Clinical and Translational Oncology (2022) 24:1580–1587 https://doi.org/10.1007/s12094-022-02798-8 RESEARCH ARTICLE Evidence‑based guidelines for hypofractionated radiation in breast cancer: conclusions of the Catalan expert working group Arantxa Eraso1 · Javier Sanz2 · Meritxell Mollà3 · Vicky Reyes4 · Agustí Pedro5 · Meritxell Arenas6 · Evelyn Martinez7 · Rosa Ballester8 · Maria José Cambra9 · Virginia García10 · Joan Lluis Prades11 · Josep M. Borras11 · Manuel Algara2 Received: 17 November 2021 / Accepted: 28 January 2022 / Published online: 21 February 2022 © The Author(s) 2022 Abstract Introduction Daily, moderate hypofractionation has become standard treatment for breast cancer following breast-conserving surgery, although substantial variation exists in its use. This paper describes the generation of consensus-based recommenda- tions for the utilisation of this therapy at the healthcare system level and compares these to American Society for Radiation Oncology (ASTRO) guidelines. Materials and methods Consensus-based guidelines were developed in three steps, including a systematic literature review and involvement of radiation oncologists specialising in breast cancer in Catalonia: (a) creation of a working group and evidence review; (b) consideration of the levels of evidence and agreement on the formulation of survey questions; and (c) performance of survey and development of consensus-based recommendations. Results were compared to the ASTRO recommendations. Results Consensus was above 80% for 10 of the 14 survey items. Experts supported hypofractionated radiotherapy for all breast cancer patients aged 40 years or more; with invasive carcinoma and breast-conserving surgery; without radiation of lymph nodes; and regardless of the tumour size, histological grade, molecular subtype, breast size, laterality, other treatment characteristics, or need for a boost. Over half favoured its use in all situations, even where available scientific evidence is insufficient. The resulting recommendations and the quality of the evidence are comparable to those from ASTRO, despite some differences in the degree of consensus. Conclusion Specialists agree that hypofractionation is the standard treatment for breast cancer following breast-conserving surgery, but some specific areas require a higher level of evidence before unequivocally extending indications. Keywords Breast cancer · Radiotherapy · Hypofractionation Introduction wall following mastectomy [7], or in patients of all ages [8]. However, there are substantial variations in the use of Following breast-conserving surgery for breast cancer, daily, hypofractionation across different centres and countries [9, moderate hypofractionation has become standard treatment 10]. In a previous study, our group assessed its use for breast [1, 2]. Results from randomised trials do not support the cancer in Catalonia, Spain [11], finding that it ranged from use of classic fractionation of 2 Gy in most patients [3, 4], 8.9 to 74.7% of patients treated with a curative intent. In and studies have confirmed the effectiveness of hypofrac- addition, specific indications for the treatment varied, both tionated regimens with similar tolerance [5]. Indications between services and among the different professionals that for its use have also broadened with the growing body of staff fed them. evidence showing its utility under other circumstances, for In light of this heterogeneity and taking as a reference example with irradiation of lymph nodes [6] or the chest the American Society for Radiation Oncology (ASTRO) consensus guidelines on hypofractionation for breast cancer [12], we decided to launch a consensus-building process to * Javier Sanz jsanz@psmar.cat establish recommendations for this breast cancer treatment in our region. Greater knowledge of the real indications and Extended author information available on the last page of the article 13 Vol:.