Sixty patients with stage III-B and IV soft tissue sarcomas were randomized to receive either ifosfamide 5 g/m2xdx1 and doxorubicin 60 mg/m2xdx1 given every 3 weeks (arm A) or ifosfamide 1.8 g/m2xdx5 and doxorubicin 60 mg/m2xdx1 given every 4 weeks (arm B). Recombinant human granulocyte colony-stimulating factor (r-met Hu G-CSF: 250 micrograms/m2xd) was applied with a prophylactic intent to patients in arm A only. The response rate was higher in arm A patients (56% versus 33%, p = 0.03). In stage III patients, the complete response rate was significantly higher (53% versus, 13.3%, p = 0.01) and the duration of response was significantly longer in arm A (20 +/- 8.2 months versus, 13.4 +/- 7 months, p = 0.05). Chemotherapy related myelotoxicity and mucositis were also less frequent in this arm as a result of prophylactic r-met Hu G-CSF administration (p = 0.04, p = 0.003). It was concluded that single dose ifosfamide and doxorubicin combinations deserve further investigation under the cover of hematopoietic growth factors, particularly in patients with stage III soft tissue sarcomas.

To investigate the hypothesis that maximal androgen blockade improves the outcome of patients with metastatic prostate cancer.

The marked progress in controlling emesis caused by cisplatin characterizes the current status of antiemetic treatment for all chemotherapy. Cisplatin has provided a model for antiemetic studies. Strategies for controlling cisplatin-induced emesis are at least as successful when applied to other chemotherapy and persistent problems such as delayed emesis and the emesis associated with consecutive-day chemotherapy are also similar to or less severe than those observed with cisplatin. The purpose of this report is twofold: first to outline briefly therapy for cisplatin-induced emesis as illustrated by several new studies, and, second, to report on a new trial that incorporates some different strategies in the control of delayed emesis after cisplatin.

Two large randomized, double-blind, placebo-controlled studies with an appropriate study design have been conducted to fully evaluate the efficacy of ondansetron in the control of cisplatin-induced delayed emesis. These studies show that ondansetron and particularly ondansetron plus dexamethasone have moderate efficacy in the control of cisplatin-induced delayed emesis and nausea. The benefit of ondansetron, with or without dexamethasone, may be greatest in patients with incomplete control of acute emesis. The efficacy of ondansetron in this setting compared to its greater efficacy during the acute phase of emesis induced by cisplatin and the more prolonged phases of acute emesis induced by cyclophosphamide and carboplatin indicates that non-5-HT3-mediated emetic mechanisms maybe are relatively more important in the delayed phase of emesis following cisplatin.

There have been few studies to determine whether the efficacy of antiemetics is maintained over repeated courses of cisplatin chemotherapy. Two large controlled studies have been undertaken by our group to address this issue. A comparison of the standard high-dose regimen of metoclopramide plus methylprednisolone versus a higher dose regimen of metoclopramide plus dexamethasone and diphenhydramine showed that the latter regimen was significantly more efficacious with regard to complete control of nausea and vomiting in chemotherapy-naïve patients. However, this difference was not maintained over repeated courses of chemotherapy. A comparison of metoclopramide and dexamethasone plus diphenhydramine with ondansetron plus dexamethasone showed that the ondansetron regimen provided even greater control of vomiting, which was maintained over subsequent cycles of chemotherapy. Various factors were analysed in both studies to determine whether they had any effect on treatment outcome. In general, age < 50 years, female gender, and higher doses of cisplatin were associated with an increased risk of emesis. However, the most significant prognostic factor was emesis response in the previous cycle. It is therefore important to aim for good antiemetic control in the first cycle of cisplatin chemotherapy.

This paper describes the only published study to date which prospectively evaluates the efficacy of a 5-HT3 receptor antagonist over repeated courses of cyclophosphamide chemotherapy. The combination of ondansetron and dexamethasone was significantly superior to metoclopramide and dexamethasone over 6 courses of chemotherapy given for the treatment of breast cancer. Importantly, patients given ondansetron benefited from a superior quality of life over the six courses of treatment. A Markov chain statistical model has been applied to these data. This model assumes that the results over subsequent courses is dependent on the efficacy of the anti-emetic therapy and the results obtained during the previous course of chemotherapy. This model successfully predicts the actual results obtained in the clinical study. Using this model it is possible to hypothesise on the results obtained following different treatment strategies. These data emphasise that it is important to give optimal anti-emetic therapy from the first course of chemotherapy as this will facilitate good control during subsequent courses.

