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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. 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. 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. 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. National Institute for Health Research Health Technology Assessment Programme.

Intraoperative radiotherapy with electrons allows the substitution of conventional postoperative whole breast irradiation with one session of radiotherapy with the same equivalent dose during surgery. However, its ability to control for recurrence of local disease required confirmation in a randomised controlled trial. This study was done at the European Institute of Oncology (Milan, Italy). Women aged 48–75 years with early breast cancer, a maximum tumour diameter of up to 2·5 cm, and suitable for breast-conserving surgery were randomly assigned in a 1:1 ratio (using a random permuted block design, stratified for clinical tumour size [<1·0 cm vs 1·0–1·4 cm vs ≥1·5 cm]) to receive either whole-breast external radiotherapy or intraoperative radiotherapy with electrons. Study coordinators, clinicians, and patients were aware of the assignment. Patients in the intraoperative radiotherapy group received one dose of 21 Gy to the tumour bed during surgery. Those in the external radiotherapy group received 50 Gy in 25 fractions of 2 Gy, followed by a boost of 10 Gy in five fractions. This was an equivalence trial; the prespecified equivalence margin was local recurrence of 7·5% in the intraoperative radiotherapy group. The primary endpoint was occurrence of ipsilateral breast tumour recurrences (IBTR); overall survival was a secondary outcome. The main analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01849133. 1305 patients were randomised (654 to external radiotherapy and 651 to intraoperative radiotherapy) between Nov 20, 2000, and Dec 27, 2007. After a medium follow-up of 5·8 years (IQR 4·1–7·7), 35 patients in the intraoperative radiotherapy group and four patients in the external radiotherapy group had had an IBTR (p<0·0001). The 5-year event rate for IBRT was 4·4% (95% CI 2·7–6·1) in the intraoperative radiotherapy group and 0·4% (0·0–1·0) in the external radiotherapy group (hazard ratio 9·3 [95% CI 3·3–26·3]). During the same period, 34 women allocated to intraoperative radiotherapy and 31 to external radiotherapy died (p=0·59). 5-year overall survival was 96·8% (95% CI 95·3–98·3) in the intraoperative radiotherapy group and 96·9% (95·5–98·3) in the external radiotherapy group. In patients with data available (n=464 for intraoperative radiotherapy; n=412 for external radiotherapy) we noted significantly fewer skin side-effects in women in the intraoperative radiotherapy group than in those in the external radiotherapy group (p=0·0002). Although the rate of IBTR in the intraoperative radiotherapy group was within the prespecified equivalence margin, the rate was significantly greater than with external radiotherapy, and overall survival did not differ between groups. Improved selection of patients could reduce the rate of IBTR with intraoperative radiotherapy with electrons. Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, and Umberto Veronesi Foundation.

BackgroundPORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated long-term outcomes combined with the results of pathology review and molecular analysis.Methods427 women with HIR endometrial cancer were randomised between 2002–2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis.ResultsMedian follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors.ConclusionLong-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.

