Results of cytotoxic chemotherapy for hormone-resistant prostate cancer are not impressive. One of the substances which seems to have a therapeutic benefit is 5-fluorouracil (5-FU). The effect of 5-FU can be modulated by addition of folinic acid (FA). We tested in a prospective, randomized phase II trial monotherapy with 5-FU versus the combination of 5-FU and high-dose FA.

The pharmacokinetics of 6-mercaptopurine, including cerebrospinal-fluid (CSF) distribution, and the erythrocyte 6-thioguanine nucleotide concentrations were determined in children randomised to receive intravenous mercaptopurine for acute lymphoblastic leukaemia (ALL), according to the EORTC protocol ALL n.58881.

Remarkable improvements in primary surgery and chemotherapy for advanced ovarian cancer have been achieved in the last decades. Nevertheless, the majority of patients still develop recurrent disease and ultimately die from ovarian cancer. Evaluation of efficient second-line treatment is of clinical relevance. This review re-analyses the published data of conventional systemic treatment for recurrent and refractory ovarian cancer. Patients were grouped according to prior chemotherapy (with or without platinum; with or without paclitaxel) and according to clinical platinum resistance. Platinum resistance is defined as having progressed during platinum based chemotherapy or having relapsed within 6 months after completion of primary platinum containing treatment. The most favourable results in platinum sensitive ovarian cancer were reported for platinum containing re-induction chemotherapy. Results in platinum refractory ovarian cancer were different. Both hormonal treatment consisting of either tamoxifen or GnRH analogues, and chemotherapy with topoisomerase blocking agents, taxanes, or alkylating agents did show similar results. Unfortunately, there are only limited data from prospectively randomised trials in these patients. Therefore, recommendations remain inconclusive. Retrospective comparisons may help the clinician to chose the currently best available treatment for an individual patient, however, these treatments have to be evaluated in prospectively randomised trials. The protocols of the ongoing studies in refractory or recurrent ovarian cancer of the AGO Ovarian Cancer Study Group are outlined.

In a double-blind, placebo controlled study, ipriflavone (600 mg/day, T.D.D.) or identical placebo tablets were given with 500 mg/day of calcium to patients treated with the gonadotropin hormone-releasing hormone agonist (Gn-RH-A) leuproreline acetate, 3.75 mg every 30 days for 6 months. In placebo-treated subjects (n = 39), urinary hydroxyproline excretion and plasma osteocalcin levels showed a significant (P < 0.01 and P < 0.05, respectively) increase, whereas spine bone density and total body bone density significantly (P < 0.001 and P < 0.05, respectively) decreased after 3 and 6 months of GnRH-A administration. Conversely, in the ipriflavone-treated group (n = 39), no significant difference in bone markers and bone density was evidenced. These data indicate that ipriflavone can restrain the bone remodeling processes and prevent the rapid bone loss that follows medically induced hypogonadism.

This study compared the antiemetic efficacy and safety of two different intravenous (i.v.) dolasetron dosing regimens in patients receiving their first course of high-dose (> or = 80 mg/m2) cisplatin. Of 30 patients enrolled, 14 received a single i.v. dolasetron dose (0.6 mg/kg) before cisplatin and 16 received a multiple i.v. dose regimen (0.6 mg/kg x 3) given before and after cisplatin. Complete plus major responses were achieved by 71% (10/14) of patients who received single-dose dolasetron and by 50% (8/16) of those who received the multiple-dose regimen. Forty-three percent (6/14) of patients who received the single dose had a complete response compared with 25% (4/16) who received multiple doses. Multiple doses resulted in less nausea at 24 hr following cisplatin; however, differences were not statistically significant. Both regimens were well tolerated, with mild headache (33%) and diarrhea (13%) the most common adverse events. This study demonstrated that a single 0.6-mg/kg dose of dolasetron given before chemotherapy provides equivalent antiemetic efficacy to three 0.6-mg/kg doses given before and after high-dose cisplatin chemotherapy; thus, there was no additional antiemetic benefit by using the multiple-dose regimen.

