A prospective randomised study was performed to test the hypothesis that total androgen ablation, achieved by combining an LHRH analogue, goserelin acetate (Zoladex), with an antiandrogen, cyproterone acetate (Cyprostat), is more effective than conventional monotherapy in delaying the time to progression of metastatic prostatic cancer. 525 patients were recruited at 18 UK centres between May 1986 and January 1989, 175 patients being allocated to each arm. Patients were clinically and biochemically assessed at 1, 2, 3, 6, 9 and 12 months after initiation of therapy and then every 6 months until a maximum duration of 48 months. There was no statistically significant difference in terms of median time to progression between the combination treatment arm and either monotherapy arm, although there was a statistically significant difference between goserelin acetate alone and cyproterone acetate alone, in favour of goserelin acetate (p = 0.016). All treatment regimens were well tolerated and cyproterone acetate reduced both tumour flare reactions and hot flushes in patients receiving goserelin acetate. It is concluded that total androgen ablation using cyproterone acetate (300 mg/day) and goserelin acetate (3.6 mg every 28 days) confers no advantage in terms of time to progression, to conventional monotherapy, but can reduce certain side effects caused by LHRH analogue treatment alone.

Androgen suppression, using gonadotrophin-releasing hormone analogues (leuprorelin), is being developed as an effective treatment of advanced prostate carcinoma. Treatment with leuprorelin acetate 1-month depot is already well established all over the world. In order to increase patients' acceptability of this treatment, by reducing frequency of administration, a 3-month depot formulation has been developed in Takeda's research laboratories. A single-shot pharmacokinetic study was conducted to confirm efficacy in terms of hormone suppression and safety of the 3-month depot formulation. Thereafter, a parallel-group, open-labelled, randomized trial was performed to compare clinical efficacy and safety profiles of the 1- and 3-month depot formulations. Patients with a histologically and/or cytologically confirmed advanced prostate carcinoma, without prior hormonal or surgical androgen deprivation, are included. According to 1:2 randomization, patients are treated with either the 1- or 3-month depot for 9 months. To prevent initial flare-up, a concomitant antiandrogen therapy might be administered within 2 weeks prior to first injection and continued for up to 3 weeks. The clinical efficacy of the formulations is assessed by both objective response, EORTC and NPCTG response criteria, and subjective response by using WHO performance status. In addition, the level of prostate-specific antigen is determined every 3 months. The efficacy of the two formulations is also evaluated by determination of serum testosterone, dihydrotestosterone, luteinizing hormone and follicle stimulating hormone. To date, 106 patients have been treated with the 3-month depot and 53 patients with the 1-month depot. Preliminary evaluation shows a satisfying level of testosterone suppression with both the 3- and 1-month depot formulations. Therapeutic equivalence was assumed. The 3-month depot is tolerated as well as the 1-month depot.

It was our intention to verify if increases of granulocyte colony stimulating factor (G-CSF) dose were able to reduce treatment delays due to leukopenia in our weekly regimen of cisplatin (40 mg/m2), epidoxorubicin (35 mg/m2), 6S-leucovorin (250 mg/m2) and 5-fluorouracil (500 mg/m2), usually supported by G-CSF at a dose of 5 mu g/kg. Forty five patients with advanced gastric carcinoma (30 males and 15 females; median age 64 years) were randomized to receive three different doses of G-CSF (5, 8 and 10 mu g/kg) by s.c. injection. We did not observe any difference in the mean value of neutrophil counts at each of the 8 weeks of treatment; while we registered a higher incidence of severe neutropenia (< 500/mm3) in patients receiving higher G-CSF doses: two patients in the group at 5 mu g/kg, four in the group at 8 mu g/kg and seven in the group at 10 mu g/kg. Furthermore, low doses of G-CSF allowed a similar number of chemotherapeutic administrations in the eight study weeks. The results arising from our study do not seem to support the use of higher doses of G-CSF, at least in not such a weekly regimen.

Maximum androgen blockade, a relatively recent development in the treatment of prostate cancer, combines medical or surgical castration with antiandrogen therapy. A large randomized study comparing the non-steroidal antiandrogen, bicalutamide, with flutamide, each in combination with luteinizing hormone-releasing hormone (LHRH) analogs, showed that after a median follow-up of 49 weeks, the time to treatment failure was significantly longer for the bicalutamide patients compared with the flutamide patients (p = 0.005). After a median follow up to 95 weeks, bicalutamide in combination with LHRH analog therapy produced at least equivalent efficacy with flutamide in combination with LHRH analog therapy in terms of time to treatment failure and equivalent efficacy in terms of survival. The tolerability profile of bicalutamide, as based on reported findings and a literature review, indicates a superior tolerability to that of currently available antiandrogens, particularly with respect to diarrhea with a low incidence of treatment-related withdrawals.