(1234567890) Clinical and Translational Oncology (2022) 24:1580–1587 1581 agreement among professionals should lead to an expan- were radiation oncologists specialising in breast cancer and sion of its use as a standard indication in Catalonia, pro- working in the 10 public treatment centres in Catalonia; mote equitable access, reduce differences between public experts in evidence-based medicine, project management healthcare services, and improve patients’ quality of life by and biostatistics; collaborators with experience in searching avoiding the need for unnecessary travel and its associated and managing bibliographic databases; and managers and inconveniences. This study describes the methods used to administrators involved in breast cancer treatment (heads of reach a consensus as well as the resulting recommendations services, plus the Director of the Catalonian Cancer Plan) as they compare to the ASTRO guidelines [12]. (Fig. 1). Altogether, a total of 26 professionals were invited to join the working group, and all accepted. A steering committee of four members was created, Materials and methods bringing together professionals with responsibilities in clini- cal and technical leadership as well as project management Process and monitoring. Its functions were to define the objectives of the guidelines and the criteria for the bibliographic review; In 2018, the Catalonian Cancer Plan approved the pro- formulate the final clinical questions; synthesise and evalu- cess to develop consensus-based guidelines on the use of ate the evidence; and draft the final document. hypofractionation for breast cancer. Work began in Febru- In May 2018, the first in-person meeting of the consen- ary 2018 and ended in May 2019, and consisted of three sus-building process took place. Fourteen questions were phases: (a) creation of a working group and systematic selected to answer the main controversial issues. The 14 review of the evidence; (b) consideration of the levels of survey questions were approved, and the most current lit- evidence and consensus on the formulation of survey ques- erature was reviewed. The questions were then subjected to tions; and (c) performance of the survey and development an independent vote among all experts of the working group. of consensus-based recommendations. Main invited experts The vote was conducted online to avoid any influence from Fig. 1  Participating centres and number of surveyed experts 13 1582 Clinical and Translational Oncology (2022) 24:1580–1587 other experts of the group and enable a response after col- lating all the information. In January 2019, the draft recommendations were pre- sented to the working group during a second physical meet- ing to reach a final consensus among all the experts. The information gathered and the collective responses from the group were presented for each question, one by one, and the discrepancies and justifications were considered in turn. The recommendations were then drafted by consensus, and the direction and strength of each were finalised by May 2019. The methodological process is shown in Fig. 2. Literature review The consensus-based guidelines were informed by an initial Fig. 3  Results of the bibliographic search systematic literature review of records published in English between 1 January 2004 and 30 January 2019 and indexed in MEDLINE (PubMed). The primary search terms used were and the American Society for Clinical Oncology (ASCO) “hypofractionated”, “radiotherapy” and “breast neoplasm”. for their recommendations on hypofractionation in breast The selection criteria for inclusion were randomised and prostate cancer [12, 15]. controlled trials (RCTs), meta-analyses of RCTs, and pro- The recommendations were classified as strong or con- spective observational studies that involved more than 100 ditional, according not only to the quality of evidence, but participants. The intervention under assessment was hypo- also to other factors like the risk–benefit trade-off, the val- fractionated external beam radiotherapy for early or locally ues and preference of patients and professionals, and the advanced breast cancer, regardless of lymph node irradiation costs and resources involved. The members of the working or additional boost. The outcomes of interest were control of group completed the survey by marking their agreement in breast cancer (disease-free survival, cancer-specific survival, the items on a scale of 0 to 10, with higher scores indicat- and overall survival) and acute and late toxicity. The bib- ing stronger agreement. liographic search yielded 141 records. After screening the A strong recommendation indicates that the work- abstracts, 31 full-text records were evaluated, all of which ing group concluded that the benefits of the intervention fulfilled the established selection criteria (Fig. 3). clearly outweighed the harms (or