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Combined Immunochemotherapy With Reduced Whole-Brain Radiotherapy for Newly Diagnosed Primary CNS Lymphoma

Gaurav D. Shah, Joachim Yahalom, Denise D. Correa, Rose K. Lai, Jeffrey J. Raizer, David Schiff, Renato LaRocca, Barbara Grant, Lisa M. DeAngelis, Lauren E. Abrey

From the Memorial-Sloan Kettering Cancer Center, New York, NY; Northwestern University, Feinberg School of Medicine, Chicago, IL; Department of Neurology, University of Virginia Health Science Center, Charlottesville, VA; Kentuckiana Cancer Institute, Louisville, KY; and the University of Vermont, Burlington, VT

Address reprint requests to Lauren E. Abrey, MD, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: abreyl{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose: Our goals were to evaluate the safety of adding rituximab to methotrexate (MTX)-based chemotherapy for primary CNS lymphoma, determine whether additional cycles of induction chemotherapy improve the complete response (CR) rate, and examine effectiveness and toxicity of reduced-dose whole-brain radiotherapy (WBRT) after CR.

Patients and Methods: Thirty patients (17 women; median age, 57 years; median Karnofsky performance score, 70) were treated with five to seven cycles of induction chemotherapy (rituximab, MTX, procarbazine, and vincristine [R-MPV]) as follows: day 1, rituximab 500 mg/m²; day 2, MTX 3.5 gm/m² and vincristine 1.4 mg/m². Procarbazine 100 mg/m²/d was administered for 7 days with odd-numbered cycles. Patients achieving CR received dose-reduced WBRT (23.4 Gy), and all others received standard WBRT (45 Gy). Two cycles of high-dose cytarabine were administered after WBRT. CSF levels of rituximab were assessed in selected patients, and prospective neurocognitive evaluations were performed.

Results: With a median follow-up of 37 months, 2-year overall and progression-free survival was 67% and 57%, respectively. Forty-four percent of patients achieved a CR after five or fewer cycles, and 78% after seven cycles. The overall response rate was 93%. Nineteen of 21 CR patients received the planned 23.4 Gy WBRT. The most commonly observed grade 3 to 4 toxicities included neutropenia (43%), thrombocytopenia (36%), and leukopenia (23%). No treatment-related neurotoxicity has been observed.

Conclusion: The addition of rituximab to MPV increased the risk of significant neutropenia requiring routine growth factor support. Additional cycles of R-MPV nearly doubled the CR rate. Reduced-dose WBRT was not associated with neurocognitive decline, and disease control to date is excellent.

	INTRODUCTION

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Treatment of primary CNS lymphoma (PCNSL) typically consists of methotrexate (MTX)-based chemotherapy with or without the addition of whole-brain radiotherapy (WBRT). Although this treatment strategy results in high rates of disease remission, more than half of patients eventually progress, and few patients are cured of their disease. Furthermore, the addition of WBRT significantly increases the risk of treatment-related neurotoxicity, particularly in the elderly.^1,2 Therefore, a treatment regimen that is both more effective and less toxic is required to improve patient outcome.

We recently reported long-term follow-up on a series of 57 patients treated with a high-dose MTX-based regimen with or without WBRT.³ In this series, median overall survival (OS) with more than a decade of follow-up was 51 months; 48% of patients developed tumor progression, and 33% developed treatment-related neurotoxicity. In an effort to improve on these results, we modified both the chemotherapy and WBRT regimen. Rituximab, a chimeric monoclonal antibody designed to target the CD20 antigen present on B lymphocytes, was incorporated into our chemotherapy regimen. It enhances the efficacy of standard chemotherapy regimens for comparable systemic non-Hodgkin's lymphoma (NHL) and has been incorporated into all initial combination chemotherapy regimens.^4-6 Clinical experience with rituximab in PCNSL is limited; however, a number of reports suggest that it may be an active agent despite its large size and difficulty crossing an intact blood-brain barrier.^7,8 We also extended the chemotherapy cycles in an effort to improve the complete response (CR) rate.

