Randomized phase III trial of bleomycin, vindesine, mitomycin-C, and cisplatin (BEMP) versus cisplatin (P) in disseminated squamous-cell carcinoma of the uterine cervix: an EORTC Gynecological Cancer Cooperative Group study.

PURPOSE: Three previous mitomycin-cisplatin-based chemotherapy trials conducted within the EORTC Gynecological Cancer Cooperative Group (GCCG) in patients with disseminated squamous-cell carcinoma of the uterine cervix (SCCUC) suggested that with such regimens a higher overall response rate and a higher complete response rate could be obtained compared to what might have been expected from cisplatin alone. In that respect the combination of bleomycin, vindesine (Eldesine), mitomycin C and cisplatin (BEMP) was the most promising. In the present study BEMP has been compared with the best single agent, cisplatin (P) in the expectation that improved response rates might translate into a better survival. PATIENTS AND METHODS: Eligible patients were those with SCCUC and disseminated measurable disease outside previously irradiated areas, aged < or = 75 years, with a WHO performance status < or = 2 and adequate bone marrow, renal, hepatic and pulmonary function, who gave consent according to regulations followed in individual institutions. Patients were randomized to BEMP: E 3 mg/m2 day 1, P 50 mg/m2 day 1, B 15 mg (24-hour infusion) day 2-4 and M 8 mg/m2 (at alternate cycles), or P 50 mg/m2. The first four cycles were given every 3 weeks (induction phase). Subsequent cycles were given every four weeks (maintenance phase), during which B was deleted from BEMP (MEP). Patients failing on P could be treated with BEM. Of the 287 patients entered, 235 were eligible and 201 evaluable for response. RESULTS: BEMP induced a significantly higher response rate than P (42% vs. 25%, P = 0.006). There was no difference in complete response rate (11% vs. 7%). BEMP was significantly more toxic than P (+/- BEM), both with respect to hematologic and nonhematologic toxicities. After a median follow-up of 6.1 years, survival curves were not significantly different. Median progression-free survival and overall survival were 5.3 and 10.1 months with BEMP and 4.5 and 9.3 months with P (+/- BEM), respectively. In a multivariate analysis of prognostic factors for survival, a lower age (P = 0.003), a lower performance status (P = 0.0001) and a short (<1 year) interval since diagnosis (P = 0.0152) were all associated with an increased risk of dying. For progression-free survival, lower age, prior radiotherapy, locoregional involvement and no prior surgery were associated with a high risk. Treatment with BEMP or P had no significant impact on survival, but for progression-free survival there was a trend in favor of BEMP (P = 0.0893). Adjusting for prognostic factors did not change the effect of treatment. CONCLUSIONS: Combination chemotherapy with BEMP produces more toxicity and more responses compared with cisplatin alone in patients with disseminated SCCUC, but this does not translate into a better survival. Therefore, in the palliative setting single-agent cisplatin should remain the standard therapy for these patients.

EORTC 10941: A phase II study of liarozole in postmenopausal patients with 'chemotherapy-resistant' or 'potentially hormone sensitive' metastatic breast cancer.

Liarozole is an imidazole compound that inhibits enzymes involved in steroid hormone aromatisation and retinoid metabolism. The IDBBC branch of the EORTC has performed a series of phase II studies of the agent in four groups of postmenopausal women with metastatic breast cancer. This paper reports the results of the first two groups: 'Chemotherapy Resistant' (unrestricted ER status, 1 or 2 prior chemotherapy regimens, 0-2 prior hormonal therapies) and 'Potentially Hormone Sensitive' (ER positive or unknown, 1 or 2 prior hormonal therapies with a substantial disease free interval or progression free survival, and no history of chemotherapy for metastatic disease). Liarozole was administered at 150-300 mg orally bid. The objective response rate was 12% in the 'Chemotherapy Resistant' group (n = 34), and 22% in the 'Potentially Hormone Sensitive' group (n = 37), with median response durations of 9 and 14 months, respectively. Median time to treatment failure was only 2 months in both groups, due largely to the significant percentage (24%) of patients who ceased treatment following excessive mucocutaneous and gastrointestinal toxicity. This adverse event profile will limit its use in breast cancer. Results of the 'ER negative' and 'Tamoxifen Refractory' groups will be reported in a future paper.

Cyclophosphamide or ifosfamide in patients with advanced and/or recurrent endometrial carcinoma: a randomized phase II study of the EORTC Gynecological Cancer Cooperative Group.

