Anthracycline and concurrent radiotherapy as adjuvant treatment of operable breast cancer: a retrospective cohort study in a single institution

In the case of radical mastectomy or breast conservative therapy (BCT), adjuvant radiotherapy (RT), improves local control [1–9]. Adjuvant chemotherapy (CT) is equally mandatory for diminishing metastatic recurrences [10–12].

The optimal sequence of CT and RT remains controversial. The delivery of RT can be planned before or after CT, concurrently, or within 2 cycles of CT (''sandwich'' therapy). However, the current standard is CT followed by whole-breast-irradiation (WBI). The delay of CT increased the incidence of spared metastasis [13–16], and the delay of RT induced more frequent local recurrences [17–19].

Concurrent treatment shortens the duration of therapy, allows RT and CT to start temporally, and potentially improves local control via the radiation sensitizing effects of CT. Concurrent chemoradiotherapy (CCRT) has successfully been achieved with cyclophosphamide, methotrexate and fluorouracil (CMF) [20–22]. The concurrent use of taxanes and WBI seems feasible [23].

Anthracycline regimens improve survival in the adjuvant setting [24]. Unfortunately, concomitant use of epirubicin or doxorubicin produced 30% to 44% rate of high grade radiation dermatitis (RD) [25, 26], and concurrent mediastinal irradiation with doxorubicin induced intense cardiac dysfunction [27]. This was discouraging the use of anthracyclines and radiation concurrently.

However, in a previous study conducted in our institute we showed that CCRT using anthracycline and WBI produced only 4.5% of ≥ grade 2 RD, and improved the locoregional control over the treatment based on CMF [28]. And recently, in another study, the authors confirmed the feasibility of partial breast irradiation (PBI) with concurrent dose-dense doxorubicin and cyclophosphamide in early breast cancer [29].

The present work, by including more patients, had the objective to confirm our previous results and to support the feasibility and efficiency of concomitant use of anthracycline [28, 30]. It was based on the study of a data base of 400 patients treated by radical surgery (mastectomy or breast conservative therapy [BCT]) and adjuvant CCRT. We compared the efficacy, and tolerability of two concomitant protocols, the first with anthracycline based regimens and the second with CMF regimen.

The main advantages of CCRT are: 1. delivering both treatments of CT and RT at same time; 2. biological synergy effect that can increase the efficacy of the treatment [34]. A CT based on liposomal doxorubicin, paclitaxel and vinorelbine, with concomitant RT in non operable and recurrent disease, was found to be of good efficacy and tolerability [34, 35]. Reirradiation with concomitant CT was shown to have positive effect [34, 36]. In adjuvant setting, CCRT has successfully been achieved by the concurrent use of CMF or taxanes with WBI [20–23].

Few prospective studies investigated CCRT using anthracycline regimen. The authors showed high rate of high grade skin toxicity, and more cardiac dysfunction, and concluded that this protocol cannot be used in practice [25–27]. However, in a recent phase I trial, the authors showed that PBI with concurrent dose dense doxorubicin and cyclophosphamide induced an acceptable hematologic and nonhematologic toxicity profile with likelihood of RD ≥ grade 2 is ≤ 11% [29]. These results were in favor of the use of CCRT based on anthracycline regimen and this is why we suggest the evaluation of concurrent versus sequential therapy in early stage breast cancer using anthracycline and modern radiation techniques. In our previous investigation we evaluated two concurrent protocols administered either with anthracycline regimen or with CMF in adjuvant setting and confirmed the beneficial effect of anthracycline based protocol in locoregional control with acceptable toxicity profile over the CMF [28].

After 74.5 months median follow-up, we found no statistical difference in the OS between the two therapeutic groups A and B, which can be explained by the fact that group A was characterized by poorer prognosis (more lymph node involvement). However, we showed a trend toward significance for EFS in favor of anthracycline (log-rank P = .057). In addition, when only the isolated locoregional events were considered, the LRFS at 5 years was significantly higher in group A than group B (98.7% vs 95.3%; log-rank P = .034). To confirm the beneficial effect of anthracycline we conducted subgroup analyses. The first subgroup concerned patients treated with ≥ 2 cycles of concurrent CT (n = 288 from A and B) and we showed that LRFS, EFS and OS were statistically higher in the anthracycline based treatment than in CMF. The second sub group concerned patients treated with BCT (n = 61 from A and B) and we showed that LRFS and EFS were statistically higher in anthracycline than in CMF. In addition, using the multivariate Cox proportional hazard regression models analysis, we confirmed that the anthracycline regimen favorably influenced the LRFS (type 1) (P = .062), the EFS (P = .007), and OS (P = .046) (table 2).