We conducted a randomized controlled study to evaluate the clinical usefulness of (2"R) -4'-O-Tetrahydropyranyladriamycin (THP)-based combination therapy subsequent to induction therapy which was consisted with THP, 5'-DFUR, and CPA in the treatment of advanced or recurrent breast cancer. In maintenance therapy, Arm C received CPA and TAM, and Arm T received these two drugs plus THP. Survival time of 50% for all cases in which maintenance therapy was conducted was 26.9 months in Arm T and 20.9 months in Arm C, showing no significant difference by the log-rank test (p = 0.64). Survival time in all cases in which therapy had been completed was 54.6 months in Arm T and 28.1 months in Arm C, showing a significant difference by the log-rank test (p = 0.03) although the number of cases was few. A few cases showed a decrease in total leukocyte count to below 2,000/mm3 at the time of induction therapy, but this was transient in all cases. No significant difference in count was noted between two arms at the time of maintenance therapy. However, many cases in Arm T showed decreased total leukocyte count and hemoglobin content, and thrombocytopenia. These results suggest that combination therapy including THP conducted as maintenance therapy after induction is useful in the prolongation of survival time in patients with advanced or recurrent breast cancer.

We studied the role of dexamethasone (DEX) administered on day 1 in controlling cisplatin-induced delayed emesis. Forty patients were randomly allocated to receive either granisetron (GRN) and DEX on day 1, or the same dose of GRN alone. On days 2-5, all the patients received metoclopramide and DEX. They were crossed over to the other antiemetic regimen with their second course of chemotherapy. Thirty-one patients were evaluable for efficacy. The mean visual analogue scale scores for nausea on days 1 and 2 were 9.1 and 18.8 mm for GRN and DEX, and 16.3 and 28.5 mm for GRN alone, respectively (P<0.05 on day 2). The mean numbers of emetic episodes on days 1-3 were 0.036, 0.46 and 0.36 for GRN and DEX, and 0.39, 0.89 and 0.57 for GRN alone, respectively (P<0.01 on day 1). Hiccups and restlessness were noted in 38% and 33% of cycles, respectively. Addition of DEX to GRN on day 1 thus enhanced the control of delayed emesis.

The objective of this multicenter study was to compare the therapeutic index of two different doses of paclitaxel given as a 3-hour infusion in patients with metastatic breast cancer (MBC), who had failed to respond to previous chemotherapy. A total of 471 patients with MBC were randomized to receive intravenous paclitaxel at a dose of 175 or 135 mg/m2 every 3 weeks.

This intergroup trial was developed to determine the toxicity of relatively low doses of difluoromethylornithine (DFMO) administered to humans for 1 year. The goal was to find an appropriate DFMO dose for use in human chemoprevention trials. Patients with resected superficial bladder cancers were studied. Following stratification, they were randomized to daily DFMO doses of 0.125, 0.25, 0.5, or 1.0 g/day for a planned period of 1 year. Patients were followed closely for evidence of drug toxicity. Seventy-six patients were evenly randomized (19 per group) to receive each dose of DFMO. Forty-nine patients received DFMO for more than 200 days while 35 received the drug for > or = 350 days. No substantial drug-related toxicity was observed at any dose. DFMO doses of > or = 1 g/day for periods up to 1 year appear to be without significant toxicity in most patients. This dose range may be appropriate for use in future human cancer chemoprevention trials.

