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Summary of Trial Results

Trial and patient characteristics

Recommendations and statements of evidence have been made on the basis of the patient populations of the randomised trials. In some instances, patient populations included in sub-group analysis including age, tumour size and grade, use of tumour bed boost and use of adjuvant systemic therapies were smaller than required to infer broad clinical recommendations.

Table 1 identifies trial populations and primary outcomes measured. Of note:

  • Five trials identified the patient population characteristics as early invasive breast cancer T1-3, N0-1, M0.6-12
  • RMH/GOC and the Canadian trial limited the trial populations to those who had breast conserving surgery only.6-7, 9, 11
  • Women participating in the Spooner, START A or START B trials had breast conserving surgery or mastectomy.8, 10, 12

Table 1: Trial characteristics

Trial Population Median follow-up (range) years Intervention Comparator Outcomes measured
Post breast conserving surgery
RMH/GOC7, 9

T1-3, N0-1, M0

<75 years

9.7

(7.8-11.8)  

39 Gy in 13 fractions over 5 weeks

(n=474)

42.9 Gy in 13 fractions over 5 weeks

(n=466)

50 Gy in 25 fractions over 5 weeks

(n=470)

Local recurrence
Cosmetic outcomes
Canadian6,11 Invasive carcinoma with negative axillary nodes

12

(range not reported)

42.5 Gy in 16 fractions over 22 days

(n=622)

50 Gy in 25 fractions over 35 days

(n=612)

Local recurrence

Overall survival

Adverse events and toxicity

Cosmetic outcome

Post breast conserving surgery or mastectomy
START A10 T1-3a, N0-1, M0

5.1

(4.4-6.0)

39 Gy in 13 fractions over 5 weeks

(n=737)

41.6 Gy in 13 fractions over 5 weeks

(n=750)

50 Gy in 25 fractions over 5 weeks

(n=749)

Local recurrence

Overall survival

Adverse events and toxicity

Cosmetic outcome

Quality of life

START B12 T1-3a, N0-1, M0

6.0

(5.0-6.2)

40 Gy in 15 fractions over 3 weeks

(n=1110)

50 Gy in 25 fractions over 5 weeks

(n=1105)

Local recurrence

Overall survival

Adverse events and toxicity

Cosmetic outcome

Quality of life

Spooner8

Note: Conference abstract only, limited information available.

Stage 1 and 2 Median tumour size 2.0cms

16.9

(15.4-18.8)

40 Gy in 15 daily fractions

or

50 Gy in 25 daily fractions

Delayed salvage treatment



Time to first relapse
n=707

Table 2 identifies key characteristics of patients involved in four of the randomised controlled trials

Table 2: Patient characteristics

 

RMH/GOC

n=1410

Yarnold9

Canadian

n=1234

Whelan11

START A

n=2236

Bentzen10

START B

n=2215

Bentzen12

  n % n % n % n %
Treated with breast conserving surgery 1410 100% 1234 100% 1900 85% 2038 92%
Age >50 years 987 70% 929 75% 1727 77% 1758 79%
T0-2 1383 98% 994 81% 1741 78% 1987 90%
N0 564 40% 1234 100%16 1547 69% 1635 74%
Adjuvant treatment
None 289 21% 593 48% 172 8% 84 4%
Tamoxifen only 918 65% 505 41% 1210 54% 1592 72%
Chemotherapy only 40 3% 136 11% 245 11% 155 7%
Tamoxifen + chemotherapy 156 11% 0 0% 548 25% 336 15%
Other 7 1% 0 0% 47 2% 27 1%
High tumour grade  NR NR 233 19% 629 28% 509 23%

NR=Not Reported

Local Recurrence

Four trials reported on local recurrence.6-7, 10-12 There was no evidence that hypofractionated radiotherapy regimens were associated with a statistically significant difference in local recurrence rate when compared with the control arms of 50 Gy in 25 fractions over 5 weeks.6-7, 10, 12RMH/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


Subgroup analyses

Table 3 includes the local tumour recurrence rates reported by the randomised trials. Subgroup analyses for local recurrence were performed in one trial.6 Analyses showed that treatment effect was similar regardless of age, tumour size, oestrogen-receptor status, and use of systemic therapy.

The Canadian, START A and START B trials included 19%, 28% and 23% of patients with high-grade tumours respectively. Among these women at 12 years follow-up, the Canadian trial reported a 10-year local recurrence rate of 15.6% for patients treated with hypofractionated radiotherapy compared to 4.7% for patients who received conventionally fractionated radiotherapy.6 Results of the START A and START B trials at 8 years follow-up concluded that hypofractionated radiotherapy was equally effective for high and non-high grade breast cancers.16

In addition, a retrospective cohort study of patients with grade 3 tumours reported no evidence for inferiority in local control for hypofractionated radiotherapy (42.5-44 Gy in 16 fractions). The 10-year cumulative incidence of local relapse was 6.9% (95% CI 5.4-8.5%) for the hypofractionated group (n=1083) and 6.2% (95% CI 3.6-9.8%) for the conventional fractionation group (n=252) (p=0.99).19 

