Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial.

PURPOSE: The aim of the study was to evaluate the efficacy of antiandrogen therapy on overall survival and response in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 244 patients with unresectable HCC were included in this multicentric double-blind trial. According to a two-by-two factorial design, patients were randomly assigned to receive one of the following treatments: pure antiandrogen plus placebo (A+P group, 60 patients); luteinizing hormone-releasing hormone (LHRH) agonist plus placebo (LHRH+P group, 62 patients); pure antiandrogen plus LHRH agonist (A+LHRH group, 62 patients); or placebo plus placebo (P+P group, 60 patients). Pure antiandrogen consisted of Anandron (Roussel-Uclaf Laboratory, Romainville, France) administered orally (300 mg daily for 1 month, then 150 mg daily). LHRH consisted of goseriline acetate (3.6 mg) or triptoreline (3.75 mg) administered monthly by subcutaneous injection. Treatment was given until death. Response was evaluated every 8 weeks according to World Health Organization (WHO) criteria. RESULTS: Six patients were considered ineligible. One patient had a complete response (A+P arm) and three had a partial response (two in the LHRH+P arm and one in the A+LHRH arm). An overall log-rank test did not demonstrate any significant difference in survival among the four arms. Taking the factorial design into account, comparison of survival showed no significant difference between Anandron-containing regimens and others, or between LHRH-containing regimens and others. No serious side effects occurred for any regimen. CONCLUSION: This controlled study shows clearly the lack of efficacy of androgen treatment in unresectable HCC.

[Familial cancer of the breast]. / Cancro da mama familiar.

Genetic, cultural and environmental factors are influences shared in familial breast cancer. The objective of this study was to evaluate the prevalence of familial breast cancer and its association with social and clinical characteristics of women. A hospital-based descriptive study was made, and 300 patients with the diagnosis of breast cancer, made in 1992, were investigated. 17,4% of the women had a history of familial breast cancer. The presence of a positive history for familial breast cancer was associated with high social level for post-menopausal women. Age at diagnosis was older for women whose affected relative was their sister, not their mother. The need for the continuing efforts of epidemiologists, pathologists and geneticists to recognize the explanatory model of the disease is emphasized.

Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer.

PURPOSE: In a randomized clinical trial (European Organization for the Research and Treatment of Cancer [EORTC] no. 40813) on adjuvant chemotherapy in gastric cancer, results obtained after administration of the FAM2 regimen (fluorouracil [5-FU], doxorubicin, and mitomycin) were compared with results obtained after surgery alone to assess the effect of this regimen on overall survival, time to progression, and disease-free interval. PATIENTS AND METHODS: Three hundred fourteen patients who had undergone curative resection for stage II or stage III (International Union Against Cancer [UICC] 1978) gastric adenocarcinoma were randomized to receive chemotherapy (treatment arm) or no further treatment (control arm). The chemotherapy schedule was repeated every 43 days for seven cycles. The log-rank test and the Cox model were used for statistical analysis. RESULTS: Of 314 patients, 159 comprised the control group and 155 the FAM2 group. Nineteen FAM2 patients never received chemotherapy. The median number of cycles was five. Of the patients started on adjuvant treatment, severe hematologic and nonhematologic toxicity (grades 3 or 4, World Health Organization [WHO] scale) occurred, respectively, in 6% to 9% and in 1% to 29% of cases. The overall 5-year survival rate was 70% for stage II and 32% for stage III patients. No statistically significant difference was found between overall survival of the two treatment arms (P = .295). However, time to progression was significantly delayed in the FAM2 arm (P = .020) and disease-free survival showed borderline significance (P = .068). CONCLUSION: FAM2, in view of its high toxicity, cannot be advocated as standard adjuvant treatment for gastric cancer. Large-scale clinical trials using more active, less toxic regimens are required to demonstrate whether adjuvant chemotherapy provides any real benefit.

Prognostic factors in resectable gastric cancer: results of EORTC study no. 40813 on FAM adjuvant chemotherapy.

BACKGROUND: The high incidence of locoregional recurrences and distant metastases after curative surgery for gastric cancer calls for improved locoregional control and systemic adjuvant treatment. METHODS: In a randomized clinical trial on adjuvant FAM2 chemotherapy, quality of surgery was evaluated by comparing surgical and pathology data. Univariate and multivariate analysis was made to evaluate the effect of prognostic factors on survival and time of recurrence in relation to patients, tumor, and therapy. RESULTS: Of 314 patients randomized from 28 European institutions, 159 comprised the control and 155 the FAM2 group. After a median follow-up of 80 months, no statistically significant difference was found between survivals. However, for recurrence time, treated patients had a significant advantage over controls (p = 0.02). At univariate analysis, statistically significant differences in survival and time to progression emerged for T, N, disease stage and "adequacy" of surgery. The multivariate analysis retained preoperative Hb level, T, N, and "adequacy" of surgery for time of survival; and T, N, "adequacy" of surgery and adjuvant chemotherapy for recurrence time. CONCLUSIONS: Disease stage is the most important prognostic factor. "Adequate" surgery has an important effect. Adjuvant FAM2 delayed time of recurrence, but did not influence overall survival.

