Abstract
Background/Aim: Many breast cancer patients receive adjuvant radiotherapy. Tumor bed boost may reduce risk of local failure in high risk patients. We compared hypofractionated whole-breast irradiation (WBI) plus boost (HF+boost) and conventionally fractionated WBI plus boost (CF+boost). Patients and Methods: One-hundred-and-twenty-eight patients receiving HF-WBI (40 Gy in 15 fractions) plus boost (group A) were matched to 127 patients receiving CF-WBI (50.4 Gy in 28 fractions) plus boost (group B), utilizing 10 characteristics. Results: Grade ≥2 dermatitis rates were 16.4% in group A vs. 44.1% in group B (p<0.0001), and grade ≥2 pneumonitis rates were 1.6% vs. 2.4% (p=0.68). Four-year rates of local control, metastases-free survival, and overall survival were 100% vs. 99% (p=0.81), 98% vs. 100% (p=0.29), and 98% vs. 100% (p=0.17), respectively. Conclusion: HF+boost was associated with significantly less grade ≥2 dermatitis with similar disease control and survival.
Breast cancer patients generally receive adjuvant radiotherapy (RT) if treated with breast-conserving surgery (1). In the majority of these patients, RT is administered as whole-breast irradiation (WBI) with those at high risk of developing a local failure receiving an additional boost to the tumor bed (2). The tumor bed boost can be given following (sequential boost) or concurrently with WBI (simultaneous integrated boost, SIB). In the German IMRT-MC2 trial, both techniques of tumor bed boost were associated with similar late toxicity and similar 5-year outcomes in terms of local control (LC), metastases-free survival (MFS), and overall survival (OS) (3, 4). However, using a SIB leads to a reduction of the overall treatment time.
Another option to shorten the overall treatment time is the use of hypo-fractionation (HF) with doses per fraction of >2.0 Gy. Common regimens of HF include 42.5 Gy in 16 fractions and 40 Gy in 15 fractions. Four large randomized trials, each with more than 1,000 patients, demonstrated that these regimens were not inferior to 50 Gy of CF with respect to LC and cosmetic outcomes (5-9). However, in these four trials, only 0.0%, 23.2%, 42.6%, and 51.5% of the patients, respectively, had received a radiation boost to the primary tumor bed (5-9). This likely reflects the pattern-of-practice that radiation oncologists tended to use a boost significantly more often after CF than after HF (10-12).
Few studies have compared HF and CF in which all patients received a boost in addition to WBI (13-16). Thus, additional studies are required comparing HF+boost and CF+boost for adjuvant RT of breast cancer. Our study compares both RT regimens with respect to dermatitis, pneumonitis, LC, MFS, and OS in patients with early breast cancer.
Patients and Methods
A total of 255 patients with unilateral, node-negative breast cancer were included in this retrospective study, which had received approval from the ethics committee of the University of Lubeck (file numbers 21-088 and 2023-538_1). All patients received WBI plus a boost to the primary tumor bed between 2016 and 2019. One-hundred-and-twenty-eight patients were treated with hypofractionated WBI (40 Gy in 15 fractions of 2.667 Gy over 3 weeks) plus a sequential boost of 10 Gy (5×2.0 Gy over 1 week), resulting in an overall treatment time of 4 weeks (group A). These patients were matched to 127 patients receiving conventionally fractionated WBI (50.4 Gy in 28 fractions of 1.80 Gy over 5.5 weeks) plus a sequential boost of 10 Gy (5×2.0 Gy over 1 week, n=80) or a SIB (0.3 Gy per fraction, n=47), resulting in overall treatment times of 6.5 and 5.5 weeks, respectively (group B=control group).
For the matching of both groups, ten characteristics (Table I) were considered that were available for all patients, namely age (≤60 vs. ≥61 years), primary tumor stage (T1 vs. T2-3), histologic grading (G1-2 vs. G3), hormone receptor status (negative vs. positive), affected side (right vs. left breast), use of a deep-inspiration breath-hold (DIBH) technique (no vs. yes), history of chronic inflammatory disease (no vs. yes), systemic breast cancer treatment (chemotherapy, immunotherapy, hormonal therapy) prior to and/or during RT (no vs. yes), history of hypertension (no vs. yes), and history of diabetes mellitus (no vs. yes).
Distribution of investigated patient and tumor characteristics in patients treated with hypo-fractionated whole-breast irradiation plus boost (HF+Boost, n=128) and patients treated with conventional fractionation plus boost (CF+Boost, n=127).
Groups A and B were compared for several endpoints including grade ≥2 acute dermatitis and grade ≥2 pneumonitis, LC, MFS, and OS. Dermatitis and pneumonitis were graded according to the Common Terminology Criteria of Adverse Events version 5.0 (17). LC, MFS, and OS were referenced from the day the RT-course was completed. Statistical analyses for comparing groups A and B regarding the distribution of the ten characteristics included the Chi-square test (≥5 patients in all cells) or the Fisher’s exact test (<5 patients in at least one cell). The same tests were used for comparisons with respect to grade ≥2 acute dermatitis and grade ≥2 pneumonitis. Comparisons regarding LC, MFS, and OS were performed using the Kaplan–Meier method plus the log-rank test (BlueSky Statistics 10 GA, BlueSky Statistics LLC, Chicago, IL, USA). Results were considered significant in case of p-values <0.05.
