Faculty Publications

Purpose To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel. Patients and Methods Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons. Results Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup. Conclusion Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.

PURPOSE: To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel. PATIENTS AND METHODS: Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons. RESULTS: Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup. CONCLUSION: Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.

PURPOSE: We examined the rates and determinants of appropriate and inappropriate use of postmastectomy radiotherapy (PMRT), as defined by the National Comprehensive Cancer Network (NCCN) practice guidelines, among women with Stage I-II breast cancer (American Joint Committee on Cancer, 5th edition). METHODS AND MATERIALS: Using clinical characteristics, 1,620 consecutive patients at eight NCCN institutions who had undergone mastectomy between July 1997 and June 2002 were classified into three cohorts according to whether the guidelines (1) recommended PMRT, (2) recommended against PMRT, or (3) made no definitive PMRT recommendation. We defined the absence of PMRT in the first cohort as underuse and receipt of PMRT in the second cohort as overuse. Multivariate logistic regression analysis was applied to investigate the association of clinical and sociodemographic factors with PMRT. RESULTS: Overall, 23.8% of patients received PMRT. This included 199 (83.6%) of 238 in the "recommend PMRT" cohort, 58 (5.6%) of 1,029 in the "recommend against PMRT" cohort, and 127 (38.6%) of 329 in the "consider PMRT" cohort. The only factor associated with underuse in the "recommend PMRT" cohort was nonreceipt of chemotherapy (odds ratio [OR], 0.08; p <0.0001). In addition to tumor characteristics, the factors associated with overuse in the "recommend against PMRT" cohort included age <50 years (OR, 2.28; p = 0.048), NCCN institution (OR, 1.04-8.29; p = 0.026), higher education (OR, 3.49; p = 0.001), and no reconstructive surgery (OR, 2.44; p = 0.019). The factors associated with PMRT in the "consider PMRT" cohort included NCCN institution (OR, 1.1-9.01; p <0.0001), age <50 years (OR, 2.26; p = 0.041), and tumor characteristics. CONCLUSION: The results of our study have shown that concordance with definitive treatment guidelines was high. However, when current evidence does not support a definitive recommendation for PMRT, treatment decisions appear to be influenced, not only by patient age and clinical characteristics, but also by institution-specific patterns of care.

Purpose: We examined the rates and determinants of appropriate and inappropriate use of postmastectomy radiotherapy (PMRT), as defined by the National Comprehensive Cancer Network (NCCN) practice guidelines, among women with Stage I-II breast cancer (American Joint Committee on Cancer, 5th edition). Methods and Materials: Using clinical characteristics, 1,620 consecutive patients at eight NCCN institutions who had undergone mastectomy between July 1997 and June 2002 were classified into three cohorts according to whether the guidelines (1) recommended PMRT, (2) recommended against PMRT, or (3) made no definitive PMRT recommendation. We defined the absence of PMRT in the first cohort as underuse and receipt of PMRT in the second cohort as overuse. Multivariate logistic regression analysis was applied to investigate the association of clinical and so.ciodemographic factors with PMRT. Results: Overall, 23.8% of patients received PMRT. This included 199 (83.6%) of 238 in the "recommend PMRT" cohort, 58 (5.6%) of 1,029 in the "recommend against PMRT" cohort, and 127 (38.6%) of 329 in the "consider PMRT" cohort. The only factor associated with underuse in the "recommend PMRT" cohort was nonreceipt of chemotherapy (odds ratio [OR], 0.08; p <0.0001). In addition to tumor characteristics, the factors associated with overuse in the "recommend against PMRT" cohort included age <50 years (OR, 2.28; p = 0.048), NCCN institution (OR, 1.04-8.29; p = 0.026), higher education (OR, 3.49; p = 0.001), and no reconstructive surgery (OR, 2.44; p = 0.019). The factors associated with PMRT in the "consider PMRT" cohort included NCCN institution (OR, 1.1-9.01; p <0.0001), age <50 years (OR, 2.26; p = 0.041), and tumor characteristics. Conclusion: The results of our study have shown that concordance with definitive treatment guidelines was high. However, when current evidence does not support a definitive recommendation for PMRT, treatment decisions appear to be influenced, not only by patient age and clinical characteristics, but also by institution-specific patterns of care. (C) 2008 Elsevier Inc.

