Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome

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1 J Neurosurg 81: , 1994 Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome JON GLASS, M.D., MICHAEL L. GRUBER, M.D., LAWRENCE CHER~ M.D., AND FRED H. HOCHBERG, M.D. Brain Tumor Center, Temple University Cancer Center, Philadelphia, Pennsylvania; Department of Neurosurgery, University of California, Los Angeles, California; and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts u,, The treatment of primary central nervous system lymphoma with chemotherapy prior to whole-brain radiation therapy (WBRT) has improved outcome considerably in this previously fatal disease. Complete or partial responses to intravenous methotrexate (.5 gm/sq m with leucovorin rescue every weeks for two to four cycles) were seen in 12 of 1 patients originally treated. A total of 25 patients (including the original 1) have now been treated with one to six cycles of methotrexate every 10 to 21 days prior to WBRT. Twenty-two had partial or responses, with a median duration of response of 2 months. Median survival time was months (42.5 months in those responding to therapy). Nine patients are alive and without evidence of disease 9 to 122 months following therapy. Acute and long-term toxicities were minimal. Systemic methotrexate administration prior to WBRT is well tolerated and produces long-term survival. KEY WORDS 9 primary central nervous system tumor lymphoma chemotherapy 9 methotrexate 9 whole-brain radiation therapy p RIMARY central nervous system (CNS) lymphoma is a neoplasm confined to the CNS, its coverings, or the eye. 17 Once a rare tumor, its incidence has continued to increase. 2s Untreated, the prognosis for primary CNS lymphoma is poor, with a median survival time of 4.6 months. 15 The addition of whole-brain radiation therapy (WBRT), while providing rapid clinical and radiographic responses, increases survival time, only to 10 to 18 months.,... In 1989, Gabbai, et al., 1 reported or partial radiographic responses in 12 of 1 patients given intravenous methotrexate (.5 gm/sq m) every weeks for two to four cycles prior to WBRT. Subsequent clinical trials have also suggested that preirradiation chemotherapy pro- duces high response rates as well as prolonged disease free survival.. We report the long-term outcome, including recurrence, survival, and late toxicities, in 25 patients with primary CNS lymphoma treated with methotrexate chemotherapy prior to WBRT. Clinical Material and Methods Patient Eligibility and Population One patient was treated in April, 198. From March, 1985, through May, 1990, patients without evidence of human immunodeficiency virus 1 (HIV-1) infection were considered for entry into the study if a new diagnosis of primary CNS lymphoma was made by demonstration of either malignant lymphoma on stereotactic or open brain, or monoclonal lymphocytes on cytological examination of cerebrospinal fluid (CSF) or vitreous fluid. Patients were enrolled after May, 1990, if they were ineligible for another protocol requiring more intensive chemotherapyj 4 There was no lower limit on the Karnofsky Performance Scale (KPS) score. All patients underwent lumbar puncture (except when contraindicated by tumor mass effect) as well as slit-lamp evaluations for ocular lymphoma. The possibility of systemic disease was eliminated with computerized tomography (CT) of the abdomen and chest. Bone marrow biopsies were not routinely performed. Evaluations for HIV-1 antibody were performed on patients diagnosed after A total of 25 patients were included in the study and received methotrexate at a dose of.5 gm/sq m (Table 1). Thirteen patients (Cases 1-1) were previously reported 1 and underwent treatment every weeks; the remaining 12 patients (Cases 14-25) received methotrexate every 10 days. Therapy Methotrexate Administration. Prior to infusion, adequate urine alkalinization (ph > 7.0) and urine output 188 J. Neurosurg. / Volume 81 / August, 1994

