Senior Associate Dean for Education and Student Affairs, Stanford University School of Medicine (1990 - 1997)
Director, Clinical Cancer Center at Stanford, Stanford University (1997 - 2001)
Honors & Awards
Alwin C. Rambar Award for Excellence in Patient Care, Stanford University Medical Center (1990)
Kaiser Foundation Award for Innovative and Outstanding Contribution to Medical Education, Stanford University (1993)
Alumni Achievement Award, Washington University School of Medicine (2002)
Drs. Ben and A. Jess Shenson Professorship, Stanford University School of Medicine (1997)
B.A., University of Rochester, Biology (1968)
M.D., Washington Univ Sch of Medicine (1972)
Jr Residency, Washingon Univ Sch of Medicine, Medicine (1974)
Sr Residency, Univ of California San Francisco, Medicine (1975)
Fellow, Stanford Univ School of Medicine, Oncology (1977)
Current Research and Scholarly Interests
Clinical Interests: general oncology, sarcomas. Research Interests: clinical trials in solid tumors.
A phase I pharmacokinetic study of bexarotene with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC)
CANCER CHEMOTHERAPY AND PHARMACOLOGY
2012; 69 (3): 815-824
This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin(®)) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination.Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m(2) on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m(2) weekly. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2-4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods.Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents.Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).
View details for DOI 10.1007/s00280-011-1771-0
View details for Web of Science ID 000302325600025
View details for PubMedID 22057854
The effect of bexarotene on atorvastatin pharmacokinetics: results from a phase I trial of bexarotene plus chemotherapy in patients with advanced non-small cell lung cancer
CANCER CHEMOTHERAPY AND PHARMACOLOGY
2012; 69 (2): 563-571
Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents.Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene).Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions.A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.
View details for DOI 10.1007/s00280-011-1772-z
View details for Web of Science ID 000299516700030
View details for PubMedID 22057855
The Prognostic Value of Tumor-Associated Macrophages in Leiomyosarcoma A Single Institution Study
AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS
2011; 34 (1): 82-86
High numbers of tumor-associated macrophages (TAMs) have been associated with poor outcome in several solid tumors. In 2 previous studies, we showed that colony stimulating factor-1 (CSF1) is secreted by leiomyosarcoma (LMS) and that the increase in macrophages and CSF1 associated proteins are markers for poor prognosis in both gynecologic and nongynecologic LMS in a multicentered study. The purpose of this study is to evaluate the outcome of patients with LMS from a single institution according to the number of TAMs evaluated through 3 CSF1 associated proteins.Patients with LMS treated at Stanford University with adequate archived tissue and clinical data were eligible for this retrospective study. Data from chart reviews included tumor site, size, grade, stage, treatment, and disease status at the time of last follow-up. The 3 CSF1 associated proteins (CD163, CD16, and cathepsin L) were evaluated by immunohistochemistry on tissue microarrays. Kaplan-Meier survival curves and univariate Cox proportional hazards models were fit to assess the association of clinical predictors as well as CSF1 associated proteins with overall survival.A total of 52 patients diagnosed from 1983 to 2007 were evaluated. Univariate Cox proportional hazards models were fit to assess the significance of grade, size, stage, and the 3 CSF1 associated proteins in predicting OS. Grade, size, and stage were not significantly associated with survival in the full patient cohort, but grade and stage were significant predictors of survival in the gynecologic (GYN) LMS samples (P = 0.038 and P = 0.0164, respectively). Increased cathepsin L was associated with a worse outcome in GYN LMS (P = 0.049). Similar findings were seen with CD16 (P < 0.0001). In addition, CSF1 response enriched (all 3 stains positive) GYN LMS had a poor overall survival when compared with CSF1 response poor tumors (P = 0.001). These results were not seen in non-GYN LMS.Our data form an independent confirmation of the prognostic significance of TAMs and the CSF1 associated proteins in LMS. More aggressive or targeted therapies could be considered in the subset of LMS patients that highly express these markers.
