Moderate HFRT remains the standard of care for whole breast radiotherapy based on phase III randomized studies showing non inferiority in terms of efficacy and safety (4,7,8).
Our study focuses on the evaluation of acute toxicity in real-life patients treated with whole breast or chest wall radiotherapy who may not fulfill all clinical trials inclusion criteria including patients with T3, N + or patients with large breasts who were excluded from the Ontario trial (4).
Results of this systematic, large-scale, multicentre prospective data collection, showed that both HFRT and NFRT had limited and acceptable acute toxicity in real-life patients. HFRT was associated with a significantly reduced risk of developing dermatitis, breast oedema, hyperpigmentation or pain.
In our series of 3518 patients, grade 2–3 dermatitis was observed in 8.9% of patients who received HFRT vs 35.1% of patients who received NFRT. These findings were consistent with result from a sub study of the Ontario trial, including 161 of the 1234 randomized patients showing lower acute skin toxicity in the HFRT arm (12% for HFRT vs 38% for NFRT), which correlated with an overall increased quality of life (17).
Few studies have reported pain assessment in this context. We found 33.4% of low or intense peak pain with HFRT vs 53.7% with NFRT. Consistently, a randomized series of 287 patients comparing HFRT versus NFRT for whole breast followed by a tumor bed boost also showed significantly less, low or intense maximum acute breast pain with HFRT (55% vs 74%. p = 0.001)(18).
A previous prospective population based study had included 2309 patients. All received adjuvant HFRT or NFRT to the whole breast exclusively after breast conserving surgery (19). Similar results were found in our series including patients with a mastectomy and larger tumor; HFRT was associated with reduced acute pain compared to NFRT.
To our knowledge, this study is the largest prospective study on unselected real-life patients, including whole breast or chest wall radiotherapy, with or without tumor bed boost irradiation, supporting safe applicability in daily practice, regarding acute toxicities.
In all participating centers, patients with N + disease were systematically offered locoregional radiotherapy and locoregional radiotherapy was not recommended for N0 patients. Therefore N + patients who represented 30.6% of all patients could be a good approximation of patients treated with locoregional radiotherapy. There was no significant difference reported regarding dermatitis between N0 and N + patients regardless of the fractionation schedule. However lower grades 2–3 dermatitis were reported with HFRT than NFRT in both N0 and N + group.
The reported obstacles affecting the implementation of HFRT, include concerns regarding applicability of published trials to patients with higher toxicity risk factors (20,21). Some factors such as large breast size and high BMI are known to be associated with risks of developing acute skin toxicity (22) resulting in higher rates of acute adverse events, and worse cosmetic outcomes in adjuvant breast radiotherapy, regardless of the fractionation schedule (23).
Our results confirmed independently from fractionation that obesity (BMI ≥ 25 kg/m2), large breast size (bra cup > C), and lumpectomy over mastectomy, were associated with a higher risk of grade 2–3 dermatitis. The role of lumpectomy as a risk factor of acute toxicity has to be balanced, with the use of tumor bed boost, which influences the total dose received by patients and therefore the toxicity. Interestingly the percentage of grade 2–3 dermatitis with HFRT remains lower than with NFRT in patients with risk factors for toxicity. Our reassuring data therefore suggests that these risk factors should no longer be seen as obstacles to the use of HFRT.
The main strength of our study was to further support randomized trial results, regarding acute safety of HFRT. This study also showed how the use of prospective, structured, multicenter data extraction from a large number of unselected real-life patients, could help to monitor the implementation of new standard, and may provide additional help for physicians to feel more comfortable offering HFRT. Such data extraction could also be used to provide information on the compliance to clinical standards, and provides relevant metrics for the monitoring of treatment quality, a cornerstone of clinical practice change.
This study also had limitations. First, this was an observational study differing from randomized trials by the use of real-life heterogeneous populations introducing possible selection bias. However, this method of evaluation could be implemented at a national and an international scale to support and monitor implementation of new standard in addition to randomized trials. Second, patients were not assessed with a systematic standardized evaluation form after the end of radiotherapy; therefore, these data were not included in the analysis, which may underestimate the maximum acute toxicity. This underestimation should be the same for both HFRT and NFRT as Arsenault et al. had shown a toxicity peak occurrence one week after the end of radiotherapy in both schedules . Third, the retrospective sub-study for dermatitis risk factors was only performed on data from a single center due to limitations to additional data access. Nevertheless the entire population (622 patients) of this center contributed to the sub-study.
More recently, the randomized phase III Fast-Forward trial went further into hypofractionation, showing non-inferiority of 26 Gy in 5 fractions of 5.2 Gy over 1 week versus 40 Gy in 15 fractions over 3 weeks, in terms of local tumor control and safety at 5 years for early-stage breast cancer (24,25).
Some centers could be reluctant to implement such a highly hypofractionated treatment in practice. Moving towards one-week hypofractionation may also be safe as HFRT showed fewer early toxicities.
The prospective use of structured evaluation forms in daily workflow would however, allow continuous monitoring of patients toxicities, and could be of major interest to alert physicians in case of over-toxicity. Especially in the current context of the coronavirus disease pandemic, where a Fast Forward schedule has been rapidly endorsed by international guidelines, to restrict exposure of health-care professionals and patients to the virus, the prospective use of such structured evaluation forms could be even more important (26).