Postoperative irinotecan in resected stage II-III rectal cancer: final analysis of the French R98 Intergroup trial†.

BACKGROUD: The R98 trial explores the addition of irinotecan to a 5-fluorouracil (5-FU) plus leucovorin (5-FU/LV) adjuvant regimen in optimally resected stages II-III rectal cancers. We report the updated long-term results. Disease-free survival (DFS) was the primary end point. PATIENST AND METHODS: Between March 1999 and December 2005, 357 patients were randomized: 178 in 5-FU/LV and 179 in LV5-FU2 + irinotecan arm. The trial was stratified by control arm: Mayo Clinic regimen or LV5-FU2 regimen. RESULTS: Three hundred and fifty-seven randomized patients were evaluable for efficacy. With a follow-up of 156 months, the DFS was in favour of experimental arm but did not reach statistical significance [hazard ratio (HR) = 0.80, P = 0.154]. The same was observed for overall survival (OS) (HR = 0.87, P = 0.433). The 5-year DFS was 58% in the control arm and 63% in the experimental arm. The 5-year OS was 74% in the control arm and 75% in the experimental arm. Patients allocated to the experimental arm had more grade 3-4 neutropenia when compared with the LV5-FU2 arm (33% versus 6%, P = 0.03), but not when compared with the Mayo Clinic arm (33% versus 36%, P = 0.84). Grade 3-4 diarrhoea tended to be higher in the experimental arm, but analyses stratified by control arm or by radiotherapy failed to show significant differences across strata (test for interaction P = 0.44). CONCLUSION: Even though a benefit of irinotecan in subgroups of patients cannot be excluded, due to early termination and lack of power, the study does not support the addition of irinotecan to 5-FU/LV in routine in patients with resected stage II-III rectal cancer.

Association of adverse events and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil and leucovorin: Is efficacy an impact of toxicity?

BACKGROUND: Adverse events associated with 5-fluorouracil (5FU) based adjuvant therapy in colorectal cancer (CRC) patients may predict survival. We studied whether haematological (leucopenia, neutropenia, thrombocytopenia) or non-haematological (mucositis, diarrhoea, nausea/vomiting, hand-foot syndrome or other toxicity) adverse events were associated with disease-free survival (DFS) or overall survival (OS) in a large patient material treated with 5-fluorouracil based adjuvant chemotherapy. PATIENTS AND METHODS: Data from two prospective randomised adjuvant trials were combined to achieve a dataset of 1033 radically operated stage II and III CRC patients treated with either monthly 5FU and leucovorin (LV) as bolus injections (Mayo or modified Mayo) or bi-monthly with bolus and continuous infusion (LV5FU2 or simplified LV5FU2). Toxicities were recorded at each treatment cycle according to NCI-C CTC (the Common Toxicity Criteria of the National Cancer Institute of Canada). The worst toxicity grade was taken into account. The median follow-up time of patients was 6.05 years. RESULTS: 47% of patients developed neutropenia, 54% nausea/vomiting and 43% mucositis. Any grade neutropenia was associated with improved DFS (hazard ratio (HR) 0.81), any grade nausea/vomiting with improved DFS (HR 0.79) and OS (HR 0.62) and mucositis with improved DFS (HR 0.74) and OS (HR 0.72). Patients experiencing no predefined toxicity had the worst outcome. CONCLUSION: Specific adverse events related to adjuvant fluorouracil chemotherapy are associated with improved DFS and OS in early stage CRC patients.

A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000).