2 Methotrexate in primary CNS lymphoma TABLE 1 Clinical characteristics of 25 patients with primary CNS lymphoma* Response Case Age (yrs), Mode of Tumor Type of CSF Ocular to No. Sex Diagnosis Location Lesion Cytology Disease Corticosteroids 1 27, F 2 64, F 2, M 4 9, F 5 78, M 6 71, F 7 68, M 8 6, M 9 62, M 10 4, F 11 80, M 12 62, F 1 62, M 14 51, M 15 42, M 16 47, M 17 49, F 18 47, M 19 44, M 20 1, M 21 62, M 22 70, F 2 50, M 24 61, M 25 61, F lumbar ptlnctnre lumbar puncture lumbar puncture lumbar puncture lumbar puncture lat ventricle ~ch~roid plexus) solitary + none It frontal solitary ND none It parietal solitary + none rt thalamic solitary t partial hypothalamus multiple :]: none choroid plexus solitary + + none rt thalamus solitary - - none subependymal multiple + + unknown rt parietal multiple - + unknown cerebellum solitary - unknown rt temporal solitary - unknown It thalamus solitary + unknown rt frontal solitary - + unknown midbrain, basal ganglia multiple - none multiple supratentorial multiple w - none rt parieto-occipital solitary w - unknown It frontal solitary + + none It frontal solitary - - unknown rt basal ganglia, hypotlnalamus multiple - partial rt thalamus, pontine tegmenturn solitary - partial It frontal solitary + none subependymal (fourth ventricle) solitary + partial rt frontal, basal ganglia multiple - none It internal capsule, basal ganglia, multiple - none It middle cerebellar, peduncle multiple supratentorial & multiple - - none infratentorial * CNS = central nervous system; CSF = cerebrospinal fluid; + = positive; - = negative; ND = not done. t CSF suggestive of malignancy but no cytology performed. :~ CSF cytology highly suggestive of malignancy. w CSF cytology suggestive but not diagnostic of malignancy. (> 100 cc/hr) was achieved by oral or parenteral means. Methotrexate, at a dose of.5 mg/sq m in 400 cc of 5% dextrose in water, was administered over 4 hours. Calcium leucovorin, 25 mg orally or parenterally every 6 hours, was administered beginning 4 (Cases 1-1) or 24 (Cases 14-25) hours following completion of methotrexate infusion and continued until blood methotrexate levels were below 0.05 to 0.07 x 10-6 M. Radiation Therapy. Whole-brain radiation therapy was started within weeks of completion of chemotherapy or sooner if there was clinical or radiographic progression. A minimum of 000 cgy, in 180-cGy daily fractions, was administered to the posterior orbit, whole brain, and meninges to the level of the C-2 vertebra. Intraocular disease was treated by including the entire orbit in the radiation field, blocking the anterior chamber after 2000 cgy. Additional WBRT or boosts to areas of persistently focal tumor therapy were given at the treating physician's discretion. Corticosteroid Therapy. Corticosteroid agents were tapered as indicated by the resolution of mass lesions, clinical improvement, and patient tolerance to the reduced regimen. Evaluation of Response Karnofsky Performance Scale scores were measured at both the onset and the end of chemotherapy. Contrast-enhanced CT or magnetic resonance (MR) imaging of the brain was performed at the time of diagnosis, prior to initiation and at the completion of chemotherapy (and at the investigator's discretion during therapy), following WBRT, every 2 to months for 1 year, and every 6 months thereafter. Cerebrospinal fluid and slit-lamp examinations were performed at the end of chemotherapy, following WBRT, every 6 months thereafter for 1 year, and at the time of suspected recurrence. Responses were evaluated after chemotherapy and after WBRT. Radiographic response to corticosteroids was assessed in patients undergoing CT or MR imaging prior to chemotherapy. Response to therapy in patients with ocular disease was measured only after WBRT, as ocular lymphoma is not affected by chemotherapy. All responses were defined in the setting of a stable or improved KPS score, a stable or decreased corticosteroid requirement, the resolution of positive CSF cytologies, and (following WBRT only) the resolution J. Neurosurg.? Volume 81 /August,

