Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial.

BACKGROUND: A tumour-bed boost delivered after whole-breast radiotherapy increases local cancer-control rates but requires more patient visits and can increase breast hardness. IMPORT HIGH tested simultaneous integrated boost against sequential boost with the aim of reducing treatment duration while maintaining excellent local control and similar or reduced toxicity. METHODS: IMPORT HIGH is a phase 3, non-inferiority, open-label, randomised controlled trial that recruited women after breast-conserving surgery for pT1-3pN0-3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of three treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre. The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour-bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. The boost clinical target volume was the clip-defined tumour bed. Patients and clinicians were not masked to treatment allocation. The primary endpoint was ipsilateral breast tumour relapse (IBTR) analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% CI). Adverse events were assessed by clinicians, patients, and photographs. This trial is registered with the ISRCTN registry, ISRCTN47437448, and is closed to new participants. FINDINGS: Between March 4, 2009, and Sept 16, 2015, 2617 patients were recruited. 871 individuals were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm3 (IQR 7 to 22). At a median follow-up of 74 months there were 76 IBTR events (20 for the control group, 21 for test group 1, and 35 for test group 2). 5-year IBTR incidence was 1·9% (95% CI 1·2 to 3·1) for the control group, 2·0% (1·2 to 3·2) for test group 1, and 3·2% (2·2 to 4·7) for test group 2. The estimated absolute differences versus the control group were 0·1% (-0·8 to 1·7) for test group 1 and 1·4% (0·03 to 3·8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy. Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11·5% for the control group, 10·6% for test group 1 (p=0·40 vs control group), and 15·5% for test group 2 (p=0·015 vs control group). INTERPRETATION: In all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits. FUNDING: Cancer Research UK.

Cost-effectiveness of 5 fraction and partial breast radiotherapy for early breast cancer in the UK: model-based multi-trial analysis.

PURPOSE: We estimated the cost-effectiveness of 4 radiotherapy modalities to treat early breast cancer in the UK. In a subgroup of patients eligible for all modalities, we compared whole-breast (WB) and partial breast (PB) radiotherapy delivered in either 15 (WB15F, PB15F) or 5 fractions (WB5F, PB5F). In a subgroup ineligible for PB radiotherapy, we compared WB15F to WB5F. METHODS: We developed a Markov cohort model to simulate lifetime healthcare costs and quality-adjusted life years (QALYs) for each modality. This was informed by the clinical analysis of two non-inferiority trials (FAST Forward and IMPORT LOW) and supplemented with external literature. The primary analysis assumed that radiotherapy modality influences health only through its impact on locoregional recurrence and radiotherapy-related adverse events. RESULTS: In the primary analysis, PB5F had the least cost and greatest expected QALYs. WB5F had the least cost and the greatest expected QALYs in those only eligible for WB radiotherapy. Applying a cost-effectiveness threshold of £15,000/QALY, there was a 62% chance that PB5F was the cost-effective alternative in the PB eligible group, and there was a 100% chance that WB5F was cost-effective in the subgroup ineligible for PB radiotherapy. CONCLUSIONS: Hypofractionation to 5 fractions and partial breast radiotherapy modalities offer potentially important benefits to the UK health system.

Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.

BACKGROUND: We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial. METHODS: FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132. FINDINGS: Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were -0·3% (-1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and -0·7% (-1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy. INTERPRETATION: 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial.

BACKGROUND: Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy. METHODS: IMPORT LOW is a multicentre, randomised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1-3, with a tumour size of 3 cm or less (pT1-2), none to three positive axillary nodes (pN0-1), and minimum microscopic margins of non-cancerous tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2·5% increase [non-inferiority margin] at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio [HR] was less than 2·03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified intention-to-treat population). This study is registered in the ISRCTN registry, number ISRCTN12852634. FINDINGS: Between May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the analysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72·2 months (IQR 61·7-83·2), and 5-year estimates of local relapse cumulative incidence were 1·1% (95% CI 0·5-2·3) of patients in the control group, 0·2% (0·02-1·2) in the reduced-dose group, and 0·5% (0·2-1·4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were -0·73% (-0·99 to 0·22) for the reduced-dose and -0·38% (-0·84 to 0·90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2·03 (p=0·003 for the reduced-dose group and p=0·016 for the partial-breast group, compared with the whole-breast radiotherapy group). Photographic, patient, and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appearance [p=0·007 for partial-breast] and breast harder or firmer [p=0·002 for reduced-dose and p<0·0001 for partial-breast]) compared with whole-breast radiotherapy. INTERPRETATION: We showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide. FUNDING: Cancer Research UK.

