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Purpose: The impact of the side effects of megestrol acetate on the quality of life of noncachectic women with advanced breast cancer was studied in a dose-response clinical trial of the Cancer and Leukemia Group B (CALGB 8741). Side effects of appetite increase and weight gain at higher doses were predicted to have a negative effect on quality of life., Patients and Methods: Stage IV breast cancer patients were randomized to receive either 160, 800, or 1,600 mg/d of megestrol acetate. Quality of life was assessed in 131 patients at trial entry and at 1 and 3 months while on treatment, by telephone interview, using the following measures: the Functional Living Index-Cancer (FLIC), Rand Functional Limitations Scale, Rand Mental Health Inventory (MHI), the Body Image Subscale, and linear analog scales of drug side effects., Results: At 3 months, women treated with 160 mg/d reported less severe side effects (P < .0005), better physical functioning (FLS, P < .0005), less psychologic distress (MHI, P = .008), and an improvement in overall quality of life (FLIC, P = .003) from the time of study entry as compared with those treated with 1,600 mg/d. Patients who received the 800-mg/d dose fell between the low- and high-dose arms in reported intensity of drug side effects, but responded similarly to those in the 160-mg/d group in terms of physical functioning, psychologic distress, and overall quality of life., Conclusion: Unless additional follow-up data demonstrate a survival advantage at higher doses, the 160-mg/d dose is optimal, achieving maximal treatment effect with the fewest side effects and better quality of life.

High-dose megestrol acetate has been associated with increased appetite and weight. To examine the effects of high-dose megestrol acetate in the treatment of anorexia and weight loss in patients with advanced hormone-insensitive malignant lesions, a randomized double-blind placebo-controlled trial was conducted. Patients receiving megestrol acetate for 1 month reported a significant improvement in appetite and adequacy of food intake compared with those receiving placebo. A three-item scale measuring appetite, adequacy of food intake, and concern about weight revealed a higher improvement with megestrol acetate than with placebo. Patients who worsened while receiving placebo had similar favorable changes after the cross over to megestrol acetate. These data indicate that megestrol acetate may improve appetite and food intake in patients with advanced cancer.

Empiric clinical trials have revealed new mechanisms by which hormonal therapies may exert their antitumor effects. Initial studies using escalated doses of agents like toremifene and megestrol acetate have yielded interesting results, showing responses in hormone-receptor-negative patients and in patients progressing after standard doses, respectively. A trial by Cancer and Leukemia Group B randomizing patients with advanced breast cancer to standard-dose (160 mg) megestrol acetate or to 5 or 10 times the standard dose (800 and 1,600 mg) has completed accrual. It is hoped that these results will provide a definitive answer to the dose-response issue for breast cancer. However, regardless of this trial's ultimate outcome, higher doses of megestrol acetate have demonstrated important new effects on appetite stimulation and weight gain; ongoing laboratory research promises potential roles for megestrol acetate in the reversal of chemotherapeutic drug-induced tumor resistance.

A dose-response relationship has been suggested for medroxyprogesterone acetate in the treatment of advanced breast cancer. To determine the tolerability and efficacy of increasing doses of megestrol acetate in the treatment of metastatic breast cancer, we conducted a phase I/II study among 57 patients. Three patients each received 480, 800, and 1280 mg/d; 48 patients received 1600 mg/d. Of the 57 patients, 56 patients had had disease progression on prior hormone therapy, chemotherapy, or both. Twenty-seven patients had previously received standard-dose MA (160 mg/d). Among the 37 patients with measurable disease, high-dose megestrol acetate (HDMA) produced 6 (16%) complete responses (CRs) and 6 (16%) partial responses (PRs); 11 patients achieved stable disease (SD). HDMA resulted in improvement or stabilization in 12 of the 20 patients with evaluable, non-measurable disease. There were no responses among the 6 patients with liver metastases. Among the 27 patients who were previously treated with standard-dose MA, including 9 patients with primary treatment failure, HDMA resulted in 1 CR, 3 PRs, and 10 SD. Toxicities, which were mild and reversible, included fluid retention, hypertension, hyperglycemia, and mild congestive heart failure. Two patients had superficial phlebitis. The most profound side effect was weight gain which occurred in 43 patients (75%). This study suggests a dose-response relationship for MA in the treatment of advanced breast cancer. A randomized trial to determine the optimal dose is ongoing.

