High-dose methotrexate for non-aids primary central nervous system lymphoma

Transcription

1 J Neurosurg 70: , 1989 High-dose methotrexate for non-aids primary central nervous system lymphoma Report of 13 cases ALBERTO A. GABBAI, M.D., FRED H. HOCHBERG, M.D., RITA M. LINGGOOD, M.D., RIFAAT BASHIR, M.D., AND KATHLEEN HOTLEMAN, P.A.-C. Departments of Neurology and Radiation Medicine, Massachusetts General Hospital, Boston, Massachusetts, and Department of Neurology, Escola Paulista de Medicina, S~to Paulo, Brazil v" Thirteen patients with primary lymphoma of the central nervous system (CNS) were treated with highdose intravenous methotrexate (MTX), 3.5 gm/sq m, followed by calcium leucovorin rescue, at 3-week intervals, for three cycles. Eleven patients subsequently received radiation therapy to the whole brain, 30 to 44 Gy. Before radiation therapy, eight patients responded completely and four partially; there was one nonresponder. The median Karnofsky score before high-dose MTX therapy was 60 and increased to 90 after treatment. Five of the eight complete responders reached a Karnofsky rating of 100. The three longest responders (one of whom received MTX only) were without recurrence of their disease at 29+, 32, and 32+ months posttherapy. The median response period is 9+ months. The median survival time from the date of the first MTX treatment is 9+ months, and the three longest survival times are 29+, 32+, and 54+ months. All patients received corticosteroids in either unchanging or diminishing dosages during therapy. It is concluded that primary CNS lymphoma is sensitive to high-dose MTX, which provides a safe and easily administered adjuvant to radiation therapy for this neoplasm. KEY WORDS 9 brain neoplasm 9 lymphoma 9 methotrexate p RIMARY lymphoma of the central nervous system (CNS) was first described as perithelial sarcoma. 4 The tumor, also known as microglioma and reticulum cell sarcoma, 31"41 was recognized as being of B cell origin when studies were performed using immunohistochemical surface markers. 37 Although still rare, with an estimated annual incidence of 240 cases in the United States, 2~'3~ it has trebled in frequency over the last decade.~4 There is a limited life expectancy of patients with this aggressive tumor. Following operation alone patients survive for a median of only 1 month. 24 The addition of radiation therapy extends this to 15.6 months (range 5 days to 168 months). 2'~'8'~L~2' 17-2o.22.24, o The Radiation Therapy Ontology Group (RTOG) 25 reported that patients above the age of 60 years treated with brain irradiation only had a 7.5- month median survival while younger patients survived for a median of 35 months. The major sites of relapse are local, within the brain or with a neuraxis dissemination; systemic recurrences are found in 10% of patients.~4 Chemotherapy has been relegated to treatment of recurrence after failure of radiation therapy. Several considerations suggest a role for methotrexate (MTX) in the treatment of primary CNS lymphoma: 1) both intravenous and intrathecal MTX have been used with success in two patients with recurrent primary CNS lymphoma; 9A3 2) when used as a single agent in high doses, intravenous MTX is effective for resistant systemic lymphoma in adults although with a short response duration 36"38 (the duration of response increases dramatically when MTX is used as part of combined modality therapy~'35); 3) high-dose MTX and/or intrathecal MTX improves the CNS relapse-free survival rate in cases of systemic lymphoma; z7'39 4) high-dose MTX crosses the blood-brain barrier: when given in a 3- to 7.5-gm/sq m intravenous injection it produces a "therapeutic" cerebrospinal fluid (CSF) level (> 1 umop 5) for 24 hours, 28 and when given as 24-hour intravenous infusions of 500 to 1500 mg/sq m it provides ventricular levels just below the therapeutic concentration for 24 hours before falling exponentially afterwards, 1~ and 5) in the absence of cranial irradiation, MTX given at levels below 15 gm/sq m has been associated with leukoencephalopathy in only seven pa- 190 J. Neurosurg. / Volume 70/February, 1989

