How did lomustine become standard of care in recurrent glioblastoma?

Abstract

Glioblastomas are the most common malignant primary intrinsic brain tumors. Their incidence increases with age, and males are more often affected. First-line management includes maximum safe surgical resection followed by involved-field radiotherapy plus concomitant and six cycles of maintenance temozolomide chemotherapy. Standards of care at recurrence are much less well defined. Minorities of patients are offered second surgery or re-irradiation, but data on a positive impact on survival from randomized trials are lacking. The majority of patients who are eligible for salvage therapy receive systemic treatment, mostly with nitrosoureabased regimens or, depending on availability, bevacizumab alone or in various combinations. In clinical trials, lomustine alone has been increasingly used as a control arm, assigning this drug a standard-of-care position in the setting of recurrent glioblastoma. Here we review the activity of lomustine in the treatment of diffuse gliomas of adulthood in various settings. The most compelling data for lomustine stem from three randomized trials when lomustine was combined with procarbazine and vincristine as the PCV regimen in the newly diagnosed setting together with radiotherapy; improved survival with PCV was restricted to patients with isocitrate dehydrogenase-mutant tumors. No other agent with the possible exception of regorafenib has shown superior activity to lomustine in recurrent glioblastoma, but activity is largely restricted to patients with tumors with O 6methylguanine DNA methyltransferase (MGMT) promoter methylation. Hematological toxicity, notably thrombocytopenia often limits adequate exposure.

EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood

“…Notably, the latter can necessitate treatment interruptions, dose reductions or even discontinuation and consideration of alternative treatments. Pulmonary fibrosis has been observed mainly with carmustine and is rare with lomustine 60 . Lomustine is often combined with procarbazine and vincristine in a regimen referred to as PCV.…”

“…The main systemic treatment options for patients with disease progression include nitrosoureas, temozolomide rechallenge, bevacizumab (depending on availability) or inclusion into a clinical trial. Lomustine (90-110 mg/m 2 ) has never been shown to have superiority over another agent in an RCT 60 but is increasingly considered as the most appropriate standard of care on the basis of its activity as the control arm of several RCTs 65,115 and is also used in the AGILE trial 116 , with 6-month PFS rates of ~20% 60 . Similar results have been reported with alternative dosing schedules of temozolomide but activity is probably limited to patients with tumours with MGMT promoter methylation 117,118 .…”

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

“…Before Tmz, CCNU was the first-line of treatment in GBM patients (110 mg/m 2 orally every six weeks) [43]. Currently, CCNU is administered in recurrent GBM patients [41,42,44]. CCNU is highly lipophilic, enabling BBB penetration, making it an ideal candidate in GBM and treating other HGGs [40,44].…”

“…Currently, CCNU is administered in recurrent GBM patients [41,42,44]. CCNU is highly lipophilic, enabling BBB penetration, making it an ideal candidate in GBM and treating other HGGs [40,44]. CCNU induces alkylation of DNA and RNA strands resulting in the formation of O6chloroethylguanine lesions [44].…”

A New Landscape for Systemic Pharmacotherapy of Recurrent Glioblastoma?

“…Once tumors progress, treatment options are limited, and the management of recurrent glioblastoma remains challenging. The standard of care for second-line treatment has not been defined; options include surgery, re-irradiation, systemic pharmacotherapy, and, in Europe, mostly lomustine [2,3]. The general and neurological health status of the patient, the molecular findings, the time to first recurrence, the pattern of recurrence, and previous treatment have to be considered.…”