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Statements of Evidence

No.	STATEMENTS OF EVIDENCE	Level of evidence	Reference
In women with early (operable) breast cancer who have undergone total mastectomy:
1	There is insufficient evidence to inform the safety and efficacy of hypofractionated chest wall irradiation in women who have undergone mastectomy (total of 512 out of 8,367 (6%) patients across all studies).	I and II	Haviland 2013¹⁰ (START A and B) Spooner 2012¹¹ UK FAST trial 2011¹² Whelan 2010⁶ (Canadian trial) Owen 2006⁷ (RMH/GOC trial)
In women with early (operable) breast cancer who have undergone breast conserving surgery:
	Patient and tumour characteristics
2	Hypofractionated radiotherapy is equivalent to conventionally fractionated regimens of radiotherapy in women aged over 50 years (79% of included patients), with pathological stage T1-2 (78% of included patients), N0 (75% of included patients), M0 breast cancer (100% of included patients)	I and II	Haviland 2013¹⁰ (START A and B) Spooner 2012¹¹ UK FAST trial 2011¹² Whelan 2010⁶ (Canadian trial) Owen 2006⁷ (RMH/GOC trial)
3	Due to the relatively small numbers of patients in sub-group analyses of randomised trials, there is only limited evidence to inform the safety and efficacy of hypofractionated radiotherapy for women: aged less than 50 years with locally advanced breast cancer with node positive disease who receive chemotherapy and/or targeted biological therapies.	II	Haviland 2013¹⁰ (START A and B) Spooner 2012¹¹ UK FAST trial 2011¹² Whelan 2010⁶ (Canadian trial) Owen 2006⁷ (RMH/GOC trial)
	Tumour grade
4	An unplanned sub-group analysis of the Canadian trial showed that for patients with high grade tumours, the hypofractionated radiotherapy regimen of 42.5 Gy in 16 fractions over 22 days was associated with a higher local recurrence rate compared with conventionally fractionated radiotherapy at 12 years follow-up (p=0.01). An updated analysis of the Canadian trial reported no statistically significant difference for local recurrence between grade 1-2 and grade 3 breast cancers (p=0.11).	II II	Whelan 2010⁶ (Canadian trial) Bane 2014¹⁴
5	A meta-analysis of the START A, START B trial and their pilot study reported no statistically significant difference in locoregional relapse between grade 1 and 2 tumours and grade 3 tumours (p=0.12).	I	Haviland 2013¹⁰
6	A retrospective population based cohort study 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).	IV	Herbert 2011¹⁵
	Optimal schedule
7	Two 3-week hypofractionated schedules, from three randomised controlled trials with 9.9 to16.9 years follow-up, demonstrated comparable rates of optimal tumour control and radiation therapy effects: 40 Gy in 15 fractions given at the rate of one fraction per day, 5 fractions per week over 21 days 42.5 Gy in 16 fractions given at the rate of one fraction per day, 5 fractions per week over 22 days	II	Haviland 2013¹⁰ (START B) Whelan 2010⁶ (Canadian trial) Spooner 2012¹¹
	Overall survival
8	No statistically significant difference in overall survival rates were reported for women treated with hypofractionated radiotherapy compared with patients treated with conventionally fractionated radiotherapy at 10-16.9 years follow-up.	II	Haviland 2013¹⁰ (START A) Spooner 2012¹¹ Whelan 2010⁶ (Canadian trial)
9	One randomised controlled trial reported that a hypofractionated radiotherapy regimen of 40 Gy in 15 fractions over 21 days was associated with a statistically significant lower all-cause mortality, with up to 10 years follow-up, compared with conventionally fractionated radiotherapy; HR=0.80 (95% CI 0.65-0.99), p=0.042.	II	Haviland 2013¹⁰ (START B)
	Disease-free survival
10	One randomised controlled trial reported no significant difference in disease-free survival between the hypofractionated radiotherapy schedules and the conventionally fractionated radiotherapy regimen (41.6 Gy vs. 50 Gy HR=0.94, 95% CI 0.75-1.17, p=0.57; 39 Gy vs. 50 Gy HR=1.08, 95% CI 0.87-1.35, p=0.48).	II	Haviland 2013¹⁰ (START A)
