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Originally published as JCO Early Release 10.1200/JCO.2003.04.056 on November 3 2003 © 2003 American Society for Clinical Oncology Primary Central Nervous System Lymphoma: Results of a Pilot and Phase II Study of Systemic and Intraventricular Chemotherapy With Deferred Radiotherapy
From the Departments of Neurology, Internal Medicine, Pediatric Hemato-Oncology, and Neurosurgery, Institute of Biostatistics, and Department of Epileptology, Neuropsychological Unit, University of Bonn, Bonn; Departments of Internal Medicine and Neuropathology, University of Cologne, Cologne; Departments of Neurosurgery, Neurology, and Internal Medicine, University of Dresden, Dresden; and Departments of Neurology and Internal Medicine, University of Heidelberg, Heidelberg, Germany. Address reprint requests to U. Schlegel, MD, Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str 25, D-53105 Bonn, Germany; e-mail: uwe.schlegel{at}uni-bonn.de.
Purpose: To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. Patients and Methods: From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)–based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. Results: Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). Conclusion: Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.
OPTIMAL THERAPY of primary CNS lymphoma (PCNSL) has not yet been established.1 Its incidence has been steadily increasing during the last two decades, such that PCNSL today represents 4% of all primary brain tumors in the United States.2 It is a highly aggressive tumor with a poor prognosis in untreated patients.3 Radiotherapy alone results in a median survival of approximately only 12 to 18 months.4 The addition of a high-dose (> 1 g/m2) methotrexate (MTX)-based chemotherapy to radiotherapy substantially improved median survival.5–10 However, long-term evaluation of patients treated with combination chemotherapy and radiotherapy revealed that patients over 60 years of age carry a high risk of severe long-term treatment-related neurotoxicity.8,11 Several studies have investigated the efficacy of chemotherapy alone. In 14 patients treated with systemic high-dose MTX, thiotepa, vincristine, dexamethasone, and intraventricular MTX and cytarabine (ARA-C), a 79% complete response (CR) was achieved, with a median progression-free survival of 16.5 months and a projected minimum median overall survival (OS) of 40 months.12 In another series of 74 patients treated with intra-arterial cyclophosphamide and MTX (2.5 g/m2 per cycle) after osmotic blood-brain barrier opening, median survival was 40.7 months.13 There are conflicting data on the efficacy of high-dose systemic MTX alone. The CR rate was 65% in a single-center study of 31 patients receiving high-dose systemic MTX (3.5 to 8 g/m2 per cycle) alone.14 However, these results were not confirmed in two recent phase II multicenter trials. A German study was terminated after 37 assessable patients were accrued because repeated cycles of intravenous (IV) MTX (8 g/m2) resulted in a CR rate of 30%.15 A United States study using the same regimen reported a 52% CR rate and a median progression-free survival of 12.8 months.16 It has been reported that chemotherapy alone does not compromise health-related quality of life14 and cognitive function13; however, single cases of severe leukoencephalopathy were observed under combined high-dose systemic and intraventricular chemotherapy.12 In a single-center pilot study of 20 consecutive PCNSL patients evaluating a novel chemotherapy regimen consisting of high-dose systemic MTX, ARA-C, vinca-alkaloids, ifosfamide, and cyclophosphamide in combination with intraventricular MTX, prednisolone, and ARA-C, we observed a CR rate of 55%, a partial response (PR) rate of 10%, a median time to treatment failure (TTF) of 20.5 months, and a median OS of 54 months.17 Here, we report the extended follow-up data of these first 20 patients and treatment results of 45 additional patients enrolled onto a multicenter phase II trial. This study addresses the question of whether this combined systemic and intraventricular chemotherapy results in durable tumor responses with preservation of cognitive function.
Eligibility Criteria All eligible patients had newly diagnosed histologically proven non-Hodgkin’s lymphoma (NHL) according to the Revised European-American Lymphoma and WHO classification.18,19 Patients with lymphoma that involved sites other than the brain, meninges, CSF, or the eyes were not included. Exclusion criteria were age less than 18 years or greater than 75 years, inadequate bone marrow capacity (defined as neutrophils < 1.5 x 109/L, platelets < 100 x 109/L, and hemoglobin level < 8 g/dL), known cause of immunosuppression (ie, HIV type I infection), any previous malignancy, creatinine clearance below 60 mL/min, heart insufficiency (New York Heart Association classification of heart disease class IIIB or IV), uncontrolled infection, or noncompensated active pulmonary or liver disease. Patients previously treated for PCNSL, except by corticosteroids, were not included. The study was approved by the local ethics committees of all participating centers. All patients provided informed consent.