Standard adjuvant chemoradiotherapy (60–66 Gy) following surgery for HPV-associated oropharyngeal squamous cell carcinoma has excellent oncological control but high treatment morbidity. We aimed to compare toxicity of a 30–36 Gy regimen of de-escalated adjuvant radiotherapy and standard of care treatment. We did this phase 3, open-label, randomised controlled trial in two academic sites in the USA. Eligible participants were adults aged 18 years or older, with American Joint Committee on Cancer 7th edition pathological stage III–IV HPV-associated oropharyngeal squamous cell carcinoma and had more than 70% p16-immunoreactivity on immunohistochemistry evaluation of the surgical specimen. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less and at least one intermediate pathological risk factor. Patients were stratified by the presence of extranodal extension and smoking status (<10 packs per year vs ≥10 packs per year) Eligible patients were randomly assigned (2:1) using a minimisation method with a random element to receive de-escalated adjuvant radiotherapy (30–36 Gy in 1·5–1·8 Gy fractions twice per day over 2 weeks plus intravenous docetaxel 15 mg/m2 on days 1 and 8 of treatment) or standard of care (60 Gy in 2 Gy fractions once daily over 6 weeks plus intravenous cisplatin 40 mg/m2 once a week). The primary endpoint was cumulative, chronic grade 3 or higher toxicity rate 3–24 months after radiotherapy. Primary analysis was done in patients who received treatment and had no missing data. This trial is registered with ClinicalTrials.gov, NCT02908477, and is complete. Between Oct 11, 2016, and Aug 20, 2020, 254 patients with newly diagnosed oropharyngeal squamous cell carcinoma were assessed for inclusion. Nine did not meet inclusion criteria and 17 declined to participate. 228 patients were enrolled, with 194 proceeding to protocol treatment and analysis (130 in the de-escalated adjuvant radiotherapy group and 64 in the standard of care group). Median patient age was 59·4 years (range 37·9–81·6). 173 (89%) of 194 patients were male and 21 (11%) were female. 183 (95%) of 194 patients were White, four (2%) were Hispanic, three (2%) were Asian, and one (1%) was Native American. Median follow-up was 37·3 months (IQR 27·6–49·2). Seven patients were excluded from analysis of the primary late toxicity endpoint (five patients in the de-escalated adjuvant radiotherapy group and two patients in the standard of care group). The cumulative chronic grade 3 or higher toxicity rate at 3–24 months was 3% (four of 125 patients) in the de-escalated adjuvant radiotherapy group and 11% (seven of 62 patients) in the standard of care group (p=0·042) with a cumulative chronic percutaneous endoscopic gastric (PEG) tube rate of 2% (two of 125 patients) in the de-escalated adjuvant radiotherapy group and 8% (five of 62 patients) in the standard of care group (p=0·039). The most common grade 3 or higher toxic effects in the de-escalated adjuvant radiotherapy group were dysphagia (two [2%] of 125 patients), oesophagitis (one patient [1%]) and hearing impairment (one patient [1%]). The most common grade 3 or higher toxic effects in the standard of care group were dysphagia (five [8%] of 61 patients), oesophagitis (one patient [2%]), fatigue (one patient [2%]), pain (one patient [2%]), and osteonecrosis of the jaw (one patient [2%]). De-escalated adjuvant radiotherapy was a more tolerable treatment in terms of chronic toxicities, demonstrating less cumulative grade 3 or higher toxicity compared with standard of care. Further clinical trials exploring indications for the DART regimen are warranted. The Department of Radiation Oncology, Mayo Clinic, Minnesota and Arizona, the Braillier Family Research Fund, and the Matteson Family Research Fund.

The optimal schedule of radiation treatment after breast-conserving surgery for invasive breast cancer is unknown. In this study, two groups of patients received either hypofractionated radiation or a standard schedule of radiation treatment. Ten years later, the two groups had similar risks of local recurrence and a similar appearance of the breast. Two groups of patients received either hypofractionated radiation or a standard schedule of radiation treatment. Ten years later, the two groups had similar risks of local recurrence and a similar appearance of the breast. In women with breast cancer who undergo breast-conserving surgery, whole-breast irradiation reduces the risk of local recurrence and can prevent the need for mastectomy. 1 – 4 An update of a meta-analysis conducted by the Early Breast Cancer Trialists' Collaborative Group showed that breast irradiation after breast-conserving surgery reduces mortality from breast cancer. 5 However, up to 30% of women in North America who undergo breast-conserving surgery do not undergo breast irradiation, in part because of the inconvenience of the therapy and its cost. 6 In the original trials that evaluated whole-breast irradiation after breast-conserving surgery, 50.0 Gy of radiation was commonly given in . . .

Background Human papillomavirus-positive oropharyngeal squamous cell carcinoma is increasing in incidence worldwide. Current treatments are associated with high survival rates but often result in significant long-term toxicities. In particular, long-term dysphagia has a negative impact on patient quality of life and health. The aim of PATHOS is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in this favourable prognosis disease will result in better long-term swallowing function whilst maintaining excellent disease-specific survival outcomes. Methods/Design The study is a multicentre phase II/III randomised controlled trial for patients with biopsy-proven Human papillomavirus-positive oropharyngeal squamous cell cancer staged T1-T3 N0-N2b with a primary tumour that is resectable via a transoral approach. Following transoral surgery and neck dissection, patients are allocated into three groups based on pathological risk factors for recurrence. Patients in the low-risk pathology group will receive no adjuvant treatment, as in standard practice. Patients in the intermediate-risk pathology group will be randomised to receive either standard dose post-operative radiotherapy (control) or reduced dose radiotherapy. Patients in the high-risk pathology group will be randomised to receive either post-operative chemoradiotherapy (control) or radiotherapy alone. The primary outcome of the phase II study is patient reported swallowing function measured using the MD Anderson Dysphagia Inventory score at 12 months post-treatment. If the phase II study is successful, PATHOS will proceed to a phase III non-inferiority trial with overall survival as the primary endpoint. Discussion PATHOS is a prospective, randomised trial for Human papillomavirus-positive oropharyngeal cancer, which represents a different disease entity compared with other head and neck cancers. The trial aims to demonstrate that long-term dysphagia can be lessened by reducing the intensity of adjuvant treatment without having a negative impact on clinical outcome. The study will standardise transoral surgery and post-operative intensity-modulated radiotherapy protocols in the UK and develop a gold-standard swallowing assessment panel. An associated planned translational research programme, underpinned by tumour specimens and sequential blood collected as part of PATHOS, will facilitate further empirical understanding of this new disease and its response to treatment. Trial registration This study is registered with ClinicalTrials.gov identifier NCT02215265 .

