The effects of steroid hormones are pleiotropic. Similarly, non-steroidal oestrogen receptor antagonists such as tamoxifen exert partial agonistic effects with a species- and tissue-specific pattern. Conversely, little is known of the biological effects of non-steroidal anti-androgens, whose role has been investigated in the palliative treatment of prostate cancer. We studied the effects of the non-steroidal anti-androgen nilutamide on parameters of red blood cells, an androgen-dependent cell compartment, in 24 men with prostate cancer and compared the results with those obtained in 38 historical control patients treated with D-tryptophan-6-LHRH. Administration of the anti-androgen induced a limited rise in testosterone concentrations (from 14.1 +/- 1.8 up to a maximum of 19.6 +/- 2.3 nmol l-1) and a significant increase with time in haemoglobin and haematocrit (y = 12.6 g dl-1 + 0.15 months and y = 37.3% + 0.46 months respectively, P = 0.008 for both), while no change occurred in red blood cell count (y = 4.19 x 10(6) mm-3 + 0.02 months, P = 0.2). Conversely, no variation in erythroid parameters was observed in the patients treated with the LHRH analogue (haemoglobin = 12.7 + 0.02 months, P = 0.59; haematocrit = 38.1 + 0.02 months, P = 0.9; red blood cells = 4.34 x 10(6) mm-3 + 0.15 months, P = 0.4). The difference between the linear regression slopes of haemoglobin in the two treatment groups was significant (F-ratio = 3.39, P = 0.03). While the stimulation of erythropoiesis induced by the anti-androgen might be due to incomplete neutralisation of endogenous androgens at the bone marrow level, a cell-specific agonistic effect of the drug cannot be excluded, thus calling into question the designation of pure antagonists which has been attributed to this class of compounds. Ongoing randomised trials should address this issue.

One hundred patients with advanced carcinoma undergoing highly cytotoxic chemotherapy were enrolled in a prospective randomized trial comparing subcutaneous G-CSF, thymopentin, a combination of the two, and placebo as preventive treatment of febrile leukopenia. Data from this study show that G-CSF was very active in reducing the incidence of chemotherapy-related fever and leukopenia as compared to placebo (22% versus 64%). This difference was statistically highly significant (P < 0.001). Thymopentin was associated with a reduction in febrile episodes as compared to placebo (52% versus 64%), but this difference did not reach statistical significance. Moreover, the addition of thymopentin to G-CSF did not result in a statistically significant improvement of results obtained with G-CSF alone. Similar results were achieved for fungal infections. Tolerance to thymopentin was excellent, while less than 9% of patients on G-CSF treatment complained of mild nausea and generalized bone pain.

We designed a prospective randomized trial to compare vinorelbine and cisplatin (NVB-P) with vindesine and cisplatin (VDS-P) and to evaluate whether the best of these regimens affords a survival benefit compared with vinorelbine alone (NVB), an outpatient regimen, in patients with non-small-cell lung cancer (NSCLC).

We have conducted a clinical trial of a novel pure antiestrogen, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5,(1 0)-triene-3,17 beta-diol (ICI 182780), to assess its tolerance, pharmacokinetics, and short term biological effects in women with primary breast cancer. Fifty-six patients were randomized to either a control group (n = 19), in which they received no preoperative treatment, or a treatment group (n = 37), in which they received daily i.m. injections of ICI 182780 at doses of 6 mg (n = 21) or 18 mg (n = 16) for 7 days prior to primary breast surgery. Serum drug concentrations, gonadotropin levels, and sex hormone-binding globulin levels were measured during the study period by radioimmunoassay. Expression of estrogen receptors (ER), progesterone receptors, the estrogen-induced protein pS2, and the cell proliferation-related antigen Ki67 was determined immunocytochemically in pre- and poststudy tumor samples. Treatment with ICI 182780 caused no serious drug-related adverse events and had no effect on serum gonadotropin or sex hormone-binding globulin levels. Minor adverse events occurred in 5 patients receiving the 6-mg dose and 3 patients receiving the 18-mg dose. The serum concentration of ICI 182780 was dose dependent but showed variation between individuals. There was evidence of an approximately 3-fold drug accumulation over the short treatment period but steady state levels were not reached by the end of the 7 days. In patients with ER-positive tumors, treatment with ICI 182780 was associated with significant reductions in the tumor expression of ER (median ER index, 0.72 before versus 0.02 after treatment; P < 0.001), progesterone receptor (median progesterone receptor index, 0.50 before versus 0.01 after treatment; P < 0.05), and Ki67 (median Ki67 labeling index, 3.2 before versus 1.1 after treatment; P < 0.05). Treatment with ICI 182780 also resulted in a significant reduction in pS2 expression (P < 0.05) but this appeared unrelated to tumor ER status. In conclusion, ICI 182780 was well tolerated after short term administration and produced demonstrable antiestrogenic effects in human breast tumors in vivo, without showing evidence of agonist activity. These properties identify ICI 182780 as a candidate agent with which to evaluate whether a pure estrogen antagonist offers any additional benefit in the treatment of human breast cancer over conventional nonsteroidal antiestrogens, typified by tamoxifen, which exhibit variable degrees of agonist activity.

