns that demand more attention; and (2) depression should be considered a comorbidity in common disease.NCT03154346.
View details for DOI 10.1136/bmjopen-2021-054741
View details for PubMedID 34983769
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Chemotherapy Plus Immunotherapy Versus Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone in EGFR-Mutant NSCLC After Progression on Osimertinib.
Clinical lung cancer
2021
Abstract
INTRODUCTION: Patients with EGFR-mutant lung cancer who have had disease progression on osimertinib commonly receive platinum doublet chemotherapy, but whether adding immunotherapy or bevacizumab provides additional benefit is unknown.MATERIALS AND METHODS: This was a retrospective analysis at 2 university-affiliated institutions. Patients with EGFR-mutant lung cancer who had progression on osimertinib and received next-line therapy with platinum doublet chemotherapy (chemo), platinum doublet chemotherapy plus immunotherapy (chemo-IO), or platinum doublet chemotherapy plus bevacizumab (chemo-bev), were identified; patients who continued osimertinib with these regimens were included. Efficacy outcomes including duration on treatment (DOT) and overall survival (OS) from the start of chemotherapy were assessed. Associations of treatment regimen with outcomes were evaluated using adjusted Cox regression models, using pairwise comparisons between groups.RESULTS: 104 patients were included: 57 received chemo, 12 received chemo-IO, and 35 received chemo-bev. In adjusted models, patients who received chemo-IO had worse OS than did those who received chemo (hazard ratio (HR) 2.66, 95% CI 1.25-5.65; P= .011) or those who received chemo-bev (HR 2.37, 95% CI 1.09-5.65; P= .030). A statistically significant difference in OS could not be detected in patients who received chemo-bev versus those who received chemo (HR 1.50, 95% CI 0.84-2.69; P= .17).CONCLUSION: In this retrospective study, giving immunotherapy with platinum doublet chemotherapy after progression on osimertinib was associated with a worse OS compared with platinum doublet chemotherapy alone. Platinum doublet chemotherapy without immunotherapy (with consideration of continuation of osimertinib, in selected cases) is a reasonable choice in this setting, while we await results of clinical trials examining optimal next-line chemotherapy-based regimens in EGFR-mutant lung cancer.
View details for DOI 10.1016/j.cllc.2021.11.001
View details for PubMedID 34887193
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Impact of Facility Treatment Volume on Stereotactic Ablative Radiotherapy (SABR) Outcomes in Early-Stage Non-Small Cell Lung Cancer (NSCLC).
International journal of radiation oncology, biology, physics
2021; 111 (3S): e447
Abstract
PURPOSE/OBJECTIVE(S): Prior research suggests that radiation oncologist provider experience may influence outcomes for radiation treatment modalities requiring greater technical expertise for given disease sites. We investigated whether institution treatment volume (TV) for SABR technique impacted survival outcomes for patients with NSCLC.MATERIALS/METHODS: We conducted a retrospective cohort study using the Veteran's Affairs Informatics and Computing Infrastructure (VINCI) database to identify patients who underwent treatment for NSCLC between 2012 and 2017 at Veteran's Health Administration Medical Centers (VHAMCs). Patients were included in the cohort if they had tumor (T) stage 1 or 2 disease, node negative (N0) disease, and underwent SABR radiation treatment based on associated Current Procedural Terminology codes. We conducted univariate and multivariate analyses for overall survival (OS) and cause-specific survival (CSS) using Cox regression models accounting for age, sex, race, histology, T stage, tobacco history, ECOG status, and VHAMC facility TV. TV was calculated as the total number of SABR treatments performed per facility over the study period and was categorized into high and low volume groups based on a median TV cutoff.RESULTS: The observational cohort included N = 433 patients with early-stage NSCLC who underwent treatment with SABR across 25 VHAMC facilities. Most patients (83.1%) had T stage 1 disease, and nearly equal proportions had SCC (31.2%) and adenocarcinoma (32.5%) histologies, with the remaining having clinical diagnoses of NSCLC. Median facility TV was 29 SABR treatments (interquartile range 19-33). Median follow up was 657 days. Estimated 2-year overall and cause-specific survival rates were 78.4% (95% CI: 73.9% - 82.1%) and 87.0% (95% CI: 83.2% - 90.0%), respectively. On univariate analysis, high versus low facility TV was not significantly associated with OS (hazard ratio (HR) 1.08, 95% CI: 0.74-1.58) or CSS (HR 1.06, 95% CI: 0.65 - 1.73). Similarly, facility volume was not associated with OS or CSS on multivariate analysis. In a sensitivity analysis, facility volume was not associated with survival outcomes when treated as a continuous variable. Covariates associated with decreased OS included male sex (HR 4.5, P < 0.05), age over 65 (HR 1.77, P < 0.05), ECOG status 2 or greater (HR 1.94, P < 0.05), SCC histology (HR 1.66, P < 0.05), and T stage 2 disease (HR 1.68, P < 0.05).CONCLUSION: In this observational cohort of patients treated at VHAMCs, facility TV was not associated with survival outcomes for early-stage NSCLC radiation treatment using SABR technique. Research is ongoing to account for factors including baseline pulmonary function, comorbidities, and variations in institutional treatment patterns such as propensity for treatment with surgery versus radiation.
View details for DOI 10.1016/j.ijrobp.2021.07.1262
View details for PubMedID 34701476
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Impact of Facility Treatment Volume on Stereotactic Ablative Radiotherapy (SABR) Outcomes in Early-Stage Non-Small Cell Lung Cancer (NSCLC)
ELSEVIER SCIENCE INC. 2021: E447
View details for Web of Science ID 000715803800920
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A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR)
ELSEVIER SCIENCE INC. 2021: S89-S90
View details for Web of Science ID 000715803801515
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Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2021: E435
View details for Web of Science ID 000715803800895
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Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents
ELSEVIER SCIENCE INC. 2021: E423
View details for Web of Science ID 000715803800868
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A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR).
