Phase I-II study of hypofractionated simultaneous integrated boost using volumetric modulated arc therapy for adjuvant radiation therapy in breast cancer patients: a report of feasibility and early toxicity results in the first 50 treatments

Marta Scorsetti 0 Filippo Alongi 0 Antonella Fogliata 2 Sara Pentimalli 0 Pierina Navarria 0 Francesca Lobefalo 0 Carlos Garcia-Etienne 1 Alessandro Clivio 2 Luca Cozzi 2 Pietro Mancosu 0 Giorgia Nicolini 2 Eugenio Vanetti 2 Marco Eboli 1 Carlo Rossetti 1 Arianna Rubino 1 Andrea Sagona 1 Stefano Arcangeli 0 Wolfgang Gatzemeier 1 Giovanna Masci 4 Rosalba Torrisi 4 Alberto Testori 3 Marco Alloisio 3 Armando Santoro 4 Corrado Tinterri 1 0 Radiotherapy and radiosurgery, Humanitas Cancer Center, Istituto Clinico Humanitas , Rozzano, Milano , Italy 1 Breast Surgery, Humanitas Cancer Center, Istituto Clinico Humanitas , Rozzano, Milano , Italy 2 Oncology Institute of Southern Switzerland, Medical Physics Unit , Bellinzona , Switzerland 3 Thoracic Surgery, Humanitas Cancer Center, Istituto Clinico Humanitas , Rozzano, Milano , Italy 4 Medical Oncology, Humanitas Cancer Center, Istituto Clinico Humanitas , Rozzano, Milano , Italy Background: To report results in terms of feasibility and early toxicity of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery. Methods: Between September 2010 and May 2011, 50 consecutive patients presenting early-stage breast cancer were submitted to adjuvant radiotherapy with SIB-VMAT approach using RapidArc in our Institution (Istituto Clinico Humanitas ICH). Three out of 50 patients were irradiated bilaterally (53 tumours in 50 patients). All patients were enrolled in a phase I-II trial approved by the ICH ethical committee. All 50 patients enrolled in the study underwent VMAT-SIB technique to irradiate the whole breast with concomitant boost irradiation of 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. Skin toxicities were recorded during and after treatment according to RTOG acute radiation morbidity scoring criteria with a median follow-up of 12 months (range 8-16). Cosmetic outcomes were assessed as excellent/good or fair/ poor. Results: The median age of the population was 68 years (range 36-88). According to AJCC staging system, 38 breast lesions were classified as pT1, and 15 as pT2; 49 cases were assessed as N0 and 4 as N1. The maximum acute skin toxicity by the end of treatment was Grade 0 in 20/50 patients, Grade 1 in 32/50, Grade 2 in 0 and Grade 3 in 1/50 (one of the 3 cases of bilateral breast irradiation). No Grade 4 toxicities were observed. All Grade 1 toxicities had resolved within 3 weeks. No significant differences in cosmetic scores on baseline assessment vs. 3 months and 6 months after the treatment were observed: all patients were scored as excellent/good (50/50) compared with baseline; no fair/poor judgment was recorded. No other toxicities or local failures were recorded during follow-up. Conclusions: The 3-week course of postoperative radiation using VMAT with SIB showed to be feasible and was associated with acceptable acute skin toxicity profile. Long-term follow-up data are needed to assess late toxicity and clinical outcomes. - Background Breast-conserving surgery (BCS) with subsequent whole breast irradiation (WBI) is considered the standard of care for the majority of cases with early-stage breast carcinoma [1]. Mastectomy is reserved for patients ineligible for BCS due to clinical or technical surgical contraindications, or based on patients preference. Radiotherapy is delivered within 24 weeks after BCS, excluding patients receiving chemotherapy where radiotherapy starts usually within 34 weeks after the last cycle. Conventional radiotherapy after BCS is represented by WBI generally using two tangential fields for doses of 4550 Gy/ 1.82 Gy per fraction. A boost irradiation with electron or photon beams to deliver a total tumour bed dose of 6066 Gy is usually prescribed [2]. Although it is still not possible to definitively demonstrate the real radio sensitivity of breast cancer, the / of breast cancer is estimated to be around 4 [3]. This assumption suggests that hypofractionated regimens should be more effective than conventional fractionation. Moreover, to enforce the radiobiological rationale of hypofractionation in breast cancer is the shorter treatment time from 6 weeks to 3 weeks: the shorter the total treatment time, the lower the potential of repopulation of cancer cells, thus improving local control [3]. Starting from this radiobiological background, over the last 20 years, several randomized trials involving more than 7,000 women compared hypofractionated adjuvant radiotherapy to a standard regimen of 50 Gy in 25 fractions: START-A trial [4], START-B trial [5], RMH/GOC trial [6], ONTARIO trial [7]. Long-term results of these trials indicated similar rates of loco-regional relapse comparing the two radiation treatment arms. Evaluation of breast cosmesis at a median follow-up greater than 10 years was equivalent in both treatment arms [7]. It was largely confirmed that a 1316 fraction regimen delivered over 34 weeks is as safe and effective as 50 Gy in 25 fractions. However, there is limited evidence from prospective randomized trials about the tolerability and efficacy of the tumour bed boost after hypofractionated WBI [8]. RapidArcW (Varian, Palo Alto, California, USA) is a relatively recently introduced volumetric modulated arc therapy (VMAT) technique based on simultaneous optimisation of multi leaf collimator (MLC) shapes, dose rate and gantry rotation speed [9]. The technology was investigated in several studies on different sites [10-13], showing a general improvement in sparing of organs at risk and healthy tissue, comparable target coverage, reduced beam-on time and lower number of monitor units (MU) compared to other intensity modulated radiotherapy (IMRT) approaches. RapidArc was introduced in our clinical practice since October 2009. We present our clinical experience using VMAT for hypofractionated irradiation of the breast with simultaneous integrated boost (SIB) to the tumour bed. Methods Fifty patients presenting early-stage breast carcinoma were enrolled at Humanitas Cancer Center of the Istituto Clinico Humanitas (Rozzano-Milan, Italy) between September 2010 and May 2011, in an institutional phase I-II prospective non-randomized trial of adjuvant radiotherapy with simultaneous integrated boost (SIB) delivered with RapidArc technology. The study was approved by the internal ethical committee and patient consent was obtained. The study will include 200 patients with a maximum period of enrolment of 48 months and a total period of duration of 10 years of follow-up. Primary endpoint of the study is to evaluate the feasibility of VMAT and hypofractionation with simultaneous integrated boost in breast cancer patients at early stage and undergoing conservative surgery. The feasibility is estimated in terms of: a) respecting of dose coverage for target volumes; b) respecting of dose tolerance levels (...truncated)