11	One randomised controlled trial reported that a hypofractionated radiotherapy regimen of 40 Gy in 15 fractions over 21 days is associated with a statistically significant higher rate of disease-free survival than conventionally fractionated radiotherapy; HR=0.79 (95% CI 0.65-0.97), p=0.022.	II	Haviland 2013¹⁰ (START B)
	Relapse-free survival
12	One randomised controlled trial reported no statistically significant difference in relapse-free survival between hypofractionated radiotherapy and conventionally fractionated radiotherapy; HR=0.98 (95% CI 0.75-1.29).	II	Spooner 2012¹¹
	Local relapse
13	Five randomised trials reported no statistically significant difference in rates of local relapse for women treated with hypofractionated radiotherapy and conventionally fractionated radiotherapy at 9.7 to 16.9 years follow-up.	II	Haviland 2013¹⁰ Spooner 2012¹¹ Whelan 2010⁶ (Canadian trial) Owen 2006⁷ (RMH/GOC trial)
14	A hypofractionated radiotherapy regimen of 39 Gy in 13 fractions over 35 days is associated with a statistically significant higher rate of local recurrence compared with a hypofractionated radiotherapy regimen of 42.9 Gy in 13 fractions over 35 days at 10 years follow- up.	II	Owen 2006⁷ (RMH/GOC trial)
	Local-regional relapse
15	Two randomised controlled trials reported no statistically significant difference in 10 year local-regional relapse rates between hypofractionated radiotherapy and conventionally fractionated radiotherapy.	II	Haviland 2013¹⁰ (START A and START B)
16	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 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.	II	Haviland 2013¹⁰ (START A and START B)
	Distant relapse
17	No statistically significant difference in distant relapse was reported in three randomised controlled trials between women receiving hypofractionated radiotherapy and patients receiving conventionally fractionated radiotherapy.	II	Haviland 2013¹⁰ (START A) Spooner 2012¹¹
18	One randomised controlled trial reported that a hypofractionated radiotherapy regimen of 40 Gy in 15 fractions over 21 days is associated with a statistically significant lower rate of distant relapse up to 10 years follow-up, than conventionally fractionated radiotherapy; HR=0.74 (95% CI 0.59-0.94), p=0.014.	II	Haviland 2013¹⁰ (START B)
	Adverse events
19	At 10 years follow-up, women receiving the hypofractionated radiotherapy regimens of 39 Gy in 13 fractions over 35 days (START A) and 40 Gy in 15 fractions over 21 days (START B) were statistically significantly less likely to experience moderate or marked breast shrinkage, telangiectasia, and breast oedema compared to the conventionally fractionated radiotherapy regimen.	II	Haviland 2013¹⁰ (START A and START B)
20	In a combined sub-group analysis of START A, START B and their pilot study the incidence of any moderate or marked physician-assessed normal tissue effects in the breast was not statistically significantly different between hypofractionated radiotherapy and conventionally fractionated radiotherapy irrespective of age, breast size, use of tumour bed boost radiotherapy, adjuvant chemotherapy, or tamoxifen.	II	Haviland 2013¹⁰ (START A and START B)
21	One randomised controlled trial reported that global cosmetic outcome worsened over time for women treated with either hypofractionated radiotherapy or conventionally fractionated radiotherapy, however there were no statistically significant differences observed over 10 years between the hypofractionated regimen of 42.5 Gy in 16 fractions over 22 days and the conventionally fractionated regimen.	II	Whelan 2010⁶ (Canadian trial)
22	One randomised controlled trial demonstrated a statistically significant dose response between 28.5 Gy in five once-weekly fractions of 5.7 Gy and 30 Gy in five once-weekly fractions of 6 Gy regimens, with worse results for change in photographic breast appearance at 2 years (p=0.002) in the 30 Gy patients and comparable rates for 28.5 Gy, compared with conventionally fractionated radiotherapy.	II	UK FAST trialists 2011¹²
