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ABSTRACT: To determine the 1-year survival, response rate, and toxicity for patients with limited stage small cell lung cancer treated with the combination of cisplatin plus etoposide plus paclitaxel with delayed concurrent (starting with cycle 3) high dose thoracic radiotherapy.
Patients with previously untreated limited stage small cell lung cancer, Easter Cooperative Oncology Group performance status of 0-2 and adequate organ function were eligible. Cycles 1 and 2 of chemotherapy consisted of paclitaxel 170 mg/m intravenous day 1, etoposide 80 mg/m intravenous days 1 to 3, and cisplatin 60 mg/m intravenous day 1 followed by filgrastim 5 microg/kg subcutaneously days 4 to 13. Cycles 3 and 4 of chemotherapy consisted of a reduced dose of paclitaxel 135 mg/m intravenous day 1, and the same dose of etoposide and cisplatin with concurrent thoracic radiation therapy 1.8 Gy in 35 fractions (total 63 Gy) administered over 7 weeks.
Sixty-three patients were entered, 61 patients were eligible. The most common grade 4 toxicity seen was granulocytopenia (62%). Nonhematologic toxicities included febrile neutropenia in 19% of patients, grade 3 and 4 esophagitis in 32% of patients, and grade 3 peripheral neuropathy in 14% of patients. Two patients suffered lethal toxicities. The overall response rate was 79%. The 1-year survival rate was 64%. The median overall survival was 15.7 months, and the median progression-free survival was 8.6 months.
The combination of cisplatin plus etoposide plus paclitaxel chemotherapy and concurrent delayed thoracic radiotherapy as administered in this trial provide no apparent advantage with respect to response, local control, or survival compared with historical controls.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2009; 4(4):527-33. · 4.55 Impact Factor
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ABSTRACT: The designated institution official (DIO) is responsible for monitoring all residency programs within an institution. Although program-evaluation tools have been developed for residency program directors to use, there are currently no such published evaluation tools for DIOs. This manuscript describes the development and implementation of a standardized, dimensional program report card for the more than 60 residency and fellowship programs at our institution. This report card measures the theoretical construct of residency program performance and is divided into four sections: (1) quality of candidates recruited, (2) the resident educational program, (3) graduate success, and (4) overall house officer satisfaction. Each section is measured by objective and subjective metrics that allow the DIO to record programmatic strengths and weaknesses. These results are confidentially shared with the residency program director and encourage a partnership between the DIO and the program director. It is difficult to provide concrete construct validity with this instrument. The process used to develop the report card seems valid. The authors recognize that this report card is a surrogate for each program's RRC's perception of quality. In the future, the authors hope to work closely with the Accreditation Council for Graduate Medical Education and/or the group on resident affairs of the Association of American Medical Colleges to set national benchmark criteria for acceptable residency program performance for each medical discipline. They hope that DIOs and program directors will be able to compare residency programs objectively and identify areas for improvement at a local and national level.
Academic Medicine 07/2007; 82(6):608-15. · 3.52 Impact Factor
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Afshin Dowlati,
Shanmuga Subbiah,
Matthew Cooney,
Kimberly Rutherford,
Tarek Mekhail,
Pingfu Fu,
Robert Chapman,
Anne Ness,
Tania Cortas,
Joel Saltzman, Nathan Levitan,
Gregory Warren
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ABSTRACT: Extensive-stage small cell lung cancer (SCLC) is a highly aggressive malignancy for which little therapeutic progress has been made over the past 20 years. SCLC is a highly angiogenic tumor and targeting angiogenesis is being investigated. The putative mechanism of action of thalidomide is through inhibition of new blood vessel formation. This trial was designed to evaluate thalidomide in ES-SCLC.
Patients who had received first-line chemotherapy without disease progression were eligible. Patients received thalidomide 200 mg daily as maintenance therapy starting 3-6 weeks after completion of chemotherapy.
Thirty patients were enrolled. Toxicity was minimal with grade 1 neuropathy in 27% of patients and only one case of grade 3 neuropathy. Median survival from time of initiation of induction chemotherapy was 12.8 months (95% CI: 10.1-15.8 months) and 1-year survival of 51.7% (95% CI: 32.5-67.9%). Median duration on thalidomide was 79 days.
Thalidomide 200mg daily is well tolerated when given as maintenance therapy for ES-SCLC after induction chemotherapy. Further evaluation of anti-angiogenic agents in SCLC is warranted.