BACKGROUND: Standard adjuvant chemotherapy regimens for patients with node positive (N+) breast cancer consisted of anthracycline followed by taxane. The European Association for Research in Oncology embarked in 2000 on a phase III trial comparing 6 cycles of FEC100 versus 4 FEC100 followed by 4 Taxol. Primary end-point was disease free survival. Secondary end-points were overall survival, local recurrence free interval, metastases free interval and safety. PATIENTS AND METHODS: Between March 2000 and December 2002, 837 patients were randomised between 6FEC100 for 6 cycles (417patients) or FEC100 for 4 cycles then Taxol 175mg/m(2)/3 weeks for 4 cycles (4FEC100-4T) (420 patients). One thousand patients had been planned initially but the trial was closed earlier due to slow accrual. RESULTS: Hazard ratios (HRs) were 0.99 for disease-free survival (DFS) (95%CI: 0.77-1.26; p=0.91), and 0.85 for overall survival (OS) (95%CI: 0.62-1.15; p=0.29). Nine-year DFS were 62.9% versus 62.5% for 6FEC100 and 4FEC100-4T, respectively. Nine-year OS were 73.9% versus 77% for 6FEC100 and 4FEC100-4T, respectively. Toxicity analyses based on 803 evaluable patients showed that overall grade 3-4 toxicities were similar in both arms (63% versus 58% for 6FEC100 arm and 4FEC100-4T arm, respectively; p=0.16). CONCLUSION: In this trial replacing the last 2 FEC100 cycles of 6FEC100 regimen by 4 Taxol does not lead to a discernable DFS or OS advantage. The lack of a significant difference between the randomised treatment arms may however be due to a lack of power of this trial to detect small, yet clinically worthwhile, treatment benefits.

Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial.

Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.

Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial.

BACKGROUND: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. PATIENTS AND METHODS: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. RESULTS: CNS relapse occurred in 4.0% of control patients and 3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. CONCLUSION: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse.

Impact of on-site initiation visits on patient recruitment and data quality in a randomized trial of adjuvant chemotherapy for breast cancer.

PURPOSE: To provide empirical evidence on the impact of on-site initiation visits on the following outcomes: patient recruitment, quantity and quality of data submitted to the trial coordinating office, and patients' follow-up time. PATIENTS AND METHODS: This methodological study was performed as part of a randomized trial comparing two combination chemotherapies for adjuvant treatment of breast cancer. Centers participating to the trial were randomized to either receive systematic on-site visits (Visited group), or not (Non-visited group). RESULTS: The study was terminated after two years, while the main randomized trial continued. Of the 135 centers that had expressed an interest in the trial, only 69 randomized at least one patient (35/68 in the Visited group, 34/67 in the Non-visited group). Almost two-thirds of the patients were entered by 17 centers (10 in the Visited group, seven in the Non-visited group) that accrued more than 10 patients each. None of the prespecified outcomes favored the group of centers submitted to on-site initiation visits (ie, mean number of queries par patient: 6.1 +/- 9.7 versus 5.4 +/- 6.4, respectively for the Visited and Non-visited groups). Spontaneous transmittal of case report forms, although required by protocol, was low in both randomized groups (mean number of pages per patient: 1.5 +/- 2.0 versus 2.1 +/- 2.3, respectively), with investigators submitting about one-third of the expected forms on time (29% and 39%, respectively). LIMITATIONS: This study could not evaluate the impact of repeated on-site visits on clinical outcomes. CONCLUSION: Systematic on-site initiation visits did not contribute significantly to this clinical trial.

Dose-finding study of paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.

This dose-finding study was designed to determine the maximum tolerated dose (MTD), efficacy and toxicity of combined paclitaxel and carboplatin in 35 previously untreated patients with advanced non-small cell lung cancer (NSCLC). Paclitaxel was given as a 3-h infusion at escalating dose levels (100-250 mg/m2) immediately followed by carboplatin as a 30-min infusion (325 or 350 mg/m2) every 3 weeks. The dose-limiting toxicity, paresthesia, occurred at the highest dose level, therefore the recommended dose was established one level below (paclitaxel 225 mg/m2 with carboplatin 325 mg/m2). Neutropenia was the most common hematotoxicity; dose dependency was not apparent. Two patients, at different dose levels, had febrile neutropenia. Thrombocytopenia was rare. Non-hematological toxicities grade 3 or higher included infection, anorexia, alopecia and paresthesia. One patient had a hypersensitivity reaction (transient hypotension). The overall response rate was 23% and median survival time was 7.5 months. Promising activity and acceptable toxicity supports the development of this combination as a useful chemotherapeutic option in advanced NSCLC.

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.