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.