Parts of this report are reproduced or adapted with permission from Brunt et al. 2020,1 Brunt et al. 20212 and Brunt et al. 2016.3 Sections of this report have also been reproduced from the FAST-Forward study protocol document, available from the NIHR Funding and Awards website.4 These are Open Access articles distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.
Background
Breast cancer and the multidisciplinary team
Breast cancer is globally the most commonly occurring cancer in women with over 2 million new cases in 2018, including 58,000 in the UK. It is rare in men, with around 300–400 cases per year in the UK. Since the early 1990s, breast cancer incidence rates in females have increased by around a quarter (24%).5 Despite increased incidence, UK mortality rates from breast cancer have fallen, due to advances in all aspects of breast cancer diagnosis and treatment, including radiotherapy (RT).
Breast cancer usually presents as symptoms such as a lump, nipple changes or a finding of an abnormal mammogram. Patients are generally assessed in a specific Breast clinic where they have a triple assessment involving clinical assessment, imaging (mammography/ultrasound) and a biopsy. A plan for treatment is then made in a multidisciplinary meeting which nearly always involves surgery to resect the cancer. In the modern era this is a wide local excision (breast-conserving therapy), or a mastectomy, along with nodal surgery. The resected tissue is examined by a pathologist to determine the size, grade, type, receptor profile and resection margins of the cancer along with other features. The lymph nodes may be selectively sampled (sentinel node biopsy) or all removed if involved (axillary clearance).
In larger, or more biologically aggressive cancers [triple negative and human epidermal growth factor receptor-2 (HER-2) positive] chemotherapy is now often given prior to surgery to downstage the cancer in the breast and the axilla, and to assess response to therapy, which may well alter subsequent treatment, including surgery, post-operative drug therapy and RT. Similarly in larger hormone receptor-positive HER-2 negative cancers, upfront antihormonal therapy may be given with similar intent. However, surgery is still used after the neoadjuvant therapy to remove any remaining cancer and to assess residual cancer burden.
Benefits and adverse effects of radiotherapy for patients with breast cancer
Radiotherapy uses high-energy X-rays to destroy cancer cells remaining in the breast after the main lump has been removed. Many studies have shown that this treatment substantially reduces the risk of cancer recurring in the breast and or lymph glands and improves overall survival. A meta-analysis from the Early Breast Cancer Trials Collaborative Group (EBCTCG) showed that after breast-conserving surgery, RT reduces relapse and breast cancer death.6 Increased risk of local relapse is associated with age under 50 years and grade 3 cancers. Other risk factors include cancer size, cancer biology, negative hormonal receptor status, HER-2 positive status, the presence of lymphovascular invasion and axillary node involvement. The absolute benefits of RT are greatest in those with the highest risk factors. The EBCTCG meta-analysis included individual patient data for 10,801 women in 17 randomised trials of RT versus no RT after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease. Overall, RT reduced the 10-year risk of any (i.e. locoregional or distant) first relapse from 35.0% to 19.3% [absolute reduction 15.7%, 95% confidence interval (CI) 13.7 to 17.7; 2p < 0.00001] and reduced the 15-year risk of breast cancer death from 25.2% to 21.4% (absolute reduction 3.8%, 1.6–6.0; 2p = 0.00005). In women with pN0 disease (n = 7287), RT reduced the first relapse risk from 31.0% to 15.6% (absolute relapse reduction 15.4%, 13.2 to 17.6; 2p < 0.00001) and risk of breast cancer death from 20.5% to 17.2% (absolute mortality reduction 3.3%, 0.8 to 5.8; 2p = 0.005), respectively. In these women with pN0 disease, the absolute relapse reduction varied according to age, grade, oestrogen-receptor (ER) status, tamoxifen use and the extent of surgery. These characteristics were used to predict large (≥ 20%), intermediate (10–19%), or lower (< 10%) absolute reductions in the 10-year relapse risk. The absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7.8% (95% CI 3.1 to 12.5), 1.1% (–2.0 to 4.2) and 0.1% (–7.5 to 7.7), respectively (trend in absolute mortality reduction 2p = 0.03). In the smaller number of women with pN+ disease (n = 1050), RT reduced the 10-year relapse risk from 63.7% to 42.5% (absolute reduction 21.2%, 95% CI 14.5 to 27.9; 2p < 0.00001) and the 15-year risk of breast cancer death from 51.3% to 42.8% (absolute reduction 8.5%, 1.8–15.2; 2p = 0.01). Overall, about one breast cancer death was avoided by year 15 for every four relapses avoided by year 10. The mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease.