Little is known about patient compliance with oral adjuvant chemotherapy. It is estimated to be poor especially in Japan, where it is still unusual for patients to be directly informed of their diagnosis of malignancy. 5-Fluorouracil (5-FU) was measured in hair samples to assess patient exposure to 5-FU, and its potential usefulness is discussed as an index of compliance with postoperative adjuvant chemotherapy.

Between January 1992 and September 1993, 813 patients with stage D2 prostate cancer were enrolled in a multicentre, double-blind (for antiandrogen therapy) trial and randomised to antiandrogen therapy with Casodex (bicalutamide, 50 mg once daily) or flutamide (250 mg three times daily) and to luteinising hormone-releasing hormone (LHRH) analogue therapy with Zoladex (goserelin, 3.6 mg every 28 days) or leuprolide (7.5 mg every 28 days). Time to treatment failure was the primary efficacy endpoint. At a median follow-up time of 49 weeks, there was a significant (p = 0.005) difference between groups in time to treatment failure in favour of Casodex plus LHRH analogue. Overall, 168 (42%) of 404 patients in the Casodex plus LHRH analogue group and 218 (53%) of 409 patients in the flutamide plus LHRH analogue group reached a treatment failure endpoint. Although a cause-specific treatment-failure analysis was not performed, the difference between groups in treatment failure attributed to adverse events (mainly diarrhoea) was evident primarily in the first 7 months of therapy. The difference between groups in treatment failure for objective progression was most evident after 1 year of therapy. With further follow-up (median time of 95 weeks), the result for time to treatment failure, although no longer statistically significant, were consistent with the previous finding of an improvement in time to treatment failure associated with Casodex plus LHRH analogue therapy. With a median of 95 weeks of follow-up, 34% of deaths had occurred. The survival analysis was not dissimilar between the 2 groups. At 49 weeks median follow up, the incidence of diarrhoea was significantly (p < 0.001) lower among patients in the Casodex plus LHRH analogue group. Diarrhoea led to withdrawal from therapy for 2 patients in the Casodex plus LHRH analogue group, compared with 25 patients in the flutamide plus LHRH analogue group. In conclusion, Casodex plus LHRH analogue is well tolerated and effective with an improvement in time to treatment failure over flutamide plus LHRH analogue. Survival was not dissimilar between the 2 treatment groups.

The aim of the study was to compare granisetron (GRA) with ondansetron (OND) in the prevention of acute emesis in consecutive chemotherapy-naive patients admitted to our department to receive a cytotoxic treatment containing cisplatinum (CP) at a dose > or = 50 mg/m2. Eligible patients were randomised at their first cycle to receive either OND or GRA with cross-over of the anti-emetic treatment on the second cycle. The cytotoxic treatments included five different multidrug regimens containing CP (median dose 60 mg/m2, range 50-70 mg/m2) administered on day 1 and repeated every 21-28 days. OND was administered at the dose of 8 mg x 3 i.v. on day 1 and 8 mg x 2 orally on day 2. GRA was always administered at the dose of 3 mg i.v. on day 1. 124 patients entered the study. 58 patients received OND at their first cycle and 66 received GRA. Complete protection of acute emesis with OND and GRA was observed, with the first and second cycles combined as follows: nausea 53 and 60%, vomiting 68 and 71%, respectively (no statistically significant difference). The cross-over analysis comprising 101 patients confirmed no difference between the two anti-emetic treatments. 21 patients (19%) on OND and 14 patients (12%) on GRA suffered headaches (P = 0.15). 25 (25%) patients preferred OND, 45 (45%) preferred GRA, while 31 (30%) expressed no preference (P = 0.003). However, these differences also depended on the sequence of anti-emetics in the cross-over. In conclusion, in this study, a single dose of GRA is demonstrated to be as effective as multiple doses of OND in the prevention of acute emesis.

