The results of the use of chemotherapy in patients with advanced gastrointestinal malignancies have been disappointing. Complete responses are rare, and even partial responses are generally few with no benefit on survival. Since its introduction in clinical trials more than 30 years ago, fluorouracil has remained the most effective single agent in the treatment of these diseases. Doxifluridine is a new fluoropyrimidine derivative, that is converted into fluorouracil, its active component. Experimental data confirm cytotoxic selectivity for human tumor cells.

To compare the efficacy and safety of bicalutamide and flutamide, each used in combination with luteinizing hormone-releasing analogue (LHRH-A) therapy, in patients with untreated metastatic (Stage D2) prostate cancer.

GnRH Analogues therapy of estrogen-dependent gynaecological diseases aims at suppression of physiologic ciclic ovaric function producing a hypogonadotropic condition. The first consequence of GnRH Analogues administration is hypoestrogenism; this condition permits the disease regression but, on the other, it causes a negative impact on bone metabolism particularly for prolonged therapeutic schemes (6 months). This study has evaluated the faculty of bone mass protection combining GnRH Analogues therapy with Ipriflavone that stimulates, both "in vivo" and "in vitro", Osteoblastic cells activity. The result of this study showed a significant bone loss in patients treated with GnRH Analogues only. The Ipriflavone association prevented bone loss.

Thirty-three women with breast cancer have undergone high dose chemotherapy with autologous stem cell support at Huddinge Hospital. Twenty-eight patients had stage IV disease while five patients had disease stage II or III with involvement of > 10 axillary lymph nodes. Patients who received peripheral stem cells had a shorter duration of neutropenia than patients who received autologous bone marrow (p < 0.001). The transplant related mortality was 3 per cent. The calculated progression free survival was 39 per cent at 24 months after high dose therapy in women with stage IV chemosensitive breast cancer. Patients who got a complete remission after standard dose chemotherapy had a better survival rate than patients who got a partial remission. All women with refractory disease progressed within five months from therapy. Four out of five patients with disease stage II or III are progression free with the longest follow-up time of 46 months. High dose chemotherapy with stem cell support can be given with acceptable toxicity. The follow-up time is short but the results are promising, in particular for women who obtain a complete remission before the high dose therapy starts.

Multiple genetic and environmental steps may underpin the development of human colorectal neoplasia, and experimental evidence suggests that promoters of colorectal cancer also induce colorectal epithelial cell hyperplasia. In vitro crypt cell production rate (CCPR) was measured to determine the effect of calcium, epidermal growth factor (EGF), vitamin D3 metabolites and synthetic analogues on human rectal epithelial cell proliferation. In a double-blind trial of oral calcium supplementation, CCPR was reduced by 49% in patients with familial adenomatous polyposis (FAP), but there was no effect on established neoplasia. In control tissue, the active form of vitamin D3 (1,25(OH)2D3) reduced rectal CCPR by 57% at 1 microM, 55% at 10 nM and 45% at 100 pM. Likewise, in tissue taken from patients with FAP, 1,25(OH)2D3 reduced CCPR by 52%. Vitamin D3 has profound effects on calcium metabolism, but synthetic analogues can avoid these. The effects of a synthetic analogue (MC-903) on human rectal CCPR were therefore studied. MC-903 (10(-7) M) reduced CCPR in control tissue by 51%, and in FAP tissue by 52% at 10(-6) M and 51% at 10(-7) M. In addition, MC-903 and a related analogue, EB 1089, produced a clear-cut dose-dependent inhibition of both HT-29 and Caco2 colorectal cancer cells maintained in culture. Hence, vitamin D3 and its analogues can reduce the rate of cell proliferation in normal, premalignant and malignant colorectal epithelial cells and might therefore have future therapeutic uses as chemoprotective or chemotherapeutic agents. Lastly, EGF increases CCPR by 102% in FAP tissue that expresses the EGF receptor. Thus, human colorectal cell proliferation is influenced by a variety of luminal and humoral agents and a greater understanding of these actions should help plan future treatments.

Nausea and vomiting have been recognized as the most distressing side effects of chemotherapy, and are experienced by 66-91% of chemotherapy patients in Japan. Relaxation measures have been used for patients with various other diagnoses, but this technique has never been applied to patients receiving cancer chemotherapy. This pilot study examined the effects of progressive muscle relaxation (PMR) to reduce nausea, vomiting, and anxiety associated with chemotherapy in Japanese patients. Data for eight subjects who were randomly assigned to a treatment group or a control group were analyzed. Both treatment and control groups showed decrease in nausea and vomiting; therefore, the effect of PMR was not verified. However, there was an average decrease of 2.5 points in state-anxiety scores in the treatment group. In addition, some positive effects of PMR were shown by the subjects in the treatment group.

