Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer.

Jun 7, 2021

Contributor: R A El Shafie,K Seidensaal,F Bozorgmehr,D Kazdal,T Eichkorn,M Elshiaty,D Weber,M Allgäuer,L König,K Lang,T Forster,N Arians,S Rieken,C-P Heussel,F J Herth,M Thomas,A Stenzinger,J Debus,P Christopoulos

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer.

The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC).
This study included all epidermal growth factor receptor-mutated (EGFR, n = 108) and anaplastic lymphoma kinase-rearranged (ALK, n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases.
Median overall survival (OS) was 49.1 months for ALK and 19.5 months for EGFR patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and 'short' EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR and ALK subsets.
Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR/ALK NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management.

Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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About The Expert

R A El Shafie

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany. Electronic address: rami.elshafie@med.uni-heidelberg.de.

K Seidensaal

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.

F Bozorgmehr

Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.

D Kazdal

Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

T Eichkorn

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.

M Elshiaty

Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.

D Weber

Institute of Medical Biometry and Informatics (IMBI), Heidelberg University Hospital, Heidelberg, Germany.

M Allgäuer

Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

L König

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.

K Lang

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.

T Forster

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.

N Arians

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.

S Rieken

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; University Medical Center Göttingen, Department of Radiation Oncology, Göttingen, Germany.

C-P Heussel

Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.

F J Herth

Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Department of Pneumology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.

M Thomas

Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany.

A Stenzinger

Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

J Debus

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany; Clinical Cooperation Unit Radiation Oncology (E050), German Cancer Research Center (DKFZ), Heidelberg, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberger Ionenstrahltherapie-Zentrum (HIT), Heidelberg, Germany.

P Christopoulos

Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany. Electronic address: petros.christopoulos@med.uni-heidelberg.de.

References

PubMed