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.
| Trial | Median follow-up (range) years | Treatment group | Five year local tumour recurrence rate (%) |
|---|---|---|---|
|
RMH/GOC7 |
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 |
12 (range not reported) |
50 Gy in 25 fractions over 5 weeks |
3.2^ |
|
42.5 Gy in 16 fractions over 22 days |
2.8^ |
||
|
Spooner 2012 |
16.9 (3.7-21.8) |
50 Gy in 25 fractions over 5 weeks |
9.6 |
|
40 Gy in 15 fractions over 3 weeks |
6.6 |
^6.7% and 6.2% at 10 years
Table 6: START A and START B relapses
| Events (n/patients; %) | Estimated proportion of patients with event by 5 years (%; 95% CI) | Estimated proportion of patients with event by 10 years (%; 95% CI) | Crude hazard ratio (95% CI) | P value | |
|---|---|---|---|---|---|
|
START A |
|||||
|
Local relapse |
|||||
|
50 Gy |
40/749 (5.3%) |
3.4% (2.3-5.1) |
6.7% (4.9-9.2) |
1.00 |
|
|
41.6 Gy |
37/750 (4.9%) |
3.1% (2.0-4.7) |
5.6% (4.1-7.8) |
0.90 (0.57-1.40) |
0.63 |
|
39 Gy |
47/737 (6.4%) |
4.4% (3.1-6.2) |
8.1% (6.1-10.7) |
1.20 (0.79-1.83) |
0.39 |
|
Local-regional relapse |
|||||
|
50 Gy |
45/749 (6.0%) |
4.0% (2.8-5.7) |
7.4% (5.5-10.0) |
1.00 |
|
|
41.6 Gy |
42/750 (5.6%) |
3.8% (2.6-5.5) |
6.3% (4.7-8.5) |
0.91 (0.59-1.38) |
0.65 |
|
39 Gy |
52/737 (7.1%) |
5.1% (3.7-7.1) |
8.8% (6.7-11.4) |
1.18 (0.79-1.76) |
0.41 |
|
Distant relapse |
|||||
|
50 Gy |
100/749 (13.3%) |
9.8% (7.9-12.3) |
14.7% (12.2-17.7) |
1.00 |
|
|
41.6 Gy |
110/750 (14.7%) |
9.5% (7.6-11.9) |
16.8% (14.0-20.0) |
1.08 (0.82-1.41) |
0.58 |
|
39 Gy |
121/737 (16.4%) |
11.8% (9.7-14.4) |
18.0% (15.1-21.2) |
1.24 (0.95-1.61) |
0.11 |
|
START B |
|||||
|
Local relapse |
|||||
|
50 Gy |
50/1105 (4.5%) |
3.3% (2.4-4.6) |
5.2% (3.9-6.9) |
1.00 |
|
|
40 Gy |
36/1110 (3.2%) |
1.9% (1.2-3.0) |
3.8% (2.7-5.2) |
0.70 (0.46-1.07) |
0.10 |
|
Local-regional relapse |
|||||
|
50 Gy |
53/1105 (4.8%) |
3.5% (2.5-4.8) |
5.5% (4.2-7.2) |
1.00 |
|
|
40 Gy |
42/1110 (3.8%) |
2.3% (1.5-3.4) |
4.3% (3.2-5.9) |
0.77 (0.51-1.16) |
0.21 |
|
Distant relapse |
|||||
|
50 Gy |
158/1105 (14.3%) |
10.5% (8.8-12.5) |
16.0% (13.8-18.5) |
1.00 |
|
|
40 Gy |
121/1110 (10.9%) |
7.5% (6.0-9.2) |
12.3% (10.3-14.6) |
0.74 (0.59-0.94) |
0.014 |
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.
| Key outcomes | START A | START B | Spooner 2012 | Canadian trial | RMH/GOC trial |
|---|---|---|---|---|---|
|
Local recurrence |
Equivalent 41,6 Gy HR=0.90, p=0.63; 39 Gy HR=1.20, p=0.39 |
Equivalent HR=0.70, p=0.10 |
Equivalent HR and p-value NRc |
Equivalent 6.2% in hypofractionated vs. 6.7% in control at 10yrsd |
Equivalent hypofractionated vs. control. Superior for 42.9Gy vs. 39Gy 9.6% vs. 14.8% p=0.027 e |
|
Local-regional recurrence |
Equivalent 41.6 Gy HR=0.91, p=0.65; 39 Gy HR=1.18, p=0.41a |
Equivalent HR=0.77, p=0.21b |
NR |
NR |
NR |
|
Distant relapse |
Equivalent 41.6 Gy HR=1.08, p=0.58; 39 Gy HR=1.24, p=0.11 |
Superior for hypofractionated radiotherapy HR=0.74, p=0.014 |
Equivalent HR and p-value NR |
NR |
NR |
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