54 patients with advanced breast cancer were randomised into a prospective, non-blinded, controlled trial to receive: mitoxantrone 28 mg/m2 intravenous day 1 and granulocyte-colony stimulating factor (G-CSF) 5 micrograms/kg/day subcutaneously days 2 to 16 (n = 27) or the same regimen plus thymostimulin (TS) 50 mg/day intramuscular at days 2 to 16 (n = 27). The median time to reach a neutrophil count greater than 0.5 x 10(9)/l was lower in the G-CSF+TS treated group (9.13 versus 3.24 days; P < 0.0005). More patients experienced neutropenic fever in the G-CSF group than in the G-CSF+TS group (59.3% versus 22.2%, P = 0.0119). The incidence, duration and severity of clinically or bacteriologically documented infection were lower in patients who received TS. 16 patients (59.3%) in the G-CSF group contracted infection, and 4 patients (14.8%) receiving G-CSF+TS (P = 0.0016). These data indicate that the combination of G-CSF and TS is well-tolerated and may enhance haematological recovery following myelosuppressive chemotherapy in patients with advanced breast cancer.

A third series of randomized tests was undertaken to evaluate the efficacy of postoperative adjuvant hormone therapy (tamoxifen, diethylstilbestrol, orimethen amino glutethymide) in breast cancer patients. Tamoxifen was studied in 176 patients with T1-2N0M0 tumors. Five-year recurrence-free survival was registered in 85.2% of menopausal patients treated with tamoxifen versus 71.1% in control (P < 0.05). Five-year recurrence-free survival in menopausal females with breast tumors, stage IIb, was 71.1% among those treated with diethylstilbestrol and as low as 57.4% in the tamoxifen group (P < 0.05). Untoward side-effect incidence was much higher in the diethylstilbestrol group (30.4%) as compared with tamoxifen (3.5%). No significant difference was found for the relationship between orimethen and tamoxifen treatment with respect to 5-year survival and recurrence-free survival.

Intravenous dolasetron has been shown to be an effective antiemetic agent in patients receiving high-dose cisplatin-containing chemotherapy. Previous studies have suggested that 1.8 mg/kg is an optimal dose for achieving control of emesis and nausea. The objective of this study was to compare the efficacy and safety of a single intravenous (IV) dose of dolasetron with an equal divided multiple dose.

Two new drugs from two new chemotherapy compound families were developed concomitantly: Taxoter (docetaxel), a taxane derivate and CPT 11 (irinotecan) a topoisomerase inhibitor. Six phase I trials of Taxoter were performed. The limiting toxicity is neutropenia. The recommended dosage for phase II trial is 100 mg/m2 administered in 1 hour perfusion, every 21 days. Neutropenic fever is unfrequent. Other toxicities are mucositis, skin toxicity, hypersensibility reaction, weight gain and oedema. None of these toxicities were limiting. Six phase I studies were conducted to determine the maximum tolerated dose of CPT 11 (irinotecan). Two different schedules were studied: the weekly 30-90 minutes infusion and an infusion administered every three weeks in one day or daily over three or five consecutive days. The limiting toxicity of the weekly schedule is diarrhea. Therefore the recommended dosage is 100-150 mg/m2/week. While dose limiting toxicities in the three week schedule are diarrhea as well as neutropenia. The recommended dose is 350 mg/m2. Since diarrhea appeared to be the major problem in achieving high dose intensity with CPT 11, a dose escalation trial with drug support against diarrhea was performed. A recommended dosage of 500 mg/m2 is therefore described. These two drugs are under evaluation in a large spectrum of tumors. Their original mechanism of action suggests interesting therapeutic properties. Clinical studies in combination with other drugs are in progress to define the role of topoisomerase I inhibitors and taxane in cancer therapy.

Recent advances in biochemical pharmacology have revealed the basis for the biological modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and folinic acid (FA). Sequential use of MTX given 24 h prior to 5-FU has resulted in enhanced cell kill in vitro and in vivo. In addition, administration of FA prior to 5-FU has led to potentiation of 5-FU action by stabilization of the ternary complex of thymidine synthase. In the present randomized study, two groups of patients with advanced colorectal cancer were treated as follows: 43 patients (pts) in group A received 5-FU + FA, whereas 45 pts in group B received 5-FU + FA + MTX. The dosage was as follows: group A received FA i.v. at 300 mg/m2 per day, prior to i.v. 5-FU at 500 mg/m2 per day on days 1-4; group B was given MTX i.v. at 130 mg/m2 per day on day 0, followed 24 h later by FA at 15 mg q6h x 6, and 5-FU + FA was started on day 1 and given at the same doses and schedule described for group A. Objective responses were achieved by 8/43 pts in group A (1 complete response and 7 partial responses) and by 18/45 pts in group B (3 complete and 15 partial responses), all occurring in the liver. There was no significant difference in the median time to progression (group A 6.1 months, group B 6.8 months) or the median survival (group A 9.2 months, group B 10.3 months). Toxicity was significantly greater in group B [grade 2-3 mucositis 20% versus only 2% in group A (P < 0.0001); grade 3 diarrhea in group B 15% versus 3% in group A (P < 0.001)]. According to our results, double biological modulation of 5-FU with MTX + FA led to an enhanced response rate with increased toxicity as compared with the 5-FU + FA regimen given at less than its maximally tolerated dose.