Treatment of patients with irresectable liver metastases from colorectal cancer by chemo-occlusion with degradable starch microspheres.

Chemo-occlusion of the liver increases the tumour concentration of drugs. Thirty-nine patients with colorectal liver metastases received a monthly bolus administration of mitomycin C (10 mg/m2 on day 1) plus a continuous infusion of 5-fluorouracil (500 mg/m2 daily from days 1 to 5). Drugs were given via both portal (one-third of the dose) and arterial (two-thirds) routes to control large and small metastases. Arterially administered mitomycin C was mixed with individualized doses of degradable starch microspheres. In 16 patients treatment was not started or was interrupted early because of arterial or portal catheter problems. In 23 patients who received two or more cycles of treatment the mean(s.d.) microsphere dose was 835(399) mg. Toxicity was mild, consisting mainly of pain. Five complete and five partial responses were seen, and six patients had stable disease. The median time to progression and length of survival were 6 and 16 months respectively. The relatively high rates of complete and overall response in hypovascular tumours (six of 12 lesions) may support the rationale of chemo-occlusion.

Phase II trial of mitomycin C (MMC) in advanced gallbladder and biliary tree carcinoma. An EORTC Gastrointestinal Tract Cancer Cooperative Group Study.

BACKGROUND: Based on a recent pharmacokinetic study suggesting that high biliary levels of mitomycin C (MMC) may be achieved as a result of an entero-hepatic recycling mechanism, we conducted a Phase II EORTC trial which involved MMC administration to patients with non-resectable biliary tract carcinoma. PATIENTS AND METHODS: Of the 34 patients entered in the study, 30 were eligible (11m + 19f, median age 58 yrs). I.V. bolus injections of 15 mg/m2 MMC were administered at six-week intervals. The tumors were confined to the liver in 17 patients and 13 had extra-hepatic localizations. RESULTS: All 30 eligible patients were evaluable for toxicity and response. Mild thrombocytopenia was the main toxic side effect. Severe, WHO grade III/IV thrombocytopenia was limited to 4 patients. The haemolytic uraemic syndrome was not observed and there were no toxic deaths. Of 30 patients, 3 had partial remissions (overall response 10%, 95% confidence interval 2%-27%). CONCLUSIONS: This study, the largest such ongoing phase II trial, shows no significant activity of single-agent MMC in patients with advanced biliary tract carcinoma.

The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.

BACKGROUND: In 1986, the European Organization for Research and Treatment of Cancer (EORTC) initiated a research program to develop an integrated, modular approach for evaluating the quality of life of patients participating in international clinical trials. PURPOSE: We report here the results of an international field study of the practicality, reliability, and validity of the EORTC QLQ-C30, the current core questionnaire. The QLQ-C30 incorporates nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale. Several single-item symptom measures are also included. METHODS: The questionnaire was administered before treatment and once during treatment to 305 patients with nonresectable lung cancer from centers in 13 countries. Clinical variables assessed included disease stage, weight loss, performance status, and treatment toxicity. RESULTS: The average time required to complete the questionnaire was approximately 11 minutes, and most patients required no assistance. The data supported the hypothesized scale structure of the questionnaire with the exception of role functioning (work and household activities), which was also the only multi-item scale that failed to meet the minimal standards for reliability (Cronbach's alpha coefficient > or = .70) either before or during treatment. Validity was shown by three findings. First, while all interscale correlations were statistically significant, the correlation was moderate, indicating that the scales were assessing distinct components of the quality-of-life construct. Second, most of the functional and symptom measures discriminated clearly between patients differing in clinical status as defined by the Eastern Cooperative Oncology Group performance status scale, weight loss, and treatment toxicity. Third, there were statistically significant changes, in the expected direction, in physical and role functioning, global quality of life, fatigue, and nausea and vomiting, for patients whose performance status had improved or worsened during treatment. The reliability and validity of the questionnaire were highly consistent across the three language-cultural groups studied: patients from English-speaking countries, Northern Europe, and Southern Europe. CONCLUSIONS: These results support the EORTC QLQ-C30 as a reliable and valid measure of the quality of life of cancer patients in multicultural clinical research settings. Work is ongoing to examine the performance of the questionnaire among more heterogenous patient samples and in phase II and phase III clinical trials.

Activity of cisplatin in adenocarcinoma of the pancreas.

The activity of cisplatin in metastatic adenocarcinoma of the pancreas was assessed in 33 patients. Cisplatin was administered in a dose of 100 mg/m2, every 4 weeks. There were 2 complete responses and 5 partial responses (a response rate of 21%). The median duration of response was 5 months (range, 2+ to 15 months). Cisplatin is a modestly active drug in advanced pancreatic cancer.

Phase II study of cytarabine in Hodgkin's disease. The EORTC Lymphoma Cooperative Group.

Cytarabine was administered to 24 patients with previously treated Hodgkin's disease in the EORTC Lymphoma Cooperative Group. The drug was administered at the dose of 80 mg/m2 subcutaneously twice a day on 5 consecutive days every 3 weeks. The overall response rate was 17.6% (3 responses among 17 evaluable patients) with a short duration (2-6 months). The main toxicity was myelosuppression. Our experience in the EORTC Lymphoma Cooperative Group could not demonstrate a significant activity at this dose and schedule in Hodgkin's disease.