3 J. Glass, et al. TABLE 2 Response to therapy & 25 patients with primary CNS lymphoma* Case MTX Response Initial/ WBRT Response Response Survival to Final After Duration Time No. Cycles MTX KPS Score (cgy) WBRT (mos) (mos) 1 80/ none NA boost / / / partial 60/90 50/ complctc 0/90 60/ major partial 50/ partial major partial 50/70 50/ / / / major partial 70/ progressive disease NA boost none major partial 50/ major partial / major partial 60/ / / major partial 20/ boost progressive disease NA / * CNS = central nervous system; MTX = methotrexate; KPS = Karnofsky Performance Scale; NA = not applicable, - = whole-brain radiation therapy (WBRT) not performed. For description of the responses, see Clinical Material and Methods section. t Whole-brain radiation therapy was deferred until time of recurrence. of ocular lymphoma. The responses were defined as follows: response, the disappearance of all contrast-enhancing abnormalities; major partial response (a category added in this study), a reduction of greater than 90% in the cross-sectional area; partial response, a greater than 50% decrease in the cross-sectional tumor area; progressive disease, a greater than 25% increase in the cross-sectional area of at least one lesion or the appearance of new lesions; and stable disease, all other conditions. Tumor recurrence was defined as the appearance of new or recurrent enhancing lesions, or of ocular or meningeal lymphoma. Recurrence was categorized as: local, if occurring at one or more original tumor sites; neuraxial, if intraparenchymal but at a new location; ocular; meningeal; or systemic. The persistence of nonenhancing hypodense areas on CT scans, hypointense signal on Tl-weighted MR images, or hyperintense signal on T:-weighted MR images in the setting of clinical stability or improvement was not considered to be active disease. Time to recurrence and survival time were measured from the date of diagnosis. Survival curves were drawn using the Kaplan-Meier product-limit methodj 9 Potential prognostic factors were evaluated by Cox proportional hazards analysis for both survival and time to recurrence. 9 Clinical Characteristics Results The clinical characteristics of Cases 1 through 1 were previously described t and are presented with those of Cases 14 through 25 in Table 1. The first patient in this study was treated in April, 198. During the study period (March, 1985, through May, 1990), 24 patients meeting the entry criteria were evaluated. Three refused participation, and a postsurgical brain abscess prevented enrollment of one patient; three of the four subsequently received WBRT, and whether the other underwent further therapy is unknown. Four patients (Cases 22-25) were enrolled after the trial closure date as they were deemed ineligible for another (current) trial because of prior chemotherapy, thirddegree bums, unclear diagnosis (later confirmed), and respiratory failure. There were 16 men and nine women, aged 27 to 80 years (median 61 years). Two patients had known predisposing factors for primary CNS lymphoma: one (Case 4) had received chronic corticosteroid therapy for systemic lupus erythematosus and the other (Case 22) had undergone radiotherapy for nasopharyngeal carcinoma 20 years previously, a short course of prednisone years earlier for Crohn's disease, and chemotherapy for ovarian carcinoma J. Neurosurg. / Volume 81 / August, 1994

4 Methotrexate in primary CNS lymphoma year previously (none of which was considered active at the time of diagnosis). Diagnosis was made by stereotactic or open brain in 20 patients and by CSF cytology in four. In the remaining patient (Case 5), diagnosis was based on a CSF cytology highly suggestive of lymphoma and the finding of periventricular enhancing mass lesions on a CT scan of the head. There were no surgical complications. Cerebrospinal fluid cytology was positive in four additional cases and suggestive (pleocytosis with atypical lymphocytes) in two. Ocular lymphoma was found in five cases. Response to Therapy Seventeen patients were evaluable for radiographic response to corticosteroids prior to chemotherapy. There were 1 with stable or progressive disease and four with partial responses; no patient responded ly (Table 1). None of the remaining eight patients had resolution of neurological deficits. Fourteen patients responded ly to chemotherapy, six achieved a major partial response, and two had partial responses (Table 2). Three patients had progressive disease during chemotherapy. Two