WBRT is an effective treatment modality that contributes to disease control, but the risk of late neurotoxicity associated with combined MTX-based chemotherapy and WBRT is unacceptably high. Up to 90% of PCNSL patients older than 60 years treated with combined-modality therapy develop leukoencephalopathy; the risk to younger patients is poorly defined because symptoms do not develop for several years after treatment.⁹ As a result, recent investigations have focused on using chemotherapy alone and reserving WBRT for tumor recurrence. An alternate strategy may be to deliver a lower dose of WBRT to patients in radiographic remission after chemotherapy. The current dose recommended for PCNSL (45 Gy) was derived in part when WBRT was the sole treatment modality before the use of MTX-based chemotherapy.¹⁰ It is possible that a lower total dose would retain efficacy in terms of disease control with less neurocognitive morbidity. In recent years, several studies have indicated that lowering the dosage of consolidation radiotherapy from 40 to 45 Gy down to the 20- to 30-Gy range in Hodgkin's lymphoma and NHL has not compromised disease control. In light of these results in systemic lymphoma, the dose of WBRT was decreased to 23.4 Gy in our PCNSL patients who achieved a CR to induction chemotherapy.^11-13

	PATIENTS AND METHODS

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Patient Characteristics
Immunocompetent patients with newly diagnosed, histologically confirmed B-cell PCNSL were eligible to participate. This prospective multicenter trial recruited patients between 2002 and 2005 from Memorial Sloan-Kettering Cancer Center (New York, NY), Northwestern University (Chicago, IL), University of Virginia Health Science Center (Charlottesville, VA), University of Vermont (Burlington, VT), and the Kentuckiana Cancer Institute (Louisville, KY). All patients signed written informed consent before participation, and the protocol was approved by the institutional review board at each participating institution.

Pretreatment evaluation included 24-hour urine collection for creatinine clearance (minimum required 50 mL/min); CSF cytology; complete ophthalmologic examination including slit lamp; computed tomography scan of the chest, abdomen, and pelvis; bone marrow biopsy; and a baseline neuropsychological evaluation. Adequate bone marrow, renal, and liver functions were required for participation. Patients with evidence of systemic lymphoma or other active malignancy were excluded. All patients were HIV-1 negative, and none had received any prior therapy for PCNSL. There were no limits with regard to age or performance status. Patients whose CSF was positive for malignant cells had an Ommaya reservoir placed for intrathecal MTX administration.

Induction Chemotherapy
Induction chemotherapy consisted of five to seven biweekly cycles of rituximab, MTX, procarbazine, and vincristine (R-MPV; Fig 1). Rituximab 500 mg/m² was administered intravenously on day 1 of each cycle as a 5-hour infusion with standard premedications. MTX 3.5 gm/m² was infused over 2 hours on day 2 of each cycle, with standard pretreatment hydration and alkalinization of urine (target urine pH > 7.0). Leucovorin rescue (20 to 25 mg every 6 hours) was begun 24 hours after MTX infusion and continued for at least 72 hours or until the serum MTX level fell below 1 x 10^–8 mg/dL. Leucovorin was increased to 40 mg every 4 hours if MTX levels were toxic (48-hour level > 1 x 10^–5 mg/dL, or 72-hour level > 1 x 10^–8 mg/dL). Vincristine 1.4 mg/m² (maximum dose, 2.8 mg) was administered on day 2 of each cycle. Procarbazine 100 mg/m²/d for 7 days was administered during odd-numbered cycles only. Intra-Ommaya MTX 12 mg was administered between days 5 and 12 of each cycle to patients with positive CSF cytology.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Schematic of study design. R-MPV, rituximab, methotrexate, procarbazine, and vincristine; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; WBRT, whole-brain radiotherapy.

Radiotherapy
WBRT was started 3 to 5 weeks after the completion of R-MPV. Patients who attained a CR after R-MPV received WBRT to a total dose of 23.4 Gy (1.8 Gy/fraction x 13 daily). Patients who attained less than a CR after seven courses of R-MPV received a total dose of 45 Gy (1.8 Gy/fraction x 25 daily). Patients with ocular involvement were irradiated without orbital shielding to the full dose of 23.4 Gy for patients with CR, and to a dose of 36 Gy for patients with less than a CR.