2 High-dose methotrexate for primary CNS lymphoma TABLE 1 Summary of clinical course in 13 patients in this series* No. Karnofsky Case No. Age (yrs), Tumor Location Histology MTX Infu- Score~" Pre- Post- CR PR NR XRT Response Survival Location of Time~ Time~t Recurrence Sex sions MTX MTX 1 27, F choroid plexus malignant iympho neuraxis cytes in CSF 2 66, F It frontal large cell I , M It parietal large cell , F rt frontal large cell , M hypothalamus atypical lympho cytes in CSF 6 7 l, F choroid plexus & eyes immunoblastic neuraxis large cell 7 69, M rt temporal & meninges large cell neuraxis 8 63, M periventricular & eyes large cell CSF 9 62, M rt parietal & eyes immunoblastic lost to large cell follow-up l0 38, F rt cerebellum, rt pons large cell , M rt parietal large cell , F It basal ganglion large cell , M rt frontal & eyes large cell * MTX = methotrexate; CR = complete response; PR = partial response; NR = no response; XRT = radiation therapy; CSF = cerebrospinal fluid. t Karnofsky score prior to irradiation. Time (months) after first MTX treatment. tients, 3 whereas a greater number of patients are at risk if the drug is provided after irradiation, which argues strongly for preirradiation drug administration. Highdose MTX therapy mandates calcium leucovorin rescue to prevent life-threatening toxicities. 7 Patient Population Clinical Material and Methods Thirteen consecutive patients (seven men and six women) aged 27 to 80 years (median 62 years) with primary CNS lymphoma received high-dose MTX between April,, and February, In all cases, MTX was given prior to irradiation. Eleven patients had biopsy-proven confirmation of tumor. One patient (Case 1, Table 1), had both a choroid plexus mass and malignant lymphocytes in the CSF. One patient (Case 5) received therapy following the demonstration of a hypothalamic mass on magnetic resonance (MR) imaging and "atypical" lymphocytes in the lumbar CSF. Based on the new working formulation classification of Jaffe,'6 nine patients had large-cell lymphomas and two had immunoblastic large-cell lymphomas. Radiographic presentation of the tumors was supratentorial in 12 patients, three of whom had involvement of the chorold plexus or ependyma. A pontocerebellar mass was seen in one patient. On slit-lamp ophthalmic examination, four patients had uveitis/vitreitis without retroorbital masses. None of the 13 patients had clinical evidence of systemic lymphoma (intraocular excluded) or of acquired, congenital, or drug-induced immunosup- pression. Routine computerized tomography (CT) scans of the chest and abdomen or bone marrow were not performed, so occult systemic disease cannot absolutely be excluded. Therapy All patients received intravenous high-dose MTX followed by calcium leucovorin rescue, at 3-week intervals. This was given prior to any radiation therapy. With the exception of a single nonresponder (Case 2) all patients received at least the planned course of three cycles (Table 1). Patients received corticosteroid in either unchanging or diminishing dosages during MTX therapy. Patients who had been complete responders to corticosteroids had clinical or CT evidence of recurrent disease prior to high-dose MTX administration. The other patients had either been weaned from steroids or had recurrent disease with increasing steroid dosage. The maximum steroid dose for any patient entering this study was 16 mg of dexamethasone per day. Methotrexate therapy consisted of a 4-hour infusion of MTX 3.5 gm/sq m in 400 ml of 5% dextrose. The MTX dose was reduced in one patient with altered creatinine clearance (Case 11). Chemotherapy followed oral or parenteral alkalinized hydration to establish a urinary output greater than 100 ml/hr and a urinary ph greater than 7.0. In patients with intracranial hypertension, mannitol (10 gm/hr) was used to establish osmotic diuresis. Rescue with calcium leucovorin (25 mg by intramuscular injection) was begun 4 hours after termination of the MTX infusion and was continued orally every 6 hours for 12 doses or until the plasma J. Neurosurg. / Volume 70/February,