Docetaxel (RP 56976) is a new chemotherapeutic agent that has shown promise in a number of animal studies and is currently undergoing phase I and phase II trials. Early in the phase I trials, it was noted that a significant number of patients were experiencing a variety of cutaneous complaints, so we elected to prospectively evaluate the cutaneous reactions occurring during the first three courses of therapy in the first 12 patients enrolled for phase I chemotherapy at our institutions.

To evaluate the efficacy and safety of Navoban (tropisetron) three different Nordic multicentre trials were conducted during the period 1988-92. In all, 1050 patients were recruited from 15 centres. In the first study, Navoban monotherapy was compared with a high-dose metoclopramide cocktail. In the second, Navoban +/- dexamethasone was evaluated for those patients not fully protected by Navoban alone. In the third trial, Navoban was evaluated for various chemotherapy regimens, for long-term efficacy, and for various risk groups of patients. Spontaneous intercycle variations were also evaluated. Navoban was found to be as effective as the antiemetic cocktail but with a more favourable spectrum of side effects and a simpler schedule of administration. Navoban was more effective during the acute than the delayed phase. Addition of dexamethasone significantly improved prevention of both acute and delayed emesis. Long term efficacy seemed to be stable up to 10 cycles of chemotherapy. Patients treated with noncisplatin regimens showed significantly higher protection rates than patients treated with cisplatin. Various cancer diagnoses and cytostatic agents were also evaluated. Gender and age were important risk factors. Navoban was found to be an efficacious antiemetic agent, especially regarding acute nausea and vomiting. Addition of a corticosteroid significantly improved the effect during highly emetogenic chemotherapy. The role of Navoban for delayed emesis must be evaluated in future trials. The two most common side effects were headache and constipation. Overall, Navoban was well tolerated and patient compliance with the drug was high.

Even with the availability of potent and selective serotonin antagonists, chemotherapy-induced nausea and vomiting remain a major problem for many patients. This study aims to evaluate the benefit of combination therapy based on Navoban (tropisetron) in patients who had incomplete control of nausea and/or vomiting induced by chemotherapy when using Navoban as a single antiemetic agent. In their first chemotherapy course, 1072 patients planned to receive at least two identical cycles of emetogenic chemotherapy were treated with 5 mg Navoban once daily. To evaluate three treatments additional to the recommended 5 mg once-daily Navoban regimen during Course 2 in those patients who had shown incomplete control of nausea and/or vomiting on any day of Course 1, a 2 x 2 x 2 factorial design was employed. Of these patients, 445 were centrally randomised to receive an additional dose of open-label dexamethasone (Day 1, 0.2 mg/kg i.v.; Days 2-6, 8 mg p.o.) and/or open-label alizapride (Day 1, 100 mg i.v. and 4 x 50 mg p.o.; Days 2-6, 4 x 5 mg p.o.) and/or double-blind Navoban--that is, doubling the dose to 10 mg once daily or placebo. Complete response rates during Course 1 (CRR, no nausea and no vomiting) were, for Day 1, 72% and for Days 1-6, 48%. More complete responders were observed when dexamethasone was added during Course 2, both on Day 1 (76% vs. 66%, p = 0.020) and on Days 1-6 (50% vs. 34%, p = 0.0004).(ABSTRACT TRUNCATED AT 250 WORDS)

Interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) are proinflammatory cytokines which may be involved in the pathogenesis of MS. IFN-alpha counteracts many of the proinflammatory actions of IFN-gamma and TNF-alpha. We treated 20 patients with relapsing-remitting (RR) MS with 9 MIU of recombinant IFN-alpha-2a (rIFN-alpha) (n = 12) or placebo (n = 8) intramuscularly every other day for 6 months. Clinical exacerbations or new or enlarging lesions at serial MRI occurred in 2/12 rIFN-alpha-treated and in 7/8 placebo-treated patients (P < 0.005). Only one new MRI lesion was detected in the rIFN-alpha group, while 27 new or enlarging lesions were detected in placebo group (P < 0.01). Baseline lymphocyte IFN-gamma (19.10 +/- 7.12 U ml-1) and TNF-alpha (18.05 +/- 5.34 pg ml-1) production significantly decreased to 3.03 +/- 0.66 (P < 0.04) (for IFN-gamma) and to 5.78 +/- 0.90 (P < 0.04) (for TNF-alpha) after rIFN-alpha treatment. IFN-gamma and TNF-alpha production was unchanged in the placebo group. rIFN-alpha was tolerated without drop-outs or serious side-effects, but fever, malaise, fatigue (interfering with daily activities in two patients) and leukopenia frequently occurred. High-dose chronic systemic rIFN-alpha might reduce clinical and MRI signs of disease activity in RRMS. The changes in cytokine production suggest that the effect is probably mediated by a down-regulation of proinflammatory cytokine.

