Introduction

Background and Rationale {6a}

Breast Cancer Burden and role of Radiotherapy

Breast cancer is the commonest cancer occurring in Indian females and also the cause of the greatest degree of cancer-related mortality and disability amongst our population(1). Adjuvant radiation therapy reduces the ten-year Locoregional Recurrence Rates (LRR) from 35% to 19.6%. This advantage translates into an improved breast cancer survival (25.2% versus 21.4%) at fifteen years in patients undergoing breast conservation(2). A similar benefit is seen in patients who have undergone mastectomy (3).
Unfortunately, despite the important role that adjuvant radiotherapy plays in the management of breast cancer, access to radiotherapy is a limiting factor impacting control rates(4,5). It is known that access to radiotherapy impacts the type of surgery performed, and improving accessibility increases uptake of breast conservation therapy(6). One of the important methods by which access to scarce radiotherapy can be improved in resource-limited settings is by adopting a shorter hypofractionated course of radiotherapy where the radiation is delivered in higher daily doses (> 2 Gy) for a fewer number of fractions.

Radiobiological basis of Hypofractionation in Breast Cancers

Breast cancer is one of the few malignancies where the fraction sensitivity is high, which in turn implies that use of a higher dose per fraction is associated with lower cell survival. The “recovery exponent” for breast cancer was quite similar to that of the normal skin, making protracted fractionation ineffective in these tumours (7). Based on this data, a randomized trial investigating two experimental schedules of 13 fraction (39 Gy and 42.9 Gy) against the standard arm of 50 Gy in 25 fractions was completed at the Royal Marsden Hospital and Gloucestershire Oncology Center in 1998. The results of this trial were used to derive point estimates of the α/β ratio for both late normal tissue reactions (which ranged between 3 - 4 Gy)(8), as well as for tumour control (which was 4.1 Gy)(9). Subsequently when the results of the Canadian hypofractionation trial(10), and the two START trials(11) were combined it became apparent that the point estimate for the α/β ratio of tumour control was 3.5 (95% CI: 1.2 - 5.7)(11).

Hypofractionation in Breast Cancer

Following the results of the RMH / GOC trial(12), several subsequent trials investigated the role of hypofractionated radiotherapy with a dose reduction delivered over 3 weeks in breast cancers. A meta-analysis of these trials has shown that hypofractionated radiotherapy is similar to conventionally fractionated radiotherapy in terms of locoregional control, disease-free survival and overall survival(13). Additionally, it is associated with reduced acute toxicity and similar late toxicity. Taken together these trials have investigated more than 8000 women with breast cancers (12) and have established the safety of this approach.

Further Hypofractionation

While 3 weeks of radiation is a reduction in the total time, further hypofractionation is biologically plausible based on the fraction sensitivity of mammary carcinoma. Courdi et al had reported a case series of elderly unfit patients who underwent definitive radiotherapy with once-weekly hypofractionated radiotherapy of 6.5 Gy for 5 fractions followed by a boost of 6.5 Gy for 1 - 3 fractions to the tumour site along with endocrine therapy(14). They reported a 5-year local progression-free survival of 78%. Subsequently the UK FAST trial tested two 5 fractions weekly regimen of hypofractionated radiotherapy (28.5 Gy or 30 Gy) against the standard arm of 50 Gy(15). The acute toxicity results, as well as the results of the photographic assessment of breast appearance, showed that the regimen of 28.5 Gy was equivalent to 30 Gy. Locoregional control was similar in both arms, with no difference in cosmesis or late toxicity profile. Additional studies investigating the safety and efficacy of a once-weekly regimen have demonstrated similar results(16,17).
Based on the results of the FAST trial, and as there was a possibility of gain in the tumour control with a reduction in the overall treatment time, the FAST-FORWARD trial was designed to evaluate two schedules of 5 fraction radiotherapy delivered in 1 week against the standard arm of 15 fraction radiotherapy delivered in 3 weeks. The results of acute skin toxicity originating from this protocol have been reported. The regimen of 26 Gy delivered in 5 fractions is associated with a grade 3 RTOG toxicity of 5.8%, versus 13.6% for the control arm (18). None of the patients had a CTCAE grade 3 toxicity in either of the arms (18).

Simultaneous Integrated Boost (SIB)

An important contributor to the overall treatment time is the tumour bed boost in patients receiving adjuvant radiotherapy after breast conservation surgery. The results of the seminal European Organisation for Research and Treatment of Cancer (EORTC) trial have demonstrated that boost significantly improves the local control after breast conservation surgery(19).
We reviewed the published literature in Pubmed using the search terms SIB OR Simultaneous Integrated Boost OR SMART OR Concomitant Boost AND Breast cancer. 521 articles were found, of which 83 articles were found to be relevant. Ten of these studies are prospective trials, and medium to long-term outcomes have been reported for seven. These are summarized below.
Table of salient details of major prospective trials investigating simultaneous integrated boost in breast cancer.