patients proceeded to WBRT after one and two cycles, respectively, of methotrexate because of clinical progression. All others d three or more cycles; of these, 18 began WBRT (000 to 5000 cgy) within weeks of completion of chemotherapy. Ten of the 14 patients who achieved a response under,vent WBRT (000 cgy in eight, 700 cgy in one, 4140 cgy in one) immediately following chemotherapy (Table 2). All maintained responses. One patient (Case 1) received WBRT (000 cgy) at the time of recurrence, 2 months following methotrexate administration. Three with a response did not receive WBRT. All eight patients who achieved a partial response received WBRT (000 cgy in five, 060 cgy in two with a 240-cGy tumor boost in one, and 400 cgy in one). All but one of these patients had responses to WBRT. The patient with progressive disease after one cycle subsequently received 4400 cgy WBRT and responded ly. Of the 22 patients responding to therapy, the median initial KPS score was 60 (range 20 to 80) and the median KPS score at completion of chemotherapy was 90 (range 60 to 100) (Table 2). The mean increase in KPS score was approximately 0 points. Recurrence, Further Therapy, and Survival Twenty-two patients responding to chemotherapy were evaluable for recurrence (Table ). Recurrent disease developed in 1 patients at to 52 months (Fig. 1 left); median time to recurrence was 2 months. Local recurrences were seen in five patients, neuraxial in three, meningeal in one, both neuraxial and local in one, neuraxial and meningeal in two, and an unknown location in one. One patient who did not respond to methotrexate therapy achieved a response after WBRT lasting months. Two patients successfully received further therapy at the time of recurrence. One patient (Case 1), who Case No. l TABLE Recurrence data ]Or 25 patients with primary CNS lymphoma* Site of Recurrence neuraxial, meningeal 2 progressive local disease none 4 local, neuraxial 5 none 6 neuraxial 7 neuraxial 8 meningeal 9 unknown 10 none 11 local 12 none 1 local 14 none 15 local 16 none 17 progressive with neuraxial dissemination 18 local 19 local 20 none 21 neuraxial 22 neuraxial, meningeal 2 none 24 progressive local and neuraxial disease 25 none Comments treated with MTX only at onset; on recurrence, received WBRT followed by intrathecal MTX progressive disease with prolonged response to WBRT systemic lupus erythematosus as predisposing factor died with no evidence of active disease treated with intrathecal MTX at recurrence; died with necrotizing leukoenccphalopathy, no evidence of disease died due to recurrent disease, site unknown progression and dissemination of tumor despite chemotherapy and WBRT cognitive decline with apparent leukoencephalopathy 1 year following MTX and WBRT prior nasopharyngeal irradiation, corlicosteroid therapy for Crohn's disease, and chemotherapy for ovarian carcinoma extensive second- and third-degree burns at time of diagnosis initial nondiagncstic, repeat diagnostic; aspiration pneumonia and other medical problems; progression despite chemotherapy respiratory failure, with extensive disease * CNS = central nervous system; MTX = methotrexate; WBRT = whole-brain radiation therapy. had not undergone previous WBRT, received 000 cgy irradiation followed by intrathecal methotrexate administration. The other patient (Case 8) also underwent intrathecal methotrexate therapy. All 25 patients were evaluated for length of survival (Table 2). Median survival time was months in the entire population (Fig. 1 right) and 42.5 months in those responding to therapy. Sixteen patients have died, two with no evidence of disease. Of these two, one (Case 8) died 8 months following diagnosis with a necrotizing leukoencephalopathy but no evidence of J. Neurosurg. / Volume 81 / August,