View details for DOI 10.1097/COC.0b013e3181d26d5e
View details for Web of Science ID 000286624100017
View details for PubMedID 23781555
Antiangiogenesis Agents in the Treatment of Soft Tissue Sarcomas
2010; 116 (5): 1177-1183
Soft tissue sarcomas (STSs) are a heterogeneous group of malignancies that includes >50 different subtypes, each with unique clinical and pathologic qualities. In general, there is a 50% cure rate, and most cures are achieved with complete surgical resection with or without radiation therapy. The results from chemotherapeutic agents for unresectable or metastatic disease have been disappointing with minimal long-term benefit. New targeted and novel agents are needed to improve response and survival. Tumor angiogenesis has been an intense focus in cancer therapy over the past decade. Several of numerous antiangiogenesis agents have been developed, and many already have been approved for the treatment of both solid and liquid tumors. Certain STSs are highly vascular tumors that often demonstrate angiogenesis markers. The objective of this review was to evaluate these angiogenesis markers in defining the role of angiogenesis in the treatment of patients with STS. In addition, the authors conducted an in-depth review of the results from using key antiangiogenesis agents in the treatment of STS.
View details for DOI 10.1002/cncr.24859
View details for Web of Science ID 000274772300006
View details for PubMedID 20052715
Breast Angiosarcoma: Case Series and Expression of Vascular Endothelial Growth Factor.
Case reports in oncology
2009; 2 (3): 242-250
PURPOSE: Angiosarcoma of the breast is a rare, malignant tumor for which little is known regarding prognostic indicators and optimal therapeutic regimens. To address this issue, we performed a retrospective analysis of breast angiosarcoma cases seen at Stanford University along with immunohistochemical analysis for markers of angiogenesis. METHODS: Breast angiosarcoma cases seen between 1980 and 2008 were examined. Viable tissue blocks were analyzed for expression of vascular endothelial growth factor and its receptors. RESULTS: A total of 16 cases were identified. Data was collected regarding epidemiology, treatment, response rates, disease-free survival, and the use of various imaging modalities. Five tissue blocks remained viable for immunohistochemical analysis. Vascular endothelial growth factor-A was positively expressed in 3 of these samples. CONCLUSION: Angiosarcoma of the breast is an aggressive malignancy with a propensity for both local recurrence and distant metastases. Angiogenesis inhibition may represent a novel therapeutic modality in this rare, vascular malignancy.
View details for PubMedID 20737044
View details for PubMedCentralID PMC2914389
The value of surgery for retroperitoneal sarcoma.
2009; 2009: 605840-?
Introduction. Retroperitoneal sarcomas are uncommon large malignant tumors. Methods. Forty-one consecutive patients with localized retroperitoneal sarcoma were retrospectively studied. Results. Median age was 58 years (range 20-91 years). Median tumor size was 17.5 cm (range 4-41 cm). Only 2 tumors were <5 cm. Most were liposarcoma (44%) and high-grade (59%). 59% were stage 3 and the rest was stage 1. Median followup was 10 months (range 1-106 months). Thirty-eight patients had an initial complete resection; 15 (37%) developed recurrent sarcoma and 12 (80%) had a second complete resection. Patients with an initial complete resection had a 5-year survival of 46%. For all patients, tumor grade affected overall survival (P = .006). Complete surgical resection improved overall survival for high-grade tumors (P = .03). Conclusions. Tumor grade/stage and complete surgical resection for high-grade tumors are important prognostic variables. Radiation therapy or chemotherapy had no significant impact on overall or recurrence-free survival. Complete surgical resection is the treatment of choice for patients with initial and locally recurrent retroperitoneal sarcoma.
View details for DOI 10.1155/2009/605840
View details for PubMedID 19826633
- Acute myeloid leukemia in patients with gastrointestinal stromal tumors treated with Gleevec LEUKEMIA & LYMPHOMA 2009; 50 (11): 1882-1884
Tamoxifen for salivary gland adenoid cystic carcinoma: report of two cases
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
2008; 134 (10): 1151-1153
Adenoid cystic carcinoma of the salivary gland (ACC-SG) is a slow-growing tumor that is refractory to most chemotherapeutic agents. Estrogen receptor (ER) antagonists provide a novel approach for recurrent disease.We report two cases of ACC-SC in which Tamoxifen/Toremifene were used.Both patients obtained long-term stability of disease with no associated toxicity.Given the relatively unsuccessful treatments for ACC-SC and the low toxicity of ER antagonists, such therapy should be considered in these patients for its potential disease-stabilizing effects.
