Early breast cancer is defined as tumours not more than five centimetres in diameter, with either impalpable lymph nodes or palpable but freely moveable lymph nodes, and with no evidence of distant metastases.¹ Primary treatment of early breast cancer usually involves surgery to remove the tumour (breast conserving surgery or mastectomy) and management of the axilla.¹ Complete pathology reporting following surgery will inform the adjuvant treatment options for individual women.

Several trials have shown that breast conserving surgery followed by whole breast radiotherapy is effective in reducing the risk of local recurrence and improving the long-term outcomes of appropriately selected patients with early breast cancer.² Consequently, adjuvant radiotherapy is recommended for women who have undergone breast conserving surgery ¹.  Adjuvant chemotherapy may also be used in this patient population, but the circumstances of its use are beyond the scope of this guideline.

Conventional adjuvant whole breast radiotherapy is typically delivered over a period of 5 weeks using a standard dose of 2 Gray (Gy) per treatment episode (fraction) in 25 fractions to a total dose of 50 Gy.³ A tumour bed boost of 10-16 Gy in 2 Gy fractions ⁴,⁵ is sometimes delivered after whole breast radiotherapy.

Hypofractionated whole breast radiotherapy involves fewer fractions; however each fraction contains a larger daily dose of radiation than the conventional 2 Gy per fraction. The total dose of radiation used in a course of hypofractionated radiotherapy is reduced to compensate for the increased toxicity effect of larger daily fractions.

Compared to conventional radiotherapy regimens, the duration of a hypofractionated radiation treatment course is shorter by several days or weeks, as fewer fractions are required.  A hypofractionated regimen may be more convenient for patients and less-resource intensive than a conventionally fractionated regimen. ⁶

Conventional radiotherapy and hypofractionated radiotherapy can be hypothesised to have a similar effect, based on radiobiological principles. The aim of hypofractionated radiotherapy is to balance as high a daily dose as possible in order to kill tumour cells, against a dose low enough to minimise the side-effects of treatment.

Sensitivity of tissues to radiation fraction size is described by the α/β ratio. Low α/β values indicate greater sensitivity to fraction size than higher α/β values. It has been hypothesised that breast cancer is as sensitive to fraction size as normal breast tissue with a low α/β value, and confirmation would indicate that fewer, larger fractions are as effective as conventional 2 Gy fractions.⁷

It is important to note that research on hypofractionated whole breast radiotherapy for early breast cancer is continuing. Clinical judgement should be applied in the context of the currently available evidence and emerging findings from the continuing body of research.

The Recommendations are based on Statements of Evidence on the use of hypofractionated radiotherapy for the treatment of early (operable) breast cancer. Practice points are also provided to help guide clinical decisions for the use of hypofractionated radiotherapy for the treatment of early (operable) breast cancer. Practice points are based on expert opinion when the evidence to make a recommendation is insufficient or where the evidence is outside the scope of the systematic review.

All Recommendations have been graded using the National Health and Medical Research Council (NHMRC) FORM methodology.^8,9 The NHMRC grades (A-D) assigned to the recommendation given are intended to indicate the strength of the body of evidence underpinning the recommendation (refer to Table 1).  Appendix 1 provides further detail of the NHMRC FORM grading methodology and the process undertaken in the grading of all Recommendations contained in this guideline. See also Appendix 2 for Evidence Statements for Grading the Recommendations.

Table1: Definition of NHMRC grades of Recommendations^8,9

This clinical guideline is intended for all members of the multidisciplinary team responsible for the care of a woman with early breast cancer. Ideally, the recommendations regarding the use of different fractionation schedules should be considered prior to breast surgery.

Recommendations and practice points should be considered in the context of clinical judgement for each patient. Considerations should include the absolute benefits and harms of treatments, other treatments in use, patient preferences and quality of life issues. These factors should be discussed with the patient and their family or supporters, tailored to their preferences for information and decision-making involvement.

Patients

Optimal Schedules

Adverse Events And Toxicity

The Statements and Recommendations on the use of hypofractionated radiotherapy for early (operable) breast cancer are based on two Cancer Australia systematic reviews:

1. Cancer Australia systematic review of RCTs which included available evidence published from January 2001 to March 2010,¹⁹ that informed the clinical practice guidelines on the use of hypofractionated radiotherapy for early (operable) breast cancer published by Cancer Australia in November 2011.
2. Updated Cancer Australia systematic review of RCTs to identify new and updated evidence published from January 2010 to November 2013.²⁰

The primary search strategy was based on the 2011 systematic review. A total of 384 citations were identified, and following application of the exclusion criteria, six articles and three conference abstracts were identified for inclusion in the updated systematic review.

The total body of evidence on hypofractionated radiotherapy for early (operable) breast cancer from these two systematic reviews includes:

• Six primary Randomised Controlled Trials (RCTs): START A trial, START B trial, a trial by Spooner et al, the UK FAST trial, the Canadian trial and the United Kingdom Royal Marsden Hospital/Gloucestershire Oncology Centre (RMH/GOC) trial
• Three RCTs published as conference abstracts only.

Of the six primary RCTs, all but one (UK FAST) were included in the evidence base for the 2011 Cancer Australia Guidelines. Thus, the evidence base for the current guideline includes the most current data from these five trials together with data from the UK FAST trial.

The RMH/GOC, START A and the UK FAST trials tested two hypofractionated radiotherapy regimens. The Canadian trial, the START B and Spooner trial each tested one hypofractionated radiotherapy regimen.  In all trials, the conventional radiotherapy regimen used as a comparator was 50 Gy in 25 fractions, delivered over 5 weeks.