Stepwise improvements in many aspects of patient management have led to a steady reduction in the absolute risk of relapse and death for patients over the decades. This reduction is due to many factors such as improved screening, better surgery with closer adherence to guidelines on achieving negative margins and advances in systemic therapy and RT techniques. A local relapse risk of around 2% at 5 years is a reasonable target to aim for in the current era, although the absolute risk will be higher in younger patients with grade 3 tumours and may be lower in elderly patients with grade 1 tumours. Currently patients at extremely low risk of relapse following surgery are commonly recommended no adjuvant RT based on studies such as PRIME.7
The absolute benefit of RT for each patient is considered by the multidisciplinary team based on the biological and pathological staging of the tumour, type of surgery and patient factors, including age and comorbidities. The main short-term side effects of RT are tiredness, skin colour changes, discomfort and swelling (oedema). Long-term side effects may develop over many years following RT and these are thought to be due to damage to the small blood vessels supplying tissue that has been irradiated. Long-term side effects include the following: (1) skin changes, where the treatment area appears permanently tanned after treatment has finished, although this is not harmful. Later, the skin might appear to have very tiny broken veins in the skin called telangiectasia. (2) Breast shrinkage or distortion; RT can make the breast tissue contract so that the breast gradually gets smaller. This can happen to natural breast tissue or a reconstructed breast. An implant in a reconstructed breast can become hard (capsular contracture) and may need replacing. (3) Breast induration, where the breast feels hard and less stretchy; this is due to a side effect called radiation fibrosis. (4) Cough and breathlessness may occur in some patients who have RT to the chest area although this is not common. The problems are due to changes in the lung tissue called chronic radiation pneumonitis. They might start many months or a few years after treatment. The chances of this happening increase if the volume of lung irradiated increases, or if the patient has pre-existing lung conditions. (5) Irradiation of the ribs or clavicle may lead to radiation osteitis or rarely to osteoradionecrosis which may cause non-healing fractures. (6) Radiotherapy may cause nerve damage in the arm on the treated side, which can develop many years after treatment. Symptoms include tingling, numbness, pain, and weakness, and in some people it may cause some loss of movement in the arm and shoulder. This is extremely rare with modern RT. (7) Radiotherapy treatment may cause another type of cancer in many years’ time. These include lung cancers, especially in smokers, and the rare angiosarcoma.
Partial breast radiotherapy in low relapse risk patient subgroups
Instead of irradiating the whole breast, partial-breast RT restricted to the region of the original tumour in low relapse risk patients reduces the morbidity of RT without compromising its ability to cure the cancer. This technique is based on international reports of reductions in local relapse incidence, and the recognition that the majority of ipsilateral local relapses occur close to the region of the index tumour (the so-called tumour bed). Several studies have assessed partial-breast RT compared with whole breast RT.8–12 Most of them show comparable rates of local control in patients receiving partial-breast RT compared with whole breast RT. However, most of the studies not only compared partial versus whole breast RT, but also used differing RT techniques and doses in the treatment groups, making toxicity comparisons difficult.