International journal of radiation oncology, biology, physics
2021; 111 (3S): S89-S90
Abstract
PURPOSE/OBJECTIVE(S): Stereotactic ablative radiotherapy (SABR) is an effective treatment for lung tumors, but can result in toxicity such as chest wall pain and life-threatening damage to central lung structures. We hypothesized that while larger tumors require higher dose, small tumors up to 10cc in volume can be controlled with biologically effective dose < 100Gy. In this phase II single-arm trial, we tested the hypothesis that individualizing lung SABR dose and fractionation to tumor size, location, and histology would result in excellent local control with acceptable toxicity. The trial was conducted at two centers in the United States and Japan (NCT# redacted for blinded review).MATERIALS/METHODS: Patients in three groups were enrolled: initial diagnosis of non-small cell lung cancer (NSCLC), AJCC 7th edition stage T1-3 N0 M0 (group 1); new primary NSCLC with history of NSCLC, or multiple synchronously diagnosed NSCLCs (group 2); and lung metastases from NSCLC or another primary site (group 3). Up to four tumors could be treated with once-daily SABR. There were six dose/fractionation schedules used, depending on gross tumor volume (≤10cc, 10-30cc, > 30cc) and location (peripheral vs. central). Larger tumors received higher dose and central tumors generally received lower dose per fraction. Dose ranged from 25Gy in one fraction for 0-10cc peripheral tumors to 60Gy in 8 fractions for > 30cc central tumors. Colorectal cancer metastases were treated to higher dose, at least 50Gy in 4 fractions. The primary endpoint was per-group cumulative incidence of local recurrence at 1 year (recurrence of treated tumor within same lobe), with distant recurrence and death as competing risks. Treated tumor recurrence (recurrence with epicenter within 1cm of PTV) and toxicity were also analyzed.RESULTS: A total of 217 patients were enrolled from 2011-2018 (some patients were enrolled multiple times). Median age was 72, 59% were male, and 69% were current/former smokers. There were 240 treatment courses and 285 tumors treated (range 1-3 tumors per course). 211 tumors were peripheral and 74 were central. Tumor size distribution was: ≤10cc, 74%; 10-30cc, 19%; > 30cc, 7%. The most common dose was 25Gy in one fraction (158 tumors). Median follow-up was 30 months (range 2-95). Median overall survival was 57 months. Local recurrence data are currently being updated and will be presented at the meeting. The rate of grade 2 or higher pneumonitis was 16/217 (7%) and grade 3 or higher pneumonitis was 3/217 (1%). The rate of grade 2 or higher chest wall pain was 13/217 (6%). One patient had a grade 5 adverse event, developing pulmonary hemorrhage that was possibly related to radiotherapy, 17 months after treatment of a large central NSCLC.CONCLUSION: Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile.
View details for DOI 10.1016/j.ijrobp.2021.07.212
View details for PubMedID 34700657
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Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer.
International journal of radiation oncology, biology, physics
2021; 111 (3S): e435
Abstract
PURPOSE/OBJECTIVE(S): Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR.MATERIALS/METHODS: This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test.RESULTS: Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n = 214), T2 (25.4%, n = 87) and T3 (12.0%, n = 41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 - 12.4) and 10.1 (6.8 -13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P = 0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n = 8), chemotherapy and RT (CRT) (43.3 %, n = 13), chemotherapy alone (13.3%, n = 4) or observation (16.7%, n = 5). RT regimens included standard fractionation (38.0%, n = 8), hypofractionation (52.4%, n = 11) or SABR (9.5%, n = 2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 - 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P < 0.01) and PFS (2 year est: 63.9 vs 0 %, P < 0.01) over RT alone. Similarly, CRT was associated with improved OS (91.7 vs 25.0 %, P < 0.01) and PFS (63.9 vs 0%, P < 0.01) over chemotherapy alone. Median follow-up time after INR was 21.7 months.CONCLUSION: INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation.
View details for DOI 10.1016/j.ijrobp.2021.07.1235
View details for PubMedID 34701446
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Impact of Tumor Suppressor Gene Co-Mutations on Differential Response to EGFR TKI Therapy in EGFR L858R and Exon 19 Deletion Lung Cancer.
Clinical lung cancer
2021
Abstract
BACKGROUND: In most studies, patients with EGFR L858R mutant non-small cell lung cancer (NSCLC) have a shorter duration of response to EGFR tyrosine kinase inhibitor (TKI) therapy than do patients with EGFR exon 19 deletion NSCLC. The role that co-mutations play in this observation is unknown.METHODS: We performed a single-institution retrospective analysis of patients with EGFR-mutant NSCLC (exon 19 deletion or L858R mutation) who received frontline EGFR TKI for metastatic disease between 2014 and 2019, and who had STAMP next-generation sequencing (NGS), a 130-gene platform. Time to treatment failure (TTF) and overall survival were calculated using Cox models adjusted for age, race, and brain metastases. Co-mutations in key tumor suppressor genes (TP53, RB1, KEAP1, CDKN2A, or CTNNB1) were identified and their effects on outcomes were evaluated. Analyses were stratified according to receipt of osimertinib versus nonosimertinib as frontline EGFR TKI.RESULTS: Of 137 patients, 72 (57%) had EGFR exon 19 deletions and 65 (43%) had EGFR L858R mutations. Median TTF and OS on frontline TKI was shorter for the L858R cohort versus the exon 19 deletion cohort in univariate analysis. In adjusted models, this difference persisted for TTF but was no longer significant for OS. The difference in TTF in L858R mutant tumors was driven by the presence of co-mutations in key tumor suppressor genes.CONCLUSION: Patients with metastatic NSCLC with mutations in EGFR L858R had shorter TTF on frontline TKI compared to patients with EGFR exon 19 deletions. Co-mutations in tumor suppressor genes may play an important role in the differential response to TKI therapy.
View details for DOI 10.1016/j.cllc.2021.09.004
View details for PubMedID 34838441
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Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents
LIPPINCOTT WILLIAMS & WILKINS. 2021: S105
View details for Web of Science ID 000701779700169
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Advances in Treatment of Recurrent Small Cell Lung Cancer (SCLC): Insights for Optimizing Patient Outcomes from an Expert Roundtable Discussion.
