Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: A prospective and single‐arm study

Abstract

The prognosis of leptomeningeal metastasis (LM) from solid tumors is extremely poor, especially for patients with adverse prognostic factors. In this phase II clinical trial, we evaluated the efficacy and safety of intrathecal chemotherapy (IC) combined with concomitant involved‐field radiotherapy (IF‐RT) for treating LM from solid tumors with adverse prognostic factors. Fifty‐nine patients with LM from various solid tumors were enrolled between May 2010 and December 2014. Concurrent therapy consisted of concomitant IC (methotrexate 12.5–15 mg and dexamethasone 5 mg, weekly) and IF‐RT (whole brain and/or spinal canal RT, 40 Gy/20f). For patients with low Karnofsky performance status (KPS) score and radiotherapy intolerance, induction IC (1–3 times) was given before concurrent therapy. Thirty‐eight patients (64.4%) received subsequent treatments. All patients were followed up at least 6 months after LM diagnosis or until death. Primary endpoint evaluated was clinical response rate. Secondary endpoints were overall survival (OS) and safety. The pathological types included lung cancer (n = 42), breast cancer (n = 11) and others (n = 6). Median KPS score was 40 (range 20–70). Fifty‐one patients (86.4%) completed concurrent therapy. The overall response rate was 86.4% (51/59). OS ranged from 0.4 to 36.7 months (median 6.5 months), and 1‐year‐survival rate was 21.3%. Treatment‐related adverse events mainly included acute meningitis, chronic‐delayed encephalopathy, radiculitis, myelosuppression and mucositis. Twelve patients (20.3%) had grade III–V toxic reactions. We concluded that IC combined with concomitant IF‐RT, with significant efficacy and acceptable toxicity, may be an optimal therapeutic option for treatment of LM from solid tumors with adverse prognostic factors. LM, in which cancer cells spread to membranes enveloping the brain and spinal cord, is a devastating complication of solid cancers. Existing LM therapies center on IC. In this prospective clinical study, the authors combined intrathecal methotrexate with involved‐field radiotherapy in a concomitant regimen, showing that the approach can potentially improve quality of life for patients with adverse prognostic factors. Concurrent radiotherapy‐bolstered IC by contributing to prolonged remission of neurological symptoms and increasing OS. The findings suggest that the concomitant regimen could be an optimal treatment option for LM.

Leptomeningeal metastasis from systemic cancer: Review and update on management

“…Radiation may also restore CSF flow and relieve hydrocephalus by reducing tumor bulk and, in doing so, facilitate the use of IT chemotherapy . In addition to the long‐term side effects of radiotherapy alone, there may also be an increased risk of late leukoencephalopathy when combined with other chemotherapeutic agents, such as intravenous or IT methotrexate . Radiation is unlikely to prolong survival based on retrospective studies in patients with breast and lung cancers, but it can result in rapid symptom improvement .…”

“…47 In addition to the long-term side effects of radiotherapy alone, there may also be an increased risk of late leukoencephalopathy when combined with other chemotherapeutic agents, such as intravenous or IT methotrexate. 35,[48][49][50][51][52] Radiation is unlikely to prolong survival based on retrospective studies in patients with breast and lung cancers, but it can result in rapid symptom improvement. 53,54 Eradication of tumor cells from the leptomeninges would require craniospinal irradiation, which carries significant potential CNS and systemic toxicities, including myelosuppression, that may compromise future cytotoxic chemotherapy options.…”

Great efficacy of bevacizumab plus erlotinib for leptomeningeal metastases from non-small cell lung cancer with initially positive EGFR mutation: a case report

“…Before tyrosine kinase inhibitors (TKIs) and anti-angiogenesis drugs were used in NSCLC, the management of LMs relied on chemoradiotherapy but with great heterogeneity and outcomes were disappointing. 7,[10][11][12][13][14] The data from a retrospective study including 519 cases with LMs from solid tumors indicated MST was only 3 months with 10% of 1-year survival rate. 7 Even for patients treated with chemoradiotherapy, MST was just 5 months.…”

State of the art of chemotherapy for the treatment of central nervous system metastases from non-small cell lung cancer

“…In addition to the most frequently used drugs, intrathecal administration of gemcitabine (85) or etoposide (86) has resulted in clinical activity in some case reports. Finally, a more recent prospective, single-arm study evaluated the efficacy and safety of intrathecal chemotherapy (methotrexate) combined with concomitant involved-field radiotherapy in 59 patients with LM from various solid tumors (42 lung cancers) and showed an encouraging efficacy (RR of 86.4% and median OS of 6.5 months), with acceptable toxicity (87). P r o s p e c t i v e d a t a o n t h e e f f i c a c y o f s y s t e m i c chemotherapy in the treatment of LC from NSCLC are lacking.…”