Lung Cancer 07/2007; 56(3):377-81. · 3.43 Impact Factor
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Afshin Dowlati,
Robert Chapman,
Shanmuga Subbiah,
Pingfu Fu,
Anne Ness,
Tania Cortas,
Lauren Patrick,
Sherrie Reynolds,
Natalie Xu, Nathan Levitan,
Percy Ivy,
Scot C Remick
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ABSTRACT: Rebeccamcyin analogue (RA) is an antitumor antibiotic that results in DNA intercalation and topoisomerase I and II inhibition. Phase I trials of the daily x 5 schedule and once every 3 week schedule have been completed. Antitumor activity was observed during the phase I trials. The purpose of this study is to primarily determine the response rate of 2 different schedules of administration of RA in patients with advanced non-small cell lung cancer (NSCLC) who had progressed on one prior chemotherapy regimen. Secondary endpoints were median and 1-year survival rates. A two-stage Simon design was employed for both arms of the study. Patients were randomly assigned to either of two RA treatment schedules of 500 mg/m(2) as a 1 hr infusion repeated every 3 weeks (Arm A) or 140 mg/m(2)/day x 5 days repeated every 3 weeks (Arm B). Forty-two patients were randomized. No confirmed objective responses were seen. Stable disease was seen in 52% of patients on arm A and 37% on arm B. Median survival and 1 year survival rates were 5.6 months and 33.3% for arm A, 9.7 months and 42.1% for arm B respectively. Cox regression model demonstrated increased risk of death in patients younger than the age of 61 and for patients treated on arm A. RA failed to demonstrate a significant response rate in this disease setting, although the proportion of patients with stable disease and 1-year survival were encouraging and similar to other published studies of approved single agents for second-line therapy of NSCLC.
Investigational New Drugs 01/2006; 23(6):563-7. · 3.36 Impact Factor
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ABSTRACT: In recent decades, cancer treatment has evolved from a purely surgical approach to the complex coordination of sophisticated
surgery, radiotherapy, and chemotherapy. The technology associated with pain and nutrition management has improved, and the
importance of psychosocial factors in the treatment of cancer patients has been recognized. The knowledge base pertaining
to cancer treatment has become so vast that many physicians have developed subspecialty expertise in a focused aspect of cancer
care. Quality of care analyses have indicated that the improved outcomes of certain cancer treatments occur when they are
provided at high-volume facilities.
12/2005: pages 184-193;
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ABSTRACT: To assess the overall and progression-free survival, response rate, and toxicity of combined docetaxel and celecoxib in the treatment of patients with non-small cell lung cancer progressing after initial chemotherapy for advanced disease.
Patients with non-small cell lung cancer and either measurable or evaluable disease experiencing progression after one or more platinum-based chemotherapy regimens given for advanced or metastatic disease, ECOG performance status 0-2, and adequate hematologic and biochemistry parameters were eligible for study inclusion; exclusion criteria included symptomatic brain metastases and full dose anti-coagulation. Therapy consisted of docetaxel 75 mg/m(2) every 21 days for a maximum of six cycles and celecoxib 400 mg orally twice daily commencing 7 days prior to docetaxel and continuing until disease progression.
A total of 41 patients were enrolled of whom 39 were deemed eligible and received at least one course of docetaxel. The mean age of enrolled patients was 60.5 years (range, 44-77); 67% were men and 79% white. All but one patient had an Eastern Clinical Oncology Group (ECOG) performance status of 0 or 1. Most (72%) had been treated with a prior taxane. Overall survival was 11.3 months (95% confidence interval [CI]: 7.9, 15.7) and progression-free survival 19.6 weeks (95% CI: 13.5, 25.0). A response rate of 10.2% (95% CI: 3%, 24%) for all eligible and treated patients was found. Grade 3 or 4 neutropenia occurred in 10/39 patients (25.6%); one death due to neutropenic sepsis occurred. No grade 3 or 4 renal or hepatic toxicities were documented.
Treatment with combination celecoxib and docetaxel is a safe regimen with a toxicity profile similar to that of docetaxel alone. Survival data are encouraging compared to historical controls and may prolong time to disease progression compared with single-agent docetaxel.
