A retrospective, quantitative assessment of disease burden in patients with leptomeningeal metastases from non-small-cell lung cancer

Abstract

Background: Improvements in detection and molecular characterization of leptomeningeal metastasis from lung cancer (LC-LM) coupled with cerebrospinal fluid (CSF)-penetrating targeted therapies have altered disease management. A barrier to formal study of these therapies in LM is quantification of disease burden. Also, outcomes of patients with targetable mutations in LC-LM are not well defined. This study employs molecular and radiographic measures of LM disease burden and correlates these with outcome.

Methods: We reviewed charts of 171 patients with LC-LM treated at Memorial Sloan Kettering. A subset had MRI and CSF studies available. Radiographic involvement (n = 76) was scored by number of gadolinium-enhancing sites in 8 locations. CSF studies included cytopathology, circulating tumor cell (CTC) quantification (n = 16), and cell-free DNA (cfDNA) analysis (n = 21). Clinical outcomes were compared with Kaplan-Meier log-rank test and Cox proportional hazards methodologies.

Results: Median overall survival was 4.2 months (95% CI: 3.6-4.9); 84 patients (49%) harbored targetable mutations. Among bevacizumab-naïve patients with MRI and CSF cytology at time of LC-LM diagnosis, extent of radiographic involvement correlated with risk of death (hazard ratio [HR]: 1.16; 95% CI: 1.02-1.33; P = 0.03), as did CSF CTC (HR: 3.39, 95% CI: 1.01-11.37; P = 0.048) and CSF cfDNA concentration (HR: 2.58; 95% CI: 0.94-7.05; P = 0.06). Those without a targetable mutation were almost 50% more likely to die (HR: 1.49; 95% CI: 1.06-2.11; P = 0.02).

Conclusions: Extent of radiographic involvement and quantification of CSF CTC and cfDNA show promise as prognostic indicators. These findings support molecular characterization and staging for clinical management, prognostication, and clinical trial stratification of LC-LM.

Keywords: cell-free DNA; circulating tumor cells; leptomeningeal metastases; lung cancer.

© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Fig. 1

Eight defined sites of radiographic involvement of LC-LM. (A) Cerebrum. (B) Ventricle. (C) Brainstem (pons and medulla included in this category). (D) Cerebellum. (E) Cranial nerves. (F) Cervical spinal cord. (G) Thoracic spinal cord. (H) Lumbosacral spinal cord. (I) Among the 76 patients with complete staging of LC-LM who did not receive bevacizumab within 30 days prior to MRI, there was a significantly increased risk of death with 3+ radiographic sites of disease versus 0–2 sites of disease (HR for 3+ sites of disease: 1.95; 95% CI: 1.16–3.30; P = 0.01).

Fig. 2

Survival in patients with LC-LM using quantification of cell-free DNA and circulating tumor cells. (A) Patients with 50 or greater CTCs were more than 3 times more likely to die than those with fewer than 50 CTCs (HR for patients with 50 CTCs: 3.39, 95% CI: 1.01–11.37; P = 0.048). (B) An increased cfDNA concentration was associated with increased risk of death; using the median cutpoint, there was an increased risk of death among those patients with cfDNA concentration equal to or above the median value (HR for patients with cfDNA concentration 0.02 ng/mL: 2.58; 95% CI: 0.94–7.05; P = 0.06).

Fig. 3

Patients harboring LM from primary tumors with targetable mutations demonstrate improved overall survival. (A) Eighty-four of 171 patients (49%) harbored a targetable mutation. Patients with a targetable mutation had a significantly improved survival compared with those without a targetable mutation (log-rank P = 0.02). (B) Breakdown of specific mutation types among the 84 patients in this study with targetable mutations.

Fig. 4

Proposed methods of quantification of burden of disease in patients with LM. Radiographic assessment, CTC quantification, and cfDNA concentration can be used as quantitative measures of disease burden at the time of LM diagnosis. Increasing burden of disease (more radiographic sites of disease, elevated CTCs, and higher CSF cfDNA concentration) are associated with shorter survival times in patients with LC-LM.