Absence of survival advantage and toxicity of whole brain radiotherapy makes SRS a good option for select patients

Encouraging outcomes were observed in patients with small cell lung cancer (SCLC) brain metastases treated with first-line stereotactic radiosurgery (SRS), with overall survival (OS) outcomes similar to those reported in other settings where SRS has become the established standard-of-care, a retrospective analysis found.

In a study of 710 patients with SCLC brain metastases treated with first-line SRS, median OS was 8.5 months (95% CI, 7.9-9.5 months) and the median time to central nervous system progression (TTCP) was 8.1 months (95% CI, 7.1-9.4 months), Chad Rusthoven, MD, University of Colorado School of Medicine, Aurora, Colorado, and colleagues reported in JAMA Oncology.

On a propensity score-matched analysis, whole-brain radiotherapy (WBRT) was associated with a 62% improved TTCP compared with SRS at a hazard ratio (HR) of 0.38 (95% CI, 0.26-0.55; P<0.001), but it did not improve OS at a median of 5.2 months (95% CI, 4.4-6.7 months; P=0.003) for WBRT versus a median of 6.5 months (95% CI, 5.5-8.0 months) for SRS, investigators added.

“The absence of an overall survival advantage to justify the toxic effects of WBRT on cognitive function and quality of life made SRS alone the preferred treatment for limited brain metastases in most settings,” Rusthoven and colleagues explained.

“This study provides a benchmark for stereotactic radiosurgery outcomes and suggests that this treatment alone is a potential option for select patients with small cell lung cancer,” they suggested.

The First-line Radiosurgery for Small-Cell Lung Cancer (FIRE-SCLC) was a multicenter analysis of patients with SCLC brain metastases treated with SRS without receiving prior prophylactic cranial irradiation (PCI) or WBRT. “The analysis included a comparison of SRS outcomes with the outcomes from a cohort of patients treated with first-line WBRT,” researchers wrote.

However, the primary objective of the study was to describe the clinical outcomes in this patient cohort treated with first-line SRS without prior PCI or WBRT.

Patients were treated between 1994 and 2018 but 87.5% of them were treated in the year 2000 or later. The median age of the cohort was 68.5 years and almost three-quarters of the group were men. “The median (IQR) [interquartile range] number of brain metastases treated with 2.5,” the authors pointed out. Over three-quarters of patients were treated in Asia, the remainder being treated in North America and Europe.

Stratified by the number of brain metastases treated, the median OS at 11.0 months (95% CI, 8.9-13.4 months) was “particularly impressive” among patients with a single brain metastasis compared with those who had more brain lesions (P<0.001).

In fact, median OS became progressively shorter as the number of treated brain lesions increased:

  • 8.7 moths (95% CI, 7.7-10.4 months) for those with 2 to 4 lesions.
  • 8.0 months (95% CI, 6.4-9.6 months) for those with 5 to 10 lesions.
  • 5.5 months (95% CI, 4.3-7.6 months) for those with 11 or more lesions.

Again, for patients with a single brain metastasis, the median TTCP was significantly longer at 11.7 months (95% CI, 8.8 months to not reached) compared to patients with greater numbers of brain lesions (P<0.001).

Median TTCPs intervals were as follows:

  • 6.8 months (95% CI, 5.7-8.3 months) for those with 2 to 4 lesions.
  • 6.1 months (95% CI, 4.9-7.7 months) for those with 5 to 10 lesions.
  • 4.7 months (95% CI, 3.2 months to not reached) for those with 11 lesions or more.

SRS versus WBRT

Importantly, patients in the WBRT cohort had worse performance scores and more brain metastases compared to patients in the SRS cohort, so their prognosis could have been inherently worse than those treated with SRS, the authors noted.

However, when investigators confined their comparison of WBRT versus SRS to a propensity-matched cohort consisting of 187 patients in each treatment group, “Overall survival outcomes in the matched data set were more similar than in the unmatched analysis but remained in favor of SRS versus WBRT,” Rusthoven and colleagues reported.

For example, median OS was 6.5 months (95% CI, 5.5-8.0 months) for SRS versus a median of 5.2 months (95% CI, 4.4-6.7 months) for WBRT (P=0.003).

In contrast, no difference was seen between the 2 treatment modalities in the time to central nervous system (CNS) progression-free survival rates at a median of 4.0 months for SRS compared with a median of 3.8 months for WBRT, investigators noted.

“Local failures after SRS were rare, with most of the CNS progression occurring in the form of new lesions, similar to SRS in other settings,” they added.

Among those who received salvage therapy following CNS progression, 33.5% received salvage SRS and only 16.1% received salvage WBRT.

The authors cautioned that these data should not be construed to mean that OS is superior with SRS. “[Rather], the findings of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP, are similar to other settings in which SRS alone is well established by multiple randomized clinical trials,” they wrote.

Limitations of the study include the fact that the analysis was not controlled for systemic therapy which in itself has prognostic implications for OS and CNS disease control in SCLC.

Commenting on the findings, Cecile Le Pechoux, MD, Institut d’Oncologie Thoracique, Gustave Roussy, Villejuif, France and Antonin Levy, MD, PhD, INSERM Molecular Radiotherapy, Gustave Roussy, Universite Paris-Saclay, Villejuif, France, noted that management of SCLC brain metastases has not changed over the past two decades and it still relies largely on WBRT for the treatment of symptomatic lesions plus or minus chemotherapy.

However, “because of concerns of WBRT-related neurotoxic effects, there has been a shift toward delivering SRS also for patients with SCLC with brain metastases,” they said.

Le Pechoux and Levy also felt that the authors should be commended for carrying out this “important” research as well as for acknowledging the inherent limitations of retrospective data. As they pointed out, OS rates may not be directly compared between the SRS and the WBRT groups because of inherent selection bias. There was also a great difference in the use of baseline brain MRI between the 2 groups. For example, over three-quarters of the SRS group included patients from Japan where there is the highest ratio of MRI units in the world.

“In the WBRT group, MRI of the brain was recommended only in symptomatic patients after irradiation,” Le Pechoux and Levy pointed out. [“And] fewer than half (46%) of the patients had at least 1 follow-up brain MRI after WBRT versus 89%… after SRS,” they added.

This is an important difference, because MRI scans are able to rule out occult brain metastases, they suggested.

“Intracranial metastases from SCLC are also responsive to systemic treatments, but delivered chemotherapy was not recorded in the FIRE-SCLC study,” the editorialists noted.

“[So i]n conclusion, prospective data are eagerly needed for patients with SCLC with brain metastases,” they wrote.

Currently, the only randomized trial comparing SRS with WBRT is the German ENCEPHALON trial, to be carried out in patients with SCLC with up to 10 brain metastases and whose primary end point is neurocognitive function at 3 months.

  1. First-line stereotactic radiosurgery (SRS) delivered survival outcomes in SCLC brain metastases comparable to those in other settings where SRS has become standard-of-care and may now be considered an option in SCLC brain mets as well.

  2. Whole-brain radiation therapy (WBRT) improved time to CNS progression over SRS but it did not prolong overall survival.

Pam Harrison, Contributing Writer, BreakingMED™

Rusthoven reported receiving research funding from Takeda, as well as honoraria from Genentech and AstraZeneca.

Le Pechoux reported receiving institutional honoraria for participation in advisory boards from AstraZeneca, Nanobiotix, and Roche; institutional honoraria for participation in educational meetings from Amgen, AstraZeneca, Medscape, and Eli Lilly and Company.

and personal honoraria from PRIME Oncology.

Levy had no conflicts of interest to declare.

Cat ID: 115

Topic ID: 78,115,730,115,24,129,192,65