Results
In groups A and B, the distribution of characteristics was identical or almost identical with respect to age, primary tumor stage, histologic grading, hormone receptor status, affected side, use of a DIBH technique, systemic treatment, and history of hypertension (Table I). The difference in prevalence between the subgroups regarding these characteristics ranged between 0% and 2%, and the corresponding p-values between 0.84 and 0.98). The distribution regarding the history of chronic inflammatory disease (difference=3%, p=0.42) and hypertension (difference=5%, p=0.19) was also similar (Table I). Thus, groups A and B were considered well balanced.
Median follow-up periods were 46 months (range=10-76 months) in the entire cohort, 40 months (range=10-70 months) in group A, and 56 months (range=12-76 months) in group B. Rates of grade ≥2 acute dermatitis were 16.4% in group A vs. 44.1% in group B (p<0.0001) (Table II). Grade ≥2 pneumonitis rates were not significantly different (1.6% vs. 2.4%, p=0.68) (Table II). Four-year rates of LC were 100% in group A and 99% in group B (p=0.81, Table II). Corresponding rates of MFS were 98% and 100%, respectively (p=0.29), and OS-rates were 98% and 100%, respectively (p=0.17). Two patients in group A died due to newly developed distant metastases after 10 and 30 months, respectively. Thus, OS was identical with the cancer-specific survival.
Comparison of patients treated with hypo-fractionated whole-breast irradiation plus boost (HF+Boost, n=128) and patients treated with conventional fractionation plus boost (CF+Boost, n=127) with respect to grade ≥2 acute dermatitis, grade ≥2 pneumonitis, and treatment outcomes.
Discussion
Many patients with node-negative breast cancer are treated with lumpectomy followed by WBI (1). In patients with a high risk of an intra-breast recurrence, WBI is generally supplemented by a sequential or simultaneous boost to the primary tumor bed (2). In order to reduce the overall treatment time, hypofractionation has been increasingly used (3-10, 18). The recommendation of HF-RT is based on the results of four randomized trials with a total of more than 7,000 patients, demonstrating that HF-RT was not inferior to CF-RT (5-8, 14). However, the majority of patients included in three of these trials did not receive a boost in addition to WBI (5-8). Also, the fourth trial investigated only acute and short-term toxicities (14). Three other studies were identified that compared HF+boost and CF+boost (13, 15, 16). However, in one of these studies, median follow-up was limited to 16 months, and one study evaluated only acute toxicity (13, 15). The third of these studies provided longer-term (5-year) results of LC, MF, and OS (16). However, its results regarding acute skin toxicity were conflicting. In patients treated with HF+boost, grade ≥2 erythema occurred significantly more often than in patients receiving CF+boost. Interestingly, grade ≥2 moist desquamation was significantly more common in the CF+boost group (16). Thus, additional studies of HF+boost vs. CF+boost are required that consider several endpoints including OS and have a longer median follow-up period.
In our study, we investigated toxicity, LC, MFS, and OS, and median follow-up was 46 months. Rates of grade ≥2 pneumonitis, LC, MFS, and OS were not significantly different (Table II). However, grade ≥2 acute dermatitis occurred significantly more common in group B (CF). Our results regarding pneumonitis were in line with those of other studies. In two studies comparing HF+boost vs. CF+boost, no grade ≥2 pneumonitis was observed in both treatment groups (14, 15). In the study of Kawaguchi et al., where 21.6% and 21.8% of the patients, respectively, received a boost in addition to HF-WBI and CF-WBI, pneumonitis rates were 2.3% (HF) and 1.6% (CF), respectively (p=0.69) (19). Moreover, in a meta-analysis and systematic review of patients irradiated following mastectomy, acute lung toxicity was similar after HF-RT and CF-RT (odds ratio=0.94, 95% confidence interval=0.74-1.20, p=0.62) (20).
