Clinical Study
A single centre study of the treatment of relapsed primary central nervous system lymphoma (PCNSL) with single agent temozolomide

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Abstract

Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. Although recommendations for first-line treatment usually incorporate high-dose methotrexate, there is substantial heterogeneity in the types of salvage therapies used at relapse. Phase II data supported the use of temozolomide as a well-tolerated treatment modality in this setting. Therefore, we reviewed the treatment and outcomes of patients with relapsed PCNSL who were treated with salvage temozolomide at our institution. Seven patients were treated with salvage temozolomide between January 2000 and May 2011. The objective response rate was 14%. Progression-free survival was 2 months (95% confidence interval [CI]: 0–5.9) and median overall survival was 4 months (95% CI: 0–13). Toxicity was mild, with one episode of grade 3 neutropenia during 25 cycles of chemotherapy. Although these results are consistent with previous phase II results, the outcomes for these patients remain extremely poor. The low toxicity of temozolomide raises the possibility of combining temozolomide with other chemotherapeutic agents or targeted agents in future clinical trials.

Introduction

Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin’s lymphoma (NHL) and accounts for only 4% of all primary brain tumours.1 PCNSL typically affects patients over the age of 60 years in the immunocompetent population.2 It is also seen in immunocompromised patients, including those with acquired immunodeficiency syndrome,3 and can affect a younger population with a median age of 35 years. Although the incidence of PCNSL has been reported to be as high as 10% in autopsy series, the introduction of highly active anti-retroviral therapy has now substantially reduced this.4, 5

High dose methotrexate generally forms the backbone of first-line treatment for PCNSL.6, 7 There are data suggesting that methotrexate in combination with cytarabine-based regimes8 have superior response rates (RR) compared to methotrexate alone (RR of 69% compared to 40%), with a non-significant 3-year overall survival (OS) of 46% compared to 32%. However, combination therapy is associated with a higher rate of treatment-related toxicities and up to 8% mortality. As such, these regimes have not been universally adopted. Other chemotherapeutic agents, including those used in extra-cranial NHL, are not widely utilised as there are concerns about their ability to cross the blood brain barrier and their toxicities in this population.9

Progression after first-line methotrexate is common, with 10% to 15% of patients having primary resistance and 35% to 60% of patients relapsing after an initial response.10, 11 The optimal salvage therapy is unclear. Many patients are re-challenged with high dose methotrexate, with one multi-institutional review showing a RR > 91% in both the first and second-line salvage settings,12 and this accords with our experience. Salvage whole brain radiotherapy (WBRT) is also efficacious, with RR of 60% to 74%.13 However, WBRT is associated with significant neurotoxicity, occurring at rates of 4% to 36%, with patients older than 60 years of age being particularly vulnerable.14 Radiotherapy does remain a valid option in many instances as the neurotoxicity is often delayed with a median time of 7 months.15 Less frequently used salvage therapies include high-dose chemotherapy with autologous stem-cell rescue, combination procarbazine, lomustine, and vincristine; and topotecan.16

Temozolomide, an oral second-generation alkylating agent, has attracted interest as a potential therapy for PCNSL based on its low toxicity profile, its activity in other primary CNS malignancies, ability to effectively penetrate the blood brain barrier as well as in vitro additive cytotoxic activity when combined with radiotherapy.11 Patients with relapsed PCNSL were recruited into a phase II trial of temozolomide for relapsed PCNSL17, 18 to receive temozolomide at 150 mg/m2 on day 1 to day 5 every 4 weeks. The objective RR was 31%, median progression-free survival (PFS) was 2.8 months and median OS was 3.9 months. Although encouraging, the efficacy of temozolomide has not been documented outside the confines of small clinical trials with highly selected patients. As such, we report on our experience in utilising single agent salvage temozolomide for patients with relapsed PCNSL in a tertiary centre specialising in PCNSL.

Section snippets

Materials and methods

Patients with PCNSL treated with temozolomide between January 2000 and May 2011 were identified by examining our institution’s health information, pharmacy and anatomical pathology records. Patients were excluded if they did not have PCNSL, had never received temozolomide, had a history of extra-cranial systemic lymphoma that preceded their diagnosis of PCNSL or were missing required data from their patient records. The required data were extracted by a single author (S.F. Wong) and comprised

Patient characteristics and treatment at initial diagnoses

Between January 2000 and May 2011, 46 patients with a diagnosis of PCNSL were identified from our institutional records. Of these, 39 patients were excluded from this review because they did not have PCNSL, had a pre-existing diagnosis of extracranial NHL, had not received temozolomide or had incomplete patient records (Fig. 1). The remaining seven patients were included in this analysis. Their characteristics at the time of diagnosis are shown in Table 1.

Six of seven patients had diffuse large

Discussion

This study is a retrospective review of the small subset of patients at our institution, a major Australian neuro-oncology unit, who received salvage temozolomide for relapsed PCNSL. The review aimed to compare outcomes for salvage treatment with temozolomide in the community setting, compared to the published literature from phase II trials. All patients initially received a high dose methotrexate-based treatment in the first line setting (RR of 70% and median PFS of 6 months) and 42% were

Conflicts of interest/disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

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