Advances in therapy
2021
Abstract
Second-line treatment options for patients with relapsed, extensive-stage small cell lung cancer (ES-SCLC) are limited, and even with currently available treatments, prognosis remains poor. Until recently, topotecan (a topoisomeraseI inhibitor) was the only drug approved by the United States (US) Food and Drug Administration (FDA) for the management of ES-SCLC following progression after first-line treatment with etoposide plus a platinum derivative (EP; carboplatin preferred). With the most recent approval of EP plus a programmed death ligand1 (PD-L1) inhibitor, there are now more therapeutic options for managing ES-SCLC. A number of novel agents have emerging data for activity in relapsed ES-SCLC, and single-agent lurbinectedin (an alkylating drug and selective inhibitor of oncogenic transcription and DNA repair machinery in tumor cells) has conditional FDA approval for use in this patient population. Trilaciclib, a short-acting cyclin-dependent kinase4/6 (CDK4/6) inhibitor, has also been recently approved as a supportive intervention for use prior to an EP or a topotecan-containing regimen to diminish the incidence of chemotherapy-induced myelosuppression. The current review is based on a recent expert roundtable discussion and summarizes current therapeutic agents and emerging data on newer agents and biomarkers. It also provides evidence-based clinical considerations and a treatment decision tool for oncologists treating patients with relapsed ES-SCLC. This paper discusses the importance of various factors to consider when selecting a second-line treatment option, including prior first-line treatment, available second-line treatment options, tumor platinum sensitivity, and patient characteristics (such as performance status, comorbidities, and patient-expressed and perceived values).
View details for DOI 10.1007/s12325-021-01909-1
View details for PubMedID 34564806
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Pharmacovigilance analysis of cardiac toxicities associated with targeted therapies for metastatic non-small cell lung carcinoma.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
Abstract
INTRODUCTION: Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung carcinoma (NSCLC). We compared cardiovascular adverse events between and within targeted therapy classes.METHODS: We used WHO pharmacovigilance database VigiBase to compare odds of heart failure, conduction disease, QT prolongation, supraventricular tachycardia (SVT), and ventricular arrhythmias between inhibitors of EGFR (erlotinib, gefitinib, afatinib, osimertinib), BRAF (dabrafenib), MEK (trametinib), and ALK ± ROS1 (alectinib, brigatinib, ceritinib, crizotinib, lorlatinib).RESULTS: Of 98,765 adverse reactions reported with NSCLC targeted therapies, 1,783 (1.8%) were arrhythmias and 1,146 (1.2%) were heart failure. ALK/ROS1 inhibitors were associated with increased odds of conduction disease (reporting odds ratio [ROR] 12.95, 99% CI: 10.14-16.55) and QT prolongation (ROR 5.16, 99% CI: 3.92-6.81) relative to BRAF and EGFR inhibitors. Among ALK/ROS1 inhibitors, crizotinib had highest odds of conduction disease (ROR 1.75, 99% CI: 1.30-2.36) and QT prolongation (ROR 1.91, 99% CI: 1.22-3.00). Dabrafenib (ROR 2.24, 99% CI: 1.86-2.70) and trametinib (ROR 2.44, 99% CI: 2.03-2.92) had higher odds of heart failure than other targeted therapies. Osimertinib was strongly associated with QT prolongation (ROR 6.13, 99% CI: 4.43-8.48), heart failure (ROR 3.64, 99% CI: 2.94-4.50), and SVT (ROR 1.90, 99% CI: 1.26-2.86) relative to other targeted therapies.CONCLUSIONS: ALK/ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than other targeted therapies. Osimertinib is strongly associated with QT prolongation, SVT, and heart failure relative to other EGFR inhibitors and targeted therapies. Monitoring for heart failure and arrhythmias should be considered with NSCLC targeted therapies, especially osimertinib.
View details for DOI 10.1016/j.jtho.2021.07.030
View details for PubMedID 34418561
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EGFR exon 20 Insertion NSCLC and Response to Platinum-Based Chemotherapy.
Clinical lung cancer
2021
Abstract
INTRODUCTION: In classical EGFR mutant non-small-cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitor (TKI) therapy yields better outcomes than platinum-based chemotherapy. However, EGFR exon 20 insertion (ex20ins) NSCLC is relatively resistant to currently available EGFR TKIs. Though platinum-based chemotherapy is the frontline standard of care for EGFR ex20ins NSCLC, its efficacy is not fully described.STUDY DESIGN: A retrospective, single-center, case series METHODS: Patients were identified through an electronic research database at a single institution and included if they had advanced EGFR ex20ins NSCLC, received platinum-based chemotherapy for metastatic disease, and had scans evaluable for response. Each patient's demographics, tumor characteristics, and clinical course were recorded. Treatment response was evaluated using RECIST v1.1 criteria, and the PFS was calculated by the Kaplan-Meier method.RESULTS: Among 27 patients identified with EGFR ex20ins NSCLC at our institution, 18 (67%) received platinum-based chemotherapy for metastatic disease and had scans evaluable for response. These patients received platinum-based chemotherapy in the first-line (N=17, 94%) and second-line settings (N=1, 6%). The objective response rate (ORR) to platinum-based chemotherapy was 39% (7 of 18 patients; 95% confidence interval [CI] 16-61). The median PFS with platinum-based chemotherapy was 7.1 months (95% CI, 6.3 -13.7), and the median overall survival was 3.2 years (95% CI, 1.92 - NR).CONCLUSIONS: The efficacy of platinum-based chemotherapy in EGFR ex20ins NSCLC is similar to that expected for TKI sensitive EGFR mutant NSCLC. Novel agents designed to specifically target ex20ins mutant EGFR should additionally improve outcomes.
