Explore the vast range of titles available.

The oligometastatic paradigm suggests that some patients with a limited number of metastases might be cured if all lesions are eradicated. Evidence from randomised controlled trials to support this paradigm is scarce. We aimed to assess the effect of stereotactic ablative radiotherapy (SABR) on survival, oncological outcomes, toxicity, and quality of life in patients with a controlled primary tumour and one to five oligometastatic lesions. This randomised, open-label phase 2 study was done at 10 hospitals in Canada, the Netherlands, Scotland, and Australia. Patients aged 18 or older with a controlled primary tumour and one to five metastatic lesions, Eastern Cooperative Oncology Group score of 0–1, and a life expectancy of at least 6 months were eligible. After stratifying by the number of metastases (1–3 vs 4–5), we randomly assigned patients (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus SABR to all metastatic lesions (SABR group), using a computer-generated randomisation list with permuted blocks of nine. Neither patients nor physicians were masked to treatment allocation. The primary endpoint was overall survival. We used a randomised phase 2 screening design with a two-sided α of 0·20 (wherein p<0·20 designates a positive trial). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, number NCT01446744. 99 patients were randomised between Feb 10, 2012, and Aug 30, 2016. Of 99 patients, 33 (33%) were assigned to the control group and 66 (67%) to the SABR group. Two (3%) patients in the SABR group did not receive allocated treatment and withdrew from the trial; two (6%) patients in the control group also withdrew from the trial. Median follow-up was 25 months (IQR 19–54) in the control group versus 26 months (23–37) in the SABR group. Median overall survival was 28 months (95% CI 19–33) in the control group versus 41 months (26–not reached) in the SABR group (hazard ratio 0·57, 95% CI 0·30–1·10; p=0·090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the SABR group (p=0·026), an absolute increase of 20% (95% CI 5–34). Treatment-related deaths occurred in three (4·5%) of 66 patients after SABR, compared with none in the control group. SABR was associated with an improvement in overall survival, meeting the primary endpoint of this trial, but three (4·5%) of 66 patients in the SABR group had treatment-related death. Phase 3 trials are needed to conclusively show an overall survival benefit, and to determine the maximum number of metastatic lesions wherein SABR provides a benefit. Ontario Institute for Cancer Research and London Regional Cancer Program Catalyst Grant.

Background and objectiveThe optimal management of large vestibular schwannomas continues to be debated. We constituted a task force comprising the members of the EANS skull base committee along with international experts to derive recommendations for the management of this problem from a European perspective.Material and methodsA systematic review of MEDLINE database, in compliance with the PRISMA guidelines, was performed. A subgroup analysis screening all surgical series published within the last 20 years (January 2000 to March 2020) was performed. Weighted summary rates for tumor resection, oncological control, and facial nerve preservation were determined using meta-analysis models. This data along with contemporary practice patterns were discussed within the task force to generate consensual recommendations regarding preoperative evaluations, optimal surgical strategy, and follow-up management.ResultsTumor classification grades should be systematically used in the perioperative management of patients, with large vestibular schwannomas (VS) defined as > 30 mm in the largest extrameatal diameter. Grading scales for pre- and postoperative hearing (AAO-HNS or GR) and facial nerve function (HB) are to be used for reporting functional outcome. There is a lack of consensus to support the superiority of any surgical strategy with respect to extent of resection and use of adjuvant radiosurgery. Intraoperative neuromonitoring needs to be routinely used to preserve neural function. Recommendations for postoperative clinico-radiological evaluations have been elucidated based on the surgical strategy employed.ConclusionThe main goal of management of large vestibular schwannomas should focus on maintaining/improving quality of life (QoL), making every attempt at facial/cochlear nerve functional preservation while ensuring optimal oncological control, thereby allowing to meet patient expectations. Despite the fact that this analysis yielded only a few Class B evidences and mostly expert opinions, it will guide practitioners to manage these patients and form the basis for future clinical trials.

A randomized trial showed noninferiority of stereotactic body radiotherapy to conventionally or moderately hypofractionated radiotherapy in preventing biochemical recurrence in selected men with localized prostate cancer.

