To discover whether tamoxifen is able to extend the survival of patients with advanced hepatocellular carcinoma, we included 80 patients with cirrhosis and advanced hepatocellular carcinoma in a multicenter, double-blind, placebo-controlled trial in order to analyze the influence of treatment with tamoxifen on survival. The patients were randomized to receive tamoxifen, 40 mg/day (group 1), or placebo (group 2). Both groups were similar in age, sex, etiology of cirrhosis, biochemical, hematologic and hormonal parameters, morphology of the tumor (nodular vs multinodular or massive), Child-Pugh's score, and Okuda's stage. The 1-year survival rate was similar in both groups (30% in group 1 vs 37.8% in group 2; p = 0.31). Tamoxifen treatment was well tolerated by the patients. We conclude that tamoxifen does not extend the survival of patients with cirrhosis and advanced hepatocellular carcinoma.

Interferon alfa alone has shown antitumor activity against Kaposi's sarcoma (KS), and phase I and II clinical trials showed that interferon and zidovudine could be administered safely to patients with human immunodeficiency virus (HIV)-associated KS. These observations led to our trial of zidovudine with two dose levels of interferon alfa.

To evaluate a sustained release chemotherapy for treating condylomata acuminata with an injectable gel containing fluorouracil and adrenaline (5-FU/adrenaline gel). Study 1-- To assess contributions of the components of 5-FU/adrenaline gel to efficacy. Study 2--To assess therapeutic contribution of adrenaline and safety and efficacy of the formulations.

Metastatic renal cell carcinoma (RCC) has a poor prognosis. Conventional treatment strategies, including chemotherapy and hormonal therapy, have limited value. Although encouraging results have been achieved in terms of objective response using immunological manipulations, no conclusive studies yet exist with a controlled comparative evaluation of survival. Therefore, the present study was undertaken, which compared one of the present (and presumed best) treatments, interleukin 2/interferon-alpha (IL-2/IFN-alpha) and tamoxifen, with a control arm of tamoxifen only. Tamoxifen has been shown to potentiate in vivo anti-tumour activity of IL-2, and because of its non-toxic behaviour it was included in both groups. The study was open, randomized and included seven institutions in Sweden. The patients were stratified according to the different centres involved. An interim analysis was planned when a minimum of 100 patients were evaluable. The 128 patients finally included had a histologically documented metastatic RCC, with a life expectancy of more than 3 months, a performance status WHO 0-2 and no prior chemo- or immunotherapy. Informed consent was obtained from each patient. The patients randomized to the control arm (n = 63) received only tamoxifen 40 mg p.o. daily for at least 1 year or until progression. The patients (n = 65) randomized to biotherapy received subcutaneous recombinant IL-2, leucocyte IFN-alpha in a treatment cycle of 42 days, as well as tamoxifen p.o. In the absence of undue toxicity or disease progression, these patients received one additional treatment cycle of 42 days followed by maintenance treatment, consisting of 5 days therapy every 4 weeks, for 1 year, or until proven progression. Only two patients in the tamoxifen-only group received immunotherapy when the disease progressed, but without any beneficial effect. All patients received appropriate local treatment when indicated. The interim analysis demonstrated no survival advantage for either group, and therefore further inclusion of patients was stopped. The median follow-up was 11 months (range 0.4-48 months). The final survival analysis showed no significant differences between the two treatment arms in so far as comparison from the day of diagnosis of primary disease, from the day of first evidence of metastatic spread, or from the onset of treatment. This was valid both when the evaluation was performed with regard to intention to treat and when the analysis was directed only to patients that managed at least one treatment cycle (42 days) of IL-2/IFN-alpha. The adverse effects were more pronounced in the IL-2/IFN-alpha group. Although the number of patients is limited, the results raise doubt concerning immunotherapy with IL-2 and IFN-alpha as a routine treatment in the management of advanced RCC. The difference in cost of drugs and health care (drug costs per patient: IL-2/IFN-alpha $27000 vs tamoxifen $360) as well as adverse effects caused by IL-2/IFN-alpha are also factors of importance. The study emphasizes the need for more effort to find the 'optimal schedule' of immunotherapy, as well as the need for randomized controlled studies before approval of a new treatment in the routine setting.

