Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial.

BACKGROUND: No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients. METHODS: In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594. FINDINGS: Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity. INTERPRETATION: In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population. FUNDING: Schering-Plough/Merck and French Government.

Platine and cytarabine-based salvage treatment for primary central nervous system lymphoma.

The aim of this study was to evaluate the efficacy and toxicity of two chemotherapy regimens based on platinum and cytarabine in association with etoposide and methylprednisolone (ESHAP) or with dexamethasone (DHAP) with or without Rituximab (± R) in patients with refractory or a relapsed Primary Central Nervous System Lymphoma (PCNSL). All consecutive patients from two French centers with refractory or relapsed PCNSL treated with ESHAP/DHAP ± R were included. We analyzed the overall response rate (ORR), toxicity and overall survival (OS) after salvage chemotherapy. Intensive chemotherapy and hematopoietic stem cell rescue (IC + HCR) was offered to patients less than 65 years of age and consisted of high-dose thiotepa, busulfan and cyclophosphamide. These results were compared with two previously reported series of PCNSL patients treated with the CYVE (high-dose cytarabine and etoposide) regimen at relapse. Twenty-two patients received a total of 60 DHAP/ESHAP cycles (median 3; range 1-5). The median age was 59 years. The ORR after salvage chemotherapy was 59%. Toxicity was mainly hematological, 18% of patients showing febrile neutropenia. There was no treatment-related death. ESHAP or DHAP regimens led to similar ORRs compared to the CYVE regimen in relapsed or refractory PCNSL, although they seemed less toxic. The therapeutic results of the ESHAP/DHAP regimens in relapsed or refractory PCNSL were also similar to those for relapsed systemic non-Hodgkin's lymphomas (sNHL). Both chemotherapies, CYVE regimen and ESHAP/DHAP are treatment options to be considered in relapsed or refractory PCNSL, especially when IC + HCR is planned as a consolidation treatment. More efforts are still needed to improve the ORR at relapse.

Up-front temozolomide in elderly patients with anaplastic oligodendroglioma and oligoastrocytoma.

Optimal treatment of anaplastic oligodendroglial tumors (AOT) in elderly patients is debatable. We report a retrospective study of 44 consecutive patients aged 70 years or older [median age: 74 years; median Karnofsky performance status (KPS): 70] treated with up-front chemotherapy using temozolomide (TMZ) at conventional doses until tumor progression. O(6)-methylguanine-DNA methyltransferase promoter (MGMTP) methylation was assessed in 38 patients. Of the 41 evaluable patients, partial response (PR) was seen in 13 (32%) patients, 17 (41%) patients achieved stable disease, while the disease progressed in 11 (27%) patients. Median progression-free survival (PFS) and overall survival (OS) were 6.9 and 12.4 months, respectively. Hematotoxicity grades 3-4 occurred in nine patients (20%). MGMTP was methylated in 50% of patients and was associated with both longer PFS (8.7 versus 5.7 months, P = 0.01) and longer OS (16.1 versus 12.4 months, P = 0.05). The rate of responders to chemotherapy was similar in MGMTP-methylated (38%) and in MGMTP-unmethylated patients (31%), but duration of response was significantly longer in responders with methylated MGMTP than in responders with unmethylated MGMTP (16.1 versus 9.6 months, P = 0.0004). This study demonstrates that a substantial number of elderly patients with AOT can achieve prolonged survival with up-front chemotherapy using TMZ. Further investigation is needed to determine whether this treatment is preferable to initial radiation therapy.