Background: Although many quality measures have been created, there is no consensus regarding which are the most important. We sought to develop a simple, explicit strategy for prioritizing breast cancer quality measures based on their potential to highlight areas where quality improvement efforts could most impact a population. Methods: Using performance data for 9019 breast cancer patients treated at 10 National Comprehensive Cancer Network institutions, we assessed concordance relative to 30 reliable, valid breast cancer process-based treatment measures. We identified 4 attributes that indicated there was room for improvement and characterized the extent of burden imposed by failing to follow each measure: number of nonconcordant patients, concordance across all institutions, highest concordance at any I institution, and magnitude of benefit associated with concordant care. For each measure, we used data from the concordance analyses to derive the first 3 attributes and surveyed expert breast cancer physicians to estimate the fourth. A simple algorithm incorporated these attributes and produced a final score for each measure; these scores were used to rank the measures. Results: We successfully prioritized quality measures using explicit, objective methods and actual performance data. The number of nonconcordant patients had the greatest influence on the rankings. The highest-ranking measures recommended chemotherapy and hormone therapy for hormone-receptor positive tumors and radiation therapy after breast-conserving surgery. Conclusions: This simple, explicit approach is a significant departure from methods used previously, and effectively identifies breast cancer quality measures that have broad clinical relevance. System-atically prioritizing quality measures could increase the efficiency and efficacy of quality improvement efforts and substantially improve outcomes.

Epithelial ovarian cancer is initially a chemosensitive neoplasm, with overall response rates to systemic platinum-based therapy exceeding 80% in conjunction with cytoreductive surgery. However, long-term survival remains poor due to eventual tumor recurrence and emergence of drug resistance. While platinum (cisplatin or carboplatin) and taxanes remain at the core of primary treatment, there has been increased interest in the evaluation of doublet and triplet combinations with diverse cytotoxic agents, including docetaxel, topotecan, gemcitabine, and PEG-liposomal doxorubicin. This has been prompted by single-agent activity in the setting of recurrent platinum-resistant disease and encouraging data from nonrandomized phase I-II trials. As a result, beginning in 1998, the international cooperative groups collaborated on a series of phase III trials to improve long-term outcomes through the development of new platinum-based combinations. More than 10,000 women have been randomized on these trials, and preliminary data from several studies have been reported. Although final data are pending, there is not currently any evidence to recommend adopting a new two- or three-drug combination, and carboplatin with paclitaxel remains the standard regimen of choice. Rapid developments in molecular-targeted therapy are challenging our paradigm for future clinical trials, and our priorities need to be carefully considered.

Purpose. Selection of a feasible sequence and schedule of carboplatin in combination with topotecan for evaluation in advanced epithelial ovarian cancer (EOC). Patients and methods. Women with stages III-IV EOC or primary peritoneal carcinoma without prior chemotherapy were assigned to consecutive cohorts evaluating a "forward" (carboplatin day 1, topotecan days 1-3), "reverse" (carboplatin day 3, topotecan days 1-3), or "extended reverse" sequence (carboplatin day 5, topotecan days 1-5). Patients received 4 cycles carboplatin-topotecan followed by 4 cycles carboplatin-paclitaxel. Feasibility was defined according to the cumulative proportion of patients with dose-limiting events (DLEs) during the first four cycles. Results. Sixty-eight patients were enrolled across 5 cohorts. The forward sequence demonstrated unacceptable hematologic DLEs at the lowest topotecan dose (0.75 mg/m(2)/day X 3 days). The reverse sequence was feasible at 1.25 mg/m(2)/day X 3 days, with only 1/15 patients experiencing a DLE within 4 cycles, and 14/15 patients were able to receive 4 subsequent cycles of carboplatin-paclitaxel. The extended reverse sequence was associated with excessive DLEs at 1.00 mg/m(2)/day X 5 days. Prophylactic hematopoietic growth factors were not required. Conclusion. Higher doses of topotecan could be safely administered with reduced toxicity over multiple cycles using the reverse sequence, which was selected for phase III evaluation. The relative efficacy of the forward and reverse sequence is unknown. (c) 2006 Elsevier Inc. All rights reserved.

SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Gynecol Oncol Grp, Gynecol Canc Intergrp, Philadelphia, PA USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA

Gemcitabine (2'2'-difluorodeoxycytidine [dFdC]) is a synthetic analog of deoxycytidine with two fluorine atoms at the 2' position of the carbohydrate. As a hydrophobic molecule, dFdC competes for intracellular access via membrane-associated nucleoside transporter proteins. Following intracellular transport, dFdC is phosphorylated sequentially by deoxycytidine kinase to gemcitabine triphosphate, which inhibits ribonucleotide metabolism, hinders DNA processing, and increases accumulation of intrastrand adducts and interstrand cross-links, thereby leading to a G1 block in the cell cycle. dFdC monotherapy has been extensively evaluated at doses of 800-1250 mg/m2. dFdC is generally well tolerated, with the most frequently occurring dose-limiting toxicities being hematologic, noncumulative, and easily managed by dose alteration. Several studies involving treatment of recurrent ovarian cancer patients with dFdC monotherapy, most of whom had platinum-resistant disease and/or prior exposure to paclitaxel, led to overall response rates of 14-22% and a median duration of response of 4.0-10.6 months. An additional one third of the participants experienced stable disease for an overall clinical benefit in approximately one half of the treated patients. Tumor cells with a multidrug resistance phenotype have increased sensitivity to dFdC (collateral sensitivity). As dFdC is unaffected by platinum resistance, and not susceptible to classic multidrug resistance, it could be particularly beneficial to administer following treatment with agents that induce multidrug resistance. Integration of dFdC with platinum and/or radiation should also be investigated. [References: 34]

Ovarian cancer arises from the specialized surface epithelium, which routinely expresses receptors for reproductive hormones and growth factors. However, as a group, ovarian tumors are less responsive to hormonal therapy than either breast or endometrial cancer. The complex factors that govern hormonal response and associated molecular interactions are under intensive investigation, with the generation of new hypotheses that merit clinical evaluation. As such, it is reasonable to consider a number of potential hormonal interventions related to the prevention and treatment of ovarian cancer.

Purpose. To determine the feasibility of administering a minimum of four cycles of carboplatin, paclitaxel, and gemcitabine (CPG) every 21 days without excessive dose modification or cycle delay in patients with previously untreated epithelial ovarian cancer or primary peritoneal cancer. Methods. Paclitaxel 175 mg/m(2) was given over 3 h followed by carboplatin concentration time curve (AUC) 5 (day 1) and gemcitabine g/m(2) (days 1 and 8) in the first cohort. A second cohort received paclitaxel 135 mg/m2 over 3 h followed by carboplatin AUC 5 (day 1) and gemcitabine 800 mg/m(2) (days 1 and 8). A maximum of eight cycles was administered. Results. Fourteen patients received 89 cycles during the first cohort. Seven patients experienced 19 hematologic dose-limiting events (DLEs) within the first four cycles, including grade 4 thrombocytopenia (n = 9), febrile neutropenia (n = 3), and omission of gemcitabine on day 8 (n = 7). This exceeded the threshold for nonfeasibility. In the second, less intense regimen, 36 patients were entered. Thirty-one evaluable patients received a total of 200 and median of 6 (range: 2-8) cycles. Thirteen of the thirty-one had 27 DLEs within the first four cycles including grade 4 thrombocytopenia (n = 5), prolonged grade 4 neutropenia (it = 2), febrile neutropenia (n = 2), and omission of day 8 gemcitabine (n = 18). There was one patient death secondary to a wound abscess and febrile neutropenia. Myelosuppression as expected was the dose-limiting toxicity. Conclusion. The schedule of paclitaxel 135 mg/m(2) (day 1, 3 h), carboplatin AUC 5 (day 1), and gemcitabine 800 mg/m(2) (days 1 and 8) is feasible, with an acceptable toxicity profile. (C) 2003 Elsevier Inc. All rights reserved.