A range of hypofractionated radiotherapy regimens were examined, including:

• 39 Gy in 13 fractions over 35 days(RMH/GOC trial^7,18 and START A^10,16)
• 40 Gy in 15 fractions over 21 days (START B^10,17 and Spooner trial¹¹)
• 41.6 Gy in 13 fractions over 35 days (START A^10,16)
• 42.5 Gy in 16 fractions over 22 days(Canadian trial^6,13)
• 42.9 Gy in 13 fractions over 35 days(RMH/GOC trial ^7,18)
• 30 Gy in 5 once weekly fractions of 6Gy over 5 weeks (UK FAST²¹)
• 28.5 Gy in 5 once weekly fractions of 5.7Gy over 5 weeks (UK FAST²¹)

Figure 1 provides a summary of hypofractionated radiotherapy regimens used in the RCTs. Four trials included women undergoing regional nodal radiotherapy: 14% in START-A; 7.3% in START-B; 20.6% in RMH/GOC and 100% in the Spooner trial.

Four trials included women who had undergone breast conserving surgery only (Spooner trial, UK FAST trial, Canadian trial, RMH/GOC).^{6,7,11,13,18,21} Two trials included women who had undergone breast conserving surgery or mastectomy (START A and START B).^10,16,17

Median follow up ranged from 37.3 months in the UK FAST trial to 16.9 years in the Spooner trial.

Figure 1: hypofractionated radiotherapy schedules of RCTs²²

Table 2 summarises the trial populations and primary outcomes measured in the six RCTs comparing hypofractionated radiotherapy to conventionally fractionated radiotherapy. Of note:

• Six trials identified the patient population characteristics as early invasive breast cancer T1-3, N0-1, M0.^{6,7,10,11,13,16-18,21}
• The Spooner trial, UK FAST trial, the Canadian trial and the RMH/GOC, limited the trial populations to those who had breast conserving surgery only.^{6,7,11,13,18,21}
• Women participating in the START A or START B trials had breast conserving surgery or mastectomy.^10,16,17

Table 2 - Trial characteristics

Table 3 identifies key characteristics of patients involved in the six randomised controlled trials.

Table 3: Patient characteristics

Overall survival

Four trials, START A, START B, Spooner 2012, and the Canadian trial, reported on overall survival. START B reported that the 10 year all-cause mortality rate was significantly lower in the hypofractionated radiotherapy arm than the standard radiotherapy arm; HR=0.80 (95% CI 0.65-0.99), p=0.042.¹⁰. The three other trials reported similar overall survival rates between hypofractionated radiotherapy and standard radiotherapy with no statistically significant differences.^6,10,11

Disease-free survival

Both START A and START B reported disease-free survival (DFS). START B reported a significantly higher rate of DFS in patients receiving hypofractionated radiotherapy compared to standard radiotherapy; HR=0.79 (95% CI 0.65-0.97), p=0.022.¹⁰ Whereas START A reported no significant difference in DFS between the hypofractionated radiotherapy schedules and standard radiotherapy.¹⁰

Relapse-free survival

The trial by Spooner et al (2012) reported no significant difference between short- and long-course radiotherapy for relapse-free survival estimates at 2, 5, 10 and 15 years; HR=0.98; (95% CI 0.75-1.29), p-value not reported.¹¹

Table 4: Survival outcomes of RCTs comparing hypofractionated radiotherapy and standard radiotherapy.

Local Relapse

Five trials reported on local recurrence (START A, START B, Spooner 2012, RMH/GOC trial, Canadian trial). All trials reported similar rates of local relapse for women treated with hypofractionated radiotherapy and standard radiotherapy.^6,7,10,11 See Tables 4 and 5.  RMH/GOC noted a statistically significant difference in recurrence rates between the two hypofractionated regimens (42.9 Gy vs. 39 Gy: 9.6% vs. 14.8%, p=0.027) but not when either of the hypofractionated regimens was compared to 50 Gy in 25 fractions.⁷

Table 5: Five year rates for local recurrence rates in RMH/GOC and Canadian trials.

^6.7% and 6.2% at 10 years

Table 6: START A and START B relapses

Local-regional relapse

Both START A and START B reported local-regional relapse rates. For both START A and START B there was no significant difference in 10 year local-regional relapse rates between hypofractionated radiotherapy and conventionally fractionated radiotherapy, see Table 5.¹⁰ In a combined sub-group analysis of START A, START B and their pilot study there was no significant difference in local-regional relapse rates between hypofractionated radiotherapy and conventionally fractionated radiotherapy by age, type of primary surgery, axillary node status, tumour grade, adjuvant chemotherapy use, or use of tumour bed boost radiotherapy.¹⁰

Distant relapse

START A, START B, and Spooner 2012 trials reported distant relapses.

START B reported the hypofractionated radiotherapy regimen to be associated with a statistically significant lower rate of distant relapse than standard radiotherapy; HR=0.74 (95% CI 0.59-0.94), p=0.014.¹⁰ See Table 5. Similar rates of distant relapse were reported between patients receiving hypofractionated radiotherapy and patients receiving conventionally fractionated radiotherapy in the START A, Spooner 2012 and UK FAST trials.^10,11,21

Table 7: Recurrence outcomes of RCTs comparing hypofractionated radiotherapy and standard radiotherapy.

Yellow shaded cells indicate primary outcome for the trial.

^a Target sample size 2000 patients to provide 80% power to detect a difference of 5%.
^b Target sample size 1840 patients to provide 95% power to exclude an increase of 5% in local-regional relapse rate in the 40 Gy schedule compared to control.
^c To detect a minimum of 10% excess in relapse in patients to radiotherapy or no radiotherapy (from 10 to 20% 5 year relapse rate) 300 patients in each treatment group were needed using 5% α level of significance and 90% power.
^d The sample size for the trial, 600 patients per group, was based on earlier trial assumptions and a power of 80% with a one-sided alpha level of 5%.
^e For an estimated 90% power and 5% significance level, 2250 patients would be needed to detect a 5% absolute increase in the risk of recurrence in either experimental group, compared with an expected 5-year local recurrence of 10% in the control group. Accrual was stopped before the target was reached, because this trial was superseded by the START trial, with tumour control as the primary endpoint.

Impact of tumour grade

Early evidence reported higher local recurrence rates for patients with high grade tumours. Recent analyses, as well as follow-up of the initial analysis, have demonstrated no significant difference for recurrence for high grade tumours.