vice versa), and that ‘all or almost all of informed professionals would follow the Level of evidence, recommendations, recommendation. Conditional recommendations were and consensus‑building methodology made when the risks and benefits were similar or uncer- tain. According to our assessment scale, scores of 8 or The GRADE system was applied to classify the quality of above were considered a strong endorsement. the body of evidence and the strength of the recommenda- The quality of evidence for each recommendation tions [13, 14], in line with the approach used by ASTRO was initially deemed high or low using ASTRO’s criteria Fig. 2  Methodology for the consensus-building process 13 Clinical and Translational Oncology (2022) 24:1580–1587 1583 [12] and Balsheim’s grades of evidence [14], according Our results are comparable to the ASTRO guidelines [12] to whether the evidence was generated in experimental or in terms of the final recommendations and the quality of observational studies. Other considerations were then taken evidence supporting them. However, there were some dif- into account to finalise the level of evidence as high, moder- ferences in the level of consensus achieved, for example in ate, or low (Table 1). patients under the age of 40 years: compared to ASTRO consensus, the agreement on the use of hypofractionation • High: We are confident that the true effect is similar to in these cases was 93%, compared to 63% in our analysis. the estimated effect. These differences are probably due to our classification of • Moderate: We believe that the true effect is probably patient age into three brackets: less than 40 years, 40 to close to the estimated effect but substantially difference 50 years, and more than 50 years. also is possible. Unlike the ASTRO guidelines, we included questions • Low: We have limited confidence in the estimated effect: about hypofractionation in patients receiving a mastectomy the true effect might be markedly different from the esti- or who required irradiation of the lymph node chain. For mated effect. these indications, the degree of consensus was low at 64% and 59%, respectively, in consonance with the low quality of evidence. In addition, experts’ opinions were integrated in the pro- cess using ASCO’s modified Delphi approach [16], produc- ing a percentage of consensus among the working group. Discussion Members took an online survey, registering their level of agreement on a scale of 0 to 10. The pre-defined cutoff for Despite the growing evidence of the association between consensus was 80%. hypofractionated treatment and improved clinical and care Results were compared to the ASTRO recommendations quality for patients with breast cancer, the direct translation also considering quality of evidence and the consensus to clinical practice has been limited. The possible reasons for reached. this lag are numerous and range from missed opportunities following positive results from clinical trials, to knowledge gaps and uncertainty, controversies, irrelevant or conflicting evidence, and vested or conflicting interests [28]. The con- Results siderable volume of scientific publications makes it difficult to attain deep knowledge based on the analysis of available All the invited centres participated in every meeting held, evidence; rather, this is often synthesised at an individual all controversial issues were discussed and finally answered level. to the corresponding questionnaires submitted. Uptake of hypofractionation has been slow for breast With regard to the 14 questions considered, these are cancer in public hospitals in Catalonia, with considerable detailed in Table 2, along with the level of evidence, degree variability in clinical practice, as reported by Prades et al. of consensus, and strength of the recommendation. [11]. This delay in the translation of evidence to practice Table 1  American Society for Clinical Oncology (ASCO) criteria for assessing the quality of evidence Rating Quality criteria Definition High - ≥ 2 well-conducted RCTs with generalisable results or meta- It is very likely that the true effect is close to the estimated effect, analysis of these trials based on the body of evidence Moderate - 1 well-conducted, generalisable RCT or meta-analysis of trials; It is likely that the true effect is close to the estimated effect, based or on the body of evidence, but it is possible that it