UNLABELLED: Currently, available chemotherapy regimens for patients with advanced or recurrent endometrial cancer are generally not curative. Thus, there is a need to identify more active single agents in this disease. In this study patients pre-treated and not pre-treated with first line combination chemotherapy were entered into a randomized phase II study of either cyclophosphamide (CYCLO) or Ifosfamide (IFOS). PATIENTS AND METHOD: Sixty one eligible patients with recurrent or metastatic histologically proven, adenocarcinoma of the uterine corpus entered the study. The median age at entry was 62 (range 40-74) years. Twenty patients (33%) had prior hormonal treatment and 31 (51%) prior chemotherapy. CYCLO was given at a dose of 1200 mg/m2 and IFOS at a dose of 5 g/m2. Both drugs were administered i.v. over 24 hours on day one every three weeks. Adequate pre- and post hydration as well as use of Mesna in the Ifosfamide arm were mandatory. RESULTS: A median of two treatment cycles (range 1-12) per patient were given. In the chemotherapy-naive patients, in the CYCLO arm two PRs (RR 14%, C.I. 2-43%) were seen and in the IFOS arm two CRs, two PRs, (RR 25%, C.I. 7-52%) were observed. No responses were seen in pre-treated patients. The duration of responses were: 15+, 7+ months for the CRs, 15+ and 5 months for PRs in IFOS arm and 67+, 4 months in CYCLO arm. The hematological toxicity was dose-limiting and similar in both treatment arms. No serious non hematological toxicities were reported, but a transient increase of the creatinine blood level was seen in two IFOS patients (6%). CONCLUSION: Ifosfamide is an active drug in the treatment of chemotherapy-naive patients with advanced endometrial cancer and its application in currently used (combination) regimens should be considered.

Radical surgery and postoperative radiotherapy as combined treatment in rectal cancer. Final results of a phase III study of the European Organization for Research and Treatment of Cancer.

BACKGROUND: There is controversy whether adjuvant radiotherapy should be given before or after surgery for locally advanced, resectable rectal cancer. Preoperative radiotherapy substantially reduces local recurrence rates but may increase postoperative complications. In addition, patients found to have early cancers are treated unnecessarily. This study is a randomized trial of postoperative radiotherapy in patients who had a potentially curative resection for locally advanced rectal carcinoma. METHODS: Following complete excision of a Dukes B or C rectal cancer, 172 patients were randomized to adjuvant radiotherapy (46 Gy 5 days per week in 30-38 days) (84 patients) or controls (88 patients). RESULTS: After a median follow-up of 85 months, no benefit from postoperative radiotherapy had been observed in disease-free survival (P = 0.81), overall survival (P = 0.52), local recurrence-free interval (P = 0.46) or in the number and sites of recurrence. Acute toxicity following radiotherapy included diarrhoea (20 per cent), cystitis (13 per cent), delayed wound healing (7 per cent), pneumonia (5 per cent) and seizures (1 per cent). Late complications included reoperation for small bowel obstruction (5 per cent), chronic diarrhoea (20 per cent), chronic cystitis (12 per cent) and persistent perineal sinus (9 per cent). In the group who had surgery alone, late morbidity was found in 11 per cent. CONCLUSION: This trial failed to demonstrate any improvement in overall survival or local control when postoperative irradiation was given following resection of locally advanced rectal carcinoma.

Entry and evaluation of elderly patients in European Organization for Research and Treatment of Cancer (EORTC) new-drug-development studies.

BACKGROUND: This study aimed to determine the extent to which elderly patients (> or = 65 years) currently are being entered in Phase II single-agent studies, and if advanced age is associated with increased toxicity. METHODS: This analysis was based on the age distribution of 2344 patients with various solid tumors entering 16 Phase II EORTC single-agent trials from January 1983 to February 1992. RESULTS: Of the study group, 22% were 65 years or older and 8% were 70 years or older. Delay in dose administration and dose reduction were significantly higher for elderly patients compared with younger patients (P < 0.05). When adjusting for previous chemotherapy pretreatment, no difference between elderly and nonelderly patients was noted in the frequency of grade 3 and 4 hematological toxicity, nausea, vomiting, and diarrhea. A significant higher frequency of episodes of severe oral toxicity (P < 0.05) and alopecia were observed for elderly patients, but a higher proportion (P < 0.05) of elderly patients received drugs for which stomatitis was an established side effect. No significant difference in the frequency of complete plus partial responses was observed between older and younger patients (9% versus 7%). Treatment discontinuation significantly increased with age, ranging from 24% for those younger than 50 years to 33% among elderly patients (x for trend = 12.83, P < 0.001). There was not evidence that excess toxicity was an obstacle to treatment continuation for elderly patients, whereas treatment discontinuation did occur for the older age group more frequently because of loss to follow-up and treatment refusal. CONCLUSION: Selected elderly patients can and should enter new-drug-development protocols without an increased risk of more severe or frequent side effects. A priori exclusion based on an arbitrary chronologic age limit no longer should occur.