Clinical investigation: brain
Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate

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Abstract

Purpose: To evaluate the optimal dose of methotrexate (MTX) and the efficacy of other drugs, intrathecal chemotherapy (CHT), and radiotherapy (RT) in primary brain lymphomas.

Methods and Materials: Two hundred eighty-eight immunocompetent patients with histologically documented, previously untreated primary brain lymphomas, receiving CHT containing high-dose MTX (≥1 g/m2) with or without RT were selected from 19 prospective series. The impact on survival of the MTX dose (<3 g/m2 vs.≥3 g/m2), the main drugs, intrathecal CHT, and combination CHT (mono-CHT vs. poly-CHT) was assessed, according to the intention-to-treat principle. The role of post-CHT irradiation (immediate vs. delayed RT) was evaluated in 119 patients with a complete response to CHT. The whole brain and tumor bed dose (<40 Gy vs. ≥40 Gy) was assessed in 70 irradiated complete responders.

Results: No difference in overall survival (OS) was detected between mono-CHT and combination CHT (p = 0.38). MTX ≥3 g/m2 (p = 0.04), thiotepa (p = 0.03), and intrathecal CHT (p = 0.03) improved the OS, and nitrosoureas (p = 0.01) correlated with a worse survival. In multivariate analysis, limited to patients receiving MTX ≥3 g/m2, only the addition of cytarabine improved the OS; nitrosoureas reduced MTX efficacy. Of the 119 complete responders, 70 received immediate RT. A RT dose of ≥40 Gy to the whole brain or tumor bed did not improve OS. The 3-year OS was similar between the immediate and delayed RT groups. In multivariate analysis, RT delay had no negative impact on survival.

Conclusions: MTX ≥3 g/m2 seems to improve survival in primary brain lymphoma patients. The efficacy of additional drugs, except for cytarabine, remains unproved. Randomized trials are needed to confirm that RT withdrawal yields no detrimental effect in complete responders.

Introduction

The optimal treatment for primary central nervous system lymphomas (PCNSL) has not been characterized. Uncertainties reflect the heterogeneous management in retrospective series, limited number of published prospective studies, and paucity of randomized trials (1).

Radiotherapy (RT) has been considered the treatment of choice, providing a complete response in most patients, with a median survival of 12–17 months 2, 3 and a 5-year survival of 14–26% 3, 4. When RT was the exclusive treatment, the suggested doses were at least 40 Gy to the whole brain (WB), followed by a boost to the tumor bed (TB) to reach 50 Gy (5).

Some prospective series 6, 7, 8, 9, 10 and critical reviews 4, 5, 11, 12 have demonstrated that the combination of chemotherapy (CHT) with high-dose (≥1 g/m2) methotrexate (HD-MTX) and RT improves the outcome, achieving a median survival of 33–42 months and a 5-year survival of 22–40% 4, 9, 10, 13. However, neither the optimal CHT regimen (5) nor the optimal RT dose and field extent in the combined-treatment modality have been identified.

Severe late toxicity in the range of 32–36% 10, 14 and a poor quality of life in long-term survivors have been reported in patients receiving brain irradiation after CHT. Pursuant to such neurotoxicity, which is responsible for death in one-third of affected patients, it has been proposed to treat PCNSL patients with CHT alone, reserving RT for refractory or recurrent disease. Preliminary results in a few small series with short follow-up times have suggested that survival is not compromised by RT delay 15, 16, 17, 18.

In practice, because of the rarity of PCNSL, prospective randomized trials to address various therapeutic issues that have not been clearly defined are unlikely to be feasible (1). We therefore conducted a retrospective analysis of published prospective series to identify the optimal dose of HD-MTX and to assess the efficacy of other parenteral and intrathecal drugs. In addition we assessed the impact on survival of different RT doses and of RT at recurrence in patients obtaining a complete response (CR) to upfront HD-MTX-containing CHT.

Section snippets

Methods and materials

The clinical and therapeutic data from 357 patients reported in 19 prospective series (Table 1) 6, 8, 9, 10, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 were analyzed. Patients had received HD-MTX-based chemotherapy, alone or with subsequent RT. Studies published in the English language and dealing with primary lymphoma of the brain and HD-MTX were identified using a MEDLINE search. We considered for analysis only patients without a known cause of immunosuppression, with

Drug efficacy (all eligible patients)

Twenty-one different CHT regimens were used. HD-MTX was used as mono-CHT (n = 102) or with other cytostatics (n = 186). No difference in survival was detected between these two groups of patients (p = 0.38) (Table 2). The MTX doses ranged from 1 to 8.4 g/m2. Patients receiving doses ≥3 g/m2 had a significant survival benefit compared with those receiving doses <3 g/m2 (p = 0.04) (Fig. 1 and Table 2). Of the 144 patients assessable for response who received the higher MTX dose, 92 (64%)

Discussion

Although exclusive RT was considered the standard treatment for PCNSL for some time, none of the irradiation parameters were clearly defined in either prospective trials or retrospective experience. These trials principally consisted of small series of patients treated with heterogeneous RT volumes, doses, and fractionation schedules. Some literature reviews have suggested that WB RT ≥40 Gy followed by a boost of ≥10 Gy to the TB was the most effective treatment in patients receiving exclusive

References (44)

  • J.Y Blay et al.

    High-dose methotrexate for the treatment of primary cerebral lymphomasAnalysis of survival and late neurologic toxicity in a retrospective series

    J Clin Oncol

    (1998)
  • L DeAngelis et al.

    Combined modality therapy for primary CNS lymphoma

    J Clin Oncol

    (1992)
  • A.A Gabbai et al.

    High dose methotrexate therapy of primary brain lymphoma

    J Neurosurg

    (1989)
  • E.M Bessell et al.

    Primary non-Hodgkin’s lymphoma of the CNS treated with BVAM or CHOD/BVAM chemotherapy before radiotherapy

    J Clin Oncol

    (1996)
  • J Glass et al.

    Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine and dexamethasone

    J Neurooncol

    (1996)
  • L.E Abrey et al.

    Long term survival in primary CNS lymphoma

    J Clin Oncol

    (1998)
  • H.A Fine et al.

    Primary central nervous system lymphoma

    Ann Intern Med

    (1993)
  • K.A Jellinger et al.

    Primary central nervous system lymphoma—An update

    J Cancer Res Clin Oncol

    (1992)
  • J Glass et al.

    Pre-irradiation methotrexate chemotherapy of primary central nervous system lymphomaLong-term outcome

    J Neurosurg

    (1994)
  • B Desablens et al.

    Primary central nervous system lymphomaLong-term results of the GOELAMS LCP 88 trial with a focus on neurological complications among 152 patients

    Ann Oncol

    (1999)
  • R.J Freilich et al.

    Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients

    Neurology

    (1996)
  • V Sandor et al.

    Phase II trial of chemotherapy alone for primary CNS, and intraocular lymphoma

    J Clin Oncol

    (1998)
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