View details for DOI 10.1007/s00432-008-0377-3
View details for Web of Science ID 000258655700015
View details for PubMedID 18347813
Primary paraspinal leiomyosarcoma invading the cervical spinal canal successfully treated with surgery, radiotherapy, and chemotherapy - Case report
JOURNAL OF NEUROSURGERY-SPINE
2007; 6 (5): 441-446
A primary paraspinal leiomyosarcoma invading the spine is an exceedingly rare neoplasm that may clinically mimic a schwannoma. The authors report a case involving a 45-year-old man with a primary leiomyosarcoma of the cervical paraspinal musculature that invaded the spinal canal at C1-2 and subsequently metastasized to the lungs and pancreas. Aggressive treatment consisting of resection of the primary tumor, adjunctive radiation therapy and chemotherapy, and surgical debulking of metastatic disease resulted in local tumor control at the primary site and long-term survival of the patient.
View details for Web of Science ID 000246048100011
View details for PubMedID 17542511
A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance
ANNALS OF ONCOLOGY
2005; 16 (12): 1968-1973
The aim of this study was to determine (i) the maximum tolerated dose (MTD) of liposomal doxorubicin (L-DOX) and paclitaxel (DP), (ii) the MTD of DP plus valspodar (DPV) and (iii) pharmacokinetic (PK) interactions of valspodar with L-DOX and paclitaxel.Twenty-three patients with metastatic cancers received DP, followed 4 weeks later by DPV. Dose levels of DP were (mg/m2 for L-DOX/paclitaxel): 30/135 (n = 7), 30/150 (n = 4), 35/150 (n = 8) and 40/150 (n = 4). Dose levels of DPV were 15/70 (n = 10) and 15/60 (n = 10). Serial, paired PK studies were performed.The MTD of DP was 40/150. For DPV at 15/70, five of 10 patients experienced grade 4 neutropenia. In the next cohort, a reduced dose of 15/60 was well tolerated. Valspodar produced reversible grade 3 ataxia in seven patients, requiring dose reduction from 5 to 4 mg/kg. Paired PK studies indicated no interaction between L-DOX and valspodar, and a 49% increase in the median half-life of paclitaxel. Two partial and one minor remissions were noted.The use of valspodar necessitated dose reductions of DP, with neutropenia being dose limiting. Valspodar PK interactions were observed with paclitaxel but not L-DOX.
View details for DOI 10.1093/annonc/mdi396
View details for Web of Science ID 000233489600018
View details for PubMedID 16126736
Plasmablastic lymphoma presenting in a human immunodeficiency virus-negative patient: a case report
ANNALS OF HEMATOLOGY
2003; 82 (8): 521-525
Plasmablastic lymphoma (PBL), an aggressive non-Hodgkin's lymphoma that carries a poor prognosis, previously has been identified almost exclusively in patients infected with the human immunodeficiency virus (HIV). We present a case of a 42-year-old HIV-negative patient presenting with an isolated nasal cavity mass, the typical presentation for PBL. The patient was given systemic chemotherapy, central nervous system prophylaxis, and consolidative locoregional radiotherapy and achieved a complete clinical response. This case suggests PBL should be considered in HIV-negative patients with characteristic findings.
View details for DOI 10.1007/s00277-003-0684-3
View details for Web of Science ID 000184757100013
View details for PubMedID 12783213
Impact of a program to diminish gender insensitivity and sexual harassment at a medical school
2000; 75 (5): 464-469
To measure the effect of an intervention to reduce gender insensitivity and sexual harassment at one medical school.Stanford University School of Medicine undertook a multifaceted program to educate faculty and students regarding gender issues and to diminish sexual harassment. The authors developed a survey instrument to assess the faculty's perceptions regarding environment (five scales) and incidences of sexual harassment. Faculty were surveyed twice during the interventions (1994 and 1995).Between the two years, the authors measured significant improvements in mean ratings for positive climate (p = .004) and cohesion (p = .006) and decreases in the faculty's perceptions of sexual harassment (p = 0006), gender insensitivity (p = .001), and gender discrimination (p = .004). The faculty also reported fewer observations of harassing behavior during the study period.An intervention program to diminish gender insensitivity and sexual harassment can measurably improve a medical school's environment.
View details for Web of Science ID 000086996900015
View details for PubMedID 10824771
Lymphomas of the head and neck
SEMINARS IN ONCOLOGY
1999; 26 (3): 338-345
Lymphomas of the head and neck arise in Waldeyer's ring, the salivary glands, nasal cavity, paranasal sinuses, thyroid gland, and orbit. Though anatomically in close proximity, lymphomas arising in these sites have distinct clinical characteristics. Factors that appear to influence the pattern of disease include concurrent conditions, such as Sjögren's syndrome, and geographic factors, particularly with regard to nasal lymphomas. The treatment and prognosis of patients with head and neck lymphoma depends on the histologic grade of disease and extent of involvement at time of presentation. Most lymphomas are of intermediate-grade histology and early stage at presentation. A thorough understanding of clinical disease patterns and treatment options will allow the optimum management of these patients.