23	One randomised controlled trial reported that three-year rates of physician-assessed moderate/marked adverse effects in the breast were significantly higher in women receiving hypofractionated radiotherapy regimen of 30 Gy in 5 once weekly fractions of 6 Gy over 5 weeks compared with conventionally fractionated radiotherapy (p=<0.001) and the hypofractionated regimen of 28.5 Gy in 5 once weekly fractions of 5.7Gy over 5 weeks (p=<0.006). The rates were not statistically significantly different between the 28.5 Gy and 50 Gy groups.	II	UK FAST trialists 2011¹²
24	One randomised controlled trial reported that the hypofractionated radiotherapy regimen of 39 Gy in 13 fractions over 35 days was associated with a lower risk of developing any late radiation effect than a conventionally fractionated radiotherapy regimen at 10 years follow-up. However, the hypofractionated regimen of 42.9 Gy in 13 fractions over 35 days was associated with a higher risk of developing any late radiation effect than a conventionally fractionated radiotherapy regimen at 10 years follow-up.	II	Owen 2006⁷ (RMH/GOC trial)
	Cardiac toxicity
25	Although follow-up of 9.3 to 9.7 years is shorter than desired for late cardiac effects (i.e., 15-20 years), two randomised controlled trials observed no major difference between fractionation schedules for the number of women with left-sided primary tumours who subsequently experienced cardiac disease related death.	II	Haviland (2013) (START A and START B)
26	A third randomised controlled trial with only 3.1 years of follow-up observed no difference in the rates of cardiac disease related deaths for left- versus right-sided tumours.	II	UK FAST trialists 2011¹²
	Quality of life
27	No statistically significant differences in quality of life scores were found in women undergoing radiotherapy after surgery between hypofractionated and conventionally fractionated radiotherapy regimens at 5 years follow-up.	II	Bentzen 2008¹⁶ (START A) Bentzen 2008¹⁷ (START B)
	Regional nodal radiotherapy
28	There is insufficient evidence due to small or unreported sub-groups of patients in the included trials to support the use of hypofractionated regional nodal radiotherapy.	II	Bentzen 2008¹⁶ (START A) Bentzen 2008¹⁷ (START B) Yarnold 2005¹⁸ (RMH/COG trial)
29	A four-field radiotherapy technique targeting the breast, ipsilateral axillary and supraclavicular lymph nodes was used in the Spooner study. At median follow-up of 16.9 years, hypofractionated radiotherapy was equivalent to conventionally fractionated radiotherapy.	II	Spooner 2012¹¹
	Tumour bed boost
30	In a post hoc combined sub-group analysis (n=5,861) of START A, START B and their pilot study, patients received a boost of 10 Gy in 5 fractions (planned before randomisation). There was no statistically significant difference in local-regional relapse rates nor 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.	I	Haviland 2013¹⁰ (START A and START B, RMH/COG trial)
31	All irradiated patients in the Spooner trial (n=358) received a supplementary boost to the tumour bed with a direct 10-14 mega electronvolt (MeV) electron field of 15 Gy in five daily fractions. At median follow-up of 16.9 years, hypofractionated radiotherapy was equivalent to conventionally fractionated radiotherapy, including tumour bed boost.	II	Spooner 2012¹¹
	Chemotherapy/targeted therapies
32	There is insufficient evidence due to small or unreported sub-groups of patients in the included trials to determine the safety and efficacy of hypofractionated radiotherapy for women who receive chemotherapy and/or targeted biological therapies.	II	Whelan 2010⁶ (Canadian trial) Bentzen 2008¹⁶ (START A) Bentzen 2008¹⁷ (START B) Owen 2006⁷ (RMH/COG trial)

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