Baseline Studies
Treatment Protocol and Study Design
Treatment consisted of six chemotherapy cycles separated by intervals of 2 weeks between each cycle. Details of the protocol are listed in Table 1
Evaluation of Response and Toxicity Response was determined after the second and sixth chemotherapy cycles by contrast-enhanced MRI of the brain. CR was defined as disappearance of all enhancing lesions on MRI of the brain in patients who were off corticosteroids. PR was defined as a reduction of enhancing tumor volume by more than 50%. Progressive disease was defined as an increase of tumor volume of more than 25% or occurrence of new lesions, and stable disease was defined as any other situation.21 Treatment failure was defined as progressive or stable disease, relapse after initial response, death, or discontinuation of chemotherapy because of complications or because of patient’s or center’s decision. One patient, who discontinued treatment after the fourth cycle because he had achieved CR already, was categorized as CR and not as treatment failure. Acute toxicity was graded according to the WHO grading system.22
Follow-Up and Neuropsychologic Testing
Statistics
Patient Characteristics and Treatment Sixty-five patients from four centers were accrued. The median age was 62 years (range, 27 to 75 years), and the median Karnofsky performance score (KPS) was 70 (range, 20 to 90). Further characteristics of patients, surgical procedure, and neuropathology are listed in Table 2  . During enrollment, eight additional patients were not included because of lacking informed consent (n = 2), bacterial pneumonia (n = 1), idiopathic pulmonary fibrosis (n = 1), severe nephrotic syndrome (n = 1), renal insufficiency (n = 1), platelet count below 90 x 109/L (n = 1), and chronic hepatitis C (n = 1).
In total, 318 cycles of chemotherapy were administered. Complete treatment without any modification was given to 23 patients. Reasons for incomplete treatment were early death (six patients), discontinuation of therapy by the patient (three patients) or by the center (one patient), and treatment-associated complications (32 patients), which were most frequently a transient decrease of creatinine clearance. MTX dose was reduced in 22 patients (up to 25% in seven patients and up to 50% in 15 patients). In seven patients, ifosfamide was omitted in one cycle; and in three patients and one patient cyclophosphamide was omitted in one and two cycles, respectively, because of systemic toxicity. Vinca-alkaloids were omitted because of nerve conduction study results in eight patients in one to five cycles. In one patient, the final ARA-C–based cycle was not administered because pre-existing heart insufficiency progressed under therapy from New York Heart Association class IIIA to class IIIB. In 15 patients, one to five treatment cycles were administered without concomitant intraventricular therapy because of reservoir infection (12 patients), periventricular tumor bleeding (one patient), incorrect catheter position (one patient), or patient’s refusal (one patient). In four patients, severe protocol violations took place; in three patients, cycle C1 was given as a first treatment cycle for different reasons, and in one patient, radiotherapy was initiated after the first cycle despite stable disease.
Treatment Response
TTF, OS, and Response Duration Follow-up was 0 to 87 months (median, 26 months). During follow-up, 38 events defined as treatment failures, including 28 deaths, occurred. The Kaplan-Meier estimate for median TTF was 21 months (95% CI, 10 to 33 months), and for median OS, it was 50 months (95% CI, 31 months to not estimable). The estimated 2- and 5-year survival rates were 69% (95% CI, 57% to 80%) and 43% (95% CI, 26% to 60%), respectively. In 30 patients younger than 61 years, neither median OS nor median TTF have yet been reached. In this subgroup, the estimated 2-year survival rate was 80% (95% CI, 66% to 94%), and the estimated 5-year survival rate was 75% (95% CI, 59% to 91%). For patients older than 60 years, median OS was 34 months (95% CI, 12 to 50 months), and median TTF was 15 months (95% CI, 2.5 to 21 months; Figs 1 and 2). In this age group, the estimated 2-year and 5-year survival rates were 59% (95% CI, 43% to 76%) and 19% (95% CI, 0% to 38%), respectively. The median response duration in 43 assessable patients with PR or CR was 33 months (95% CI, 29 months to not estimable); in the 18 patients older than 60 years, the median response duration was 24 months (95% CI, 18 to 33 months), and in the 25 patients younger than 61 years, the median response duration has not yet been reached (Fig 3). Worse outcome according to older age was statistically significant for TTF (P < .001), OS (P = .0038), and response duration (P = .0104).