is substantially - ≥ 2 RCTs with some limitations or lack of generalisability; or different - ≥ 2 well-conducted observational studies with consistent results Low - 1 RCT with some limitations or lack of generalisability; or The true effect may be substantially different from the estimated - ≥ 1 RCTs with serious shortcomings, lack of generalisability, effect. There is a risk that future research may significantly alter or extremely small sample sizes; or the estimated size of effect or the interpretation of the results - ≥ 2 observational studies with inconsistent findings, small sample sizes, or other problems that may cloud the interpreta- tion of data RCT​randomised controlled trial 13 1584 Clinical and Translational Oncology (2022) 24:1580–1587 Table 2  Indications on the use of hypofractionated radiation therapy for breast cancer in Catalonia, with consensus-based recommendations (> 80% agreement among working group members) marked with an asterisk 1. Hypofractionation is indicated in patients who have undergone breast-conserving surgery, regardless of tumour size* Recommendation: strong Justification RCTs have shown hypofractionated treatment to be effec- Quality of evidence: high tive in tumours of up to 5 cm in diameter, so it is indicated following Degree of consensus: 95% breast-conserving treatment in T1–T2 tumours [1, 2] 2. Hypofractionation is indicated in patients who have undergone breast-conserving surgery, including in women with nuclear grade 3 tumours* Recommendation: strong Justification RCTs have not found any unfavourable effects associated Quality of evidence: high with a high nuclear grade. In one trial, a second pathological review Degree of consensus: 98% confirmed this issue [17, 18]. This could be related to the different pathological grading methodology applied by pathologists [19] 3. Hypofractionation is indicated in patients who have undergone breast-conserving surgery, independently of molecular subtype* Recommendation: strong Justification In some included RCTs, molecular subtypes were not Quality of evidence: moderate differentiated, or some were poorly represented, so the quality of the Degree of consensus: 97% available evidence on the equivalence of hypofractionated treatment is not high. Despite the data showing good local tumour control, this tends to be lower for luminal B and basal molecular subtypes [17] 4. Hypofractionation is indicated in patients who have undergone breast-conserving surgery, independently of the laterality of the breast requir- ing treatment* Recommendation: strong Justification Although RCTs have not stratified their results by lateral- Quality of evidence: high ity, indirectly it can be inferred that there are no differences in the Degree of consensus: 99% fractionation scheme nor greater toxicity per dose in critical organs, or greater toxicity on the left side. Also, non-randomised trials with long follow-up have not found differences according to the side affected by the tumour [1, 2] 5. Hypofractionation is indicated in patients who have undergone breast-conserving surgery, independently of whether they receive neoadju- vant chemotherapy* Recommendation: strong Justification Hypofractionation studies included patients receiving adju- Quality of evidence: low vant chemotherapy, with no unfavourable impact. Thus, the consensus Degree of consensus: 89% of the working group was that this intervention was safe in patients receiving primary systemic treatment with chemotherapy, targeted therapy, or hormone therapy [19] 6. Hypofractionation is indicated in patients who have undergone breast-conserving surgery, independently of whether they receive adjuvant chemotherapy* Recommendation: strong Justification Although adjuvant chemotherapy was used in only 11% to Quality of evidence: high 36% of participants in RCTs, Shaikh’s meta-analysis shows the safety Degree of consensus: 95% of this treatment in hypofractionated patients [8] 7. Hypofractionation is indicated in patients who have undergone breast-conserving surgery and whose age is 40 to 50 years* Recommendation: strong Justification There is enough evidence to support hypofractionated Quality of evidence: high treatment in patients of all ages [1, 2] Degree of consensus: 88% 8. Hypofractionation is indicated in patients who have undergone breast-conserving surgery and whose age is less than 40 years Recommendation: conditional