In regard to "The Italian Association of Radiotherapy and Oncology Recommendation for Breast Tumor Recurrence: Grades of Recommendation, Assessment, Development and Evaluation Criteria".

We congratulate Bottero et al. [1] on the publication of the Italian Association of Radiotherapy and Clinical Oncology recommendations in cases of ipsilateral breast tumor recurrence. The aim of this review was to compare oncological outcomes after a second conservative treatment (2nd CT) based on lumpectomy plus re-irradiation of the tumor bed vs. salvage mastectomy (SM), which has been considered a priority clinical question by the authors. As mentioned by the panel, currently there is no phase III prospective randomized trial comparing these tow salvage treatment options. The results reported by the authors give rise to four important remarks.

First, as pointed out, the comparative studies (2nd CT vs. SM) reported by the authors were biased due to different selection criteria, leading to debatable conclusions. However, in this setting, the Breast Cancer-Working Group of the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology (GEC-ESTRO) recently compared the oncological outcomes after a 2nd CT (377 pts) or SM (377 pts) by using a propensity score-matched cohort analysis [2]. With a median follow-up of 75.4 months, a comparison of 5-year oncological outcome between 2nd CT and SM cohorts showed no significant difference in terms of cumulative incidence of local (2.8% vs. 2.3%), regional (2.3% vs. 1.6%) or metastatic (9.3% vs. 14.1%) relapses as well as disease-free (82.5% vs. 78.6%), cause-specific (91.2% vs. 91.8%) or overall survival (OS; 86.7% vs. 87.5%). No significant differences were observed at 10 years either [2].

Second, the toxicity analysis was always performed without taking into account late side effects after the first breast CT. Consequently, the late toxicity analysis reported is the result of two lumpectomies and two breast irradiations. In the GEC-ESTRO study, the rate of late toxicity was 47.7%, 42.8%, 8.8% and 0.7% for G1, G2, G3 and G4 respectively with a rate of telangiectasia ≥ G2 of 11.4%. Cutaneous and sub-cutaneous fibrosis were the most frequent late side effects [2]. However, late side effects after a 2nd CT have to be discussed in terms of the physical and psychological consequences of a SM with or without reconstruction [3].

Third, with regard to selection criteria, the authors consider that a 2nd CT can be proposed for local relapses occurring at least 5 years after the primary breast cancer. However, early local relapse (≤ 36 months) was considered as an independent prognostic factor in multivariate analysis for distant metastasis, disease-free, cause-specific and OS but not for local relapse [2]. Consequently, is it necessary to impose a SM while the real risk remains a systemic one?

Fourth, the authors acknowledged that all the studies analyzed were observational, retrospective and based on small samples and short follow-up. However, in order to properly answer this crucial question, we used the best statistical method (propensity score-matched cohort analysis) when a randomization is not possible. Indeed, to accurately compare 2nd CT vs. SM, a randomized phase III trial should be considered. This study should be designed to demonstrate that 2nd CT is non-inferior compared to SM in terms of OS (null hypothesis), leading to the conclusion that “keeping the breast” has no significant oncological impact on the remaining life expectancy of the patient. With such a design and in the most optimistic scenario, a total number of 3,604 evaluable patients (1,802 patients in each arm/number of events: 560) is needed to properly investigate the null hypothesis [2]. Such a trial is not feasible [45].

Finally, even if brachytherapy remains the best documented re-irradiation technique, new approaches are under investigation in order to facilitate a conservative salvage treatment [6]. In case of ipsilateral breast cancer recurrence, SM is not the only salvage option and can no longer be considered the standard treatment. A 2nd CT combining lumpectomy plus re-irradiation of the tumor bed has to be proposed as an alternative to SM after clear, detailed and open discussion with the patient.