Three studies examined hypofractionated radiotherapy in patients with high grade tumours; the Canadian trial and START trials as well as an additional retrospective population based cohort study by Herbert et al (2012).¹⁵

The 2010 publication of the Canadian trial by Whelan et al included an unplanned sub-group analysis including tumour grade.⁶ The analysis reported that for patients with high grade tumours, the cumulative incidence of local recurrence at 10 years was 15.6% in those receiving hypofractionated radiotherapy compared with 4.7% in those receiving conventional radiotherapy (p=0.01).⁶However, an updated  analysis of the Canadian trial by Bane et al (2014) based on longer-term data, reported no statistically significant difference for local recurrence between grade 1-2 and grade 3 breast cancers (p=0.11).¹⁴

A meta-analysis of the START A, START B trial and their pilot study reported no significant difference in locoregional relapse between grade 1 and 2 tumours and grade 3 tumours (p=0.12).¹⁰

A retrospective population based cohort study by Herbert et al (2012) of patients with grade 3 breast cancer reported the 10-year cumulative incidence of local relapse was 6.9% in  the hypofractionated group and 6.2% in the conventionally fractionated radiotherapy group (p=0.99).¹⁵

Adverse events and cosmetic outcomes

Five trials reported on adverse events and cosmetic outcomes (START A, START B, UK FAST trial, RMH/GOC trial and the Canadian trial).

START A and START B trial results

Late normal tissue effects[*]

The most common normal tissue effects at 10 years were breast shrinkage and induration in both START trials. START A reported that in comparison to standard radiotherapy, patients in the 39 Gy regimen were significantly less likely to have moderate or marked breast induration, telangiectasia, and breast oedema.¹⁰ Moderate or marked normal tissue effects did not differ significantly between the hypofractionated radiotherapy regimen of 41.6 Gy and the 50 Gy group. In START B those receiving hypofractionated radiotherapy were significantly less likely to experience moderate or marked breast shrinkage, telangiectasia, and breast oedema compared to standard radiotherapy.¹⁰

Late adverse effects

For both START A and START B, ischaemic heart disease, symptomatic rib fracture and symptomatic lung fibrosis were rare at 10 years and incidence was similar between radiotherapy schedules.¹⁰

Change in breast appearance

START A reported that according to patient self-assessments of five normal tissue effects on the breast or breast area[†], the rates of moderate or marked effects at five years were similar for 41.6 Gy and 50 Gy.¹⁶ Rates of moderate or marked normal tissue effects tended to be lower after treatment in the 39 Gy group compared to the 50 Gy group, with a significantly lower rate of change in skin appearance (p=0.004). Changes in breast appearance and breast hardness were the most common changes reported.¹⁶

START A also measured change in breast appearance using photographic assessment; the hazard ratios for any change in breast appearance compared to the 50 Gy arm was 1.09 (p=0.62) after 41.6 Gy and 0.69 (p=0.01) after 39 Gy.¹⁶

Although mostly not statistically significant, the patient quality of life self-assessments of normal tissue effects in START B suggested that cosmetic outcomes were favourable in the 40 Gy group in most of the assessed normal tissue effects, with a significantly lower rate of change in skin appearance compared to the 50 Gy treatment arm (p=0.02).¹⁷ Changes in breast appearance and breast hardness were the most common changes reported. Photographic assessments also showed that change in breast appearance was less likely after treatment in the 40 Gy arm than the 50 Gy arm with a hazard ratio of 0.83 (p=0.06).¹⁷

Combined results of the START A and START B trials found that any change in skin appearance occurred significantly less often in the 39 Gy and 40 Gy arms when compared with the control arm of 50 Gy in 25 fractions over five weeks (39 Gy HR 0.63 95% CI 0.47-0.84, p=0.0019 and 40 Gy HR 0.76 95% CI 0.60-0.97, p=0.0262).²⁴

UK FAST trial results

The UK FAST trial’s primary endpoint was change in photographic breast appearance measured by photographic assessments at baseline and at 2 years and 5 years.²¹ Assessments of 2-year change in photographic breast appearance were available for 81% of patients still alive and disease free. The trial reported the risk ratio for mild or marked change in 2 year photographic breast appearance for 30 Gy vs. 50 Gy was 1.70 (95% CI 1.26-2.29, p=<0.001) and for 28.5 Gy vs. 50 Gy the risk ratio was 1.15 (95% CI 0.82-1.60, p=0.489). The trial demonstrated a clear and statistically significant dose response between 28.5 Gy and 30 Gy with worse results for change in photographic breast appearance at 2 years in the 30 Gy patients. Outcomes were comparable between the 28.5 Gy schedule and 50 Gy schedule.²¹

Moderate or marked adverse effects in the breast were reported in 155 patients overall.²¹ Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%) for 30 Gy and 11.1% (7.9-15.6%) for 28.5 Gy compared with 9.5% (6.5-13.7%) after 50 Gy; the rate in the 30 Gy group was significantly higher than in 50 Gy (p=<0.001) and in 28.5 Gy (p=<0.006). The rates were similar between the 28.5 Gy and 50 Gy groups (p=0.18).²¹ Results for breast shrinkage were also significantly higher among patients in the 30 Gy group; 30 Gy vs. 50 Gy p=0.002 and 30 Gy vs. 28.5 Gy p=0.016 and similar between the 28.5 Gy and 50 Gy groups; p=0.455.

