Debate: adjuvant whole brain radiotherapy or not? More data is the wiser choice

Abstract

Every year 170,000 patients are diagnosed with brain metastases (BMs) in the United States. Traditionally, adjuvant whole brain radiotherapy (AWBRT) has been offered following local therapy with neurosurgery (NSx) and/or stereotactic radiosurgery (SRS) to BMs. The aim is to increase intracranial control, thereby decreasing symptoms from intracranial progression and a neurological death. There is a rapidly evolving change in the radiation treatment of BMs happening around the world. AWBRT is now being passed over in favour of repeat scanning at regular intervals and more local therapies as more BMs appear radiologically, BMs that may never become symptomatic. This change has happened after the American Society for Radiation Oncology (ASTRO) in Item 5 of its “Choosing Wisely 2014” list recommended: “Don't routinely add adjuvant whole brain radiation therapy to SRS for limited brain metastases”. The guidelines are supposed to be based on the highest evidence to hand at the time. This article debates that the randomised controlled trials (RCTs) published prior to this recommendation consistently showed AWBRT significantly increases intracranial control, and avoids a neurological death, what it is meant to do. It also points out that, despite the enormity of the problem, only 774 patients in total had been randomised over more than three decades. These trials were heterogeneous in many respects. This data can, at best, be regarded as preliminary. In particular, there are no single histology AWBRT trials yet completed. A phase two trial investigating hippocampal avoiding AWBRT (HAWBRT) showed significantly less NCF decline compared to historical controls. We now need more randomised data to confirm the benefit of adjuvant HAWBRT. However, the ASTRO Guideline has particularly impacted accrual to trials investigating this, especially the international ANZMTG 01.07 WBRTMel trial. This is an RCT investigating AWBRT following local treatment in patients with one to three BMs from melanoma. WBRTMel has accrued 196 of a required 220 to date but accrual has slowed. HAWBRT may now never be tested in a randomised setting. Encouraging more data in AWBRT is the wiser choice.

A matched-pair analysis comparing whole-brain radiotherapy with and without a stereotactic boost for intracerebral control and overall survival in patients with one to three cerebral metastases

“…When adding a stereotactic boost to WBRT two additional aspects need to be considered. A stereotactic boost will likely be associated with an increased risk of radionecrosis, particularly when combined with modern targeted therapies such as ipilimumab that are increasingly used in cancer patients [ 18 , 19 ]. Another aspect, which needs to be considered, is cost-effectiveness [ 18 ].…”

BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy

“…While these randomized studies illustrate the efficacy of SRS, MBM were not highly represented. Furthermore, there are several criticisms regarding study design and interpretations of the mentioned trials 15,16. To address these gaps, a prospective Phase 3 clinical trial is currently ongoing that compares local control (LC) and neurocognitive preservation with SRS versus WBRT for patients with more than three MBM (ClinicalTrials.gov NCT01644591).…”

Repeated in-field radiosurgery for locally recurrent brain metastases: Feasibility, results and survival in a heavily treated patient cohort

“…Stereotactic radiosurgery (SRS) is an established primary treatment for newly diagnosed, untreated brain metastases as well as for resection cavities after previous neurosurgical operation, with high level of evidence for both indications [ 2 – 5 ]. More important, stand-alone SRS is considered as standard-of-care treatment method, especially when patients have a limited number of lesions (usually 1–4) and is represented in the most national recommendations and guidelines [ 6 , 7 ]. SRS provides excellent 1-year-local control rates (LCR) of 65%-90% regardless of histology, as has been already shown in many prospective and retrospective studies [ 2 , 3 , 8 – 10 ].…”