However, in adjuvant setting, it has been demonstrated that anthracycline and taxanes containing regimens decreased relapse and improved survival. Consequently, our results may be explained by the effect of anthracycline regimen and not by the use of CCRT [24, 37].

Three recent randomized phase III trials were conducted to compare the sequential protocol to the concomitant protocol. In the first trial, 716 patients were treated by BCT and randomized into 2 groups (ARCOSEIN study) [38]. In the first group, the patients were treated by the FNC protocol (5-fluoro-uracil 500 mg/m2, mitoxantrone 12 mg/m² and cyclophosphamide 500 mg/m²) with concomitant RT. In the second group, the patients were treated by the FNC protocol followed by RT. Arcangely et al. [39], randomly assigned 206 patients (after quadrantectomy and axillary dissection) to concurrent or sequential treatments using CMF based CT. In the third trial, Rouessé et al. [40], randomly assigned 638 patients with prior breast surgery and positive axillary dissection (from which 416 were BCT) to receive CCRT (FNC protocol) or CT (fluorouracil, epirubicin, and cyclophosphamide protocol) followed by RT. No differences in 5-years LRFS, disease-free survival and OS were observed between the 2 treatment groups in the 3 trials. Nevertheless, in the ARCOSEIN study the authors identified a significant decrease in the risk of locoregional recurrence with CCRT for node-positive patients. Rouessé et al. [40], showed that concurrent treatment has a significantly better locoregional control in node-positive breast cancer after BCT.

In our study we found significantly higher locoregional control of the disease and a trend for a higher rate of 5 years EFS in anthracycline group vs CMF group. And we found a superior effect of concurrent use of anthracycline over CMF in terms of LRFS and EFS in the subgroup of patients treated with BCT. In addition, in the subgroup of patient treated with ≥ 2 cycles of concurrent CT, we confirmed the significant beneficial effect of the anthracycline in terms of LRFS, EFS and OS.

The main limitation of the 3 European trials was the use of CMF protocol and FNC protocol which have a safer toxicity profile when radiation treatment was used without the use of anthracycline and taxane regimens. CMF and FNC are older CT regimen used in the past; however more recently anthracyclines and taxanes containing regimens have become standard, and are demonstrated to have improved survival and local recurrence outcomes.

In ARCOSEIN study, moderate acute locoregional toxicities were found in the concomitant arm. Rouessé et al. [40] presented more frequent grade 2 skin toxicities in the concomitant arm, and more subclinical LVFE events at 1 year. In our study we showed more haematologic toxicity when the treatment was based on anthracycline with significantly more grade 3-4 neutropenia. Grade 2-3 anemia and grade ≥ 2 thrombopenia were more frequent in anthracycline group but the differences were not significant.

In our study, we found more respiratory symptoms and high grade (≥ grade 2) RD toxicity (4.8% vs 1.3%) in anthracycline group versus CMF group. We note however that dermatitis toxicity was not routinely evaluated like other adverse events as we would expect much higher dermatitis rates with concurrent taxane/radiation.

Our retrospective study showed different limitations, because it implicated potential bias in the choice of treatment. In addition to the lack of cardiac toxicity evaluation which constituted the major limitation (only 2% [n = 9] had assessment of cardiac function via LVEF measurement). However, 50% of the cases were left-sided breast cancers and would probability induce a high risk of cardiac toxicity.

From the present 5 years nonrandomized investigation we concluded that the treatment based on anthracycline and concurrent RT reduced breast cancer relapse rate including locoregional relapses and significantly improved LRFS, EFS and OS in the patients receiving more than 1 cycle of concurrent CT. In multivariate analysis we confirmed that the anthracycline regimens had a positive effect on LRFS, EFS and OS. There were more hematologic and non hematologic toxicities in the anthracycline group. Anthracyclines and WBI cannot be administered concurrently before further investigations to determine efficacy and safety of anthracycline based treatment.