5 J. Glass, et al. F~6. 1. Graphs showing time to recurrence for 22 evaluable patients (left) and survival times for all 25 patients (righo. Median time to recurrence is 2 months, and median survival time is months. FIG. 2. Graphs demonstrating time to recurrence (left) and survival time (righ 0 for all evaluable patients by age: less than 60 years (open squares) and 60 years or older (closed squares). An advantage for the younger age group is evident. meningeal or parenchymal disease on postmortem examination, and the other (Case 5) succumbed to bladder cancer 8 months after diagnosis. None of the following potential prognostic factors significantly affected time to recurrence or length of survival: patient age, sex, number of lesions, presence of ocular or meningeal disease, response to corticosteroids prior to chemotherapy, methotrexate treatment schedule (every 10 or 21 days), timing of leucovorin administration, or radiation dose (000 cgy vs. -> 4000 cgy). However, there appeared to be an advantage for age (Fig. 2) in both time to recurrence and length of survival. Toxici~es A total of 79 cycles of methotrexate were administered. There were three occurrences of mucositis, one of chest and back pain associated with dyspnea, nausea, and vomiting (occurring in the fifth and sixth cycles), two of deep vein thrombosis, and one each of pulmonary embolism, transient encephalopathy, isolated nau- sea, acute renal failure (rapidly reversed), and skin rash. Agranulocytosis and thrombocytopenia were seen in one patient in the setting of an ileus and presumed realabsorption of oral leucovorin. Late toxicities occurred in two patients. One patient, who received intrathecal methotrexate at recurrence, was found to have a necrotizing leukoencephalopathy at autopsy. Although we did not perform routine neuropsychological testing, one patient was noted to have a progressive cognitive decline 1 year following completion of therapy. Discussion Although WBRT provides responses in over 80% of primary CNS lymphoma patients, disease control is short-lived, with the majority surviving less than 1 year. 26 The combination of systemic methotrexate administration in moderately high doses and WBRT appears to prolong the duration of response and survival in patients with primary CNS lymphoma. Methotrex- 199 J. Neurosurg. / Volume 81 / August, 1994

6 Methotrexate in primary CNS lymphoma ate, an agent known to be active against lymphoma, was chosen for this study because of its relatively low CNS toxicity profile when administered prior to radiation therapy 1,1 and its ability to produce therapeutic CSF levels for 24 hours at the doses given. 5,H,1,2~ Whole-brain radiation therapy was provided following chemotherapy, as the efficacy of methotrexate therapy in resistant systemic lymphoma is only short-lived when given as monotherapy,4 and improves when administered in combination with other agents. 2'2 Our median response duration of 2 months and median length of survival of months is less than observed in prior studies, 1~ although well above that noted for WBRT alone?,12,16-18,2z25,26 The median survival time of 42.5 months in patients responding to chemotherapy parallels the longest published median survival times. 1~ This is of significance as it represents the first safe, noninvasive approach utilizing systemic chemotherapy prior to WBRT with such a survival advantage. Only a few large series of other neo-adjuvant chemotherapeutic approaches have been published. Chemotherapy for standard lymphoma (cyclophosphamide, hydroxydaunomycin/doxorubicin, vincristine (Oncovin), and prednisone (CHOP)) in -week cycles produced responses that were short-lived, with recurrence prior to radiation therapy] a while another chemotherapeutic protocol MACOP-B (methotrexate (400 mg/sq m), doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisolone, and bleomycin) given over 12 weeks appeared to have no effect on survival. 6 In one small study, the administration of lipophilic agents appeared to confer no advantage over WBRT alone. 