3 A. A. Gabbai, et al. MTX levels were below 10 -s M. Radiation therapy was given to 11 patients starting 3 weeks after the last MTX infusion. The total dose of radiation to the whole brain was 30 Gy in 10 patients and 44 Gy in one patient (Case 13) who was treated elsewhere. Two patients (Cases 4 and 5) were complete responders to chemotherapy and refused to have radiation therapy. Evaluation of disease response was based on changes in CT scans and the Karnofsky performance scale 23 with patients receiving isodose or diminished steroids. Complete response was defined as clinical improvement (Karnofsky scale score _ 80) with complete disappearance of lesion(s) and of abnormalities on contrastenhanced CT. The CT scans were obtained every 3 weeks during chemotherapy, every month thereafter for 1 year, then every 4 to 6 months during the 2nd to 4th years after treatment. Partial response included an improved Karnofsky score (< 80) with stable or diminished CT abnormality. Nonresponse was indicated in cases of clinical deterioration or any increase in steroid requirement with stable or enlarged CT abnormality. The duration of response was measured from the first dose of MTX, which was instituted in all patients within 6 weeks of diagnosis. Survival was measured from the first dose of MTX until death. Tumor recurrence was defined as: 1) clinical deterioration upon tapering of steroids; 2) reappearance of enhanced CT lesion at isodose or diminished steroids; or 3) new appearance or persistence of "atypical" or malignant lymphocytes in the CSF, irrespective of the clinical or CT status. Patients with meningeal or ventricular presentation underwent lumbar CSF examination following each MTX therapy. Methotrexate leukoencephalopathy was defined as neurological deterioration without evidence of recurrent expanding tumor, hydrocephalus, or meningeal seeding as revealed by contrast-enhanced CT scanning and CSF examinations. Careful attention was paid to facial, oropharyngeal, or peripheral myoclonus and intellectual deterioration as well as white matter involvement shown by either CT or MR imaging. Results The 13 patients in this series were followed for a median of 9+ months. Eight patients were complete responders to high-dose MTX prior to irradiation; following radiation therapy they remained complete responders for a median time of 14 months. There were four partial responders to high-dose MTX; these remained disease-free for 2, 4+, 5+, and 6+ months. There was one nonresponder (Case 2); she received one cycle of high-dose MTX, following which increased dysphasia and steroid requirement necessitated the institution of radiation therapy. She is still alive 17 months after the initial chemotherapy. The complete and partial responders showed improved Karnofsky scores. The median Karnofsky rating for all 13 patients was 60 before administration of MTX and increased to 90 after the treatment. The median survival time in the present series is 9+ months. The three longest survival times are 29+, 32+, and 54+ months; one of these patients (Case 4) received MTX only. Eye involvement was present in four patients, and did not respond to MTX or to whole-brain radiation therapy; three patients responded partially to irradiation directed to the eyes, and one patient (Case 6) had no treatment of her vitreitis. Treatment toxicities were minimal and included nausea, confusion, mucositis, and skin rash (one occurrence each in 38 MTX treatment cycles). One patient (Case 8) died without any evidence of primary CNS lymphoma (either parenchymatous or meningeal) after 20 intrathecal MTX injections (total 300 mg MTX in 2.5 months) for recurrent disease. The autopsy revealed necrotizing leukoencephalopathy in the brain and spinal cord. One patient (Case 5), who was originally in coma, had impaired memory after therapy. Another patient (Case 11) required therapy for severe depression but was otherwise without symptoms; this patient also had hematocrit reduction from 30% to 19% as well as elevated serum creatinine to 3.4 rag% during MTX treatment. Three patients (Cases 1, 6, and 8) who were originally complete responders and one (Case 7) who was