Phase II trial of weekly patupilone in patients with castration-resistant prostate cancer.

BACKGROUND: Drug resistance mechanisms can reduce response rate and duration in men with castration-resistant prostate cancer (CRPC) receiving docetaxel-based therapy. Patupilone (epothilone B), a microtubule-targeting agent, may be unaffected by some resistance mechanisms. Therefore, a phase II study assessed the patupilone safety and activity in CRPC patients with and without previous chemotherapy. METHODS: CRPC patients received patupilone 2.5 mg/m(2) weekly for 3 weeks of a 4-week cycle. Patients were required to have measurable disease or prostate-specific antigen (PSA) progression (levels>20 ng/ml). RESULTS: All 45 enrolled patients (median age, 69 years) were safety and response assessable. Sixty-four percent had previous chemotherapy (55% had previous taxane therapy). Patients received a median of three patupilone cycles. Patupilone was generally well tolerated. Ten (22%) patients experienced grade 3 diarrhea, six (13%) grade 3 fatigue, and one (2%) grade 3 neuropathy with no neutropenia or thrombocytopenia incidence. Six (13%) patients had >or= 50% decline in PSA (three had previous taxane therapy). No patient with measurable disease had a response. Median overall survival was 13.4 months. CONCLUSIONS: The safety profile of weekly patupilone in CRPC patients compares favorably with that of other microtubule inhibitors. At the dose and schedule tested, patupilone demonstrated minimal activity in CRPC.

High-dose chemotherapy without autologous bone marrow transplantation in melanoma.

High-dose chemotherapy with BCNU, melphalan, or both, followed by autologous bone marrow transplantation (ABMT) has been reported to produce response rates in excess of 60% in patients with advanced melanoma. We tested doses of BCNU associated with reversible bone marrow toxicity and acceptable extramedullary toxicity without the use of ABMT in 19 patients with a diagnosis of advanced malignant melanoma. All patients were evaluable for toxicity and 18 were evaluable for response; one patient had a new primary tumor. The patient population had a median age of 44 years (range, 16 to 71) and a median Karnofsky performance status of 80 (range, 50 to 100). Ten were women and nine were men, all had visceral dominant disease, and none had received previous chemotherapy. Our purpose was to test the feasibility of treatment without ABMT, its toxicity and efficacy, and the possibility of administering sequential repeated courses of therapy. Vincristine was added to the regimen to potentially increase efficacy. Treatment consisted of BCNU (750 mg/m2) and vincristine (2 mg days 1 and 8). Six patients who recovered bone marrow function received melphalan (60 mg/m2) and vincristine (2 mg days 1 and 8). Twenty-two percent (95% confidence limits, 3% to 39%) of patients had remissions (all partial) and these were of short duration. Toxicity was substantial with 16% early lethality and 29% incidence of lethal drug-related complications. Two patients (11%) died toxic after a second course of BCNU. Our results suggest that there is no practical role for high-dose BCNU in the treatment of melanoma.

Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo.

PURPOSE: To investigate the efficacy and safety of oral ondansetron in the control of cisplatin-induced delayed emesis in patients who do not require rescue antiemetic therapy for acute emesis. PATIENTS AND METHODS: Five hundred thirty-eight chemotherapy-naive patients who received cisplatin chemotherapy (> or = 70 mg/m2), and who were not rescued for acute emesis, were eligible to be randomized to receive one of the three oral regimens to control delayed emesis. Group I received placebo on days 2 to 6; group II received ondansetron 8 mg twice daily on days 2 and 3 and placebo on days 4 to 6; group III received ondansetron 8 mg twice daily on days 2 to 6. All patients received intravenous ondansetron (0.15 mg/kg every 4 hours for three doses) for the control of acute emesis on day 1. The number of emetic episodes on days 2 and 3 combined (days 2/3, when incidence and severity of delayed emesis were expected to be greatest) was considered the primary measure of efficacy. RESULTS: Patients who received odansetron had significantly fewer emetic episodes on days 2/3, 4, and 5 than those who received placebo (P < or = .002 on each day). Additionally, significantly more patients who received ondansetron had a complete plus major response (C+MR; < or = two two emetic episodes) than those who received placebo on days 2/3 (56% v 37%, P = .001), 4 (94% v 85%, P = .005), and 5 (98% v 88%, P = .006). Patients who received ondansetron had significantly less nausea on day 2/3 when day-1 nausea was used as the baseline score (P = .025). Patients who received ondansetron also had significantly less nausea on day 4 (P = .042) and the results approached significance on day 5 (P = .066). CONCLUSION: Oral ondansetron had a significant effect in the control of cisplatin-induced delayed emesis and nausea in patients who had not required rescue antiemetics during the acute emesis period. The control of delayed nausea and vomiting was most notable in the immediate 2 days following cisplatin administration, with the clinical difference narrowing between the two treatment arms on subsequent days.

High-dose megestrol acetate for the treatment of advanced breast cancer: dose and toxicities.