View details for Web of Science ID 000080809400010
View details for PubMedID 10375090
Outcome measurement in postgraduate year one of graduates from a medical school with a pass fail grading system
1999; 74 (5): 547-549
To measure the performances of first-year residents who had graduated from a medical school with a pass/fail grading system and to compare the preparedness of these graduates with that of their peers.All 169 graduates of Stanford University School of Medicine's classes of 1993 and 1994 were included in this study. First-year program directors rated the performance of each Stanford graduate in 11 areas, compared the graduate's clinical preparedness with that of his or her peer group, and rated the accuracy of the dean's letter in presenting the graduate's capabilities.Responses were obtained for 144 of the 169 graduates (85%). The program directors rated the overall clinical competencies of most of the graduates as "superior" (76%) or "good" (22%); they rated very few as "unsatisfactory" (2%). When the Stanford graduates were compared with their peers, their clinical preparedness was judged "outstanding" (33%), "excellent" (44%), and "good" (20%); very few were judged "poor" (3%). Stratification of programs by either hospital or medical specialty did not reveal significant differences in overall clinical competence. Ninety-one percent of the responses reported that the dean's letters had accurately presented the capabilities of the graduates.Graduates from a medical school with a two-interval, pass/fail system successfully matched with strong, highly-sought-after postgraduate training programs, performed in a satisfactory to superior manner, and compared favorably with their peer group.
View details for Web of Science ID 000080442700027
View details for PubMedID 10353289
Non-Hodgkin's lymphoma of the paranasal sinuses: Clinical and pathological features, and response to combined-modality therapy
1997; 3 (5): 303-311
Lymphomas of the paranasal sinuses may have poorer prognoses compared with other extranodal lymphomas of the head and neck, and are not well defined as a particular clinicopathologic entity. The outcome of combined-modality therapy and central nervous system (CNS) prophylaxis has not been fully determined.We retrospectively reviewed our experience with 16 consecutive, carefully defined patients, all treated with both chemotherapy and radiotherapy.There were 11 men and five women, mean age 52. All presented with local symptoms; 13 had stage I or II disease. Thirteen had diffuse large cell lymphoma, two diffuse mixed, and one small noncleaved. Phenotyping revealed 10 B-cell, four T-cell, and two T or natural killer (NK). Most received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy; the order of chemotherapy and radiotherapy varied. Twelve received CNS prophylaxis. Of 12 complete responses, six relapsed, all at distant sites, and two died during initial therapy. Five-year survival was 29%, and median survival 18 months. Four of 10 B-lineage patients were relapse-free at 4 years; all six T- or T/NK-lineage patients relapsed or were dead within 6 months. Tumors of T or NK lineage often expressed CD56 and showed evidence of Epstein-Barr viral infection; otherwise, pathological features were not predictive of lineage or outcome. Neither age nor lactate dehydrogenase predicted prognosis. No complete responder recurred in the CNS as site of first relapse.Despite localized stage at presentation, sinus lymphoma is an aggressive disease, characterized by distant relapse and early mortality. Combined-modality therapy with CNS prophylaxis improves outcome compared with radiotherapy alone; however, prognosis remains poor. Patients with T-lineage disease appear to have a particularly bad outcome. Autologous bone marrow transplantation should be evaluated as first-line therapy for those at high risk of relapse.
