Association of Maximal Extent of Resection of Contrast-Enhanced and Non–Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma

Annette M. Molinaro, PhD; Shawn Hervey-Jumper, MD; Ramin A. Morshed, MD; Jacob Young, MD; Seunggu J. Han, MD; Pranathi Chunduru, MS; Yalan Zhang, MS; Joanna J. Phillips, MD, PhD; Anny Shai, PhD; Marisa Lafontaine, MS; Jason Crane, PhD; Ankush Chandra, BS; Patrick Flanigan, MD; Arman Jahangiri, MD, PhD; Gino Cioffi, MPH; Quinn Ostrom, PhD; John E. Anderson, MD; Chaitra Badve, MD; Jill Barnholtz-Sloan, PhD; Andrew E. Sloan, MD; Bradley J. Erickson, MD, PhD; Paul A. Decker, MS; Matthew L. Kosel, BS; Daniel LaChance, MD; Jeanette Eckel-Passow, PhD; Robert Jenkins, MD, PhD; Javier Villanueva-Meyer, MD; Terri Rice, MPH; Margaret Wrensch, PhD; John K. Wiencke, PhD; Nancy Ann Oberheim Bush, MD, PhD; Jennie Taylor, MD; Nicholas Butowski, MD; Michael Prados, MD; Jennifer Clarke, MD; Susan Chang, MD; Edward Chang, MD; Manish Aghi, MD, PhD; Philip Theodosopoulos, MD; Michael McDermott, MD; Mitchel S. Berger, MD 

JAMAOncol.2020;6(4):495-503.doi:10.1001/jamaoncol.2019.6143 PublishedonlineFebruary6,2020.CorrectedonMarch12,2020.

IMPORTANCE Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)–wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non–contrast-enhanced (NCE) disease is poorly understood. OBJECTIVE To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019. MAIN OUTCOMES AND MEASURES Overall survival. RESULTS Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients with IDH–wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients with IDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients with IDH–wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients with IDH–wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients with IDH–wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. CONCLUSIONS AND RELEVANCE This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless of IDH status, and among patients with IDH–wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma. JAMA Oncol. 2020;6(4):495-503. doi:10.1001/jamaoncol.2019.6143 Published online February 6, 2020. Corrected on March 12, 2020.

중요성 (IMPORTANCE)

• WHO 2016 기준에 따라 교모세포종(GBM)은 IDH 돌연변이 여부로 분류됨.

  • IDH-wildtype: 평균 생존 1.2년

  • IDH-mutant: 평균 생존 3.6년

• 지금까지는 조영 증강 병변(CE tumor)의 광범위 절제가 생존율 향상과 관련 있다고 알려져 있었으나,

  • 비조영 병변(NCE tumor)의 절제와

  • 분자 아형별 절제 효과(유전적 또는 분자생물학적 특성에 따라 나뉜 각 아형에서, 최대 절제가 생존에 어떤 영향을 주는지)는 불분명했음.

    
    

목적 (OBJECTIVE)

• CE와 NCE 병변 절제의 생존율과의 연관성을

• IDH status 및 MGMT promoter methylation 같은 분자 생물학적 정보와 함께 분석해

• 맞춤형 수술 전략 수립에 기여하려는 것

연구 설계, 장소, 대상자 (DESIGN, SETTING, AND PARTICIPANTS)

• 후향적, 다기관 코호트 연구

  • 개발 코호트: UCSF(University of California, San Francisco) (n=761)

    (진단 시기: 1997년 1월 1일 ~ 2017년 12월 31일, 추적관찰: 평균 9.6년)

  • 검증 코호트: Mayo Clinic (n=107) (2004년 1월 1일 ~ 2014년 12월 31일, 평균 추적관찰 5.7년), Ohio Brain Tumor Study (n=99) (2008년 1월 1일 ~ 2011년 12월 31일, 중앙 추적관찰 10.9개월)

• 포함 기준: 새로 진단된 교모세포종에 대해 수술적 절제 + 분자/임상/영상 데이터 완비

            (자료 분석 기간 : 2018년 11월 15일 ~ 2019년 3월 15일)

  
  

주요 결과 지표 (MAIN OUTCOMES AND MEASURES)

• 전체 생존 기간 (Overall survival, OS)
  

결과 (RESULTS)

• 개발 코호트(761명) 중:

  • 남성 468명 (61.5%),

  • 중앙 연령: 60세 (IQR: 51.6–67.7세)

• 젊은 IDH-wild-type 환자 중에서

  조영 증강(CE)과 비조영 증강(NCE) 병변 모두 적극적으로 절제한 경우

  ➤ IDH-mutant 환자와 유사한 생존율을 보임

  → 중앙 생존 기간: 37.3개월 (95% CI, 31.6–70.7)

• CE 병변만 절제하고 NCE 병변은 잔존한 젊은 IDH-wild-type 환자는

  ➤ 예후가 더 나쁨

  → 중앙 생존 기간: 16.5개월 (95% CI, 14.7–18.3)

• 고령 IDH-wild-type 환자의 경우

  ➤ CE 병변 절제만으로도 생존 이득

  → 중앙 생존 기간: 12.4개월 (95% CI, 11.4–14.0)

• 이 결과는 외부 두 코호트(Mayo, Ohio)에서도 검증됨.

• IDH-wild-type 환자에서 CE 및 NCE 병변에 대한 적극적 절제와 생존율 간의 연관성은,

  O6-methylguanine-DNA methyltransferase(MGMT)라는 DNA 복구 효소의 프로모터 영역의 메틸화 여부와 관계없이 유지되었음.
  

결론 및 의의 (CONCLUSIONS AND RELEVANCE)

·         본 연구는 모든 교모세포종 분자 아형에서 CE 병변의 최대 절제가 전체 생존율과 연관된다는 것을 확인하였다.

·         NCE 병변의 최대 절제 또한

o    젊은 환자(IDH status와 무관)와

o    IDH-wild-type 환자(MGMT 메틸화 여부와 무관)에서생존률 증가와 연관되어 있었다.

이러한 결과는, 새로 진단된 교모세포종 환자에 대한 개별 맞춤형 수술 전략을 재고하는 데 도움을 줄 수 있다.