The extreme anorexia and cachexia associated with cancer and other disease states often have important physical and psychologic impact on both patients and their families. Weight gain resulting from megestrol acetate therapy in breast cancer patients suggests that progestins may be useful for alleviation of disease-associated appetite and weight loss. Early breast cancer experience, as well as preliminary data from a randomized, placebo-controlled trial of high-dose megestrol acetate in cancer anorexia and wasting, is therefore reviewed. Although the precise mechanism by which megestrol acetate exerts its effect remains unclear, weight gain was observed in 75% of patients in the high-dose study and in nearly all of those who remained on therapy for 6 weeks. It was concluded that, although megestrol acetate cannot be expected to directly affect the prognosis of patients with hormone-insensitive tumors, it may increase host resistance by improving nutritional status and/or enhancing the quality of life.

The quality of life of patients with advanced cancer depends to a large degree on the presence of disease or treatment-related symptoms. Anorexia is frequent in cancer patients, but has received less attention than other symptoms such as pain or nausea. Yet, anorexia is important because it reduces caloric intake and leads to malnutrition. Further, lack of appetite can disrupt basic activities of daily living, such as eating, and may also interfere with family and social interactions. To test the efficacy of drugs that reverse anorexia, we need accurate and reliable parameters to quantitate this symptom. The effects of anorexia and its reversal on the patients' clinical progress, food intake, nutritional status, and quality of life need to be evaluated. Our ongoing studies demonstrate that megestrol acetate can reverse cancer anorexia and that appetite changes strongly correlate with changes in weight, food intake, and quality of life scores.

We recently observed significant weight gain in patients with advanced breast cancer treated with high-dose megestrol acetate. However, the mechanisms of this effect are completely unknown. As the analysis of the action of steroids in vivo is complex, we chose to examine the effects of megestrol acetate on the differentiation of a preadipocyte clone (L1) of the Swiss 3T3 mouse fibroblast cell line. Addition of insulin, fetal bovine serum, dexamethasone, and methyl-isobutylxanthine to confluent 3T3-L1 cells induced adipocyte differentiation, as verified by morphologic studies and analysis of the activity of the enzyme glycerol-3-phosphate dehydrogenase (G-3-PD), a specific and sensitive indicator of lipocyte function. Substitution of megestrol acetate for dexamethasone also resulted in greatly increased lipocyte differentiation. Tumor necrosis factor (TNF) alpha blocked the adipocyte differentiation induced by the combination of insulin, dexamethasone, and methyl-isobutylxanthine. Addition of megestrol acetate failed to reverse the inhibitory effect of TNF. Thus, megestrol acetate, in vitro, is a potent inducer of lipocyte differentiation. Further studies on the regulation of adipocyte differentiation and function in this model system may be important to clarify megestrol acetate's mechanism of action.

Weight loss and anorexia are significant complications of a variety of disorders and add morbidity to the underlying process. We observed marked weight gain (median, 5.1 kg; range, 0.9 to 20.1 kg) and appetite enhancement in 27 of the 28 patients with breast cancer receiving treatment consisting of high doses of oral megestrol acetate (480 to 1600 mg/d). Weight gain occurred regardless of pretreatment weight, extent of metastases, or response to therapy. Our results suggest a possible role for megestrol acetate in reversing anorexia and weight loss, thereby improving the quality of life of patients with cachexia. Further research is needed to establish the mechanism of weight gain and potential clinical applications.

Cachexia is often a severe problem in the management of cancer and other illnesses because it adds to the morbidity of the underlying disease and complicates its treatment. Megestrol acetate has been observed anecdotally to produce weight gain. A review of our experience, and our ongoing phase I/II study of high-dose megestrol acetate for breast cancer, revealed that weight gain occurred in nearly one third (27%) of patients at conventional doses (160 mg/d), and that a marked weight gain (median, 5.1 kg; range, 0.9 to 20.1 kg) occurred in 27 of 28 patients with breast cancer during treatment with high doses of megestrol acetate. Subjective improvement in appetite occurred in most patients at low doses and in most patients at high doses. Further, nearly one half (48%) of patients at conventional doses and virtually all patients at high doses experienced an increased sense of well-being. Our data suggest that megestrol acetate has a potential role in producing subjective improvement, sense of well-being, and increase in appetite and weight, and that the effect may be dose related. Further research is necessary to understand the mechanism of appetite stimulation and/or anabolic effect.

