16Radiotherapy dose fractionation Third edition
3.
Breast cancer
Background
Breast cancer is the most common cancer in women in the UK and most patients are
diagnosed at an early stage due the NHS Breast Screening Programme. Radiotherapy has
long been established as an important treatment modality in the adjuvant and palliative
setting in breast cancer. Technological advances and results of pivotal trials have led to
signicant changes in practice in the UK in the last few years.
Adjuvant radiotherapy to the breast or chest wall
Radiotherapy increases both local control and overall survival in the conservation
management of primary breast cancer in selected patients after mastectomy (Level 1a).
1–3
It
also reduces ipsilateral breast tumour recurrence following breast conservation in patients
with a diagnosis of ductal carcinoma in situ (DCIS).
4,5
Although radiotherapy reduces the risk of recurrence for both DCIS and invasive disease
for all patient groups, given the small benets of adjuvant radiotherapy following breast-
conserving surgery in low-risk patient groups, it is reasonable to consider omission of
radiotherapy in patients with oestrogen receptor positive, node negative tumours which
are less than 3 centimetres (cm) in maximum diameter and who are aged over 70 years,
with low-risk biological features such as low-grade, no lymphovascular invasion and HER-2
negativity (Level 1b).
3,6,7
The previous standard breast fractionation was a regimen of 50 Gray (Gy) in 25 fractions
over ve weeks as reported in the National Surgical Adjuvant Breast and Bowel Project
(NSABP) breast cancer trials.
8
Currently the most widely used UK regimen is the
hypofractionated regimen of 40 Gy in 15 fractions over three weeks as used in the UK
START Study B.
9
Mature data from the START B trial and a Canadian study demonstrate
the equivalence of hypofractionationed regimens to the previous standard of 2 Gy daily
fractionation (Level 1b).
3,10
There are no trials comparing 40 Gy in 15 fractions versus 50 Gy in 25 fractions following
breast reconstruction, but there is no radiobiological reason to recommend 50 Gy in 25
fractions in this situation. The results of the START B trial demonstrate that 40 Gy in 15
fractions leads to fewer late eects.
9
Recommendation
For adjuvant radiotherapy of breast or chest wall:
40 Gy in 15 daily fractions of 2.67 Gy over 3 weeks (Grade A)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based medicine.
3
Further hypofractionation for breast radiotherapy is currently under investigation. In the
FAST study, 915 women aged ≥50 years with node negative early breast cancer were
randomly assigned after microscopic complete tumour resection to 50 Gy in 25 fractions
versus 28.5 or 30 Gy in ve, once-weekly fractions of 5.7 or 6.0 Gy respectively, to the whole
breast. The primary endpoint was two-year change in photographic breast appearance.
At three years median follow-up, 28.5 Gy in ve fractions was comparable to 50 Gy in 25
fractions, and signicantly milder than 30 Gy in ve fractions, in terms of adverse eects in
17Radiotherapy dose fractionation Third edition
the breast. There were two local recurrences which were both in the 50 Gy in 25 fractions
arm. Mature local recurrence and late eects data are awaited.
11
The FAST Forward trial is investigating 40 Gy in 15 fractions vesus 26 or 27 Gy in ve
fractions over one week. The main trial closed in 2014. Five-year local control data will
be available in 2019. The FAST Forward nodal study opened in 2015 with normal tissue
endpoints.
12
In 2018, this was modied to a two-arm study comparing 40 Gy in 15 fractions
over three weeks against 26 Gy in ve fractions over one week.
Partial breast irradiation
It is recognised that whole-breast radiation (WBI) can cause signicant toxicity in patients
with large breasts. Partial breast radiation may improve this outcome, though accelerated
partial breast irradiation (APBI) could reduce acute and late side-eects. A meta-analysis
has shown that APBI is associated with a higher local recurrence rate, albeit still low,
compared to WBI (Level 1a).
13
However, this meta-analysis included studies covering
a broad range of APBI techniques and selection criteria. The UK Intensity Modulated
and Partial Organ Radiotherapy Following Breast Conservation Surgery for Early Breast
Cancer (IMPORT LOW) Trial compared two schedules of partial breast radiation versus
whole-breast 40 Gy in 15 fractions and was presented at the European Breast Cancer
Conference in March 2016.
14
For each of the test groups, non-inferiority, assessed against
the prespecied 2.5% threshold, was demonstrated. Local relapse (LR) rates were very
low across all groups, as were moderate/marked normal tissue events, with a statistically
signicant improvement for breast appearance and breast hardness (median follow-up 72
months) for partial breast radiotherapy.
Two trials of intraoperative radiation therapy (IORT) have reported: the External
Radiotherapy for Early Breast Cancer (ELIOT) trial reported an ipsilateral breast tumour
recurrence rate of 4.4% at ve years with IORT and 0.4% with WBI.