A prospective randomized study was conducted to try to answer two questions: is a loading dose of medroxyprogesterone acetate (1000 mg p.o. q.d.s. for 48 h) superior to conventional dosing; and does an oral maintenance dose of 1000 mg daily offer any advantage over 500 mg daily in women with advanced breast cancer who have failed to respond to, or have relapsed after, tamoxifen? Of 211 patients randomized, 207 were evaluable. There was no improvement in response rates, time to response, response duration or overall survival as a result of the loading dose. When comparing high and low maintenance doses, there was a significant difference in response rates (48% versus 32%; chi 2 = 10.09, df = 2, P = 0.006) and survival (66% versus 41% alive at 12 months; chi 2 = 9.06, df = 1, P = 0.003) in favour of the higher dose regimen, although there was no significant difference in the duration of response. There was no additional toxicity attributable to the loading dose regimen, but side effects were more frequent with the high dose maintenance schedule (141 of 201 adverse effects occurring in these two groups) although the incidence of severe toxicity was similar with both high dose and low dose treatments.

Didemnin B, a dipsipeptide isolated from the Caribbean tunicate Trididemnum with antitumor and antiviral activity was evaluated in a phase II trial in the treatment of metastatic, hormonally refractory adenocarcinoma of the prostate. Thirteen patients were treated with didemnin B at 3.5 mg/m2 and 20 patients were treated at 6.3 mg/m2 intravenously every 28 days. Response was assessed every 8 weeks. Of 32 evaluable patients there was one partial response for an overall response rate of 3% (95% confidence interval of 0.1-16%). The most common toxicities were nausea, vomiting, and diarrhea. Serious cardiac and pulmonary toxicities were also noted. This drug does not appear to warrant further evaluation in this disease as a single agent.

Leucovorin (LV) is commonly used as a modulator of 5-fluorouracil (5-FU) cytotoxicity. In patient with colon cancer, the addition of LV to 5-FU improves response rates, and in some trials has improved survival in advanced disease and in the adjuvant setting. Leucovorin is generally administered as a racemic mixture, but the isomers differ substantially in pharmacokinetics and biological activity, with 6S-LV the predominant active component. The current study was undertaken to determine the effect of 6R on the pharmacokinetics of 6S-LV, and to characterize the toxicity and antitumor effect of 5-FU when administered with 6S-LV to patients with advanced colorectal carcinoma. Thirty patients were treated with weekly 5-FU plus high dose 6S-LV. To determine the effects of 6R-LV on the pharmacokinetics of S6-LV, 20 patients were randomly assigned to receive either 250 mg/m2 6S-LV or 500 mg/m2 6R,S-LV as a 2 hour IV infusion on day -2, and the other preparation on day -1, with pharmacokinetics measured each day. The presence of 6R-LV had no effect on the AUC, Clp, Cmax, or terminal phase t1/2 of 6S-LV. The overall response rate was 40% (C.I. 23-60%). The most frequent toxicities were gastrointestinal. In this small cohort, scheduled and delivered dose intensity was positively associated with response (p = 0.05). These results show that there is no pharmacokinetic advantage to the use of 6S-LV rather than 6R,S-LV as a modulator of 5-FU.

Fifty-five patients with metastatic non-small cell lung cancer (NSCLC) were entered into this phase II randomized study for evaluating three new agents: gallium nitrate, amonafide and teniposide. The patients had to have ECOG performance status 0 or 1, no prior chemotherapy, and adequate hematological, hepatic and renal functions. Forty-seven patients were eligible and evaluable. Fourteen were randomized to receive gallium nitrate, 18 to amonafide and 15 to teniposide. Seventy-four percent of eligible patients were male. The majority of patients (89%) had an ECOG performance status 1. ECOG grade 4 toxicity occurred twice in patients on gallium nitrate, seven times on amonafide and 18 times on teniposide. The cause of death was attributed to amonafide in one patients (from sepsis) and to teniposide in two patients (due to infection and leukopenia). There was no objective response in all the patients entered. The overall survival times ranged from 2 weeks to 156 weeks with a medium of 23 weeks. There were no survival differences among the three treatment arms. We conclude that gallium nitrate, amonafide and teniposide are inactive in metastatic NSCLC and do not warrant any further testing in this disease.