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)

Pharmacoeconomics of nutritional support in cancer.

Physicians are increasingly asked to consider the cost of interventions, including procedures and drugs, when making medical decisions. This article provides some practical information about the cost and efficacy of a variety of nutrition support measures for patients with cancer or acquired immunodeficiency syndrome-associated anorexia and undernutrition. Nutrition counseling, liquid homemade or commercially available food supplements, and appetite stimulants are relatively low-cost, effective means of nutrition support. Enteral nutrition requires invasive procedures, is more expensive, is associated with more potentially serious complications, and should be reserved for patients whose nutritional status cannot be maintained with less aggressive measures. Total parenteral nutrition is exceedingly expensive and seldom helpful; it should be reserved for those patients whose gastrointestinal tract is nonfunctional. In addition to nutritional parameters and cost, the clinician should consider patient preferences. Specific tools to assess the impact of nutrition support measures on patients' quality of life are under development.

High-dose megestrol acetate in the treatment of postmenopausal women with advanced breast cancer.

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.

Treatment of anorexia and weight loss with megestrol acetate in patients with cancer or acquired immunodeficiency syndrome.

Anorexia is a symptom of cancer and a cause of decreased caloric intake and weight loss. Successful treatment for anorexia can improve the patient's well-being and prevent or reverse the effects of anorexia on nutrition. Following reports of appetite enhancement and weight gain in uncontrolled studies of high-dose (320 to 1,600 mg/d) megestrol acetate in patients with cancer or AIDS (acquired immunodeficiency syndrome), several randomized, placebo-controlled trials have been completed. These trials demonstrate that megestrol acetate therapy improves appetite and food intake in patients with anorexia and advanced cancer, leading to weight gain in a subset of patients. The mechanisms of action of megestrol acetate (a progesterone derivative) probably include both behavioral and metabolic effects. Several carefully designed randomized trials are under way to establish the optimal dose and to determine the mechanism of weight gain. Patients with cancer or AIDS who complain of anorexia and whose nutritional status is compromised may benefit from megestrol acetate therapy.

High-dose megestrol acetate in the treatment of advanced 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.

Studies of high-dose megestrol acetate: potential applications in cachexia.

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.

Appetite stimulation with megestrol acetate in cachectic cancer patients.

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.

Appetite stimulation and weight gain with megestrol acetate.

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.

Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion.

A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m2 per day for 5 days and repeated every 21-28 days. The patient population had a median age of 55 years (range 38-76) and a median Karnofsky performance status of 80 (range 60-100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/microliter (range 100-4800) in 8 heavily pretreated patients treated at 350 mg/m2 per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m2 and had WBC nadirs of 800/microliter and 600/microliter. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m2 per day, nadir 85,000/microliter). Neither hyponatremia nor symptomatic hypo-osmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m2 per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09-6.79 micrograms/ml. Steady state was achieved in 14.5 +/- 5.9 h (mean +/- SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t 1/2 of 5.3 +/- 3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543 +/- 150 micrograms/ml h and reflected a cyclophosphamide total-body clearance (CLTB) of 103 +/- 31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6-4.3 micrograms/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3% +/- 7.6% and 15.1% +/- 2.0% of the administered daily dose, respectively. The t1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m2 as an i.v. bolus.(ABSTRACT TRUNCATED AT 400 WORDS)

Costs and benefits of nutrition support in cancer.

Patients with advanced cancer or AIDS are frequently bothered by anorexia, decreased food intake, fatigue, weight loss, muscle wasting, and a decline in functional status. Nutritional support may afford these patients a better, although not longer life. Available interventions include nutrition counseling, homemade or commercial food supplements, appetite stimulants, enteral nutrition, and parenteral nutrition. Conservative cost estimates for these interventions range from $52/month for homemade supplements to $8,400/month for home parenteral nutrition. Clinicians need to be familiar with the benefits, risks, and costs of these therapies in order to suggest appropriate options.

Treatment of cancer anorexia with megestrol acetate: impact on 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.

Assessment and maintenance of nutrition in older cancer patients.

Variables that the clinician can assess to determine the nutritional status of cancer patients include percent and rate of weight loss from usual body weight, current weight compared to calculated ideal body weight, and levels of appetite and food intake. Our studies show that two-thirds of patients with advanced cancer over the age of 65 have had some degree of weight loss, and that more than half are underweight, have loss of appetite, or complain of a decrease in food intake. Ongoing support and education, food supplementation, and attention to activity level may all contribute to preserve the patient's nutritional status and quality of life. Severe, persistent anorexia that does not respond to dietary counseling can be reversed with megestrol acetate. Enteral and parenteral nutrition have specific indications but should not be routinely used in anorectic patients.

Hormonal and metabolic abnormalities in the malnourished cancer patient: effects on host-tumor interaction.