Consolidation Chemotherapy
After completion of WBRT, two cycles of cytarabine were administered at 3 gm/m²/d (maximum daily dose, 6 gm) for 2 days, infused over approximately 3 hours. Granulocyte colony-stimulating factor support was administered to all patients for 10 days starting 48 hours after completion of the day-2 cytarabine infusion. A second cycle of cytarabine was administered 1month later.

Evaluation During Treatment
Treatment response was evaluated after five and/or seven cycles of R-MPV, after WBRT, and at completion of all treatment. Response was determined according to the International Criteria for PCNSL.¹⁴

Neuropsychological evaluations were performed in a subset of patients at baseline, after R-MVP and before WBRT, and 6 and 12 months after completion of all therapy. The neuropsychological test battery included tests of attention (Digit Span subtest, WAIS-III), executive functions (Trail Making Test Parts A & B; Brief Test of Attention, Controlled Oral Word Association Test; Stroop Color-Word Test), verbal memory (Hopkins Verbal Learning Test, Revised), psychomotor speed (Grooved Pegboard Test), Language (Boston Naming Test; Semantic Fluency), and visual-construction (Clock Drawing Test).

In patients with an Ommaya reservoir, serum and CSF were collected for measurement of rituximab levels. CSF and serum samples were collected within 1 hour of completing the rituximab infusion and at 18 and 24 hours. Trough levels of both serum and CSF were sent on days 15, 29, 43, 57, and 62 before each subsequent dose of rituximab.

End Points and Data Analysis
This study was designed to test the feasibility of our planned treatment regimen. The primary end points were 2-year progression-free survival (PFS) and acute treatment-related toxicity. Secondary end points included response rate, relapse rate after CR, OS, PFS, and long-term neurocognitive outcome. PFS and OS were calculated from the date of diagnosis to the date of first relapse, death, or last follow-up. Survival curves were calculated using the Kaplan-Meier product limit method. On the basis of a planned sample size of 30 patients, survival data were estimated with CIs of ±18%. All patients who began this treatment regimen were included in the survival analysis in an intention-to-treat fashion. Follow-up extended to May 1, 2007.

	RESULTS

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Demographics
Thirty eligible patients were enrolled and treated (Table 1). All 30 patients were assessable for toxicity; 27 completed treatment and were assessed for response. There were 17 women and 13 men. The median age was 57 years (range, 30 to 76 years). The median KPS was 70 (range, 50 to 90). Six patients (20%) had CSF involvement, and three (10%) had ocular involvement at diagnosis.

Response to Therapy
In total, 23 (77%) of the enrolled thirty patients achieved a CR by the completion of all planned therapy. Twenty-seven patients were assessed for response to R-MPV. Twelve (44%) achieved a CR after five or fewer cycles. Thirteen patients with less than CR received a total of seven cycles of R-MPV. After completion of all chemotherapy, 21 achieved CR (78%), four PR (15%), and two (7%) progression (Table 2).

Survival
With a median follow-up for surviving patients of 37 months (range, 18 to 55+ months); more than half of patients are alive and free of disease progression. The estimated 2-year OS and PFS are 67% (95% CI, 49% to 85%) and 57% (95% CI, 39 to 75; Fig 2), respectively, and estimated median PFS is 40 months. For the 19 patients who received reduced-dose WBRT, the estimated 2-year OS and PFS are 89% and 79% (Fig 3), respectively; median OS and PFS have not been reached.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier survival curve showing overall survival (OS; solid line) and progression-free survival (PFS; dashed line) of the entire cohort (N = 30).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier survival curves of the 19 patients treated with reduced-dose whole-brain radiotherapy showing overall survival (OS; solid line) and progression-free survival (PFS; dashed line).

Neurocognitive Outcome
Longitudinal neuropsychological assessments have been performed on 12 of 19 patients who received low-dose WBRT at baseline, after R-MPV and before WBRT, and 6 and 12 months after completion of all planned treatment. Among the patients who did not complete follow-up cognitive evaluations, one relapsed early, four died, one declined WBRT, and one declined cognitive testing.