To assess the feasibility and efficacy of rhGM-CSF in ameliorating chemotherapy-induced leukopenia in patients with advanced non-small-cell lung cancer, we conducted a double-blind placebo controlled phase III study in a multicenter setting. Patients were eligible if they had cytologically or histologically proven cancer, no prior chemotherapy, stage IIIB or IV disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an age of less than 76 years, and no symptomatic brain metastasis, disseminated bone metastasis, or previous vertebral/pelvic irradiation. The chemotherapy regimen consisted of mitomycin given at 8 mg/m2 on day 1, cisplatin given at 100 mg/m2 on day 1, and vindesine given at 3 mg/m2 i.v. on days 1 and 8 (MVP). If the granulocyte nadir count recorded after the first cycle of MVP was less than 1,000/mm3, patients were randomly assigned to receive recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or placebo during the second cycle of MVP. The dose of rhGM-CSF was 125 micrograms/m2 given daily s.c. for 14 consecutive days starting on day 2. Of the 52 patients enrolled, 45 were evaluable. The nadir of granulocytes was significantly lower in the placebo group (P = 0.007). The period during which the granulocyte count was less than 1,000/mm3 was significantly longer in the placebo group (median, 6 vs 10 days; P = 0.04). The incidence of adverse effects related to rhGM-CSF, such as fever (> or = 38 degrees C) and skin rash, was significantly higher in the rhGM-CSF group (P = 0.011). The rate of response to chemotherapy did not significantly differ between the two groups. In conclusion, rhGM-CSF reduced the duration of chemotherapy-induced granulocytopenia. The clinical usefulness of this agent may be deminished because of the adverse effects encountered when it is used in combination with a moderately myelotoxic chemotherapy regimen.

OBJECTIVE. To compare the efficacy and tolerability of standard dosage of tropisetron and ondansetron in controlling emesis induced by chemotherapeutic regimen not containing cisplatin. DESIGN. Open, comparative, parallel-group, randomized study. SETTING. Day hospital to which patients were admitted only on the day on chemotherapy when the antiemetic was given intravenously.

This randomised, open, parallel group study compared the antiemetic efficacy and tolerability of tropisetron with metoclopramide plus lorazepam in 102 patients receiving a first course of non-cisplatin-containing chemotherapy. Control of acute vomiting by tropisetron was significantly superior to that of the metoclopramide regimen, with total control (no vomiting) in 45% of 51 patients in the tropisetron group compared with 22% of 51 patients in the metoclopramide group (P = 0.013); total and partial control (< 5 vomits) occurred in 67 and 47% of patients, respectively (P = 0.044). The incidences of acute nausea and of delayed nausea and emesis were similar in the two treatment groups. Both tropisetron and metoclopramide were well tolerated; no adverse effects were attributed to tropisetron administration with the exception of headache. One patient in the metoclopramide group reported confusion and tremor thought to be related to the antiemetic therapy. Tropisetron is an effective and well-tolerated agent in the prevention of chemotherapy-induced vomiting. The control of acute nausea was similar in the two treatment groups, but tropisetron was superior to a metoclopramide-based regimen in the control of acute vomiting.

