Original Article Phase II trial of temozolomide plus concurrent whole‑brain radiation followed by TNV regimen as adjuvant therapy for patients with newly diagnosed primary CNS lymphoma

Yong Wang, Baoyan Liu1, Dezhi Xu, Haitao Zhao, Yufang Zhu, Jun Xu, Rongjie Tao

Department of Neurosurgery, Shandong Cancer Hospital, Jinan 250117, 1Department of Cardiology, Second Affliated Hospital, Shandong University of Traditional Chinese Medicine, Jinan 250000, China

Abstract

Background: Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non‑Hodgkin’s lymphoma limited to the CNS. Treatment of PCNSL with high‑dose methotrexate (HD‑MTX)‑based chemotherapy and whole‑brain radiotherapy (WBRT) is associated with high rates of relapse and severe treatment‑related neurotoxicity. Aim: To report our experience of treating newly diagnosed PCNSL with temozolomide, nedaplatin, and vincristine (TNV), as the replacement of HD‑MTX, in combination with concurrent chemoradiotherapy. Materials and Methods: Newly diagnosed PCNSL patients were given concurrent temozolomide (75 mg/m2, orally) daily during WBRT. Then, the TNV regimen was given after four weeks. The TNV regimen consisted of temozolomide (200 mg/m2 orally: Days 1-5), nedaplatin (80 mg/m2 intravenous: Day 1), and vincristine (1.4 mg/m2 intravenous: Day 1). Each cycle was of a duration of four weeks and a maximum of six cycles were applied. The primary end point was response to treatment obtained by magnetic resonance imaging (MRI). Secondary end points were progression‑free survival (PFS) Address for correspondence: and fewer toxic effects. Results: The study subjects included 14 patients (median age: Dr. Rongjie Tao, 53.5, median Karnofsky Performance Scale (KPS): 75). The median number of TNV Department of Neurosurgery, cycles given was five. Response to treatment: Complete response in 12 (85.7%) patients, Shandong Cancer Hospital, partial response in 2 (14.3%) patients, and none with progressive disease. The objective 440 Jiyan Road, Jinan - 250117, Shandong Pro. Peoples’ response rate was 100%, and median PFS was 21.4 months. Toxicity was relatively mild, Republic of China. which mainly included nausea in six and fatigue in five, grade 3-4 hematotoxicity in one, E‑mail: [email protected] and abnormal liver functions in five patients. No neurotoxicity has been observed till date. Received : 28‑01‑2013 Conclusion: The efficacy outcomes in this study are comparable to other reported Review completed : 07‑03‑2013 HD‑MTX‑based regimens plus WBRT, with an added favorable toxicity profile. Prospective, Accepted : 09‑06‑2013 randomized controlled trials are warranted to confirm such results.

Key words: Chemotherapy, primary central nervous system Access this article online lymphoma, radiotherapy, temozolomide Quick Response Code: Website: www.neurologyindia.com Introduction PMID: *** Primary central nervous system lymphoma (PCNSL) DOI: is an aggressive extranodal non‑Hodgkin’s lymphoma 10.4103/0028-3886.115065 (NHL) involving the brain, spinal cord, meninges, and

