INTRODUCTION

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ChooseTop of pageAbstractINTRODUCTION <<PATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of P...Author ContributionsREFERENCES

Primary CNS lymphoma (PCNSL) is a malignant non-Hodgkin's lymphoma of B-cell origin that is confined to the brain, spinal cord, leptomeninges, or eyes. It is widely accepted that high-dose methotrexate (MTX) is the most effective chemotherapeutic agent, but the optimal treatment regimen for PCNSL is controversial.¹ Combined-modality therapy using high-dose MTX and whole brain radiotherapy (WBRT) has improved survival; however, patients treated with both MTX and WBRT are at significant risk for delayed treatment-related neurotoxicity.^2,3

We previously reported a series of patients treated with high-dose MTX-based chemotherapy, with or without WBRT.⁴ At the time of our initial report, the estimated median survival was 60 months and this was the longest survival reported for newly diagnosed PCNSL patients. The purpose of this article is to update our initial results and provide long-term data regarding overall survival, patterns of relapse, and the risk of treatment-related neurotoxicity.

PATIENTS AND METHODS

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ChooseTop of pageAbstractINTRODUCTIONPATIENTS AND METHODS <<RESULTSDISCUSSIONAuthors' Disclosures of P...Author ContributionsREFERENCES

Fifty-seven immunocompetent patients (33 men and 24 women) with a histologic diagnosis of PCNSL received MTX-based chemotherapy with or without WBRT between 1992 and 1998 (Table 1). The median age was 65 years (range, 22 to 89 years). Thirty-four patients (60%) were age 60 or older. The median Karnofsky performance score (KPS) at diagnosis was 70 (range, 30 to 100). The average duration of symptoms before diagnosis was 30 days, and the most common presenting symptoms were mental status changes and headache. All patients had a staging evaluation before treatment that included magnetic resonance imaging of the brain with gadolinium, computed tomography of the chest/abdomen/pelvis, CSF cytology, bone marrow biopsy, ophthalmologic examination including slit lamp, and HIV-1 testing. No patient had HIV-1 infection or systemic lymphoma. All patients had a 24-hour creatinine clearance of 50 mL/min or greater.

All patients had parenchymal brain involvement; 10 (18%) had positive CSF cytology and 11 (19%) had ocular involvement; The diagnosis of lymphoma was established by brain biopsy in 49 patients, positive CSF cytology in five patients, and vitreal biopsy in three patients. Diffuse large B-cell lymphoma was the most common histologic subtype seen in 39 of patients (68%); seven patients had large-cell immunoblastic lymphoma, one patient had a T-cell lymphoma and no further characterization was possible in 10 patients.

The details of the treatment regimen and response to therapy are reported elsewhere.³ Chemotherapy consisted of five cycles of MTX 3.5 g/m² and vincristine. Intra-Ommaya MTX was given on alternate weeks. Procarbazine was given with the first, third, and fifth cycles of systemic MTX. Chemotherapy was followed by WBRT to a total dose of 45 Gy. After completion of WBRT, patients received two cycles of intravenous cytarabine, each consisting of two doses of 3 g/m² separated by 24 hours. WBRT was deferred routinely in all patients older than 60 years who were diagnosed during or after 1995 (n = 22); in addition, four patients younger than age 60 (54, 51, 49, and 22) refused initial therapy with WBRT in an effort to minimize the cognitive impact of treatment. Therefore, 26 patients were treated with chemotherapy alone.

All patients have been observed longitudinally with surveillance magnetic resonance imaging scans and neurologic examinations at regular intervals. Formal neuropsychological testing was not performed. Treatment-related neurotoxicity was defined as progressive neurologic or cognitive impairment as documented on serial clinical examinations in the absence of recurrent lymphoma.

Time to progression and survival were from the date of diagnosis to the date of first relapse, death, or last follow-up. Survival curves were drawn using the Kaplan-Meier product-limit method. All patients who began this treatment regimen were included in the analysis in an intent-to-treat fashion. Follow-up extends through December 31, 2005.

