In CG patients, the residual breast (PTV2) was irradiated with a dose of 50.4 Gy in 28 daily fx and the PTV1 with a sequential boost of 10 Gy in 4 fx. In MARA-1 patients, PTV2 was irradiated with a total dose of 40 Gy in 16 fx with a concomitant 3D-RT boost of 4 Gy in 0.25 Gy/ fx. RT was performed after at least 3 weeks from the end of systemic treatments in patients undergoing adjuvant chemotherapy. Toxicity was assessed in both groups, using the same timing. Patient’s clinical examinations were performed at least once a week during RT. All patients applied Biafin cream (Janssen-Cilag AG, Zug, Switzerland) at least once a day on the irradiated skin, and in case of Grade 2 toxicity supportive therapy with topical steroids was given.

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All patients underwent clinical examinations every 6 months and bilateral mammography every 12 months. Late toxicity was graded using Radiation Therapy Oncology Group/European Organization for Research and Treatment Cancer (RTOG/EORTC) criteria13 in both groups of patients (Table 1) and was assessed every 6 months for the first 2 years and annually thereafter. Information on possible predictors of late toxicity was collected at the first medical examination.

(To view a larger version of Table 1, click here.) 

Statistical analysis

Ten patients with missing information on PTV volume (n=8) or diabetes (n=2) were excluded from the main analysis (list wise deletion). In the descriptive tables, summary statistics were expressed as numbers (percentages) or medians (interquartile range). Survival curves were plotted using the Kaplan–Meier method and compared through log-rank test. We fit Cox proportional-hazards regression models to estimate HR of Grade 1 and 2 skin and subcutaneous toxicity and 95% CIs using time since diagnosis as the main temporal axis. HRs of Grade 3 late skin and subcutaneous toxicity were not estimated due to the limited number of events (two for each outcome). Covariates to be introduced in the multivariable models were selected based on backward stepwise strategy (P inclusion <0.1; Pexclusion ≥0.1). A possible nonlinear association between PTV volume and the risk of late skin and subcutaneous toxicity was explored using natural cubic splines, but no evidence of nonlinear relationship was observed. Therefore, PTV volume was included in the models as a continuous variable with one degree of freedom. Statistical analyses were performed using Stata 12.1 SE (Stata Corp, College Station, TX, USA). We defined as statistically significant a two-sided P-value <0.05. The statistical significance in the actuarial analyses was evaluated considering the outcomes as continuous variables and not as a specific time point.

Ethical issues

All patients signed a written informed consent to treatment. The study was approved by the institutional review board of the Catholic University. The study is registered in an international public registry ( NCT03461224).


Four hundred and forty-seven patients were included in this analysis: MARA-1 (317) and CG (130). The median follow-up was 52 months (range: 3–115). In Table 2 patient characteristics and in Table 3 treatment characteristics are shown, respectively. Five patients (1.1%) had local or regional relapses: 4 (3.1%) in CG and 1 (0.3%) in MARA-1 group. Five-year LC was 96.7% and 100% in CG and MARA-1 groups, respectively (P=0.02).

(To view a larger version of Table 2, click here.)  

(To view a larger version of Table 3, click here.)

Late skin and subcutaneous toxicity were acceptable: 5-year G1 skin late toxicity-free survival (LTFS) was 61.1% in CG and 56.1% in MARA-1 (P: NS) while G2 skin LTFS was 93.3% in CG and 92.9% in MARA-1 (P: NS), respectively (Table 4; Figures 2 and 3). G3 skin LTFS was 98.2% in CG while no G3 toxicity was observed in MARA-1 (P: NS) (Table 4). On multivariate analysis, tobacco smoking and larger PTV2 volume were significantly associated with an increased risk of late G1 skin toxicity, whereas only larger PTV volume was significantly associated with G2 late skin toxicity (Table 5). G1 subcutaneous LTFS was 73.4% and 49.1% in CG group and MARA-1 (P<0.001), respectively, and G2 subcutaneous LTFS was 96.5% in CG group and 89.6% in MARA-1 (P: 0.03), respectively (Table 6). Multivariate analysis confirmed that late subcutaneous toxicity was significantly associated with RT modality (Table 7). The use of the AHF regimen increased the risk of late G1 and G2 toxicity (HR 2.35, 95% CI: 1.61–3.41 and HR 3.07, 95% CI: 1.11–8.53, respectively). Furthermore, patients with a larger PTV presented an increased risk of G1 and G2 late subcutaneous toxicity. Moreover, diabetes was associated with increased G1 late subcutaneous toxicity (Table 7). G3 late LTFS were 99.2% in CG and 99.6% in MARA-1 (P: NS), respectively.



(To view a larger version of Table 5, click here.)


(To view a larger version of Table 7, click here.)