Background Long-term prospective patient-reported outcomes (PRO) after breast cancer adjuvant radiotherapy is scarce. TomoBreast compared conventional radiotherapy (CR) with tomotherapy (TT), on the hypothesis that TT might reduce lung-heart toxicity. Methods Among 123 women consenting to participate, 64 were randomized to CR, 59 to TT. CR delivered 50 Gy in 25 fractions/5 weeks to breast/chest wall and regional nodes if node-positive, with a sequential boost (16 Gy/8 fractions/1.6 weeks) after lumpectomy. TT delivered 42 Gy/15 fractions/3 weeks to breast/chest wall and regional nodes if node-positive, 51 Gy simultaneous-integrated-boost in patients with lumpectomy. PRO were assessed using the European Organization for Research and Treatment of Cancer questionnaire QLQ-C30. PRO scores were converted into a symptom-free scale, 100 indicating a fully symptom-free score, 0 indicating total loss of freedom from symptom. Changes of PRO over time were analyzed using the linear mixed-effect model. Survival analysis computed time to > 10% PRO-deterioration. A post-hoc cardiorespiratory outcome was defined as deterioration in any of dyspnea, fatigue, physical functioning, or pain. Results At 10.4 years median follow-up, patients returned on average 9 questionnaires/patient, providing a total of 1139 PRO records. Item completeness was 96.6%. Missingness did not differ between the randomization arms. The PRO at baseline were below the nominal 100% symptom-free score, notably the mean fatigue-free score was 64.8% vs. 69.6%, pain-free was 75.4% vs. 75.3%, and dyspnea-free was 84.8% vs. 88.5%, in the TT vs. CR arm, respectively, although the differences were not significant. By mixed-effect modeling on early ≤2 years assessment, all three scores deteriorated, significantly for fatigue, P  ≤ 0.01, without effect of randomization arm. By modeling on late assessment beyond 2 years, TT versus CR was not significantly associated with changes of fatigue-free or pain-free scores but was associated with a significant 8.9% improvement of freedom from dyspnea, P  = 0.035. By survival analysis of the time to PRO deterioration, TT improved 10-year survival free of cardiorespiratory deterioration from 66.9% with CR to 84.5% with TT, P  = 0.029. Conclusion Modern radiation therapy can significantly improve long-term PRO. Trial registration Trial registration number ClinicalTrials.gov NCT00459628 , April 12, 2007 prospectively.

Background Microvascular invasion (MVI) is considered to be one of the important prognostic factors that affect postoperative recurrence in patients with hepatocellular carcinoma (HCC) with variable results across their treatment options. This study was carried out to investigate efficacy of postoperative adjuvant RT in HCC patients with MVI. Methods This was single center, prospective study carried out in HCC patients with MVI, aged 35–72 years. All patients were non-randomly allocated to receive standard postoperative treatment of HBV/HCV and nutritional therapy or RT in addition to standard postoperative treatment (1:1). The primary endpoints assessed were relapse-free survival and overall survival. The prognostic factors associated with survival outcomes were also analyzed. The safety events were graded according to NCI-CTCAE v4.03 criteria. Results Of the 115 patients eligible for study, 59 patients were included in analysis. Univariate analysis revealed that MVI classification ( P  = 0.009), post-operative treatment strategies ( P  = 0.009) were prognostic factors for worst RFS; tumor size ( P  = 0.011), MVI classification ( P  = 0.005) and post-operative treatment ( P  = 0.015) were associated for OS. The 1-, 2-, 3-year RFS rates were 86.2, 70.5 and 63.4% for patients in RT group, and 46.4, 36.1, and 36.1% in control group. For OS, corresponding rates were 96.6, 80.7, and 80.7% for patients in RT group and 79.7, 58.3, and 50.0% in control group. Subgroup classification of HCC patients according to low risk MVI showed significantly longer RFS ( P  = 0.035) and OS ( P  = 0.004) in RT group than control group, while for high risk MVI, RT depicted longer OS than control group with no significance ( P  = 0.106). Toxicities were usually observed in acute stage with no grade 4 toxicities. Conclusion Postoperative adjuvant RT following hepatectomy offers better RFS for HCC patients with MVI than with standard postoperative therapy. Also, it will be useful to control microscopic lesions in both M1 (low risk) and M2 (high risk) subgroups of HCC patients with MVI. Trial registration Trial Registration number: ChiCTR1800017371 . Date of Registration: 2018-07-26. Registration Status: Retrospectively registered.

