Nodal Sub-Study

Recruitment

The original target accrual for the Nodal Sub-Study was 627 patients to be recruited over 2 years. The first patient was recruited into the sub-study on 11 April 2016. Accrual was suspended from 6 December 2017 until 23 January 2018 while the substantial protocol amendment to close accrual into Test Group 1 (27 Gy/5 fractions) for the sub-study was being processed for approval. At this stage a total of 109, 104 and 97 patients had been recruited into the 40 Gy/15 fractions, 27 Gy/5 fractions and 26 Gy/5 fractions groups, respectively. In Protocol v5.0 (14 December 2017) target recruitment for the sub-study was changed to 344 patients (172 in each of the Control Group and Test Group 1). Including the additional 104 patients randomised to Test Group 1 before the protocol amendment the revised overall target sample size was 448. Having reached the revised target accrual into the Nodal Sub-Study, centres were contacted on 29 August 2018 and asked not to approach any new patients regarding the trial. A few additional patients were subsequently randomised who had been previously approached and given information about the trial prior to this date, and the last patient was randomised on 2 October 2018.

The final number of patients entered into the Nodal Sub-Study was 469 from 28 RT centres and 22 referral centres (183 for 40 Gy/15 fractions, 104 for 27 Gy/5 fractions and 182 for 26 Gy/5 fractions). Four hundred and sixteen patients were recruited into the photographic assessment sub-study, 442 patients consented to donate a blood sample and 465 patients consented to donate their primary tissue sample. Recruitment figures according to centre are presented in Appendix 2, Table 32. Cumulative recruitment over time compared with the target recruitment rate is shown in Figure 18.

FIGURE 18 Target and actual recruitment for Nodal Sub-Study. (Figure not reproduced here; see the original article.)

The original target for recruitment was based on five centres opening to recruitment once the Nodal Sub-Study opened with a further two centres expected to open per month until a total of 49 centres were open to recruitment. Each centre was predicted to recruit two patients per month with a maximum of 30 patients per month. Using these figures it was predicted that recruitment would take 24 months to attain. Radiotherapy centres were asked to obtain and additional QA approval procedure and only 32 centres undertook this. Fifty-two centres opened to recruitment to the Nodal Sub-Study with a maximum of 31 patients recruited in any 1 month. Two centres did not recruit any patients.

Deviations and withdrawals

Two patients withdrew consent for use of data and were removed from the intention-to-treat population, therefore Nodal Sub-Study results are reported for 467 consenting patients. A total of 18 patients (8 in 40 Gy, 4 in 27 Gy, 6 in 26 Gy) did not receive the allocated therapy (see Figure 19); compliance with allocated treatment was therefore 96% (449/467). These 18 patients included two found to be ineligible after randomisation: 1 in the 40 Gy group (Non-Hodgkins lymphoma), and 1 in 26 Gy (no axillary staging due to comorbidities).

FIGURE 19 FAST-Forward Nodal Sub-Study profile (CONSORT diagram). (Figure not reproduced here; see the original article.)

By 3 years’ follow-up 10 patients had withdran from clinical follow-up (9 in 40 Gy and 1 in 26 Gy), and 49 had died (19 in 40 Gy, 10 in 27 Gy, 20 in 26 Gy).

Data returns

Data return rates were calculated as % of CRFs or questionnaires received at ICR-CTSU out of those expected (expected numbers exclude patients who have died or withdrawn). Baseline CRFs were available for 99% of patients. As of 24 January 2022, annual clinical follow-up forms had been returned to the trials office for 98% (441 received out of 451 expected) for year 1, 99% (433/435) for year 2, and 90% (376/420) for year 3. As of the date of this report, all Nodal Sub-Study patients have reached the 3-year time point and further follow-up is ongoing, hence the Consolidated Standards of Reporting Trials diagram and results for the Nodal Sub-Study presented in this report include data up to 3 years. Analysis of follow-up beyond 3 years in the Nodal Sub-Study will be done in the future once data collection is complete.

Return rates for the patient self-completed questionnaires up to 2 years’ follow-up were 98% (460 received out of 467 expected) at baseline, 89% (386/434) at 3 months, 89% (379/427) at 6 months, 87% (359/415) at 1 year and 89% (367/414) at 2 years. As of the date of this report, collection of 5-year questionnaires is underway, with the last one due in October 2023.