Lung Cancer 06/2005; 48(2):267-73. · 3.43 Impact Factor
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ABSTRACT: This Eastern Cooperative Oncology Group phase II trial was conducted to study the effectiveness of docetaxel in patients with malignant mesothelioma. Patients were treated with docetaxel 100 mg/m2 intravenously administered as a 1-hour infusion repeated every 3 weeks. The study accrued a total of 20 patients, 1 of whom was considered ineligible. Of the 19 eligible patients, 1 patient (5%) achieved a partial response, 3 patients (16%) had stable disease, 11 patients (58%) had progressive disease, and 4 patients (21%) were unevaluable. The study was terminated after the first accrual stage because of an insufficient number of complete or partial responses. To date, only 1 patient (with stable disease) has not relapsed. The estimated median survival time is 4 months and the estimated median time to treatment failure is 2.2 months. There were 3 early deaths associated with the treatment regimen: severe gastrointestinal toxicity, hemorrhage, and an acute pulmonary event. Docetaxel as a single agent does not demonstrate evidence of activity in malignant mesothelioma.
Clinical Lung Cancer 08/2004; 6(1):43-7. · 2.94 Impact Factor
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Matthew M Cooney,
Tomas Radivoyevitch,
Afshin Dowlati,
Beth Overmoyer, Nathan Levitan,
Kelly Robertson,
Sandra L Levine,
Kathleen DeCaro,
Carol Buchter,
Anne Taylor,
Bruce S Stambler,
Scot C Remick
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ABSTRACT: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors. Experimental Design: CA4P was administered in a dose-escalating fashion starting at 18 mg/m(2) i.v. every 21 days, and the maximal dosage was 90 mg/m(2). Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett's formula QTc = QT/(R-R interval)(1/2), and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C(max) versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed.
After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion.
CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.
Clinical Cancer Research 01/2004; 10(1 Pt 1):96-100. · 7.74 Impact Factor
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ABSTRACT: Patients with non-small cell lung cancer (NSCLC) typically receive platinum-based combination chemotherapy. In spite of improvements in symptoms and survival, response rates remain low and newer agents are being investigated. The newer agents may offer increased efficacy and reduced toxicity compared with established agents and regimens. The topoisomerase-I inhibitor, topotecan, achieves single-agent response rates of 4-25% in NSCLC. Topotecan has also been studied in combinations: a combination of topotecan, administered using the standard 5-day schedule, with cisplatin was effective but was associated with myelosuppression. The combination of topotecan plus carboplatin may be better tolerated and warrants further investigation. Topotecan was also combined with newer agents (gemcitabine, vinorelbine, docetaxel, paclitaxel) using a range of different administration schedules of topotecan. Response rates of up to 30% were achieved. A weekly schedule of topotecan was effective and well tolerated and was also convenient for healthcare professionals and patients.
Lung Cancer 09/2003; 41 Suppl 4:S23-6. · 3.43 Impact Factor
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ABSTRACT: EUS-measured reduction in tumor size after neoadjuvant therapy has previously been correlated with downstaging and improved survival in patients with esophageal cancer. The aim of this study was to determine whether tumor changes measured by EUS correspond to pathologically assessed chemoradiotherapy-induced tumor regression.
Forty-one patients with esophageal cancer treated with combined modality treatment were studied. After initial EUS, patients completed a cisplatin/carboplatinum, 5-fluorouracil, and radiotherapy regimen and underwent repeat EUS before resection. A positive response on EUS was defined as a 50% reduction in maximal tumor cross-sectional area. Chemoradiotherapy-induced tumor regression was assessed in resection specimens by using a previously defined pathologic scoring system based on the extent of tumor proliferation into adjacent fibrosis.
Pathologic tumor regression was present in 23, indeterminate in 5, and minimal or absent in 13 patients. EUS measured a positive response in 20 of 23 (87%) patients with CRT-induced tumor regression and a negative response in 10 of 13 (77%) patients with absent tumor regression (p < 0.001). EUS had a positive predictive value of 80% for pathologic tumor regression.
Measurement of tumor size by EUS is a reliable clinical method for assessing pathologic tumor regression before surgery.