This multicentre, double-blind, double-dummy, randomised trial was designed to compare the efficacy and safety of single intravenous doses of dolasetron mesilate and granisetron in the prevention of acute emesis and nausea due to high-dose (> or = 80 mg/m2) cisplatin. Single intravenous doses of 1.8 or 2.4 mg/kg of dolasetron mesilate or 3 mg of granisetron hydrochloride were administered in a volume of 50 ml over a 5-min period, beginning 30 min prior to cisplatin (> or = 80 mg/m2) administration. The number and timing of emetic episodes, time to administration of escape anti-emetic medication, severity of nausea by visual analogue scale (VAS), and safety were monitored for 24 h after the start of cisplatin-containing chemotherapy. Investigators' evaluations of overall efficacy and patients' satisfaction with therapy were recorded at the end of the 24-h study period. Of the 474 patients evaluable for efficacy, complete responses were achieved by 54, 47 and 48% of patients given dolasetron mesilate 1.8 mg/kg, dolasetron mesilate 2.4 mg/kg and granisetron, respectively. Statistically, treatment groups had comparable complete and complete plus major responses, times to first emesis, and use of escape medication; patient maximum nausea severity and treatment satisfaction ratings; and physician nausea severity and overall efficacy assessments. For the majority of efficacy endpoints, 1.8 mg/kg dolasetron mesilate produced numerically superior responses compared with the 2.4 mg/kg dose. Gender and prior chemotherapy were significant predictors of complete response; males and chemotherapy-naive patients had higher responses. The overall incidences of adverse events were comparable among the treatment groups; headache and diarrhoea were most common. In conclusion, 1.8 and 2.4 mg/kg of dolasetron mesilate and granisetron (3 mg) were equally effective in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, because no additional benefit was observed with 2.4 mg/kg of dolasetron mesilate and numerically greater responses were observed with the 1.8 mg/kg dose, the lower dose of 1.8 mg/kg is optimal for further clinical development.

This study compared the efficacy and tolerability of oral ondansetron (8 mg twice daily [BID] for up to 3 days) with those of phenothiazine prochlorperazine (10 mg BID for up to 3 days) in 133 cancer patients receiving cyclophosphamide-based chemotherapy. In addition, the study evaluated the impact of these treatments on patients' health-related quality of life, measured with both the Functional Living Index--Cancer and the Functional Living Index--Emesis questionnaires. The first dose of study drug was administered 30 minutes before initiation of chemotherapy. Patients received a rescue antiemetic at their request or if the investigator deemed it necessary. There was a statistically significant difference in the number of patients with no emetic episodes over the 3-day study period: 60% in the ondansetron group compared with 21% in the prochlorperazine group. Twenty-five percent of ondansetron-treated patients compared with 68% of prochlorperazine-treated patients experienced three or more emetic episodes, rescue medication use, or withdrawal from the study due to adverse events or lack of efficacy of the study drug. Among patients with at least one emetic episode, the mean time to emesis was significantly longer (13 hours and 37 minutes) in the ondansetron group compared with the prochlorperazine group (9 hours and 30 minutes). Nausea and appetite scores did not differ significantly between groups. The score on the vomiting subscale of the Functional Living Index--Emesis was significantly more favorable in the ondansetron group compared with the prochlorperazine group, indicating better maintenance of health-related quality of life in ondansetron-treated patients. Both treatments were well tolerated. The most common potentially drug-related adverse event was headache, which occurred in significantly more (16%) ondansetron-treated patients compared with prochlorperazine-treated patients (3%). The results of this study demonstrate that oral ondansetron 8 mg BID for up to 3 days is more effective than prochlorperazine 10 mg BID for up to 3 days in the prevention of emesis associated with moderately emetogenic chemotherapy.

To assess the cardioprotective efficiency of an antioxidant regimen (vitamins E, C and N-acetylcysteine) in patients receiving high dose chemo- and/or radiotherapy for malignant disease.