IMPORT LOW was a multicentre, randomised, controlled, phase 3, non-inferiority trial comparing the safety and efficacy of standard whole breast RT (control, whole breast group) with experimental schedules of RT to the whole breast and partial breast (reduced-dose group), and to the partial breast only (partial-breast group).12 Patients assigned to whole breast RT (control) received 40 Gy in 15 fractions (daily doses) to the whole breast. Those assigned to the reduced-dose group received 36 Gy in 15 fractions to the whole breast and 40 Gy in 15 fractions to the partial breast containing the tumour bed, and those assigned to the partial-breast group received 40 Gy in 15 fractions to the partial breast only. Women who were aged 50 years or older who had breast-conserving surgery for unifocal invasive ductal adenocarcinoma (excluding invasive carcinoma of classical lobular type) of any grade (1–3) were recruited. Other inclusion criteria were pathological tumour size of 3 cm or less (pT1–2), axillary lymph-node negative or one to three positive lymph nodes (pN0–1), and a minimum microscopic margins of non-cancerous tissue of 2 mm or more. A total of 2018 patients were randomly assigned to the three groups, with around 670 patients per group. Patients were clinically assessed yearly for local relapse and toxicity, and around half completed questionnaires included self-assessments of side effects and health-related quality of life. After a median follow-up of 72.2 months, local relapse had been reported for 18 patients, nine (1%) of whom were in the whole breast group, three (< 1%) in the reduced-dose group, and six (1%) in the partial-breast group. The 5-year estimated cumulative incidence of local relapse was 1.1% (95% CI 0.5 to 2.3) in the whole breast group, 0.2% (95% CI 0.02 to 1.2) in the reduced-dose group, and 0.5% (95% CI 0.2 to 1.4) in the partial-breast group. At 5 years patients reported fewer moderate or marked normal tissue effects (NTE) in terms of skin change, change in overall breast appearance, breast being smaller, and breast being harder or firmer to touch in the partial-breast group than in the whole breast group although this reduction was statistically significant for change in breast appearance only (p < 0.0001). At 5 years, change in breast appearance had the highest cumulative incidence of items reported as moderate or marked by patients in all groups. Reports of breast becoming harder or firmer were significantly reduced in both the reduced-dose group (p = 0.002) and partial-breast group (p < 0.0001) compared with the whole breast group. The conclusions from IMPORT LOW were that for patients over 50, with smaller, generally lymph node-negative breast cancer, partial-breast RT was non-inferior to whole breast RT with regards local control and had less toxicity. Reduced-volume breast cancer treatment will also reduce lung and cardiac doses. Follow-up to 10 years is ongoing in the IMPORT LOW trial to collect data on longer-term efficacy and toxicity outcomes.
The control arm in IMPORT LOW was 40 Gy in 15 fractions to whole breast, which has been adopted as the standard of care for partial-breast RT. The control arm for the FAST-Forward Trial was the same. Therefore, if the 40 Gy/15 fractions schedule was found to be isoeffective for either of the test arms, then it was deemed that this would also be the same for partial-breast RT. It would make no biological sense to have different fractionation schedules with reduced-field RT (partial-breast). For FAST-Forward whole breast RT was still the standard-of-care when the study was conceived and recruiting.
Simplifying radiotherapy dose schedules for patients with breast cancer
For many years, and still in some countries, the international standard regimen for whole breast RT delivers a total dose of 50 Gy in 25 fractions over 5 weeks following surgical resection of primary tumour in women with early breast cancer. Attempts to reduce the number of fractions in the 1970s made inadequate downward adjustments to total dose, resulting in unacceptable rates of late complications.13 These miscalculations inhibited further research in breast RT fractionation for decades, but interest in fewer larger fractions delivered over a shorter overall treatment time has been rekindled by randomised clinical trials based on a better understanding of normal tissue and tumour responses (radiobiology). Fractionation sensitivity describes responses of normal and malignant tissues to RT fraction size and is quantified in terms of the α/β ratio, expressed in Gy. The lower the α/β ratio, the greater the effect on normal and malignant tissues of changes in fraction size.
