Primary CNS lymphoma: Combined treatment with chemotherapy and radiotherapy L.M. DeAngelis, MD; J. Yahalom, MD; M-H. Heinemann, MD; C. Cirrincione, MS; H.T. Thaler, PhD; and G. Krol, MD
Article abstract-Primary central nervous system lymphoma (PCNSL), an uncommon tumor, is occurring with increasing frequency. Conventional therapy with corticosteroids and cranial radiotherapy (RT) usually gives a dramatic initial response, but median survival is only 10 to 18 months. Chemotherapy is more successful in comparable systemic lymphoma and has been employed for PCNSL at relapse, causing remission but not cure. Between June 1985 and June 1988, we prospectively staged 32 patients with PCNSL at Memorial Sloan-Kettering Cancer Center and treated 28 on a new protocol that combined chemotherapy and radiotherapy at diagnosis. None had occult systemic lymphoma, but 19% had ocular and 69% had definite or probable leptomeningeal lymphoma. There were no complications in 19 stereotactic biopsies, but 4/10 patients who had a complete resection suffered a severe postoperative deficit. Four patients received RT alone, and 28 received chemotherapy and cranial RT, 17 of whom (group A) received a combination regimen usingpre-RT systemic (1g/m2)and intra-Ommaya methotrexate (MTX), 4,000 cGy whole-brain RT with a 1,440 cGy boost, and 2 courses of post-RT high-dose cytosine arabinoside; 5 other patients received an identical regimen but with a decreased dose of MTX (200 mg/m2). Sixty-three percent of assessable patients had a response to MTX independent of corticosteroid and prior to RT. Eighteen of 26 (69%)assessablepatients who receivedcombined therapy are alive with a median follow-up of 25.4 months. Twelve of 16 (75%)assessable group A patients are alive in the same period. Chemotherapy-related toxicity was minimal, and no late toxicities have occurred to date. A vigorous multimodality approach to PCNSL was well tolerated, and survival is markedly improved over conventional therapy. NEUROLOGY 1990;4080-86
Primary central nervous system lymphoma (PCNSL) is a rare neoplasm, accounting for only 0.85 to 1.5% of intracranial Its prevalence in the immunocompromised and the AIDS population is well established; however, the incidence is increasing even among immunocompetent ~ a t i e n t sUnlike .~ brain tumors of glial origin, PCNSL is highly responsive to conventional treatment with whole-brain radiotherapy (WBRT) and corticosteroids, nevertheless, median survival is only 10 to 18 m o n t h ~ . ~ Chemotherapy v~-~~ at relapse, particularly high-dose rnethotrexate (MTX),causes remission but not cure.11J2There is suggestive evidence that chemotherapy in combination with cranial irradiation at the time of initial treatment is superior to RT alone.13-16In 1985 we began a multimodality approach using chemotherapy and RT as initial treatment for immunocompetent patients with PCNSL. Several early patients received modifications of what subsequently became our standard chemotherapeutic approach. Our results suggest that combined treatment with RT and chemotherapy is superior to conventional cranial RT alone. Methods. From June 1985 through June 1988, 32 patients were treated at Memorial Sloan-Kettering Cancer Center for
PCNSL. Pretreatment evaluation included a lumbar puncture, abdominal CT, bone marrow aspirate and biopsy, an ophthalmologic examination including slit lamp, and HIV-1 antibody titers in the majority of patients. At the time of diagnosis and at relapse, the extent of neurologic disease was assessed in the brain by CT or MRI, in the leptomeninges by lumbar puncture or sample from an Ommaya reservoir, and in the eyes by slit-lamp examination. Response to treatment was determined exclusively by CT or MRI to assess parenchymal brain disease, and was calculated using the greatest dimensions along 2 perpendicular axes of the enhancing component of the tumor. A subjective assessment was made by a neuroradiologist when comparable CT/ MRI sections were not available. All films were measured by a neuroradiologist blinded to the patient’s treatment. A complete response (CR) constituted the absence of tumor for a minimum of 4 weeks; partial response (PR) represented a 250% reduction in tumor size, minor response (MR) a 25 to 50% regression, stable disease (SD) no objective change, and progressive disease (PD)unequivocal increase in tumor size or the appearance of new lesions. CTs were obtained before administration of corticosteroids, before each step of chemotherapy and radiation, and after completion of all treatment. Response of leptomeningeal tumor was assessed by the CSF cytology and the patient’s clinical course, and ocular disease was followed by repeat ophthalmologic examination.
From the Departmentsof Neurology (Dr. DeAngelis), Radiation Oncology (Dr. Yahalom), and Medical Imaging (Dr. Krol), and the Divisions of Ophthalmology (Dr. Heinemann) and Biostatistics (C. Cirrincione and Dr. Thaler), Memorial Sloan-Kettering Cancer Center, New York, NY. Dr. DeAngelis is a recipient of an American Cancer Society Clinical Oncology Career Development Award.