View details for DOI 10.1016/j.cllc.2021.07.001
View details for PubMedID 34391686
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Machine Learning Radiomics Model for Early Identification of Small-Cell Lung Cancer on Computed Tomography Scans.
JCO clinical cancer informatics
2021; 5: 746-757
Abstract
PURPOSE: Small-cell lung cancer (SCLC) is the deadliest form of lung cancer, partly because of its short doubling time. Delays in imaging identification and diagnosis of nodules create a risk for stage migration. The purpose of our study was to determine if a machine learning radiomics model can detect SCLC on computed tomography (CT) among all nodules at least 1 cm in size.MATERIALS AND METHODS: Computed tomography scans from a single institution were selected and resampled to 1 * 1 * 1 mm. Studies were divided into SCLC and other scans comprising benign, adenocarcinoma, and squamous cell carcinoma that were segregated into group A (noncontrast scans) and group B (contrast-enhanced scans). Four machine learning classification models, support vector classifier, random forest (RF), XGBoost, and logistic regression, were used to generate radiomic models using 59 quantitative first-order and texture Imaging Biomarker Standardization Initiative compliant PyRadiomics features, which were found to be robust between two segmenters with minimum Redundancy Maximum Relevance feature selection within each leave-one-out-cross-validation to avoid overfitting. The performance was evaluated using a receiver operating characteristic curve. A final model was created using the RF classifier and aggregate minimum Redundancy Maximum Relevance to determine feature importance.RESULTS: A total of 103 studies were included in the analysis. The area under the receiver operating characteristic curve for RF, support vector classifier, XGBoost, and logistic regression was 0.81, 0.77, 0.84, and 0.84 in group A, and 0.88, 0.87, 0.85, and 0.81 in group B, respectively. Nine radiomic features in group A and 14 radiomic features in group B were predictive of SCLC. Six radiomic features overlapped between groups A and B.CONCLUSION: A machine learning radiomics model may help differentiate SCLC from other lung lesions.
View details for DOI 10.1200/CCI.21.00021
View details for PubMedID 34264747
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Immune Checkpoint Inhibitor Pneumonitis: Heterogeneity in Clinical Management
AMER THORACIC SOC. 2021
View details for Web of Science ID 000685468901382
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Pragmatic Application of Computed Tomography Lung Texture Analysis in Immune Checkpoint Inhibitor Pneumonitis: An Exploratory Study
AMER THORACIC SOC. 2021
View details for Web of Science ID 000685468901148
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Chemotherapy with or without immunotherapy or bevacizumab for EGFR-mutated lung cancer after progression on osimertinib
ELSEVIER SCIENCE INC. 2021: S773–S774
View details for Web of Science ID 000634855900139
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Circulating tumor DNA kinetics to identify genomic predictors of rapid response to chemoradiation in non-small cell lung cancer.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000641160600097
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Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000641160600087
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Healthcare Utilization with an Electronic Patient Reported Outcome (ePRO) tool for Symptom Management in Thoracic Cancers
ELSEVIER SCIENCE INC. 2021: S170–S171
View details for Web of Science ID 000631349600192
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Giant Magnetoresistive Nanosensor Analysis of Circulating Tumor DNA Epidermal Growth Factor Receptor Mutations for Diagnosis and Therapy Response Monitoring.
Clinical chemistry
2021
Abstract
Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA.We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients.The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0-97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9-98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7-99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P < 0.0001) longer PFS compared to nonresponders (N/A vs. 12 weeks, respectively).The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.
View details for DOI 10.1093/clinchem/hvaa307
View details for PubMedID 33393992
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Brief Report: Role of Consolidation Durvalumab in patients with EGFR and HER2 Mutant Unresectable Stage III NSCLC.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
Abstract
Despite the recent advance of consolidation durvalumab in the treatment of unresectable stage III non-small cell lung cancer (NSCLC), not every patient benefits from durvalumab and predictive markers of response have been difficult to identify.We performed a retrospective analysis of patients with unresectable stage III NSCLC treated with consolidation durvalumab following definitive chemoradiation from January 2018 to March 2020.Thirty-six patients with unresectable stage III NSCLC were treated with consolidation durvalumab. Fourteen of these patients had tumor mutations in the ERBB family including 11 EGFR and 3 ERBB2. The ERBB2/EGFR tumor mutation cohort was more likely to be non-smokers; otherwise the two groups were similar in age, sex, PD-L1 expression and type of prior chemotherapy regimen. Patients in the ERBB2/EGFR cohort had a significantly shorter disease free survival compared to the EGFR/ERBB2 wildtype cohort (7.5 months vs NR, p= 0.04).Consolidation durvalumab appears to be less efficacious in patients with ERBB2/EGFR mutant tumors. Future work should seek to evaluate this in the prospective setting and provide insight into the optimal treatment of ERBB2/EGFR-mutant stage III NSCLC.
View details for DOI 10.1016/j.jtho.2020.12.020
View details for PubMedID 33539970
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A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7445.AM2020-5666
View details for Web of Science ID 000590059306446
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Systemic Therapy of Extensive Stage Small Cell Lung Cancer in the Era of Immunotherapy.
Current treatment options in oncology
2020; 21 (8): 64
Abstract
OPINION STATEMENT: In March 2019, the FDA approved the use of the anti-programmed death ligand 1 (PD-L1) antibody atezolizumab, as a first-line treatment option in combination with platinum-etoposide (PE) for patients with extensive stage small cell lung cancer (ED SCLC) based upon the results of the IMpower133 trial. More recently, the FDA approved the anti-PD-L1 antibody durvalumab in March 2020 , also in the frontline setting for SCLC based upon the results of the CASPIAN trial. Both these trials demonstrated a small, but significant overall survival (OS) benefit with the addition of a PD-L1 antibody to standard chemotherapy in the treatment of ED SCLC, thereby altering the treatment paradigm for this aggressive disease. Previously, the FDA had approved the anti-PD1 antibodies nivolumab and pembrolizumab as single-agent third-line treatment options based upon encouraging phase 1/2 data in patients with relapsed SCLC who had not received prior immunotherapy (IO). Despite these recent advances, the overall benefit of IO in SCLC remains somewhat disappointing in comparison with the results seen in non-small cell lung cancer (NSCLC). To date, no reliable biomarkers exist to predict responsiveness to IO in SCLC, and the utility of second- or third-line immunotherapy is questionable in patients who have received IO as part of first-line treatment. There has also been minimal success in identifying targetable mutations in SCLC. Novel approaches include combination approaches with IO, including PARP inhibitors and CDK inhibitors. Few ongoing trials, however, have enrolled patients who have received frontline immunotherapy given the only recent change in standard of care. Consequently, the results of current trials evaluating second- and third-line therapies need to be interpreted and translated into clinical practice with caution. The most significant challenge in SCLC remains the identification of molecular targets for which drugs can be developed that can improve survival over the current standard of care.