Abstract BACKGROUND Stereotactic radiosurgery (SRS) for benign intracranial meningiomas is an established treatment. OBJECTIVE To summarize the literature and provide evidence-based practice guidelines on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS Articles in English specific to SRS for benign intracranial meningioma, published from January 1964 to April 2018, were systematically reviewed. Three electronic databases, PubMed, EMBASE, and the Cochrane Central Register, were searched. RESULTS Out of the 2844 studies identified, 305 had a full text evaluation and 27 studies met the criteria to be included in this analysis. All but one were retrospective studies. The 10-yr local control (LC) rate ranged from 71% to 100%. The 10-yr progression-free-survival rate ranged from 55% to 97%. The prescription dose ranged typically between 12 and 15 Gy, delivered in a single fraction. Toxicity rate was generally low. CONCLUSION The current literature supporting SRS for benign intracranial meningioma lacks level I and II evidence. However, when summarizing the large number of level III studies, it is clear that SRS can be recommended as an effective evidence-based treatment option (recommendation level II) for grade 1 meningioma.

In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up. ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181. Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference −19·76, 95% CI −30·33 to −9·19). After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain. National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.

The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy. Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181. Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14–0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management. The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Moderately hypofractionated radiotherapy (MHRT) is a standard treatment for prostate cancer. Stereotactic body radiotherapy (SBRT) is also effective, and has been shown to be non-inferior to MHRT in a lower-risk group of patients who did not require hormone therapy (PACE-B), but randomised data on toxicity for higher-risk patients are lacking. We aimed to compare the early toxicity of MHRT and SBRT. The randomised, open-label, phase 3, non-inferiority PACE-C trial, conducted at 53 hospitals across the UK, Republic of Ireland, and New Zealand, recruited men aged at least 18 years with intermediate-risk or high-risk histologically confirmed prostate adenocarcinoma (T1–T3a, Gleason 7–8, and prostate specific antigen 10–30 ng/mL) and with WHO performance status of 0–2. Participants were centrally randomly assigned (1:1; non-masked; permuted block size of four and six; stratified by centre and risk group) to MHRT (60 Gy; 20 daily fractions over 4 weeks) or SBRT (36·25 Gy; five daily or alternate day fractions; over 1–2 weeks) with an additional mandatory clinical target volume dose target of 40 Gy (no margin) to the prostate, and proximal 1 cm of seminal vesicles. 6 months of androgen deprivation therapy was planned and was started before commencement of radiotherapy. The primary outcome of PACE-C is freedom from biochemical or clinical failure, the data for which are not yet mature. The co-primary endpoints for this preplanned safety analysis were the percentages of Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicities at any point during or within 12 weeks of completion of radiotherapy (the early or acute period). Analyses are by treatment received, with participants included if they had one or more fractions of MHRT or SBRT, regardless of their allocated treatment. Late toxicity and efficacy data are awaited as the trial remains in follow-up. The study was prospectively registered with ClinicalTrials.gov, NCT01584258. Between Nov 13, 2019, and June 24, 2022, 1208 participants were randomly assigned (601 to MHRT and 607 to SBRT). 608 patients received MHRT and 584 received SBRT, and thus were included in the study analysis. 1136 (95%) of 1192 patients were White, 20 (2%) were Black or Black British, 17 (1%) were Asian or Asian British, and seven (1%) were Chinese or other. During the early period (within 12 weeks of treatment), the co-primary endpoint of RTOG grade 2 or worse genitourinary toxicity was observed in 166 (27%) of 608 patients (95% CI 23·8 to 31·1) receiving MHRT and 162 (28%) of 582 patients (24·3 to 31·7) after SBRT (absolute difference 0·5%, 95% CI –4·7 to 5·7; p=0·89). For grade 2 or worse genitourinary Common Terminology Criteria for Adverse Events (CTCAE), 170 (28%) of 604 patients had events after MHRT and 195 (34%) of 581 patients had events after SBRT (p=0·050). Grade 3 CTCAE genitourinary toxicity was observed in three (<1%) patients receiving MHRT and three (1%) patients receiving SBRT. For grade 2 or worse gastrointestinal CTCAE, 60 (10%) of 604 patients had an event after MHRT and 96 (17%) of 581 patients had an event after SBRT (p=0·0011). Grade 3 CTCAE gastrointestinal toxicity was observed in three (<1%) patients receiving MHRT and four (1%) patients receiving SBRT. During the early period, the co-primary endpoint of RTOG grade 2 or worse gastrointestinal toxicity was observed in 69 (11%) of 608 patients (95% CI 9·0 to 14·2) receiving MHRT and 74 (13%) of 584 patients (10·2 to 15·8) receiving SBRT (absolute difference 1·4%, 95% CI –2·5 to 5·2; p=0·53). There were no treatment-related deaths. Despite an accelerated treatment schedule and a larger treated volume than PACE-B, SBRT and MHRT had similar rates of early RTOG toxicity. The Royal Marsden Cancer Charity.