Four randomised trials involving a total of > 8000 women have compared a lower total dose in fewer larger fractions against 50 Gy in 25 fractions, and all have reported favourable results in terms of local tumour control and late adverse effects (AE).14–18 The Royal Marsden Hospital/Gloucestershire Oncology Centre (now sometimes referred to as START-P) and Ontario Clinical Oncology Group (OCOG) trials totalling 2644 women with mainly axillary lymph node-negative tumours < 5 cm diameter were the subject of a 2008 Cochrane review of altered RT fractionation in early breast cancer.19 Radiotherapy fractions larger than 2.0 Gy did not appear to affect: (1) local relapse-free survival (absolute difference 0.4%, 95% CI −1.5% to 2.4%), (2) breast appearance [risk ratio (RR) 1.01, 95% CI 0.88 to 1.17; p = 0.86], (3) survival at 5 years (RR 0.97, 95% CI 0.78 to 1.19; p = 0.75), (4) late skin toxicity at 5 years (RR 0.99, 95% CI 0.44 to 2.22; p = 0.98 or (5) late radiation toxicity in subcutaneous tissue (RR 1.0, 95% CI 0.78 to 1.28; p = 0.99). The review concluded that the use of unconventional fractionation regimens did not affect breast appearance or toxicity, nor appear to affect local cancer relapse. The results of the UK START trials (N = 4451) were published too late to be included in the overview but were consistent with the findings. The START Trials tested the effects of RT schedules using fraction sizes larger than 2.0 Gy. The START-A Trial tested two dose levels of a 13-fraction regimen delivered over 5 weeks in order to measure the sensitivity of normal and malignant tissues to fraction size. Patients in START-A were randomly assigned to either 50 Gy in 25 fractions (control group) or 41.6 Gy in 13 fractions or 39 Gy in 13 fractions over 5 weeks. Patients in the START-B trial were randomly assigned to either 50 Gy in 25 fractions (control group) over 5 weeks or 40 Gy in 15 fractions over 3 weeks. The START-A trial (N = 2236) showed that the estimated absolute differences in 5-year local-regional relapse rates compared with the control schedule of 50 Gy in 2.0 Gy fractions were 0.2% (95% CI −1.3% to 2.6%) after 41.6 Gy and 0.9% (95% CI −0.8% to 3.7%) after 39 Gy. In START A, photographic and patient self-assessments suggested lower rates of late AE after 39 Gy than with 50 Gy, with a hazard ratio (HR) for late change in photographic breast appearance of 0.69 (95% CI 0.52 to 0.91; p = 0.01). In the START-B trial (N = 2215) the estimated absolute difference in 5-year local-regional relapse rates for 40.05 Gy compared with 50 Gy was −0.7% (95% CI −1.7% to 0.9%), and the HR for late change in photographic breast appearance was 0.83 (95% CI 0.66 to 1.04). Therefore, the START trials reported similar local tumour control with some evidence of lower rates of late AE after schedules with fraction sizes larger than 2.0 Gy compared with the international standard 25-fraction regimen.18
A 15-fraction schedule has been the UK standard-of-care recommended by the National Institute for Health and Care Excellence (NICE) since 2009, but it was thought to be unlikely to represent the useful limits of hypofractionation for whole breast RT. There is a history of prescribing once-weekly fractions of whole breast RT for women too frail or otherwise unable to attend for conventional schedules. In a French series of 115 patients undergoing primary RT without surgery for non-metastatic breast cancer from 1987 to 1999, the whole breast was treated with two tangential fields and received five once-weekly fractions of 6.5 Gy.20 One hundred and one were given additional tumour bed boost doses, 7 with 1 fraction, 69 with 2 fractions and 25 with 3 once-weekly fractions of 6.5 Gy using electrons. Kaplan–Meier estimates of late effects in the breast were 24% grade 1, 21% grade 2 and 6% grade 3 at 48 months. The 5-year local progression-free rate was 78% (95% CI 66.6 to 88.4). In a separate French series, five once-weekly fractions of 6.5 Gy to the whole breast with no boost were given to 50 women after local tumour excision.21 Grade 1 or 2 induration was reported in 33% of the patients at a median follow-up of 93 months (range 9–140). The 7-year local relapse-free survival was 91%.