Justification There is sufficient evidence to support hypofractionated Quality of evidence: moderate treatment in patients regardless of age, even though the proportion of Degree of consensus: 63% younger women in trials is lower; moreover, evidence indicates that younger patients show better tolerance to hypofractionated treatment [21] 9. Hypofractionation is indicated in patients who have undergone breast-conserving surgery, including for histology that is exclusively carci- noma in situ Recommendation: conditional Justification Despite the low quality of evidence, the same criteria were Quality of evidence: low applied to hypofractionated radiotherapy for pure carcinoma in situ Degree of consensus: 72% as to invasive tumours, pending results from an ongoing RCT (RTOG 9804) that specifically assesses this question [20] 10. Hypofractionation is indicated in patients who have undergone breast-conserving surgery, regardless of the size of the breast* Recommendation: strong Justification State-of-the-art technologies allow a greater homogeneity Quality of evidence: high of the dose, so increasing the dose per fraction would imply that the Degree of consensus: 95% size of the breast is irrelevant [22–24] 13 Clinical and Translational Oncology (2022) 24:1580–1587 1585 Table 2  (continued) 11. Hypofractionation is indicated in patients who have undergone radical treatment and mastectomy Recommendation: conditional Justification Only one RCT has included patients who underwent mas- Quality of evidence: moderate tectomy showing that hypofractionation was not inferior in efficacy Degree of consensus: 64% and had similar toxicities, so the level of evidence cannot be consid- ered high [25], and the degree of consensus was low 12. Hypofractionation is indicated in patients receiving surgery for breast cancer who require nodal irradiation due to the involvement of lymph nodes Recommendation: conditional Justification Given the lack of evidence, further studies are needed Quality of evidence: low to specifically analyse the safety of regional lymph node irradiation Degree of consensus: 59% using hypofractionated schemes, as evidence only exists for irradiation of the lower axilla, not for an intentional target volume encompassing the axillary region [26]. For this reason, the level of consensus was low 13. Hypofractionation is indicated in patients who have undergone breast-conserving surgery and have an indication for a tumour bed boost* Recommendation: strong Justification RCTs included a tumour bed boost following hypofraction- Quality of evidence: high ated treatment of the breast when indicated confirming the safety of Degree of consensus: 97% this modality [2] 14. Hypofractionation of the tumour bed boost is indicated in patients receiving breast-conserving surgery for breast cancer* Recommendation: strong Justification The boost can be performed with standard or hypofrac- Quality of evidence: low tionation (14–16 Gy to 2 Gy or 10–12.5 Gy to 2.5 Gy). The level of Degree of consensus: 94% consensus was high because the use of 2.5 Gy per fraction has already been considered [27] RCT​randomised controlled trial has also been observed by other authors, for example Gilbo breast-conserving surgery for invasive breast carcinoma et al. [29], who observed an improvement in utilisation rates and without nodal irradiation. The use of hypofractiona- from 49 to 80% in the 4 years following dissemination of tion schemes in these cases is recommended regardless of the ASTRO guidelines, implementation of clinical practice other tumour characteristics, like size, histological grade, directives, and follow-up through departmental discussions or molecular subtype; patient characteristics such as size or about clinical indications. As Recht commented in an edito- laterality of the breast; or treatment characteristics, including rial [30], the use of hypofractionation will only reach recom- neoadjuvant or adjuvant chemotherapy, or need for a boost. mended levels if specialists are engaged and adherence to The degree of agreement did not meet our 80% cutoff guidelines is monitored. for consensus in cases where available evidence was insuf- Underpinning this perspective is the assumption that the ficient at the time of the review, that is, hypofractionation adoption of healthcare innovations (including process-based in patients younger than 40 years, receiving mastectomy, innovations