SS 22 - Late-Breaking Abstracts Special Session
LBA9 - Preservation of Neurocognitive Function (NCF) with Conformal Avoidance of the Hippocampus during Whole-Brain Radiotherapy (HA-WBRT) for Brain Metastases: Preliminary Results of Phase III Trial NRG Oncology CC001
Tuesday, October 23
7:45 AM - 7:55 AM
Location: Room 007 C/D
Vinai Gondi, MD
Northwestern Medicine Cancer Center Warrenville
Northwestern Medicine Cancer Center Warrenville and Northwestern Medicine Chicago Proton Center: Director of Research & Education, Director of CNS Radiation Oncology: Independent Contractor; Radiation Oncology Consultants, Ltd.: Physician: Partner
Radiation Oncology Consultants, Ltd.: Partnership
NRG Oncology: NRG CC001, NRG CC003 and NRG BN001
Preservation of Neurocognitive Function (NCF) with Conformal Avoidance of the Hippocampus during Whole-Brain Radiotherapy (HA-WBRT) for Brain Metastases: Preliminary Results of Phase III Trial NRG Oncology CC001
V. Gondi1, S. Deshmukh2, P. D. Brown3, J. S. Wefel4, W. A. Tome5, D. W. Bruner6, J. A. Bovi7, C. G. Robinson8, D. Khuntia9, D. R. Grosshans4, A. A. Konski10, D. Roberge11, V. Kundapur12, K. Devisetty13, S. A. Shah14, K. Y. Usuki15, B. M. Anderson16, M. P. Mehta17, and L. A. Kachnic18; 1Northwestern Medicine Chicago Proton Center and Northwestern Medicine Cancer Center Warrenville, Warrenville, IL, 2American College of Radiology, Philadelphia, PA, 3Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 4University of Texas MD Anderson Cancer Center, Houston, TX, 5Department of Radiation Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, 6Nell Hodgson Woodruff School of Nursing, and Winship Cancer Institute at Emory University, Atlanta, GA, 7Medical College of Wisconsin, Milwaukee, WI, 8Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, 9East Bay Radiation Oncology Center/Eden Medical Center, Castro Valley, CA, 10Chester County Hospital, West Chester, PA, 11Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada, 12Saskatoon Cancer Centre, Saskatoon, SK, Canada, 13Wayne State University/McLaren Cancer Institute, Flint, MI, 14Delaware/Christiana NCI Community Oncology Research Program, Newark, DE, 15Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, 16University of Wisconsin Hospital and Clinics, Madison, WI, 17Miami Cancer Institute, Baptist Health South Florida, Miami, FL, 18Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
Based on preliminary evidence that radiation to the neuroregenerative hippocampal stem cells plays a role in NCF decline, the phase II NRG/RTOG 0933 trial demonstrated memory-preservation following HA-WBRT. The phase III NRG-CC001 trial of WBRT plus memantine without (WBRT+M) or with hippocampal avoidance (HA-WBRT+M) sought to validate these findings.
Materials/Methods: Adult patients with brain metastases were stratified by RPA and receipt of prior radiosurgery/surgery and randomized to WBRT+M versus HA-WBRT+M (30 Gy in 10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was time to NCF failure defined as decline using the reliable change index on at least one of the following tests: Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence was used to estimate time to NCF failure (death without NCF failure was treated as a competing risk). Between-arms differences were tested using Gray’s test. To detect an 11% absolute reduction in 6-month NCF failure, 382 analyzable patients were required for 90% power with two-sided α=0.05. Due to possible non-compliance, the sample size was increased by 25% (510 patients).
Results: 518 patients were randomized from July 2016 to March 2018. Median age was 61.5 years. Treatment arms did not differ in baseline characteristics. Grade≥3 toxicity did not differ (p=0.88). Median follow-up for alive patients was 6.1mos. NCF testing compliance was 69% at 6mos and 61% at 12mos. Treatment arms did not differ in baseline NCF, overall survival (hazard ratio (HR)=1.13, 95% confidence interval (CI): 0.89-1.44, p=0.31) or intracranial progression-free survival (HR 1.12, 95% CI 0.90-1.39, p=0.33). Time to NCF failure was significantly longer in favor of HA-WBRT+M. The NCF failure rates following WBRT+M vs. HA-WBRT+M were 12.8% (95% CI 8.5-18.0%) vs. 11.2% (7.1-16.3%) at 2mos, 63.0% (55.6-69.5%) vs. 53.7% (46.1-60.8%) at 4mos, and 69.1% (61.8-75.3%) vs. 58.0% (50.2-64.9%) at 6mos (p=0.012). In analyses adjusted for stratification factors, HA-WBRT+M (HR=0.72; 95% CI: 0.56-0.94, p=0.016) and age ≤61 years (HR=0.61, 95% CI: 0.46-0.81, p=0.0006) predicted for longer time to NCF failure. Test for interaction between treatment arm and age was non-significant (p=0.67).
Conclusion: Preliminary analysis confirms our hypothesis that conformal avoidance of the hippocampal neuro-regenerative stem cell niche during WBRT preserves NCF while achieving similar intracranial control and survival. While age independently predicts for NCF, the NCF benefit of hippocampal avoidance does not differ by age.
Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.
Author Disclosure: V. Gondi: Independent Contractor; Northwestern Medicine Cancer Center Warrenville and Northwestern Medicine Chicago Proton Center. Partner; Radiation Oncology Consultants, Ltd. Partnership; Radiation Oncology Consultants, Ltd. S. Deshmukh: None. P.D. Brown: Honoraria; UpToDate, Novella DSMB. J.S. Wefel: Consultant; Novocure, Juno. Advisory Board; Bayer. W.A. Tome: Research Grant; Varian Inc. Honoraria; Varian Inc. Travel Expenses; Varian Inc. Royalty; Wisconsin Alumni Research Foundation. Patent/License Fees/Copyright; Wisconsin Alumni Research Foundation. Working Group for SBRT; AAPM. D.W. Bruner: Research Grant; Radiation Therapy Oncology Group. Travel Expenses; Radiation Therapy Oncology Group. member; NCI Symptom Mgmt & HRQOL Comm, NCAB, RTOG Foundation Board. Deputy Chair, Publications; NRG Oncology. J.A. Bovi: None. C.G. Robinson: Research Grant; Varian Medical Systems, Elekta. Speaker's Bureau; Varian Medical Systems, DFINE. Advisory Board; Radialogica. Stock Options; Radialogica. D. Khuntia: Consultant; Procertis, Inc. Board of Directors; Medical Physics Publshing. D.R. Grosshans: None. A.A. Konski: Stock; General Electric Stock. President-elect; American Radium Society. Board of Chancellors; American College of Radiology. D. Roberge: Independent Contractor; University of Montreal/CHUM. honoraria/research support; Brainlab, Varian Medical Systems, Accuray. Editor in Chief; Cureus CARO Channel. V. Kundapur: None. K. Devisetty: Employee; Laxmi Devisetty. Advisory Board; Novocure. Stock; Abbott Laboratories, Abbvie. Partner; Radiation & Retina Research, PLLC. S. Shah: None. K.Y. Usuki: None. B.M. Anderson: Partner; University of Wisconsin. M.P. Mehta: Consultant; Abbvie, AstraZeneca. Stock Options; Oncoceutics. Member, Board of Directors; Oncoceutics. Board Member; Proton Collaborative Group. L.A. Kachnic: Research Grant; NCI NCORP, SWOG. Honoraria; Up-to-Date. President; ABR.