1. We report a single-blind randomized crossover trial comparing the efficacy of tropisetron plus dexamethasone (TROPDEX) vs conventional combination of metoclopramide, dexamethasone and diphenhydramine (METDEX) in prevention of acute and delayed vomiting in Chinese patients receiving high dose cisplatin. 2. Thirty-six consecutive patients with nasopharyngeal carcinoma were entered into the study, all received cisplatin at a dose range of 60-100 mg/m2. Patients were randomized in the sequence of antiemetic regimens used in two consecutive cycles. 3. The TROPDEX regimen consisting of tropisetron 5 mg i.v. and dexamethasone 20 mg i.v. given on day 1 of chemotherapy, followed by oral maintenance with tropisetron 5 mg daily and dexamethasone 4 mg twice daily from day 2 to 6. The METDEX regimen consisting of metoclopramide 1 mg kg-1 i.v., dexamethasone 20 mg i.v. and diphenhydramine 25 mg i.v. given before chemotherapy and then 2 hourly for two more doses on day 1, followed by oral metoclopramide 20 mg 6 hourly from day 2 to 6. 4. Complete control of acute vomiting was observed in 64% of patients with TROPDEX as compared with 14% with METDEX (P < 0.01). While complete plus major control of acute vomiting was observed in 84% with TROPDEX as compared with 58% with METDEX. The mean vomiting episodes on day 1 were 1.4 with TROPDEX as compared with 3.5 with METDEX (P < 0.01). There was, however, no significant difference between the two regimens in the control of delayed vomiting. 5. When patients randomized to TROPDEX in the second cycle were compared with those with TROPDEX in the first cycle, the antiemetic efficacy was reduced, with mean acute vomiting episodes of 2 in the former compared with 0.8 in the latter (P < 0.01). 6. The most common adverse effect observed was headache in TROPDEX (27%) and dizziness in METDEX (40%). 7. In conclusion, the antiemetic regimen TROPDEX is effective in Chinese patients receiving high dose cisplatin chemotherapy and is well tolerated. It is better than conventional METDEX regimen in the control of acute vomiting, but not in the control of delayed vomiting.

We conducted a prospective randomized study to compare granisetron, a 5-hydroxytryptamine-3 receptor antagonist with standard anti-emetics (control group) consisting mainly of metoclopramide, in the prophylaxis of emesis induced by conditioning prior to stem cell transplantation. Fifty-eight patients were evaluable for analysis. The number of emetic episodes expressed in terms of patient-days was significantly lower in the granisetron group than in the control group (P < 0.001). During the first 24 h of conditioning, 27 of the 31 patients (87.1%) in the granisetron group achieved control of emesis with less than three emetic episodes (major < or = ) a day compared with 37.0% in the control group (P < 0.001). The same degree of emesis control was maintained throughout the conditioning period in 51.% of patients in the granisetron group compared with 0% in the control group (P < 0.001). Adverse reactions were observed in 11.4% of patients in the granisetron group and in 25.9% in the control group. None of the events were serious. Based on these data, we conclude that granisetron is superior to standard antiemetics in protecting against the vomiting induced by conditioning for stem cell transplantation.

To evaluate single-agent liposomal daunorubicin chemotherapy in the management of early HIV-related Kaposi's sarcoma (KS).

The circadian rhythm-modulated delivery of anticancer drugs has been shown to reduce toxicity and improve anticancer efficacy. The aim of this phase I trial was to compare the feasibility and tolerability of carboplatin (CBDCA) administered at circadian-modulated or flat infusion rate in 24 patients with advanced cancer. Each treatment cycle consisted of a 5-day continuous intravenous infusion of CBDCA, to be repeated at 28-day intervals. Three dose levels were determined, with a CBDCA dose 15%, 40% and 60% over that calculated using Calvert's formula. Two schedules were compared: schedule A (forty-four courses), with a at circadian rhythm-modulated rate (peak at 16.00 hr) and schedule B (fifty courses), at a constant rate. At the first and second dose level neither of the administered cycles were accompanied by hematologic toxicity higher than Grade 3. At the third dose level, two cycles out of 15 for schedule A and two out of 20 for schedule B were accompanied by Grade 4 thrombocytopenia. The repeat cycles were delayed from day 28 to 42 in some patients, with no differences between circadian-modulated and flat infusion. Three partial responses out of 9 evaluable patients were observed in schedule A and 2 out of 10 evaluable patients in schedule B. We showed no potential advantage of the chronomodulated 5-day CBDCA continuous infusion method over the flat rate method. Although antitumor effects were observed in this pilot study, this treatment cannot be assessed for efficacy relative to other schedules.

Glaucoma filtering surgery usually fails from postoperative fibroblast proliferation, collagen deposition, and subsequent sclerostomy or bleb scarring. Daunorubicin inhibits fibroblast proliferation in vivo and in vitro. The authors studied the effect of a sustained subconjunctival release of daunorubicin by way of a bioerodible polymer on the success of glaucoma filtration surgery in a rabbit model.