The advent of recombinant DNA technology will soon produce for the market a product that has pure follicle-stimulating hormone (pFSH) but no luteinizing hormone. A prospective randomized study was performed to see if pFSH (Metrodin) was able to stimulate the same in vitro fertilization parameters as human menopausal gonadotropin when preceded by gonadotropin suppression by leuprolide acetate. The results showed similar parameters between the two drugs, i.e., number of oocytes, number of embryos, endometrial thickness at time of human chorionic gonadotropin, fertilization rates and pregnancy rates in a protocol purposely designed to stimulate as many follicles as safely as possible because of a shared oocyte and successful cryopreservation program.

This report is the final analysis of an EORTC Genito-Urinary Group Phase III trial (Protocol 30805) comparing orchidectomy, orchidectomy plus cyproterone acetate 50 mg 3 times a day and stilboestrol 1 mg daily in the management of metastatic carcinoma of the prostate. Three hundred and twenty-eight eligible patients admitted into the study have been followed up for a median period of 4 years. There was no difference in time to metastatic progression and overall survival between the treatment arms. The cardiovascular toxicity of stilboestrol 1 mg daily has resulted in more cardiovascular deaths as compared with the orchidectomy treatment arm. The outcome for individual patients has been determined by on-study prognostic factors, especially the performance status, rather than the treatment given.

Alpha-interferon (IFN) has been shown to produce antitumor responses among patients with advanced renal cell carcinoma. While responses have been observed over a range of IFN doses and schedules, significant toxicities can be experienced from relatively high doses given three to five times weekly. Based upon the report of a pilot study indicating that low dose daily IFN could produce antitumor responses with minimal toxicity, the Southwest Oncology Group investigated this schema in a phase II trial. Patients with bidimensionally measurable disease were treated with Roferon-A 1 million units subcutaneously daily and tumor assessments were conducted on a monthly basis. There were no dose escalations and no dose reductions for toxicity. The treatment was well tolerated with only two patients withdrawing from treatment because of side effects. Among 56 eligible patients treated, there were five partial responses and one complete response for an overall response rate of 11% (95% confidence interval, 4 - 22%). However, objective antitumor responses could not be determined for 16 of the 56 patients. Among the 40 fully evaluable patients the 6 objective responses yields a response rate of 15% (95% confidence interval, 5.7-30%). It is concluded that this dose and schedule of IFN has activity against advanced renal cell carcinoma. A randomized trial would be required to determine if this low dose regimen is as effective as the higher doses which have been used traditionally.

The effects of medroxyprogesterone acetate (MPA) therapy on advanced or recurrent breast cancer and its influence on blood coagulation and the fibrinolytic system were compared among three different therapy regimens consisting of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) + MPA and CAF or MPA alone. A clinical response was observed in 42.9% (9/21) of the patients for CAF + MPA, 36.4% (8/22) for CAF and 23.8% (5/21) for MPA alone. No marked thrombosis or its prodromal condition was observed in any group. The effects on the test values for blood coagulation and the fibrinolytic system did not significantly change in the CAF group. However, both AT-III and protein C significantly increased above the normal ranges in the CAF+MPA and MPA groups. Increases in factor X, plasminogen, and alpha 2-plasmin inhibitor/plasmin complex (PIC) and decreases in fibrinogen, tissue plasminogen activator, and D-dimer, were all observed in the MPA and CAF + MPA groups, especially in the MPA group, although these changes remained within the normal ranges. The data indicated that MPA has various influences on blood coagulation and the fibrinolytic system, but these changes did not suggest activation of the blood coagulation system.

The study purpose was to determine whether the framing of treatment information influenced patients' reported preferences for participating in treatment decision making and for trial entry. Ninety cancer patients read either neutrally-, positively-, or negatively-framed information about a chemotherapeutic treatment, then indicated their preferences for participating in the treatment decision, and whether they would participate in a clinical trial incorporating this protocol. There was no difference across information groups in preferences for participating in treatment decision making or willingness to enter such a clinical trial. Preference for participation in treatment decision making was significantly related to age (t = 2.54; p = 0.022), sex (x2 = 3.89; p = 0.05), and education (t = 2.54; p = 0.018); trial entry preferences were unrelated to these demographic variables. These results imply that, in this clinical context, attitudes towards participation in treatment decision making may be associated with characteristics of the patient, and attitudes towards trial entry may be dependent upon the clinical characteristics of a particular trial, but neither set of attitudes is influenced by the framing of protocol information.