Many common metastatic cancers are associated with marked weight loss at the time of diagnosis. Anorexia clearly plays a major role in weight loss in the cancer patient, but cannot explain all of the weight loss noted. Malnourished patients with localized cancers under metabolic ward conditions fail to gain weight when given apparently adequate calories for anabolism, thus suggesting that these patients are hypermetabolic. Increased whole body protein breakdown, increased lipolysis, and increased gluconeogenesis have been repeatedly demonstrated in malnourished cancer patients. Protein and glucose metabolism are closely linked, and both are regulated by a number of the same hormones and metabolites. For example, when increased glucose production in malnourished cancer patients is inhibited pharmacologically, protein catabolism is proportionally decreased. Studies of glucose, growth hormone, cortisol, and insulin secretion following an oral glucose load in well-nourished cancer patients are consistent with insulin resistance but no other hormonal abnormalities. Malnourished cancer patients have elevated levels of growth hormone that are further stimulated by arginine and insulin infusion. No abnormalities of thyroid function were noted in cancer patients. Current studies are underway to determine the mechanisms and effects of progestational steroids and cytokines on both food intake and intermediary lipid metabolism.

Nutrition in advanced cancer: anorexia as an outcome variable and target of therapy.

The endpoints used as outcome variables in clinical cancer treatment trials, including nutrition intervention studies, should contain items that are meaningful to the patient. Variables to consider are appetite, food intake, physical performance, psychological and social functioning, response to cancer therapies, survival time, nutrition status, associated morbidity, and costs. Ideally, the design and conduct of nutrition trials should be carried out by a multidisciplinary team comprising medical oncologists, physician specialists in nutrition, dietitians, and social scientists. Anorexia has not been a focus of nutrition support trials in the past partly because of the lack of effective strategies to reverse it. Anorexia is one important cause of cancer starvation, and it also causes patient discomfort. This paper describes outcome variables that include patient derived subjective factors such as anorexia, and outlines new strategies to reverse anorexia. Pharmacologic strategies tested to reverse anorexia include corticosteroids, anabolic steroids, cyproheptadine, hydrazine sulfate, cannabinoids, and megestrol acetate. Of these, only the latter has been consistently well tolerated and effective, with significant improvements in appetite and food intake demonstrated in large-scale, randomized, controlled trials involving more than 600 cancer patients. Dose-response studies have demonstrated increasing efficacy with increasing doses of megestrol acetate from 160 to 800 mg/day. Doses in excess of 800 mg/day are not currently recommended. The mechanisms of action of megestrol acetate involve both behavioral and metabolic effects, and its impact on energy expenditure, appetite, body composition, endocrine function, and lipid metabolism is the subject of ongoing research.(ABSTRACT TRUNCATED AT 250 WORDS)

Special studies of the Hickman catheter of a patient with recurrent bacteremia and candidemia.

A patient with acute non-lymphocytic leukemia developed Staphylococcus epidermidis bacteremia and candidemia after maintenance chemotherapy and was treated satisfactorily. He returned 3 months later with abdominal pain due to an abdominal aortic aneurysm. At laparotomy, the aneurysm was found to be infected with Candida albicans. Following surgery, repeated positive blood cultures for C. albicans led to removal of his Hickman catheter. Culture of the catheter tip yielded C. albicans and S. epidermidis. Study of the catheter by scanning and transmission electron microscopy demonstrated yeast-like cells and gram-positive cocci in a biofilm. These studies suggest that the Hickman catheter was the source of the persistent candidemia and that it may have been the origin of the infection of the aneurysm.

Treatment of anorexia with megestrol acetate.

Anorexia and involuntary weight loss are prevalent problems in oncology and AIDS patients. Cytokines are suspected but not proven causes of cachexia. Megestrol acetate has been found to increase appetite, food intake, and weight in randomized, placebo-controlled trials in patients with advanced malignancies and in patients with AIDS. This hormone derivative probably has both central nervous system and peripheral metabolic effects. No significant effect on survival has been demonstrated in these trials. The optimal dose for appetite enhancement is unknown; we have chosen 320 mg/d as our initial dose. Megestrol acetate is usually well tolerated, and it may be helpful in the symptomatic and palliative therapy of patients with anorexia and weight loss.

Clinical approaches to nutritional support in cancer.

Anorexia and weight loss are frequent complications of cancer and AIDS. Assessment of dietary records and nutritional requirements in patients with decreased food intake and weight loss will assist the dietitian, nurse, or physician in initially addressing the problem. Patients may respond well to nutritional counseling and food supplements, but persistent severe anorexia is common. Various pharmacologic strategies to reverse anorexia and weight loss have been tested, including corticosteroids, anabolic steroids, cyproheptadine, hydrazine sulfate, dronabinol, and megestrol acetate. Dronabinol was recently found to improve appetite in AIDS patients. Megestrol acetate is so far the only agent associated with improvements in appetite and weight in patients with cancer and AIDS. Enteral and parenteral nutrition may be helpful in selected patients with gastrointestinal obstruction or dysfunction, but it is not generally indicated in patients with end-stage disease.