Krook, James E.

8085 Background: Historically, tumor response has been the primary endpoint in phase II (P2) trials in ED-SCLC. We investigated the suitability of alternate PFS based endpoints to predict OS as early evidence of efficacy in the P2 setting. Methods: Individual patient (pt) data from 942 pts from 11 previously untreated ED-SCLC P2 and phase III (P3) platinum- or paclitaxel-based treatment trials were pooled. Best response (BR), response confirmed (RC), objective status at 16 weeks (RR16), and PFS rate at 5 and 6 months were considered. Percent agreement (PA) and kappa (k) for PFS5, PFS6, BR, RC, and RR16 with OS at 12 months (OS12) was calculated on a per-pt basis and predictive utility was assessed using the area under the receiver operating characteristic (A- ROC) curve in logistic models. Cox models were used to assess the prognostic impact of the endpoints on subsequent survival, using landmark analysis. Results: The median OS and PFS were 9.6 m and 5.5 m, respectively. PFS5 and PFS6 had the highest PA, k, and A-ROC values, and were predictive of subsequent survival in the landmark analysis (p <0.0001; c-statistics ≥ 0.60). While RR16 and BR were significantly associated with subsequent survival (p<0.0001, c-statistics of 0.61 and 0.57, respectively) the PA, k, and A-ROC values were lower. Conclusions: PFS rate at 5 and 6 months is more predictive of 12-month OS and subsequent survival than tumor response in untreated ED-SCLC. PFS based endpoints should be routinely used as primary endpoints in P2 trials within ED-SCLC. [Table: see text] No significant financial relationships to disclose.

9005 Background: Hot flashes can be a major problem in men with prostate cancer; effective non-hormonal options are needed. Methods: A four-arm, double-blinded, placebo-controlled randomized trial was developed to evaluate gabapentin for hot flashes. Men with bothersome hot flashes (at least 14/week) related to androgen deprivation therapy were randomized to receive either a placebo or gabapentin doses of 300 mg qd, 300 mg bid or 300 mg tid; men were treated for 4 weeks. Hot flashes numbers and scores (hot flash number times mean severity) were measured using a validated daily hot flashes diary. A one-week baseline period preceded initiation of study tablets. The primary endpoint was the average intrapatient difference in hot flash score between baseline and treatment termination. With the planned sample size of 50 evaluable patients per arm, the study provided 80% power to detect a difference in change from baseline at 4 weeks between each gabapentin arm and the placebo arm of 1.3 hot flashes per day or 3.3 points in hot flash score. Results: 223 patients were randomized between 12/21/2001 and 11/10/2006. The study arms were well balanced. The following table illustrates the percentage of baseline hot flash scores and frequencies during the fourth treatment week, compared to the baseline week for 179 eligible patients, utilizing the data available at time of this abstract preparation. Patients receiving 900 mg/d dose of gabapentin also reported significantly less hot flash distress and more hot flash control satisfaction than did the placebo group. The gabapentin was remarkably well tolerated, without any statistically significantly worse patient-reported side effects on the gabapentin arms. Conclusion: Gabapentin at the 900 mg/d dose can reduce hot flashes, in men receiving androgen deprivation therapy for prostate cancer. No significant financial relationships to disclose. [Table: see text]

PURPOSE: This article summarizes the third step of a research program to identify variables that supplement the predictive power of the the Eastern Cooperative Oncology Group (ECOG) performance status (PS) for survival. The objective was to produce a simple, practical, stratification factor for phase III oncology clinical trials involving patients with advanced malignant disease. PATIENTS AND METHODS: A questionnaire was administered to 729 patients with metastatic colorectal or lung cancers. Patients provided a Karnofsky index and appetite rating while physicians provided a survival estimate and the ECOG-PS. Scores for each item were categorized as having a positive, neutral, or negative indication for survival. A patient was classified as having a relatively good prognosis if three or more of the four items showed a positive indication, a bad prognosis if three or more items were negative, and an uncertain prognosis otherwise (Good/Bad/Uncertain [GBU] index). RESULTS: The GBU index improved on the prognostic power of a Cox model quartile index and PS alone and increased the accuracy of survival classification estimates by 5% to 10% more than ECOG-PS alone. For patients with PS of 0 or 1, significant survival patterns exist between GBU groups (P= .002 and .0001, respectively). CONCLUSION: The GBU index may be recommended as a supplementary stratification factor for certain future phase III trials in metastatic lung or colorectal cancer where patient heterogeneity is a particular concern. The GBU represents a relatively modest increase to the cost and patient burden of a clinical trial given the additional control that is achieved over the potentially confounding concomitant to the treatment variable.