Canadian trial results

The Canadian trial reported on toxic effects of irradiation on the skin and subcutaneous tissue five and ten years after randomisation.⁶ The incidence of reported effects increased over the follow-up period, although the proportion of women with grade 3 radiation-associated skin and subcutaneous tissue morbidity was 4% or less, with no reports of grade 4 morbidity. At 10 years, there were no skin toxic effects for 70.5% of women in the conventional radiotherapy group, compared to 69.8% of women in the hypofractionated radiotherapy group. There were no toxic effects in subcutaneous tissue in 45.3% of women in the conventional radiotherapy group, compared with 48.1% of women in the hypofractionated radiotherapy group.⁶

Following assessments at baseline, three, five and ten years after randomisation, the global cosmetic outcome worsened over time however there were no significant differences observed between the 42.5 Gy group and the 50 Gy group at any time.⁶ At ten years follow-up, 71.3% of women in the 50 Gy group compared to 69.8% of women in the hypofractionated radiotherapy treatment group had an excellent or good cosmetic outcome.⁶ Cosmetic outcome was shown to be affected by time from randomisation, patient’s age and tumour size but there was no interaction with the treatment.⁶

RMH/GOC trial results

After a minimum follow-up of five years, the proportion of patients who recorded any change in breast appearance after 50 Gy in 25 fractions, 39 Gy in 13 fractions and 42 Gy in 13 fractions was 39.6%, 30.3% and 45.7% respectively.¹⁸

For photographically assessed changes in breast appearance, the trial found a higher risk of developing any radiation effect for patients allocated to 42.9 Gy in 13 fractions, compared to those allocated to 39 Gy in 13 fractions or 50 Gy in 25 fractions (p=<0.001 for comparison of three fractionation schedules).¹⁸ 

Clinical assessment of patients also indicated significant differences between the three fractionation schedules, with the 42.9 Gy group experiencing the highest incidence of events for overall breast cosmesis (p=<0.001), breast shrinkage (p=0.026), breast distortion (p=0.005), breast oedema (p=0.004), induration (p=0.001) and shoulder stiffness (p=0.001).¹⁸

Other adverse events

Three trials investigated the incidence of symptomatic lung fibrosis and symptomatic rib fracture.^13,16,17 The reported rates were low at 5 years follow-up, and balanced between the regimens.  One woman in the 41.6 Gy arm of the START A trial developed pneumonitis nine months after treatment; another developed mild signs of brachial plexopathy two years following treatment.¹⁶ The Canadian trial reported four cases of pneumonitis (two women in the 42.5 Gy group, and two women in the 50 Gy treatment group).¹³ One woman in the 50 Gy treatment group experienced rib fracture attributed to radiation therapy.¹³

While damage to the pectoral muscle has been highlighted as a possible concern,¹² none of the trials reported this outcome

Table 8: Key cosmetic outcomes of RCTs comparing hypofractionated radiotherapy and standard radiotherapy

Cardiac toxicity

The 2013 Haviland article on the START trials reported on deaths from cardiac disease. In START A after 9.3 years median follow-up, 26/392 (6.6%) deaths were related to cardiac disease (seven with 50 Gy, 13 with 41.6 Gy, and six with 39 Gy). Fifteen (57.7%) of the 26 deaths from cardiac disease were in women with left-sided primary tumours (four of seven with 50 Gy, ten of 13 with 41.6 Gy, and one of six with 39 Gy). In START B, after 9.9 years median follow-up, 17/351 (4.8%) deaths were related to cardiac disease (12 with 50 Gy and five with 40 Gy). Eleven (64.7%) of the 17 deaths from cardiac disease were in women with left-sided primary tumours (eight of 12 with 50 Gy and three of five with 40 Gy). In UK FAST after 3.1 years median follow-up, 4/23 (17.4%) deaths were attributed to cardiac disease, with two deaths in women with left sided tumours, and two deaths in women with right-sided tumours. However, the UK FAST publication does not report the treatment group assignment for any of these cardiac disease related deaths.

In addition, while the Canadian trial did not report results for left- and right-sided breast cancers, the authors did note that at a median follow-up of 12 years few cardiac-related deaths were observed and no increase occurred in patients who received the hypofractionated regimen⁶.

When interpreting the mortality rates from START A, B and UK FAST a number of factors should be kept in mind. The number of events in each study is low and although women with pre-existing heart disease were excluded from START A and START B, none of the three studies stratified patients at baseline by cardiac risk factors. Furthermore, interpretation of the available evidence is potentially confounded by differences in the subsequent chemotherapy regimens administered to the women.

Haviland et al (2013) concluded that the START A and B trial results showed that although follow-up was still shorter than would be desired for cardiac events (i.e., 15-20 years ^{16, 17}), there was no major difference between the fractionation schedules for the number of cases of heart disease in women with left-sided primary tumours.¹ Haviland et al (2013) also note that the heart is sensitive to radiation whatever fractionation is used with no lower dose threshold for adverse effects. A commentary on the 2013 START trial results agreed with the START trial authors that techniques to protect the heart are important for both radiotherapy schedules and the choice of fractionation should not be affected by whether the tumour is in the left or right breast.²⁵

Supplementary non-randomised trial evidence was also sourced on cardiotoxicity (refer to section on cardiotoxicity in technical document). A key population-based retrospective study by Chan et al was reported in two 2014 publications. The first (median follow-up 13.2 years; Ontario) determined if there is an increase in hospital-related morbidity from cardiac causes with either hypofractionated radiotherapy (40-44 Gy in 16 fractions) or conventional radiotherapy (45-50 Gy in 25 fractions or 50.4 Gy in 28 fractions).²⁶ The second (median follow-up 14 years; Ontario) reported on if there is an increase in cardiac mortality with hypofractionated radiotherapy relative to conventional radiotherapy.²⁷ Overall the authors concluded that for women with left-sided early-stage breast cancer who received postoperative radiation therapy to the whole breast or chest wall, there was no difference in the 15-year cardiac mortality or cumulative morbidity due to cardiac causes, between conventionally fractionated and hypofractionated treatment schedules.

