Prognostic factors in leptomeningeal metastases

We appreciate the interest of our colleagues Dankner and Maritan in our efforts to delineate prognostic disease patterns in leptomeningeal metastasis. In their communication, they specifically address the role of prior surgery for brain metastasis in this patient population. The authors perceive a discrepancy between our findings and those of previous studies. These previous studies had reported that patients, who had surgery for brain metastases and developed leptomeningeal metastases thereafter, fared better if they had nodular disease rather than linear disease.

However, what we report is that only in the absence of tumor cells in the cerebrospinal fluid (CSF), nodular disease is an indicator of inferior outcome, which likely corresponds to tumor burden driving the disease course. The previous studies^1,2 report on imaging defined leptomeningeal metastases and did not distinguish patients with or without positive CSF cytology.

In our cohort, a history of brain metastases prior to the diagnosis of leptomeningeal metastases was noted in 32 type II patients (defined as patients without positive CSF cytology), of whom only 11 had surgery which was combined with radiotherapy in all cases: stereotactic radiosurgery (SRS) in 5, whole brain radiotherapy (WBRT) in 5, and SRS plus WBRT in 1 patient).

We understand the interest in the history of prior surgery, but to analyze these data would have been beyond the scope of our study, especially considering the small number of patients in this subgroup. Further, MRI was not centrally collected and re-reviewed, further, data on the location and distance of leptomeningeal nodules to the site of surgically approached brain metastases and the extent of resection, and surgical technique used, including potential opening of the ventricle during surgery, were not collected.

Accordingly, we fully agree with the authors that further efforts at better defining risk profiles for the development of leptomeningeal metastases are needed, but we also would like to caution against underestimating the complexity of such studies, notably in a multicenter retrospective design. Heterogeneity of patients and tumors included in such studies also need to be considered. Accordingly, ideally, well-planned prospective cohort studies could try to resolve some of the important issues raised by our colleagues.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest statement. E.L.R. has received honoraria for lectures or advisory board from Tocagen, AbbVie, and Daiichi Sankyo. P.D. has nothing to disclose. J.W. has nothing to disclose. K.S. has received honoraria for advisory board participation from Roche. F.M. has nothing to disclose. A.C. has nothing to disclose. A.S.B. has research support from Daiichi Sankyo (≤10 000€), Roche (>10 000€), and honoraria for lectures, consultation, or advisory board participation from Roche Bristol-Myers Squibb, Merck, and Daiichi Sankyo (all <5000€) as well as travel support from Roche, Amgen, and AbbVie. J.L.M.J. has nothing to disclose. F.W. has received travel support from Roche. R.R. has received honoraria for lectures or consultation from UCB and Novocure. D.B. has nothing to disclose. M.V.D.B. has received honoraria for consultation from AbbVie, Agios, Carthera, Celgene, Bayer, Nerviano, Karyopharm, and Boehringer Ingelheim. M.P. has received honoraria for lectures, consultation, or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dohme, and Tocagen. The following for-profit companies have supported clinical trials and contracted research conducted by M.P. with payments made to his institution: Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dohme, Novocure, GlaxoSmithKline, and AbbVie. U.H. reports grants and personal fees from Roche, personal fees and non-financial support from Medac and Bristol-Myers Squibb, and personal fees from Novocure, Novartis, Daichii Sankyo, Riemser, and Noxxon. M.W. has received research grants from AbbVie, Adastra, Dracen, Merck Sharp & Dohme (MSD), Merck (EMD), and Novocure, and honoraria for lectures or advisory board participation or consulting from AbbVie, Basilea, Bristol-Myers Squibb (BMS), Celgene, Medac, Merck Sharp & Dohme (MSD), Merck (EMD), Nerviano Medical Sciences, Orbus, Philogen, Roche, and Tocagen.