a partial responder had recurrence of their disease at 32, 4, 3, and 2 months, respectively, after high-dose MTX. Three tumors recurred in the neuraxis at the site of the presenting neoplasm and one recurred in the CSF. These patients were treated with new courses of MTX intravenously in Case 6, intrathecally in Cases 7 and 8, and by both routes in Case 1, and responded well for 5+, 7+, 5, and 22+ months, respectively. One patient (Case 9) is lost to follow-up review. Discussion Primary CNS lymphoma is sensitive to high-dose MTX. The majority of the 13 patients in this series responded well to the drug, eight were complete responders before radiation therapy, and all responded with improvement to a Karnofsky performance scale score of at least 80 (five improved to a score of 100). Four patients with recurrent disease responded to new courses of MTX, administered either intravenously, intrathecally, or by both routes, and three are in remission at the present time. Toxicities from highdose MTX were minimal. White matter abnormalities were seen in only one patient who had received 15 gm of MTX by vein, 15 mg by lumbar injection, and 285 mg by ventricular injection. Although over time these changes may become more evident, our use of highdose MTX prior to radiation therapy appears to be less toxic for cranial and spinal white matter. High-dose MTX provides a safe, easily administered adjuvant to radiation therapy for primary CNS lymphoma. The common multifocal manifestation of this disease precludes surgical extirpation. High-dose MTX crosses the blood-brain barrier and provides "therapeutic" CSF (micromolar) levels for 24 hours when given 192 J. Neurosurg. / Volume 70~February, 1989

4 High-dose methotrexate for primary CNS lymphorna by intravenous injection at 3 to 7.5 gm/sq m. 2s The same results were achieved in nine instances in this series, when the MTX was measured in the lumbar CSF after intravenous infusions. Lumbar CSF levels in four patients, measured 24 hours after intravenous MTX, were in the 10-6 M range. Those fell to 10-7 M after 48 hours and to 10-8 M after 72 hours. Radiation therapy for primary CNS lymphoma clearly improves survival times beyond the median of 4 months expected following surgery, but it is clearly not curative. Following whole-brain irradiation (20 to 80 Gy), the average median survival time reported in the literature is 15.6 months (range 5 days to 168 months) with an average 1-year survival rate of 55% (range 0% to 100%) and 2-year survival rate of 32% (range 0% to 66~o). 2"6"8"11"12"17-20"22"24"29"32'40 The recent RTOG study 25 reported 45 patients who received cranial irradiation only; these patients experienced an overall median survival time of 11.6 months with an estimated l-year survival rate of 49% and 2-year survival rate of 35%. Common sites of tumor recurrence following irradiation are localized to the brain parenchyma and subarachnoid space, ~4 raising the possibility that multifractionation and spinal irradiation may be of value. Very few patients have received drug therapy for primary CNS lymphoma. Between 1976 and 1986, 37 patients with recurrent lymphoma received, alone or in combination: MTX; cytosine arabinoside (AraC); 1,3-bis(2-chloroethyl)- 1 nitrosourea (BCNU); (1-4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)- 3-nitrosourea (ACNU); l-(2-chloroethyl)-3-cyclohexyl- 1-nitrosourea (CCNU, Lomustine); CHOP (cyclophosphamide, hydroxydaunomycin/doxorubicin, Oncovin (vincristine), prednisone); BCOP (BCNU, cyclophosphamide, Oncovin, and prednisone); VENP (vincrisfine, Endoxan (cyclophosphamide), Natulan (matulan procarbazine), and prednisone); dacarbazide (DTIC- Dome); or procarbazine. ~'s'9"~,. ~ 3. ~ , In those patients, the median survival time after diagnosis was 13 months (range 2 to 48 months) with a 1-year survival rate of 68% and a 2-year survival rate of 27%. Methotrexate has been used intravenously or intrathecally as the sole chemotherapeutic agent for primary CNS lymphoma in five patients in the literature, in all cases following radiation therapy. ~'9"13"24 All of these patients responded well to the