Quality of life

Two trials reported quality of life outcomes using the European Organisation for Research and Treatment of Cancer (EORTC) breast cancer module.^16,17 Three subscales were used in the analysis: breast symptoms (pain, swelling, oversensitivity, and skin problems in the breast); arm or shoulder symptoms subscale (swelling in the arm or hand, arm or shoulder pain, and difficulty moving the arm); and body image subscale. Based on these measures, there was no evidence that a hypofractionated radiotherapy regimen was associated with a statistically significant difference in quality of life scores.²⁴ Sub-group analysis by surgery type was performed. The small numbers of patients and events in some sub-groups limited the statistical power of these analyses. There were no statistically significant differences in outcomes based on trial groups; nor were any interaction tests significant overall. ^16,17

No other assessment of patient quality of life was available. Authors of the Canadian trial suggested that the inconvenience of a prolonged course of daily treatment made a substantial contribution to the decreased quality of life experienced by women treated with radiotherapy for breast cancer.¹³ A shorter fractionation schedule lessens the practical burden of treatment for women, and will have important quality of life benefits with respect to convenience and less time away from home and work.

Regional nodal radiotherapy

Regional nodal radiotherapy is the delivery of radiation to lymph nodes located in the breast region, namely the axillary and supraclavicular nodes on the same side as the affected breast. Four trials included women undergoing regional nodal radiotherapy (START A, START B, Spooner and RMH/GOC trial). None of these trials delivered radiation to the nodes of the internal mammary chain.

START A reported that the decision to administer regional nodal radiotherapy was made pre-randomisation and was used in approximately 14% of patients.¹⁶ One patient developed mild symptoms of brachial plexopathy but it was not reported if the patient received regional nodal radiotherapy. In two patients randomised to the 41.6 Gy arm and prescribed radiotherapy to the breast and supraclavicular fossa, the total dose was reduced to 39 Gy because of concerns regarding sensitivity of brachial plexus to fraction size.¹⁶

START B reported that 7.3% of patients received regional nodal radiotherapy.¹⁷ No cases of brachial plexopathy were reported among the women given radiotherapy to the supraclavicular fossa, axilla or both.¹⁷

Spooner et al (2012) reported that a four-field technique was used in all patients to irradiate the breast and ipsilateral axillary, and supraclavicular lymph nodes.¹¹

RMH/GOC trial reported that 20.6% of patients underwent regional nodal radiotherapy to the axilla and/or supraclavicular fossa.¹⁸ There were no recorded cases of brachial plexopathy among these women. 

[*] Normal tissue effects in the breast, arm, and shoulder were assessed by physician, photographic comparison with baseline, and patient self-reports.

[†] Patient quality of life self-assessments include the following changes since radiotherapy - breast shrinkage; breast hardness; change in skin appearance; swelling in area of affected breast; change in breast appearance. 

Use of tumour bed boost

Tumour bed boost was used in four of the randomised trials; START A, START B, Spooner 2012 and the RMH/GOC trial. Outcomes were reported for START A, START B and their pilot study, RMH/GOC, in a post hoc combined sub-group meta-analysis (n=5,861).¹⁰ Between January 1986 and July 1997, patients in the RMH/GOC trial were randomly assigned to receive a boost or not. Subsequently, all patients were offered an elective boost. The proportion of women who received a tumour bed boost was similar among the treatment groups. There was a statistically significant reduced risk of induration (p=0.001) and telangiectasia (p=0.026) in patients randomised to no boost.¹⁸

The proportion of women who received a tumour bed boost was similar among the treatment groups in the START A and START B trials. However, sub-group analysis on tumour bed boost was not reported.^16,17 In a combined sub-group analysis of START A, START B and their pilot study there was no statistically significant difference in local-regional relapse rates or moderate or marked physician-assessed normal tissue effects in the breast between hypofractionated radiotherapy and conventionally fractionated radiotherapy in patients who received tumour bed boost radiotherapy and those who did not receive tumour bed boost radiotherapy (Haviland 2013). This analysis provides support of equivalence between hypofractionated radiotherapy with boost and conventional radiotherapy without boost for tumour control and improved late tissue effects, with the inclusion of 5,861 patients and lengthy follow-up. While the 2011 ASTRO guidelines state “there were few data to define the indications for and toxicity of a tumour bed boost in patients treated with hypofractionated radiotherapy” this guideline was published in 2011, prior to the 2013 START trial publication of tumour bed boost data.

In the Spooner et al trial (2012), all irradiated patients received a supplementary boost to the local tumour site of a direct 10-14 MeV electron field of 15 Gy in five daily fractions.¹¹

Delivery of radiotherapy

All trials provided information on the radiotherapy techniques used. Patients in all six trials were treated in a supine position. The RMH/GOC and Canadian trials specified that patients were treated with one or both arms raised above the shoulder and Spooner noted patients had arm abducted to 90⁰.

In five trials, 6-megavoltage x-rays were used for most patients but higher energy megavoltage x-rays or cobalt x-rays were also used.^{6,7,13,16-18,21} Where regional radiotherapy was indicated, the target volume included the supraclavicular nodes with or without the axillary nodes.^7,16,17

Four trials reported that the maximum dose to the breast on the central axis was no less than 93% to 95% and no more than 105% to 107% of the prescribed dose.^6,7,13,16-18. The Canadian trial excluded patients whose separation along the central axis exceeded 25cm; however the other trials used higher energy x-rays for patients with larger breasts to achieve acceptable dose homogeneity.^6,7,13,16,17 RMH/GOC and Canadian trials reported the use of wedge tissue compensators to ensure a uniform dose distribution throughout the target volume.^7,13,18

Four trials included women allocated to receive a tumour bed boost. Women allocated to receive a boost in RMH/GOC received a dose of 14 Gy to the 90% isodose (15.5 Gy to 100%) in 7 daily fractions.¹⁸ Ten Gy in 5 daily fractions to the 100% isodose was delivered after whole breast radiotherapy to women allocated to receive a boost in the START A and START B trials.^16,17 All irradiated patients in the Spooner  trial  received a supplementary boost to the local tumour site of a direct 10-14 MeV electron field of 15 Gy in five daily fractions.¹¹

Use of adjuvant systemic therapies

Five trials included women who received adjuvant systemic therapies; START A, START B, Spooner 2012, the Canadian trial and RMH/GOC trial. In the Canadian trial, 11% of women received chemotherapy in both the conventional and hypofractionated radiotherapy regimens; and 41% received tamoxifen in both the conventional and hypofractionated radiotherapy regimens.⁶ Sub-group analysis of the rates of local recurrence showed no statistically significant difference between the conventional and hypofractionated regimens at five years and ten years.⁶

