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Meta-Analysis
. 2023 Feb 1;6(2):e230475.
doi: 10.1001/jamanetworkopen.2023.0475.

Association of Brain Metastases With Survival in Patients With Limited or Stable Extracranial Disease: A Systematic Review and Meta-analysis

Alyssa Y Li  1 , Karolina Gaebe  1 , Amna Zulfiqar  1 , Grace Lee  1 , Katarzyna J Jerzak  1   2 , Arjun Sahgal  1   3 , Steven Habbous  4   5 , Anders W Erickson  1   6 , Sunit Das  1   6   7
Affiliations
Meta-Analysis

Association of Brain Metastases With Survival in Patients With Limited or Stable Extracranial Disease: A Systematic Review and Meta-analysis

Alyssa Y Li et al. JAMA Netw Open. .

Abstract

Importance: Intracranial metastatic disease (IMD) is a severe complication of cancer with profound prognostic implications. Patients with IMD in the setting of limited or stable extracranial disease (IMD-SE) may represent a unique and understudied subset of patients with IMD with superior prognosis.

Objective: To evaluate overall survival (OS), progression-free survival (PFS), and intracranial PFS (iPFS) in patients with IMD-SE secondary to any primary cancer.

Data sources: Records were identified from MEDLINE, EMBASE, CENTRAL, and gray literature sources from inception to June 21, 2021.

Study selection: Studies in English reporting OS, PFS, or iPFS in patients with IMD-SE (defined as IMD and ≤2 extracranial metastatic sites) and no prior second-line chemotherapy or brain-directed therapy were selected.

Data extraction and synthesis: Author, year of publication, type of study, type of primary cancer, and outcome measures were extracted. Random-effects meta-analyses were performed to estimate effect sizes, and subgroup meta-analysis and metaregression were conducted to measure between-study differences in February 2022.

Main outcomes and measures: The primary end point was OS described as hazard ratios (HRs) and medians for comparative and single-group studies, respectively. Secondary end points were PFS and iPFS.

Results: Overall, 68 studies (5325 patients) were included. IMD-SE was associated with longer OS (HR, 0.52; 95% CI, 0.39-0.70) and iPFS (HR, 0.63; 95% CI, 0.52-0.76) compared with IMD in the setting of progressive extracranial disease. The weighted median OS estimate for patients with IMD-SE was 17.9 months (95% CI, 16.4-22.0 months), and for patients with IMD-PE it was 8.0 months (95% CI, 7.2-12.8 months). Pooled median OS for all patients with IMD-SE was 20.9 months (95% CI, 16.35-25.98 months); for the subgroup with breast cancer it was 20.2 months (95% CI, 10.43-38.20 months), and for non-small cell lung cancer it was 27.5 months (95% CI, 18.27-49.66 months). Between-study heterogeneity for OS and iPFS were moderate (I2 = 56.5%) and low (I2 = 0%), respectively.

Conclusions and relevance: In this systematic review and meta-analysis of patients with IMD-SE, limited systemic disease was associated with improved OS and iPFS. Future prospective trials should aim to collect granular information on the extent of extracranial disease to identify drivers of mortality and optimal treatment strategies in patients with brain metastases.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Jerzak reported receiving personal fees from Amgen (honoraria/consulting/advisory board member), personal fees from AstraZeneca (honoraria/consulting/advisory board member), personal fees from ApoBiologix (honoraria/consulting/advisory board member), personal fees from Eli Lilly (honoraria/consulting/advisory board member), personal fees from Eisai (honoraria/consulting/advisory board member), personal fees from Exact Sciences (honoraria/consulting/advisory board member), personal fees from Gilead Sciences (honoraria/consulting/advisory board member), personal fees from Knight Therapeutics (honoraria/consulting/advisory board member), personal fees from Merck (honoraria/consulting/advisory board member), personal fees from Myriad Genetics Inc (honoraria/consulting/advisory board member), personal fees from Pfizer (honoraria/consulting/advisory board member), personal fees from F. Hoffmann-La Roche Ltd (honoraria/consulting/advisory board member), personal fees from Novartis (honoraria/consulting/advisory board member), personal fees from Seagen (honoraria/consulting/advisory board member), personal fees from Viatris (honoraria/consulting/advisory board member), grants from AstraZeneca, grants from Eli Lilly, and grants from Seagen outside the submitted work; in addition, Dr Jerzak had a patent for compounds of treating cancer and methods of use thereof (Awarded March 3, 2020; Patent No. 10576056 [US] and EP 16877052.7 [Europe]). Dr Das reported receiving nonfinancial support from Congress of Neurological Surgeons, nonfinancial support from American Association of Neurological Surgeons, grants from Alkerme, and personal fees from Cancer Care Ontario outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Selection
ASCO indicates American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; ICTRP, International Clinical Trials Registry Platform; IMD-SE, intracranial metastatic disease in the setting of stable extracranial disease; SNO, Society for Neuro-Oncology.
Figure 2.
Figure 2.. Random-Effects Meta-analysis of the Primary Outcome of OS in Patients With IMD-SE Vs Patients With IMD-PE
The size of the squares is proportional to the weight of the study. The light blue diamond represents the pooled estimate within a 95% CI, while the horizontal lines indicate the 95% CI of each study. The orange bar represents the prediction interval, and the vertical dotted line is the pooled estimated HR. The number of patients with IMD-SE and IMD-PE were not reported in 2 studies and were not included in the total number of patients., AHRQ indicates Agency for Healthcare Research and Quality; BC, breast cancer; HR, hazard ratio; IMD-PE, intracranial metastatic disease in the context of progressive extracranial disease; IMD-SE, intracranial metastatic disease in the context of stable extracranial disease; NOS, Newcastle-Ottawa Scale; NR, not reported; NSCLC, non–small cell lung cancer; OS, overall survival.
Figure 3.
Figure 3.. Pooled Summary Overall Survival (OS) of Patients With IMD-SE
Light gray lines represent OS curves for individual studies. The solid orange lines represent the summary survival curves, and the dashed orange lines represent 95% CI. IMD-SE, intracranial metastatic disease in the context of stable extracranial disease; NSCLC, non–small cell lung cancer.
Figure 4.
Figure 4.. Random-Effects Meta-analysis of iPFS in Patients With IMD-SE Compared With Patients With IMD-PE
The size of the squares is proportional to the weight of the study. The light blue diamond represents the pooled estimate within a 95% CI, while the horizontal lines indicate the 95% CI of each study. The orange bar represents the prediction interval, and the vertical dotted line is the pooled estimated HR. The number of patients with IMD-SE and IMD-PE were not reported in one study and were not included in the total number of patients. AHRQ indicates Agency for Healthcare Research and Quality; HR, hazard ratio; IMD-PE, intracranial metastatic disease in the context of progressive extracranial disease; IMD-SE, intracranial metastatic disease in the context of stable extracranial disease; iPFS, intracranial progression-free survival; NOS, Newcastle-Ottawa Scale; NR, not reported.
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