The UK FAST trial (N = 915) tested two dose levels of a 5-fraction regimen delivering one fraction per week against a control schedule of 50 Gy in 25 fractions, defining RT AE as the primary endpoint.22 The two test dose levels delivered 5 fractions of 5.7 Gy or 6.0 Gy (total dose 28.5 Gy or 30 Gy), estimated to be isoeffective with the control regimen assuming α/β values of 3.0 Gy or 4.0 Gy, respectively. Nine hundred and fifteen patients were recruited from October 2004 to March 2007. The mean age of participants was 62.7 years. Only 17 patients (5.2%) developed moist desquamation (12 after 50 Gy, 3 after 30 Gy, 2 after 28.5 Gy) out of 327 with Radiation Therapy Oncology Group (RTOG) skin toxicity data available. At a median follow-up of 28.3 months [interquartile range (IQR) 24.1–33.6], 729 patients had 2-year photographic assessments available, with mild and marked change in breast appearance in 19.3% and 1.7% after 50 Gy, 26.2% and 9.3% after 30 Gy, and 20.3% and 3.7% after 28.5 Gy. RRs for mild and marked change for 30 Gy versus 50 Gy were 1.48 (95% CI 1.06 to 2.05) and 6.06 (2.14 to 17.20); p < 0.001 for trend, favouring 50 Gy; and for 28.5 Gy versus 50 Gy were 1.07 (0.75 to 1.54) and 2.25 (0.70 to 7.18); p = 0.26 for trend, favouring 50 Gy. Any clinically assessed moderate or marked AE in the breast were increased for 30 Gy compared with 50 Gy (HR 2.19, 95% CI 1.46 to 3.29; p < 0.001), but similar for 28.5 Gy (HR 1.33, 95% CI 0.86 to 2.08; p = 0.19). At a median follow-up of 37.3 months two local tumour relapses had been recorded.
The 10-year results from the FAST trial were subsequently published in 2020,23 confirming that as far as late toxicity is concerned, the 28.5 Gy schedule was isoeffective to the 50 Gy schedule. The 30 Gy schedule had an increased rate of late toxicity compared with 50 Gy. Any moderate or marked physician-assessed NTE in the breast (shrinkage, induration, telangiectasia, oedema) was reported for 92/774 (11.9%) at 5 years and 55/392 (14.0%) at 10 years. The most prevalent individual effect was breast shrinkage. Five-year prevalence of any moderate or marked breast NTE was estimated to be 10% higher (95% CI 5% to 16%) for 30 Gy versus 50 Gy (p < 0.001), with no statistically significant difference between 28.5 Gy and 50 Gy (2%, 95% CI −2% to +7%; p = 0.349). At 5 years, RRs for moderate or marked breast shrinkage versus 50 Gy were 2.03 (95% CI 1.15 to 3.58; p = 0.017) for 30 Gy and 1.20 (95% CI 0.63 to 2.27; p = 0.604) for 28.5 Gy. There were no statistically significant differences between schedules in 5-year prevalence of moderate or marked breast induration, telangiectasia and breast oedema, nor in 10-year prevalence of any moderate/marked effects, with few marked events. At 10 years, the estimated absolute differences in prevalence of any moderate or marked breast NTE compared with 50 Gy were 9% (95% CI 1% to 18%; p = 0.032) for 30 Gy and 5% (95% CI −2% to +13%; p = 0.184) for 28.5 Gy.
Five- and 10-year cumulative incidence rates of moderate or marked NTE in the breast were higher for 30 Gy compared with 50 Gy, with statistically significant differences for any NTE in the breast, breast shrinkage, breast induration, and breast oedema. Cumulative incidence rates of any moderate or marked NTE in the breast and breast induration were significantly higher for 28.5 Gy versus 50 Gy. Modeling all annual physician assessments over follow-up, rates of moderate or marked effects were statistically significantly higher for 30 Gy compared with 50 Gy [odds ratio (OR) for any breast NTE 2.12, 95% CI 1.55 to 2.89; p < 0.001], but with no significant difference between 28.5 Gy and 50 Gy (OR 1.22, 95% CI 0.87 to 1.72; p = 0.248; Statistically significant differences between the test schedules were found for breast shrinkage, telangiectasia, and breast oedema, with higher rates for 30 Gy compared with 28.5 Gy. The prevalence of breast shrinkage and telangiectasia increased over time, with a decline in breast oedema.