No sub-group analysis on the use of systemic therapies was reported in the RMH/GOC, START A or START B trials or Spooner trial.^7,16-18 In each trial, the proportions of women who received systemic therapies including tamoxifen and/or chemotherapy were similar among the study groups. The START trials required a two week gap between exposure to chemotherapy and radiotherapy.^16,17 In the Spooner trial the authors noted that the study was conducted at a time when few patients were given adjuvant chemotherapy and all patients received tamoxifen because hormone receptor status was not routinely available. Patients in the trial received tamoxifen (20mg once daily) for a minimum of 2 years, after which there was a subsequent sub-randomisation to discontinue or continue for at least another 3 years.¹¹

No trials specifically assessed the use of hypofractionated radiotherapy in conjunction with chemotherapy or other biological therapies.

Overall the evidence included in the systematic review was based on six randomised controlled trials which were considered to be of high quality.

All trials were randomised, with the methods of randomisation considered high quality. The trials were open label and not blinded. Survival outcomes by intention-to-treat analysis were reported by most trials and limited numbers of patients were lost to follow-up (less than 5%). All trials had standardised assessment of outcomes and had well matched population characteristics between treatment arms at baseline.

All reported outcomes need to be considered in the context of the range of hypofractionated radiotherapy regimens that were evaluated. Although 50 Gy in 25 fractions was used as a control arm in all trials, seven different hypofractionated radiotherapy regimens were investigated.

Important unanswered questions about the use of hypofractionated radiotherapy in early breast cancer are outlined below. Some of these questions may be addressed in ongoing trials:

• Treatment outcomes for patients who received hypofractionated radiotherapy in relation to age and tumour size.
• Optimal hypofractionated radiotherapy schedule.
• Safety and efficacy of different tumour bed boost protocols administered after hypofractionated radiotherapy.
• Safety and efficacy of hypofractionated regional nodal radiotherapy.
• Hypofractionated radiotherapy for DCIS.
• Potential interactions between adjuvant systemic therapies and hypofractionated radiotherapy.
• Long-term effects of hypofractionated radiotherapy on cardiac toxicity.
• Long-term effects of hypofractionated radiotherapy on rib morbidity.
• Psychosocial outcomes for women receiving hypofractionated radiotherapy, including impact of hypofractionated radiotherapy on quality of life, such as side-effects and practical implications of a shorter treatment schedule.
• Health economic considerations of hypofractionated radiotherapy.

The following randomised controlled trials are investigating the use of hypofractionated radiotherapy for early breast cancer:

• NCT0000156130 trial compares 42.5 Gy in 16 fractions over 22 days with 50 Gy in 25 fractions over 35 days in patients diagnosed with early (invasive) breast cancer followed by breast conserving surgery or mastectomy.
• NCT01349322 trial compares accelerated hypofractionated radiotherapy with a concurrent boost 5 days a week for 3 weeks, with standard whole-breast radiotherapy for a 5 days a week for 3-5 weeks followed by sequential radiotherapy boost, in patients diagnosed with early stage breast cancer removed by surgery. Accelerated fractionation refers to schedules where the dose per fraction is unchanged but the daily dose is increased and the total treatment time is reduced.
• NCT00005587 trial compares patients receiving radiotherapy 5 times a week for 3 weeks for a total dose of 40 Gy for patients with microscopic evidence of invasive or in situ cancer at, or within 1mm of, a resection margin receive radiotherapy for 5 fractions in 1 week for a total boost of 10 Gy, with patients receiving a control dose of 50 Gy in 25 fractions over 5 weeks. All patients were diagnosed with early stage breast cancer removed by local excision or mastectomy.
• ‘Fast-forward’ trial compares 27 Gy or 26 Gy in five fractions over 5 days, with a control dose of 40 Gy in 15 fractions over 15 days in patients diagnosed with invasive carcinoma of the breast removed by breast conservation surgery.
• ‘SHARE’ trial compares 42.5 Gy in 16 fractions or 40 Gy in 15 fractions over 3 weeks or 40 Gy in 10 fractions over 3 weeks, with a control dose of 50 Gy in 25 fractions over 35 days followed by a 10 to 16 Gy boost in 5 to 8 fractions. All patients were diagnosed with invasive carcinoma of the breast.

The following international guidelines have been identified which include guidance on the use of hypofractionated radiotherapy for early breast cancer:

• The American Society for Radiation Oncology (ASTRO) guidelines on fractionation for whole breast irradiation, 2010
• The New Zealand Ministry of Health Guidelines for Management of Early Breast Cancer, 2009
• NICE Guidelines for early and locally advanced breast cancer, 2009
• Scottish Intercollegiate Guidelines Network (SIGN) guidelines, 2009
• BC Cancer Agency Breast cancer management consensus guidelines 2013
• European Journal of Medical Oncology (ESMO) guidelines on primary breast cancer diagnosis, treatment and follow-up, 2013
• German Society of Radiation Oncology (DEGRO) guidelines on radiotherapy of breast cancer, 2013
• Nice-Saint-Paul de Vence guidelines on adjuvant radiotherapy in the management of axillary node negative invasive breast cancer, 2013

The BC Cancer Agency consensus based guidelines for the management of early breast cancer include recommendations on the use of radiotherapy and recommend a hypofractionated radiotherapy regimen as standard. The guideline recommends the following dose fractionation for radiotherapy following breast conserving therapy (T1, T2; N0):

1. Standard whole breast dose is 42.5 Gray (Gy) in 16 daily fractions
2. Certain patients are at risk for inferior cosmetic outcome from the 16-fraction course. Extended fractionation should be considered for patients with very large breast size, and those with significant post-operative induration, oedema, erythema, hematoma or infection. Patients with these indications for extended fractionation should receive 45Gy in 25 daily fractions plus a boost dose of 10Gy in 5 fractions or 50.4 Gy in 28 daily fractions.
3. If a boost is used, an additional dose of 6-16 Gy in 3-8 fractions is recommended.