IntroductionRadiosurgery (SRS) or stereotactic fractionated radiotherapy (SFRT) is increasing in the treatment of brain metastases (BMs). Aim of the present study was to evaluate the safety and effectiveness of SRS/SFRT for BMs, using a new mono-isocenter non-coplanar solution (HyperArc™ Varian Medical System).MethodsBMs patients with a diameter inferior to 3 cm, a life expectancy of more than 3 months and a good performance status, were eligible for Linac-based volumetric modulated arc therapy (VMAT) SFRT/SRS with HyperArc™. A retrospective analysis of patients and BMs was performed.ResultsFrom August 2017 to May 2018, 381 BMs in 64 patients were treated and 246 BMs (43 patients, median number of BMs: 5) of them were suitable for analysis. With a median FU time of 6 months, 244 out 246 (99%) BMs were controlled (18% complete response; 41% partial response, 40% stable disease), 2 BMs showed a progression, at the first control. No acute or late toxicities were reported. Median overall survival (OS) has not yet been achieved, while median time to progression was 5 months. In univariate analysis, statistically negative prognostic factors for OS were histology of primary tumor (p = 0.009): lung/breast cancer had better survival rates as compared to others. Cumulative intracranial volume disease ≥ 15 cc and systemic progression disease were independent prognostic factors for OS at univariate (p = 0.04; p = 0.005) and multivariate (p = 0.04; p = 0.009) analysis, respectively.ConclusionThe present first clinical data show that SFRT/SRS with HyperArc™ is safe and effective for BMs patients. The utilization of SFRT/SRS for BMs is promising and should be further explored in randomized trials.

There is paucity of investigations into immunotherapy or targeted therapy for postoperative locally recurrent pancreatic cancer. We aimed to assess the efficacy of stereotactic body radiotherapy (SBRT) plus pembrolizumab and trametinib in these patients. In this open-label, randomised, controlled, phase 2 study, participants were recruited from Changhai Hospital affiliated to Naval Medical University, Shanghai, China. Eligible patients were aged 18 years or older with histologically confirmed pancreatic ductal adenocarcinoma characterised by mutant KRAS and positive immunohistochemical staining of PD-L1, Eastern Cooperative Oncology Group performance status of 0 or 1, and documented local recurrence after surgery followed by chemotherapy (mFOLFIRINOX or 5-fluorouracil). Eligible participants were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive SBRT with doses ranging from 35-40 Gy in five fractions, intravenous pembrolizumab 200 mg once every 3 weeks, and oral trametinib 2 mg once daily or SBRT (same regimen) and intravenous gemcitabine (1000 mg/m ) on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the as-treated population in all participants who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02704156, and is now complete. Between Oct 10, 2016, and Oct 28, 2017, 198 patients were screen, of whom 170 patients were enrolled and randomly assigned to receive SBRT plus pembrolizumab and trametinib (n=85) or SBRT plus gemcitabine (n=85). As of the clinical cutoff date (Nov 30, 2020), median follow-up was 23·3 months (IQR 20·5-27·4). Median overall survival was 24·9 months (23·3-26·5) with SBRT plus pembrolizumab and trametinib and 22·4 months (95% CI 21·2-23·6) with SBRT plus gemcitabine (hazard ratio [HR] 0·60 [95% CI 0·44-0·82]; p=0·0012). The most common grade 3 or 4 adverse effects were increased alanine aminotransferase or aspartate aminotransferase (ten [12%] of 85 in SBRT plus pembrolizumab and trametinib group vs six [7%] of 85 in SBRT plus gemcitabine group), increased blood bilirubin (four [5%] vs none), neutropenia (one [1%] vs nine [11%]), and thrombocytopenia (one [1%] vs four [5%]). Serious adverse events were reported by 19 (22%) participants in the SBRT plus pembrolizumab and trametinib group and 12 (14%) in the SBRT plus gemcitabine group. No treatment-related deaths occurred. The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase 3 trials are needed to confirm our findings. Shanghai Shenkang Center and Changhai Hospital. For the Chinese translation of the abstract see Supplementary Materials section.