At baseline, patients had mild to moderate impairments (ie, 1 to 2 standard deviations [SDs] below the normative mean) in most cognitive domains including executive functions (mean z-score, –1.5; SD, 0.485), memory (mean z-score, –1. 67; SD, 0.93), psychomotor speed (mean z-score, –1.91; SD, 1.3), and language (mean z-score, –1.78; SD, 0.82). There was improvement across most cognitive domains after each follow-up period, particularly after R-MPV, which may be related to both decreased tumor burden and practice effects. Memory and psychomotor speed mean scores remained in the mildly impaired range at all follow-ups (ie, mean z-scores ranged from –1.06 to –1.59). These results suggest no evidence of neurocognitive decline within the 12-month post-WBRT follow-up period (Table A1, online only).

Pharmacokinetic Studies
Serum and CSF levels of rituximab were performed in four of six patients with leptomeningeal disease who had an Ommaya reservoir placed (Table A2, online only). There was a progressive increase in median baseline serum rituximab levels with subsequent R-MPV treatments (58,500 ng/mL on day 15 to 162,000 ng/mL by day 62). Medians could not be calculated for CSF levels because all values less than 250 ng/mL were categorized together. All pretreatment CSF levels were less than 250 ng/mL. CSF levels of rituximab ranged from less than 250 ng/mL to 11,700 ng/mL (3.3% of the corresponding median serum levels) at 1 hour postinfusion, from less than 250 ng/mL to 12,000 ng/mL (4.4% of the corresponding median serum levels) 18 hours postinfusion, and from less than 250 ng/mL to 10,200 ng/mL (4.1% of the corresponding median serum levels) for 24 hours postinfusion.

	DISCUSSION

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The initial results of this clinical trial suggest that response-adapted therapy may be an effective strategy for the management of PCNSL. This approach has been used to improve the management of patients with systemic NHL and may be an important way to advance our management of PCNSL.¹⁵ Assessment of response after five cycles of induction chemotherapy allowed us to identify those patients with a partial but incomplete radiographic response in whom administration of two additional cycles of chemotherapy resulted in a significant augmentation of the observed CR rate. This was a critical issue because our strategy for WBRT was also response adapted, allowing patients in complete remission to receive a substantially reduced dose of radiotherapy. Furthermore, it is possible that increasing the CR rate to induction chemotherapy could have an independent positive effect on patient outcome. Increased CR rates have been associated with improved outcome in patients with systemic NHL,¹⁶ and 2-year disease-free survival was significantly increased in NHL patients who had an early CR to chemotherapy (80%).¹⁷

The addition of rituximab to MPV resulted in significant neutropenia requiring routine use of growth factor support; however, this is similar to the support required to deliver R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in systemic NHL. No other unexpected toxicities were observed. Pharmacokinetic studies demonstrated that rituximab penetrated into CSF, with levels ranging from 0.1% to 4.4% of serum levels. This is consistent with the 1% to 2% range reported previously.⁸ However, measured CSF levels had both inter- and intrapatient variation precluding reliable estimates of CNS penetration.

Because the radiographic response rates seen with MPV alone are in excess of 90%, we were not able to demonstrate an incremental response benefit resulting from the addition of rituximab to MPV chemotherapy. The primary benefit of adding rituximab to CHOP for patients with systemic NHL has been an improvement in patient survival. Ongoing follow-up of our patients will be required to determine whether a similar benefit might be derived from the use of immunochemotherapy in PCNSL.