The guideline recommends the following dose fractionation following mastectomy or BCS (T1,T2; N1, and T3;N0):

1. Standard whole breast dose is 42.5 Gy in 16 daily fractions, chest wall dose is 40 Gy in 16 fractions, nodal dose is 37.5-40 Gy/16 fractions.
2. Those at risk for increased toxicity post-BCS should be treated with the breast doses described above in the T1, T2, N0 section. Nodal dose should be 45 Gy/25 fractions.
3. Those at risk for increased toxicity post-mastectomy, e.g. postoperative infection, and those undergoing reconstruction post-mastectomy should also be considered for extended fractionation. Patients with indications for extended fractionation post-mastectomy should receive 50.4 Gy in 28 daily fractions to the chest wall, and 45 Gy in 25 fractions to the nodal regions.
4. For those with close or positive margins post-mastectomy, a higher chest wall dose (e.g. 42.5-44 Gy in 16 fractions) may be used, or a boost dose of 10Gy in 4 fractions or 16Gy in 8 fractions may be considered, if the anatomic area requiring the boost dose can be accurately delineated.

1. National Breast Cancer Centre. Clinical practice guidelines for the management of early breast cancer (2nd edition). Commonwealth of Australia, Canberra, 2001.
2. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Darby S, McGale P, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707-16.
3. James ML, Lehman M, Hider PN, et al. Fraction size in radiation treatment for breast conservation in early breast cancer. Cochrane Database Syst Rev. 2008;3):CD003860.
4. Faculty of Radiation Oncology and The Royal Australian and New Zealand College of Radiologists. RANZCR The Clinicians guide to radiation oncology. M Barton, Editor, Sydney, 2002.
5. Poortmans PM, Collette L, Bartelink H, et al. The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer. A summary of the results of EORTC 22881-10882 "boost versus no boost" trial. Cancer Radiother. 2008;12(6-7):565-70.
6. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362(6):513-20.
7. Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006;7(6):467-71.
8. Hillier S, Grimmer-Somers K, Merlin T, et al. FORM: An Australian method for formulating and grading recommendations in evidence-based clinical guidelines. BMC Medical Research Methodology. 2011;11(23):11-23.
9. National Health and Medical Research Council (NHMRC). NHMRC additional levels of evidence and grades for recommendations for developers of guidelines. NHMRC, Commonwealth of Australia, 2009.
10. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14(11):1086-94.
11. Spooner D, Stocken DD, Jordan S, et al. A Randomised Controlled Trial to Evaluate both the Role and the Optimal Fractionation of Radiotherapy in the Conservative Management of Early Breast Cancer. Clinical Oncology. 2012;24(10):697-706.
12. Yarnold J, Bentzen SM, Coles C and Haviland J. Hypofractionated whole-breast radiotherapy for women with early breast cancer: myths and realities. Int J Radiat Oncol Biol Phys. 2011;79(1):1-9.
13. Whelan T, MacKenzie R, Julian J, et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst. 2002;94(15):1143-50.
14. Bane AL, Whelan TJ, Pond GR, et al. Tumor Factors Predictive of Response to Hypofractionated Radiotherapy in a Randomized Trial Following Breast Conserving Therapy. Ann Oncol. 2014;.
15. Herbert C, Nichol A, Olivotto I, et al. The Impact of Hypofractionated Whole Breast Radiotherapy on Local Relapse in Patients with Grade 3 Early Breast Cancer: A Population-based Cohort Study. Int J Radiat Oncol Biol Phys. 2012;82(5):2086-92.
16. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008;9(4):331-41.
17. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008;371(9618):1098-107.
18. Yarnold J, Ashton A, Bliss J, et al. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial. Radiother Oncol. 2005;75(1):9-17.
19. National Breast and Ovarian Cancer Centre. A systematic literature review of hypofractionated radiotherapy for the treatment of early breast cancer. NBOCC, Surry Hills NSW, 2010.
20. Cancer Australia. Hypofractionated radiotherapy for the treatment of early breast cancer: an updated systemantic review. Cancer Australia, Surry Hills, 2014.
21. FAST Trialists group, Agrawal RK, Alhasso A, et al. First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015). Radiother Oncol. 2011;100(1):93-100.
22. Fisher CM and Rabinovitch R. Frontiers in radiotherapy for early-stage invasive breast cancer. J Clin Oncol. 2014;32(26):2894-901.
23. Smith BD, Bentzen SM, Correa CR, et al. Fractionation for Whole Breast Irradiation: An American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline. Int J Radiat Oncol Biol Phys. 2011;81(1):59-68.
24. Hopwood P, Haviland JS, Sumo G, et al. Comparison of patient-reported breast, arm, and shoulder symptoms and body image after radiotherapy for early breast cancer: 5-year follow-up in the randomised Standardisation of Breast Radiotherapy (START) trials. Lancet Oncol. 2010;11(3):231-40.
25. Haffty BG and Buchholz TA. Hypofractionated breast radiation: preferred standard of care? Lancet Oncol. 2013;14(11):1032-4.
26. Chan EK, Woods R, McBride ML, et al. Adjuvant hypofractionated versus conventional whole breast radiation therapy for early-stage breast cancer: long-term hospital-related morbidity from cardiac causes. Int J Radiat Oncol Biol Phys. 2014;88(4):786-92.
27. Chan EK, Woods R, Virani S, et al. Long-term mortality from cardiac causes after adjuvant hypofractionated vs. conventional radiotherapy for localized left-sided breast cancer. Radiother Oncol. 2014.

Membership of Hypofractionated Radiotherapy Working Group

In 2014, the update was overseen by a multidisciplinary working group convened by Cancer Australia:

• Dr Marie-Frances Burke (Chair) - Radiation Oncologist
• Ms Jan Rice - Breast care nurse
• Dr Kirsty Stuart - Radiation Oncologist
• Dr Patsy Soon - Breast Surgeon
• Ms Bronwyn Wells - Consumer representative

The orginal guideline was developed by a multidisciplinary working group convened by NBOCC ^[1].