View details for Web of Science ID A1997XX75500011
View details for PubMedID 9327155
The relationship of clinical knowledge to months of clinical training among medical students
1997; 72 (4): 305-307
To assess the correlation of the number of months of clinical training with clinical knowledge, as measured by the United States Medical Licensing Examination (USMLE) Step 2.The total number of months of clinical training and percentile scores on USMLE Step 2 were determined for 217 Stanford. University School of Medicine graduates from 1992 through 1994. Percentile scores on each subsection of the Medical College Admission Test (MCAT) and the National Board of Medical Examiners Part 1 or USMLE Step 1 (Part 1/Step 1) for the graduates were also determined. For some analyses the graduates were separated into three groups according to the duration of clinical training. The Pearson product-moment correlation coefficient was used to quantify and define the significance of correlations. The Jorickheere-Terpstra nonparametric test was used to assess trends across the three groups. A multiple linear regression model was used to test the effects of confounding variables.The total numbers of clerkship months ranged from 12 to 23; the median was 18. A highly significant correlation was found between increasing months of clinical training and increasing scores on Step 2 (p = .002); a weaker significant correlation was found with scores on Part 1/Step 1 (p = .03). The correlation for Step 2 scores did not diminish appreciably (p = .004) when scores for Part 1/Step 1 and each MCAT subsection were introduced into the regression model.A highly significant correlation was found between the amount of clinical training and the acquisition and utilization of clinical knowledge. In the current climate of concerns about the rising costs of medical education, the impulse to solve these concerns by decreasing the amount of medical students' clinical training should be approached with caution.
View details for Web of Science ID A1997WV34100023
View details for PubMedID 9125948
A climate survey for medical students - A means to assess change
Annual Meeting of the American-Educational-Research-Association
SAGE PUBLICATIONS INC. 1996: 30–47
An instrument was developed to assess the perceptions of students regarding six aspects of school climate and their experience of and attitudes toward sexual harassment and gender insensitivity. During clerkship orientation, 77 students (92% return rate), half female, were given the survey. Cronbach alpha reliabilities for the six scales ranged from .71 to .85. One significant female/male difference among the three scales of general school climate was observed; two significant female/male differences occurred among the three scales relating to gender concerns. Seventy percent of both males and females reported having observed sexually harassing behavior during the previous year; 46% of females and 15% of males reported experiencing sexually harassing behavior during the year. Observing and/or personally experiencing sexual harassment was associated with a decrease in positive climate ratings and an increase in negative climate ratings.
View details for Web of Science ID A1996TZ21700003
View details for PubMedID 10186902
A multicenter maintenance study of oral pilocarpine tablets for radiation-induced xerostomia.
Oncology (Williston Park, N.Y.)
1996; 10 (3): 16-20
Two hundred sixty-five patients with head and neck cancer who had previously participated in either a fixed-dose, dose-titration, or dose-ranging trial of oral pilocarpine hydrochloride tablets were enrolled in a 36-month multicenter maintenance study to evaluate the long-term safety and efficacy of oral pilocarpine for the treatment of radiation-induced xerostomia. In this open-label study, the initial drug dose was 5.0 mg tid, with possible adjustments from 2.5 to 10.0 mg tid or bid. Efficacy was evaluated by subjective measures of oral function. Safety evaluations were based on self-report of symptoms (or of adverse effects), various examinations, and laboratory tests. There was significant improvement in all criteria of oral function. Sweating was the most frequent adverse experience (55%). Less frequent side effects, mild to moderate in nature, included increased urinary frequency, lacrimation, and rhinitis. Side effects usually diminished within hours after the cessation of therapy. We conclude that oral pilocarpine at these doses effectively and safely reduces the symptoms of radiation-induced xerostomia.
View details for PubMedID 8723429
- Status of the Medical Oncology Workforce Journal of Clinical Oncology 1996; 14 (9): 2612-2621.
- Adjuvant and neoadjuvant treatment of head and neck cancers: The next chapter SEMINARS IN ONCOLOGY 1995; 22 (6): 540-552
The value of medical student research: The experience at Stanford University School of Medicine
1995; 29 (5): 342-346
At Stanford University School of Medicine, students are encouraged to conduct research, requiring a substantial amount of funding and effort on the part of teaching staff. We questioned one graduating class and all medical teachers to determine the value of the research experience to students, as well as staff satisfaction. Seventy-three per cent of students and 80% of teaching staff responded. Ninety per cent of students had performed research resulting in at least one published manuscript for 75% and a presentation at a national meeting for 52%. Almost all thought the experience taught them to ask questions, review the literature critically, and analyse data. Three-quarters responded that the experience motivated them to pursue further research, and 60% indicated that they plan a full-time academic career. The majority of teaching staff who worked with students found it rewarding and thought the student had had a valuable experience. We conclude that our curriculum provides a positive opportunity for students to develop an investigative approach to medical problems.