Etoposide phosphate is a water-soluble prodrug of etoposide. The plasma pharmacokinetics of etoposide following oral administration of etoposide phosphate or oral etoposide were compared. Seventeen patients with solid tumours were enrolled to receive oral etoposide phosphate 125 mg m(-2) on days 1-5 every 3 weeks, with escalation to 175 mg m(-2) from course 3 when possible. Patients were randomized to receive oral etoposide phosphate or oral etoposide on day 1 of course 1 and the alternative compound on day 1 of course 2. Fifteen patients received two or more courses and were evaluable for pharmacokinetic comparisons. The median AUC(inf) (area under the concentration vs time curve from zero to infinity) of etoposide was 77.7 mg l(-1) h after etoposide phosphate (95% CI 61.3-100.5) and 62.0 mg l(-1) h after oral etoposide (95% CI 52.2-76.9). The difference in favour of etoposide phosphate was borderline significant: median 9.9 mg l(-1) h (95% CI 0.1-32.8 mg l(-1) h; P = 0.05). However, the inter-patient variability of etoposide AUC(inf) was not improved (coefficients of variation 42.3% and 48.4%). Etoposide phosphate was undetectable in plasma after oral administration. Toxicities of oral etoposide phosphate were not different from those known for etoposide. In conclusion, oral etoposide phosphate does not offer a clinically relevant benefit over oral etoposide.

Radical nephrectomy is the standard therapy for low-stage renal cell carcinoma. However, recurrence sometimes develops even in patients who are considered to have undergone a curative resection of the primary tumor. The purpose of this study was to evaluate the usefulness of UFT (a 1:4 mixture of tegafur and uracil) adjuvant and the risk factors for recurrence in renal cell carcinoma.

The plasma pharmacokinetics of a second generation anthracycline derivative, idarubicin (Ida), have been studied in 17 patients with acute myelocytic leukemia (AML) and high risk features. The drug (10 mg/m2) was given in a randomized cross-over design as 3 min and 2 h infusions for three consecutive days. Cytosine arabinoside (Ara-C, 1 g/m2) was given on days 1-4. The plasma concentration time course of Ida was most properly described by the three-compartment pharmacokinetic model, independent of administration time. The maximum plasma concentration (Cmax) of Ida was reduced by a factor of 3 by increasing the infusion time from 3 min to 2 h. The pharmacokinetic pattern of the active metabolite idarubicinol (IdaOH) was only to a minor extent affected by the longer infusion time. The time course of IdaOH following each dose of Ida was accurately described by the one-compartment model with a first-order formation phase. The are under the plasma concentration versus time curves (AUC) of Ida and IdaOH were not affected by the administration time. Following Ida in combination with Ara-C, the medial duration of leukopenia (< 1.0 x 10(9)/l) was 14 days (range 5-56) and of thrombocytopenia (< 50 x 10(9)/l) was 22 days (range 7-120). The large majority of patients developed infectious complications. Two patients with MDS-AML showed a good response. The results of the present study give no evidence of reduced hematologic toxicity by increasing the administration time of Ida from 3 min to 2 h. However, minimizing Cmax, by administration of Ida as prolonged infusion during a 3 day course, might be clinically important in order to reduce cardiotoxicity and hopefully to increase anti-tumor efficacy through an increased accumulation of Ida and IdaOH in leukemic cells.

To evaluate the combined effect of granisetron and methylprednisolone against acute emesis induced by cytotoxic agents, we investigated the clinical response and the urinary excretion of 5-HIAA in 85 patients with ovarian cancer who received the same anticancer chemotherapeutic regimen in a prospective randomized trial. Each patient received one of three different regimens (granisetron alone, methylprednisolone plus granisetron, and metoclopramide alone). The combination therapy of granisetron and methylprednisolone is effective for preventing acute emesis induced by cytotoxic chemotherapy.

Anthracyclines are the most frequent cause of iatrogenic congestive heart failure ranging from acute reversible minor, irreversible reduction in the left ventricular ejection fraction and death despite preventive measures. Sensitive methods are needed to detect earliest preclinical cardiotoxicity along with the development of new protective agents. Thirty breast cancer patients were randomly treated with q 21 120 mg/m2 Epirubicin (EPI) x 3, alone (10 patients), or + ICRF-187 (1000 mg/m2) (10 patients) or + C0Q10 (50 mg/day) (10 patients) and monitored by Thoracic Electrical Bioimpedance (TEB) cardiography before (T0) and at the end of chemotherapy (T1), then at 1, 3, 6 months of follow up (F1, F2, F3). a) The group treated with EPI alone showed, between F1-F2, a significant (p < 0.05) decrease in Stroke Index (S1). Acceleration Index (ACI) and a significant (p < 0.05) increase in Systemic Vascular Resistance Index (SVRI), while between F2 and F3 it showed a significant (p < 0.05) recovery in S1 and ACI. b) The group treated with EPI + ICRF-187 showed, between F1 and F2 a significant decrease in S1 and ACI (p < 0.05, p < 0.01 respectively) and a significant (p < 0.05) increase in SVRI: between F2-F3 ACI had a significant (p < 0.05) recovery: c) The group treated with EPI +C0Q10 showed no modification in Sl, ACI, and SVRI during the study. The ejection Fraction (EF) remained unchanged during the study in all the groups. C0Q10 seems to prevent early decreases in cardiac performance and contractiling, thus avoiding an SVRI increase, while ICRF-187 did not. Since ICRF-187 acts by binding iron, we deem that the earliest cardiac involvement, may occur before iron overload; therefore the role of ICRF-187 and C0Q10 in acute or chronic heart toxicity was correlated with high-dose anthracycline and needs to be further investigated.