Presented in part at the 40th annual meeting of the American Academy of Neurology, Cincinnati, OH, April 1988. Received April 21,1989. Accepted for publication in final form June 13,1989. Address correspondence and reprint requests to Dr. L.M. DeAngelis, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. 80 NEUROLOGY 40 January 1990
Diagnosis 1 Dexamethasone 16mg/day 1 Ommaya placement 1 IV MTX (1 gm/M2) Day 1,s Intra-Ommaya MTX (12 mgldose) Day 1,4,S,11,15,18 Taper dexamethasone (off by completlon of RT) 1 WBRT 200 cGyx20 (total 4000 cGy) Coned-down 180 cGyx8 (total 1440 cGy) 4 3 week rest 1 I V cytosine arablnoslde (3 gm/M2/dose) 1 doselday for 2 consecutive days 1 3 week rest 1
IV cytosine arablnoside (3 mg/MZ/dose) 1 doselday for 2 consecutive days
Figure 1. Treatment plan of PCNSL at diagnosis using chemotherapy and cranial radiotherapy.
The protocol (figure 1) begins with pre-RT systemic methotrexate (MTX), and is followed within 1 week by 4,000 cGy WBRT with a 1,440-cGyboost to the tumor bed. Completion of the RT is followed by a 3-week rest, and 2 courses of high-dosecytosinearabinoside (ara-C)are then administered, each course consisting of 2 doses of 3 g/m2intravenous ara-C infused over 3 hours. The doses were separated by 24 hours, and the courses were separated by 3 weeks. This plan of treatment was identical for all patients; however, the dose of pre-RT MTX differed for 2 groups of patients. Group A (17 patients) received 2 doses of 1g/m2intravenousMTX administered on a weekly basis. MTX was followed by leucovorin rescue, 10 mg orally q6h, for 72 hours beginning 24 hours after MTX infusion. Vigorous hydration was accompanied by alkalinization of the urine. Regardless of CSF cytology, all patients had placement of an Ommaya reservoir and received 6 doses of intra-Ommaya MTX (12 mg per dose); the intraOmmaya MTX began simultaneously with the 1st systemic dose of MTX, and was administered on a twice-weeklyschedule. All MTX therapy was completed prior to the start of cranial irradiation. Fifteen patients completed this treatment regimen; 2 died before treatment could be completed. Group B ( 5 patients) received a lower dose of systemic MTX (200 mg/ m2) on the same schedule as outlined above. Leucovorin, hydration,and sodium bicarbonate are not required for MTX
Article abstract-Primary central nervous system lymphoma (PCNSL), an uncommon tumor, is occurring with increasing frequency. Conventional therapy with corticosteroids and cranial radiotherapy (RT) usually gives a dramatic initial response, but median survival is only 10 to 18 months. Chemotherapy is more successful in comparable systemic lymphoma and has been employed for PCNSL at relapse, causing remission but not cure. Between June 1985 and June 1988, we prospectively staged 32 patients with PCNSL at Memorial Sloan-Kettering Cancer Center and treated 28 on a new protocol that combined chemotherapy and radiotherapy at diagnosis. None had occult systemic lymphoma, but 19% had ocular and 69% had definite or probable leptomeningeal lymphoma. There were no complications in 19 stereotactic biopsies, but 4/10 patients who had a complete resection suffered a severe postoperative deficit. Four patients received RT alone, and 28 received chemotherapy and cranial RT, 17 of whom (group A) received a combination regimen usingpre-RT systemic (1g/m2)and intra-Ommaya methotrexate (MTX), 4,000 cGy whole-brain RT with a 1,440 cGy boost, and 2 courses of post-RT high-dose cytosine arabinoside; 5 other patients received an identical regimen but with a decreased dose of MTX (200 mg/m2). Sixty-three percent of assessable patients had a response to MTX independent of corticosteroid and prior to RT. Eighteen of 26 (69%)assessablepatients who receivedcombined therapy are alive with a median follow-up of 25.4 months. Twelve of 16 (75%)assessable group A patients are alive in the same period. Chemotherapy-related toxicity was minimal, and no late toxicities have occurred to date. A vigorous multimodality approach to PCNSL was well tolerated, and survival is markedly improved over conventional therapy. NEUROLOGY 1990;4080-86
Primary central nervous system lymphoma (PCNSL) is a rare neoplasm, accounting for only 0.85 to 1.5% of intracranial Its prevalence in the immunocompromised and the AIDS population is well established; however, the incidence is increasing even among immunocompetent ~ a t i e n t sUnlike .~ brain tumors of glial origin, PCNSL is highly responsive to conventional treatment with whole-brain radiotherapy (WBRT) and corticosteroids, nevertheless, median survival is only 10 to 18 m o n t h ~ . ~ Chemotherapy v~-~~ at relapse, particularly high-dose rnethotrexate (MTX),causes remission but not cure.11J2There is suggestive evidence that chemotherapy in combination with cranial irradiation at the time of initial treatment is superior to RT alone.13-16In 1985 we began a multimodality approach using chemotherapy and RT as initial treatment for immunocompetent patients with PCNSL. Several early patients received modifications of what subsequently became our standard chemotherapeutic approach. Our results suggest that combined treatment with RT and chemotherapy is superior to conventional cranial RT alone. Methods. From June 1985 through June 1988, 32 patients were treated at Memorial Sloan-Kettering Cancer Center for