View details for Web of Science ID A1995TM12500004
View details for PubMedID 8699971
- A MULTIMODALITY APPROACH TO PREPARATION FOR CLINICAL MEDICINE ACADEMIC MEDICINE 1995; 70 (5): 441-442
- A SEXUAL HARASSMENT WORKSHOP FOR MEDICAL-STUDENTS ACADEMIC MEDICINE 1995; 70 (5): 434-435
- Head and neck cancer - combined modality therapy and chemotherapy. Brian MC and Carbone PP (eds), Current Therapy in Hematology-Oncology, Mosby, St. Louis, 1995: 352-358.
- Head and neck cancers Macdonald JS, Haller DG, Mayer RJ (eds), Manual of Oncologic Therapeutics, Third Edition, JB Lippincott, Philadelphia 1995: 162-169.
- Adjuvant and neoadjuvant treatment of head and neck cancers: the next chapter. Seminars in Oncology. 1995; 22 (6): 540-52.
Distant metastases from head and neck squamous cancer: the role of adjuvant chemotherapy.
Cancer treatment and research
1995; 74: 243-262
View details for PubMedID 7779619
A PHASE-III RANDOMIZED STUDY COMPARING CISPLATIN AND FLUOROURACIL AS SINGLE AGENTS AND IN COMBINATION FOR ADVANCED SQUAMOUS-CELL CARCINOMA OF THE HEAD AND NECK
JOURNAL OF CLINICAL ONCOLOGY
1992; 10 (2): 257-263
To determine whether combination chemotherapy is superior to single agents for recurrent/metastatic head and neck cancer, we compared the efficacy and toxicity of cisplatin (CP) and fluorouracil (5-FU), alone and in combination in a phase III trial.Two hundred forty-nine patients with recurrent head and neck cancer were randomized to one of three treatments: CP (100 mg/m2) and 5-FU (1 g/m2 x 4), CP, or 5-FU every 3 weeks.The overall response rate to the combination (32%) was superior to that of CP (17%) or 5-FU (13%) (P = .035). Response was associated with good performance status (PS) but not with primary site, site of recurrence, histology, prior irradiation, or relative dose intensity. Median time to progression was less than 2.5 months, and there was no significant difference in median survival (5.7 months) among the groups. By multivariate analysis, patients with better PS and poorly differentiated tumors had superior survival. Hematologic toxicity and alopecia were worse in the combination arm.Although the response rate to the combination of CP plus 5-FU was superior to that achieved with single agents, survival did not improve.
View details for Web of Science ID A1992HB27000011
View details for PubMedID 1732427
- ADJUVANT AND NEOADJUVANT TREATMENT OF HEAD AND NECK CANCERS SEMINARS IN ONCOLOGY 1991; 18 (6): 504-514
CHEMOTHERAPY FOR RECURRENT AND METASTATIC HEAD AND NECK-CANCER
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
1991; 5 (4): 667-686
At the present time, the treatment of recurrent and metastatic head and neck squamous and salivary gland cancers with chemotherapy is palliative. Pain relief, improvement in functional parameters, and improved survival are important goals. Although survival benefits are small, palliation can be significant. For squamous cancers, the median duration of response to chemotherapy is 2 to 4 months, and overall survival is about 6 months. Responses can be achieved with acceptable toxicity for good palliation in approximately 30% of patients treated with the standard regimens. Although more intensive chemotherapy regimens often result in higher response rates in pilot trials, they do not offer significant gains in effectiveness or survival. In salivary gland malignancies, results are substantially better, but this may only reflect the different natural history of this heterogeneous group of tumors. A small number of patients will have excellent and very durable responses to chemotherapy. Unfortunately, at this time we are unable to select these patients or determine which regimen will produce this desired result. The optimal use of currently available drugs is in the process of refinement. The timing of palliative chemotherapy represents a major challenge to oncologists and patients. Chemotherapy may in the future have a role in the cure of patients with recurrent disease, but innovative therapy, combined modality approaches, and new drug development will all need to be investigated. We look forward toward a new understanding of tumor biology and the development of agents that may substantially improve the control of these tumors.