like hypofractionation) depends to some extent requiring irradiation of the lymph nodes, and with ductal on how they are communicated and disseminated, not only carcinoma in situ. However, over half of the experts sup- on the quality of evidence that supports them. To that end, ported hypofractionation in all these situations. the work described in the present paper followed a consen- Overall, our results are quite similar to the consensus sus-based methodology that incorporates direct knowledge reached by ASTRO [12] and reflected on the guidelines, related to clinical practice into the scientific debate. The despite the consideration of the age grouping in our survey involvement of 11 clinical departments in an open research and the inclusion of questions about the use of hypofrac- and deliberation process converged in a shared vision about tionation in mastectomized patients or in whom node irra- the use of hypofractionation, both where a high level of diation is indicated. scientific evidence supports its use and where the strength Future lines of work, following the application of the of the evidence is more limited. Following the literature consensus-based recommendations, will include an analysis review and the pooling of knowledge among experts with of whether these contribute to changing the use of hypofrac- regard to the consensus-based recommendations on the use tionation in breast cancer, standardising practice across the of hypofractionation in breast cancer, it is significant that network of Catalan public hospitals. We will also analyse the 10 of the 14 questions posed yielded full agreement about use of hypofractionation where it is more controversial, for the intervention. According our results, hypofractionation example in cases of immediate reconstruction with prosthe- is appropriate in all patients aged 40 years or more with an sis or autologous graft, concomitant hypofractionated boost indication for adjuvant external beam radiotherapy following 13 1586 Clinical and Translational Oncology (2022) 24:1580–1587 following intraoperative radiotherapy, or in the presence of (Frequently Asked Questions) and facts. Breast. 2014;23:299– autoimmune diseases. 309. https://​doi.​org/​10.​1016/j.​breast.​2014.​01.​011. 6. Leong N, Truong PT, Tankel K, Kwan W, Weir L, Olivotto IA. Hypofractionated nodal radiation therapy for breast cancer was not associated with increased patient-reported arm or brachial plexop- Funding Open Access funding provided thanks to the CRUE-CSIC athy symptoms. Int J Radiat Oncol Biol Phys. 2017;99:1166–72. agreement with Springer Nature. https://​doi.​org/​10.​1016/j.​ijrobp.​2017.​07.​043. 7. Khan AJ, Poppe MM, Goyal S, Kokeny KE, Kearney T, Kirstein Declarations L, et al. Hypofractionated postmastectomy radiation therapy is safe and effective: first results from a prospective phase II trial. J Clin Oncol. 2017. https://​doi.​org/​10.​1200/​JCO.​2016.​70.​7158. Conflict of Interest None of the authors declare any conflict of inter- 8. Shaikh F, Chew J, Hochman T, Purswani J, Maisonet O, Peat E, ests. et al. Hypofractionated whole-breast irradiation in women less than 50 years old treated on 4 prospective protocols. Int J Radiat Ethics approval Not applicable. Oncol Biol Phys. 2018;101:1159–67. https://​doi.​org/​10.​1016/j.​ ijrobp.​2018.​04.​034. Consent to participate Not applicable. 9. Chan S, Sutradhar R, Yao Z, Chow E, Lee J, Wan BA, et al. Frac- tionation in adjuvant radiotherapy for invasive breast cancer and Consent for publication All authors consent to publish the present ductal carcinoma in situ in Ontario, Canada from 2009 to 2015. work. Breast J. 2020;26:602–16. https://​doi.​org/​10.​1111/​tbj.​13515. 10. Ong WL, Millar JL, Foroudi F, Khor R. Are we choosing Avalability of data and material Not applicable. wisely?—pattern of hypofractionated radiation therapy use for early breast cancer in Victoria, Australia from 2012 to 2017. Int Code availability Not applicable. J Radiat Oncol. 2019;105:E30. https://​doi.​org/​10.​1016/j.​ijrobp.​ 2019.​06.​684. Open Access This article is licensed under a Creative Commons Attri- 11. Prades J, Algara M, Espinàs JA, Farrús B, Arenas M, Reyes V, bution 4.0 International License, which permits use, sharing, adapta- et al. Understanding variations in the use of hypofractionated radi- tion, distribution and reproduction in any medium or format, as long otherapy and its specific indications for breast cancer: a mixed- as you give appropriate credit to the original author(s) and the source, methods study. Radiother Oncol. 