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The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19–1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. Research for Patient Benefit Programme from the UK National Institute for Health Research.

Abstract BACKGROUND Cavity stereotactic radiotherapy has emerged as a standard option following resection of brain metastases. However, the optimal approach with either single-fraction or hypofractionated stereotactic radiotherapy (HSRT) remains a significant question. OBJECTIVE To report outcomes for 5-fraction HSRT to the surgical cavity, based on contouring according to a recently reported international consensus guideline. METHODS Patients treated with cavity HSRT were identified from a prospective institutional database. Local brain control (LC), distant brain failure (DBF), leptomeningeal disease (LMD), and overall survival rates were determined. Univariate and multivariable analyses were performed on potential predictive factors. RESULTS One hundred thirty-seven cavities in 122 patients were treated at a median total dose of 30 Gy (range, 25-35 Gy). The median follow-up was 16 mo (range, 1-60 mo). Nonsmall cell lung cancer was the most common histology (44%), followed by breast cancer (21%). In 57% of surgical cavities, the preoperative tumor diameter was >3 cm. One-year LC, DBF, LMD, and overall survival rates were 84%, 45%, 22%, and 62%, respectively. Multivariable analyses identified colorectal (hazard ratio [HR] 4.1, P = .0066) and melanoma (HR 2.4, P = .012) metastases as predictors of local recurrence; preoperative tumor diameter >2 cm (HR 8.9, P = .012) and absence of targeted therapy (HR 4.4, P = .03) as predictors of DBF; and breast cancer histology (HR 2.1, P = .05) and subtotal resection (HR 2.6, P = .009) as predictors of LMD. Symptomatic radiation necrosis was observed in 7 patients (6%). CONCLUSION High rates of LC were observed following this 5-fraction HSRT regimen. Superiority as compared to single-fraction SRS requires a randomized trial.

Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0–4·5) for patients in the standard-of-care group versus 7·2 months (4·5–10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35–0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2–not reached] vs 2·2 months [95% CI 2·0–4·5]; HR 0·41, 95% CI 0·22–0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5–8·7] vs 4·2 months [1·8–5·5]; 0·78, 0·43–1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. National Cancer Institute.

With a median follow-up of 13 years, a randomized comparison of radiotherapy with or without antiandrogen therapy in patients with a rising PSA level after prostatectomy showed that 2 years of antiandrogen therapy resulted in a significantly higher overall survival rate. Patients with localized prostatic cancer are often treated with radical prostatectomy. More than 30% of such patients will subsequently have recurrence. This recurrence manifests first as a rising serum level of prostate-specific antigen (PSA), 1 – 3 termed biochemical recurrence. Large, retrospective studies suggest that salvage radiation therapy after biochemical recurrence may be associated with long-term freedom from cancer recurrence. 4 , 5 However, 50% of the patients who are treated with salvage radiation therapy will have further disease progression, particularly when there are aggressive disease features. 4 – 7 The combination of radiation therapy and either androgen-deprivation therapy or antiandrogen therapy prolongs survival among some . . .

After brain metastasis resection, whole brain radiotherapy decreases local recurrence, but might cause cognitive decline. We did this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved time to local recurrence compared with that for surgical resection alone. In this randomised, controlled, phase 3 trial, we recruited patients at a single tertiary cancer centre in the USA. Eligible patients were older than 3 years, had a Karnofsky Performance Score of 70 or higher, were able to have an MRI scan, and had a complete resection of one to three brain metastases (with a maximum diameter of the resection cavity ≤4 cm). Patients were randomly assigned (1:1) with a block size of four to either SRS of the resection cavity (within 30 days of surgery) or observation. Patients were stratified by histology of the primary tumour, metastatic tumour size, and number of metastases. The primary endpoint was time to local recurrence in the resection cavity, assessed by blinded central review of brain MRI scans by the study neuroradiologist in the modified intention-to-treat population that analysed patients by randomised allocation but excluded patients found ineligible after randomisation. Participants and other members of the treatment team (excluding the neuroradiologist) were not masked to treatment allocation. The trial is registered with ClinicalTrials.gov, number NCT00950001, and is closed to new participants. Between Aug 13, 2009, and Feb 16, 2016, 132 patients were randomly assigned to the observation group (n=68) or SRS group (n=64), with 128 patients available for analysis; four patients were ineligible (three from the SRS group and one from the observation group). Median follow-up was 11·1 months (IQR 4·8–20·4). 12-month freedom from local recurrence was 43% (95% CI 31–59) in the observation group and 72% (60–87) in the SRS group (hazard ratio 0·46 [95% CI 0·24–0·88]; p=0·015). There were no adverse events or treatment-related deaths in either group. SRS of the surgical cavity in patients who have had complete resection of one, two, or three brain metastases significantly lowers local recurrence compared with that noted for observation alone. Thus, the use of SRS after brain metastasis resection could be an alternative to whole-brain radiotherapy. National Institutes of Health.

