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© 2000 American Society for Clinical Oncology Treatment for Primary CNS Lymphoma: The Next StepFrom the Departments of Neurology and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Lauren E. Abrey, MD, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email abreyl{at}mskcc.org
PURPOSE: The use of preradiotherapy (RT) methotrexate (MTX) has improved disease control and survival in patients with primary CNS lymphoma (PCNSL). The reported protocol was designed to optimize and enhance the chemotherapeutic component of treatment. PATIENTS AND METHODS: Fifty-two patients were treated with five cycles of high-dose MTX 3.5 g/m2, procarbazine 100 mg/m2/d, and vincristine 1.4 mg/m2. Thirty patients received whole-brain RT (45 Gy). Twenty-two older patients deferred RT to diminish the risk of delayed neurotoxicity; these patients are compared with 12 older patients who completed the entire treatment regimen. Most patients (n = 35) received high-dose cytarabine after RT. RESULTS: Objective response rate to the induction chemotherapy regimen was 90%; overall median survival is 60 months. Grade 3 or 4 myelosuppression was seen in 30 patients, primarily in association with cytarabine; grade 3 nephrotoxicity due to MTX was seen in two patients. Older patients had similar median survival with or without the addition of RT: 32 versus 33 months, respectively. However, late neurotoxicity was significantly more common in those older patients who received RT (P = .00004). Patients younger than 60 years who received the complete treatment regimen have not reached median disease-free or overall survival. CONCLUSION: Increasing the dose of MTX and adding procarbazine and vincristine improved disease control and overall survival in patients with newly diagnosed PCNSL. Younger patients in particular fared extremely well with this treatment regimen. In older patients, deferring whole-brain RT did not compromise overall survival but did reduce treatment-related toxicity.
PRIMARY CNS LYMPHOMA (PCNSL) is an aggressive non-Hodgkin’s lymphoma that arises within the brain, eyes, leptomeninges, or spinal cord. The addition of high-dose methotrexate (MTX) to cranial radiotherapy (RT) has improved median disease-free and overall survival to 30 to 40 months from the 12 to 18 months usually seen with RT alone1-4; however, more than one half of patients eventually relapse, and uncontrolled PCNSL remains the primary cause of death. We designed a treatment regimen that intensified the MTX and employed multiple chemotherapeutic agents; this approach has been essential to the success of systemic lymphoma therapies.5,6 Established systemic lymphoma regimens are ineffective for the treatment of PCNSL, which demands a specialized approach that takes into consideration disease that is behind an intact blood-brain barrier. The dose of MTX was increased to facilitate penetration into the CNS, and the total number of cycles was increased from two to five. Patients also received procarbazine, a lipophilic agent capable of penetrating an intact blood-brain barrier, and vincristine. Both drugs have known efficacy against lymphoma. Delayed neurologic toxicity resulting from the combined effects of MTX and cranial RT is an increasingly recognized complication, occurring in as many as 90% of patients who are older than 60 years.4,7 This is a particular challenge in PCNSL, as more than one half of patients are 60 years of age or older at diagnosis. Symptoms of neurotoxicity, such as memory impairment and ataxia, are progressive and functionally devastating, detracting from quality of life for survivors and their family. It is not known whether eliminating cranial RT from initial treatment will have a significant impact on survival or disease control. Cranial RT was a standard component of the treatment regimen used in this study; however, older patients were given the option of deferring cranial RT after a discussion of potential risks and benefits. Those older patients who deferred RT were compared with a similar group of older patients who received the complete treatment regimen.