Systemic Toxicity WHO grade 4 leukopenia and thrombocytopenia occurred in 14 (22%) and 20 (31%) patients, respectively, and was generally short lasting (range, 1 to 5 days; mean, 2.6 days and range, 1 to 8 days; mean, 2.4 days, respectively). WHO grade 3 leukopenia and thrombocytopenia occurred in 47 (72%) and 38 (58%) patients, respectively. Neutropenic fever occurred in 11 patients and during 11 cycles, with a mean duration of 2.8 days (range, 1 to 7 days). Six neutropenic febrile episodes were associated with 105 ARA-C chemotherapy cycles, whereas five episodes occurred after 213 MTX cycles. Six patients experienced WHO grade 3 and 4 infections. Six patients (9%) died as a result of treatment, and five of these deaths were a result of myelosuppression (septic syndrome with Aspergillus pneumonia in one patient and sepsis-induced multiorgan failure in four patients). These five patients were 53, 58, 70, 71, and 71 years old. Deaths occurred after MTX-based cycles in two patients and after ARA-C–based cycles in three patients. In two of these patients, ARA-C was given in the first course, fulfilling the criteria of a protocol violation. All deaths occurred after the first, second, or third course. The cause of a sudden, unexpected death of another 65-year-old patient at the second day of cycle 1 remained undetermined because autopsy was not granted. Nine patients developed episodes of transient nephrotoxicity (WHO grade 2), eight suffered from mucositis (WHO grade 3 in six patients and WHO grade 4 in two patients), and two developed a transient cutaneous vasculitis under MTX treatment. One patient with a perforated duodenal ulcer after long-lasting dexamethasone therapy underwent surgery. Three patients experienced deep venous thrombosis. In a 66-year-old nonsmoker a small-cell lung cancer developed 44 months after initiation of chemotherapy, eventually leading to death.
Neurotoxicity
Treatment at Relapse
The results of this pilot and phase II study with combined systemic and intraventricular chemotherapy and deferred radiotherapy for PCNSL were analyzed on an intent-to-treat basis. Sixty-five consecutive patients were included irrespective of their neurologic condition. This is illustrated by a minimal KPS of 20. The median age of 62 years in this trial reflects the median age of onset in PCNSL, as reported.27 Taken together, the results of this pilot and phase II trial extend and confirm the encouraging results of a single-center pilot study.17 Treatment results in the present series did not differ between participating centers. A median OS of 50 months and an event-free survival of 21 months are superior to results achieved with radiotherapy28 or with high-dose MTX alone.14–16 They are comparable to the results of other polychemotherapy trials12,13 and to the results of combination chemotherapy and radiotherapy trials.8,10 High-dose MTX is the most effective drug in PCNSL29,30; however, if given as a single compound, it is probably not sufficient with respect to response rate15 and duration.14,16 The administration of high-dose ARA-C may add to therapeutic efficacy, as discussed in large meta-analyses.29,30 Apart from high-dose MTX and ARA-C, vinca-alkaloids, cyclophosphamide, and ifosfamide are part of this treatment protocol. The rationale for this may be questioned because all these substances do not readily cross the blood-brain barrier. Yet, they have a high efficacy in systemic NHL, and many tumor cells in PCNSL may reside behind a disintegrated blood-brain barrier. For that reason, it can be assumed that these compounds can enter bulky enhancing tumor tissue. The theoretical rationale for intraventricular drug administration is long-lasting continuous drug concentration in the CSF31 to treat or prevent leptomeningeal tumor seeding.5 Delayed neurotoxicity is a major concern with combination chemotherapy and radiotherapy, particularly in patients over 60 years of age. During long-term follow-up, Abrey et al8,11 found that the majority of patients in this age group were affected by treatment-induced leukoencephalopathy and deep-brain atrophy clinically presenting as dementia, ataxia, and urine incontinence. Neurotoxicity, in particular, may be attributable to the combination of intraventricular MTX, radiotherapy, and high-dose systemic ARA-C after radiotherapy. However, several reports and meta-analyses of other combination MTX-based chemotherapy and radiotherapy protocols showed a rate of late neurotoxic effects between 20% and 33%.6,7,29,32 In the present series, detailed standardized neuropsychologic examination was performed in 22 patients from one center at baseline, 4 months after completion of therapy, and during follow-up. Data of long-term serial neuropsychologic test results in 15 of