Accelerated partial breast irradiation (APBI) represents a valid option for adjuvant therapy of selected early breast cancer (BC). This single-institution prospective randomized study compares the health-related quality of life (HRQoL) between women treated with the highly conformal-external beam APBI technique and those with the more commonly used moderately hypofractionated whole breast irradiation (hypo-WBI). Eligible patients were women over 50 years with early BC (G1/2 DCIS ≤ 25 mm or G1/2 invasive non-lobular luminal-like HER2 negative carcinoma ≤ 20 mm) after breast-conserving surgery with negative margins. APBI arm consisted of 30 Gy in 5 consecutive daily fractions and WBI arm of 40 Gy in 15 fractions plus 10 Gy in 5 fractions boost to the tumor bed. Patients were requested to complete the official Czech translation of the EORTC QoL questionnaires, including QLQ-C30 and QLQ-BR45, before radiation (baseline), at the end of radiation (M0) and 1 (M1), 3 (M3), 6 (M6), 12 (M12), and 24 (M24) months after radiation. Linear regression models were used to analyze differences in HRQoL between the arms. The 85 enrolled patients exhibited no differences in HRQoL scores between the two arms at baseline. Patients in the APBI arm reported more favorable global health status at M6 ( p  = 0.055). Other functional scales showed a decrease in the WBI arm at M0 ( p  = 0.027 for physical functioning). During radiation, symptoms scores increased. Significant between-group differences were observed for the pain ( p  = 0.002), systemic therapy side effects ( p  = 0.004), and breast symptoms ( p  < 0.001) scales at M0, with higher scores in the WBI arm. During follow-up, scores on symptoms scales returned to at least the baseline values. Early BC patients treated with APBI showed non-inferior short-term and late HRQoL outcomes compared to hypo-WBI. In addition to previous findings regarding toxicity, promising pain and breast symptoms results, suggest that APBI should be strongly considered as a treatment option for selected low-risk patients. Trial registration NCT06007118, August 23, 2023 (retrospectively registered).

Background and purpose The study evaluated the concordance between patient-reported outcomes (PRO) and clinician-reported outcomes (CRO) of acute radiation dermatitis (RD) symptoms following adjuvant radiotherapy for early-stage and locally advanced breast cancer. Material and methods This is a secondary analysis of a multi-center randomized phase 3 trial (376 patients). Ordinal logistic regression analysis was used to compare the Skin Symptom Assessment (SSA) independently reported by both patients and clinicians. Concordance between patient- and clinician-reported SSAs for RD symptoms was measured by percent concordance, concordance index ( C -statistic), and Cohen’s Kappa. Analyses were performed across all patients in the original modified intention-to-treat analysis and those with only grade 2–3 (CTCAE) RD. Results PROs were significantly more severe than CROs across all RD symptoms (Odds Ratio [OR] > 1; p  < 0.0001). Pigmentation (OR 5.4), blistering/peeling (OR 4.0), and pain/soreness (OR 3.9) were the most differentially reported symptoms. Poor-to-low concordance was noted between patient- and clinician-reported SSAs for all RD symptoms for the entire cohort (percent concordance < 50%, C -statistic 0.52–0.63, Cohen’s Kappa 13.9–23.4%) and those with grade 2–3 RD (percent concordance < 50%, C -statistic 0.56–0.66, Cohen’s Kappa 2.0–24.5%). Similarly, poor-to-low concordance was noted in both Mepitel film and standard-of-care arms. Conclusion PROs and CROs have poor concordance in breast RD, and patients report worse outcomes than clinicians, regardless of RD severity or prophylaxis. PROs must be further integrated into routine clinical practice and clinical trial design to reduce the risk of underreporting symptoms.