Baseline data

Baseline demographic, clinical and treatment characteristics according to treatment group are shown in Table 22, enabling the following comparisons: (1) all patients randomised to 40 Gy versus all those randomised to 26 Gy, and (2) patients randomised to 40 Gy up to end 2017 versus all those randomised to 27 Gy. The median age of all Nodal Sub-Study patients was 60 years (IQR 51–70; overall range 31–89), and it included four men. A total of 250 (53%) were grade 2 and 182 (39%) grade 3. Just over half (255, 55%) had BCS, and 43/212 (20%) mastectomy patients had an immediate breast reconstruction. The majority of patients had axillary clearance (254/467, 54%). Median pathological tumour size was 2.6 cm (IQR 0.9–7.2). The majority of patients were ER positive, HER-2 negative (325, 70%). A total of 113 (24%) received neo-adjuvant chemotherapy, and 216 (46%) received adjuvant chemotherapy; 13 patients received both neo-adjuvant and adjuvant chemotherapy.

Radiotherapy details for the 458 patients who received RT are shown in Table 23. Deviations from allocated treatment are described above. A tumour bed boost was prescribed for 117/458 (25%) of patients, most commonly to a dose of 10 Gy in 5 fractions (58/117, 50%). For the overall trial cohort the median breast/chest wall PTV was 870 cc (IQR 269–1954), and median nodal PTV was 134.6 cc (IQR 41.5–357.2). Bolus was used for 89 of the 209 (43%) mastectomy patients who received RT.

Follow-up

As of the data snapshot on 1 December 2021, median follow-up in each treatment group was 36 months (IQR 31–48) for all 40 Gy/15 fractions patients, 37 months (IQR 31–48) for 26 Gy/5 fractions and 48 months (IQR 37–49) for 27 Gy/5 fractions. Median follow-up in 40 Gy/15 fractions patients randomised prior to the December 2017 protocol amendment (i.e. concurrently with 27 Gy/5 fractions) was 47 months (IQR 34–48). Centres were requested to schedule annual follow-up assessments as close to the due date as possible, which was calculated from date of randomisation. Some leeway was permitted within the trial to accommodate local hospital policy that schedules follow-up based on date of surgery rather than date of trial randomisation. Annual clinical follow-ups occurred within 3 months of the due date in 86% of cases (1054 of 1220 clinical follow-ups).

Annual clinical follow-ups were primarily conducted in person at sites prior to the COVID-10 pandemic. On 1 April 2020 sites were advised that these could be done via telephone by a healthcare professional, and guidance was provided regarding the clinical assessments to be carried out at each visit.

Late normal tissue effects in Nodal Sub-Study

As stated in the Statistical Methods section (see Chapter 2), formal comparisons of NTE in the Nodal Sub-Study will await 5-year follow-up. Descriptive data for PRO up to 2 years and for clinical assessments up to 3 years are included in this report.

Patient-reported outcomes

PRO were available at baseline for 180 patients in the 40 Gy group, 181 in 26 Gy and 103 in 27 Gy, and at 24 months for 127, 135 and 89, respectively.

Symptoms in arm, shoulder or hand

Frequencies of PRO relating to arm/shoulder/hand symptoms from baseline to 24 months are shown in Table 24 for 40 Gy compared with 26 Gy (all randomised patients), and in Table 25 for 40 Gy and 27 Gy patients randomised up to the end of 2017. For all outcomes relating to arm, shoulder or hand, the number of patients reporting marked effects was small at all time points in all treatment groups. Appendix 2, Table 55 shows baseline arm/shoulder/hand symptoms according to maximal extent of axillary surgery and fractionation schedule.

The majority of patients reported no arm/hand swelling (primary outcome of the Nodal Sub-Study) from baseline up to 24 months, with 80% and 77% in 40 Gy and 26 Gy at baseline and 73% and 76% at 24 months (see Table 24). For the comparison of 40 Gy and 27 Gy, 81% and 84% reported no arm/hand swelling at baseline, and 74% and 66% at 24 months (see Table 25). Most of those reporting arm/hand swelling had mild symptoms (graded as ‘a little’ on the questionnaires). The prevalence of moderate or marked arm/hand swelling at 24 months (corresponding to ‘quite a bit’ or ‘very much’) was 10% versus 7% for 40 Gy compared with 26 Gy, and 8% versus 14% for 40 Gy compared with 27 Gy.