Gastrointestinal Endoscopy 05/2002; 55(6):655-61. · 4.88 Impact Factor
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Amitabh Chak M.D,
Marcia I. Canto M.D,
Gregory S. Cooper M.D,
Gerard Isenberg M.D,
Joseph Willis M.D,
Nathan Levitan M.D,
Julie Clayman M.D,
Arlene Forastiere M.D,
Elisabeth Heath M.D,
Michael V. Sivak Jr. M.D,
Amitabh Chak,
Marcia I. Canto,
Gregory S. Cooper,
Gerard Isenberg,
Joseph Willis, Nathan Levitan,
Julie Clayman,
Arlene Forastiere,
Elisabeth Heath,
Michael V. Sivak Jr
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ABSTRACT: BACKGROUND
Standard endosonographic (EUS) staging criteria are unreliable for staging esophageal carcinoma after neoadjuvant therapy; however, measurement of tumor size reduction can identify patients who have achieved a pathologic response. In the current study the authors prospectively compared survival between patients classified as responders and those classified as nonresponders by EUS.METHODS
The maximal transverse cross-sectional area of the tumor was measured before and after neoadjuvant therapy in patients who were candidates for multimodality treatment. Response was defined as a ≥ 50% reduction in tumor area.RESULTSA total of 59 patients at 2 centers were followed for a median of 19 months. EUS assessed response in 34 patients (58%). Overall, responders had a median survival of 17.6 months compared with 14.5 months for nonresponders (P < 0.005). Survival was significantly longer in responders compared with nonresponders in the patient subgroup who underwent surgical resection (19.7 months vs. 14.6 months; P < 0.005), the patient subgroup with adenocarcinoma (21.4 months vs. 10.8 months; P < 0.005), and the patient subgroup initially classified as having T3N1 disease (17.6 months vs. 14.1 months; P < 0.05). Survival was not found to differ significantly between responders and nonresponders in the subgroup of patients with squamous cell carcinoma. EUS response was the only clinical variable that was associated with survival time in a multivariate analysis (relative hazard = 0.27; P < 0.005).CONCLUSIONS
Patients with esophageal carcinoma who respond to neoadjuvant treatment as identified by EUS measurement of reduction in tumor size have a significantly better prognosis than nonresponders. Cancer 2000;88:1788–95. © 2000 American Cancer Society.
Cancer 04/2000; 88(8):1788 - 1795. · 4.77 Impact Factor
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ABSTRACT: Background: Endoscopic ultrasound (EUS) is established as the most accurate method currently available for determining the depth of primary cancer invasion (T stage). Standard EUS criteria may not be accurate in assessing depth of cancer invasion and nodal status after patients have received chemotherapy or radiotherapy. Methods: We conducted a prospective study to determine whether EUS estimation of tumor size could be used to assess response to preoperative chemoradiation. Using EUS, TNM stage was assessed in 31 patients (22 men, 9 women; mean age 62 years) with cancer of esophagus or cardia (19 adenocarcinoma, 12 squamous cell cancer) before initiation of combined radiation and 5-fluorouracil/ cisplatin (and/or carboplatinum) chemotherapy. The cross-sectional area of the tumor in the transverse plane at the location where the tumor had maximal thickness was calculated to estimate tumor size. EUS staging and measurement of maximal cross-sectional area were repeated at completion of chemoradiation just before surgery. Response to preoperative chemoradiation was defined as 50% reduction in maximal cross-sectional area. Surgical staging was compared between responders and nonresponders. Results: Eight patients who did not undergo surgery were excluded from analysis. EUS T stage in the remaining 23 patients before therapy was as follows: 3 T2, 16 T3, and 4 T4. After chemoradiation, EUS T staging was changed in 6 patients (3 T4 downstaged to T3, 2 T3 downstaged to T2, and 1 T3 downstaged to T1). At surgical pathological examination, 3 patients had no residual tumor in the esophagus (T0), 5 had T1, 3 had T2, 10 had T3, and 2 had T4 tumors. EUS T staging accuracy after adjuvant therapy was only 43%. Maximal cross-sectional area decreased from a mean of 5.5 ± 2.4 to 1.6 ± 0.9 cm2 in responders, whereas maximal cross-sectional area went from 7.0 ± 3.0 to 5.4 ± 2.2 cm2 in nonresponders (p = 0.009). Ten of thirteen patients with at least a 50% reduction in maximal cross-sectional area (responders) had T0, T1, or T2 tumors at surgery, whereas 9 of 10 nonresponders had T3 or T4 tumors at surgery (p = 0.001). Conclusions: (1) Standard EUS staging criteria are not accurate after neoadjuvant chemoradiation, (2) reduction in maximal cross-sectional area of tumor appears to be a more useful measure for assessing response of esophageal cancer to preoperative chemoradiation, and (3) responders have an increased likelihood of downstaging at surgery than nonresponders. (Gastrointest Endosc 1998;48:158-63.)
Gastrointestinal Endoscopy.
