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

Salvage chemotherapy of biweekly irinotecan plus S-1 (biweekly IRIS) in previously treated patients with advanced gastric cancer

PURPOSE: This phase II trial first describes the combination chemotherapy of biweekly irinotecan plus S-1 (biweekly IRIS) for pretreated advanced gastric cancer (AGC) patients. METHODS: Patients who had previously been treated with greater than or equal to one regimen were enrolled. They received S-1 35 mg/m(2) twice daily on days 1-14 and irinotecan 150 mg/m(2) on days 1 and 15, every 4 weeks. The primary endpoint was overall survival (OS). RESULTS: Among the 38 patients enrolled, 18 patients were treated as second line, and the remaining 20 patients were enrolled as third- or fourth line. A total of 208 cycles were administered with the median being four cycles (range 1-16). The median OS was 8.7 months [95% confidence interval (CI) 7.5-10.3], and the median progression-free survival was 6.3 months (95% CI 5.3-7.3). Low serum albumin (<3.5 mg/dL) was an independent adverse prognosticator for survival. Overall response rate was 17% (95% CI 4-30%). The major grade 3/4 toxicities were neutropenia (26%) and diarrhea (18%). CONCLUSIONS: Biweekly IRIS showed the moderate activity as salvage treatment in AGC. Considering high neutropenia and gastrointestinal toxicity, patient selection should be warranted; serum albumin may be a predictive factor for treatment decisionope

Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer : A low cost effective regimen

Recently, we reported a highly active regimen in advanced gastric cancer including a weekly administration of cisplatin, epidoxorubicin, leucovorin, 5-fluorouracil with the support of filgrastim. In order to simplify the administration and to decrease the toxicity of these drugs, mainly epidoxorubicin-induced alopecia, we designed a regimen including an infusional 5-fluorouracil schedule according to the de Gramont regimen, cisplatin and mitomycin C replacing epidoxorubicin. Forty-five patients with advanced or metastatic gastric cancer were treated with cisplatin 50 mg m−2 i.v. on day 1, every 2 weeks, 6S-stereoisomer-leucovorin 100 mg m−2 i.v. followed by 5-fluorouracil 400 mg m−2 i.v. bolus and 600 mg m−2 i.v. in a 22-h infusion, on days 1 and 2, every 2 weeks, and mitomycin C 7 mg m−2 i.v. bolus on day 2, every 6 weeks. Grades 3–4 toxicities (National Cancer Institute-Common Toxicity Criteria) consisted mainly of neutropenia and thrombocytopenia. Five patients had a complete response and 16 had a partial response for an overall response rate of 46.7% (95% confidence interval, 32.1–61.2%). The median survival was 11 months. The combination of cisplatin, 5-fluorouracil and leucovorin according to de Gramont, and mitomycin C seems to be an active and safe regimen in the treatment of advanced gastric cancer. Because of its low cost it may be suggested for patients not enrolled into clinical trials

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m−2 on day 1, FA 200 mg m−2 as a 2 h infusion followed by bolus 5-FU 400 mg m−2 and a 22 h infusion of 5-FU 600 mg m−2, repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer

Detection of occult carcinomatous diffusion in lymph nodes from head and neck squamous cell carcinoma using real-time RT–PCR detection of cytokeratin 19 mRNA

The aim of the present study was to evaluate the occult lymph node carcinomatous diffusion in head and neck squamous cell carcinoma (HNSCC). A total of 1328 lymph nodes from 31 patients treated between 2004 and 2005 were prospectively evaluated by routine haematoxylin–eosin–safran (HES) staining, immunohistochemistry (IHC) and real-time Taqman reverse–transcriptase polymerase chain reaction (real-time RT–PCR) assay. Amplification of cytokeratin 19 (CK19) mRNA transcripts using real-time RT–PCR was used to quantify cervical micrometastatic burden. The cervical lymph node metastatic rates determined by routine HES staining and real-time RT–PCR assay were 16.3 and 36.0%, respectively (P<0.0001). A potential change in the nodal status was observed in 13 (42.0%) of the 31 patients and an atypical pattern of lymphatic spread was identified in four patients (12.9%). Moreover, CK19 mRNA expression values in histologically positive lymph nodes were significantly higher than those observed in histologically negative lymph nodes (P<0.0001). These results indicate that real-time RT–PCR assay for the detection of CK19 mRNA is a sensitive and reliable method for the detection of carcinomatous cells in lymph nodes. This type of method could be used to reassess lymph node status according to occult lymphatic spread in patients with HNSCC

Phase II study of mitomycin-C and cisplatin in disseminated, squamous cell carcinoma of the uterine cervix. A European Organization for Research and Treatment of Cancer (EORTC) Gynecological Cancer Group study

The aim of this study was to investigate the tumour response rate and toxicity of a combination chemotherapy consisting of mitomycin-C and cisplatin in patients with disseminated squamous-cell carcinoma of the uterine cervix. Chemotherapy consisted of mitomycin, 6 mg/m(2) intravenously (i.v.), and cisplatin, 50 mg/m2 given i.v., both administered on day I of each cycle. The regimen was repeated at 4-weekly intervals. Mitomycin-C/cisplatin were used to treat 33 evaluable patients aged 29-67 years (median: 50 years). All patients except 1 had previously been treated with either surgery, radiation or both. At the initiation of chemotherapy, 8 patients had loco-regional and disseminated disease and 25 women had only distant metastases. The overall response rate was 42% (95% confidence interval (CI): 26-61 lo). Five complete and nine partial responses were observed with a median duration of response of 7.9 months (95 % CI: 3.7-23.5 months). 9 patients had stable disease and 10 developed progressive disease during mitomycin-C/cisplatin-treatment. World Health Organization (WHO) grade III/IV side-effects were documented in 15 women, of whom 10 had gastro-intestinal toxicity, 3 had haematological toxicity, 1 had alopecia and 1 developed an allergic reaction to cisplatin. There were neither drug-related deaths nor severe or irreversible renal or hepatic dysfunction or peripheral neuropathy. The median progression-free survival was 5.0 months (95 lo CI: 3.6-6.2 months) for all patients and 10.5 months (95% CI: 6.2-15.2 months) for the responders. The median overall survival was 11.2 months (95% CI: 6.5-18.4 months). The mitomycin-C/cisplatin combination showed antitumour activity in the treatment of advanced or recurrent squamous-cell carcinoma of the uterine cervix. The regimen was well tolerated and could be administered on an outpatient basis. (C) 2001 Elsevier Science Ltd. All rights reserved