Complete Response to Temozolomide Treatment in an Elderly Patient with Recurrent Primary Central Nervous System Lymphoma —Case Report—

Neurol Med Chir (Tokyo) 47, 229¿232, 2007

Complete Response to Temozolomide Treatment in an Elderly Patient With Recurrent Primary Central Nervous System Lymphoma —Case Report—

Keishi MAKINO,HideoNAKAMURA,MareinaKUDO,HideoTAKESHIMA, and Jun-ichi KURATSU

Department of Neurosurgery, Kumamoto University Graduate School, Kumamoto, Kumamoto

Abstract An 80-year-old woman presented with primary central nervous system (CNS) lymphoma manifesting as progressive disorientation and loss of activity. She received three cycles of high-dose methotrexate. The tumor shrank after two cycles and her mental status improved, but she suffered tumor recurrence. The second-line treatment consisted of four cycles of rituximab but the tumor enlarged. She was then treated with three cycles of temozolomide. Magnetic resonance imaging revealed no evidence of disease. Her mental status and performance status improved, and she suffered no toxicity. She is able to pursue her daily life without recurrence after 16 cycles of temozolomide. Temozolomide may be effective against relapsed primary CNS lymphoma without causing neurotoxicity in the elderly.

Key words: primary central nervous system lymphoma, temozolomide, elderly, recurrence, rituximab

Introduction pH without metabolic conversion. This metabolite depletes the deoxyribonucleic acid (DNA)-repair The introduction of high-dose methotrexate (MTX) enzyme O6 methylguanine-DNA methyltransferase treatment has resulted in markedly improved sur- in various cell types. Alkylating agents are generally vival of patients with primary central nervous sys- effective against non-Hodgkin's lymphoma, and tem (CNS) lymphoma.6,8,20) After treatment with temozolomide has good CNS penetration and a high-dose MTX, 50–65% of patients showed com- favorable toxicity profile.12,25) Therefore, temozolo- plete and 20–35% showed partial radiographic mide may be useful in the treatment of primary CNS response.2,5,10,17) However, 10–35% of patients have lymphoma. tumors which are refractory to the high-dose MTX We initially treated an 80-year-old woman with regimen and up to 60% of complete responders primary B-cell CNS lymphoma with high-dose MTX. manifest tumor recurrence during follow up.22,24) However, complete response was not obtained after Furthermore, over 90% of patients older than 60 three cycles. Her advanced age and compromised years who were successfully treated with a combina- mental status increased the risk of complications tion of chemotherapy and whole-brain radiotherapy from whole-brain irradiation after high-dose MTX, later developed treatment-related neurotoxicity so we administered three cycles of temozolomide as characterized by dementia, gait abnormalities, and a third-line therapy after four cycles of rituximab. urinary incontinence.1,2) Magnetic resonance (MR) imaging revealed no Temozolomide is an oral alkylating agent that evidence of disease. Her mental and performance spontaneously undergoes chemical conversion to status improved and there was no evidence of recur- the cytotoxic metabolite MTIC (5-(3 methyl-1-tri- rence 16 months after temozolomide therapy. azeno)immidazole-4-carboxamide) at physiological Case Report Received July 27, 2006; Accepted February 13, 2007 An 80-year-old woman had a 1-month history of

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Fig. 1 T1-weighted magnetic resonance images Fig. 3 T1-weighted magnetic resonance images with contrast medium showing a diffusely with contrast medium showing tumor enhanced lesion in the left temporal horn of shrinkage after two cycles of high-dose the lateral ventricle (B), septum pellucidum methotrexate therapy (A, B), and tumor (C), and periventricular area of the fourth enlargement after three cycles (C). ventricle (A).

Fig. 2 Photomicrographs showing neoplastic cells Fig. 4 T1-weighted magnetic resonance images in the perivascular area (A: hematoxylin with contrast medium after four cycles of and eosin stain, ×200) and positive im- rituximab showing tumor enlargement (A), munostaining for anti-CD20 antibody (B: × after three cycles of temozolomide showing 200). complete disappearance of the tumor (B), and after 13 cycles of temozolomide show- ing no signs of tumor recurrence (C). progressive mental deterioration and somnolence. MR imaging with contrast medium demonstrated enhanced lesions in the left temporal horn of the significantly (Fig. 3A, B). Her Karnofsky perfor- lateral ventricle, septum pellucidum, and periven- mance status score improved to 60 and Hasegawa tricular area of the fourth ventricle (Fig. 1). dementia scale to 17/30. However, MR imaging after On admission, her Karnofsky performance status the third cycle revealed that the tumor in the left score was 30, and her Hasegawa dementia scale was temporal lobe was enlarged (Fig. 3C). 4/30. She underwent diagnostic MR imaging-guided Since adjuvant whole-brain irradiation after high- biopsy. The histological diagnosis was B-cell lym- dose MTX can result in delayed neurotoxicity in the phoma (Fig. 2). Computed tomography of the chest, elderly, we administered four cycles of induction abdomen, and pelvis revealed no evidence of rituximab (375 mg/m2/weekfor4consecutive systemic lymphoma. She had a medical history of weeks). The infusion was started at 50 mg/hr and diabetes mellitus, hypertension, and hyper- gradually increased to 200 mg/hr. She showed no cholesteremia. Her renal function was adequate for signs of toxicity, new neurological deficits, or systemic chemotherapy with high-dose MTX (creati- mental deterioration. However, MR imaging after nine clearance 80 ml/min), so she received three completion of the fourth cycle revealed enlargement cycles of high-dose MTX (3.5 g/m2) consisting of a of the tumor in the left temporal lobe (Fig. 4A). 3-hour infusion on the 1st day of treatment and oral Therefore, a third line of treatment consisting of procarbazine (60 mg/m2) on days 1–7. Urine alkalini- three cycles of oral temozolomide (150 mg/m2/day zation was started with sodium bicarbonate before for 5 days) was implemented at intervals of 28 days. the start of MTX infusion, and citrovorum-factor Administration of temozolomide for patients with rescue was begun at 24 hours after. She manifested primary CNS lymphoma was approved by the no clinical signs of toxicity except for nausea and Institutional Review Board in our hospital. Minor appetite loss after each cycle. MR imaging after the responses were observed after the first and second second cycle revealed that the lesions had shrunk cycles of the treatment. The enhanced lesion disap-

