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The Future Is Now-Prospective Study of Radiosurgery for More Than 4 Brain Metastases to Start in 2018!

ABSTRACT: Stereotactic radiosurgery (SRS) has replaced whole brain radiotherapy (WBRT) as standard therapy for most patients with four or fewer brain metastases due to improved cognitive outcomes and more favorable health related quality of life (QoL). Whether SRS or WBRT is the optimal radiation modality for patients with five to fifteen brain metastases remains an open question. Efforts are underway to develop prospective evidence to answer this question. One of the planned trials is a Canadian Cancer Trials Group (CCTG)-lead North American intergroup trial. In general cancer treatments must have two basic aims: prolonging and improving QoL. In this vein, the selection of overall survival and QoL metrics as outcomes appear obvious. Potential secondary outcomes are numerous: patient/disease related, treatment related, economic, translational, imaging, and dosimetric. In designing a trial, one must also ponder what is standard WBRT-specifically, whether it should be associated with memantine. With the rapid accrual of an intergroup trial of hippocampal-sparing WBRT, we may find that the standard WBRT regimen changes in the course of planned trials. As up-front radiosurgery is increasingly used for more than 4 brain metastases without high level evidence, we have a window of opportunity to develop high quality evidence which will help guide our future clinical and policy decisions.

SUBMITTER: Roberge D

PROVIDER: S-EPMC6146211 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:BackgroundSurgery is an important therapeutic option for brain metastases. Currently, postoperative stereotactic radiosurgery (SRT) leads to 6-month and 1-year local control estimated at 70 and 62% respectively. However, there is an increased risk of radio-necrosis and leptomeningeal relapse. Preoperative SRT might be an alternative, providing local control remains at least equivalent. It is an innovative concept that could enable the stereotactic benefits to be retained with advantages over post-operative SRT.MethodsSTEP has been designed as a national, multicentre, open-label, prospective, non-randomized, phase-II trial. Seventeen patients are expected to be recruited in the study from 7 sites and they will be followed for 12 months. Patients with more than 4 distinct brain metastases, including one with a surgical indication, and an indication for SRT and surgery, are eligible for enrolment. The primary objective of the trial is to assess 6-month local control after preoperative SRT. The secondary objectives include the assessment of local control, radio-necrosis, overall survival, toxicities, leptomeningeal relapse, distant control, cognitive function, and quality of life. The experimental design is based on a Flemming plan.DiscussionThere is very little data available in the literature on preoperative SRT: there have only been 3 American single or two-centre retrospective studies. STEP is the first prospective trial on preoperative SRT in Europe. Compared to postoperative stereotactic radiotherapy, preoperative stereotactic radiotherapy will enable reduction in the irradiated volume, leptomeningeal relapse and the total duration of the combined treatment (from 4 to 6 weeks to a few days).Trial registration numberClinicaltrials.gov: NCT04503772 , registered on August 07, 2020. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID RCB 2020-A00403-36, registered in February 2020.Protocolversion 4, 07 December 2020.

Project description:AimsTo evaluate neurocognitive performance, daily activity and quality of life (QoL), other than usual oncologic outcomes, among patients with brain metastasis ≥5 (MBM) from solid tumors treated with Stereotactic Brain Irradiation (SBI) or Whole Brain Irradiation (WBI).MethodsThis multicentric randomized controlled trial will involve the enrollment of 100 patients (50 for each arm) with MBM ≥ 5, age ≥ 18 years, Karnofsky Performance Status (KPS) ≥ 70, life expectancy > 3 months, known primary tumor, with controlled or controllable extracranial disease, baseline Montreal Cognitive Assessment (MoCA) score ≥ 20/30, Barthel Activities of Daily Living score ≥ 90/100, to be submitted to SBI by LINAC with monoisocentric technique and non-coplanar arcs (experimental arm) or to WBI (control arm). The primary endpoints are neurocognitive performance, QoL and autonomy in daily-life activities variations, the first one assessed by MoCa Score and Hopkins Verbal Learning Test-Revised, the second one through the EORTC QLQ-C15-PAL and QLQ-BN-20 questionnaires, the third one through the Barthel Index, respectively. The secondary endpoints are time to intracranial failure, overall survival, retreatment rate, acute and late toxicities, changing of KPS. It will be considered significant a statistical difference of at least 30% between the two arms (statistical power of 80% with a significance level of 95%).DiscussionSeveral studies debate what is the decisive factor accountable for the development of neurocognitive decay among patients undergoing brain irradiation for MBM: radiation effect on clinically healthy brain tissue or intracranial tumor burden? The answer to this question may come from the recent technological advancement that allows, in a context of a significant time saving, improved patient comfort and minimizing radiation dose to off-target brain, a selective treatment of MBM simultaneously, otherwise attackable only by WBI. The achievement of a local control rate comparable to that obtained with WBI remains the fundamental prerequisite.Trial registrationNCT number: NCT04891471.