FFPE breast tumour blocks provide reliable sources of both germline and malignant DNA for investigation of genetic determinants of individual tumour responses to treatment.

BACKGROUND: Bio-banked formalin-fixed paraffin-embedded (FFPE) tissues provide an excellent opportunity for translational genomic research. Historically matched blood has not always been collected as a source of germline DNA. This project aimed to establish if normal FFPE breast tissue could be used as an alternative to blood. METHODS: Exome sequencing was carried out on matched tumour tissue, normal breast tissue and blood on five patients in the START trial. Retrieved samples had been archived at different centres for at least 13 years. Following tissue macro-dissection and DNA extraction, targeted exome capture was performed using SureSelect Human All Exome v5 reagents (Agilent). Illumina paired-end libraries were prepared from the captured target regions and sequenced on a HiSeq2500 (Illumina) acquiring 2 × 75 bp reads. Somatic variants were called using the MuTect software analysis tool and copy number abnormalities (CNA) were identified using CNVkit. Targeted sequencing and droplet digital PCR were used to validate somatic variants and CNA, respectively. RESULTS: Overlap of somatic variants and CNA called on tumour versus blood and tumour versus normal breast tissue was good. Agreement in somatic variant calling ranged from 76.9 to 93.6%. Variants with an allele frequency lower than 10% were more difficult to validate irrespective of the type of germline DNA used. Pearson's correlation coefficients for paired comparisons of CNA using blood or normal tissue as reference ranged from 0.70 to 0.94. CONCLUSIONS: There is good correlation between the somatic mutations and CNA called using archived blood or normal breast tissue as germline reference material.

Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trial.