Capecitabine (Ro 09-1978) is a novel oral fluoropyrimidine carbamate that was rationally designed to generate 5-fluorouracil (5-FU) selectively in tumors. The effect of food on the pharmacokinetics of capecitabine and its metabolites was investigated in 11 patients with advanced colorectal cancer using a two-way cross-over design with randomized sequence. Patients received repeated doses of 666 or 1255 mg/m2 of capecitabine twice daily. On study days 1 and 8, drug was administered following an overnight fast or within 30 min after consumption of a standard breakfast, and serial blood samples were collected. Concentrations of capecitabine and its metabolites [5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), 5-FU, dihydro-5-fluorouracil (FUH2), and alpha-fluoro-beta-alanine (FBAL)] in plasma were determined by high-performance liquid chromatography or liquid chromatography/mass spectroscopy. Intake of food prior to the administration of capecitabine resulted in pharmacokinetic changes of all compounds involved. The extent of these changes, however, varied considerably between the various compounds. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) values were decreased after food, and time until the occurrence of Cmax values were increased. In contrast, the apparent elimination half-life was not affected by food intake. The extent of change in Cmax and AUC was highest for capecitabine and decreased with the order of formation of the metabolites. The "before:after food" ratios of the Cmax values were 2.47 for capecitabine, 1.81 for 5'-DFCR, 1.53 for 5'-DFUR, 1.58 for 5-FU, 1.26 for FUH2, and 1.11 for FBAL. The before: after food ratios of the AUC values were 1.51 for capecitabine, 1.26 for 5'-DFCR, 1.15 for 5'-DFUR, 1.13 for 5-FU, 1.07 for FUH2, and 1.04 for FBAL. The results show that food has a profound effect on the AUC of capecitabine, a moderate effect on the AUC of 5'-DFCR, and only a minor influence on the AUC of the other metabolites in plasma. In addition, a profound influence on Cmax of capecitabine and most of its metabolites was found. Detailed information on the relationship between concentration and safety/efficacy is necessary to evaluate the clinical significance of these pharmacokinetic findings. At present, it is recommended that capecitabine be administered with food as this procedure was used in the clinical trials.

Plateau phase has been achieved in 64% of all newly diagnosed patients with multiple myeloma treated with the ABCM (adriamycin, BiCNU, cyclophosphamide and melphalan) regimen in the Medical Research Council (MRC) trials; this stable clinical stage of the disease is associated with no more than minimal symptoms. Several studies have found that alpha-interferon (alpha-IFN) maintenance therapy increases the duration of plateau phase, but it is less clear if this translates into prolonged survival. We report the effect of alpha-IFN on the duration of plateau phase and overall survival in a trial with 284 patients who were randomized to receive alpha2b-IFN (Intron-A) or no maintenance therapy during first plateau phase. The minimum follow-up after randomization was 21 months. There was no significant difference in the overall survival between the two treatment groups (X2=0.32, P=0.57). There was a trend towards longer relapse-free survival in the patients allocated alpha-IFN, but this trend to longer plateau phase was not statistically significant (X2 = 1.62, P = 0.2). Disease progression at relapse on alpha-IFN appears to be more severe with greater elevations from plateau levels of serum paraprotein (P = 0.06) and beta2-microglobulin (P= 0.03) levels. Physicians tended to start chemotherapy sooner after diagnosis of relapse when patients had received alpha-IFN (P = 0.16). Although, in common with most other studies, there is a trend for patients treated with alpha-IFN to have a longer plateau phase, this is counteracted by morbidity attributable to the treatment and a somewhat shortened survival post relapse. Meta-analysis of interferon trials is required to assess whether the minor trend for longer survival in patients maintained on alpha-IFN found in some studies is significant and, if so, the extent of this advantage.