Between February 1986 and November 1989, 166 patients who were candidates for a bone marrow transplantation entered a randomised controlled clinical trial to compare limited oral hygiene care (LIM) and intensive oral hygiene care (INT) in the prevention of mucositis. Randomisation was stratified on the initial oral status (good vs. bad IOS). Intensive oral hygiene care included an initial treatment of dental lesions and tooth and gum brushing during aplasia. Limited oral hygiene care excluded preventive dental treatment and gingival and tooth brushing. Mucositis was classified as absent, mild, moderate or severe, according to the clinical aspects of the different sites in the mouth and to two scales of pain evaluation. Of the 150 evaluable patients (75 in each group), 134 developed moderate/severe mucositis (64 in the INT group and 70 in the LIM group) (log-rank test P < 0.02). The superiority of intensive oral care was observed both in patients with and without total body irradiation (TBI) and in patients with a good or bad IOS; the observed risk of mucositis was reduced by 70% in each of these four subgroups. Duration of moderate/severe mucositis was, although not significantly, lower in the INT group (17 days, S.D. = 12) than in the LIM group (19 days, S.D. = 13). The median time of mucositis occurrence was 11 days in the INT group and 9 days in the LIM group. Contrary to a widespread belief, the percentage of documented septicaemia was not higher in patients who underwent intensive oral care. We conclude that, although statistically significant, the superiority of intensive oral hygiene care is not clinically impressive.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients receiving outpatient chemotherapy, without cisplatin, were randomised to receive four doses of either domperidone 60 mg or prochlorperazine 25 mg suppositories every 4 h, starting 30 min before the chemotherapy. They were crossed over for the next chemotherapy cycle. To enable analysis of 100 patients who had received identical chemotherapy in each course, 136 patients were randomised. Patients experienced a higher grade of nausea on domperidone (P = 0.05). Only 18% of patients vomited on domperidone and 14% on prochlorperazine, but the number of vomits was higher on domperidone (P = 0.003) and the duration was significantly increased (P = 0.02). Patients experienced significantly more diarrhoea on domperidone (P < 0.0001), although it was predominantly mild. Patients were significantly more sedated on prochlorperazine on the second course (P = 0.006), but not on the first course (P = 0.9). More patients preferred their second course (P < 0.0001), and were significantly less anxious (P = 0.0002). Patients reported tolerating their treatment similarly for both antiemetics, but more patients preferred prochlorperazine (P = 0.003), mainly due to reductions in nausea and vomiting and other side-effects, particularly diarrhoea.

A pilot randomised placebo controlled trial using tamoxifen in healthy women at increased risk of developing breast cancer, has been undertaken in order to evaluate the problems of accrual, acute symptomatic toxicity, compliance, and safety as a basis for subsequent large national multicentre trials designed to test whether tamoxifen can chemoprevent breast cancer. From October 1986 until June 1993, 2012 healthy women with an increased risk of developing breast cancer, usually because of a strong family history, were randomly allocated to receive tamoxifen 20 mgs/day or placebo for up to 8 years if possible. Accrual remained high in spite of extensive informed consent regarding potential risk. Acute symptomatic toxicity was low for participants on tamoxifen or placebo and compliance remained correspondingly high with a predicted 77% of women on tamoxifen and 82% of women on placebo continuing medication at 5 years. There was a significant increase in hot flushes (34% versus 20%) mostly in premenopausal women (p < 0.005), vaginal discharge (16% versus 4%, p < 0.005), and menstrual irregularities (14% versus 9%, p < 0.005). The requirements for hormone replacement therapy for women on tamoxifen or placebo were the same. Safety monitoring indicates no adverse anti oestrogenic effects of tamoxifen. There was no obvious effect of tamoxifen on bone mineral densities (single photon radial absorption). The fibrinogen and antithrombin III were both lowered, resulting in no observed detrimental effect on the ratio of these clotting factors. There was a significant reduction in the serum cholesterol maintained out to 5 years. Annual pelvic assessment using transvaginal ultrasound indicates an increased incidence of uterine fibromata and benign ovarian cysts.(ABSTRACT TRUNCATED AT 250 WORDS)

In a double-blind, placebo-controlled, escalating dose study, 44 children receiving cancer chemotherapy of various degrees of emetogenicity were randomly allocated to once-daily treatment with tropisetron 0.05 mg/kg (6 patients), 0.10 mg/kg (5 patients), 0.20 mg/kg (6 patients), 0.33 mg/kg (6 patients), 0.50 mg/kg (6 patients) or placebo (15 patients). All doses of tropisetron were well tolerated; no tropisetron recipient discontinued treatment because of intolerance and no adverse effect could be plausibly correlated to tropisetron administration. Therapeutic plasma concentrations of tropisetron (> 3 ng/ml) were present for 9 h after administration of doses of 0.10 mg/kg or more. Tropisetron at doses of at least 0.20 mg/kg was significantly more effective in preventing vomiting than lower tropisetron doses or placebo, both in terms of treatment failure (> four vomits) (P = 0.015) and patient and investigator efficacy ratings (P = 0.04 for investigator rating; P = 0.035 for patient rating). Further comparative studies of the efficacy of tropisetron in chemotherapy-induced emesis in children are warranted.

