Triple intrathecal chemotherapy for leptomeningeal carcinomatosis in solid tumours

Abstract

Background: The treatment of primary CNS lymphoma (PCNSL) comprises high dose Methotrexate (HDMTX) based chemotherapy followed by whole brain radiotherapy(WBRT), the major drawback of which is long term neurotoxicity. We intended to assess the feasibility of response adapted WBRT in patients with PCNSL. Methods: We screened 35 patients & enrolled 24 patients with PCNSL in a phase II trial. They underwent 5 two-weekly cycles of MVP chemotherapy with HDMTX, Vincristine & Procarbazine. Rituximab was added in 16 patients as per their preference & affordability. Patients with complete response (CR) to induction chemotherapy were given reduced dose WBRT 23.4Gy/13fractions/2.5weeks while those with partial response (PR), stable or progressive disease(PD) were given standard dose WBRT 45Gy/25fractions/5 weeks. Thereafter 2 cycles of consolidation chemotherapy with Cytarabine was given. The primary endpoints of the study were assessment of response rate & progression free survival (PFS). The secondary endpoints were assessment of overall survival (OS), toxicity profile, serial changes in quality of life & neuropsychological parameters. Results: The median age at diagnosis was 50 years. Out of 20 patients who completed induction chemotherapy, 10(50%) achieved CR, 9(45%) had PR & 1 patient had PD. After a median follow-up period of 21.05 months, the median OS and PFS had not been reached. The actuarial rates of 3 year PFS & OS were 51% & 51.4% respectively. 4 patients in reduced dose WBRT arm had recurrence & 2 of them died of PD, whereas there was one recurrence and no cancer related death in standard dose WBRT arm. On univariate analysis of PFS, age60 years(p ¼ 0.004) & use of standard dose WBRT (p ¼ 0.047) led to significantly improved outcome. Serial neuropsychological assessments showed marked improvement in general cognition, verbal fluency & motor speed after induction chemotherapy & treatment completion. Conclusions: In patients with newly diagnosed PCNSL, reduced dose WBRT after CR to HDMTX based chemotherapy may lead to suboptimal clinical outcome due to higher risk of recurrence, progression & early death.

Quantitative cerebrospinal fluid circulating tumor cells are a potential biomarker of response for proton craniospinal irradiation for leptomeningeal metastasis

“… 19 In our current study of the largest patient cohort to date, we found that pCSI is associated with similar median CNS-PFS of 6 months and OS of 8 months for patients with solid tumor LM despite many patients having been heavily pre-treated. Compared to the survival of other therapies such as systemic therapy alone (2.2 months), 21 systemic therapy with intrathecal cytarabine (3.8 months), 21 triple intrathecal chemotherapy (2 months), 22 and immune checkpoint inhibitors (2 months) 23 pCSI patients had favorable outcomes. In addition, 10% of patients were alive without CNS disease progression and 26% of patients were still alive and censored at the end of the study period, indicating that pCSI may prolong survival in select patients.…”

Intrathecal combined therapy for leptomeningeal metastasis from lung adenocarcinoma: Treatment outcomes, response and prognostic analysis

“…Previous studies suggested patients with parenchymal brain involvement was a poor prognostic factor of patients with LM (Chamberlain, 2011;Srinivasalu et al, 2021). Gong et al retrospectively reviewed 21 patients of LM with NSCLC, result indicated the OS of patients without parenchymal brain involvement was longer than with parenchymal brain involvement (11.1 months vs. 8.1 months) (Gong, Xiong, Huang, Miao, & Fan, 2015).…”

Randomized Phase II Trial of Proton Craniospinal Irradiation Versus Photon Involved-Field Radiotherapy for Patients With Solid Tumor Leptomeningeal Metastasis

“…It is difficult to conclude the effect of pCSI on OS in this heterogeneous group of patients; nevertheless, OS in this group compared favorably to recent reports of LM from gynecologic malignancies, 40 melanoma, 16 and those that include multiple histologies. 5,33,[41][42][43][44] CSF CTC count has been shown to be a valuable tool to predict survival in patients with LM. 45 In an exploratory analysis, we determined that baseline CTC count is a predictive biomarker of CNS control and survival in patients treated with pCSI, confirming our prior results.…”