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We started this trial was in 2003 to evaluate late toxicity using an AHF regimen prior to the publication of several randomized studies.8,9,14 To reduce the potential risk of increased toxicity, we opted for the use of IMRT technique. Our study reported a significant difference between AHF and conventional 3D-technique with higher rates of G1–G2 late subcutaneous toxicity after AHF and no differences between the two techniques in terms of late skin toxicity. A relevant limitation of our study is the lack of evaluation of cosmesis and patient-reported outcome measures. However, regarding the higher incidence of mild–moderate fibrosis in patients who underwent the MARA-1 protocol, in our opinion the impact was modest if not entirely irrelevant from the patient’s point of view. However, we must admit that our study had a retrospective design and the comparisons were made on a previously treated CG. Moreover, the results of our analysis are potentially affected by bias and cannot be considered as “high level of evidence.”

The 10-year results from START-A and START-B trials and from the Ontario Clinical Oncology Group trial did not show a higher toxicity after AHF in women undergoing BCT for early-stage invasive BC with clear surgical margins and negative axillary nodes.8,9

The UK randomized trials compared the standard fractionation 50 Gy in 25 fx with three schemes of HF-RT: 39 or 41.6 Gy in 13 fx over 5 weeks and 40 Gy in 15 fx over 3 weeks. In both trials a boost of 10 Gy in 5 fx was delivered after initial RT in a variable percentage of patients. In that study a nonsignificantly higher rate of breast induration and telangiectasia was recorded in the 41.6 Gy AHF group.8 The authors reported a 10-year good to excellent cosmetic outcome in 69.8% of AHF as compared with 71.3% of patients in the standard fractionation arm.8

Furthermore, the 10-year results from START A8 trial showed that normal tissue effects (like breast shrinkage, telangiectasia, and breast edema) were less common in the 39 Gy group and did not differ significantly between 41.6 Gy group and 50 Gy group.8

The reason for the differences between AHF impact on late toxicity between our study and the randomized trials could arise from the heterogeneity in the assessment of late toxicity. In fact, in START-A and B, the cosmetic outcomes (presence of breast shrinkage and hardness, change in skin appearance, breast swelling) were defined by patient self-reported assessments. Moreover, in 1,055 of 2,236 patients of START-A and in 923 of 2,215 patients of START-B, change in breast appearance was assessed by photographs taken at baseline, and then at 2 and 5 years with scores on 3-point graded scales. The physician assessments of normal tissue effects in START-A and B were scored on a 4-point scale (none, a little, quite a bit, or very much). The same authors reported variations between centers in the practice used to complete the yearly reports forms, which could equally have led to underreporting of physician assessment of normal tissue effects.8

In our study, normal tissue effects were assessed by two trained physicians (CD, AGM) using the RTOG/EORTC Scale to evaluate skin and subcutaneous tissue toxicity. We can hypothesize that the palpation of the irradiated breast is more sensitive than photographic evaluation in detecting a mild degree of fibrosis.

Another reason for the different outcomes from our study as compared to the results of the randomized trials could be the fractionation used in our CG (1.8 Gy/fraction), which was lower compared to the standard arm of the randomized trials (2 Gy/fraction). This reduced dose per fraction could have impacted on the incidence of late toxicity in the CG. In addition, the boost technique was different between CG and MARA-1 trial. In fact, in the CG the boost was delivered with a direct electron beam, while in the MARA-1 trial it was with tangential photon beams. The latter irradiation modality could have probably caused delivery of boost dose to a larger volume. Finally, the finding of a higher rate of fibrosis in MARA-1 patients could be associated to the concomitant boost while CG patients had a sequential boost. In fact, MARA-1 patients received not only a larger dose on PTV1 compared to PTV2 (44 vs 40 Gy) but even a more accelerated fractionation (2.75 vs 2.5 Gy). But comparing the Equivalent Dose in 2 Gy/fraction (EQD2) between the two treatment techniques at the boost site, the EQD2 of MARA-1 and CG groups were 50.6 and 59.4 Gy, respectively. It is therefore difficult to weigh the boost timing as the reason for the recorded differences in terms of late toxicity. Table 3 shows a clear imbalance in terms of adjuvant pharmacological treatments. The percentage of patients receiving chemotherapy was close to double in the CG compared to the MARA-1 patients (64.6% vs 33.1%). This figure may have played a role in the different late toxicity rates recorded in the two groups. However, it should be emphasized that the significant impact of RT was confirmed on multivariate analysis, in which both chemotherapy and hormone therapy were included.

Despite the higher rate of late subcutaneous toxicity in the MARA-1 group, the significant differences were limited only to the lower grades (G1–G2), whereas the absence of G3–G4 could be attributed to the IMRT technique. In fact, several studies have confirmed the role of IMRT in BC in terms of improvement of dosimetric parameters, higher homogeneity in dose distribution, and reduced severity of acute toxicity.15,16 Two retrospective cohort studies have reported late toxicity, both with positive results.17,18 The study by Harsolia et al,17 showed a significant difference between IMRT and conventional wedge-based RT, and was in favor of IMRT for chronic (G2 or greater) breast edema (3% vs 30%; P=0.007) with no differences in terms of hyperpigmentation or fibrosis. In the study of McDonald et al,18 the authors reported a trend toward a reduced incidence of lymphedema in patients treated by IMRT compared to conventional treatment (0% vs 4%; P=0.06). In contrast, the 10-year results of the Canadian randomized trial comparing IMRT with traditional RT did not show significantly different results in terms of late toxicity. The authors concluded that IMRT cannot be recommended in all BC patients treated with BCT.19

Our study also showed a significant difference in terms of 5-year locoregional control (96.7% and 100% in CG and MARA-1 groups, respectively; P=0.02). However, this result should be considered with caution considering the different inclusion criteria between the two groups. In CG group, even patients with >3 metastatic axillary nodes, in premenopausal status, with close margins, and pT4 tumors were enrolled. In fact, Table 2 shows a clear imbalance of prognostic factors in favor of MARA-1 group in terms of tumor grading and nodal stage. For these reasons, we did not compare the differences in terms of disease-free and overall survival.