View details for DOI 10.1007/s11864-020-00762-8
View details for PubMedID 32601742
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The Project Baseline Health Study: a step towards a broader mission to map human health
NPJ DIGITAL MEDICINE
2020; 3 (1): 84
Abstract
The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.
View details for DOI 10.1038/s41746-020-0290-y
View details for Web of Science ID 000538242900001
View details for PubMedID 32550652
View details for PubMedCentralID PMC7275087
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The Project Baseline Health Study: a step towards a broader mission to map human health.
NPJ digital medicine
2020; 3 (1): 84
Abstract
The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.
View details for DOI 10.1038/s41746-020-0290-y
View details for PubMedID 33597683
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Advances in the Treatment of Stage III Non-Small Cell Lung Cancer.
Clinics in chest medicine
2020; 41 (2): 211–22
Abstract
Treatment of stage III non-small cell lung cancer (NSCLC) traditionally has involved combinations of chemotherapy, radiation, and surgical resection. Although the multimodality approach remains standard, only a fraction of patients with stage III lung cancer can undergo complete resection, and long-term prognosis remains poor. The PACIFIC trial generated significant enthusiasm when it demonstrated that the programmed death ligand-1 inhibitor, durvalumab, improved survival in patients with unresectable stage III NSCLC after completion of definitive concurrent chemoradiation. This article reviews the indications for traditional therapies in stage III NSCLC and highlights ongoing advances that have led to the incorporation of novel therapeutic agents.
View details for DOI 10.1016/j.ccm.2020.02.008
View details for PubMedID 32402357
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KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368303348
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A mid-chemoradiation dynamic risk model integrating tumor features and ctDNA analysis for lung cancer outcome prediction.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368303378
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Circulating Tumor DNA Dynamics Predict Benefit from Consolidation Immunotherapy in Locally Advanced Non-Small Cell Lung Cancer.
Nature cancer
2020; 1 (2): 176-183
Abstract
Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. We applied CAPP-Seq ctDNA analysis to 218 samples from 65 patients receiving chemoradiation therapy (CRT) for locally advanced NSCLC, including 28 patients receiving consolidation immune checkpoint inhibition (CICI). Patients with undetectable ctDNA after CRT had excellent outcomes whether or not they received CICI. Among such patients, one died from CICI-related pneumonitis, highlighting the potential utility of only treating patients with MRD. In contrast, patients with MRD after CRT who received CICI had significantly better outcomes than patients who did not receive CICI. Furthermore, the ctDNA response pattern early during CICI identified patients responding to consolidation therapy. Our results suggest that CICI improves outcomes for NSCLC patients with MRD and that ctDNA analysis may facilitate personalization of consolidation therapy.
View details for DOI 10.1038/s43018-019-0011-0
View details for PubMedID 34505064
View details for PubMedCentralID PMC8425388
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Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition.
Cell
2020
Abstract
Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
View details for DOI 10.1016/j.cell.2020.09.001
View details for PubMedID 33007267
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Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer
NATURE CANCER
2020; 1: 176–183
View details for DOI 10.1038/s43018-019-0011-0
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A PHASE IIA STUDY REPOSITIONING DESIPRAMINE IN SMALL CELL LUNG CANCER AND OTHER HIGH-GRADE NEUROENDOCRINE TUMORS.
Cancer treatment and research communications
2020; 23: 100174
Abstract
A bioinformatics approach identified antitumor effects of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinomas) (G3NEC) that was subsequently validated in preclinical models with a putative mechanism of action via inhibition of neuroendocrine signaling pathways. This study was undertaken to reposition the candidate TCA desipramine in a clinical trial in SCLC and G3NEC.In this prospective, phase IIa intrapatient dose escalation clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC. Treatment with desipramine began at 75 mg nightly with escalation in increments of 75 mg weekly to a maximum of 450 mg daily.Six patients were enrolled, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreas). Tolerability of desipramine was worse than predicted. Of the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 neurocognitive adverse events. Median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6).No clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated. Intolerable low and medium grade neurocognitive side effects led to intermittent treatment and early discontinuation in most patients; given this limitation, doses achieved may be inadequate compared to the preclinical studies.A bioinformatics approach previously identified a potential antitumor effect of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinoma) (G3NEC), which was validated in preclinical models. In this prospective, phase IIa clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC (Ki-67 ≥ 20% or ≥ 20 mitoses/10 HPF). Treatment with desipramine began at 75 mg nightly with escalation by 75 mg weekly to a maximum dose of 450 mg daily. Six patients were enrolled on this clinical trial, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreatic). Tolerability of desipramine was worse than predicted. In the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 drug related dizziness, confusion, and somnolence. Though numbers are small, median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). Although preclinical evidence was promising, no clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated.
View details for DOI 10.1016/j.ctarc.2020.100174
View details for PubMedID 32413603
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KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition.
Cancer discovery
2020
Abstract
Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.
View details for DOI 10.1158/2159-8290.CD-20-0282
View details for PubMedID 33071215
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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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Circulating Tumor DNA Changes During Chemoradiation for Lung Cancer Predict Patient Outcomes
ELSEVIER SCIENCE INC. 2019: S113
View details for DOI 10.1016/j.ijrobp.2019.06.610
View details for Web of Science ID 000485671502643
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Impact of KEAP1/NFE2L2/CUL3 mutations on duration of response to EGFR tyrosine kinase inhibitors in EGFR mutated non-small cell lung cancer.