All immunocompetent adults with a new diagnosis of PCNSL seen at Memorial Sloan-Kettering Cancer Center between 1992 and 1998 were considered for treatment with this regimen. All patients underwent a staging evaluation that included cranial magnetic resonance imaging (MRI) scan, lumbar puncture, ophthalmologic evaluation (including slit-lamp examination), abdominal computed tomography scan, bone marrow biopsy, chest x-ray, and human immunodeficiency virus (HIV-1) serology. An Ommaya reservoir was placed for intrathecal MTX administration. A creatinine clearance of  50 mL/h was required for treatment. Pre-RT chemotherapy consisted of MTX 3.5 g/m2 infused over 2 hours given every other week for a total of five doses. Intra-Ommaya MTX (12 mg) was given weekly on alternate weeks after administration of systemic MTX. Leucovorin rescue was started 24 hours after each dose of systemic (10 mg every 6 hours, for at least 12 doses) and intra-Ommaya (10 mg every 12 hours for eight doses) MTX. Vincristine 1.4 mg/m2 (maximum dose, 2.8 mg) was given concomitantly with each cycle of systemic MTX. Procarbazine 100 mg/m2/d for 7 days was given with the first, third, and fifth cycle of MTX. Chemotherapy was followed by 45 Gy of whole-brain RT. All patients with evidence of ocular lymphoma received 30 to 40 Gy of ocular RT. Three weeks after the completion of RT, patients received two courses of high-dose cytarabine; each course consisted of two doses of 3 g/m2 infused over 3 hours separated by 24 hours. Response to treatment was evaluated with cranial MRI at the completion of pre-RT chemotherapy, after RT, and at the completion of the entire treatment regimen. A complete response (CR) was defined as resolution of enhancing tumor with the patient not receiving corticosteroids. Patients with a complete resolution of enhancing tumor who remained on corticosteroids were labelled as an uncertain CR (uCR). A partial response (PR) was defined as at least a 50% reduction in tumor size; the patient also had to be on a stable or decreasing dose of corticosteroids to be considered as having achieved a PR. Progressive disease (PD) was defined as an unequivocal increase in tumor size or the appearance of new lesions; stable disease (SD) represented all other situations. In addition, patients with CSF or ocular involvement at diagnosis had to have complete resolution of disease in these compartments to qualify for a CR. Tumor in either the CSF or eyes was classified as either present or absent, and no PR was assigned to these locations. No patient had evidence of an objective response in one compartment with disease progression in another; therefore, no mixed responses were observed. Patients were evaluated three to four times a year and underwent repeat neurologic examination and neuroimaging to monitor for disease control and evidence of late cognitive effects of treatment. At recurrence, all patients underwent repeat neuroimaging, CSF cytologic examination, and ophthalmologic examination. Cognitive impairment was identified by clinical examination and an assessment of the patient’s functional status as determined by the physician, patient, and patient’s caregiver. Psychometric testing was not routinely administered. Although the onset of delayed neurotoxicity may be subtle, progressive deterioration was documented in all patients so categorized, and most had ataxia and urinary incontinence in addition to loss of memory and executive function. Recurrent PCNSL was excluded in all patients before a diagnosis of delayed neurotoxicity was confirmed.
Time to progression and survival were measured 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.8 Cox stepwise regression was used for multivariate analysis of possible prognostic variables. Analysis of discrete variables was performed using the
Patient Characteristics Fifty-two patients received this combination chemotherapy with or without cranial RT between May 1992 and January 1998; all patients have completed initial treatment and are available for assessment, with a median follow-up period of 33 months (range, 10 to 77 months). Thirty-one men and 21 women were included in the study, with a median age of 65 years (range, 27 to 89 years; Table 1). The average duration of symptoms before diagnosis was 30 days. Karnofsky performance status (KPS) at diagnosis ranged from 30 to 100, with a median score of 70. No patient was HIV-1 positive or had evidence of systemic lymphoma at diagnosis.
Diagnosis and Pathology All patients had histologic confirmation of their lymphoma. Diagnosis was established on brain tissue in 44 patients; 29 underwent a stereotactic biopsy and 15 underwent surgical resection (three complete, 12 partial). CSF cytologic examination demonstrating malignant lymphocytes established the diagnosis in five patients. Of the 52 patients, 11 (21%) had positive CSF cytology, and an additional 23 had an abnormal CSF cytologic examination with suspicious or atypical (11 patients) or reactive lymphocytes (12 patients). Three patients had their diagnosis established by vitrectomy. Seven additional patients had evidence of ocular lymphoma on slit-lamp examination; three of whom also had a positive vitrectomy. In total, there was a 19% incidence (10 of 52 patients) of ocular involvement at diagnosis. A diffuse large B-cell lymphoma was the most common histologic subtype, comprising 70% of all specimens. Six patients had large-cell immunoblastic lymphoma, and one each had lymphoplasmacellular, lymphocytic, and T-cell lymphoma. The histologic subtype could not be specified in seven patients.