260 Neurology India | May-Jun 2013 | Vol 61 | Issue 3 Wang, et al.: Temozolomide combined with radiotherapy in newly diagnosed primary CNS lymphoma eyes, with few metastasis outside the CNS. The reported were given concurrent temozolomide (75 mg/m2 incidence is 3-4 cases per 100,000, and accounts for 4% orally) daily during radiotherapy until the end of of CNS malignancies and 1-2% of NHLs.[1] The incidence radiotherapy. Adjuvant chemotherapy was administered in immunocompetent individuals has increased by four weeks after radiotherapy. The regimen consisted more than 10‑fold in the past three decades, with an of temozolomide (200 mg/m2 orally: Days 1-5), annual current rate of 0.3 per 100,000 person‑years.[2] nedaplatin (80 mg/m2 intravenous: Day 1), and Approximately 90% of PCNSL are diffuse large B‑cell vincristine (1.4 mg/m2 intravenous: Day 1) (TNV lymphoma (DLBCL). Untreated patients survive only regimen). Each cycle was of a duration of four weeks for a few months. With the low incidence rate and lack and a maximum of six cycles were applied. Rapid of large‑scale clinical randomized controlled research infusion of 20% mannitol (1-2 g/kg) was given during data, the optimal therapy for PCNSL remains to be chemotherapy to help open the blood‑brain barrier. We defined. did not set a uniform salvage treatment because the end point of the study was progression‑free survival (PFS) The best reported outcomes in PCNSL treatment of the patient. are with high‑dose methotrexate (HD‑MTX)‑based chemotherapy combined with whole‑brain radiation Contrast MRI was performed to assess treatment therapy (WBRT). However, despite aggressive response at an interval of three months for two years and therapy, nearly 50% of the patients relapse within thereafter every six months for the next 3-5 years and 24 months of diagnosis. Furthermore, the application then annually. The treatment response was reassessed of the HD‑MTX‑based regimen is complex with severe according to the criteria of the International PCNSL treatment‑related toxicity.[3,4] In an attempt to improve Collaborative Group’.[5] Patients with CR or partial treatment outcomes and reduce treatment‑related response (PR) or stable disease (SD) were continued on side effects, we treated 14 PCNSL patients with the protocol. CSF examination for cell count, cytology, temozolomide concurrent chemoradiotherapy at the flow cytometry, and biochemistry was done at the time outset and then adjuvant chemotherapy for six cycles of each intrathecal treatment. Toxicity was graded with temozolomide, nedaplatin, and vincristine (TNV), according to the classification of the World Health as part of frontline therapy. In this paper, we discuss Organization (WHO). the outcomes with this treatment protocol in PCNSL patients. The study primary end point was response to treatment as assessed by MRI following concurrent Materials and Methods chemoradiotherapy and adjuvant chemotherapy. Secondary end points were PFS and fewer toxic effects. The criteria for enrollment included: Pathological PFS was defined as the time from initial diagnosis confirmation of DLBCL, extensive diagnostic workup until progression of disease. PFS and median PFS were to exclude systemic lymphoma,[5] and informed consent. analyzed using the Kaplan‑Meier product limit curve. Exclusion criteria included patients with seropositivity for the human immunodeficiency virus (HIV) and PCNSL. Results Pretreatment evaluation included contrast‑enhanced magnetic resonance imaging (MRI) of the brain and Fourteen patients (7 men and 7women) with a median total spine (if clinically indicated), slit lamp examination, age of 55 years (range: 33-68 years) were enrolled and electrocardiogram, and laboratory testing including from June 2007 to December 2011. Median Karnofsky serum lactate dehydrogenase, a complete blood count, Performance Scale (KPS) score was 75 (range: 60-90). creatinine clearance, and HIV testing. Cerebrospinal In all the patients, the histopathology diagnosis was fluid (CSF) examination was done for cell count, cytology, DLBCL. In eight patients, the lesions were multiple and flow cytometry, and biochemistry in patients with the number of lesions ranged from one to five with a suspected meningeal involvement. Clinical evaluation mean of 2 and the location of the lesions was cerebral included comprehensive neurologic evaluation, lymph hemispheric. Only three patients (33.3%) had recurrence node examination, and testicular examination in men. in situ and nearby. All the patients completed concurrent chemoradiotherapy. Two patients with positive CSF WBRT with megavoltage photon (6 MV) X‑ray was cytology received intrathecal chemotherapy with used once the diagnosis was established and was given cytarabine (50 mg twice a week) till the CSF cytology five times a week at 2 Gy/day until the WBRT dose was negative (8 times and 12 times, respectively). The reached 40 Gy. Local three‑dimensional conformal median number of adjuvant chemotherapy cycles was radiotherapy was considered when the tumor did five. All patients were followed up till October 2012, not get a complete response (CR) through a contrast and the median follow‑up was 32 months (range: enhanced MRI of the brain and spinal cord. Patients 7.2-52.5 months) [Tables 1 and 2].

Neurology India | May-Jun 2013 | Vol 61 | Issue 3 261 Wang, et al.: Temozolomide combined with radiotherapy in newly diagnosed primary CNS lymphoma

Overall response (CR and PR) was observed in all All the drug adverse side effects could be relieved the patients; 12 (85.7%) patients had CR, whereas with appropriate treatment. The other adverse two (14.3%) had achieved PR. The disease control events included fatigue (35.7%), abnormal liver rate [CR + PR + stable disease (SD)] was 100%. Of the function (35.7%), alopecia (35.7%), peripheral nerve 12 patients with CR, lesions relapsed in seven (58.3%) damage (21.4%), and constipation (57.1%). Although patients. The median progression‑free survival (PFS) was standardized neuropsychological evaluation has not 21 months (range: 2.9-42.5 + months, Figure 1). been performed, all patients have been followed by neurologists and no neurotoxicity has been observed Adverse events observed during chemotherapy are till date. summarized in Table 3. The most common adverse events were hematotoxicity (57.1%) and nausea (42.9%). Discussion

