Effect on disease-free survival of concurrent vs. sequential chemotherapy and radiotherapy after breast-conserving surgery for stage I-II breast cancer 

In high-risk breast cancer, concurrent administration of both chemotherapy and radiotherapy is feasible using selected drugs that may not have cumulative toxic effects with RT. Such a scheme may have the advantage of providing synergistic effect on tumor response and shortening the delay in the start of RT with survival benefits. In 1996, our French randomized multicenter phase III trial (ARCOSEIN) was thus initiated to compare the effect on disease-free survival of concurrent vs. sequential 5-Fluorouracil, novantrone, cyclophosphamide (FNC) chemotherapy and radiotherapy after breast-conserving surgery for stage I-II breast cancer. The current analysis of this trial, with a median follow-up time of 5 years, showed no statistically significant difference in the rates of freedom from any event, freedom from distant metastasis, or overall survival between sequential and concurrent radiochemotherapy after breast-conserving surgery for stage I - II breast cancer.However, there was a higher risk of local recurrence in node-positive women treated with chemotherapy first and radiotherapy.Two other randomized trials directly compared sequential and concomitant chemoradiotherapy programs. A study by a consortium of French national cancer centers and an Italian study ; Arcangeli et al. recently reported a randomized trial comparing sequential and concurrent CMF regimen with radiotherapy in a 206 patients-study with 5 years follow-up. They concluded that concurrent administration of CMF chemotherapy and radiotherapy was safe and might be reserved for patients at high risk of local recurrence, such as those with positive surgical margins or larger tumor diameters. In our randomised study, we find an advantage in DFS not to delay irradiation for node positive breast cancer, with a no standard concurrent chemotherapy regimen well tolerated. These benefits have come at the expense of increase grade 2 or greater late toxicity,  without need for significant interruptions or dose reductions. There are many additional developments that may help to further widen therapeutic ratio. Additional study is needed to determine optimal timing, long term toxicity and potential benefits of concurrent breast irradiation and other chemotherapy regimen like taxanes. The technical basis of intensity modulated radiation therapy, which allows for the delivery of a highly conformal 3D radiation dose distribution around intended targets, reopens many fractionation questions that are still being addressed and challenge us to determine which of these is optimal for use with IMRT alone or in combination with concomitant sensitizers as new chemotherapeutic agents and/or targeted biologic therapies in breast cancer.

Bibliographic reference:

Toledano A, Garaud P, Serin D, Fourquet A, Bosset JF, Breteau N, Body G,  Azria D, Le Floch O, Calais G: "Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conservative surgery enhances late toxicities: Long term results of the ARCOSEIN multicenter randomized study", Int J Radiat Oncol Biol Phys. 2006; 65(2):324-32

Toledano A, Azria D, Garaud P, Fourquet A, Serin D, Bosset JF, Miny-Buffet J, Favre A, Le Floch O, Calais G: "Concurrent or sequential adjuvant chemoradiotherapy after conservative surgery for early-stage breast cancer: clinical results of the ARCOSEIN phase III randomized trial", J Clin Oncol 2007; 25:405-410

Alain Toledano

Department of Radiation Oncology, Henry Kaplan, Hopital Bretonneau, Tours, France