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Clinical Trial
. 2024 Sep 5;26(9):1651-1659.
doi: 10.1093/neuonc/noae076.

Phase I trial of dose escalation for preoperative stereotactic radiosurgery for patients with large brain metastases

Erin S Murphy  1   2   3 , Kailin Yang  3 , John H Suh  1   2   3 , Jennifer S Yu  1   2   3 , Glen Stevens  1   2 , Lilyana Angelov  1   2   4 , Michael A Vogelbaum  5 , Gene H Barnett  1   2   4 , Manmeet S Ahluwalia  6 , Gennady Neyman  1   2   3 , Alireza M Mohammadi  1   2   4 , Samuel T Chao  1   2   3
Affiliations
Clinical Trial

Phase I trial of dose escalation for preoperative stereotactic radiosurgery for patients with large brain metastases

Erin S Murphy et al. Neuro Oncol. .

Abstract

Background: Single-session stereotactic radiosurgery (SRS) or surgical resection alone for brain metastases larger than 2 cm results in unsatisfactory local control. We conducted a phase I trial for brain metastases(>2 cm) to determine the safety of preoperative SRS at escalating doses.

Methods: Radiosurgery dose was escalated at 3 Gy increments for 3 cohorts based on maximum tumor dimension starting at: 18 Gy for >2-3 cm, 15 Gy for >3-4 cm, and 12 Gy for >4-6 cm. Dose-limiting toxicity was defined as grade III or greater acute toxicity.

Results: A total of 35 patients/36 lesions were enrolled. For tumor size >2-3 cm, patients were enrolled up to the second dose level (21 Gy); for >3-4 cm and >4-6 cm cohorts the third dose level (21 and 18 Gy, respectively) was reached. There were 2 DLTs in the >3-4 cm arm at 21 Gy. The maximum tolerated dose of SRS for >2-3 cm was not reached; and was 18 Gy for both >3-4 cm arm and >4-6 cm arm. With a median follow-up of 64.0 months, the 6- and 12-month local control rates were 85.9% and 76.6%, respectively. One patient developed grade 3 radiation necrosis at 5 months. The 2-year rate of leptomeningeal disease (LMD) was 0%.

Conclusions: Preoperative SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size demonstrates acceptable acute toxicity. The phase II portion of the trial will be conducted at the maximum tolerated SRS doses.

Keywords: brain metastases; dose escalation; neoadjuvant; preoperative; stereotactic radiosurgery.

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Conflict of interest statement

MSA is a consultant for Bayer, Novocure, Kiyatec, Insightec, GSK, Xoft, Nuvation, Cellularity, SDP Oncology, Apollomics, Prelude, Janssen, Tocagen, Voyager Therapeutics, Viewray, Caris Lifesciences, Pyramid Biosciences, Anheart Therapeutics, Varian Medical Systems, Cairn Therapeutics, and Theraguix; receives research funding from Seagen; serves on the Scientific Advisory Board for Cairn Therapeutics, Pyramid Biosciences, and ModifiBio; and reports holding stock share of Mimivax, Cytodyn, and MedInnovate Advisors LLC. GN is a consultant for Elekta AB. STC reports honorarium from Varian Medical Systems and Blue Earth Diagnostics, and research support from Blue Earth Diagnostics. E.S.M., K.Y., J.H.S., J.S.Y., G.S., L.A., M.A.V., G.H.B., and A.M.M. report no relevant conflict of interest.

Figures

Figure 1.
Figure 1.
Local control (with 95% CI) after dose-escalated SRS followed by surgical resection. (A) Local control of all patients. (B) Local control stratified by size group of maximal dimension. (C) Local control stratified by the maximal dimension of the index lesion (≤3.5 vs. >3.5 cm). (D) Local control stratified by volume of the index lesion (≤15 vs. >15 cc).
Figure 2.
Figure 2.
Clinical outcomes after dose-escalated SRS followed by surgical resection. (A) Freedom from distant brain failure (with 95% CI). (B) Overall survival (with 95% CI).
See this image and copyright information in PMC

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