Table 1: Clinical characteristics and outcomes of the patients Previous studies have shown that the best outcomes are Characteristics/outcomes n % HD‑MTX‑based chemotherapy combined with WBRT Patients 14 100 in patients with PCNSL. However, HD‑MTX‑based Female 7 50 chemotherapy regimen is associated with high rates Male 7 50 of adverse drug events and toxicity mortality with Age (years) complex applications. Regimen without radiotherapy Median 53.5 [6] Range 33−68 is associated with decreased PFS. Although a KPS controversial issue, radiotherapy is an important ≥70 11 78.6 <70 3 21.4 Involvement Brain only 12 85.7 Brain and ocular 2 14.3 Number of brain tumors Single 6 42.9 Multiple 8 57.1 Site of relapse Situ and nearby 3 33.3 Ectopic 6 66.7 Cerebrospinal membrane 2 22.2 Extracranial metastasis 1 11.1 Intrathecal treatment 2 14.3 Responses to treatment CR 12 85.7 PR 2 14.3 ORR 14 100 PFS Median 21.4 Range 2.9−42.5+

KPS - Karnofsky performance scale, CR - Complete response, PR - Partial Figure 1: Kaplan‑Meier curve shows progression‑free survival in response, ORR - Objective response rate, PFS - Progression‑free survival 14 primary central nervous system lymphoma (PCNSL) patients

Table 2: Patient clinical and treatment data Case no. KPS Radiotherapy (cGy) Cycles (no) Best radiological response PFS (months) 1 60 WBRT 4000/20+boost 1000/5 1 PR after cycle 1 4.9 2 70 WBRT 4000/20+boost 800/4 0 PR after cycle 0 2.9 3 90 WBRT 4000/20+boost 1400/7 6 CR after cycle 2 42.5+ 4 60 WBRT 4000/20+boost 800/4 3 CR after cycle 3 21+ 5 80 WBRT 4000/20+boost 600/3 4 CR after cycle 2 32.8 6 90 WBRT 4000/20+boost 1000/5 4 CR after cycle 4 34.5+ 7 60 Craniospinal radiation 4000/20 6 CR after cycle 2 16.3 8 70 WBRT 4000/20+boost 1400/7 6 CR after cycle 3 12.6 9 70 WBRT 4000/20+boost 600/3 6 CR after cycle 2 21.7 10 80 WBRT 4000/20+boost 1400/7 6 CR after cycle 3 23.3 11 70 WBRT 4000/20 5 CR after cycle 2 14.1 12 80 WBRT 4000/20+boost 800/3 6 CR after cycle 4 24.5+ 13 80 WBRT 4000/20+boost 800/4 6 CR after cycle 3 12.6 14 90 WBRT 4000/20+boost 1400/7 6 CR after cycle 4 22.5+ WBRT - Whole‑brain radiotherapy, CR - Complete response, PR - Partial response , KPS - Karnofsky performance scale, PFS = Progression-free survival