Approximately two thirds of our patients were treated with a substantially reduced dose of WBRT. We hypothesized that reducing the dose of WBRT would diminish the risk of treatment-related neurotoxicity without compromising disease control. To date, we have seen no evidence of treatment-related neurotoxicity in this patient cohort. This is particularly significant because patients older than 60 years typically develop initial symptoms of neurocognitive deterioration within months of completing treatment, and seven patients older than age 60 were treated with reduced-dose WBRT on this protocol. This observation is strengthened by the fact that prior reports of treatment-related neurotoxicity relied on clinical observation and, therefore, under-reported cognitive decline, whereas most of the patients on this trial had detailed neurocognitive testing designed to detect even subtle changes. Similarly, disease control in this patient cohort has been excellent, with only 26% having disease progression; of interest, two patients relapsed in compartments that were incompletely treated (eyes and CSF) by reduced-dose WBRT. These data contrast with the report by Bessell et al,¹⁸ who demonstrated that a reduced dose of WBRT compromised disease control and survival in younger patients. Thus, the major advantage of our treatment regimen is the ability to deliver combined-modality therapy without neurotoxicity. Careful long-term follow-up of our patient cohort will be necessary to monitor ongoing survival impact and delayed neurotoxicity.

Since the initial design of this clinical trial, we reported on a new prognostic scoring system that allows categorization of PCNSL patients into three risk groups.¹⁹ Although our sample size is too small to draw definitive conclusions, we analyzed our patients according to their initial recursive positioning analysis (RPA) class. We had seven patients in class 1, 14 in class 2, and nine in class 3 (Table 3). This breakdown demonstrates that our patient population reflects a range of prognostic subgroups. In particular, those patients in RPA class 3 (older patients with a poor performance status) have had an excellent outcome on this trial; only one patient in this group has died, and three have relapsed.

In conclusion, immunochemotherapy is a promising treatment approach for patients with newly diagnosed PCNSL, and our findings suggest that allowance for additional cycles of induction chemotherapy increases CR rates. Further study is needed to verify whether the addition of rituximab to standard chemotherapy results in a significant improvement in patient outcome. Reduced-dose WBRT appears to eliminate the risk of treatment-related neurotoxicity without compromising disease control. The adoption of response-adapted or risk-adapted treatment algorithms may be important strategies to improve the management of PCNSL.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Employment or Leadership Position: None Consultant or Advisory Role: Renato LaRocca, Genentech (C) Stock Ownership: None Honoraria: Jeffrey Raizer, Genentech; Renato LaRocca, Genentech Research Funding: Jeffrey Raizer, Genentech; Barbara Grant, Biogen IDEC; Lauren E. Abrey, Genentech, Biogen IDEC Expert Testimony: None Other Remuneration: Lauren E. Abrey, Genentech

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Joachim Yahalom, Rose Lai, Jeffrey J. Raizer, Lisa M. DeAngelis, Lauren E. Abrey

Financial support: Lisa M. DeAngelis, Lauren E. Abrey

Administrative support: Jeffrey J. Raizer, David Schiff, Renato LaRocca, Barbara Grant, Lisa M. DeAngelis, Lauren E. Abrey

Provision of study materials or patients: Jeffrey J. Raizer, David Schiff, Renato LaRocca, Barbara Grant, Lisa M. DeAngelis, Lauren E. Abrey

Collection and assembly of data: Gaurav D. Shah, Denise D. Correa, Lauren E. Abrey

Data analysis and interpretation: Gaurav D. Shah, Joachim Yahalom, Denise D. Correa, Lauren E. Abrey

Manuscript writing: Gaurav D. Shah, Denise D. Correa, Rose Lai, Lisa M. DeAngelis, Lauren E. Abrey

Final approval of manuscript: Gaurav D. Shah, Joachim Yahalom, Denise D. Correa, Rose Lai, Jeffrey J. Raizer, David Schiff, Renato LaRocca, Barbara Grant, Lisa M. DeAngelis, Lauren E. Abrey

	Appendix

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	NOTES

 
Supported in part by Genentech Inc.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; International Society for Neuro-Oncology/European Association for NeuroOncology Conference, May 5-8, 2005, Edinburgh, United Kingdom; and the 48th Annual Meeting of the American Society for Therapeutic Radiation and Oncology, November 5-9, 2006, Philadelphia, PA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted May 8, 2007; accepted June 27, 2007.

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This Article Abstract Full Text (PDF) Publisher's Note Erratum (v26,p340) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shah, G. D. Articles by Abrey, L. E. Search for Related Content PubMed Articles by Shah, G. D. Articles by Abrey, L. E.