BACKGROUND: Hyperbaric oxygen has been used as a therapy for patients experiencing chronic intestinal syndromes after pelvic radiotherapy for decades, yet the evidence to support the use of this therapy is based almost exclusively on non-randomised studies. We aimed to provide conclusive results for the clinical benefits of hyperbaric oxygen in patients with chronic bowel dysfunction after radiotherapy for pelvic malignancies. METHODS: HOT2 was a double-blind, sham-controlled, phase 3 randomised study of patients (≥18 years) with chronic gastrointestinal symptoms for 12 months or more after radiotherapy and which persisted despite at least 3 months of optimal medical therapy and no evidence of cancer recurrence. Participants were stratified by participating hyperbaric centre and randomly assigned (2:1) by a computer-generated list (block size nine or 12) to receive treatment with hyperbaric oxygen therapy or sham. Participants in the active treatment group breathed 100% oxygen at 2·4 atmospheres of absolute pressure (ATA) and the control group breathed 21% oxygen at 1·3 ATA; both treatment groups received 90-min air pressure exposures once daily for 5 days per week for a total of 8 weeks (total of 40 exposures). Staff at the participating hyperbaric medicine facilities knew the allocated treatment, but patients, clinicians, nurse practitioners, and other health-care professionals associated with patients' care were masked to treatment allocation. Primary endpoints were changes in the bowel component of the modified Inflammatory Bowel Disease Questionnaire (IBDQ) score and the IBDQ rectal bleeding score 12 months after start of treatment relative to baseline. The primary outcome was analysed in a modified intention-to-treat population, excluding patients who did not provide IBDQ scores within a predetermined time-frame. All patients have completed 12 months of follow-up and the final analysis is complete. The trial is registered with the ISRCTN registry, number ISRCTN86894066. FINDINGS: Between Aug 14, 2009, and Oct 23, 2012, 84 participants were randomly assigned: 55 to hyperbaric oxygen and 29 to sham control. 75 (89%) participants received 40 pressure exposures, all participants returned the IBDQ at baseline, 75 (89%) participants returned the IBDQ at 2 weeks post-treatment, and 79 (94%) participants returned the IBDQ at 12 months post-start of treatment. Patients were excluded from analyses of co-primary endpoints if they had missing IBDQ scores for intestinal function or rectal bleeding at baseline or at 12 months. In an analysis of 46 participants in the active treatment group and 23 participants in the control group, we found no significant differences in the change of IBDQ bowel component score (median change from baseline to 12 months of 4 (IQR -3 to 11) in the treatment group vs 4 (-6 to 9) in the sham group; Mann-Whitney U score 0·67, p=0·50). In an analysis of 29 participants in the active treatment group and 11 participants in the sham group with rectal bleeding at baseline, we also found no significant differences in the change of IBDQ rectal bleeding score (median change from baseline to 12 months of 3 [1 to 3] in the treatment group vs 1 [1 to 2] in the sham group; U score 1·69, p=0·092). Common adverse events in both groups were eye refractive changes (three [11%] of 28 patients in the control group vs 16 [30%] of 53 patients in the treatment group), increased fatigue (three [11%] vs two [4%]), and ear pain (six [21%] vs 15 [28%]). Eight serious adverse events were reported in eight patients: two were reported in two patients in the control group (tonsillitis requiring surgery [grade 3]; recurrent cancer of the vulva [grade 4]) and six serious adverse events were reported in six patients in the treatment group (malignant spinal cord compression requiring surgery [grade 3]; malignant paraortic lymph node involvement requiring surgery [grade 3]; recurrence of vomiting and dehydration [grade 3]; diarrhoea and fever associated with Campylobacter infection [grade 3]; recurrence of abdominal pain, bloating, diarrhoea, and urinary tract infection [grade 3]; aneurysm [grade 4]), none of which were deemed treatment-related. INTERPRETATION: We found no evidence that patients with radiation-induced chronic gastrointestinal symptoms, including those patients with rectal bleeding, benefit from hyperbaric oxygen therapy. These findings contrast with evidence used to justify current practices, and more level 1 evidence is urgently needed. FUNDING: Cancer Research UK and National Health Service (NHS) funding to the National Institute of Health Research Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research.

DNA double-strand break repair and induction of apoptosis in ex vivo irradiated blood lymphocytes in relation to late normal tissue reactions following breast radiotherapy.

This study aimed to test whether induction of apoptosis following ex vivo X-irradiation of unstimulated blood lymphocytes correlated with clinical radiosensitivity and DNA double-strand break (DSB) repair in breast radiotherapy patients and healthy volunteers. Using small molecule inhibitors, the relationship between DSB repair and radiation-induced apoptosis was examined. Sixteen breast cancer patients with minimal (controls, n = 8) or extremely marked late radiation-induced change (cases, n = 8) and eight healthy volunteers were selected. DSBs were quantified by γH2AX/53BP1 immunofluorescence, and apoptosis was measured using a fluorogenic inhibitor of caspases assay. Mean γH2AX/53BP1 focus levels 24 h after exposure to 4 Gy were higher in cases (12.7 foci per cell) than in controls (10.3 foci per cell, p = 0.002). In contrast, the mean apoptotic fraction 48 h after 8 Gy was comparable, 37.2 % in cases and 34.7 % in controls (p = 0.442). Residual focus and apoptosis levels were not correlated within individuals (Spearman's R = -0.0059, p = 0.785). However, cells treated with DNA-PK inhibitor Nu7441 had higher focus and apoptosis levels 48 h after 1 Gy compared to mock-treated cells, suggesting that apoptosis induction following irradiation is modulated by DSB repair. This effect required functional ATM since cells treated simultaneously with Nu7441 and the ATM inhibitor Ku55933 were resistant to apoptosis despite high levels of residual foci. One clinical case displayed an impaired DNA-PK-dependent end-joining cellular phenotype. In summary, clinical radiosensitivity may be associated with impaired DSB repair in some patients. Although pharmaceutical inhibition of ATM and DNA-PK affected apoptosis induction and DSB repair, no association was observed between apoptosis and residual focus levels in patients and volunteers.