This study assesses the effect of adding continuous-infusion fluorouracil to palliative thoracic radiation therapy (RT) on the rate and duration of symptom relief in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred eligible patients with NSCLC were randomized to receive either 20 Gy in five daily fractions as palliation for intrathoracic disease or the same RT with concurrent continuous infusion of 1 g m(-2) day(-1) fluorouracil for 5 days. Survival, response and rates of symptom relief in the two groups were compared according to treatment intent, and toxicities were compared according to treatment received. The overall response rate was higher in patients randomized to the combination (29%) than in patients randomized to RT alone (16%) (P = 0.035). However, there were no significant differences between the treatment arms in terms of overall or progression-free survival or in palliation of symptoms. Patients treated with RT plus fluorouracil had significantly more acute toxicity, including nausea and vomiting (P = 0.01), oesophagitis (P = 0.0003), stomatitis (P = 0.0005) and skin reaction (P = 0.003). This study suggests for the first time an interaction between RT and infusional fluorouracil in NSCLC. Although RT plus fluorouracil resulted in a significantly higher response rate than achieved with RT alone, this did not translate into more effective palliation. Because the combination produced significantly more toxicity than RT alone, it is not recommended for the palliative treatment of NSCLC. Nevertheless, these results suggest that opportunities may exist for exploitation of the observed enhancement of antitumour effect in the setting of high-dose radical RT for NSCLC.

The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer.

The purpose of this study was to evaluate the efficacy and safety of four different doses of granisetron when administered as a single intravenous (i.v.) dose for prophylaxis of cisplatin-induced emesis in a multicenter, randomized, parallel-group, double-blind investigation. A total of 353 chemotherapy-naive patients were enrolled, stratified according to cisplatin dose (moderate dose: 50-80 mg/m2, n = 169; high dose: 81-120 mg/m2, n = 184) and randomized to one of four granisetron doses: 5, 10, 20, or 40 micrograms/kg. Control of emesis was evaluated by the percentages of patients attaining complete response (no vomiting or retching, and no rescue medication) and major response (< or = 2 episodes of vomiting or retching, and no rescue medication). Patients were assessed on an inpatient basis for 18-24 h. Safety analyses consisted of adverse events and laboratory parameter changes. Complete response rates over 24 h after chemotherapy were 23%, 48%, 48%, and 44% for granisetron doses of 5, 10, 20, and 40 micrograms/kg, respectively, in the combined patient population (P = 0.011 for linear trend); 29%, 56%, 58%, and 41%, respectively, in the moderate-dose cisplatin stratum (P = 0.278 for linear trend); and 18%, 41%, 40%, and 47%, respectively, in the high-dose cisplatin stratum (P = 0.011 for linear trend). Transient headache was the most frequently reported adverse event (19%). There was no evidence of association between increased dose and headache. A single 10-, 20- or 40-micrograms/kg dose of granisetron is comparably effective in controlling nausea and vomiting associated with moderate or high-dose cisplatin chemotherapy. Granisetron was safe and well tolerated at all doses.