PURPOSE: Substantial and successful effort has been focused on decreasing the risk of local failure after rectal cancer surgery through the use of adjuvant therapies. Our study examined data from studies conducted by United States cooperative groups to investigate the impact of surgical and pathologic variables in rectal cancer outcomes. PATIENTS AND METHODS: Surgical and pathologic reports from 673 patients with stage II/III rectal cancer enrolled onto three adjuvant clinical trials were reviewed for tumor and surgical variables. Additional information on individual institutions and operating surgeon was collected. Variables were tested for association with 5-year local recurrence and survival after adjustment for adjuvant treatments and other important prognostic factors. RESULTS: Five-year local recurrence and survival rates were 16% and 59%, respectively. Surgeons treating more than 10 study cases had lower local recurrence rates than those treating ≤ 10 (11% v 17%, P = .02). Free radial margins also correlated with local recurrence (P = .01). Type of surgery, distal margins, and tumor radial spread were not significant. Tumor adherence to adjacent structures predicted local recurrence (35% v 14%, P < .001) and survival (30% v 63%, P < .001), regardless of en bloc resection. Although T and N classification predicted survival (P < .001), only N classification correlated with local recurrence. The number and percentage of positive nodes correlated with survival, but only the percentage independently predicted local recurrence. Several pathologic and surgical variables were reported suboptimally. CONCLUSION: Moderate variability in outcomes among surgeons was detected in this high-risk population. Efforts to improve surgical results will require changes in reporting practices to allow for more accurate assessment of the quality of surgery.

PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m2 given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and ½ normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m2 IV for 1 hour in 500 mL of dextrose and ½ NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m2 IV for 2 to 3 hours in 750 to1,000 mL of dextrose and 5% water onday 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P = .429) and overall survival (P = .545) were not found to differ by treatment. CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.

PURPOSE: To determine whether dronabinol administered alone or with megestrol acetate was more, less, or equal in efficacy to single-agent megestrol acetate for palliating cancer-associated anorexia. PATIENTS AND METHODS: Four hundred sixty-nine assessable advanced cancer patients were randomized to (1) oral megestrol acetate 800 mg/d liquid suspension plus placebo, (2) oral dronabinol 2.5 mg twice a day plus placebo, or (3) both agents. Eligible patients acknowledged that loss of appetite or weight was a problem and reported the loss of 5 pounds or more during 2 months and/or a daily intake of less than 20 calories/kg of body weight. RESULTS: Groups were comparable at baseline in age, sex, tumor type, weight loss, and performance status. A greater percentage of megestrol acetate-treated patients reported appetite improvement and weight gain compared with dronabinol-treated patients: 75% versus 49% (P = .0001) for appetite and 11% versus 3% (P = .02) for ≥ 10% baseline weight gain. Combination treatment resulted in no significant differences in appetite or weight compared with megestrol acetate alone. The Functional Assessment of Anorexia/Cachexia Therapy questionnaire, which emphasizes anorexia-related questions, demonstrated an improvement in quality of life (QOL) among megestrol acetate–treated and combination-treated patients. The single-item Uniscale, a global QOL instrument, found comparable scores. Toxicity was also comparable, with the exception of an increased incidence of impotence among men who received megestrol acetate. CONCLUSION: In the doses and schedules we studied, megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with dronabinol alone. Combination therapy did not appear to confer additional benefit.

PURPOSE: Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetites in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia. PATIENTS AND METHODS: Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0.75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetites and drug toxicities. RESULTS: Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P = .03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P = .06). CONCLUSION: Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.

PURPOSE: Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial. PATIENTS AND METHODS: Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m 2 × 3) and cisplatin (30 mg/m 2 × 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m 2 × 3) and cisplatin (30 mg/m 2 × 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response. RESULTS: Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis (≥ grade 3) than those who received ODTI (12.3% v 5.3%; P = .05). Although patients received thoracic irradiation encompassing the postchemotherapy volumes, only seven of 90 local failures were out of the portal of irradiation. CONCLUSION: When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI.

Purpose To evaluate clinical characteristics and survival outcomes among patients with locally advanced or metastatic colorectal cancer who achieve a complete response (CR) to systemic treatment either alone or with multimodality approach. Patients and Methods Data were collected retrospectively from CRC patients enrolled onto the phase III trial N9741, a National Cancer Institute–funded and Gastrointestinal Cancer Intergroup–sponsored study coordinated by the North Central Cancer Treatment Group. Patients were randomly assigned to combinations of oxaliplatin, fluorouracil (FU)/leucovorin (LV) and irinotecan. The three treatment arms consist of IFL (irinotecan + FU/LV), FOLFOX4 (oxaliplatin + FU/LV), and IROX (irinotecan + oxaliplatin). Median follow-up was 42.6 months. Results Sixty-two (4%) of 1,508 patients had a CR to chemotherapy alone, and an additional 32 (2%) had a CR after multimodality treatment. Factors associated with achieving CR with systemic chemotherapy alone included FOLFOX4 treatment, patients with assessable disease, or a single site of metastasis. Continuing protocol treatment beyond two cycles after documentation of CR was not associated with improved survival. The rate of curative intent resection was significantly higher for patients treated with oxaliplatin-containing regimens (P = .02). Median survival was similar between patients with CR after chemotherapy alone (44.3 months) or after multimodality approach (47.4 months; P = .81). Conclusion FOLFOX4 was more likely to produce a CR than were IFL or IROX. Oxaliplatin regimens were more likely to result in successful surgical resections. Patients who have CR to systemic chemotherapy alone can achieve impressive survival outcomes similar to those seen among patients who attained a CR status after multimodality treatment.