The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.

BACKGROUND: 5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens. METHODS: From 1999 to 2002, women with completely excised invasive breast cancer (pT1-3a, pN0-1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: START-A enrolled 2236 women. Median follow-up was 9·3 years (IQR 8·0-10·0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups (6·3%, 95% CI 4·7-8·5 vs 7·4%, 5·5-10·0; hazard ratio [HR] 0·91, 95% CI 0·59-1·38; p=0·65) or the 39 Gy (8·8%, 95% CI 6·7-11·4) and 50 Gy regimen groups (HR 1·18, 95% CI 0·79-1·76; p=0·41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9·9 years (IQR 7·5-10·1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4·3%, 95% CI 3·2-5·9) and the 50 Gy group (5·5%, 95% CI 4·2-7·2; HR 0·77, 95% CI 0·51-1·16; p=0·21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group. INTERPRETATION: Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer. FUNDING: Cancer Research UK, UK Medical Research Council, UK Department of Health.

One versus three weeks hypofractionated whole breast radiotherapy for early breast cancer treatment: the FAST-Forward phase III RCT.

Background: FAST-Forward aimed to identify a 5-fraction schedule of adjuvant radiotherapy delivered in 1 week that was non-inferior in terms of local cancer control and as safe as the standard 15-fraction regimen after primary surgery for early breast cancer. Published acute toxicity and 5-year results are presented here with other aspects of the trial. Design: Multicentre phase III non-inferiority trial. Patients with invasive carcinoma of the breast (pT1-3pN0-1M0) after breast conservation surgery or mastectomy randomised (1 : 1 : 1) to 40 Gy in 15 fractions (3 weeks), 27 Gy or 26 Gy in 5 fractions (1 week) whole breast/chest wall (Main Trial). Primary endpoint was ipsilateral breast tumour relapse; assuming 2% 5-year incidence for 40 Gy, non-inferiority pre-defined as < 1.6% excess for 5-fraction schedules (critical hazard ratio = 1.81). Normal tissue effects were assessed independently by clinicians, patients and photographs. Sub-studies: Two acute skin toxicity sub-studies were undertaken to confirm safety of the test schedules. Primary endpoint was proportion of patients with grade ≥ 3 acute breast skin toxicity at any time from the start of radiotherapy to 4 weeks after completion. Nodal Sub-Study patients had breast/chest wall plus axillary radiotherapy testing the same three schedules, reduced to the 40 and 26 Gy groups on amendment, with the primary endpoint of 5-year patient-reported arm/hand swelling. Limitations: A sequential hypofractionated or simultaneous integrated boost has not been studied. Participants: Ninety-seven UK centres recruited 4096 patients (1361:40 Gy, 1367:27 Gy, 1368:26 Gy) into the Main Trial from November 2011 to June 2014. The Nodal Sub-Study recruited an additional 469 patients from 50 UK centres. One hundred and ninety and 162 Main Trial patients were included in the acute toxicity sub-studies. Results: Acute toxicity sub-studies evaluable patients: (1) acute grade 3 Radiation Therapy Oncology Group toxicity reported in 40 Gy/15 fractions 6/44 (13.6%); 27 Gy/5 fractions 5/51 (9.8%); 26 Gy/5 fractions 3/52 (5.8%). (2) Grade 3 common toxicity criteria for adverse effects toxicity reported for one patient. At 71-month median follow-up in the Main Trial, 79 ipsilateral breast tumour relapse events (40 Gy: 31, 27 Gy: 27, 26 Gy: 21); hazard ratios (95% confidence interval) versus 40 Gy were 27 Gy: 0.86 (0.51 to 1.44), 26 Gy: 0.67 (0.38 to 1.16). With 2.1% (1.4 to 3.1) 5-year incidence ipsilateral breast tumour relapse after 40 Gy, estimated absolute differences versus 40 Gy (non-inferiority test) were -0.3% (-1.0-0.9) for 27 Gy (p = 0.0022) and -0.7% (-1.3-0.3) for 26 Gy (p = 0.00019). Five-year prevalence of any clinician-assessed moderate/marked breast normal tissue effects was 40 Gy: 98/986 (9.9%), 27 Gy: 155/1005 (15.4%), 26 Gy: 121/1020 (11.9%). Across all clinician assessments from 1 to 5 years, odds ratios versus 40 Gy were 1.55 (1.32 to 1.83; p < 0.0001) for 27 Gy and 1.12 (0.94-1.34; p = 0.20) for 26 Gy. Patient and photographic assessments showed higher normal tissue effects risk for 27 Gy versus 40 Gy but not for 26 Gy. Nodal Sub-Study reported no arm/hand swelling in 80% and 77% in 40 Gy and 26 Gy at baseline, and 73% and 76% at 24 months. The prevalence of moderate/marked arm/hand swelling at 24 months was 10% versus 7% for 40 Gy compared with 26 Gy. Interpretation: Five-year local tumour incidence and normal tissue effects prevalence show 26 Gy in 5 fractions in 1 week is a safe and effective alternative to 40 Gy in 15 fractions for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. Future work: Ten-year Main Trial follow-up is essential. Inclusion in hypofractionation meta-analysis ongoing. A future hypofractionated boost trial is strongly supported. Trial registration: FAST-Forward was sponsored by The Institute of Cancer Research and was registered as ISRCTN19906132. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/01/47) and is published in full in Health Technology Assessment; Vol. 27, No. 25. See the NIHR Funding and Awards website for further award information.