Combination chemotherapy with anti-proliferative agents is the usual treatment for patients with advanced non-small cell lung cancer (NSCLC), good performance status and no major clinical contraindications. Lonidamine (LND), a new drug with an innovative mechanism of action, might potentiate anti-cancer activity of conventional cytotoxic drugs, with no increase of specific toxicity. Following a pilot study of feasibility, we now report the results of a randomised trial evaluating MACC chemotherapy, as originally described, versus the same regimen+LND. 151 patients with advanced NSCLC were assigned at random to the two treatment arms. LND 150 mg was given orally three times daily. Treatment was continued until progression of disease, unacceptable toxicity or refusal by the patient (median number of cycles of MACC, three for both arms; median duration of LND administration, 8 weeks in the arm concerned). Actual dose intensities (DI) of MACC and LND were, respectively, 100 and 83% of those intended (median values). There was a negative correlation between duration of chemotherapy and the DI of MACC reached in each patient, but no correlation between the duration of treatment with LND and its DI. DIs of LND and MACC were not correlated with each other. In all, 15 objective responses (one complete and four partial responses in the MACC group, 10 partial responses in patients on MACC+LND) were observed. Median progression-free survivals were 20 weeks (confidence interval, CI 14-22) for the group on LND and 17 weeks (CI 12-17) for the control group (non-significant difference). Median overall survivals were, respectively, 30 weeks (CI 23-40) and 27 weeks (CI 22-34), P = non-significant. Toxicity was as expected by the use of MACC, and similar in both arms, except for more severe anaemia and gastric toxicity in the group on MACC+LND. Other uncommon side-effects, seen only in this latter group, were mild to moderate and reversible and included myalgia, asthenia, testicle pain, headache, visual troubles, incubi and dizziness. Subjective tolerance to the treatment, and perception of physical and psychological well-being were rated similarly by patients of both groups. MACC plus LND is a moderately active regimen in advanced NSCLC, with a foreseeable and reversible toxicity of low-medium grade. Potential enhancements of anti-tumour efficacy of chemotherapy, and possible host survival benefits derived from the use of LND are not substantiated by the results of this trial.

Targeted delivery of macrophage activating agents is an attractive approach to treat micrometastatic disease. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is a potent activator of monocytes/macrophages in humans, mice, and dogs. We have conducted clinical trials in dogs with malignant and highly metastatic spontaneous tumors. Presented are results of our trials evaluating L-MTP-PE in combination with surgery and chemotherapy in dogs with spontaneous osteosarcoma and hemangiosarcoma, particularly relevant malignancies having having many similarities to human cancer. Osteosarcoma dogs received chemotherapy following surgery (cisplatin q 28 days x 4). At completion of chemotherapy, dogs were randomized to receive L-MTP-PE or placebo. The L-MTP-PE group had a significantly longer median survival time compared to the placebo group (p < 0.021). Dogs with splenic hemangiosarcoma received combination chemotherapy following surgery (doxorubicin and cyclophosphamide q 21 days x 4). At the first chemotherapy, dogs were randomized to receive L-MTP-PE or placebo. The L-MTP-PE group had a significantly longer median survival time compared to the placebo group (p < 0.03). These studies show that L-MTP-PE is an effective agent for treatment of metastasis and can be safely administered in combination with chemotherapy.

The efficacy of total androgen blockade using orchiectomy and nilutamide was compared with orchiectomy with placebo in a large double-blind clinical trial with 457 patients. The median interval to objective progression was 20.8 months for total androgen blockade and 14.7 months for orchiectomy alone (P = 0.0041). The median interval to death for all patients was 37.1 months versus 29.8 months (P = 0.041). Decrease in pain was seen at months 1, 3, and 6 in a significant percentage for the total androgen blockade group. A significant difference in prostate specific antigen levels was seen at months 3 and 6, with normalization of 75% and 28%, respectively, in both groups at both times. The tolerance of the nonsteroidal antiandrogen nilutamide showed visual disturbances as a side-effect, resulting in the withdrawal of five patients from treatment. Liver and lung disturbances were transient. Total androgen blockade is a more effective treatment for metastatic prostate cancer than orchiectomy alone in this study population.

