Hypofractionated radiotherapy with concomitant boost for breast cancer: a dose escalation study.

BJR Received: 13 February 2018 © 2019 The Authors. Published by the British Institute of Radiology Revised: 04 October 2018 Accepted: 02 November 2018 https://doi.org/10.1259/bjr.20180169 Cite this article as: Ippolito E, Rinaldi CG, Silipigni S, Greco C, Fiore M, Sicilia A, et al. Hypofractionated radiotherapy with concomitant boost for breast cancer: a dose escalation study. Br J Radiol 2019; 92: 20180169. Full Paper Hypofractionated radiotherapy with concomitant boost for breast cancer: a dose escalation study Edy Ippolito, MD, Carla Germana Rinaldi, MD, Sonia Silipigni, MD, Carlo Greco, MD, Michele Fiore, MD, Antonella Sicilia, MD, Lucio Trodella, MD, Rolando Maria D’Angelillo, MD and Sara Ramella, MD Radiotherapy Unit, Campus Bio-Medico University, Rome, Italy Address correspondence to: Dr Carla Germana Rinaldi E-mail: Edy Ippolito and Carla Germana Rinaldi have contributed equally to this study and should be considered as co-first authors. Objective: To test the maximum tolerated dose (MTD) of a concomitant boost to the tumour bed for patients at high risk of recurrence treated with whole breast radiotherapy (RT). Methods: Patients with breast cancer with pathological stage pT1-2 and at least one risk factor for local recurrence such as N1 disease, lymphovascular invasion, extensive intraductal component, close margins, non-hormone sensitive disease, grading G3 were enrolled. Patients were treated with hypofractionated RT to whole breast with a dose of 40.05 Gy in 15 fractions. The dose was escalated to the tumour bed through a daily concomitant boost technique at three dose levels: 48 Gy (3.2 Gy/die), 50.25 Gy(3.35 Gy/die) and 52.5 Gy (3.5 Gy/die). Dose escalation to a higher step was carried out if all patients of the lower dose had completed the treatment without dose limiting toxicity (DLT). Skin toxicity, cosmetic evaluation and quality of life was evaluated at baseline, at treatment end and at 3 and 12 months after RT end. Results: Three patients for each dose level were enrolled. No DLT occurred. The maximum toxicity collected during RT was G2 skin toxicity in 3 (33.3%) patients, one for each dose level. No G2 toxicity at 3 and 12 months was collected. At median follow up of 21.8 months (range: 13.5 – 40.9 months), no G2 late toxicity was recorded. Conclusion: The 3 week course of post-operative RT with dose escalation to the tumour bed to 52.5 Gy has been achieved without dose limiting toxicities and can be tested in Phase II trials. Advances in knowledge: In our study, we tested the highest dose level to the tumour bed ever reported in studies using accelerated hypofractionation with concomitant boost in high risk patients. Introduction Radiotherapy (RT) after breast-conserving surgery is a standard alternative to mastectomy for most patients with Stage I and II invasive breast cancer.1 Post-lumpectomy whole breast irradiation (WBI) is now associated with control rates of 90–95%2,3 and improved overall survival.1 A boost dose to the tumour bed has shown to further reduce the rate of local failure, even if without having an impact on survival.4 Notwithstanding the benefits of RT, 15–20% of females treated with breast-conserving surgery do not undergo adjuvant treatment5 due to the duration of conventional RT to the whole breast. of post-operative RT with economic and logistic advantages for radiotherapy departments. Hypofractionation, or delivery of greater than standard 1.8–2 Gy fraction sizes per day is a method for shortening overall treatment time in breast cancer and improving patients’ compliance thereby leading to a greater utilization Moreover, given that breast cancer cells are more sensitive to the effects of fraction size with a α/β ratio of 4 Gy, the use of hypofractionation may be more effective than standard schedule. As a consequence of the larger fraction sizes used, total dose should be lowered to reduce normal tissue late toxicity.6 Four prospective randomized clinical trials have shown good results with hypofractionated schedules for WBI.7–10 With 5–10 year follow-up, there has been similar in-breast local control between the hypofractionated and standard fractionated arms. In these studies, the role of the boost dose to tumour bed was not addressed. In fact, in the Canadian trial no patient received a boost, while in the other Ippolito et al BJR three randomized trials an additional dose to tumour bed was delivered sequentially to only a percentage of patients (42–75%). Consequently, there is a lack of consistent data on how to integrate tumour bed boost to a hypofractionated regimen, and the ASTRO guidelines recommended sequential boost when hypofractionated WBI is delivered.11 Nevertheless, a radiation boost may be indicated in order to improve local control after whole-breast irradiation especially in subgroups of patients at greater risk of local failure after breast-conserving surgery and radiation therapy. Recognized clinical and pathological risk factors are: young age,12 close or positive margins,13 presence of an extensive intraductal component, absence of estrogen receptors14 and lymphovascular invasion (LVI).15 Some molecular subtypes are also associated with a higher rate of local failure.16 In these settings, a tumour bed dose escalation trial is justified by using an integrated boost to limit radiation induced side-effects. Based on the above considerations, the primary objective of this study is to test the maximum tolerated dose (MTD) of a concomitant boost to the tumour bed for patients at high risk of recurrence after having been treated with whole breast radiotherapy. The secondary objective is to evaluate the acute and late toxicity related to the treatment, the cosmetic result recorded by appropriate scales, as well as the quality of life (QoL) reported by patients. Methods and materials Eligibility Patients with histologically proven breast cancer who have undergone conservative surgery with a pathological Stage I–II and the presence of at least three inserted clips were considered eligible. Moreover, all females enrolled should have had at least one of the following factors associated with an increased risk of local recurrence: N1 disease, LVI, extensive intraductal component, close margins (<2 mm), non-hormone-sensitive disease, grading 3. Patients had to be older than 18 years, with at least 5 years of life expectancy, with an ECOG performance status <2 and adequate bone marrow (haemoglobin concentration >8 g dl−1, white blood cell count >3000 mm–3, platelet count >75,000). Patients with previous radiation treatment to the thorax, bilateral breast cancer, neoadjuvant chemotherapy, collagen diseases, pregnant or breast-feeding and male sex were excluded from the study. The Ethics Committee of Campus Biomedico University approved the protocol. Written informed consent was obtained from each patient. Radiotherapy technique For setup, patients were positioned in the supine position on a breast-bo (...truncated)