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Could the extreme conformality achieved with proton therapy in paranasal sinuses cancers accidentally results in a high rate of leptomeningeal progression?

Dear Editor, We read with great interest the article by Dagan et al, which aimed to assess the rate and risk factors of isolated leptomeningeal dissemination in a series of 120 patients with locally advanced sinonasal cancers (SNCs) undergoing surgery and postoperative proton therapy or definitive proton therapy and concurrent chemotherapy. The authors reported that progression at distant site exclusively was the major cause of failure (16.7% of patients), whereas isolated local recurrence accounted for a lower probability of recurrence (11.7% of patients). In addition, isolated leptomeningeal metastasis was the most common route of isolated distant failures representing around half of them. For clarity purpose, the authors righteously defined leptomeningeal progression when new extra-axial metastases in the brain or spine remote from the primary site occurred. Although the median time to this kind of recurrence was 6 months after primary treatment, later failures were observed in other two patients at 31 and 51 months. High-grade histology, intracranial invasion, and neuroendocrine differentiation were associated with increased likelihood of this pattern of dissemination. Few considerations can be done on the basis of the study results. Despite the heterogeneity of histological types included, the incidence of distant metastases, particularly in the leptomeninges, was surprisingly high suggesting a potential change in pattern of relapse for locally advanced SNCs treated with proton therapy. In a retrospective case series including 68 patients with SNCs of mixed histology recurring after curative treatments, including three-dimensional conformal or intensitiy-modulated radiotherapy (IMRT), the most frequently observed pattern of failure was locoregional (76%), whereas distant relapse was observed in 24% of subjects only. Another study using combined therapies including definitive or postoperative conventional radiotherapy (RT) described a higher frequency of locoregional failure, with a lower rate of distant disease (12% as in 15 out of the 125 recurring patients). Only this latter series reported one case of leptomeningeal involvement as distant metastasis. However, some reports described a handful of patients who failed distantly with isolated or diffuse leptomeningeal disease. Overall, most of these patients had esthesioneuroblastoma, undifferentiated carcinoma, adenocarcinoma, and cancer with neuroendocrine differentiation. Interestingly, in a paper by Lucas et al analyzing the outcome of eight pediatric or adolescent patients with esthesioneuroblastoma treated with proton therapy as part of their treatment, one had leptomeningeal progression (12.5%). It is well known that the main putative advantage of protons is physical, resulting in a favorable depth-dose distribution with almost no irradiation of healthy tissues surrounding the target. In a very recent editorial by Durante, protons allow up to 15 to 30 Gy of sparing of normal tissues in brain and head-and-neck tumors compared to photons. In addition, in a dosimetric comparison among treatment plans from different RT techniques (photons, protons, and carbon ions) within a prospective multicentric trial focused on combined treatment modalities for SNCs (ClinicalTrials.gov identifier: NCT02099175 and NCT02099188) protons allowed significantly lower V10, V20, and V25 for the brain (ie, the volume of the brain receiving 10, 20, and 25 Gy, respectively) than photons. Figure 1 shows a comparison in brain average dosevolume histogram among treatment plans from different RT techniques for SNCs (photon vs photons plus carbon ions boost vs protons plus carbon ions boost [p + C]). Thus, we hypothesize that the changing pattern of relapse could be partly attributable to the fact that the brain and leptomeninges received insufficient doses for controlling microscopic disease. Accordingly, one might wonder whether brain and leptomeningeal irradiation should be targeted when treating primary disease in case of high-risk histologies, thus calling for the need of prophylactic cranial irradiation (PCI) at least, excluding total spine. Generally, PCI with 25 Gy in 10 daily fractions of 2.5 Gy has been established as standard of care in patients with small cell lung cancer with intrathoracic complete remission after combination therapy. Based on level I evidence, PCI significantly decreases the risk of intracranial relapse with a survival advantage after 3 year. In order to reduce radiation-induced neurocognitive late effects of PCI, IMRT techniques allowing hippocampal sparing, and drug neuroprotection have been used in clinical Received: 30 April 2019 Accepted: 14 June 2019