15
This gave a hazard ratio
for ipsilateral relapse with IORT of 9.3 (95% condence interval [CI] 3.3–26.3) compared
to WBI. The TARGIT A trial has insucient median follow up to draw rm conclusions
(Level2b).
3,16
Multicatheter interstitial brachytherapy is an alternative approach to APBI. One large
non-inferiority trial has shown equivalence at ve years with a predened 3% dierence
comparing APBI with interstitial brachytherapy and whole-breast radiotherapy to 50 Gy in
25 fractions.
17
Breast boost
Delivery of a boost to the tumour bed following whole-breast radiotherapy reduces the risk
of ipsilateral breast cancer recurrence (Level 1b).
3,18
However, there is no impact on overall
survival and it doubles the risk of moderate or severe brosis.
The proportional benet is similar across all age groups but the absolute benet falls with
increasing age and hence the biggest absolute benet is in women under 50 years of age.
There is also a greater absolute benet of boost in high-grade (G3) cancer.
Incomplete resection margins, where further surgery is not possible, are an indication for
breast boost regardless of age. A boost dose of 16 Gy in eight fractions or equivalent is
most commonly prescribed.
18
18Radiotherapy dose fractionation Third edition
A multidisciplinary consensus meeting held at The Royal College of Radiologists
(RCR) in March 2016 concluded that it would be reasonable for the boost dose to
be hypofractionated, as given in 40 Gy in 15 fractions breast dose, rather than 2 Gy
fractionation. A dose of 16 Gy in eight fractions is equivalent to a hypofractionated dose of
13.35 Gy in ve fractions of 2.67 Gy or 12 Gy in four fractions of 3 Gy assuming an alpha/
beta value for breast carcinoma of 3 Gy.
Appreciation of the volume of the boost and the need for accurate delivery was emphasised.
It is recognised that there is no direct clinical trial evidence for this approach.
The UK dose-escalated, intensity-modulated radiotherapy (IMRT) for women treated by
breast conservation surgery and appropriate systemic therapy for early breast cancer
(IMPORT-HIGH) trial closed in 2015. Patients were randomised to sequential versus
simultaneous integrated boost (IMRT and image-guided radiotherapy [IGRT]) including
dose escalation.
19
The breast boost volume should be dened by localising the tumour bed. Surgical clips
should be routinely placed during a wide local excision to aid localisation of the tumour bed.
There is currently insucient evidence to recommend IORT for tumour bed boost; the
TARGIT B trial is currently recruiting (Clinical Trials Group, University College London, UK
Clinical Research Network ID 14208) and randomising to convention external beam boost
versus IORT boost in high-risk disease.
20
Radiotherapy technique
Two-dimensional (2-D) computed tomography-based planning is no longer recommended
for adjuvant radiotherapy to the breast or chest wall.
Simple, forward-planned, eld-in-eld IMRT reduces the late toxicity and improves cosmetic
outcome following adjuvant whole-breast radiotherapy (Level 1b).
3,21
Breast radiotherapy may increase the risk of heart disease.
22,23
For most women irradiated
in the UK, the absolute risk of developing radiation-induced heart disease is less than 1% at
20 years, but risk varies according to a woman’s pre-existing risk of heart disease and her
heart radiation dose. Techniques to limit heart dose without reducing target dose should
be considered for women with left-sided breast cancer. These include multileaf collimation
(MLC) cardiac shielding and voluntary breath holding (Level 2b).
3,24
Recommendations
For boost after whole-breast radiotherapy in women with a higher risk of
localrecurrence:
16 Gy in 8 daily fractions of 2 Gy (Grade A) or an equivalent hypofractionated
schedule:
3
13.35 Gy in ve fractions of 2.67 Gy or 12 Gy in four fractions of 3 Gy (Grade C)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based medicine.
3
Regional nodal irradiation
19Radiotherapy dose fractionation Third edition
Axilla and supraclavicular fossa
Axillary sentinel lymph node biopsy (SLNB) is now the British Association of Surgical
Oncologists (BASO) recommended standard procedure for axillary staging in early breast
cancer with clinically negative lymph nodes. For most patients with clinically positive nodes
a level III axillary lymph node dissection (ALND) remains the standard procedure.
Nodal irradiation is not recommended following a negative SLNB.
Following a positive SLNB, the AMAROS trial demonstrated an axillary recurrence rate
of 0.43% for ALND versus 1.19% for axillary radiotherapy after a median follow-up of 6.1
years.
25
The trial was underpowered for the planned non-inferiority test due to the low
number of events. Axillary radiotherapy produced lower long-term toxicity compared
to ALND (Level 2b), though the eects of RT on cardiovascular health and second
malignancies in this study are not known.