Treatment Thirty patients received the planned course of whole-brain RT. Twenty-two older patients did not receive any cranial RT. These 22 patients were compared with 12 patients older than 60 years who received the full treatment regimen, including cranial RT (Table 1). Thirty-five patients received cytarabine either at completion of RT or after neoadjuvant chemotherapy in those older adults who deferred RT. Eight older patients did not receive cytarabine because of poor clinical condition at the completion of the induction chemotherapy or RT, six patients with persistent or progressive disease were not treated with cytarabine, and three patients refused cytarabine.
Response to Therapy The overall objective response rate (CR + PR) at completion of all treatment was 94%. In total, 45 patients (87%) achieved a complete remission. Four patients had at best a PR, and two had SD despite treatment. One patient died of progressive tumor during the initial course of therapy. All six patients with residual tumor received chemotherapy and RT and were in poor clinical condition at the end of therapy; only one patient has steadily improved despite a persistently abnormal MRI that may represent an artifact related to ventriculoperitoneal shunt placement.
Acute Toxicity
Twenty-three other acute treatment-related complications occurred in 19 patients. The most frequent complication was deep venous thrombosis (five patients) followed by grade 2 vincristine-induced neuropathy (three patients) and grade 2 mucositis (three patients). Two patients each developed sepsis or an Ommaya reservoir infection. Two patients had an allergic reaction to procarbazine, and one developed a severe vincristine-induced ileus. One patient developed a stroke-like syndrome in association with the high-dose systemic MTX and required dose reduction in further cycles. Other complications included a pulmonary embolus, an acute gastrointestinal hemorrhage related to corticosteroids, and grade 4 hepatic enzyme elevation; all resolved with medical management.
Relapse
Seven patients relapsed in the brain alone, six of whom had disease distant from the initial site of tumor. Three patients each had isolated ocular or leptomeningeal relapse. Two patients relapsed simultaneously at a distant brain site and in the leptomeninges. Two patients developed isolated systemic lymphoma and one relapsed systemically and in the leptomeninges, for a 6% incidence of systemic relapse. Sixteen patients received salvage treatment at relapse. Various systemic and intrathecal chemotherapies were given to 10 patients, including carmustine; cyclophosphamide; ifosfamide, carboplatin, and etoposide; and procarbazine, lomustine and vincristine. Intra-Ommaya chemotherapy included cytarabine, thiotepa, 4-hydroxyperoxycyclo-phosphamide and hydrocortisone. Ocular RT was administered to all three patients with ocular relapse. Three older patients who had deferred initial RT received whole-brain RT (30, 35, and 45 Gy) for parenchymal brain relapse. Ten (63%) of the 16 patients who underwent salvage treatment achieved a complete remission, and median survival from time of relapse is 27 months (range, 2 to 46+ months). Five of the six patients treated with RT had a complete remission and one patient had a PR. Five of the 10 patients who received chemotherapy at relapse achieved a complete remission; however, three had leptomeningeal disease and all rapidly developed a second relapse after their initial response to chemotherapy. One patient died of complications related to his first dose of salvage chemotherapy for isolated systemic relapse. Three patients had documented progression despite salvage chemotherapy. One patient had clinical deterioration and tumor progression is presumed, but repeat imaging was not obtained.
Delayed Toxicity
Only one patient who received chemotherapy alone developed neurotoxicity after a median follow-up period of 27 months (range, 3 to 60 months). A 54-year-old woman deferred initial RT because of poor clinical status; more than 4 years later she developed characteristic signs of treatment-related neurotoxicity and died of complications 10 months later. Another 71-year-old man deferred initial RT, relapsed, then received cranial RT and developed dementia. On average, symptoms of neurotoxicity developed 7 months after completion of treatment, but several patients had initial symptoms appear during RT (n = 5), and in others, symptoms were delayed in onset for 2 years or more (n = 4). The clinical presentation was identical in all patients regardless of the timing of onset; memory deterioration and personality changes occurred early and were typically followed by gait disturbance and, later, urinary incontinence.
Survival
Patients younger than 60 years have been followed-up for a median of 50 months and have not reached median overall or disease-free survival (Fig 3). In addition, the 18 younger patients who received chemotherapy and cranial RT have a low incidence of delayed neurologic sequelae (6%). To date, only three patients in this group have died, one from recurrent tumor, one from acute complications of chemotherapy at relapse, and one from complications related to delayed neurotoxicity.