Cachexia can be a severe problem in the management of patients with cancer and other illnesses because it produces an ever-increasing spiral of anorexia, undernutrition, loss of tissue mass, muscle wasting, and increased susceptibility to infection and treatment toxicity. Megestrol acetate has been observed to produce weight gain in patients with hormone-sensitive tumors and has recently been noted to produce a similar degree of weight gain in those with hormone insensitive tumors. A review of our experience in a phase I-II study of escalating doses of megestrol acetate for advanced breast cancer revealed that weight gain occurred in more than 80% of all treated patients and in 90% of those patients who received treatment for 6 or more weeks. The median maximum weight gain was 5.5 kg, with a range of -5.6 to 44 kg. Subjective improvement in appetite occurred in most patients. These data provided the impetus for a series of further studies of the role of megestrol acetate in the control of cachexia, including a randomized study in cancer cachexia, AIDS cachexia, and anorexia nervosa. In addition, a number of laboratory trials seeking the mechanism of action have been initiated, as well as whole-animal studies to define the compartment of increased weight. Our data and the preliminary observation of weight gain in patients with hormone insensitive tumors suggest that megestrol acetate has a potential role in producing a possibly dose-related subjective improvement and an increase in appetite and weight. Further research is necessary to understand the mechanism of appetite stimulation and anabolic effect.

Endocrine maneuvers have considerable use in the management of advanced breast cancer, and progestins are hormonal agents with considerable antitumor activity. Sequential studies suggest a steep dose-response relationship for medroxyprogesterone. Megestrol acetate, (Megace, Bristol-Myers Oncology Division, Evansville, IN) an easily used progestin, has activity in advanced breast cancer, but dose response for this agent has not clearly been shown. This study was initiated to evaluate the tolerability and toxicity of escalating doses of megestrol acetate. Forty patients with advanced breast cancer who were not eligible for treatment with other conventional hormones or chemotherapy were entered into the study. All patients had disease progression on previous treatments, and all with visceral disease had disease progression while on one or more chemotherapy regimens. Using specially formulated 160-mg tablets (Bristol-Myers Oncology Division), three patients were entered at each of three dose levels: 480,800, and 1,280 mg/d. Thirty-one patients were entered at 1,600 mg/d. There were 39 postmenopausal women and one man; the median age was 58 years; the median performance status was 80%. Among 31 patients with measurable disease, there were six complete responses (CRs) and five partial responses (PRs); 11 of the 31 had stable disease. Fourteen patients had received previous megestrol acetate with disease progression on treatment: Six had had primary treatment failure. One of these 14 achieved CR, three achieved PR, and eight acheived stable disease on the high-dose regimens. Toxicities were mild (grade 0 to 1) and included mild BP elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, congestive heart failure, and other mild problems.(ABSTRACT TRUNCATED AT 250 WORDS)

The optimal dose of progesterone compounds for the treatment of breast cancer is unknown, but there is evidence to suggest a dose-response curve. We are testing the tolerability and efficacy of megestrol acetate administered orally and continuously in doses three to ten times higher than the standard dose of 160 mg/d. We have so far treated 33 patients with metastatic breast cancer and positive or unknown tumor hormone receptor status. Thirty patients had had documented disease progression with previous hormonal therapy, and 22 had failed with previous chemotherapy. Twenty-five patients had objectively measurable metastases. In this heavily pretreated group, the objective response rate was 40%; in addition, 32% of patients had stabilization of disease. Interestingly, ten of 12 patients who had developed disease progression while on standard-dose megestrol acetate therapy had objective response or stabilization on the higher dose. Toxicity was acceptable and reversible and included mild elevations of blood pressure and weight gain. Our results indicate that high-dose megestrol acetate is well-tolerated and highly active in advanced refractory breast cancer, and suggest a dose-response curve for the drug in the treatment of breast cancer.

A dose-response relationship has long been suspected for progestin compounds in the treatment of breast cancer, but only recently have trials been implemented to investigate this issue. In 1985, we began a phase I-II study of high-dose megestrol acetate in dosages of 480 mg/d to 1,600 mg/d in heavily pretreated postmenopausal patients with advanced breast cancer. After establishing the safety of this therapy, we expanded our trial, which now includes 47 patients, 34 of whom have measurable disease. Of these 34 patients, 30 had disease progression on prior hormonal therapy and 29 had progression on chemotherapy. Six of the 34 patients had complete response and six had partial response for a median time on study of 10 months (range, 8 to 30 months). Ten patients had stabilization and 12 had progression. Thirteen patients had evaluable but nonmeasurable disease, and of these, ten had improvement or stabilization for a median period of 6 months (range, 2 to 18 months) and three had progression. Of 17 patients who had experienced disease progression while receiving standard-dose megestrol acetate, 13 (76%) achieved objective remissions or stabilization with high-dose therapy. The main side effects were weight gain and appetite enhancement, which were beneficial in 13 underweight patients. These data indicate that high-dose megestrol acetate is well tolerated and effective in patients with advanced breast cancer refractory to multiple previous therapies. While optimal dose levels for clinical use remain to be established by ongoing studies, our data suggest that doses higher than the standard dose may be more effective.