4 Two additional studies showed prolonged survival with chemotherapy following WBRT: administration of PCV (procarbazine, CCNU (lomustine), and vincristine) 7,8 following WBRT produced a median survival time of 41 months but no long-term survivors; and VEPA (vincristine, cyclophosphamide (Endoxan), prednisolone, and doxorubicin (Adriamycin)) therapy 1 also produced prolonged durations of response. This suggests that systemic chemotherapy is able to remove areas of microscopic disease that may play a role in recurrence. The variability of the blood-brain barrier (BBB) within tumor masses, as well as the reported high incidence of distal recurrence and meningeal involvement at autopsy, has provoked some investigators to circumvent the BBB. One such method is the use of intraventricular methotrexate administration in combination with systemic chemotherapy. DeAngelis, et al., TM used combined systemic (1 gm/sq m) and intraventricular methotrexate therapy prior to WBRT, with two subsequent courses of high-dose cytosine arabinoside, producing a median time to recurrence of 41 months and a median survival time of 42.5 months, with minimal acute or long-term toxicities. The combination of intraventricular methotrexate and CHOP therapies has also produced long-term survival, with a concomitant high incidence of leukoencephalopathy. 21 Another method, BBB modification (with intraarterial mannitol) and methotrexate therapy combined with systemic cyclophosphamide (and procarbazine administered between treatments), has produced a median survival time of 44,5 months, with 41% maintaining responses without the need for "WBRT. 27 This regimen obligated the patient to two angiographic procedures under general anesthesia each month for 1 year, with a high incidence of acute toxicity. The patterns of recurrence noted in our study are similar to those noted in others. Previous investigations have shown that, although sites of recurrence tend to be local (at the site of original tumor or within the radiation field), z~-z5 distal recurrence (elsewhere within the CNS, ocular, meningeal, or systemic) may occur alone or in combination with local recurrence in the majority of patients. 17,24,~ It has been suggested that aggressive treatment of tile meninges is necessary because of the high incidence of meningeal involvement at autopsy. However, our data revealed meningeal recurrences in four patients, all with meningeal disease at diagnosis, suggesting that meningeal recurrence is only of concern in patients with such disease at onset. As with other chemotherapeutic regimens, 27 methotrexate administration offers little benefit to ocular lymphoma. The safety profile of this regimen appears to be more favorable than that of others. The only incidence of myelosuppression occurred when a patient received but did not absorb oral leucovorin. In 80 cycles, there were three instances of mucositis and one each of skin rash, encephalopathy, nausea, and nephrotoxicity, and an apparent allergic reaction. Pulmonary embolus in one patient and deep vein thrombosis in two others were likely not related to the methotrexate treatment. There was only one incidence of late cognitive decline, and the finding of necrotizing leukoencephalography at autopsy is likely attributable to the administration of intrathecal methotrexate at recurrence. Patient age was the only factor that appeared to affect duration of response or survival time, but was not statistically significant owing to the small numbers involved. Of interest is that the initial KPS score had no influence on response or survival times, and we were able to treat with no adverse events two respiratordependent patients with serious systemic infections. Response to corticosteroids is a critical factor. No assessable patient responded ly to corticosteroid therapy prior to initiation of chemotherapy. Effective cytoreduction of both macroscopic and microscopic tumor loci is likely responsible for the prolonged response durations and survival times. This is supported by the observation that, in patients treated with WBRT alone as initial therapy, response ( vs. partial) following WBRT influences prognosis, z6 There was no evidence, either clinical or radiographic, of responses to corticosteroids in any of our patients, suggesting that prolongations in response duration and survival were due to methotrexate therapy. About one-half of our patients were treated every weeks, and the remainder every 10 days. There was no difference in time to recurrence, survival, or toxicities in either schedule, suggesting that methotrexate need not be in- J. Neurosurg. / Volume 8t / August,

