Novotny, Paul J.

PURPOSE: In the course of conducting a series of prospective clinical trials devoted to defining new treatment opportunities for hot flashes in cancer survivors, considerable experience has been acquired with related methodologic issues. This article has been written in response to many queries regarding this methodology. PATIENTS AND METHODS: A series of seven different clinical trials that involved 968 patients was used for this work. Reliable and valid definitions of hot flash intensity were developed from patient-reported descriptions. Concomitant validity and reliability assessment of patient-completed diaries was undertaken to compare hot flash data with toxicity and quality-of-life (QOL) end points and to examine consistency across patient groups using variability analysis and correlation procedures. Parametric data from this meta-analysis was used to examine relative power considerations for the design of phase II and phase III clinical trials. RESULTS: Daily diaries used in these studies exhibited consistency and reliability and had few missing data. Hot flash frequency and hot flash score (frequency multiplied by average severity) variables produced almost identical end point results. For phase III placebo-controlled studies, 50 patients per treatment arm seem appropriate to provide sufficient power specifications to detect a clinically meaningful change in hot flash activity. For phase II trials, 25 patients per trial seem to provide reasonable estimates of eventual hot flash efficacy to screen potential agents for more definitive testing. CONCLUSION: Given the data gained from these experiences, we can plan and carry out more efficient trials to identify efficacious agents for the reduction of hot flash activity.

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: Randomized studies have suggested that sucralfate is effective in mitigating diarrhea during pelvic radiation therapy (RT). This North Central Cancer Treatment Group study was undertaken to confirm the antidiarrheal effect of sucralfate. Several other measures of bowel function were also assessed. PATIENTS AND METHODS: Patients receiving pelvic RT to a minimum of 45 Gy at 1.7 to 2.1 Gy/d were eligible for the study. Patients were assigned randomly, in double-blind fashion, to receive sucralfate (1.5 g orally every 6 hours) or an identical looking placebo during pelvic RT. RESULTS: One hundred twenty-three patients were randomly assigned and found assessable. Overall, there was no significant difference in patient characteristics between those receiving sucralfate and those receiving placebo. Moderate or worse diarrhea was observed in 53% of patients receiving sucralfate versus 41% of those receiving placebo. Compared with patients receiving placebo, more sucralfate-treated patients reported fecal incontinence (16% v 34%, respectively; P = .04) and need for protective clothing (8% v 23%, respectively; P = .04). The incidence and severity of nausea were worse among those taking sucralfate (P = .03). Analysis of patient-reported symptoms 10 to 12 months after RT showed a nonsignificant trend toward more problems in patients taking sucralfate than in those taking placebo (average, 2.3 v 1.9 problems, respectively; P = .34). CONCLUSION: Sucralfate did not decrease pelvic RT-related bowel toxicity by any of the end points measured and seems to have aggravated some gastrointestinal symptoms.

PURPOSE: Hot flashes represent a significant clinical problem for some breast cancer survivors. Safe, effective treatment is needed for this prominent clinical problem. Although it has been shown that estrogen or progesterone replacement therapy can alleviate this problem, there are continued safety concerns regarding the use of hormonal therapies in these women. Based on anecdotal information, we hypothesized that soy-derived phytoestrogens, weak estrogen-like substances in the soybean that demonstrate estrogen agonist and/or antagonist effects when they bind to estrogen receptors, could alleviate hot flashes. This current trial was designed to investigate this hypothesis.PATIENTS AND METHODS: This double-blind clinical trial involved breast cancer survivors with substantial hot flashes. After randomization, patients underwent a 1-week baseline period with no therapy. This was followed by 4 weeks of either soy tablets or placebo. The patients then crossed over to the opposite arm in a double-blind manner for the last 4 weeks. Patients completed a daily questionnaire documenting hot flash frequency, intensity, and perceived side effects.RESULTS: Of the 177 women who were randomized and started the study substance, 155 (88%) provided useable data over the first 5 weeks; 149 provided usable data over the entire 9 weeks. There was no suggestion that the soy product was more effective in reducing hot flashes than the placebo. At study completion, patients preferred the soy product 33% of the time, the placebo 37% of the time, and neither substance 31% of the time. No toxicity was observed.CONCLUSION: The soy product did not alleviate hot flashes in breast cancer survivors.

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.