DISCUSSION

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ChooseTop of pageAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSION <<Authors' Disclosures of P...Author ContributionsREFERENCES

The initial report of this regimen “PCNSL: The Next Step” estimated a median overall survival of 60 months.⁴ Prolonged follow-up with mature data confirms an excellent median survival of 51 months. Less than half of all patients developed recurrence or progression resulting in an estimated median progression-free survival of 129 months. Therefore, the outcome of our patients can be attributed to the success of our initial treatment regimen, in contrast to other PCNSL studies where overall survival largely reflects salvage therapy.^5,6 Furthermore, our patients had relatively poor prognostic factors with a high median age of 65 and low median KPS of 70 suggesting that our results are not explained by selection of patients with better than usual prognostic factors. Young patients in particular do well with this treatment regimen and 74% of young patients are alive with an average follow-up of 10 years.

These results may define the recommended treatment approach for newly diagnosed PCNSL patients younger than 60 years old. About one third of patients relapsed and salvage therapy often resulted in a durable second remission. With prolonged follow-up, the 26% risk of neurotoxicity may be acceptable to some patients and practitioners and unacceptable to others. However, data from our patients treated with chemotherapy alone suggests that deferring WBRT may significantly compromise disease control. In addition, data from Bessell et al^7,8 suggests that lowering the dose of WBRT in young patients achieving a complete response with chemotherapy compromises both progression-free and overall survival. Therefore, it would seem critical to intensify or alter the chemotherapy regimen in an effort to improve efficacy if a decision is made to defer WBRT in a young patient.

Older patients had excellent overall survival of 29 months using this MTX-based regimen, regardless of whether or not they received WBRT. This compares favorably to the 7.6-month median survival seen in this age group treated with WBRT alone.⁹ Among older patients treated with chemotherapy alone, most died from progressive tumor. In the group of older patients treated with both chemotherapy and WBRT, the most common cause of death was neurotoxicity. The fact that older patients have identical overall survival whether or not they receive WBRT as part of initial therapy suggests that the impact of treatment-related neurotoxicity and recurrent PCNSL are roughly equivalent. As a result, it is critical to design more effective and less toxic treatment regimens for older PCNSL patients. This is particularly important because patients older than 60 years comprise at least half of the PCNSL population.

Our subgroup of long-term survivors provides some important insights. More than one third of this group was older than 60 years at diagnosis and many had relatively poor performance status. Both of these factors are often given as reasons to avoid aggressive therapy, chemotherapy, or protocol participation but patients with these poor prognostic factors may enjoy prolonged survival and should be managed aggressively if there is no specific medical contraindication. A number of the long-term survivors received successful salvage therapy for recurrent lymphoma and late relapses were observed. More than one third of long-term survivors developed treatment-related neurotoxicity, which was the most common cause of death in this subgroup. Late relapses and prevalence of treatment-related neurotoxicity reinforce the importance of ongoing clinical follow-up for all PCNSL patients in remission, as well as the need to develop more effective and less toxic therapies.¹⁰

Our results are limited as this is a consecutive series of patients who received a uniform treatment regimen as opposed to a prospective clinical trial. We have made every effort to include all patients who began this treatment regimen in the specified time interval in an intent-to-treat fashion. Nevertheless, it is possible that this design, coupled with the fact that this is a single institution series, introduces a significant bias. Reviewing our patient characteristics, the average age and KPS suggest that our patients constitute a worse than usual prognostic group¹¹ and as a result, may reflect the more typical PCNSL patient. However, it remains difficult to determine whether or not our results can be more broadly generalized. Finally, it is likely that we underestimated the risk of treatment-related neurotoxicity by relying on clinical criteria as opposed to prospective neuropsychological testing. As the cognitive function of PCNSL survivors is increasingly recognized as an important outcome measure related to therapy, we would advocate inclusion of prospective neuropsychological testing in future clinical trials.

This is the first report of a PCNSL cohort that has been observed for 10 years or longer. It is likely that a number of our patients were cured as a result of their initial therapy. However, long-term follow-up of this cohort also resulted in a decrease in our original estimate of median survival from 60 to 51 months, as well as an increase in risk of relapse and neurotoxicity. Many published PCNSL studies report on patients with an average follow-up of 3 years or less.^5,6,12-15 As a result, median overall and progression-free survival can only be estimated and are often overestimated, while the risk of relapse and treatment-related toxicity may be underestimated. In conclusion, we believe that this study underscores the importance of reporting long-term follow-up and mature data.

Authors' Disclosures of Potential Conflicts of Interest

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ChooseTop of pageAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of P... <<Author ContributionsREFERENCES

The authors indicated no potential conflicts of interest.