This experience using high-dose MTX-based combination chemotherapy to treat PCNSL has resulted in an excellent overall median survival of 60 months, 18 months longer than the median survival of 42 months reported with our initial combined-modality regimen.9 The shorter duration of follow-up for patients on the current regimen limits some comparisons, particularly disease-free survival. However, 2-year survival was significantly better for patients treated with the current regimen (P = .01; 83% v 58%), despite the current patients’ older age (median age, 65 v 59 years) and worse performance status (P = .03), which are important prognostic variables in PCNSL. The major difference between the current regimen and our initial regimen is the dose of MTX and the addition of procarbazine and vincristine, suggesting that multiagent therapy and dose-intensity of MTX significantly improved disease control and overall survival. High-dose systemic MTX is the single most effective agent in the treatment of PCNSL. At a dose of 3.5 g/m2, MTX is capable of penetrating the blood-brain barrier and yields sustained therapeutic CSF levels lasting greater than 24 hours. Alternate weekly administration of intrathecal MTX was given to enhance chemotherapeutic coverage of the CSF. Other successful strategies to optimize the dose of MTX for PCNSL treatment have been reported. Blood-brain barrier disruption with administration of intra-arterial MTX (2.5 g/m2) was reported by Dahlborg et al10 to achieve a median survival of 40 months in the absence of RT. Their patients also received systemic cyclophosphamide and procarbazine in combination with the intra-arterial MTX. A substantially higher dose of MTX (8.4 g/m2) was used by Sandor et al11 in combination with vincristine and thiotepa without cranial RT. Although there was an excellent response rate to this chemotherapy regimen, median progression-free survival was only 16.5 months and more than 70% of patients had persistent or recurrent disease. Multiagent regimens using non–cross-resistant drugs have been essential to the successful treatment of aggressive systemic non-Hodgkin’s lymphoma. Although standard regimens, such as the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone, incorporate the most active drugs, these agents are incapable of penetrating into the vitreous, CSF, or brain parenchyma. Therefore, we chose agents with known efficacy against non-Hodgkin’s lymphoma that could reach these compartments. This is particularly important because malignant lymphocytes have been demonstrated in radiographically normal regions of brain in PCNSL patients and are therefore protected by an intact blood-brain barrier. Vincristine is an essential agent in most combination chemotherapy regimens for non-Hodgkin’s lymphoma, but it does not penetrate the intact blood-brain barrier. It was included to treat bulky disease visualized on MRI where the blood-brain barrier is disrupted and because it has a different mechanism of action and toxicity profile than the other chemotherapeutic agents. An intergroup trial with the Radiation Therapy Oncology Group and Southwest Oncology Group used a similar combination chemotherapeutic regimen with a slightly lower dose of MTX (2.5 g/m2); preliminary results from this trial of 102 patients demonstrate a high response rate to pre-RT chemotherapy and an overall median survival of at least 30 months.12 Improved disease control and survival were seen with our current regimen, but 35% of patients experienced relapse. The average time to and pattern of relapse were similar to prior experience, with most patients experiencing disease recurrence within 2 years of initial diagnosis. The majority relapsed in the brain at a site distant from their initial tumor, supporting the hypothesis of widespread parenchymal brain invasion. Furthermore, leptomeningeal, ocular, and systemic relapse were also observed. Ocular and leptomeningeal compartments are particularly difficult to treat, because systemic drug penetrates poorly into these locations, local chemotherapy may not be properly distributed or reach sufficient concentration, and focal RT may not encompass all disease. The prognosis at relapse is generally poor, but further treatment often results in at least transient remission. However, prolonged survival is possible, and some patients continue to be sensitive to salvage therapy despite multiple relapses. Two patients have survived more than 40 months after relapse: one patient with an isolated systemic relapse treated with ifosfamide, carboplatin, and etoposide chemotherapy subsequently relapsed in his brain and was successfully treated with procarbazine, lomustine, and vincristine chemotherapy; the other patient relapsed in his brain and was treated with chemotherapy. RT can effectively palliate ocular relapse13; intravitreal injection of chemotherapy has been reported to be effective for a few patients, but such treatment is cumbersome