Safety Results

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.