Project description:BackgroundThe benefits of adding upfront whole-brain radiotherapy (WBRT) to surgery or stereotactic radiosurgery (SRS) when compared to surgery or SRS alone for treatment of brain metastases are unclear.ObjectivesTo compare the efficacy and safety of surgery or SRS plus WBRT with that of surgery or SRS alone for treatment of brain metastases in patients with systemic cancer.Search methodsWe searched MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials (CENTRAL) up to May 2013 and annual meeting proceedings of ASCO and ASTRO up to September 2012 for relevant studies.Selection criteriaRandomised controlled trials (RCTs) comparing surgery or SRS plus WBRT with surgery or SRS alone for treatment of brain metastases.Data collection and analysisTwo review authors undertook the quality assessment and data extraction. The primary outcome was overall survival (OS). Secondary outcomes include progression free survival (PFS), local and distant intracranial disease progression, neurocognitive function (NF), health related quality of life (HRQL) and neurological adverse events. Hazard ratios (HR), risk ratio (RR), confidence intervals (CI), P-values (P) were estimated with random effects models using Revman 5.1 MAIN RESULTS: We identified five RCTs including 663 patients with one to four brain metastases. The risk of bias associated with lack of blinding was high and impacted to a greater or lesser extent on the quality of evidence for all of the outcomes. Adding upfront WBRT decreased the relative risk of any intracranial disease progression at one year by 53% (RR 0.47, 95% CI 0.34 to 0.66, P value < 0.0001, I(2) =34%, Chi(2) P value = 0.21, low quality evidence) but there was no clear evidence of a difference in OS (HR 1.11, 95% CI 0.83 to 1.48, P value = 0.47, I(2) = 52%, Chi(2) P value = 0.08, low quality evidence) and PFS (HR 0.76, 95% CI 0.53 to 1.10, P value = 0.14, I(2) = 16%, Chi(2) P value = 0.28, low quality evidence). Subgroup analyses showed that the effects on overall survival were similar regardless of types of focal therapy used, number of brain metastases, dose and sequence of WBRT. The evaluation of the impact of upfront WBRT on NF, HRQL and neurological adverse events was limited by the unclear and high risk of reporting, performance and detection bias, and inconsistency in the instruments and methods used to measure and report results across studies.Authors' conclusionsThere is low quality evidence that adding upfront WBRT to surgery or SRS decreases any intracranial disease progression at one year. There was no clear evidence of an effect on overall and progression free survival. The impact of upfront WBRT on neurocognitive function, health related quality of life and neurological adverse events was undetermined due to the high risk of performance and detection bias, and inconsistency in the instruments and methods used to measure and report results across studies.

Project description:Introduction:Due to the neurocognitive side effects of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) is being used with increasing frequency. The use of SRS is expanding for patients with multiple (>4) brain metastases (BM). This study summarizes our institutional experience with single-fraction, linear-accelerator-based SRS for multiple BM. Methods and materials:All patients who were treated between January 1, 2013, and September 30, 2015, with single-fraction SRS for ?4 BM were included in this institutional review board-approved, retrospective, single-institution study. Patients were treated with linear accelerator-based image guided SRS. Results:A total of 59 patients with ?4 BM were treated with single-fraction SRS. The median follow-up was 15.2 months, and the median overall survival for the entire cohort was 5.8 months. The median number of treated lesions per patient was 5 (range, 4-23). Per patient, the median planning target volume (PTV) was 4.8?cc (range, 0.7-28.8?cc). The prescribed dose across all 380 BM for the 59 patients ranged from 7 to 20?Gy. The median of the mean dose to the total PTV was 19.5?Gy. Although the number of treated lesions (4-5 vs ?6) did not influence survival, better survival was noted for a total PTV <10?cc versus ?10?cc (7.1 vs 4.2 months, respectively; P?=?.0001). A mean dose of ?19?Gy to the entire PTV was also associated with increased survival (6.6 vs 5.0 months, respectively; P?=?.0172). Patients receiving a dose of >12?Gy to ?10?cc of normal brain had worse survival (5.1 vs 8.6 months, respectively; P?=?.0028). Conclusion:In single-fraction SRS for patients with multiple BM, smaller total tumor volume, higher total dose, and lower volume of normal brain receiving >12?Gy were associated with increased survival. These data suggest that using SRS for the treatment of multiple BM is efficacious and that outcomes may be affected more by total tumor volume than by the number of lesions.

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The Future Is Now-Prospective Study of Radiosurgery for More Than 4 Brain Metastases to Start in 2018!

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