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Clinical Trial
. 2022 Dec 1;8(12):1809-1815.
doi: 10.1001/jamaoncol.2022.5049.

Association of Long-term Outcomes With Stereotactic Radiosurgery vs Whole-Brain Radiotherapy for Resected Brain Metastasis: A Secondary Analysis of The N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group) Randomized Clinical Trial

Joshua D Palmer  1 , Brett G Klamer  2 , Karla V Ballman  3   4 , Paul D Brown  5 , Jane H Cerhan  5 , S Keith Anderson  3 , Xiomara W Carrero  3 , Anthony C Whitton  6 , Jeffrey Greenspoon  6 , Ian F Parney  5 , Nadia N I Laack  5 , Jonathan B Ashman  7 , Jean-Paul Bahary  8 , Costas G Hadjipanayis  9 , James J Urbanic  10 , Fred G Barker 2nd  11 , Elana Farace  12 , Deepak Khuntia  13 , Caterina Giannini  5 , Jan C Buckner  5 , Evanthia Galanis  5 , David Roberge  8
Affiliations
Clinical Trial

Association of Long-term Outcomes With Stereotactic Radiosurgery vs Whole-Brain Radiotherapy for Resected Brain Metastasis: A Secondary Analysis of The N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group) Randomized Clinical Trial

Joshua D Palmer et al. JAMA Oncol. .

Abstract

Importance: Long-term outcomes of radiotherapy are important in understanding the risks and benefits of therapies for patients with brain metastases.

Objective: To determine how the use of postoperative whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) is associated with quality of life (QOL), cognitive function, and intracranial tumor control in long-term survivors with 1 to 4 brain metastases.

Design, setting, and participants: This secondary analysis of a randomized phase 3 clinical trial included 48 institutions in the US and Canada. Adult patients with 1 resected brain metastases but limited to those with 1 to 4 brain metastasis were eligible. Unresected metastases were treated with SRS. Long-term survivors were defined as evaluable patients who lived longer than 1 year from randomization. Patients were recruited between July 2011 and December 2015, and data were first analyzed in February 2017. For the present study, intracranial tumor control, cognitive deterioration, QOL, and cognitive outcomes were measured in evaluable patients who were alive at 12 months from randomization and reanalyzed in June 2017.

Interventions: Stereotactic radiosurgery or WBRT.

Main outcomes and measures: Intracranial tumor control, toxic effects, cognitive deterioration, and QOL.

Results: Fifty-four patients (27 SRS arm, 27 WBRT arm; female to male ratio, 65% vs 35%) were included for analysis with a median follow-up of 23.8 months. Cognitive deterioration was less frequent with SRS (37%-60%) compared with WBRT (75%-91%) at all time points. More patients declined by 2 or more standard deviations (SDs) in 1 or more cognitive tests for WBRT compared with SRS at 3, 6, and 9 months (70% vs 22%, 46% vs 19%, and 50% vs 20%, respectively). A 2 SD decline in at least 2 cognitive tests was associated with worse 12-month QOL in emotional well-being, functional well-being, general, additional concerns, and total scores. Overall QOL and functional independence favored SRS alone for categorical change at all time points. Total intracranial control for SRS alone vs WBRT at 12 months was 40.7% vs 81.5% (difference, -40.7; 95% CI, -68.1% to -13.4%), respectively. Data were first analyzed in February 2017.

Conclusions and relevance: The use of SRS alone compared with WBRT resulted in less cognitive deterioration among long-term survivors. The association of late cognitive deterioration with WBRT was clinically meaningful. A significant decline in cognition (2 SD) was associated with overall QOL. However, intracranial tumor control was improved with WBRT. This study provides detailed insight into cognitive function over time in this patient population.

Trial registration: ClinicalTrials.gov Identifier: NCT01372774; ALLIANCE/CCTG: N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group).

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Palmer reported grants from Varian Medical Systems, advisory board membership at Novocure, grants from Genentech, grants from the National Institutes of Health/ National Cancer Institute (NIH/NCI R702), and grants from NIH R01 outside the submitted work. Dr Ballman reported grants from NCI during the conduct of the study. Dr Brown reported personal fees from UpToDate as a contributor outside the submitted work. Dr Parney reported grants from Merck Pharmaceuticals outside the submitted work. Dr Hadjipanayis reported royalties from NX Development Corp, personal fees from Synaptive Medical, personal fees from Stryker Corp, and personal fees from Hemerion outside the submitted work. Dr Khuntia reported other from Varian Medical Systems Employed by Varian Medical Systems outside the submitted work. Dr Galanis reported personal fees from Kiyatec, Inc; personal compensation and personal fees from Karyopharm Therapeutics, Inc; compensation to institution and grants from Servier Pharmaceuticals, LLC; Celgene, MedImmune, Inc; and Tracon Pharmaceuticals (formerly Agios Pharmaceuticals, Inc) grant funds paid to institution outside the submitted work. Dr Roberge reported personal fees from Accuray, Siemens, and Zap outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. The Difference in Patients Who Had a 1.5, 2.0, or 3.0 Standard Deviation (SD) Decline in Cognitive Measures
Decline in at least 1, 2, or 3 cognitive measures. Negative values indicate stereotactic radiosurgery (SRS) had a favorable outcome compared with whole brain radiotherapy (WBRT). Circles indicate point estimates and bars indicate 95% CIs.
Figure 2.
Figure 2.. Baseline-Adjusted Estimates of Difference in Mean 12-Month Standardized Cognition Score Between Treatment Arms
Circles indicate point estimates and bars indicate 95% CIs. HVLT-R indicates the Hopkins Verbal Learning Test-Revised; SD, standard deviation; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; TM-A, Trail Making Test Part A; TM-B, Trail Making Test Part B.
Figure 3.
Figure 3.. Baseline-Adjusted Estimates of Difference in Mean 12-Month Quality of Life Between Treatment Arms
Circles indicate point estimates and bars indicate 95% CIs. FACT-Br indicates the Functional Assessment of Cancer Therapy-Brain test; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy.
See this image and copyright information in PMC

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