Low-dose total body irradiation versus combination chemotherapy for lymphomas with follicular growth pattern.

The treatment of Non-Hodgkin's lymphomas with follicular growth pattern and advanced stage of disease remains controversial. Treatments varying from no initial treatment up to aggressive combination chemotherapy have been advocated. The EORTC Lymphoma Cooperative Group has performed a randomized prospective trial comparing short duration low dose total body irradiation (TBI) vs combination chemotherapy (CHVmP) + consolidation radiotherapy. Ninety-three patients were entered; of 84 evaluable patients, 44 received TBI and 40 CHVmP. Complete remission (CR) rates were 36%--TBI and 55%--CHVmP, but overall response rates were identical, 76 versus 69%. No significant difference in freedom from progression or survival was observed. No unexpected toxicity was seen. Although numbers are small, we cannot conclude that aggressive combination chemo-radiotherapy resulted in a better survival. Our analysis confirms that there is a constant risk of relapse. Other approaches should be explored if survival benefit is the ultimate goal in treatment of this patient population.

Randomized phase II study of a combination of cisplatin (DDP), 5-fluorouracil (5-FU), and allopurinol (HPP) versus 5-FU in advanced colorectal carcinoma. An EORTC Gastrointestinal Tract Cancer Cooperative Group study.

In order to improve the therapeutic index of fluorouracil (5-FU), it has been combined with cisplatin (DDP) as synergistic agent and with allopurinol (HPP) as toxicity modulator. Patients with measurable colorectal carcinoma, previously untreated by chemotherapy, were randomized to receive either 5-FU alone 500 mg/m2 push iv days 1-5 or HPP 3 x 300 mg po, days 1-5, 5-FU 800 mg/m2 push iv, days 3-5 and DDP 50 mg/m2 d6. Treatment was repeated every 4 weeks. Of 104 patients randomized, 82 were evaluable for response and survival. Six partial responses were seen in each treatment group (15%) and the median survival time was 7 months. Hematologic toxicities were comparable in both treatment groups, with a mean nadir white blood cell count of 3500/ vs. 3800/mm3 and a mean nadir platelet count of 148,000/ vs, 203,000/mm3 for HPP-5-FU-DDP and 5-FU, respectively. This study suggests that the addition of both HPP and DDP does not improve the activity of 5-FU.

Adjuvant FAM2 in resectable gastric cancer.

In spite of the improvements in surgical techniques and intensive care, no important benefit in the prognosis of patients with gastric carcinoma has been attained in the last twenty years. Different adjuvant treatment protocols have been proposed in an attempt to improve upon the results obtained with surgery only. In western countries, the FAM chemotherapeutic regimen is one on the most widely used for the treatment of advanced gastric carcinoma. In 1982 the G.I. GROUP of the EORTC proposed a modification (FAM2) to the original FAM as an adjuvant treatment in a controlled clinical study for gastric carcinoma. It is still too early to determine any therapeutic advantages of FAM2 in this protocol. Although the FAM2 regimen is fairly well tolerated, there is some toxicity which, however, seems to be slightly higher than in the regular FAM. It remains to be seen if this is a reasonable price to pay for still unknown therapeutic advantages. In view of the scarcity of available data in this field and the conflicting results which have emerged so far, the results of our study are awaited with great interest.

Adjuvant therapy of poor prognosis colon cancer with levamisole: results of an EORTC double-blind randomized clinical trial.

From 1978 to 1985, 297 patients were entered in a double-blind randomized trial comparing levamisole to placebo as adjuvant therapy of Dukes' C carcinoma of the colon. Therapy consisted of from two to five tablets of 50 mg levamisole (or placebo) twice a week, depending on bodyweight for 1 year. Levamisole was generally well tolerated, with only four reversible cases of agranulocytosis reported among 129 patients. The trial failed to show a benefit of levamisole on disease-free survival (P = 0.53) or on survival (P = 0.35). There was no difference between the two treatment groups in terms of number of disease relapses, sites of relapse, or time to relapse. The proportion of patients still alive at 5 years was 51 per cent (standard error, 5.5 per cent) in the levamisole group versus 39 per cent (standard error, 5.4 per cent) in the placebo group.

An EORTC gastrointestinal (GI) group randomized evaluation of the toxicity of sequential high dose methotrexate and 5-fluorouracil combined with adriamycin (FAMTX) vs 5-fluorouracil, adriamycin and mitomycin (FAM) in advanced gastric cancer.

Until now advanced gastric cancer has been generally treated with the FAM chemotherapy protocol. Due to the relatively low response rates with this protocol we decided to start a randomized prospective phase II trial comparing the FAM with the FAMTX protocol. The primary aim of our trial was to compare the toxicity in both protocols. The FAMTX protocol has been demonstrated to be fully comparable with the toxicity of the FAM protocol. The trial has been extended to a phase III study. With respect to response rates and survival times it is too early for evaluation.