Patients diagnosed with early breast cancer are often recommended to have radiotherapy after surgery because research has shown that it lowers the risk of the cancer returning. However, it may cause some short- and long-term side effects. Previous clinical trials showed that the same, or even better, outcomes with a lower total dose of radiotherapy given in fewer, larger daily doses compared with older historical treatment schedules. The National Institute for Health and Care Research Health Technology Assessment Programme-funded FAST-Forward Trial aimed to see whether the number of doses could be reduced further without reducing the beneficial effects of radiotherapy. Between November 2011 and June 2014, 4096 patients agreed to take part in the FAST-Forward Main Trial testing three schedules of radiotherapy to the breast. Standard treatment given on 15 days over 3 weeks (Control Group) was compared with two different lower dose schedules where treatment was given on 5 days over 1 week (lower dose Test Groups). An additional 469 patients entered a sub-study where the gland area under the arm also received radiotherapy (Nodal Sub-Study). Main Trial 5-year results reported in April 2020 showed that the number of patients whose cancer had returned in the treated breast was low in all groups: around 2 in 100 (2.1%) for the Control Group, and 1.7% in the higher dose and 1.4% in the lower dose Test Groups. The majority of reported side effects assessed by patients and doctors up to 5 years after radiotherapy were mild for all treatment groups. Patients in the Control Group and in the lower dose Test Group experienced similar levels of side effects. More side effects were reported in the higher dose Test Group, although differences were small. Overall, the FAST-Forward findings suggest that the lower dose 1-week schedule gave similar results in terms of the cancer returning and side effects to the standard 3-week treatment and this schedule can now be used to help treat future patients.

Randomised single centre double-blind placebo controlled phase II trial of Tocovid SupraBio in combination with pentoxifylline in patients suffering long-term gastrointestinal adverse effects of radiotherapy for pelvic cancer: The PPALM study.