• A/Prof Boon Chua (Chair) - Radiation Oncologist
• Dr Marie-Frances Burke - Radiation Oncologist
• Prof Geoff Delaney - Radiation Oncologist
• Dr Jane O’Brien - Breast Surgeon
• Ms Jan Rice - Breast Care Nurse
• Ms Geraldine Robertson - Consumer Representative
• Dr Kirsty Stuart - Radiation Oncologist

Topic-specific guideline development process

Priority topic areas for guideline development are determined in consultation with key stakeholders including experts in relevant disciplines and consumer representatives. A specific multidisciplinary Working Group, including consumers, is established for each topic identified and is involved in all aspects of guideline development. A systematic evidence review is undertaken for each guideline. All members are asked to declare any conflicts of interest and these declarations are recorded.  The content of the guideline is not influenced by any external funding body. The guideline is reviewed externally by key stakeholders and the wider community and endorsement is sought from relevant professional colleges and groups in Australia.

[1] In July 2011, NBOCC amalgamated with Cancer Australia to form a single national agency, Cancer Australia, to provide leadership in cancer control and improve outcomes for Australians affected by cancer.

Grading methodology

To accurately assess the strength of evidence available, the NHMRC methodology (FORM) was used in this clinical practice guideline to grade recommendations. The aim of this approach by NHMRC is to assist clinical practice guideline developers with a structured process for evaluating the evidence base corresponding to a particular key clinical question, in the context of the setting in which it is to be applied.⁸

The grading methodology allows for both the quality of the evidence and the strength of recommendations to be determined. Where insufficient evidence exists to formulate a grade, a practice point may be assigned instead. The NHMRC grading framework allows for these practice points to be included when developers consider it is important to provide non-evidence-based guidance.⁸

The NHMRC Evidence Statement Form sets out the basis for rating five key components of the ‘body of evidence’ for each recommendation. These components are:

1. The evidence base, in terms of the number of studies, level of evidence and quality of studies (risk of bias).
2. The consistency of the study results
3. The potential clinical impact of the proposed recommendation
4. The generalisability of the body of evidence to the target population for the guideline
5. The applicability of the body of evidence to the Australian healthcare context⁹.

The first two components describe the internal validity of the study data in support of efficacy (for an intervention), accuracy (for a diagnostic test), or strength of association (for a prognosis or aetiological question). As suggested, the third component gives the likely clinical impact of the proposed recommendation. The final two components assess external factors that may influence the effectiveness of the proposed recommendation in practice, in terms of generalisability of study results to the intended target population for the Guideline and setting of the proposed recommendation, and applicability to the Australian (or other local) health care system.⁹

These described components should be rated according to the body of evidence matrix (refer to Table 9). The matrix system is used to summarise the rating of the five key components which allows each recommendation to be assigned an overall NHMRC Grade of Recommendation (A-D).⁸

Table 9: NHMRC Body of evidence matrix⁹

^#Level of evidence determined from the NHMRC evidence hierarchy
*If there is only one study, rank this component as ‘not applicable’
^{^}For example, results in adults that are clinically sensible to apply to children OR psychosocial outcomes for one cancer that may be applicable to patients with another cancer

There is also capacity to note any other relevant factors that were considered by the guideline developers and the respective Working Group when judging the body of evidence and developing the wording of the recommendation.

The NHMRC grades given (A-D) are intended to indicate the strength of the body of evidence underpinning the recommendation (refer to Table 7).  Grade A or B recommendations are generally based on a body of evidence that can be trusted to guide clinical practice, whereas Grades C or D recommendations must be applied cautiously to individual clinical and organisational circumstances and should be interpreted with care. A recommendation cannot be graded A or B unless evidence base and consistency of the evidence are both rated A and B respectively.⁸

Table 10: Definition of NHMRC grades of Recommendations^8,9 (Note: This table is replicated in "Grading of Clinical Practice Guidelines")

By referring to the statements of evidence in combination with the NHMRC body of evidence matrix, a grade for each recommendation was derived from the respective grades allocated to the five key components. Grading the components of consistency, clinical impact, generalisability and applicability, was undertaken by the Working Group members, who discussed each section, and based on consensus achieved across the Working Group, arrived at these ratings.

The use of the NHMRC evidence hierarchy Table, categorises the respective study level according to the study design (refer to Table 8). This is used to determine the respective grades for evidence base and consistency of the recommendation.

Implementing the NHMRC Evidence Hierarchy, each included study in a systematic review should be assessed according to the following three dimensions of evidence:

1. Strength of evidence (level of evidence, quality of evidence (risk of bias) and statistical precision.
2. Size of effect (assessing the clinical importance of the findings of each study and hence addressing the clinical impact component of the body of evidence matrix.
3. Relevance of evidence (translation of research evidence into clinical practice and is potentially the most subjective of the evidence assessments).

Table 11: NHMRC Evidence Hierarchy: designations of ‘levels of evidence’ according to type of research question⁹

Four Recommendations have been made based on the following key questions -

1. What is the effectiveness of hypofractionated radiotherapy compared to conventionally fractionated radiotherapy for the treatment of early breast cancer?
   
   In patients with early breast cancer who require post-operative whole breast radiotherapy who meet the following criteria:
   - aged 50 years and over
   - with pathological stage T1-2, N0, M0
   - who have undergone breast conserving surgery, with clear surgical margins
   
   Read more
   
    
2. What is the effectiveness of hypofractionated radiotherapy compared to conventionally fractionated radiotherapy for the treatment of early breast cancer?
   
   For patients who do not meet the selection criteria for Recommendation 1
   
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3. What is the optimal schedule for hypofractionated radiotherapy for the treatment of early breast cancer?
   
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4. What is the safety of hypofractionated radiotherapy compared to conventionally fractionated radiotherapy for the treatment of early breast cancer?
   
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