PCNSL. Pretreatment evaluation included a lumbar puncture, abdominal CT, bone marrow aspirate and biopsy, an ophthalmologic examination including slit lamp, and HIV-1 antibody titers in the majority of patients. At the time of diagnosis and at relapse, the extent of neurologic disease was assessed in the brain by CT or MRI, in the leptomeninges by lumbar puncture or sample from an Ommaya reservoir, and in the eyes by slit-lamp examination. Response to treatment was determined exclusively by CT or MRI to assess parenchymal brain disease, and was calculated using the greatest dimensions along 2 perpendicular axes of the enhancing component of the tumor. A subjective assessment was made by a neuroradiologist when comparable CT/ MRI sections were not available. All films were measured by a neuroradiologist blinded to the patient’s treatment. A complete response (CR) constituted the absence of tumor for a minimum of 4 weeks; partial response (PR) represented a 250% reduction in tumor size, minor response (MR) a 25 to 50% regression, stable disease (SD) no objective change, and progressive disease (PD)unequivocal increase in tumor size or the appearance of new lesions. CTs were obtained before administration of corticosteroids, before each step of chemotherapy and radiation, and after completion of all treatment. Response of leptomeningeal tumor was assessed by the CSF cytology and the patient’s clinical course, and ocular disease was followed by repeat ophthalmologic examination.
From the Departmentsof Neurology (Dr. DeAngelis), Radiation Oncology (Dr. Yahalom), and Medical Imaging (Dr. Krol), and the Divisions of Ophthalmology (Dr. Heinemann) and Biostatistics (C. Cirrincione and Dr. Thaler), Memorial Sloan-Kettering Cancer Center, New York, NY. Dr. DeAngelis is a recipient of an American Cancer Society Clinical Oncology Career Development Award.
Presented in part at the 40th annual meeting of the American Academy of Neurology, Cincinnati, OH, April 1988. Received April 21,1989. Accepted for publication in final form June 13,1989. Address correspondence and reprint requests to Dr. L.M. DeAngelis, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. 80 NEUROLOGY 40 January 1990
Diagnosis 1 Dexamethasone 16mg/day 1 Ommaya placement 1 IV MTX (1 gm/M2) Day 1,s Intra-Ommaya MTX (12 mgldose) Day 1,4,S,11,15,18 Taper dexamethasone (off by completlon of RT) 1 WBRT 200 cGyx20 (total 4000 cGy) Coned-down 180 cGyx8 (total 1440 cGy) 4 3 week rest 1 I V cytosine arablnoslde (3 gm/M2/dose) 1 doselday for 2 consecutive days 1 3 week rest 1
IV cytosine arablnoside (3 mg/MZ/dose) 1 doselday for 2 consecutive days
Figure 1. Treatment plan of PCNSL at diagnosis using chemotherapy and cranial radiotherapy.
The protocol (figure 1) begins with pre-RT systemic methotrexate (MTX), and is followed within 1 week by 4,000 cGy WBRT with a 1,440-cGyboost to the tumor bed. Completion of the RT is followed by a 3-week rest, and 2 courses of high-dosecytosinearabinoside (ara-C)are then administered, each course consisting of 2 doses of 3 g/m2intravenous ara-C infused over 3 hours. The doses were separated by 24 hours, and the courses were separated by 3 weeks. This plan of treatment was identical for all patients; however, the dose of pre-RT MTX differed for 2 groups of patients. Group A (17 patients) received 2 doses of 1g/m2intravenousMTX administered on a weekly basis. MTX was followed by leucovorin rescue, 10 mg orally q6h, for 72 hours beginning 24 hours after MTX infusion. Vigorous hydration was accompanied by alkalinization of the urine. Regardless of CSF cytology, all patients had placement of an Ommaya reservoir and received 6 doses of intra-Ommaya MTX (12 mg per dose); the intraOmmaya MTX began simultaneously with the 1st systemic dose of MTX, and was administered on a twice-weeklyschedule. All MTX therapy was completed prior to the start of cranial irradiation. Fifteen patients completed this treatment regimen; 2 died before treatment could be completed. Group B ( 5 patients) received a lower dose of systemic MTX (200 mg/ m2) on the same schedule as outlined above. Leucovorin, hydration,and sodium bicarbonate are not required for MTX