The potent serotonin receptor (5-HT3) antagonists are new highly selective agents for the prevention and control of chemotherapy-induced nausea and vomiting that have been shown to be comparable to or more effective than traditional metoclopramide regimens. This study was designed to compare the antiemetic efficacy of dolasetron and metoclopramide in chemotherapy-naive and non-naive cancer patients receiving high-dose cisplatin-containing chemotherapy. This multicentre, double-blind, randomized trial compared the efficacy and safety of single i.v. doses of dolasetron mesilate salt (1.2 or 1.8 mg/kg) and metoclopramide (7 mg/kg) in 226 patients for the prevention of acute emesis and nausea associated with the administration of high-dose (> or = 80 mg/m2) cisplatin. Efficacy and safety were evaluated for 24 h. Complete responses were achieved by 57%, 48%, and 35% of patients given dolasetron mesilate 1.8 mg/kg (P = 0.0009 vs metoclopramide), dolasetron mesilate 1.2 mg/kg (P = 0.0058 vs metoclopramide), and metoclopramide, respectively. Overall, dolasetron was significantly more effective than metoclopramide for time to first emetic episode, nausea, patient satisfaction, and investigator global assessment of efficacy. Males, chemotherapy-naive patients, and alcoholics had higher response rates. Dolasetron was well tolerated, with mild-to-moderate headache most commonly reported. Twelve percent of patients receiving metoclopramide reported extrapyramidal symptoms compared with 0% of patients receiving dolasetron. In conclusion, dolasetron mesilate was effective for the prevention of CINV with high-dose cisplatin. Single i.v. doses of dolasetron mesilate were more effective than 7 mg/kg metoclopramide in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, 1.8 mg/kg dolasetron mesilate consistently produced the highest response rates and appears to be the most effective dose for further clinical development.

To develop a nonsurgical treatment alternative for basal cell carcinomas (BCCs), we evaluated intralesional sustained-release chemotherapy with 5-fluorouracil/epinephrine injectable gel (5-FU/epi gel).

To evaluate the biologic interactions and toxicities of melphalan (L-PAM) combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes.

The role of 5-HT3 receptor antagonists in the prevention of chemotherapy-induced delayed emesis is controversial. We compared ondansetron and metoclopramide, both combined with dexamethasone, in cisplatin-treated patients.

A double-blind, parallel-group study in 189 ovarian cancer patients compared the efficacy of ondansetron 8 mg i.v. (OND) and metoclopramide 60 mg i.v. (MET) both in combination with dexamethasone 20 mg i.v. in the prevention of carboplatin-induced emesis. On day 1, complete or major control of emesis (0-2 emetic episodes) was observed in 97% patients from the OND group compared with 74% patients from the MET group (p < 0.001). Similarly, a worst-day analysis over days 1-3 showed complete or major control of emesis in 87% patients (OND) compared wth 66% patients (MET) (p < 0.001). Similar findings in favour of the OND group were observed for nausea grade on day 1 and the worst-day grade during days 1-3. OND was better tolerated than MET. Fewer patients from the OND group (13%) reported adverse events compared with the MET group (21%). Extrapyramidal type symptoms were observed in 6 (6%) patients from the MET group (paraesthesia, involuntary movement of the jaw and tongue, and restlessness), compared with none from the OND group. Ondansetron plus dexamethasone is a highly effective and well-tolerated treatment and is significantly superior to metoclopramide plus dexamethasone in the prevention of carboplatin-induced emesis.

This study was conducted to evaluate the efficacy of two different doses of ondansetron (8 mg vs. 24 mg) plus dexamethasone in the prevention of cisplatin (CDDP)-induced emesis and nausea (acute and delayed). The persistence of the anti-emetic efficacy during the second cycle of chemotherapy was also assessed. Eighty patients receiving high-dose CDDP (>80 mg/m2) were randomized to have either ondansetron 8 mg plus dexamethasone 20 mg (8 mg group) or ondansetron 24 mg plus dexamethasone 20 mg (24 mg group), given intravenously as a single dose before the CDDP infusion. From days 2-5, all patients received oral ondansetron 8 mg twice daily. Seventy-five patients (38 in the 8 mg group and 37 in the 24 mg group) were evaluable for analysis. Among these, there were 24 patients who received ifosfamide (IFO) on the 2nd day of treatment; these patients were evaluated separately for delayed emesis. Complete protection from acute emesis was obtained in 26 (68.4%) and 26 (70.3%) patients, in the two groups, respectively. Complete protection against acute nausea was achieved in 23 (60.5%) and 24 (64.9%) patients, respectively. With respect to the delayed emesis, complete protection was achieved in 14 (56%) and 13 (50%) patients not receiving IFO and in 4 (30.8%) and 3 (27.3%) of those receiving IFO. The figures for the delayed nausea were: 12 (48%) and 13 (50%), 2 (15.4%) and 2 (18.2%), respectively. Similar protection against emesis and nausea was recorded during the second cycle of chemotherapy. Both regimens have the same efficacy and thus, taking into account the cost-effectiveness, 8 mg of ondansetron plus dexamethasone in a single intravenous dose should be used for the prevention of high-dose CDDP-induced emesis.

Data from a pilot study published in 1984 suggested that tamoxifen administration (as adjuvant hormonal therapy) for more than 5 years after initial breast cancer surgery might have therapeutic benefit.