HF+boost and CF+boost resulted in similar LC, MFS, and OS up to 4 years following RT in our cohort. In a previous randomized trial comparing HF-WBI and CF-WBI without boosts, 10-year local recurrence (LR) rates were 6.2% after HF-WBI with 42.5 Gy in 16 fractions over 22 days and 6.7% after CF-WBI with 50.0 Gy in 25 fractions over 35 days, respectively (7). In the UK Standardisation of Breast Radiotherapy (START) trial A, where 51.5% of the patients received a boost, 5-year LR rates were 3.6% after CF-WBI with 50.0 Gy in 25 fractions over 5 weeks, 3.5% after HF-WBI with 41.6 Gy in 13 fractions over 5 weeks, and 5.2% after HF-WBI with 39.0 Gy in 13 fractions over 5 weeks (5). In addition, in the START B trial, where 42.6% of the patients received a boost, 5-year LR rates were 3.3% after CF-WBI with 50.0 Gy in 25 fractions over 5 weeks and 2.2% after HF-WBI with 40.0 Gy in 15 fractions over 3 weeks (6). The 10-year LR rates of the compared regimens in both START trials were also not significantly different (8). In the more recent randomized trial of Offersen et al., 23.2% of the patients received a boost (9). The 9-year LR rates were 3.3% after CF-WBI with 50.0 Gy in 25 fractions over 5 weeks and 3.0% after HF-WBI with 40.0 Gy in 15 fractions over 3 weeks, and the 9-year OS rates were 93.4% and 93.4%, respectively (9). In the randomized study of DeFelice et al. including 120 patients, LR was not observed during the follow-up period of median 16 months (15). Two of 62 patients (3.2%) treated with CF+boost (50 Gy in 25 fractions plus 10 Gy in 5 fractions) and 2 of 58 patients (3.4%) treated with HF+boost (42.5 Gy in 16 fractions plus 10 Gy in 5 fractions) developed distant metastases. Lee et al. retrospectively compared 379 patients receiving HF-WBI (39 Gy in 13 fractions plus hypo-fractionated boost (9 or 12 Gy in 3 fractions) to a matched cohort of 379 patients treated with CF-WBI (50.4 Gy in 28 fractions) plus conventionally fractionated boost (9 Gy in 5 fractions or 14 Gy in 7 fractions) (16). Five-year rates of LC, MFS, and OS were 99.2% vs. 98.4% (p=0.56), 98.4% vs. 97.6% (p=0.31), and 99.2% vs. 98.9% (p=0.48), respectively. These rates were similar to the 4-year rates found in our study.
In our study, treatment with HF+boost was associated with a significantly lower rate of grade ≥2 acute dermatitis than CF+boost (16.4% vs. 44.1%). This result also corresponds to the findings of other studies comparing HF+boost and CF+boost (13-16). In the retrospective study of Tortorelli et al., 55% of patients receiving CF-WBI with 50 Gy in 25 fractions plus boost (10-16 Gy in 5-8 fractions or 9-15 Gy in 3-5 fractions) and 37.5% of patients receiving HF-WBI with 44 Gy in 16 fractions plus boost, experienced grade ≥2 acute skin toxicity (13). In the studies of DeFelice et al. and Shaitelman et al. (described before) grade ≥2 dermatitis rates after HF-RT and CF-RT were 26.4% vs. 73.5% (p=0.02) and 69% vs. 36% (p<0.001), respectively (14, 15). In the study of Lee et al., HF+boost was associated with a significantly lower incidence of grade ≥2 moist desquamation (11.1% vs. 0.0%, p<0.01) but with a higher incidence of grade ≥2 erythema (57.4% vs. 49.1%, p<0.01) than CF+boost (16). However, this is the only finding of all studies regarding skin toxicity that is in favor of CF+boost. Thus, when considering the available data including our present study, it can be stated that HF+boost is associated with less grade ≥2 acute dermatitis than CF+boost. Otherwise, outcomes in terms of radiation pneumonitis, LC, MFS, and OS were similar between these RT-regimens. When interpreting the results of those studies comparing HF+boost and CF+boost, their limitations should be considered, which accounts also for our study. Its major limitations include the retrospective design (risk of a hidden selection bias) and the fact that several characteristics that might impact the results (e.g., body-mass index, breast size, and human epidermal growth factor receptor 2 status) were not available in many patients and, therefore, not considered. Moreover, since patients with bilateral cancer, node-positive cancers, or incomplete resection were excluded from this study, our findings may not be valid for these patient groups. However, the studies that compared HF+boost and CF+boost including our study, despite their limitations, contributed to the identification of the optimal dose-fractionation regimen for adjuvant RT of early breast cancer. Another important question, which was not investigated by the studies mentioned above but is currently addressed in prospective trials, is whether the overall treatment time of adjuvant breast irradiation can be further reduced by using HF-WBI plus SIB (21-23).
In summary, when compared to CF+boost, HF+boost was associated with similar outcomes in terms of pneumonitis, LC, MFS, and OS but with significantly less grade ≥2 dermatitis. Thus, given the limitations of this study, HF+boost appears preferable for patients irradiated for early breast cancer who require a boost to the primary tumor bed in addition to WBI.
Footnotes
Authors’ Contributions
D.R., M.C.E., and S.J. participated in the design of the study. M.C.E. collected the data that were analyzed by D.R. and N.Y.Y. The article was drafted by D.R., and subsequently reviewed and approved by all Authors.
Conflicts of Interest
The Authors indicate that there are no conflicts of interest related to this study.
- Received August 2, 2023.
- Revision received August 28, 2023.
- Accepted August 29, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).