By the time of the 10-year analysis of the FAST trial only 11 local relapses had been reported (50 Gy: 3, 30 Gy: 4, 28.5 Gy: 4), hence analysis of tumour control outcomes would be underpowered.
A gain in local tumour control due to shortening treatment time to 1 week from longer 3- to 5-week schedules is theoretically possible. Evidence based on retrospective studies for an influence of treatment time on local tumour control is conflicting with recent systematic reviews drawing different conclusions.24,25 Even without a gain in tumour control, accelerated RT is likely to be more convenient for patients, and may ease scheduling with other treatment modalities. A pilot study (N = 30) tested 30 Gy in 5 fractions of 6.0 Gy in 15 days to the whole breast in terms of acute AE and late effects at 2 years.26 In this series, 23/30 (77%) patients scored no change in post-operative photographic breast appearance at 2 years, 7/30 (23%) scored mild change and none scored marked change. The acute skin reactions were mild, with no reaction more severe than grade 2 erythema, scored in 9/30 (27%) patients. In conclusion, it is fair to say that after decades of resistance to evaluating larger RT fraction sizes in breast cancer, expert opinion is responding to an accumulating body of evidence supporting the safety and effectiveness of this approach.
Against this background, the FAST-Forward phase III randomised trial was designed, with the primary aim of testing local tumour control in women with early breast cancer following a 5-fraction schedule of adjuvant RT delivered in 1 week.
Lymph node radiotherapy for breast cancer
This sub-study to the Main Trial tested the safety of 5-fraction regimens in the context of lymphatic RT. The model of breast cancer spread that was dominant in earlier decades envisaged a limited role for regional therapy beyond protection of quality of life, typically secured by surgery. Systematic overviews of RT effects by the Early Breast Cancer Trialists Collaborative Group (EBCTG) provide level 1A evidence that prevention of local-regional relapse has a major impact on breast cancer mortality.6,27 An important conclusion to be drawn is that even heavily axillary lymph node-positive axillary patients can be cured by effective local-regional treatment, whether this is achieved by surgery, RT or systemic therapy.27 The traditional model of breast cancer spread still has some adherents. The Z11 trial randomised 891 out of a planned 1900 patients with clinically lymph node-negative, sentinel lymph node-positive disease to axillary clearance versus no further axillary treatment.28 Twenty-seven per cent allocated axillary clearance had additional positive lymph nodes. The axillary relapse rate at 5 years was 0.5% after axillary clearance and 0.9% after no axillary clearance, and there was no difference in breast cancer mortality. For some, this result reinforces the traditional model of breast cancer spread that discounts a role of nodal metastases in determining cancer spread. This interpretation fails to take account that standard post-operative tangential beam RT includes at least lower axillary lymph nodes and may be needed to eradicate residual disease. The same issue has been raised in discussion of the IBCSG 23-01 trial that compared axillary dissection versus no further axillary surgery in 929 sentinel lymph node-positive patients, 91% of whom were treated by breast conservation followed by whole breast RT.29 The disease-free survival events, including axillary relapses, were non-inferior in the group spared axillary dissection, where standard whole breast RT will have included at least level I axillary lymph nodes. Although this remains a contested area, there is a wide consensus that control of axillary disease, whether by surgery, systemic therapy or RT, is an important component of curative therapy.
The AMAROS trial is informative in determining the role of surgery or RT for axillary management.30 The study randomised 1425 patients with positive sentinel lymph nodes to either axillary lymph node dissection in 744 patients or axillary RT including photon beams to axillary apex and medial supraclavicular fossa (SCF) in 681 patients. The axillary relapse rates were low in both groups; 1.19% after RT and 0.43% after surgery, too low to assess non-inferiority. The main difference is that clinically reported arm swelling was less of a problem after RT than after surgery; 13.6% versus 28.0%, respectively, at 5 years; p < 0.0001. The implication is that lymphatic RT may increasingly be used as an alternative to surgery in this context.