Alpha interferon (IFN-alpha) is commonly used to treat patients with advanced renal cell carcinoma (RCC). We previously reported that resistance of RCCs to IFN-alpha in vitro correlated with the expression of a cell-surface glycoprotein of 160,00 kD molecular weight (gp160) which we subsequently identified as aminopeptidase A.

In an open, randomized phase II pharmacokinetic study conducted in Germany and Italy, a total of 42 patients with advanced or metastatic prostate cancer (PCa) were treated for 9 months with the luteinizing hormone-releasing hormone analogue (LH-RH-a) leuprorelin acetate depot in two different formulations. Fifteen patients received the 1-month depot and 27 patients received the newly developed 3-month depot, containing 3.75 mg and 11.25 mg, respectively. In both groups, subcutaneous injections of leuprorelin acetate injected monthly or at 3-month intervals produced a complete down-regulation of the pituitary and led to persistent suppression of testosterone and dihydrotestosterone to the castrate range (< or = 50 ng/dl for testosterone) within the first month of treatment, which thereafter could be maintained over the entire observation period of 9 months. In 10 patients, pretreatment with an antiandrogen for the prevention of clinical flare-up resulted in a slightly more profound and earlier drop in serum testosterone. The 3-month depot showed a higher median peak serum concentration (Cmax) of leuprorelin at 20.8 ng/ml than the 1-month depot at 10.7 ng/ml but, conversely, this did not influence the rise in serum testosterone levels. Cmax occurred at 3 h for the 3-month and at 1 h for the 1-month depot formulation. During the steady state, constant release could be detected, starting on day 3 and day 7 for the 1-month and 3-month depot, respectively. A marked decrease in median prostate-specific antigen levels of 97.8% (1-month depot) and 96.6% (3-month depot) compared with baseline was observed, indicating an objective clinical response for more than 80% of all patients in both arms. Based on European Organization for Research and Treatment of Cancer criteria, the best response in terms of complete/partial remissions and stabilization was comparable in the two arms at 86.7% (1-month depot) and 85.2% (3-month depot). 6.7% in the 1-month group and 3% in the 3-month depot group showed progression of the disease. The most common side effects in both treatment groups were related to hormone deprivation. Both formulations of the potent LH-RH-a leuprorelin acetate were highly effective in the treatment of advanced PCa and led to comparable endocrine and clinical effects.

To estimate the prevalence of abnormalities in visual function and ocular structures associated with the long-term use of tamoxifen citrate.

A prospective randomized study was undertaken to determine whether prophylactic maintenance instillation of epirubicin following induction treatment is beneficial in patients with superficial bladder cancer.

To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL).

Epirubicin is known to be metabolized in the liver. Therefore, drugs such as cimetidine, which inhibit the cytochrome P-450 enzyme system or reduce liver blood flow, may reduce the plasma clearance of epirubicin. In a small study, epirubicin 100 mg/m2 every 3 weeks was administered intravenously to eight patients, who also received oral cimetidine (400 mg b.d. for 7 days starting 5 days before chemotherapy) with either the first or second cycles. Epirubicin pharmacokinetics and liver blood flow (idocyanine green clearance) were assessed at each course. The areas under the plasma concentration time curves (AUCs) were used to compare the systemic exposure to epirubicin and its metabolites with each course. The estimated median percentage increase (95% confidence interval CI) in the AUC with cimetidine were: epirubicin 50% (95% CI -18 to 193, epirubicinol 41% (95% CI 1 to 92). Despite the small numbers studied, the increase in the active metabolite epirubicinol was significant (P < 0.05). These changes in exposure were not explained by reduced cytochrome P-450 activity as the 7-deoxy-doxorubicinol aglycone AUC was not reduced (357% increase: 95% CI 17 to 719) or by a decrease in liver blood flow (17% increase: 95% CI -39 to 104). Cimetidine is likely to be coprescribed or self-administered with epirubicin and therefore clinicians should be aware of this potential interaction.