BACKGROUND: Preclinical data suggest that combined gamma-tocotrienol with pentoxifylline ameliorates radiotherapy-induced gastrointestinal damage. AIM: To test whether gastrointestinal symptoms arising after radiotherapy, and persisting after maximal medical therapy, can be improved using Tocovid SupraBio 200 mg and pentoxifylline 400 mg orally twice daily for one year. Patients stratified by severity of symptoms, and randomised to active treatment or matched placebo were assessed after 12 months. The primary end point was improvement in gastrointestinal symptoms measured using the Inflammatory Bowel Disease Questionnaire, bowel subset score. Changes in bio-markers of fibrosis were assessed. RESULTS: 62 patients, median age 66, 34(55%) treated for prostate, 21(34%) gynaecological, 6(10%) anal and one(1%) rectal cancer were recruited; 40(65%) randomised to treatment, 22(35%) to placebo, 39 months (median) after radiotherapy completion. Gamma tocotrienol was not detected in serum in 41% of treated patients, despite good compliance with study medication. Treatment was completed in 28(70%) and 17(77%) patients in the treatment and placebo groups respectively. No improvement in symptom scores nor in quality of life was identified. Thirteen serious adverse events occurred. A transient ischaemic attack, was possibly related to pentoxifylline, others were assessed as unlikely to be related to treatment. Levels of EGF, PDGF and FGF were significantly reduced and consistent trends in reduced inflammation were seen during treatment but were not sustained once treatment ended. SUMMARY: This single centre study closed prematurely and therefore data interpretation is of necessity limited. No clinical benefit was demonstrated. However, biochemical data suggest that this intervention does have anti-inflammatory and anti-fibrotic effects.

Comparison of patient-reported breast, arm, and shoulder symptoms and body image after radiotherapy for early breast cancer: 5-year follow-up in the randomised Standardisation of Breast Radiotherapy (START) trials.

BACKGROUND: Few trials of adjuvant breast radiotherapy have incorporated patient-reported breast symptoms and related areas of quality of life. We assessed these measures in a quality-of-life study that was part of the randomised START (Standardisation of Breast Radiotherapy) trials. METHODS: In START trial A, 2236 patients were randomly assigned to receive either 39 Gy or 41.6 Gy delivered in 13 fractions over 5 weeks or a global standard of 50 Gy in 25 fractions. In START trial B, 2215 women were randomly assigned to receive either 40 Gy in 15 fractions over 3 weeks or the same control regimen (50 Gy in 25 fractions) as in trial A. 2739 patients were eligible for the quality-of-life study of whom 2208 (81%) were accrued (1129 patients from trial A and 1079 from trial B). Participants completed the EORTC QLQ-C30 and BR23 questionnaires and protocol-specific radiotherapy items up to 5 years after radiotherapy. We compared results across regimens with generalised estimating equations and survival analyses. The START trials are registered, ISRCTN59368779. FINDINGS: At 5 years, up to 40% women reported moderate or marked changes to the breast after radiotherapy, and arm and shoulder pain affected up to a third of patients. Breast symptoms and body image concerns reduced over time. Rates of radiotherapy adverse effects were lower for the 39 Gy regimen in trial A and the 40 Gy regimen in trial B, compared with the 50 Gy control regimen; rates of radiotherapy adverse effects were similar between the 41.6 Gy and 50 Gy regimens in trial A. Adverse change in skin appearance was significantly lower for patients who received 39 Gy compared with those who received 50 Gy (HR 0.63, 95% CI 0.47-0.84) and for those who received 40 Gy compared with those who received 50 Gy (0.76, 0.60-0.97); no significant difference was observed between patients who received 41.6 Gy and those who received 50 Gy in trial A (0.83, 0.63-1.08). Patient self-ratings of breast symptoms discriminated a 10% difference in randomised dose intensity. Up to a third of women reported moderate or marked pain in the arm and shoulder over 5 years whilst more than 10% experienced moderate or marked arm and hand swelling, with no significant difference in arm/shoulder subscale scores between the regimens in trial A or trial B; many baseline arm and shoulder symptoms were associated with prior surgery. INTERPRETATION: A substantial proportion of women report moderate or marked breast, arm, and shoulder symptoms over 5 years of follow-up after radiotherapy, but with no detriment to body image. Nonetheless, most patients stand to gain from hypofractionated radiotherapy regimens with a potential for fewer adverse effects; this strengthens the evidence from the START trials for hypofractionated regimens for women requiring radiotherapy for early breast cancer. FUNDING: Cancer Research UK, UK Medical Research Council, UK Department of Health.

TP53 modulates radiotherapy fraction size sensitivity in normal and malignant cells.