3,25
The American College of Surgeons Oncology Group (ACOS-OG) Z0011 trial demonstrated
a low axillary recurrence rate of 0.9% versus 0.5% for SLNB + standard breast RT compared
to SLNB followed by ALND + standard breast RT in a RCT comparing ANLD versus no
axillary treatment in women with T1/T2 N0 breast cancer undergoing breast-conserving
treatment.
27
Most patients were over 50 years of age and had grade 1 or 2, T1, oestrogen
receptor positive, ductal cancer with no LVI (Level 2b).
3,26
However, there are signicant
methodological concerns about the Z0011 trial, including the statistical power of the
study. There was a potential for bias in this study as the radiation oncologists were aware
of the treatment allocation and it is unclear whether this inuenced their decision about
how much of the axilla to treat with tangential radiotherapy. Generalisability of the results
is limited as some centres recruited fewer than ve patients, axillary recurrence was not
a prespecied endpoint, mastectomy patients were excluded and preoperative axillary
ultrasound was not performed in contrast to standard UK practice.
The UK pragmatic, randomised, multicentre, non-inferiority trial (POSNOC) trial is currently
recruiting patients with 1–2 positive sentinel lymph nodes and randomising them to
standard adjuvant therapy and axillary treatment (ALND or axillary radiotherapy) versus
standard adjuvant therapy alone. The primary endpoint is axillary recurrence at ve
years. When available, the results will provide a more denitive answer to the question of
managing a positive SLNB axilla.
27
Radiotherapy to the ipsilateral supraclavicular fossa (SCF) is recommended for N2 or
N3 disease following ALND. Axillary radiotherapy following ALND produces signicant
toxicity and should only be recommended in women with very high risk of recurrence (high
proportion of involved nodes, extensive extra-nodal disease or biologically aggressive
cancer). There is no evidence that radiotherapy to the axilla following ALND improves
overall survival from breast cancer.
The North American MA20 trial randomised node positive or high-risk node-negative
patients to WBI versus WBI plus regional nodal irradiation (RNI) including the ipsilateral
axilla, SCF and internal mammary chain, dose 50 Gy in 25 fractions.
28
It demonstrated
improved disease-free survival (DFS) in the RNI group (82% versus 77%, hazard ratio [HR]
0.76, p=0.01) after a median follow-up of 9.5 years. The primary end point of improved
overall survival was not met. There was a small absolute increase in the risk of acute
pneumonitis and late lymphoedema in the RNI group (Level 1b).
3,28
20Radiotherapy dose fractionation Third edition
The EORTC 22922/10925 trial randomised patients with medial or centrally located breast
cancers irrespective of nodal status or node-positive lateral tumours to WBI/chest wall
irradiation versus WBI/chest wall irradiation plus RNI dened as ipsilateral medial SCF and
internal mammary nodes, dose 50 Gy in 25 fractions.
29
After a median follow-up of ten years,
it demonstrated an improvement in DFS in the RNI group (72.1% versus 69.1%, HR 0.89,
p=0.04). The primary end point of improved overall survival was not met (Level 1b).
3,29
Both the MA20 and EORTC 22922/10925 trials demonstrated improved distant-disease-
free survival, but this did not translate to improved overall survival and the long-term eects
of RNI on cardiovascular morbidity and mortality and second cancer rates in these trials
is not known. However a meta-analysis of these studies published before the full results
became available suggests an improvement in overall survival (Level 1a-), although this
analysis was not conducted with patient level data. A Danish population based non-
randomised cohort study has shown improved survival with internal mammary nodal
(IMN) irradiation especially in women with larger (>50 millimetres [mm]) tumours or with
more than four involved nodes (Level 2b).
3,30,31
Hence RNI to include the internal mammary
chain along with ipsilateral axilla and SCF may be considered for patients tting the MA20
and EORTC 22922/10925 criteria to reduce breast cancer recurrence, but careful patient
selection is advised and the lack of data on cardiac eects of IMN irradiation and second
cancers should be taken into account.
28–31
Data for hypofractionated nodal irradiation is limited to small subsets of patients from RCTs
(14% in START A, 7% in START B) but shows no increase in toxicity compared to standard
fractionation nodal irradiation (Level 1b-).
3,32
Recommendation
Where indicated, for regional nodal irradiation:
40 Gy in 15 daily fractions (Grade B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based medicine.
3
Palliative treatment
There are no good-quality head-to-head trials evaluating the optimum schedules for
palliative radiotherapy to the breast, chest wall or regional nodes. The most common doses
range from 20 Gy to 40 Gy over 5–15 fractions. Weekly treatments over 5–6 weeks to a total
of 30–36 Gy are also commonly used (Grade D).
3
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21Radiotherapy dose fractionation Third edition
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References
