Phase II trial of hypofractionated VMAT-based treatment for early stage breast cancer: 2-year toxicity and clinical results

De Rose et al. Radiation Oncology (2016) 11:120 DOI 10.1186/s13014-016-0701-z RESEARCH Open Access Phase II trial of hypofractionated VMAT-based treatment for early stage breast cancer: 2-year toxicity and clinical results Fiorenza De Rose1, Antonella Fogliata1*, Davide Franceschini1, Piera Navarria1, Elisa Villa1, Cristina Iftode1, Giuseppe D’Agostino1, Luca Cozzi1,2, Francesca Lobefalo1, Pietro Mancosu1, Stefano Tomatis1 and Marta Scorsetti1,2 Abstract Background: To report toxicity and early clinical outcomes of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery. Methods: Patients presenting early-stage breast cancer were enrolled in a phase II trial. Eligibility criteria: age > 18 years old, invasive cancer or ductal carcinoma in situ (DCIS), Stage I-II (T < 3 cm and N ≤ 3), breast-conserving surgery without oncoplastic reconstruction. Any systemic therapy was allowed in neoadjuvant or adjuvant setting. All patients underwent VMAT-SIB technique to irradiate the whole breast and the tumor bed. Doses to whole breast and surgical bed were 40.5 Gy and 48 Gy, respectively, delivered in 15 fractions over 3 weeks. Acute and late skin toxicities were recorded. Cosmetic outcome was assessed as excellent/good or fair/poor. Results: The present study focused on results of a cohort of 144 patients with a minimum follow-up of 24 months (median 37, range 24–55 months). Median age was 62 years old (range 30–88). All patients had an invasive carcinoma (no patients with DCIS were present in this subset). At one year, the highest reported skin toxicity was G1, in 14 % of the patients; this data dropped to 4 % at the last follow-up, after more than 2 years. Breast pain was recorded in 21.6 % of the patients 6 months after treatment, while it was present in 3.5 % of the patients at the last follow-up, showing a significant improvement with time. Correlation between liponecrosis and boost target volume was found not significant. Breast pain was correlated with breast volume. No pulmonary or cardiological toxicities were recorded. After an early evaluation of clinical outcomes, only one case presented disease relapse, as liver metastases. Conclusions: The 3-week VMAT-SIB course as adjuvant treatment after breast-conserving surgery showed to be well tolerated and was associated with optimal local control. Long-term follow-up data are needed to assess late toxicity and clinical outcomes. Keywords: Breast cancer, Simultaneous integrated boost, Hypofractionation, Volumetric modulated arc therapy Background Incidence of early stage breast cancer increased in the last decade thanks to early diagnosis and screening programs. The treatment approach with breast conserving surgery (BCS) followed by whole-breast radiotherapy (WBRT) has been shown to be equivalent to mastectomy in terms of local control and survival [1–3]. Traditionally, * Correspondence: 1 Radiotherapy and Radiosurgery Department, Humanitas Research Hospital and Cancer Center, Milan-Rozzano, Italy Full list of author information is available at the end of the article conventional fractionation schedules for radiotherapy give 50 Gy in 2 or 1.8 Gy daily fractions, often with an additional sequential boost to the tumor bed, resulting in the overall treatment time (OTT) of 6–7 weeks [4]. Recently, there has been a shift in clinical studies toward the delivery of adjuvant radiotherapy using shorter treatment schedules. Clinical data showed that breast cancer might present α/β value around 4 Gy similar to the late-reacting healthy tissues, suggesting the possible benefit of hypofractionation in breast cancer treatment [5]. These radiobiological points [6] inspired phase III © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. De Rose et al. Radiation Oncology (2016) 11:120 randomized trials comparing standard schedule to different hypofractionated schemes using larger doses per treatment, resulting in shorter OTT. All published trials have used schedules involving 13 to 16 treatment sessions to the whole breast over 3 to 5 weeks, with more than 6500 patients enrolled. Ten-year data from these studies (Royal Marsden trial, Canadian trial, and the START A and B trials) demonstrated that hypofractionation is associated to equivalent or improved outcomes (both local and distant disease control), toxicity, cosmesis, and cost-effectiveness [7–11]. Moreover, shorter treatment time results also in greater patient convenience and resource efficiency. Consequently, in 2013, the American Society for Radiation Oncology (ASTRO) released a recommendation to strongly consider the use of shorter treatment schedules in the radiotherapy adjuvant treatment for women age ≥ 50 years old with early stage invasive breast cancer after BCS. This is one of the “Choosing Wisely” recommendations, as part of a campaign by the American Board of Internal Medicine Foundation to encourage the choice of evidence-based treatments (http://www.choosingwisely.org/clinician-lists/american-society-radiation-oncologywhole-breastradiotherapy/). Unfortunately, there are still open issues about the use of hypofractionated radiotherapy in early stage breast cancer. Groups most debated are as follows: young patients, patients with large breasts, patients undergoing chemotherapy (neoadjuvant or adjuvant). Another unsolved question is the association with sequential or concomitant boost [12]. As previously specified, ASTRO guidelines recommended hypofractionated radiotherapy only for patients older than 50 because of a greater risk of local recurrence and distant metastases in younger patients. Despite this recommendation, the Canadian trial confirmed the equivalence in efficacy to prevent local recurrence for both conventional and hypofractionated schemes among younger women, that represented the 25 % of the study population [7]. Moreover, the British agency NICE (National Institute for Health and Clinical Excellence) considers schedules of 50 Gy in 25 fractions or 40.05 Gy in 15 fractions as standard radiotherapy regardless of age at diagnosis [13]. As regards large breast patients, the possible dose heterogeneity associated with large breast volumes in a hypofractionation schedule could potentially worsen the cosmetic outcomes. At last, there are few consistent data concerning aesthetic results and skin toxicity in (...truncated)