Table 3: Five year rates for local recurrence20

Trial Median follow-up (range)
years
Treatment group Five year local tumour recurrence rate (%)
RMH/GOC7, 9 9.7
(7.8-11.8)  
50 Gy in 25 fractions over 5 weeks 12.1
42.9 Gy in 13 fractions over 5 weeks 9.6
39 Gy in 13 fractions over 5 weeks 14.8
Canadian6, 11 12
(not reported)
50 Gy in 25 fractions over 5 weeks 3.2^
42.5 Gy in 16 fractions over 22 days 2.8^
START A10 5.1
(4.4-6.0)
50 Gy in 25 fractions over 5 weeks 3.2
41.6 Gy in 13 fractions over 5 weeks 3.2
39 Gy in 13 fractions over 5 weeks 4.6
START B12 6.0
(5.0-6.2)  
50 Gy in 25 fractions over 5 weeks 3.3
40 Gy in 15 fractions over 3 weeks 2.0

^ 6.7% and 6.2% at 10 years

Loco-regional recurrence

Two trials reported on loco-regional recurrence rates.10, 12 There was no evidence that any hypofractionated regimen was associated with a statistically significant difference in local-regional recurrence rate when compared with the control arms of 50 Gy in 25 fractions over 5 weeks.10, 12

Distant recurrence

Two trials reported on distant recurrence.10, 12 START B reported that the hypofractionated regimen of 40 Gy in 15 fractions over 3 weeks had a statistically significantly lower rate of distant relapse when compared with the conventional regimen of 50 Gy in 25 fractions over 5 weeks (HR 0.69 95% CI 0.53-0.91 p=0.01).12 START A found no statistical difference between hypofractionated radiotherapy and the conventionally fractionated regimen (41.6 Gy arm, HR 0.92 95% CI 0.66-1.28, p=0.64; 39 Gy arm, HR 1.29 95% CI 0.95-1.76, p=0.10).10

Overall survival

Four trials reported on overall survival.6, 8, 10, 12 START B found that 40 Gy in 15 fractions over three weeks was associated with a statistically significantly lower all-cause mortality when compared to 50 Gy in 25 fractions over five weeks (HR 0.76 95% CI 0.59-0.98, p=0.03).12 The three other trials found no statistically significant difference in overall survival between hypofractionated and conventional regimens. Therefore, there was no evidence that hypofractionated radiotherapy was associated with worse overall survival in comparison to conventionally fractionated radiotherapy.

Adverse events and cosmetic outcomes

Four trials reported on adverse events and cosmetic outcomes.6, 9-10, 12 Across the four trials and radiotherapy regimens tested, 30-55% of women experienced some change in breast appearance.


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.9

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).9 

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).9


START A and START B trial results

START A found 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.10 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.10

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.10

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).12 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).12

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 arms 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).18


Other adverse events

Three trials investigated the incidence of symptomatic lung fibrosis and symptomatic rib fracture.10-12 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.10 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).11 One woman in the 50 Gy treatment group experienced rib fracture attributed to radiation therapy.11

While damage to the pectoral muscle has been highlighted as a possible concern,20 none of the trials reported this outcome. 

Cardiac toxicity

No trials reported the long-term effects of radiotherapy on cardiac tissues; however the START A authors noted the need to protect the heart from exposure to radiotherapy as a priority.10 The Canadian trial identified no significant difference in overall survival between the conventional and hypofractionated radiotherapy regimens; at a median follow-up of 12 years, few cardiac-related deaths were observed, and no increase occurred in patients who received the hypofractionated schedule.6 

The START A and START B trials report that the incidence of ischaemic heart disease was low at five years follow-up; however, the authors noted that 15-20 years of follow-up would be required to reliably measure the late normal tissue effects including cardiac damage.10, 12

Quality of life

Two trials reported quality of life outcomes using the European Organisation for Research and Treatment of Cancer (EORTC) breast cancer module.10, 12 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.18 Subgroup analysis by surgery type was performed. The small numbers of patients and events in some subgroups 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. 10, 12

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.11 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

Three trials included women undergoing regional nodal radiotherapy.9-10, 12 RMH/GOC trial reported that 20.6% of patients underwent regional nodal radiotherapy to the axilla and/or supraclavicular fossa.9 There were no recorded cases of brachial plexopathy among these women. 

START A reported that the decision to administer regional nodal radiotherapy was made pre-randomisation and was used in approximately 14% of patients.10 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.10

START B reported that 7.3% of patients received regional nodal radiotherapy.12 No cases of brachial plexopathy were reported among the women given radiotherapy to the supraclavicular fossa, axilla or both.12

Use of tumour bed boost

Tumour bed boost was used in three of the randomised trials.9-10, 12 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.10 There was a statistically significant reduced risk of induration (p=0.001) and telangiectasia (p=0.026) in patients randomised to no boost.9

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.10, 12

Use of adjuvant systemic therapies

Four trials included women who received adjuvant systemic therapies.6-7, 10, 12 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.7, 9-10, 12 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.10, 12 

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

Delivery of radiotherapy

Four trials provided information on the radiotherapy techniques used. Patients in all four 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.

In all four trials, 6-megavoltage x-rays were used for most patients but higher energy megavoltage x-rays or cobalt x-rays were also used.  Where regional radiotherapy was indicated, the target volume included the supraclavicular nodes with or without the axillary nodes.7, 10, 12

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, 9-12 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, 10-12 RMH/GOC and Canadian trials reported the use of wedge tissue compensators to ensure a uniform dose distribution throughout the target volume.7, 9, 11

Three trials included women allocated to receive a tumour bed boost.9-10, 12Women 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.9 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.10, 12

*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.  

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