A phase III randomized trial comparing adjuvant concomitant chemoradiotherapy versus standard adjuvant chemotherapy followed by radiotherapy in operable node-positive breast cancer: final results.

PURPOSE: To compare concomitant and sequential adjuvant chemoradiotherapy regimens in node-positive, operable breast cancer patients. METHODS AND MATERIALS: This was a randomized, French, multicenter, phase III trial enrolling 638 eligible women with prior breast surgery and positive axillary dissection. Patients in Arm A received 500 mg/m2 5-fluorouracil, 12 mg/m2 mitoxantrone, and 500 mg/m2 cyclophosphamide, with concomitant radiotherapy (50 Gy +/- 10-20-Gy boost). Patients in Arm B received 500 mg/m2 5-fluorouracil, 60 mg/m2 epirubicin, and 500 mg/m2 cyclophosphamide, with subsequent radiotherapy. Chemotherapy was administered on Day 1 every 21 days for 4 cycles. RESULTS: Median treatment durations were 64 and 126 days (Arms A and B, respectively), with no significant difference in overall or disease-free survival. Five-year locoregional relapse-free survival favored patients with conservative surgery (two thirds of the population), with less local and/or regional recurrence in Arm A than in Arm B (3% vs. 9%; p = 0.01). Multivariate analysis in this subgroup showed a 2.8-fold increased risk of locoregional recurrence with sequential chemoradiotherapy, independent of other prognostic factors (p = 0.027). Febrile neutropenia and Grade 3-4 leukopenia were significantly more frequent in Arm A. Subclinical left ventricular ejection fraction events at 1 year were more frequent with concomitant radiotherapy (p = 0.02). CONCLUSIONS: Concomitant radiotherapy with adjuvant fluorouracil, mitoxantrone, and cyclophosphamide has significantly better locoregional control in node-positive breast cancer after conservative surgery and 50% shorter treatment, albeit with slightly more acute toxicity. With mitoxantrone no longer available for adjuvant breast cancer treatment, alternative concomitant chemoradiotherapy studies are needed.

Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer.

CONTEXT: Adjuvant chemotherapy with new cytotoxic agents for breast cancer must be properly assessed for toxicity. OBJECTIVE: To describe adverse events associated with adjuvant chemotherapy for breast cancer, which led to premature termination of a clinical trial. DESIGN, SETTING, AND PATIENTS: We conducted a prospective randomized multicenter study (Reposant sur des Arguments Pronostiques et Predictifs [RAPP]-01) to compare the effectiveness of 2 chemotherapy regimens. Patients (women aged 18-70 years) had primary unilateral breast cancer and either a moderate number of positive axillary lymph nodes (< or =3) or no positive axillary lymph nodes (N0), but were at a high risk of relapse. Patients were treated at 11 French cancer referral centers from June 1999 through January 2003. Primary prophylaxis for febrile neutropenia was not recommended in the study protocol. INTERVENTIONS: Doxorubicin, 50 mg/m2, plus docetaxel, 75 mg/m2, or doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, given postoperatively for 4 courses. MAIN OUTCOME MEASURES: The main end point was the disease-free survival rate at 5 years, as estimated using the Kaplan-Meier product limit method. Secondary end points included safety, which is the focus of this article, and overall survival. RESULTS: A total of 627 women were enrolled. Median follow-up is currently too short (24 months) to analyze the primary end point. The trial was terminated prematurely when 2 deaths related to drug toxicity and 1 case of perforative peritonitis occurred among patients with febrile neutropenia, all in the doxorubicin-docetaxel group. The incidence of febrile neutropenia was significantly higher with the doxorubicin-docetaxel regimen (40.8%) than with the doxorubicin-cyclophosphamide regimen (7.1%) (P<.001). CONCLUSIONS: A high risk of life-threatening complications associated with the doxorubicin-docetaxel regimen was found in this open-label controlled trial. The doxorubicin-docetaxel combination should not be considered as an alternative to the doxorubicin-cyclophosphamide regimen outside carefully designed studies that include primary prophylaxis for febrile neutropenia.

Pegylated liposomal doxorubicin and carboplatin in late-relapsing ovarian cancer: a GINECO group phase II trial.

BACKGROUND: The GINECO group previously demonstrated that pegylated liposomal doxorubicin (PLD)-carboplatin combination was an effective and well-tolerated treatment for advanced ovarian cancer (AOC) patients in late relapse. The purpose of the present analysis was to confirm these results in a prospective cohort of late-relapsing AOC patients. PATIENTS AND METHODS: Eighty-one consecutive patients received PLD 30 mg/m(2), followed by carboplatin (area under the curve) 5 mg min/ml, every 28 days for 6 courses or until progression. RESULTS: The objective response (OR) rate was 65.4%. The median progression-free survival (PFS) and overall survival (OS) were 13.6 months and 38.9 months, respectively. Haematological toxicities were more common than non-haematological toxicities. Non-hematologic adverse reactions were moderate and grade 3 palmar-plantar erythrodysesthesia was limited to one patient. No cardiotoxicity was observed and no toxic death occurred. CONCLUSION: These data support the clinical efficacy and tolerability of PLD in combination with carboplatin as second-line therapy for AOC patients in late relapse.

HER2 status in ovarian carcinomas: a multicenter GINECO study of 320 patients.

BACKGROUND: Despite a typically good response to first-line combination chemotherapy, the prognosis for patients with advanced ovarian cancer remains poor because of acquired chemoresistance. The use of targeted therapies such as trastuzumab may potentially improve outcomes for patients with ovarian cancer. HER2 overexpression/amplification has been reported in ovarian cancer, but the exact percentage of HER2-positive tumors varies widely in the literature. In this study, HER2 gene status was evaluated in a large, multicentric series of 320 patients with advanced ovarian cancer, including 243 patients enrolled in a multicenter prospective clinical trial of paclitaxel/carboplatin-based chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: The HER2 status of primary tumors and metastases was evaluated by both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis of paraffin-embedded tissue on conventional slides. The prognostic impact of HER2 expression was analyzed. HER2 gene was overexpressed and amplified in 6.6% of analyzed tumors. Despite frequent intratumoral heterogeneity, no statistically significant difference was detected between primary tumors and corresponding metastases. CONCLUSIONS/SIGNIFICANCE: Our results show that the decision algorithm usually used in breast cancer (IHC as a screening test, with equivocal results confirmed by FISH) is appropriate in ovarian cancer. In contrast to previous series, HER2-positive status did not influence outcome in the present study, possibly due to the fact that patients in our study received paclitaxel/carboplatin-based chemotherapy. This raises the question of whether HER2 status and paclitaxel sensitively are linked.