View details for Web of Science ID A1991FY45400006
View details for PubMedID 1890059
THE USE OF PROBENECID AS A CHEMOPROTECTOR AGAINST CISPLATIN NEPHROTOXICITY
1991; 67 (6): 1518-1524
Probenecid inhibits cisplatin (CP) secretion in humans and protects against CP-induced nephrotoxicity in rats. The authors conducted a Phase I trial of escalating doses of CP using probenecid as a chemoprotector. Fifty-four courses of CP at doses ranging from 100 to 160 mg/m2 were given by 24-hour infusion to 36 patients. There was no renal impairment at any dose. Ototoxicity, however, became the dose-limiting toxicity; 14 patients experienced a 20 or greater decibel (dB) loss. Seven percent of courses were associated with a leukocyte count of less than 1.5 x 10/microliters, and 19% with a platelet count of less than 50 x 10(3)/microliters. Only three patients developed neurotoxicity. Correlating pharmacokinetic data and toxicity, the authors found that high cumulative dose, area under the curve (AUC) for unbound platinum, and cumulative AUC were associated with ototoxicity and peripheral neuropathy. It was concluded that probenecid may protect against CP nephrotoxicity and warrants further investigation. Its unique mechanism of action and lack of toxicity make it ideal to combine with other chemoprotectors.
View details for Web of Science ID A1991FC04000009
View details for PubMedID 1848154
THE INTERNIST IN THE MANAGEMENT OF HEAD AND NECK-CANCER
ANNALS OF INTERNAL MEDICINE
1990; 113 (10): 771-778
The general internist has an important role in the management of head and neck squamous cell cancers. This heterogeneous group of cancers must be accurately diagnosed and staged before planning treatment. Curability is directly related to stage at presentation and, because most patients with such cancers present to internists first, these physicians must be familiar with presenting symptoms and must be suspicious enough to refer patients with symptoms for appropriate evaluation. The work-up of patients with suspected unknown primary cancer presenting as adenopathy is detailed, and the physician is cautioned not to immediately proceed to open biopsy. As many as 10% of such primary cancers remain undetected, although, with proper therapy, the 5-year survival rate for squamous cell cancer of the head and neck is 60%. Those patients cured of head and neck cancer still face significant psychosocial and medical problems, including hypothyroidism, xerostomia, and a 20% rate of second primary cancer. Head and neck cancer is highly preventable; 75% of cases are related to tobacco and alcohol use. Smokeless tobacco has gained popularity among young Americans and is associated with an increased incidence of head and neck cancer at several sites. Education is crucial, and internists must seek strategies to stop patients from using tobacco products. Other etiologic factors include industrial carcinogens, Epstein-Barr virus, and diet. Retrospective serologic and dietary recall studies of vitamin A suggest an etiologic role of diet; vitamin A analogs have been tested in preneoplastic lesions. To reduce mortality from head and neck cancers, the general internist must play a central role in prevention and early detection.
View details for Web of Science ID A1990EH36300009
View details for PubMedID 2240879
MODIFICATION OF CISPLATIN TOXICITY WITH DIETHYLDITHIOCARBAMATE
JOURNAL OF CLINICAL ONCOLOGY
1990; 8 (9): 1585-1590
Diethyldithiocarbamate (DDTC), a heavy metal-chelating agent, has been shown to decrease cisplatin (CP) toxicity in preclinical studies. This phase I dose-escalation study was undertaken to investigate DDTC as a chemoprotector in patients with advanced cancer. Thirty-five courses of CP in doses ranging from 120 to 160 mg/m2 were given intravenous (IV) bolus to 19 patients. DDTC at 4 g/m2 was infused over 1 hour, starting 45 minutes after CP. There was minimal nephrotoxicity with a mean creatine clearance of 99 mL/min +/- 4 pretreatment and 86 mL/min +/- 4 on day 21. Two courses were associated with a WBC count less than 2,000/mm3 and one course with a platelet count of 15,000/mm3. Two patients had grade 2 neurotoxicity. Hearing loss occurred in 11 patients: five greater than or equal to 20 dB, five greater than or equal to 40 dB, and one greater than or equal to 60 dB. All patients who received cranial irradiation had ototoxicity compared with 43% of those without radiation (P less than .05). All patients experienced toxicity during the DDTC infusion, including hypertension, flushing, diaphoresis, agitation, and local burning. We conclude that DDTC can protect against CP nephrotoxicity at doses up to 160 mg/m2. Ototoxicity became the dose-limiting factor.