The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis. In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I–III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0–2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9–85·6), 5-year overall survival was 81·4% (95% CI 77·2–85·8) with chemoradiotherapy versus 76·1% (71·6–80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51–0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5–80·7) versus 69·1% (63·8–73·8; HR 0·70 [0·52–0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3–26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4–34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55–0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0–2·1) in both groups (HR 0·99 [95% CI 0·06–15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3–2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3–2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17–3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported. This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival. Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

In a study involving men with castration-resistant prostate cancer and bone metastases, the alpha emitter radium-223 significantly prolonged survival, as compared with placebo, and was associated with fewer adverse events. More than 90% of patients with metastatic castration-resistant prostate cancer have radiologic evidence of bone metastases, which are a major cause of death, disability, decreased quality of life, and increased treatment cost among these patients. 1 , 2 Unlike deaths from many other types of cancer, deaths from prostate cancer are often due to bone disease and its complications. 3 Current bone-targeted therapies have not been shown to improve survival, and the benefits derived from bisphosphonates, denosumab, and existing radioisotope treatments are primarily limited to pain relief and delay of skeletal events. 4 – 13 Radium-223 dichloride (radium-223) is a targeted alpha emitter that selectively . . .

Metastasis-directed therapy by stereotactic body radiotherapy (SBRT) has been shown to improve clinical outcomes in the oligometastatic prostate cancer setting. We aimed to investigate whether short-course androgen deprivation therapy (ADT) and SBRT at all oligometastatic sites versus SBRT alone improves clinical progression-free survival in men with metachronous oligorecurrent hormone-sensitive prostate cancer. The RADIOSA study was a single-centre, randomised, open-label, controlled phase 2 trial done in the European Institute of Oncology, IRCCS, Milan, Italy. Key eligibility criteria were histologically proven initial diagnosis of adenocarcinoma of the prostate, biochemical progression after radical local prostate treatment, nodal relapse in the pelvis, extra-regional nodal relapse, bone metastases at next-generation imaging with a maximum of three lesions, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and age 18 years or older. Participants were stratified according to prostate-specific membrane antigen doubling time (≤3 vs >3 months), metastases localisation (node vs bone), and diagnostic imaging (positron emission tomography vs MRI) and were randomly assigned (1:1) using a computer-generated random number to SBRT alone or SBRT in combination with 6 months of ADT. For SBRT treatment, a schedule of 30 Gy in three fractions every other day (with the equivalent dose in 2 Gy fractions being 98·6 Gy, considering α/β ratio of 1·5 Gy and biologically effective dose of >100 Gy), or equivalent regimens depending on disease site location, was administered. Patients in the SBRT with ADT group received 6 months of ADT with a luteinising hormone-releasing hormone analogue within 1 week before the start of SBRT. The allocated treatment was not masked. The primary outcome measure was clinical progression-free survival. All analyses followed a modified intention-to-treat principle, consisting of all patients assigned to a treatment group who had available data. The trial is registered at ClinicalTrials.gov, NCT02680587, and is complete. Between Aug 1, 2019, and April 30, 2023, 218 patients were assessed for eligibility, 113 were excluded, and 105 were enrolled and randomly assigned to an intervention (52 to SBRT only and 53 to SBRT with ADT). Three patients were lost to follow-up and 51 patients in each group were assessed for the primary outcome. The median age at study enrolment was 70 years (IQR 65–75); data on race and ethnicity were not collected. With a median follow-up of 31 months (IQR 16–36) for both groups, the median clinical progression-free survival was 15·1 months (95% CI 12·4–22·8) for the SBRT group versus 32·2 months (22·4–not reached) for the SBRT with ADT group (hazard ratio 0·43 [95% CI 0·26–0·72], p=0·0010]). One gastrointestinal grade 1 adverse event (SBRT group) and one genitourinary grade 3 adverse event (left ureter stenosis, SBRT with ADT group) were reported, with no late toxicities observed. 22 grade 1 ADT-related adverse events were reported, all of which had resolved at the last follow-up. No treatment-related deaths were recorded. To our knowledge, the RADIOSA trial represents the first randomised trial in the metachronous oligometastatic hormone-sensitive prostate cancer setting to report improved clinical progression-free survival with the combination of SBRT and a short course of ADT, although carefully selected patients might still benefit from SBRT alone. By demonstrating improved clinical progression-free survival, the RADIOSA trial reinforces the role of metastasis-directed therapy in delaying systemic treatment escalation. Additionally, it underscores the need for further studies to determine the optimal duration of ADT and identify biomarkers predicting response to SBRT alone. Italian Association of Cancer Research.