Neurol Med Chir (Tokyo) 47, May, 2007 Temozolomide for Recurrent Primary CNS Lymphoma 231 peared completely after the third cycle (Fig. 4B). PCV regimen (procarbazine, lomustine, and vin- Temozolomide treatment was continued at the same cristine) which is effective against recurrent prima- dosage for a total of 16 cycles. There were no epi- ry CNS lymphoma.11) In addition, temozolomide is sodes of toxicity including leukopenia or throm- bioavailable to the CNS, as one-third of orally bocytopenia. She now requires only limited medical administered temozolomide was detected in the support in daily life with Karnofsky performance cerebrospinal fluid of patients with malignant brain status score of 40, and there has been no recurrence tumors.16) Temozolomide has been used successfully for more than 1 year (Fig. 4C). as first-line chemotherapy in two cases of primary CNS lymphoma,12,13) including a 72-year-old patient Discussion with impaired renal function.13) After two cycles of treatment, complete response was obtained. Elderly patients represent an important subgroup However, the patient developed pneumonia and that accounts for approximately half of all primary expired during treatment. The etiology of pneumo- CNS lymphoma cases, but only radiotherapy has nia was unclear. Moreover, temozolomide yielded produced disappointing results.19) High-dose MTX- objective responses as salvage therapy for patients based chemotherapy regimens combined with with primary CNS lymphoma.23) A 65-year-old whole-brain radiotherapy has achieved improved patient was initially treated with high-dose MTX- clinical outcomes, but as many as 80% of elderly based treatment.23) However, the treatment was ter- patients suffered delayed neurotoxicity.1) Therefore, minated because of renal toxicity and congestive high-dose MTX and procarbazine were selected as heart failure. The patient was referred to radiother- the initial treatment in the present patient. However, apy followed by four courses of chemotherapy. tumor enlargement was noted after the third cycle. Although complete response was achieved, recur- About half of immunocompetent patients with rence of the disease was found 3 months later. primary CNS lymphoma who achieve complete The patient was treated with four courses of recovery after primary treatment suffer relapse, and temozolomide. A complete response was achieved the disease is refractory in 10–15%.7,9) The prognosis after the second course without any grade 3–4 toxic- for both recurrent and progressive primary CNS ity. Temozolomide exhibits single-agent activity lymphoma is poor and most patients die within 2–4 against primary CNS lymphoma and even patients months of neurological deterioration.7,21) with treatment failure can tolerate temozolomide The present patient underwent further therapy without major toxicity.25) Twenty-three chemotherapy with rituximab and temozolomide. patients who failed to respond to treatment includ- Rituximab is a chimeric monoclonal antibody ing high-dose MTX and/or radiation therapy were against the CD20 antigen commonly found in B-cell enrolled.25) Median age was 60 years (range 18 to 75 non-Hodgkin's lymphoma. The mechanisms of years). There were five complete remissions and one action include complement-mediated cytotoxicity, partial response for an objective response rate of antibody-mediated phagocytosis, and antibody- 26%. There was no hematological grade 3–4 toxicity. dependent growth inhibition and apoptosis.15) One patient developed grade 3 vomiting. Grade 1–2 Rituximab is effective against relapsed B-cell non- toxicity mainly consisted of nausea (15%), vomiting Hodgkin's lymphoma,14,18) but the potential efficacy (6%), fatigue (9%), and neurological symptoms (9%). is limited by its high molecular weight, which pre- The present elderly woman with relapse of prima- vents transport across the intact blood-brain barrier. ry CNS lymphoma manifested complete radiograph- Rituximab may sensitize CD20-positive B lymphoma ic response to three cycles of oral temozolomide cells to cytotoxic chemotherapy by down-regulating chemotherapy without experiencing toxicity. 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Semin Oncol 29: 2–9, Address reprint requests to: Keishi Makino, M.D., 2002 Department of Neurosurgery, Kumamoto University 16) Marzolini C, Decosterd LA, Shen F, Gander M, Graduate School, 1–1–1 Honjo, Kumamoto 860–8556, Leyvraz S, Bauer J, Buclin T, Biollaz J, Lejeune F: Japan. Pharmacokinetics of temozolomide in association e-mail:kmakino＠fc.kuh.kumamoto-u.ac.jp

Neurol Med Chir (Tokyo) 47, May, 2007