ThioTEPA is given intravesically in a variety of schedules to treat superficial bladder cancer. In this study, the influence of the dose of ThioTEPA and the volume of instillate on the dose rate to the tumour and the systemic uptake of ThioTEPA was investigated in eight patients with pTa or pTl disease. Each patient received four courses of ThioTEPA consisting of 30 mg of drug/30 ml of distilled water, 30 mg/60 ml, 60 mg/30 ml and 60 mg/60 ml. Blood and urine samples were obtained for 8 h following instillation, and ThioTEPA and TEPA levels were measured. The AUC(infinity) values (areas under the concentration-time curve, extrapolated to infinity) in plasma were approximately 2 factors higher at the two 60-mg doses. However, the AUC value in the bladder was nearly 70% higher when 60 mg of drug was instilled in 30 ml of distilled water as compared with 60 mg in 60 ml. Thus, by decreasing the volume of instillate it is possible to increase the dose rate to the tumour without increasing the systemic toxicity.

Methotrexate (MTX) is one of the most widely used drugs for the treatment of childhood acute lymphoblastic leukemia (ALL) and is commonly given in high doses. However, the rationale for high-dose MTX (HDMTX) has been challenged recently. To determine whether higher MTX polyglutamate (MTXPG) concentrations in ALL blasts translate into greater antileukemic effects, 150 children with newly diagnosed ALL were randomized to initial treatment with either HDMTX (1,000 mg/m2 intravenously over 24 h) or lower-dose MTX (30 mg/m2 by mouth every 6 h x 6). ALL blasts accumulated higher concentrations of MTXPG and long-chain MTXPG (MTXPGLC) after HDMTX (P < 0.00001). Of 101 patients evaluable for peripheral blast cytoreduction, MTXPG concentrations were higher in patients whose blast count decreased within 24 h (P = 0.005) and in those who had no detectable circulating blasts within 4 days (P = 0.004). The extent of inhibition of de novo purine synthesis in ALL blasts was significantly related to the blast concentration of MTXPGLC (IC95% = 483 pmol/10(9) blasts). The percentage of patients with 44-h MTXPGLC exceeding the IC95% was greater after HDMTX (81%) than LDMTX (46%, P < 0.0001). These data indicate that higher blast concentrations of MTXPG are associated with greater antileukemic effects, establishing a strong rationale for HD-MTX in the treatment of childhood ALL.

Despite recent advances in control of acute emesis following cisplatin-based chemotherapy regimens, delayed emesis remains a significant cause of treatment-related morbidity and factors associated with delayed emesis have not yet been evaluated. A prospective randomised trial was conducted to compare the efficacy and toxicity of granisetron, dexamethasone plus prochlorperazine with granisetron alone in controlling cisplatin-induced delayed emesis and to identify the important factors that influence its occurrence and severity. Seventy cisplatin-naive patients with inoperable solid tumors participated in the trial. Patients who received 80 mg m-2 or 100 mg m-2 of cisplatin were randomly assigned to receive either granisetron 40 micrograms kg-1 intravenously (i.v.) on day 1, dexamethasone 20 mg i.v. on days 2 and 3 and prochlorperazine 5 mg orally thrice daily on days 1-5 or granisetron 40 micrograms kg-1 i.v. on day 1 alone. There was no difference in their acute antiemetic efficacy. A combination regimen was more effective than granisetron alone in preventing delayed symptoms, with superior rates of complete plus major responses of 77% vs 51% (P = 0.0460). Treatment arm was the only determinant factor for the occurrence of delayed emesis (P = 0.0101).