Recent clinical trials in breast and prostate cancer have established that fewer, larger daily doses (fractions) of radiotherapy are safe and effective, but these do not represent personalised dosing on a patient-by-patient basis. Understanding cell and molecular mechanisms determining fraction size sensitivity is essential to fully exploit this therapeutic variable for patient benefit. The hypothesis under test in this study is that fraction size sensitivity is dependent on the presence of wild-type (WT) p53 and intact non-homologous end-joining (NHEJ). Using single or split-doses of radiation in a range of normal and malignant cells, split-dose recovery was determined using colony-survival assays. Both normal and tumour cells with WT p53 demonstrated significant split-dose recovery, whereas Li-Fraumeni fibroblasts and tumour cells with defective G1/S checkpoint had a large S/G2 component and lost the sparing effect of smaller fractions. There was lack of split-dose recovery in NHEJ-deficient cells and DNA-PKcs inhibitor increased sensitivity to split-doses in glioma cells. Furthermore, siRNA knockdown of p53 in fibroblasts reduced split-dose recovery. In summary, cells defective in p53 are less sensitive to radiotherapy fraction size and lack of split-dose recovery in DNA ligase IV and DNA-PKcs mutant cells suggests the dependence of fraction size sensitivity on intact NHEJ.

Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial.

BACKGROUND: Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. METHODS: In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. FINDINGS: All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). INTERPRETATION: This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. FUNDING: Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.

Hypofractionated adjuvant whole breast radiotherapy: progress and prospects.

Published results of randomised trials involving >7000 women confirm the safety and efficacy of hypofractionated schedules of adjuvant radiotherapy for women with early breast cancer using fraction sizes between 2 and 3 Gy assuming appropriate downward adjustments to total dose. Unnecessary concerns relating to heart tolerance, suboptimal dose distribution and duration of follow up need not discourage the routine adoption of 15- or 16-fraction schedules in women treated by breast conservation surgery for early breast cancer. Regardless of fractionation regimen, dose escalation to the index quadrant in high risk subgroups will result in a greater relative increase in late adverse effects than tumour control, a therapeutic disadvantage that can only be overcome by exploiting a marked dose-volume effect. A 15-fraction schedule of whole breast radiotherapy is unlikely to represent the lower limits of hypofractionation, and the preliminary results of a 5-fraction regimen are encouraging.

Genome-wide transcriptomic profiling of microdissected human breast tissue reveals differential expression of KIT (c-Kit, CD117) and oestrogen receptor-alpha (ERalpha) in response to therapeutic radiation.

The pathogenesis of late normal tissue fibrosis after high-dose ionizing radiation involves multiple cell types and signalling pathways but is not well understood. To identify the molecular changes occurring after radiotherapy, paired normal tissue samples were collected from the non-irradiated breast and from the treated breast of women who had undergone curative radiotherapy for early breast cancer months or years previously. As radiation may induce distinct transcriptional changes in the different components of the breast, laser capture microdissection and gene expression microarray profiling were performed separately for epithelial and stromal components and selected genes were validated using immunohistochemistry. In the epithelial compartment, a reduction of KIT (c-Kit; CD117) and a reciprocal increase in ESR1 (oestrogen receptor-alpha, ERalpha) mRNA and protein levels were seen in irradiated compared to non-irradiated samples. In the stromal compartment, extracellular matrix genes including FN1 (fibronectin 1) and CTGF (connective tissue growth factor; CCN2) were increased. Further investigation revealed that c-Kit and ERalpha were expressed in distinct subpopulations of luminal epithelial cells. Interlobular c-Kit-positive mast cells were also increased in irradiated cases not showing features of post-radiation atrophy. Pathway analysis revealed 'cancer, reproductive system disease and tumour morphology' as the most significantly enriched network in the epithelial compartment, whereas in the stromal component, a significant enrichment for 'connective tissue disorders, dermatological diseases and conditions, genetic disorder' and 'cancer, tumour morphology, infection mechanism' networks was observed. These data identify previously unreported changes in the epithelial compartment and show altered expression of genes implicated in late normal tissue injury in the stromal compartment of normal breast tissue. The findings are relevant to both fibrosis and atrophy occurring after radiotherapy for early breast cancer.