SummaryBackgroundLocal 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.MethodsIMPORT 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.FindingsBetween 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 ...

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. FindingsBetween 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 fivefraction 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 l...

Background IMPORT HIGH is a randomised, multi-centre phase III trial testing dose escalated simultaneous integrated boost (SIB) against sequential boost each delivered by intensity modulated radiotherapy (IMRT) for early stage breast cancer with higher risk of local relapse. The primary endpoint was initially breast induration at 3 years, requiring 840 patients; accrual was extended (target 2568) with the new primary endpoint of local relapse. We report adverse effects (AE) at 3 years. Methods Women age ≥18 after breast conservation surgery for pT1-3 pN0-pN3a M0 invasive carcinoma were eligible. Randomisation was 1:1:1 between 40Gy/15F to whole breast (WB) + 16Gy/8F sequential photon boost to tumour bed (40+16Gy), 36Gy/15F to WB, 40Gy to partial breast + 48Gy (48Gy) or + 53Gy (53Gy) in 15F SIB to tumour bed. AEs were assessed annually by clinicians in all patients and in a planned sub-set (840) of patients by photographs at 3 years and by patients at 6 months, 1 and 3 years. AE scores were dichotomised as none/mild vs marked for photographs and none/mild vs moderate/marked for patients and clinicians. Fisher's exact tests compared groups; principal comparison (protocol-specified) between 53Gy and 48Gy (p&lt;0.01 defined as statistical significance). Results 2617 women consented between 03/2009 and 09/2015 from 39 UK radiotherapy centres. Median follow-up was 49.1 (IQR 36.8-63.2) months. Median age was 49 (IQR 44-56); 9%, 38% & 53% were tumour grade 1, 2 & 3 respectively; 30% were node positive. 66% received chemotherapy and 73% endocrine therapy. 3-year AE data were available for 2017 clinician assessments, 641 photographs and 842 patient assessments. Proportions of patients with marked AEs were low overall. Rates of moderate/marked AEs at 3 years were broadly similar between the randomised groups; with a suggestion of a slightly increased risk for breast induration in 53Gy compared with control (borderline significance). AE at 3 years 40+16Gy n(%)48Gy n(%)53Gy n(%)ClinicianBreast induration;N656668654None451 (69)483 (72)445 (68)Mild167 (25)141 (21)146 (22)Moderate32 (5)42 (6)56 (9)Marked6 (1)2 (1)7 (1)P-value 0.57010.0102  0.0443Breast shrinkage;N655669654None442 (68)472 (71)448 (69)Mild167 (26)161 (24)166 (25)Moderate40 (6)33 (5)35 (5)Marked6 (1)3 (1)5 (1)P-value 0.25410.5772  0.6373Breast distortion;N656669654None451 (69)464 (69)442 (68)Mild169 (26)170 (25)170 (26)Moderate33 (5)32 (5)38 (6)Marked3 (1)3 (1)4 (1)P-value 0.90310.4862  0.4113PatientChange in breast appearance;N287264285None38 (13)50 (19)58 (20)Mild164 (57)151 (57)142 (50)Moderate57 (20)45 (17)54 (19)Marked28 (10)18 (7)31 (11)P-value 0.14910.9992  0.1243PhotographChange in breast appearance;N218210213None183 (84)185 (88)177 (83)Mild25 (11)23 (11)32 (15)Marked10 (5)2 (1)4 (2)P-value 0.03610.1732  0.6853148Gy v 40+16Gy; 253Gy v 40+16Gy; 353Gy v 48Gy Conclusions These results represent the largest and most mature reported AE outcomes of breast SIB within a clinical trial. At 3 years, rates of moderate/marked AEs were similar between SIB IMRT and WB + sequential boost IMRT delivered over 3 and 4.5 weeks respectively. Citation Format: Coles CE, Griffin CL, Kirby AM, Haviland JS, Titley JC, Benstead K, Brunt AM, Chan C, Ciurlionis L, Din OS, Donovan EM, Eaton DJ, Harnett AN, Hopwood P, Jefford ML, Jenkins PJ, Lee CE, McCormack M, Sherwin L, Syndikus I, Tsang Y, Twyman NI, Ventikaraman R, Wickers S, Wilcox MH, Bliss JM, Yarnold JR. Dose escalated simultaneous integrated boost radiotherapy for women treated by breast conservation surgery for early breast cancer: 3-year adverse effects in the IMPORT HIGH trial (CRUK/06/003) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-05.