Lung cancer (Amsterdam, Netherlands)
2019; 134: 42–45
Abstract
For patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), frontline EGFR-tyrosine kinase inhibitor (TKI) therapy compared to chemotherapy improves outcomes. However, resistance to these agents uniformly develops. Recently, mutations in the KEAP1-NFE2L2 pathway have been implicated as a potential mechanism of acquired EGFR TKI resistance.We examined all patients with metastatic NSCLC with mutations in both EGFR and KEAP1/NFE2L2/CUL3 identified on next generation sequencing from 2015 - 2018. These patients were compared to a NSCLC control cohort with mutations in EGFR and wild type in KEAP1/NFE2L2/CUL3 matched on the basis of sex, smoking status, age and race. Time to treatment failure on EGFR TKI therapy and overall survival were examined.Among 228 EGFR mutant NSCLCs, 17 (7%) also carried mutations in KEAP1, NFE2L2, or CUL3. The most common co-mutation in both the KEAP1/NFE2L2/CUL3 mutant and wild-type cohort was TP53. Patients with KEAP1/NFE2L2/CUL3 mutations had a shorter median time to treatment failure on EGFR TKI (4.7 months) compared with the wild-type matched cohort (13.0 months), p= 0.0014. There was no difference in overall survival.For NSCLC patients with mutations in EGFR, co-mutations in KEAP1/NFE2L2/CUL3 are associated with significantly decreased time to treatment failure. Our results suggest that these mutations represent a mechanism of intrinsic resistance to TKI treatment.
View details for DOI 10.1016/j.lungcan.2019.05.002
View details for PubMedID 31319993
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Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of non-small cell lung cancer patients.
Clinical cancer research : an official journal of the American Association for Cancer Research
2019
Abstract
Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations which activate NFE2L2, including mutations in NFE2L2,KEAP1, or CUL3,have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored.We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 stage IV NSCLC patients with KEAP1, NFE2L2, or CUL3mutations and a matched cohort of 52 wildtype patients. Time to treatment failure after front line platinum doublet chemotherapy and overall survival was compared between the two groups.Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In NSCLC patients, median time to treatment failure (TTF) after first line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared to 8.3 months in the control group (p < 0.0001) Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (p = 0.006). Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter time to treatment failure and overall survival after first line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of NSCLC patients are therefore needed.
View details for DOI 10.1158/1078-0432.CCR-19-1237
View details for PubMedID 31548347
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Invasive nodal evaluation prior to stereotactic ablative radiation for non-small cell lung cancer.
Lung cancer (Amsterdam, Netherlands)
2018; 124: 76–85
Abstract
INTRODUCTION: Invasive nodal evaluation (INE) is used to improve staging for early stage non-small cell lung cancer (NSCLC), including when stereotactic ablative radiation (SABR) is used. Consensus guidelines from the NCCN recommend performing INE for patients with T2N0 tumors and considering INE for those with T1N0 tumors. We reasoned that if INE results in significant stage migration in the form of substantially fewer patients with occult nodal involvement, then patients treated with SABR who do not undergo INE should have worse overall survival (OS).METHODS: Patients diagnosed 2004-2014 with stage T1-2N0M0 NSCLC and treated with SABR were identified from the National Cancer Database. Factors associated with INE were determined using mixed effects logistic regression. We tested for an association between INE and OS for patients diagnosed 2004-2013 using mixed effects proportional hazards regression methods.RESULTS: 24,603 SABR patients were identified. 6% of the 19,322 patients with T1 tumors and 9% of the 5281 patients with T2 tumors had INE. Median OS was 2.8 years for the no-INE group and 2.7 years for the INE group (log-rank P=0.69). No significant association was observed between the use of INE and OS in the univariate analysis (HR 1.02, 95% CI 0.94-1.11) or the multivariate analysis (HR 0.94, 95% CI 0.86-1.02). These findings were confirmed using propensity score matched and instrumental variable analysis. On subgroup analysis, INE was associated with a non-significant trend for improved OS in patients with T2 tumors (HR 0.87, 95% CI 0.76-1.00) but not T1 tumors (HR 0.98, 95% CI 0.88-1.09).CONCLUSIONS: Despite current NCCN recommendations, the rate of INE was low for patients with stage T1 or T2 tumors. While omitting INE represents a compromise in the completeness of nodal evaluation, we found that it was not associated with a detriment in overall survival.
View details for PubMedID 30268484
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Invasive nodal evaluation prior to stereotactic ablative radiation for non-small cell lung cancer
LUNG CANCER
2018; 124: 76–85
View details for DOI 10.1016/j.lungcan.2018.07.033
View details for Web of Science ID 000448100600012
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A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies
CANCER CHEMOTHERAPY AND PHARMACOLOGY
2018; 82 (3): 541–50
View details for DOI 10.1007/s00280-018-3646-0
View details for Web of Science ID 000442431600017
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A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies.
Cancer chemotherapy and pharmacology
2018
Abstract
PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules.METHODS: Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine Cmax, and AUC. Patients remained on study until progressive disease or unacceptable AEs.RESULTS: In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set.CONCLUSIONS: For oral XL647, the MTD was 4.68mg/kg or 350mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.
View details for PubMedID 30030583
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Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Metastatic Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2018: E1–E2
View details for Web of Science ID 000432447200003
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Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Lung Cancer
ELSEVIER SCIENCE INC. 2017: S20–S21
View details for DOI 10.1016/j.ijrobp.2017.06.061
View details for Web of Science ID 000411559106127
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Patterns of Care and Health Disparities for Patients With Stage I Non-small Cell Lung Cancer in the US
ELSEVIER SCIENCE INC. 2017: E399
View details for DOI 10.1016/j.ijrobp.2017.06.1556
View details for Web of Science ID 000411559103118
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Diagnosis and Treatment of Adenocarcinomas and Squamous Cell Carcinomas of the Lung.