The highest priority uncertainty for people with symptomatic cerebral cavernous malformation is whether to have medical management and surgery or medical management alone. We conducted a pilot phase randomised controlled trial to assess the feasibility of addressing this uncertainty in a definitive trial. The CARE pilot trial was a prospective, randomised, open-label, assessor-blinded, parallel-group trial at neuroscience centres in the UK and Ireland. We aimed to recruit 60 people of any age, sex, and ethnicity who had mental capacity, were resident in the UK or Ireland, and had a symptomatic cerebral cavernous malformation. Computerised, web-based randomisation assigned participants (1:1) to medical management and surgery (neurosurgical resection or stereotactic radiosurgery) or medical management alone, stratified by the neurosurgeon's and participant's consensus about the intended type of surgery before randomisation. Assignment was open to investigators, participants, and carers, but not clinical outcome event adjudicators. Feasibility outcomes included site engagement, recruitment, choice of surgical management, retention, adherence, data quality, clinical outcome event rate, and protocol implementation. The primary clinical outcome was symptomatic intracranial haemorrhage or new persistent or progressive non-haemorrhagic focal neurological deficit due to cerebral cavernous malformation or surgery during at least 6 months of follow-up. We analysed data from all randomly assigned participants according to assigned management. This trial is registered with ISRCTN (ISRCTN41647111) and has been completed. Between Sept 27, 2021, and April 28, 2023, 28 (70%) of 40 sites took part, at which investigators screened 511 patients, of whom 322 (63%) were eligible, 202 were approached for recruitment, and 96 had collective uncertainty with their neurosurgeon about whether to have surgery for a symptomatic cerebral cavernous malformation. 72 (22%) of 322 eligible patients were randomly assigned (mean recruitment rate 0·2 [SD 0·25] participants per site per month) at a median of 287 (IQR 67–591) days since the most recent symptomatic presentation. Participants’ median age was 50·6 (IQR 38·6–59·2) years, 68 (94%) of 72 participants were adults, 41 (57%) were female, 66 (92%) were White, 56 (78%) had a previous intracranial haemorrhage, and 28 (39%) had a previous epileptic seizure. The intended type of surgery before randomisation was neurosurgical resection for 19 (26%) of 72, stereotactic radiosurgery for 44 (61%), and no preference for nine (13%). Baseline clinical and imaging data were complete for all participants. 36 participants were randomly assigned to medical management and surgery (12 to neurosurgical resection and 24 to stereotactic radiosurgery) and 36 to medical management alone. Three (4%) of 72 participants withdrew, one was lost to follow-up, and one declined face-to-face follow-up, leaving 67 (93%) retained at 6-months’ clinical follow-up. 61 (91%) of 67 participants with follow-up adhered to the assigned management strategy. The primary clinical outcome occurred in two (6%) of 33 participants randomly assigned to medical management and surgery (8·0%, 95% CI 2·0–32·1 per year) and in two (6%) of 34 participants randomly assigned to medical management alone (7·5%, 1·9–30·1 per year). Investigators reported no deaths, no serious adverse events, one protocol violation, and 61 protocol deviations. This pilot phase trial exceeded its recruitment target, but a definitive trial will require extensive international engagement. National Institute for Health and Care Research.