Granisetron is a novel, highly specific 5-hydroxytryptamine receptor antagonist given prophylactically to patients undergoing chemotherapy. An open, randomized, crossover trial was performed with 37 patients (24 females and 13 males) undergoing cytotoxic chemotherapy for malignant disease to compare an oral tablet (1-mg tablet given twice daily) with a clinical-trial capsule (1-mg capsule given twice daily). Complete pharmacokinetic data were determined for 24 patients (14 females and 10 males). The concentration of granisetron in plasma was measured by HPLC; the limit of quantitation was 0.2 ng/mL. The bioavailability evaluation was based mainly on the area under the curve (AUC) (mean values: 52.1 ng.h/mL for the capsule and 54.2 ng.h/mL for the tablet) and the maximum concentration (Cmax) (mean values: 7.42 ng/mL for the capsule and 8.18 ng/mL for the tablet) measured at the steady state after 7 days of continuous therapy. Wide interpatient variability in plasma granisetron levels after oral administration was observed. The 90% standard confidence interval for the geometric mean ratio overlapped the critical range, 0.8-1.25. Point estimates for AUC and Cmax based on two one-sided t tests and log-transformed data showed that the upper limit of the confidence interval was not within 20% of the mean for the capsule; the corresponding power analysis values for AUC and Cmax were 0.89 and 0.81, respectively. Despite bioequivalence not being proven, any differences that exist between the two formulations are likely to be small. There was no difference in efficacy or safety between the two formulations assessed.

Trilostane and Aminoglutethimide, each given with a physiological replacement dose of hydrocortisone, were randomly allocated to 72 eligible postmenopausal advanced breast cancer patients; following treatment failure on either drug the patient continued with the other drug, if in a suitable clinical condition. Thirty-eight patients initially received Trilostane of whom 19 subsequently received Aminoglutethimide; 34 patients initially had Aminoglutethimide and seven of these then received Trilostane. Both groups of patients were comparable in all respects. There was no difference in the objective response rate to either drug, Trilostane 11/38 = 29%, Aminoglutethimide 12/34 = 35%, nor in the average time to disease progression for the two drugs, Trilostane 64 weeks, Aminoglutethimide 68 weeks. Of the 26 patients who received both drugs, four showed a response to both suggesting no cross resistance. Side effects were seen to both drugs in approximately half of the patients, but were mainly gastro-intestinal with Trilostane and rash and drowsiness with Aminoglutethimide. There was no evidence of cross over patient susceptibility to side effects.

The role of total parenteral nutrition (TPN) in reducing toxicity related to cancer chemotherapy (CT) is presently a controversial issue. To evaluate the effectiveness of TPN in reducing CT-associated toxicity and correcting and preventing CT-related impairments of nutritional status, a prospective crossover controlled study was performed in 43 cancer patients (19 normally nourished and 24 malnourished) randomly divided into two groups (A and B). Group A patients received TPN concomitantly with the first course of chemotherapy, and the second course was administered 21 to 28 days later without TPN support; group B patients were treated in the opposite sequence. The rates of myelotoxicities and gastrointestinal toxicities after CT courses with or without TPN were essentially similar in normally nourished and malnourished patients. No changes in nutritional indexes were detected in normally nourished subjects after each course. Conversely, in undernourished subjects, prealbumin, retinol-binding protein, and nitrogen balance increased in CT+TPN courses (p < .02). In CT-only courses, undernourished subjects showed a decrease in prealbumin and nitrogen balance. Significant changes of nitrogen balance in CT vs CT+TPN courses were detected in malnourished subjects. TPN appears to be unable to reduce CT-associated toxicity. CT administration does not result in any impairment of the nutritional status in normally nourished cancer patients. From our study, it appears that TPN should be limited to severely malnourished neoplastic patients undergoing CT, because of its ability to prevent further impairment of nutritional status and to improve the nitrogen balance and the levels of fast-turnover visceral proteins.

We studied the efficacy and safety of itraconazole for the prevention of fungal infection in neutropenic patients given cytotoxic chemotherapy for hematologic malignancies. Patients were randomly allocated to receive either itraconazole (200 mg bd) or placebo in addition to oral amphotericin B until the patient either developed fungal infection or had completed antileukemic treatment. Forty six patients (83 neutropenic episodes) treated with itraconazole and 46 placebo treated patients (84 neutropenic episodes) were evaluable. No specific toxicity was noted. Nine fungal infections developed in the itraconazole group, of which four were histologically or microbiologically proven and 15 in the patients given placebo (eight proven) (p < 0.12). All these patients received IV amphotericin B. The incidence of Candida albicans infections tended to be lower in the itraconazole group, but overall, there was no measurable improvement in the prevention of fungal infections and mortality by itraconazole.

This open, randomized, controlled study was designed to assess the efficacy of fluconazole in comparison with oral amphotericin B in preventing clinically suspected fungal infection. A total of 178 chemotherapy-induced neutropenic episodes expected to last more than 10 days in 51 patients with haematological malignancies were randomly treated with fluconazole, 200 mg once a day, or amphotericin B, 800 mg three times a day orally. Defining the end points as (1) documented fungal infection or (2) use of empiric intravenous amphotericin B for suspected fungal infection including an episode of fever lasting more than 5 days or fever developed during the use of broad-spectrum antibiotics, no difference was observed between the two groups.