2017;123:22–8. https://​doi.​org/​ provide a link to the Creative Commons licence, and indicate if changes 10.​1016/j.​radonc.​2017.​01.​014. were made. The images or other third party material in this article are 12. Smith BD, Bellon JR, Blitzblau R, Freedman G, Haffty B, hahn included in the article's Creative Commons licence, unless indicated C, et al. Radiation therapy for the whole breast: Executive sum- otherwise in a credit line to the material. If material is not included in mary of an American Society for Radiation Oncology (ASTRO) the article's Creative Commons licence and your intended use is not evidence-based guideline. Pract Radiat Oncol. 2018;8:145–52. permitted by statutory regulation or exceeds the permitted use, you will https://​doi.​org/​10.​1016/j.​prro.​2018.​01.​012. need to obtain permission directly from the copyright holder. To view a 13. Andrews J, Guyatt G, Oxman AD, Alderson P, Dahm P, Falck- copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. Ytter Y, et al. GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recom- mendations. J Clin Epidemiol. 2013;66:719–25. https://​doi.​org/​ 10.​1016/j.​jclin​epi.​2012.​03.​013. 14. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz References R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:401–6. https://​doi.​org/​10.​ 1. Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, 1016/j.​jclin​epi.​2010.​07.​015. Parpia S, et al. Long-term results of hypofractionated radia- 15. Morgan SC, Hoffman K, Loblaw DA, Buyyounouski MK, Pat- tion therapy for breast cancer. N Engl J Med. 2010;362:513–20. ton C, Barocas D, et al. Hypofractionated radiation therapy for https://​doi.​org/​10.​1056/​NEJMo​a0906​260. localized prostate cancer: executive summary of an ASTRO, 2. Yarnold J. Changes in radiotherapy fractionation—breast cancer. ASCO, and AUA evidence-based guideline. Pract Radiat Oncol. Br J Radiol. 2018. https://​doi.​org/​10.​1259/​bjr.​20170​849. 2018;8:354–60. https://​doi.​org/​10.​1016/j.​prro.​2018.​08.​002. 3. Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett- 16. Loblaw DA, Prestrud AA, Somerfield MR, Oliver TK, Brouwers Lee PJ, et al. The UK Standardisation of Breast Radiotherapy MC, Nam RK, et al. American Society of Clinical Oncology clini- (START) trials of radiotherapy hypofractionation for treatment of cal practice guidelines: formal systematic review-based consensus early breast cancer: 10-year follow-up results of two randomised methodology. J Clin Oncol. 2012;30:3136–40. https://​doi.​org/​10.​ controlled trials. Lancet Oncol. 2013;14:1086–94. https://d​ oi.o​ rg/​ 1200/​JCO.​2012.​42.​0489. 10.​1016/​S1470-​2045(13)​70386-3. 17. Bane AL, Whelan TJ, Pond GR, Parpia S, Gohla G, Fyles AW, 4. Society A, Oncology R. American Society for Radiation Oncol- et al. Tumor factors predictive of response to hypofractionated ogy Ten Things Physicians and Patients Should Question Don’t radiotherapy in a randomized trial following breast conserving initiate whole breast radiotherapy as a part of breast conservation therapy. Ann Oncol. 2014;25:992–8. https://​doi.​org/​10.​1093/​ American Society for Radiation Oncology ten things physicians annonc/​mdu090. and patients should question. 2018;2013:23–6. https://w ​ ww.c​ hoos​ 18. Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, ingwi​sely.​org/​wp-​conte​nt/​uploa​ds/​2015/​02/​ASTRO-​Choos​ing-​ Eusebi V, et al. Breast cancer prognostic classification in the Wisely-​List.​pdf. molecular era: the role of histological grade. Breast Cancer Res. 5. Montero A, Sanz X, Hernanz R, Cabrera D, Arenas M, Bayo E, 2010;12(12):207. https://​doi.​org/​10.​1186/​bcr26​07. et al. Accelerated hypofractionated breast radiotherapy: FAQs 19. Diwanji TP, Molitoris JK, Chhabra AM, Snider JW, Bentzen SM, Tkaczuk KH, et al. Utilization of hypofractionated whole- breast radiation therapy in patients receiving chemotherapy: a 13 Clinical and Translational Oncology (2022) 24:1580–1587 1587 National Cancer Database analysis. Breast Cancer Res Treat. Oncol. 2019;20:352–60. https://​doi.​org/​10.​1016/​S1470-​2045(18)​ 2017;165:445–53. https://​doi.​org/​10.​1007/​s10549-​017-​4345-y. 30813-1. 