To our knowledge, no randomised study has compared postmastectomy hypofractionated radiotherapy with conventional fractionated radiotherapy in patients with breast cancer. This study aimed to determine whether a 3-week schedule of postmastectomy hypofractionated radiotherapy is as efficacious and safe as a 5-week schedule of conventional fractionated radiotherapy. This randomised, non-inferiority, open-label, phase 3 study was done in a single academic hospital in China. Patients aged 18–75 years who had undergone mastectomy and had at least four positive axillary lymph nodes or primary tumour stage T3–4 disease were eligible to participate. Patients were randomly assigned (1:1) according to a computer-generated central randomisation schedule, without stratification, to receive chest wall and nodal irradiation at a dose of 50 Gy in 25 fractions over 5 weeks (conventional fractionated radiotherapy) or 43·5 Gy in 15 fractions over 3 weeks (hypofractionated radiotherapy). The modified intention-to-treat population (including all eligible patients who underwent randomisation but excluding those who were considered ineligible or withdrew consent after randomisation) was used in primary and safety analyses. The primary endpoint was 5-year locoregional recurrence, and a 5% margin was used to establish non-inferiority (equivalent to a hazard ratio <1·883). This trial is registered at ClinicalTrials.gov, number NCT00793962. Between June 12, 2008, and June 16, 2016, 820 patients were enrolled and randomly assigned to the conventional fractionated radiotherapy group (n=414) or hypofractionated radiotherapy group (n=406). 409 participants in the conventional fractionated radiotherapy group and 401 participants in the hypofractionated radiotherapy group were included in the modified intention-to-treat analyses. At a median follow-up of 58·5 months (IQR 39·2–81·8), 60 (7%) patients had developed locoregional recurrence (31 patients in the hypofractionated radiotherapy group and 29 in the conventional fractionated radiotherapy group); the 5-year cumulative incidence of locoregional recurrence was 8·3% (90% CI 5·8–10·7) in the hypofractionated radiotherapy group and 8·1% (90% CI 5·4–10·6) in the conventional fractionated radiotherapy group (absolute difference 0·2%, 90% CI −3·0 to 2·6; hazard ratio 1·10, 90% CI 0·72 to 1·69; p<0·0001 for non-inferiority). There were no significant differences between the groups in acute and late toxicities, except that fewer patients in the hypofractionated radiotherapy group had grade 3 acute skin toxicity than in the conventional fractionated radiotherapy group (14 [3%] of 401 patients vs 32 [8%] of 409 patients; p<0·0001). Postmastectomy hypofractionated radiotherapy was non-inferior to and had similar toxicities to conventional fractionated radiotherapy in patients with high-risk breast cancer. Hypofractionated radiotherapy could provide more convenient treatment and allow providers to treat more patients. National Key Projects of Research and Development of China; the Chinese Academy of Medical Science Innovation Fund for Medical Sciences; and Beijing Marathon of Hope, Cancer Foundation of China.

How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy. This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475. Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% [95% CI 75–84] vs 62% [57–67]; hazard ratio [HR] 0·50, 95% CI 0·38–0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 [8%] of 366 patients had a grade 2 or worse event; 30 patients [8%] had hot flushes and five patients [1%] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the radiotherapy alone group vs 26 [7%] in the radiotherapy plus goserelin group) and sexual disorders (20 [5%] vs 30 [8%]). No treatment-related deaths occurred. Adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population. French Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.