A randomized study was conducted to evaluate the protective activity of amifostine (A) against the dose-limiting toxicities of radiochemotherapy (RCT). Patients with head and neck cancer received radiotherapy (2 Gy/day 5 days a week up to 60 Gy) with carboplatin 70 mg/m2 on days 1-5 and 21-25 inclusive. Patients either received RCT alone (n = 14) or RCT + A at a dose of 500 mg prior to treatment with carboplatin (n = 25). There was a significant reduction in the incidence of grade 3/4 mucositis (P < 0.0001), acute grade 2 xerostomia (P < 0.0001) and grade 3/4 thrombocytopenia (P = 0.012) in these patients who received A. The incidence of grade 2 late xerostomia at 12 months is 16.7% and the incidence of loss of taste is 0% in patients treated with A, as opposed to 54.5% and 63.6% in patients who received RCT alone. There were 18 (72%) complete responses (CR) and 6 (24%) partial responses (PR) in patients who received A, compared with 6 (43%) CR and 6 PR (43%) in patients treated with RCT alone. The disease-free survival at 12 months is 85.7% in the RCT + A arm and 78.6% in the RCT alone arm. The use of amifostine reduces the incidence and severity of acute and late toxicities associated with RCT whilst preserving antitumour activity.

For patients with pulmo-mediastinal malignancies, the antimetic effect of granisetron was studied in the following two ways. Firstly in the standard method, 40 micrograms/kg of granisetron was infused for 30 minutes, 30 minutes before CDDP infusion. Secondly, in the simultaneous method, granisetron was mixed with CDDP in a 500 microliters infusion bottle, and then infused over 0.5-3 hours. Over a 24-hour time course, significantly effective rates (nausea less than mild, and vomiting 2 times less) were 72.7% in the simultaneous group (n = 22) and 52.6% in the standard group (n = 19). The non-effective rates were 18.2% and 15.8%, respectively. Although the results were not statistically significant, the simultaneous method is easier to perform and it seems to confer a slightly better clinical outcome than the conventional method.

In a randomized cross-over trial, 11 patients received ifosfamide (IFOS) in 21-day cycles, which alternated between 3 g m(-2) x (2 or 3) days given as a 1-h bolus doses, or the same total dose as a continuous infusion. Patients who received four or more cycles also alternated between two cycles on dexamethasone 4 mg 8 hourly for 3 days starting 8 h before IFOS, and two cycles off dexamethasone. A total of 34 patient cycles were studied and serum and urinary levels of IFOS, 2 dechloroethylifosfamide (2DC), 3 dechloroethylifosfamide (3DC), carboxyifosfamide (CX) and isophosphoramide mustard (IPM) were measured by thin-layer chromatography. No significant differences could be detected in the areas under the curve (AUCs) of serum concentration, nor in the proportion of IFOS or its metabolites found in the urine. There was no significant effect of dexamethasone on IFOS metabolism. These results indicate that there is no identifiable pharmacokinetic basis for insistence on either bolus or infusional methods of IFOS administration.

The Fenretinide (4-HPR) Breast Cancer Study is a randomized multicenter clinical trial originally designed and conducted by the investigators of the Istituto Nazionale Tumori of Milan. The study is sponsored by the National Cancer Institute of Bethesda and by the Italian National Research Council. The trial was designed to evaluate the effectiveness of the synthetic retinoid 4-HPR, at a dose of 200 mg per os every day for 5 years, in reducing the incidence of contralateral breast cancer in a population of patients previously operated on for breast cancer. Between 1987 and 1993, the Istituto Nazionale Tumori of Milan and 9 other collaborating Centers enrolled 2,972 women between the ages of 30 and 70 years who had been previously operated on for T1-T2 N- M0 breast cancer. This paper describes the rationale, design, methodology, organization, data management, statistics and accrual of the participating population.