View details for Web of Science ID A1990DX47500017
View details for PubMedID 2167955
A PHASE-II TRIAL OF CARBETIMER FOR THE TREATMENT OF COLORECTAL-CANCER - A TRIAL OF THE NORTHERN-CALIFORNIA-ONCOLOGY-GROUP
AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS
1990; 13 (4): 324-326
Carbetimer (carboxyimamidate) was administered at a dose of 6,500 mg/m2/day intravenously for 5 consecutive days to 14 patients with measurable metastatic or recurrent colorectal cancer in a single institution phase II study of the Northern California Oncology Group. A total of 38 cycles of therapy were administered; nine patients completed at least three cycles of treatment. No partial or complete responses were observed. One patient did have a greater than 50% response in the liver while developing new retroperitoneal lymphadenopathy and is considered a nonresponder. Carbetimer was well tolerated with elevations of calcium from 10.2 to 12.5 mg/dl in nine patients, prolongation of prothrombin time and partial thromboplastin time in 14 patients, proteinuria in 10 patients, dizziness in six patients, nausea in two patients, and venous pain during infusion in three patients. Myelosuppression was not observed. Carbetimer at this dose and schedule is inactive in the treatment of colorectal cancer.
View details for Web of Science ID A1990DT05600012
View details for PubMedID 2198795
EFFICACY OF ADJUVANT CHEMOTHERAPY FOR PATIENTS WITH RESECTABLE HEAD AND NECK-CANCER - A SUBSET ANALYSIS OF THE HEAD AND NECK CONTRACTS PROGRAM
JOURNAL OF CLINICAL ONCOLOGY
1990; 8 (5): 838-847
To evaluate the efficacy of adjuvant chemotherapy for patients with advanced head and neck squamous cancer, the Head and Neck Contracts Program conducted a three-arm study comparing standard surgery and radiation, induction chemotherapy (cisplatin and bleomycin) plus standard therapy, and induction chemotherapy plus standard therapy followed by maintenance cisplatin for 6 months. As previously reported, this trial of 462 patients demonstrated no significant difference in disease-free survival or survival, but a significantly lower metastatic rate in the maintenance arm. To determine whether particular subgroups may have benefited from adjuvant therapy, we evaluated results based on primary site, and tumor (T) and node (N) stage. Of the 192 patients with oral cavity cancer, those on the maintenance arm had a significantly improved 3-year disease-free survival (67%) compared with the standard arm (49%) or induction arm (44%) (overall P = .05). For hypopharyngeal and laryngeal cancers there was no marked overall benefit. For the 106 patients with T1 plus T2 disease, there was marginal improvement in disease-free survival for the maintenance group (72%) compared with the standard group (47%) or induction group (43%) (overall P = .09). There was no advantage for patients with T3 and T4 disease. There was superior disease-free survival for patients with N1 disease on the maintenance arm (70%) compared with the standard arm (42%) (P = .024). The same was true for disease-free survival in 109 patients with N2 disease: standard (52%), induction (30%), maintenance (84%) (overall P less than .001). There was no benefit for N3 disease. A significant survival advantage with maintenance chemotherapy was only seen for N2 disease (overall P = .04). Since head and neck cancer patients are a heterogeneous group, there may be particular sites and stages for which adjuvant chemotherapy would be advantageous, and subset analysis can help indicate directions for new trials.
View details for Web of Science ID A1990DB98600012
View details for PubMedID 2185340
Head and neck squamous cancers.
Current problems in cancer
1990; 14 (1): 1-72
Head and neck squamous cancers are a heterogeneous group of neoplasms with varying etiologic factors, presenting symptoms, staging, treatment, and expected outcome. In this monograph, we discuss principles of management common to all sites as well as individual differences. The presenting symptoms of disease are reviewed, stressing the importance of early diagnosis. Accurate pathologic diagnosis can be improved on in difficult cases by newer immunohistochemical techniques. Following diagnosis, accurate clinical staging must be performed, and the evaluation of an unknown primary in the neck is described. We review general considerations for planning the treatment of head and neck cancer, and then discuss specific guidelines for individual sites, stressing the optimal integration of surgery and radiation therapy, particularly brachytherapy. Controversial management issues and new, innovative approaches are discussed. The conventional use of chemotherapy in head and neck cancer is for palliation of recurrent disease. In recent years, chemotherapy has been added to the primary treatment program in an induction role, as a radiosensitizer, as an adjunct following standard therapy, and for organ preservation. The current status of these roles is reviewed. This is a cancer for which there are known etiologic agents. Future efforts in this disease should be directed toward early detection and prevention.
View details for PubMedID 2194750
- ADJUVANT CHEMOTHERAPY FOR HEAD AND NECK-CANCER JOURNAL OF CLINICAL ONCOLOGY 1989; 7 (7): 823-826