these patients were assessable for analysis of possible treatment-related neurotoxicity. It is of note that none of these patients showed a significant decline of cognitive function as proven by standardized tests. However, two patients, who were not formally tested, suffered from disorientation and cognitive dysfunction after therapy. In both of these patients, however, either residual or relapsing tumor probably contributed to these symptoms. One third of the study population developed MRI signs of leukoencephalopathy. However, all of them had either preserved or improved cognitive function after therapy. Therefore, these imaging abnormalities have to be interpreted as MTX-induced asymptomatic leukoencephalopathy.23 The predominant systemic toxicity was myelosuppression. Five patients died from a septic syndrome as a consequence of infectious complications caused by neutropenia. Of these five patients, two were older than 70 years, and one had a KPS of 40. Infection of the Ommaya reservoir occurred in 12 of 64 patients. This rate is higher than reported in other series.5,12 The reasons for this are probably several-fold. First, many patients had been immunocompromised before initiation of specific therapy because of delay of diagnosis and corticosteroid treatment initiated in other institutions. Second, therapy-induced myelosuppression put them at additional risk. And third, intraventricular drug administration made 26 (phase II study) to 30 (pilot study) injections into the reservoir necessary. In all cases, meningitis was successfully managed; however, it represented a serious complication in some patients, and it led to interruption or delay of chemotherapy. A recent meta-analysis and a retrospective analysis of a single-center experience suggest that patients with PCNSL do not benefit from an additional application of cytostatic drugs via an Ommaya reservoir.30,33 In light of the previously mentioned infection rate, the theoretical advantage of intraventricular drug administration probably does not outweigh the additional risk implemented by Ommaya reservoir implantation and repeated intraventricular injections.
In this series, a striking difference of treatment results between patients younger than 61 years of age and older individuals was found (Figs 1
The encouraging treatment results in the younger population suggest that a substantial fraction of these patients has been definitely cured. The Kaplan-Meier curve for OS did not show any further decline after the second to third year beyond the 75th percentile (Fig 2
The authors indicated no potential conflicts of interest.
Presented in part at the Annual Meeting of the American Society of Hematology 2002. Both H.P. and I.G.H.S.-W. contributed equally to this work.
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8. Abrey LE, Yahalom J, DeAngelis LM: Treatment for primary CNS lymphoma: The next step. J Clin Oncol 18:3144–3150, 2000 9. Ferreri AJ, Reni M, Dell’Oro S, et al: Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients. Oncology 60:134–140, 2001[CrossRef][Medline]
10. DeAngelis LM, Seiferheld W, Schold SC, et al: Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20:4643–4648, 2002 11. Abrey LE, DeAngelis LM, Yahalom J: Long-term survival in primary CNS lymphoma. J Clin Oncol 16:859–863, 1998[Abstract]
12. Sandor V, Stark-Vancs V, Pearson D, et al: Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 16:3000–3006, 1998 13. McAllister LD, Doolittle ND, Guastadisegni PE, et al: Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 46:51–60, 2000[CrossRef][Medline] 14. Guha-Thakurta N, Damek D, Pollack C, et al: Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: Response to therapy and quality of life of patients. J Neurooncol 43:259–268, 1999[CrossRef][Medline] 15. Herrlinger U, Schabet M, Brugger W, et al: German Cancer Society Neuro-Oncology Working Group NOA-03 multicenter trial of single-agent high-dose methotrexate for primary central nervous system lymphoma. Ann Neurol 51:247–252, 2002[CrossRef][Medline]
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31. Bleyer WA, Poplack DG, Simon RM: "Concentration x time" methotrexate via a subcutaneous reservoir: A less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms. Blood 51:835–842, 1978 32. Bessell EM, Graus F, Lopez-Guillermo A, et al: CHOD/BVAM regimen plus radiotherapy in patients with primary CNS non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 50:457–464, 2001[CrossRef][Medline] 33. Khan RB, Shi W, Thaler HT, et al: Is intrathecal methotrexate necessary in the treatment of primary CNS lymphoma? J Neurooncol 58:175–178, 2002[CrossRef][Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60 years and 56% for patients older than 60 years, are listed in Table 3