Journal of the advanced practitioner in oncology
2017; 8 (3): 267–72
Abstract
Following years in which there were only modest gains in treatment options for non-small cell lung cancer, recognition of targetable mutations and immunogenicity of lung cancer now impact treatment decisions.
View details for PubMedID 29928550
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ERBB2-Mutated Metastatic Non-Small Cell Lung Cancer: Response and Resistance to Targeted Therapies.
Journal of thoracic oncology
2017
Abstract
Erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (also called HER2) has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers in which amplification of this gene confers sensitivity to treatment with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-directed agents. More recently, somatic mutations in ERBB2 have been reported in 1% to 2% of patients with lung adenocarcinoma. Previous case series have suggested clinical tumor responses using anti-ERBB2 small molecules and antibody therapies.Here we report the outcomes of nine patients with metastatic lung adenocarcinoma with ERBB2 mutations being treated with ERBB2-targeted therapies.Four of the nine patients had response to targeted therapies, with durations of response ranging from 3 to 10 months. We identified a de novo phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation and ERBB2 copy number gain as potential resistance mechanisms.We showed patients with ERBB2-mutated lung adenocarcinoma can respond to targeted therapies, and we identified potential resistance mechanisms upon progression to targeted therapies.
View details for DOI 10.1016/j.jtho.2017.01.023
View details for PubMedID 28167203
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Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction
LUNG CANCER
2015; 89 (3): 280-286
Abstract
Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.
View details for DOI 10.1016/j.lungcan.2015.06.011
View details for Web of Science ID 000360513200010
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Angiogenesis and lung cancer: ramucirumab prolongs survival in 2(nd)-line metastatic NSCLC.
Translational lung cancer research
2014; 3 (6): 397-399
Abstract
In the REVEL trial, ramucirumab, a monoclonal antibody to VEGFR-2, improved overall survival in combination with docetaxel compared to docetaxel alone in the second-line setting of non-small cell lung cancer (NSCLC). Along with bevacizumab and nintedanib, ramucirumab is the third anti-angiogenic agent that has yielded positive overall survival results in a phase III trial of patients with advanced NSCLC. Given the lack of effective therapies in the relapsed setting and the disappointing results of many other VEGF-targeted agents in lung cancer, the results from REVEL are encouraging. One of the major remaining hurdles is the identification of reliable predictive biomarkers in order to predict which patients are most likely to benefit from anti-angiogenic therapies. Despite the positive results seen in REVEL, the exact role of ramucirumab in the treatment paradigm of lung cancer remains to be seen given the modest survival benefit of 1.4 months and the lack of predictive biomarkers at this time.
View details for DOI 10.3978/j.issn.2218-6751.2014.09.05
View details for PubMedID 25806332
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A multicenter randomized phase II trial of erlotinib with and without hydroxychloroquine (HCQ) in TKI-naive patients (pts) with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC)
AMER SOC CLINICAL ONCOLOGY. 2014
View details for Web of Science ID 000358613204150
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Assessment of patients' satisfaction of an innovative oncology telemedicine clinic.
AMER SOC CLINICAL ONCOLOGY. 2014
View details for Web of Science ID 000358613200967
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Anti-angiogenic Agents in Metastatic NSCLC
LUNG CANCER,4TH EDITION
2014: 527–40
View details for Web of Science ID 000354798900035
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ERLOTINIB (E) AND DOVITINIB (TKI258) (D) IN PATIENTS (PTS) WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): A SIGNIFICANT PHARMACOKINETIC (PK) INTERACTION
LIPPINCOTT WILLIAMS & WILKINS. 2013: S1185–S1186
View details for Web of Science ID 000339624905335
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VIETNAMESE NON-SMALL CELL LUNG CANCER PATIENTS IN CALIFORNIA: MOLECULAR PROFILES AND CLINICAL CHARACTERISTICS
LIPPINCOTT WILLIAMS & WILKINS. 2013: S208–S209
View details for Web of Science ID 000339624901009
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PALLIATIVE CARE AND ANTI-CANCER CARE INTEGRATION: DESCRIPTION OF THREE MODELS OF CARE DELIVERY AT A TERTIARY MEDICAL CENTER
LIPPINCOTT WILLIAMS & WILKINS. 2013: S1324
View details for Web of Science ID 000339624906208
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A Case Series of Lengthy Progression-Free Survival With Pemetrexed-Containing Therapy in Metastatic Non-Small-Cell Lung Cancer Patients Harboring ROS1 Gene Rearrangements.
Clinical lung cancer
2013; 14 (5): 592-595
View details for DOI 10.1016/j.cllc.2013.04.008
View details for PubMedID 23810364
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A Case Series of NSCLC Patients with Different Molecular Characteristics and Choroidal Metastases Improvement in Vision with Treatment Including Pemetrexed and Bevacizumab
JOURNAL OF THORACIC ONCOLOGY
2013; 8 (2): E17-E18
View details for DOI 10.1097/JTO.0b013e31827690da
View details for Web of Science ID 000316204900003
View details for PubMedID 23328555
View details for PubMedCentralID PMC3552378
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Anti-angiogenic agents in Non-Small-Cell Lung Cancer (NSCLC): a perspective on the MONET1 (Motesanib NSCLC Efficacy and Tolerability) study
JOURNAL OF THORACIC DISEASE
2012; 4 (6): 558-561
View details for DOI 10.3978/j.issn.2072-1439.2012.10.02
View details for Web of Science ID 000314790400004
View details for PubMedID 23205278
View details for PubMedCentralID PMC3506785
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Angiogenesis inhibitors.