20. McCormick B, Winter K, Hudis C, Kuerer HM, Rakovitch E, 26. Bellefqih S, Elmajjaoui S, Aarab J, Khalil J, Afif M, Lachgar Smith BL, et al. RTOG 9804: a prospective randomized trial for A, et al. Hypofractionated regional nodal irradiation for women good-risk ductal carcinoma in situ comparing radiotherapy with with node-positive breast cancer. Int J Radiat Oncol Biol Phys. observation. J Clin Oncol. 2015;33:709–15. https://​doi.​org/​10.​ 2017;97:563–70. https://​doi.​org/​10.​1016/j.​ijrobp.​2016.​11.​010. 1200/​JCO.​2014.​57.​9029. 27. Palumbo I, Mariucci C, Falcinelli L, Perrucci E, Lancellotta V, 21. Meattini I, Lambertini M, Desideri I, De Caluwé A, Kaidar-Per- Podlesko AM, et al. Hypofractionated whole breast radiotherapy son O, Livi L. Radiation therapy for young women with early with or without hypofractionated boost in early stage breast cancer breast cancer: current state of the art. Crit Rev Oncol Hematol. patients: a mono-institutional analysis of skin and subcutaneous 2019;137:143–53. https://​doi.​org/​10.​1016/j.​critr​evonc.​2019.​02.​ toxicity. Breast Cancer. 2019;26:290–304. https://d​ oi.o​ rg/1​ 0.1​ 007/​ 014. s12282-​018-​0923-z. 22. Hannan R, Thompson RF, Chen Y, Bernstein K, Kabarriti 28. Andermann A, Pang T, Newton JN, Davis A, Panisset U. Evidence R, Skinner W, et al. Hypofractionated whole-breast radiation for Health II: overcoming barriers to using evidence in policy and therapy: does breast size matter? Int J Radiat Oncol Biol Phys. practice. Health Res Policy Syst. 2016;14:17. https://​doi.​org/​10.​ 2012;84:894–901. https://​doi.​org/​10.​1016/j.​ijrobp.​2012.​01.​093. 1186/​s12961-​016-​0086-3. 23. Patel AK, Ling DC, Richman AH, Champ CE, Huq MS, Heron 29. Gilbo P, Potters L, Lee L. Implementation and utilization of hypo- DE, et al. Hypofractionated whole-breast irradiation in large- fractionation for breast cancer. Adv Radiat Oncol. 2018;3:265–70. breasted women—is there a dosimetric predictor for acute skin https://​doi.​org/​10.​1016/j.​adro.​2018.​04.​001. toxicities? Int J Radiat Oncol Biol Phys. 2019;103:71–7. https://​ 30. Recht A. Breast cancer fractionation patterns: why aren’t they doi.​org/​10.​1016/j.​ijrobp.​2018.​08.​024. uniform, and should they be? Breast J. 2020;26:599–601. https://​ 24. Ratosa I, Jenko A, Oblak I. Breast size impact on adjuvant radio- doi.​org/​10.​1111/​tbj.​13578. therapy adverse effects and dose parameters in treatment plan- ning. Radiol Oncol. 2018;52:233–44. https://​doi.​org/​10.​2478/​ Publisher's Note Springer Nature remains neutral with regard to raon-​2018-​0026. jurisdictional claims in published maps and institutional affiliations. 25. Wang SL, Fang H, Song YW, Wang WH, Hu C, Liu YP, et al. Hypofractionated versus conventional fractionated postmas- tectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial. Lancet Authors and Affiliations Arantxa Eraso1 · Javier Sanz2 · Meritxell Mollà3 · Vicky Reyes4 · Agustí Pedro5 · Meritxell Arenas6 · Evelyn Martinez7 · Rosa Ballester8 · Maria José Cambra9 · Virginia García10 · Joan Lluis Prades11 · Josep M. Borras11 · Manuel Algara2 1 7 Radiation Oncology Department, Institut Català d’Oncologia Radiation Oncology Department, Institut Català d’Oncologia, Girona, Avda de França,0, 17007 Girona, Spain Hospital Duran i Reynals, Avda Gran Via de l’Hospitalet, 2 199‑203, 08908 L’Hospitalet de Llobregat, Spain Radiation Oncology Department, Hospital del Mar, Edifici B, 8 ‑2. C/ del Gas s/n, 08003 Barcelona, Spain Radiation Oncology Department, Institut Català d’Oncologia 3 Badalona, Carretera del Canyet s/n, 08916 Badalona, Spain Radiation Oncology Department, Hospital Clínic de 9 Barcelona, C/ Villarroel 170, 08036 Barcelona, Spain Radiation Oncology Deparment, Hospital General de 4 Catalunya, C/ Pere i Pons 1, 08190 Sant Cugat del Vallés, Radiation Oncology Department, Hospital Universitari Vall Spain d’Hebron, Pass. de la Vall d’Hebron 119, 08035 Barcelona, 10 Spain Radiation Oncology Departement, Hospital Universitari 5 Arnau de Vilanova, Av. Alcalde Rovira Roure, 80, Radiation Oncology Department, Hospital de la Santa Creu i 25198 Lleida, Spain Sant Pau, C/ Sant Antoni Maria Claret 167, 08025 Barcelona, 11 Spain Pla Director d’Oncologia de Catalunya, Institut Català 6 d’Oncologia, Hospital Duran i Reynals, Avda Gran Via de Radiation Oncology Department, Hospital Universitari Sant l’Hospitalet, 199‑203, 08908 L’Hospitalet de Llobregat, Joan de Reus, Avda Doctor Josep Laporte 2, 43204 Reus, Spain Spain 13