7 ,1. Glass, et al. tensively administered. The majority of patients rcceived 000 cgy of WBRT, a lower dose than in previous reports, without influencing outcome. A number of our patients had prolonged response durations without radiation therapy, and there are published examples of prolonged response durations without WBRT. 27 This suggests that, in selected cases, primary CNS lyrephoton may be managed with a minimal amount of, or even without, WBRT if preirradiation chemotherapy is given. Conclusions Preirradiation chemotherapy with methotrexate is effective in prolonging response duration and survival time in primary CNS lymphoma, especially in patients under 60 years of age, with an excellent safety profile. This suggests possible use in the growing immunocompromised population. Dose escalations of methotrexate with or without the addition of other BBB permeable agents active against lymphoma, such as cytosine arabinoside or cyclophosphamide, and with or without subsequent WBRT may improve overall outcome and will be the subject of future trials. References 1. Allen JC, Rosen G, Mehta BM, et al: Leukoencephalopathy following high-dose IV methotrexate chemotherapy with leucovorin rescue. Cancer Treat Rep 64: , Bernstein Jl, Coleman CN, Strickler JG: Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt's and non-burkitt's types). J Clin Oncol 4: , Berry MP, Simpson WJ: Radiation therapy in the management of primary malignant lymphoma of the brain. Inl J Radiat Oncol Biol Phys 7:55-59, Bessell EM, Punt J, Firth J, et al: Primary non-hodgkin's lymphoma of the central nervous system: Phase II study of chemotherapy (BVAM) prior to radiotherapy. Clin Oncol :19-198, Borsi JD, Moo PJ: A comparative study on the pharmacokinetics of methotrexate in a dose range of 0.5 g to.6 g/m 2 in children with acute lymphoblastic leukemia. Cancer 60:5-1, Brada M, Dearnaley D, Horwich A, et al: Management of primary cerebral lymphoma with initial chemotherapy: preliminary results and comparison with patients treated with radiotherapy alone. Int J Radiat Oncol Biol Phys 18: , Chamberlain MC, Levin VA: Adjuvant chemotherapy for primary lymphoma of the central nervous system. Arch Neurol 47: , Chamberlain MC, Levin VA: Primary central nervous system lymphoma: a role for adjuvant chemotherapy. J Neurooncol 14: , Cox DR: Regression models and life tables. J R Slat Soc (B) 4: , DeAngelis LM, Yahalom J, Thaler HT, etal: Combined modality therapy for primary CNS lymphoma. J Clin Oncol 10:65-64, Ervin T, Canellos GP: Successful treatment of recurrent primary central nervous system lymphoma with high-dose methotrexate. 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Pitman SW, Frei E III: Weekly methotrexate-calcium leu- 194 J. Neurosurg. / Volume 81 / August, 1994

8 Methotrexate in primary CNS lymphoma covorin rescue: effect of alkalinization of nephrotoxicity; pharmacokineties in the CNS; and use in CNS non-hodgkin's lymphoma. Cancer Treat Pep 61: , Pollack IF, Lunsford LD, Flickinger JC, et ai: Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 6:99-947, Shibamoto Y, Tsutsui K, Dodo Y, et al: Improved survival rate in primary intracranial lymphoma treated by highdose radiation and systemic vineristine-doxorubicincyclophosphamide-prednisolone chemotherapy. Cancer 65: , Skarin AT, Canellos GP, Rosenthal DS, et al: Improved prognosis of diffuse histiocytic and undifferentiated lymphomas by use of high dose methotrexate alternating with standard agents (M-BACOD). J Clin Oncol 1:91-98, 198. Skarin AT, Zuckerman KS, Pitman SW, et al: High-dose methotrexate with folinic acid in the treatment of advanced non-hodgkin lymphoma including CNS involvement. Blood 50: , Turman S, Coleman M, Silver RT, et al: High dose methotrexate with citrovorum factor in adult resistant lymphoma. Cancer 40: , 1977 Manuscript received June 8, Accepted in final form October 8, 199. Address for Dr. Gruber: Department of Neurosurgery, University of California, Los Angeles, California. Address for Drs. Cher and Hochberg: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Address reprint requests to: Jon Glass, M.D., Brain Tumor Center, Temple University Comprehensive Cancer Center, P.O. Box 846, 22 North Broad Street, Philadelphia, Pennsylvania J. Neurosurg. / Volume 81 / August,