The Carotene and Retinol Efficacy Trial (CARET), a randomized, placebo-controlled lung cancer chemoprevention trial of 30 mg of beta-carotene and 25,000 IU of retinyl palmitate, was prematurely terminated when a 46% excess lung cancer mortality was found in subjects on the active arm. Before the CARET intervention ended, 21 men were recruited to participate in a 6-month biomarker study using the same intervention as CARET that determined the effect of this supplementation on lung nutrient levels. Plasma and bronchoalveolar lavage (BAL) cell nutrient levels were measured before and after the intervention. The group in the active arm (n = 10) had plasma carotene level increases of over 10-fold, with a small increase in plasma retinol levels BAL cell levels of beta-carotene in the active group also increased 10-fold, from 4.5 to 46.3 pmol/10(6) cells (P = 0.0008), with no change in BAL cell retinol levels. Surgically obtained lung tissue from three CARET subjects in the active arm showed elevated carotene lung tissue levels but no increase in lung retinol levels compared to a group of surgical controls. Combined with our previous work showing a strong correlation between BAL and lung tissue nutrient levels, these findings suggest that supplementation with beta-carotene and vitamin A results in increased lung tissue as well as BAL cell levels of beta-carotene, with little change in lung retinol.

To assess whether chlorambucil or cyclophosphamide may have a better therapeutic index in patients with idiopathic membranous nephropathy, we compared two regimens based on a 6-mo treatment, alternating every other month methylprednisolone with chlorambucil or methylprednisolone with cyclophosphamide. Patients with biopsy-proven membranous nephropathy and with a nephrotic syndrome were randomized to be given methylprednisolone (1 g intravenously for 3 consecutive days followed by oral methylprednisolone, 0.4 mg/kg per d for 27 d) alternated every other month either with chlorambucil (0.2 mg/kg per d for 30 d) or cyclophosphamide (2.5 mg/kg per d for 30 d). The whole treatment lasted 6 mo; 3 mo with corticosteroids and 3 mo with one cytotoxic drug. Among 87 patients followed for at least 1 yr, 36 of 44 (82%; 95% confidence interval [CI], 67.3 to 91.8%) assigned to methylprednisolone and chlorambucil entered complete or partial remission of the nephrotic syndrome, versus 40 of 43 (93%; 95% CI, 80.9 to 98.5%) assigned to methylprednisolone and cyclophosphamide (P = 0.116). Of patients who attained remission of the nephrotic syndrome, 11 of 36 in the chlorambucil group (30.5%) and 10 of 40 in the cyclophosphamide group (25%) had a relapse of the nephrotic syndrome between 6 and 30 mo. The reciprocal of plasma creatinine improved in the cohort groups followed for 1 yr for both treatment groups (P < 0.01) and remained unchanged when compared with basal values in the cohort groups followed for 2 and 3 yr. Six patients in the chlorambucil group and two in the cyclophosphamide group did not complete the treatment because of side effects. Four patients in the chlorambucil group but none in the cyclophosphamide group suffered from herpes zoster. One patient per group developed cancer. It is concluded that in nephrotic patients with idiopathic membranous nephropathy both treatments may be effective in favoring remission and in preserving renal function for at least 3 yr.

The safety and efficacy of granisetron (10 micrograms/kg and 40 micrograms/kg) were evaluated during a second (n = 393) and third (n = 200) cycle of chemotherapy in this multicenter, double-blind, randomized, parallel-group study. Granisetron was administered as a single intravenous dose before the start of cisplatin chemotherapy (> or = 60 mg/m2). Total control (no vomiting, no retching, no nausea, and no use of antiemetic rescue medication) after the first 24 hr following chemotherapy was achieved in 40% and 49% of patients in Cycles 2 and 3, respectively, for the 10 micrograms/kg group, and in 42% and 38% of patients in Cycles 2 and 3, respectively, for the 40 micrograms/kg group. Both dose levels of granisetron were well tolerated. The results demonstrate comparable efficacy between the 10 micrograms/kg and 40 micrograms/kg doses of granisetron in preventing nausea and vomiting during repeat cycles of high-dose cisplatin-based chemotherapy. The results of this study show that granisetron 10 micrograms/kg is safe and well tolerated, and remains effective with repeat cycle use.

To evaluate the roles of granisetron and dexamethasone for emesis control on days 2 through 7 after the administration of cisplatin in doses of 50 mg/m2 or greater to patients who had not previously received chemotherapy.