Journal of thoracic oncology
2012; 7 (16): S397-8
View details for DOI 10.1097/JTO.0b013e31826df227
View details for PubMedID 23160332
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BIOMARKERS FOR ANTI-ANGIOGENIC THERAPY
ELSEVIER SCIENCE INC. 2012: S442–S443
View details for Web of Science ID 000428093300114
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ERCC1 expression in circulating tumor cells (CTCs) using a novel detection platform correlates with progression-free survival (PFS) in patients with metastatic non-small-cell lung cancer (NSCLC) receiving platinum chemotherapy.
Lung cancer
2012; 77 (2): 421-426
Abstract
To utilize a novel circulating tumor cell (CTC) technology to quantify ERCC1 expression on CTCs and determine whether ERCC1 expression levels predict efficacy of platinum-based chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC).ERCC1 expression was measured in 17 metastatic NSCLC patients who received platinum-based therapy and had ≥2 intact CTCs with acceptable ERCC1 expression assay results. ERCC1 levels were determined from average expression on individual CTCs in each sample. Progression-free survival (PFS) was calculated from the date of therapy initiation.PFS decreased with increasing ERCC1 expression (p<0.04, F-test, linear regression). Lack of ERCC1 expression was associated with longer PFS (266 days versus 172 days, log-rank, p<0.02) in a Kaplan-Meier analysis using ERCC expression level of 1 as a cutoff (range 0-30). The difference in survival was statistically significant with a hazard ratio of 4.20 (95% CI 1.25-14.1, p<0.02, log-rank). PFS was also observed to decrease with increased cytokeratin (CK) expression (p<0.01 long-rank (Cox regression) and F-test (linear regression)). The hazard ratio is 4.38 (95% CI 1.76-10.9) for each log-change in CK value until progression was noted on imaging.Low expression of ERCC1 on CTCs correlates with PFS in patients with metastatic NSCLC receiving platinum-based therapy.
View details for DOI 10.1016/j.lungcan.2012.04.005
View details for PubMedID 22555222
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Angiogenesis Inhibitors
JOURNAL OF THORACIC ONCOLOGY
2011; 6 (11): S1801-S1802
View details for DOI 10.1097/01.JTO.0000407564.91781.ab
View details for PubMedID 22005536
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Results from a Single Institution Phase II Trial of Concurrent Docetaxel/Carboplatin/Radiotherapy Followed by Surgical Resection and Consolidation Docetaxel/Carboplatin in Stage III Non-Small-Cell Lung Cancer
CLINICAL LUNG CANCER
2011; 12 (5): 280-285
Abstract
The optimal treatment of locally advanced non-small-cell lung cancer (NSCLC) remains controversial. We hypothesized that using a trimodality approach in selected patients with stage IIIA/IIIB disease would be both feasible and efficacious with reasonable toxicity.We enrolled 13 patients with resectable stage III NSCLC on a prospective phase II trial of trimodality therapy. Induction treatment consisted of weekly docetaxel 20 mg/m(2) and weekly carboplatin at an area under curve (AUC) of 2 concurrent with 45 Gy thoracic radiotherapy. Resection was performed unless felt to be unsafe or if patients had progressive disease. Postoperative consolidation consisted of docetaxel 75 mg/m(2) and carboplatin at an AUC of 6 every 3 weeks for 3 cycles with growth factor support.All patients responded to induction chemoradiotherapy as measured by total gross tumor volume reductions of 43% on average (range, 27%-64%). Twelve patients underwent resection of the tumor and involved nodes, yielding a resectability rate of 92%. The primary endpoint of 2-year overall survival (OS) was 72% (95% confidence interval [CI], 36%-90%), and 2-year progression-free survival (PFS) was 36% (95% CI, 9%-64%). The maximal toxicity observed per patient was grade II in 5 patients (38%); grade III in 7 patients (54%); grade IV in 1 patient (8%); and grade V in none.This trimodality approach resulted in promising outcomes with reasonable toxicity in carefully selected patients with stage III NSCLC at a single institution.
View details for DOI 10.1016/j.cllc.2011.06.003
View details for PubMedID 21752720
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Stage IIIB and IV NSCLC: Primary Therapy
LUNG CANCER: A MULTIDISCIPLINARY APPROACH TO DIAGNOSIS AND MANAGEMENT
2011: 183–95
View details for Web of Science ID 000283895900015
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Vascular Disrupting Agents
JOURNAL OF THORACIC ONCOLOGY
2010; 5 (12): S482-S483
View details for PubMedID 21102249
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Alternatives to Surgery for Early Stage Non-Small Cell Lung Cancer-Ready for Prime Time?
CURRENT TREATMENT OPTIONS IN ONCOLOGY
2010; 11 (1-2): 24-35
Abstract
Surgery is the standard of care for early stage non-small cell lung cancer (NSCLC), with lobectomy being the most oncologically sound resection. Medically inoperable patients and high-risk surgical candidates require effective alternatives to surgery; even operable patients may opt for less invasive options if they are proven to achieve similar outcomes to surgery. Minimally invasive local treatment modalities including dose-intensified conformal radiation therapy, most notably stereotactic ablative radiotherapy (SABR; also known as stereotactic body radiation therapy), and thermal ablation methods such as radiofrequency ablation (RFA) and microwave ablation (MWA) are emerging as promising treatment options whose roles in the treatment of early stage lung cancer are being defined. Early clinical experience and a rapidly growing body of prospective clinical trials, primarily in medically inoperable patients, are demonstrating encouraging effectiveness and safety outcomes in some cases approaching historical results with surgery. Given the very poor prognosis of the medically inoperable patient population, these alternatives to surgery, particularly SABR, are starting to be considered appropriate first-line therapy in properly selected patients, and prospective cooperative group trials to evaluate and optimize RFA and SABR in specific patient subsets are being conducted. For operable patients, prospective multi-center and cooperative groups trials of SABR are ongoing or completed, and international randomized trials of SABR vs. surgery have been initiated. Thus, promising alternatives to surgery for early stage NSCLC are ready for prime time evaluation in the setting of clinical trials, and participation in ongoing trials for both operable and medically inoperable patients is strongly encouraged.
View details for DOI 10.1007/s11864-010-0119-z
View details for PubMedID 20577833