Very little internal mammary chain (IMC) RT has been given in the UK in recent decades, but a modest reduction in breast cancer mortality is suggested by the NCIC MA20 trial and confirmed by the European Organisation for Research and Treatment of Cancer (EORTC) 229922 trial.6,31 Both tested IMC and SCF RT, so it is possible that therapeutic effects are attributable solely to the SCF component. This does not seem likely since, if SCF RT is needed in order to enhance cure of patients with positive IMC nodes, it is reasonable to assume that the latter require managing too. The same argument might apply to the infraclavicular (ICF) lymph nodes (level III axilla), which are usually included in unshielded (rectangular) fields to the SCF. In the EORTC trial, 4004 patients with axillary lymph node-positive disease or had cancers that were centrally or medially situated but axillary lymph node-negative were randomised to receive IMC/medial SCF RT or not. At a median of 10.9 years of follow-up, the primary endpoint of overall survival improved from 80.75% to 82.3% with the addition of IMC/SCF RT (HR 0.87, 95% CI 0.76 to 1.00; p = 0.0556; p = 0.0496 after adjustment). It is not currently clear how these results will impact on practice. In conclusion, there was a need to test the safety of a 5-fraction schedule of lymphatic RT if the FAST-Forward Trial is to remain relevant to the 25% of patients referred for treatment with lymph node-positive disease. Whereas most are currently referred following axillary dissection, international and UK practices are changing, and more patients are likely to be referred in future for RT to axillary, SCF/ICF and perhaps IMC lymph node groups. When hypofractionation for breast cancer was first introduced in the 1960s, inappropriate dose regimens and uncertain dosimetry combined to cause unacceptably high rates of brachial plexopathy in patients with early breast cancer.32–44 Even with hindsight, it is difficult to be sure how much of the morbidity was related to technical factors, especially beam overlap, and how much to dose-time factors. The only series describing brachial plexopathy after total dose ≤ 50 Gy delivered in 1.8–2.0 Gy fractions to breast and axilla/SCF reported 3/724 (0.6%) affected patients treated between 1968 and 1985, of whom two resolved and one progressed at 6.5 years median follow-up.44 All patients were treated at the Joint Center, Boston, in a supine treatment position using a three-field technique with hanging block. A review of all published evidence available in 2005, suggested that brachial plexopathy after local-regional RT for early breast cancer is uncommon (< 1%) at doses < 55 Gy in 2.0 Gy equivalents.45 Dose regimens were normalised using a linear quadratic model, assuming α/β value of 2.0 Gy.
The dose–response relationships are not difficult to reconcile with current practices in head and neck cancer, where total doses of 60 Gy in 30 fractions are standard. One recent example modelled the relationship between total dose in 2.0 Gy fractions and probability of brachial plexopathy in 330 patients systematically screened for evidence of sensorimotor symptoms a median of 56 months (range 6–135) after radical RT for head and neck cancer. Patients treated with definitive RT received a median dose of 70 Gy, and for those treated post-operatively the median dose was 60 Gy. Intensity-modulated RT was used on 62% cases, and 40% had concurrent chemotherapy, usually cisplatin. The brachial plexus was outlined using RTOG criteria on X-ray computerised tomography (CT) scans.46
Against this background, the FAST-Forward Trial was extended beyond its original target accrual in order to test the safety of hypofractionated lymphatic RT. It is realistic to test only the common dose-limiting AE, including arm swelling and overall arm function. Very uncommon AE, including brachial plexopathy, cannot be formally tested in such a protocol, since a non-inferiority trial wishing to exclude an excess 1% risk with standard statistical power would require tens of thousands of patients.
Aims and objectives
Main Trial: to identify a 5-fraction schedule of curative RT delivered in once-daily fractions, that is at least as effective and safe as the current UK standard 15-fraction regimen after primary surgery for early breast cancer, in terms of local tumour control, AE, patient-reported outcomes (PRO) and health economic (HE) consequences.
Nodal Sub-Study (from Protocol v3.0, 8 July 2015): to show that a 5-fraction (1 week) schedule of adjuvant RT to level I–III axilla and/or level IV axilla (SCF) is non-inferior to a 15-fraction (3 weeks) standard in terms of patient-reported arm swelling and function, and to contribute additional information to the endpoints of the Main Trial.