Cisplatin-induced emesis is one of the most feared side effects in cancer treatment. High-dose metoclopramide may prevent only 30-40% of cases of acute emesis. Investigations to test the efficacy of new antiemetics are mandatory. We compared the efficacy, toxicity, and patients' preference for tropisetron, a new 5-hydroxytryptamine3 (HT3) receptor antagonist, with those of a combination of high-dose metoclopramide, dexamethasone, diphenhydramine, and lorazepam (metoclopramide cocktail) in a randomized crossover study for the control of nausea and vomiting during cisplatin-containing chemotherapy. A total of 62 chemotherapy-naive women were included and followed over 3 consecutive courses. Detailed analysis comparing the incidence of acute emesis for each 4 h period following cisplatin infusion was also performed. Complete protection from acute emesis was obtained in 48% of patients receiving tropisetron and 29% of patients receiving the metoclopramide cocktail over the first two courses of chemotherapy (P = 0.029). When the frequency of acute emesis in all patients was compared on a daily basis, no significant difference was found. When emesis frequency was compared over each 4 h period following infusion of cisplatin, tropisetron was superior to the metoclopramide cocktail during the first, the second, and the first and second periods (P = 0.0001, P = 0.01 and P = 0.0006, respectively). This superiority reversed after 12 h but did not reach statistical significance (P = 0.112). Tropisetron was more effective in controlling acute nausea, but metoclopramide provided better control of delayed emesis. A drop in efficacy over successive courses was observed in patients receiving metoclopramide first but was not seen in tropisetron-first patients. A tendency for tropisetron preference was observed. Tropisetron is more effective than the metoclopramide cocktail in the control of chemotherapy-induced vomiting within 8 h of the implementation of cisplatin and in the control of nausea on the 1st day. To improve the control of chemotherapy-induced emesis, further investigations on the additional tropisetron dosing at 8 h after cisplatin infusion or the combination use of tropisetron and other antiemetics by a continuous 4 h period of observation and comparison are mandatory.

Thirteen postmenopausal women with advanced breast cancer were enrolled in an open randomized Phase I trial of a new p.o. active aromatase inhibitor, CGS 20267 (letrozole). The primary aim of the trial was to assess the impact of two doses of letrozole (0.5 and 2. 5 mg/day) on the peripheral aromatization of androstenedione to estrone. An in vivo isotopic technique was used to measure peripheral aromatization in each patient before treatment. The patients were then randomly assigned to one of the two doses, and measurements of aromatization were repeated after 6 weeks. At 0.5 mg and 2.5 mg/day, letrozole inhibited aromatization by 98.4% (97.3 to >99.1) and >98.9% (98.5 to >99.1; geometric means and ranges), respectively. Plasma estrogen levels were also measured before and during treatment. At the dose of 0.5 mg/day estrone and estradiol levels fell by 82.0% and 84.1% (geometric means), respectively. At the dose of 2.5 mg/ day, the estrogens fell by 80.8% and 68.1%, respectively. There were no significant differences between the doses in aromatase inhibition. No formal statistical analysis was performed on the estrogen data. Letrozole is therefore a highly effective inhibitor of aromatase, causing near complete inhibition of the enzyme in peripheral tissues at the doses investigated. The falls in estrogen levels were greater than those seen with earlier generation aromatase inhibitors.

To determine the minimum effective dosage, most effective route of administration and long-term effects of mitomycin C for prevention of recurrence after pterygium surgery.

Dexniguldipine-HCl is a new dihydropyridine derivative with antineoplastic activity and potency for overcoming multidrug resistance. In this pharmacokinetic study the bioavailability of 3 doses of an oral formulation of dexniguldipine was to be determined. Fourteen patients with malignant disease not eligible for higher priority treatment and sufficient general condition were included. In 12 patients all pharmacokinetic investigations were available for evaluation. A single 4-h infusion of 2 mg per kg body weight of dexniguldipine was given as reference. Thereafter 3 increasing oral dosages (750, 1,500, 2,250 mg/d) were given on a 3-time daily basis for 3 consecutive weeks. On day 7 (under steady state conditions) of each period, a pharmacokinetic profile was done. Absolute bioavailability at the 3-dose levels was 3, 4, and 5%, respectively, thus slightly increasing with dose, but generally low. After intravenous administration terminal half life was 22.4 h, clearance 36.9 l/h and volume of distribution 1,193 1. Toxicity was tolerable with main adverse events being loss of appetite, nausea, and vomiting. Cardiovascular effects and a decrease in serum calcium were reported in several patients. Patients were allowed to continue treatment if a benefit was expected, and 2 patients showed tumor regression during treatment. One patient with renal cell carcinoma achieved a partial remission. Bioavailability of this oral formulation seems too low for routine clinical use, despite the fact that clinical effects have been observed.