262 Neurology India | May-Jun 2013 | Vol 61 | Issue 3 Wang, et al.: Temozolomide combined with radiotherapy in newly diagnosed primary CNS lymphoma component of various treatment regimens, therefore to alkylation of the MGMT gene promoter, whose establishing that more effective chemotherapy region is rich in guanine‑cytosine sequences with high regimens with a lower incidence of drug adverse cisplatin affinity.[12] Platinum drugs can inhibit MGMT events and long‑term remission are necessary.[7] In transcription and downregulate the expression of view of these limitations, we tried a new regimen, MGMT.[13] This is the basis for the synergistic effect of temozolomide‑based chemotherapy in combination temozolomide and platinum drugs. So, nedaplatin was with radiotherapy. added to our chemotherapy in an attempt to improve upon therapeutic efficacy. Temozolomide is an oral alkylating drug with a moderate toxicity profile and can penetrate the intact blood‑brain Nedaplatin (cis‑diammine‑glycoplatinum), a derivative barrier. It was initially developed with the intent to of cisplatin, was developed in 1983 by the Shionogi treat malignant melanoma brain metastases and has Pharmaceutical Company in Japan with the aim of also been shown to be effective in patients with PCNSL developing a drug with similar effectiveness as that relapse. In a phase II trial assessing the effectiveness of of cisplatin but with lesser renal and gastrointestinal temozolomide in recurrent PCNSL, of the 36 patients, toxicity.[14] The lower incidence of nephrotoxicity as nine patients had a CR and two had a PR.[8] Although compared to cisplatin is related to renal clearance. temozolomide is an active chemotherapeutic agent for Phase II studies conducted in Japan suggest that salvage therapynot all patients benefit and its efficacy nedaplatin has a favorable clinical efficacy. Moreover, is limited. as nedaplatin does not require adequate hydration, it can be given in an outpatient setting. On the basis of One of the mechanisms for resistance to temozolomide these advantages, nedaplatin has been used clinically is high intracellular levels of O6‑methylguanine‑DNA in this study as an alternative to cisplatin for patients methyltransferase (MGMT) involved in DNA repair with PCNSL.[15] The addition of platinum drugs to processes transferring an alkyl group from DNA temozolomide might overcome the in vivo resistance to to another cysteine residue. Therefore, cells with temozolomide with unmethylated MGMT promoter. increased concentrations of MGMT or with a deficiency in mismatch repair may develop resistance to This is the first report of the use of temozolomide‑based temozolomide.[9,10] In vitro studies have shown that chemotherapy combined with concurrent radiotherapy cisplatin reduces intracellular MGMT levels and this in newly diagnosed PCNSL. Our objective was to assess effect is dependent on the duration of exposure of the efficacy and toxicity of temozolomide‑based adjuvant the cells to the drug.[11] The effect seems to be due chemotherapy plus concurrent chemoradiotherapy in such patients. The outcomes of this study show that this treatment regimen is feasible and effective with Table 3: Toxicity data according to WHO classification in manageable side effects and no treatment‑related 14 patients mortality. The treatment response rate was 100% (12 CRs), Toxicity measure 0 (%) I (%) II (%) III (%) IV (%) median PFS was 21 months, similar to HD‑MTX‑based Anemia 11 (78.6) 2 (14.3) 1 (7.1) 0 None regimens in combination with WBRT [Table 4]. Leukopenia 6 (42.9) 4 (28.6) 3 (21.4) 1 (7.1) Thrombocytopenia 10 (71.4) 3 (21.4) 1 (7.1) 0 Furthermore, acute toxicity compares favorably to Fatigue 9 (64.3) 4 (28.6) 1 (7.1) 0 other regimens and no delayed neurotoxicity has been Nausea 8 (57.1) 5 (35.7) 1 (7.1) 0 documented till date. SGOT/SGPT 9 (64.3) 3 (21.4) 2 (14.3) 0 Alopecia 9 (64.3) 3 (21.4) 2 (14.3) 0 Peripheral nerve dysfunction 11 (78.6) 2 (14.3) 1 (7.1) 0 Conclusion Constipation 6 (42.9) 6 (42.9) 2 (14.3) 0 WHO - World Health Organization, SGOT - Serum glutamic oxaloacetic Outcomes in this study with temozolomide‑based transaminase, SGPT - Serum glutamic pyruvic transaminase chemoradiotherapy in newly diagnosed PCNSL

Table 4: Result of studies using MTX‑based protocols with radiation in PCNSL patients Reference No. of Median Radiation WBRT Chemotherapy PFS Toxicity patients age (boost) (months) Omuro[16] 17 53 41.1 Gy (14.4 Gy) MTX, Thio, Pro, Leu+IT 18 29% Grade 3, 4 myelosuppression, 29% neurotoxicity DeAngelis[17] 98 56.5 45 Gy MTX, Vin, Pro, Leu, Dex, Cyt 24 53% Grade 3, 4 myelosuppression, 15% neurotoxicity Thiel[18] 154 63 45 Gy MTX, ifosfamide 18 5% toxic deaths, 49% neurotoxicity O’Brien[19] 46 58 45 Gy MTX, IT 2 year 65% 2% toxic deaths, 13% neurotoxicity Korfel[20] 56 61 WBRT MTX, BCNU, Pro 10 11% toxic deaths, 18% neurotoxicity WBRT - Whole brain radiotherapy, PFS - Progression‑free survival, Thio - Thiotepa, Pro - Procarbazine, Leu - Leucovorin, IT - Intrathecal, Vin - Vincristine, Dex - Dexamethasone, Cyt - Cytarabine, BCNU - Bischloroethyl nitrosourea (carmustine), MTX - Methotrexate

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