The most frequently reported effect in the arm, shoulder or hand across all time points was pain in the arm or shoulder, with symptoms (any grade) reported at baseline by 64% in 40 Gy, 60% in 26 Gy and 67% in 27 Gy. However, most of these were mild symptoms, with moderate or marked arm or shoulder pain reported at baseline by 15%, 22% and 20% in 40 Gy, 26 Gy and 27 Gy, respectively. At 24 months moderate or marked arm or shoulder pain was reported by 18%, 14% and 25% in 40 Gy, 26 Gy and 27 Gy, respectively.

The prevalence of moderate/marked neuropathic symptoms was low (see Tables 24 and 25). Pins and needles of any grade were reported at baseline by 28% in 40 Gy, 28% in 26 Gy and 28% in 27 Gy on the affected side and by 15% in 40 Gy, 18% in 26 Gy and 15% in 27 Gy on the non-affected side. Pins and needles of any grade were reported at 24 months by 34% in 40 Gy, 35% in 26 Gy and 44% in 27 Gy on the affected side and by 21% in 40 Gy, 18% in 26 Gy and 28% in 27 Gy on the non-affected side. However, most of these were mild symptoms, with moderate or marked pins and needles reported at baseline by 7%, 5% and 3% in 40 Gy, 26 Gy and 27 Gy, respectively on the affected side and by 5%, 3% and 2% in 40 Gy, 26 Gy and 27 Gy, respectively on the non-affected side. At 24 months moderate or marked pins and needles were reported by 9%, 9% and 6% in 40 Gy, 26 Gy and 27 Gy, respectively on the affected side and by 4%, 5% and 9% in 40 Gy, 26 Gy and 27 Gy, respectively on the non-affected side.

Symptoms in breast or chest wall

Frequencies of PRO relating to breast/chest wall symptoms from baseline to 24 months are shown in Table 26 for 40 Gy compared with 26 Gy (all randomised patients), and in Table 27 for 40 Gy and 27 Gy patients randomised up to the end of 2017. For outcomes relating to breast or chest wall symptoms, the number of patients reporting marked effects was generally small at all time points in all treatment groups.

The most frequently reported moderate or marked effect at 24 months was change in overall appearance of breast (as a result of any of the breast cancer treatments), which was reported by 47%, 38% and 58% of 40 Gy, 26 Gy and 27 Gy, respectively. Prevalence of moderate or marked effects were higher for the protocol-specific items than for the breast symptoms from the EORTC QLQ-BR23 breast module, which generally improved over time from 3 to 24 months following RT. Compared with PRO in the Main Trial, prevalence of symptoms from the EORTC QLQ-BR23 breast module for patients in the Nodal Sub-Study were similar, but frequencies of moderate or marked effects on the protocol-specific breast items were higher than reported in the Main Trial (see Chapter 5).

Frequencies of clinician assessments of radiation-related AE in the breast/chest wall and arm from 1 to 3 years following RT are shown in Table 28 for 40 Gy compared with 26 Gy (all randomised patients), and in Table 29 for 40 Gy and 27 Gy patients randomised up to the end of 2017.

The prevalence of clinician-reported arm lymphoedema remained relatively stable from 1 to 3 years following RT, with 8%, 12% and 11% in 40 Gy, 26 Gy and 27 Gy, respectively at year 3. Clinician-reported breast lymphoedema declined from 1 to 3 years, with 4%, 10% and 5% in 40 Gy, 26 Gy and 27 Gy, respectively at year 3. Frequencies of marked clinician-assessed AE in the breast or chest wall (graded as ‘very much’) were low across 1–3 years’ follow-up. The most frequently reported AE graded as moderate or marked by clinicians was breast distortion, with 20%, 8% and 14% in 40 Gy, 26 Gy and 27 Gy, respectively at 3 years.

Discussion of Nodal Sub-Study results is in the main Discussion section (see Chapter 8).