drug, with a median survival time of 19 months after diagnosis (range 13 to 48 months), a 1-year survival rate of 100%, and a 2- year survival rate of 40%. After the relative success and minimal toxicity of our present approach to primary lymphoma of the CNS we have decided, in order to try to increase our efficacy, to shorten the interval between the MTX courses to 10 days and to prolong the time before calcium leucovorin rescue to 24 hours. References 1. Abelson HT, Kufe DW, Skarin AT, et al: Treatment of central nervous system tumors with methotrexate. Cancer Treat Rep 65 (Suppl 1): , Alic L, Haid M: Primary lymphoma of the brain: a case report and review of the literature. 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5 A. A. Gabbai, et al. phoma of the central nervous system. Computerized tomography scan characteristics and treatment results for 12 cases. Cancer 52: , 23. Mor V, Laliberte L, Morris JN, et al: The Karnofsky performance status scale. An examination of its reliability and validity in a research setting. Cancer 53: , Murray K, Kun L, Cox J: Primary malignant lymphoma of the central nervous system. Results of treatment of 11 cases and review of the literature. J Neurosurg 65: , Nelson DF, Martz KL, Newall J, et al: Definitive radiation therapy in the treatment of primary non-hodgkin's lymphoma of the central nervous system (CNS): preliminary report of RTOG Study Proc Am Sue Clin Oncol 7:82, 1988 (Abstract) 26. Neuwelt EA, Balaban E, Diehl J, et al: Successful treatment of primary central nervous system lymphomas with chemotherapy after osmotic blood-brain barrier opening. Neurosurgery 12: , 27. Perez-Soler R, Smith TL, Cabanillas F: Central nervous system prophylaxis with combined intravenous and intrathecal methotrexate in diffuse lymphoma of aggressive histological type. Cancer 57: , Pitman SW, Frei E III: Weekly methotrexate-calcium leucovorin rescue; effect of alkalinization on nephrotoxicity; pharmacokinetics in the CNS; and use in CNS non- Hodgkin's lymphoma. Cancer Treat Rep 61: , Rampen FHJ, van Ander JG, Sizoo W, et al: Radiation therapy in primary non-hodgkin's lymphomas of the CNS. Eur J Cancer 16: , Rosenblum ML, Levy RM, Bredesen DE: Overview of AIDS and the nervous system, in Rosenblum ML, Levy RM, Bredesen DE (eds): AIDS and the Nervous System. New York: Raven Press, 1988, pp Russell DS, Marshal AHE, Smith FB: Microgliomatosis. A form of reticulosis affecting the brain. Brain 71:1-15, Sagerman RH, Collier CH, King GA: Radiation therapy of microgliomas. Radiology 149: , 33. Shapiro WR, Young DF, Mehta BM: Methotrexate: distribution in cerebrospinal fluid after intravenous ventricular and lumbar injections. N Engl J Med 293: , Silverberg E, Lubera JA: A review of American Cancer Society estimates of cancer cases and deaths. CA 33:2-8, 35. Skarin AT, Canellos GP, Rosenthal DS, et al: Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M-BACOD). J Clin Oneul 1:91-98, 36. 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: , Tanaka T, Nishimoto A, Doi A, et al: Primary intracranial malignant lymphomas with particular reference to their pathogenesis. Acta Pathol Jpn 27: , Turman S, Coleman M, Silver RT, et al: High dose methotrexate with citrovorum factor in adult resistant lymphoma. Cancer 40: , Voakes JB, Jones SE, McKelvey EM: The chemotherapy of lymphoblastic lymphoma. Blood 57: , Yasunaga T, Takahashi M, Uozomi H, et al: Radiation therapy of primary malignant lymphoma of the brain. Acta Radiol [Oncoll 25:23-28, Yuile CL: Case of primary reticulum cell sarcoma of the brain. Relationship of microglia cells to histiocytes. Arch Pathol 26: , 1938 Manuscript received April 21, This work was supported by the Narragansett Foundation, the Anne Blittner Fund, and the National Council for Scientific and Technological Development (CNPq), Brazil. This paper was presented in part at the Annual Meeting of the American Academy of Neurology, Cincinnati, Ohio, April 17-23, Address reprint requests to: Fred H. Hochberg, M.D., Neurology Service, Cox One, Massachusetts General Hospital, Boston, Massachusetts J. Neurosurg. / Volume 70/February, 1989