and may cause local hemorrhage.14 Older patients who defer initial RT and recur in the brain remain responsive to RT but frequently develop subsequent neurotoxicity. The issue of the best treatment for older patients remains controversial. Our results illustrate several important findings with regard to the therapeutic approach and outcome of these patients. First, older patients can tolerate aggressive chemotherapy without undue toxicity. Second, chemotherapy with or without RT results in a median survival of 32 to 33 months for patients older than 60 years; this is substantially longer than the median survival of 7.6 months reported with whole-brain RT alone.3 Finally, withholding RT does not significantly impact overall survival. The difference between older patients who either defer or receive RT is primarily one of disease control. Older patients who defer RT are more likely to relapse, whereas those who receive RT are significantly more likely to develop delayed neurotoxicity. However, the proportion of older patients who defer RT and relapse is similar to that of younger patients who receive the full treatment regimen. Therefore, we recommend deferring cranial RT in patients who are older than 60 years and achieve a complete response to initial chemotherapy.15,16 This study is limited to a single-institutional experience, but a large number of patients were accrued and treated over a relatively short time interval. Unlike some reported series this patient group did not have a better than usual prognosis; the majority of our patients were older than 60 years at diagnosis, and patients with an initial KPS as low as 30 were included. This accurately reflects the typical population of PCNSL patients. The majority completed the planned course of chemotherapy; however, more than one third of patients did not receive cranial RT. Young patients fared extremely well with this regimen; neither median disease-free or overall survival have yet been reached in this group. Future studies should address the optimal role of RT in the treatment of older patients. Further modifications of the chemotherapy regimen may improve disease control and outcome for all patients. Prospective psychometric testing should be performed to better characterize the impact of treatment-related neurotoxicity.
1. Glass J, Gruber ML, Cher L, et al: Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: Long-term outcome. J Neurosurg 81: 188-195, 1994[Medline] 2. Neuwelt EA, Goldman DL, Dahlborg SA, et al: Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: Prolonged survival and preservation of cognitive function. J Clin Oncol 9: 1580-1590, 1991[Abstract] 3. Nelson DF, Martz KL, Bonner H, et al: Non-Hodgkin’s lymphoma of the brain: Can high-dose, large-volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG:8315. Int J Radiat Oncol Biol Phys 23: 9-17, 1992[Medline] 4. Abrey LE, DeAngelis LM, Yahalom J: Long-term survival in primary CNS lymphoma. J Clin Oncol 16: 859-863, 1998[Abstract]
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Schultz C, Scott C, Sherman W, et al: Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: Initial report of Radiation Therapy Oncology Group Protocol 88-06. J Clin Oncol 14: 556-564, 1996 7. Abrey LE, Yahalom J, DeAngelis LM: Relapse and late neurotoxicity in primary central nervous system lymphoma. Neurology 48: A18, 1997 (abstr) 8. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958
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DeAngelis LM, Yahalom J, Thaler HT, et al: Combined modality therapy for primary CNS lymphoma. J Clin Oncol 10: 635-643, 1992 10. Dahlborg SA, Braziel R, Crossen JR, et al: Non-AIDS primary CNS lymphoma: First example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy. Cancer J Sci Am 2: 166-174, 1996[Medline]
11.
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 12. DeAngelis LM, Seiferheld W, Schold SC, et al: Combined modality treatment of primary central nervous system lymphoma (PCNSL): RTOG 93-10. Proc Am Soc Clin Oncol 18: 140A, 1999 (abstr 537) 13. Peterson K, Gordon KB, Heinemann MH, et al: The clinical spectrum of ocular lymphoma. Cancer 72: 843-849, 1993[Medline] 14. Fishburne BC, Wilson DJ, Rosenbaum JT, et al: Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma. Arch Ophthalmol 115: 1152-1156, 1997[Abstract]
15.
Freilich RJ, Delattre JY, Monjour A, et al: Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurology 46: 435-439, 1996 16. Hoang-Xuan K, Chinot O, Frenay M, et al: Chemotherapy alone as initial treatment of primary central nervous system lymphoma (PCNSL) in older patients. Neurology 48: A17, 1997 (abstr)[Medline] Submitted October 19, 1999; accepted May 1, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 method, with Yates correction for expected values less than 5. All patients who began this treatment regimen were included in the analysis in an intent-to-treat fashion. Follow-up extends through May 31, 1999. 
