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|Year : 2013 | Volume
| Issue : 3 | Page : 260-264
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 Wang1, Baoyan Liu2, Dezhi Xu1, Haitao Zhao1, Yufang Zhu1, Jun Xu1, Rongjie Tao1
1 Department of Neurosurgery, Shandong Cancer Hospital, Jinan 250117, China
2 Department of Cardiology, Second Affliated Hospital, Shandong University of Traditional Chinese Medicine, Jinan 250000, China
|Date of Submission||28-Jan-2013|
|Date of Decision||07-Mar-2013|
|Date of Acceptance||09-Jun-2013|
|Date of Web Publication||16-Jul-2013|
Department of Neurosurgery, Shandong Cancer Hospital, 440 Jiyan Road, Jinan - 250117, Shandong Pro.
Source of Support: None, Conflict of Interest: None
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/m 2 , orally) daily during WBRT. Then, the TNV regimen was given after four weeks. The TNV regimen consisted of temozolomide (200 mg/m 2 orally: Days 1-5), nedaplatin (80 mg/m 2 intravenous: Day 1), and vincristine (1.4 mg/m 2 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) and fewer toxic effects. Results: The study subjects included 14 patients (median age: 53.5, median Karnofsky Performance Scale (KPS): 75). The median number of TNV cycles given was five. Response to treatment: Complete response in 12 (85.7%) patients, partial response in 2 (14.3%) patients, and none with progressive disease. The objective response rate was 100%, and median PFS was 21.4 months. Toxicity was relatively mild, which mainly included nausea in six and fatigue in five, grade 3-4 hematotoxicity in one, and abnormal liver functions in five patients. No neurotoxicity has been observed till date. Conclusion: The efficacy outcomes in this study are comparable to other reported HD-MTX-based regimens plus WBRT, with an added favorable toxicity profile. Prospective, randomized controlled trials are warranted to confirm such results.
Keywords: Chemotherapy, primary central nervous system lymphoma, radiotherapy, temozolomide
|How to cite this article:|
Wang Y, Liu B, Xu D, Zhao H, Zhu Y, Xu J, Tao R. 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. Neurol India 2013;61:260-4
|How to cite this URL:|
Wang Y, Liu B, Xu D, Zhao H, Zhu Y, Xu J, Tao R. 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. Neurol India [serial online] 2013 [cited 2019 Dec 8];61:260-4. Available from: http://www.neurologyindia.com/text.asp?2013/61/3/260/115065
| » Introduction|| |
Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin's lymphoma (NHL) involving the brain, spinal cord, meninges, and eyes, with few metastasis outside the CNS. The reported incidence is 3-4 cases per 100,000, and accounts for 4% of CNS malignancies and 1-2% of NHLs.  The incidence in immunocompetent individuals has increased by more than 10-fold in the past three decades, with an annual current rate of 0.3 per 100,000 person-years.  Approximately 90% of PCNSL are diffuse large B-cell lymphoma (DLBCL). Untreated patients survive only for a few months. With the low incidence rate and lack of large-scale clinical randomized controlled research data, the optimal therapy for PCNSL remains to be defined.
The best reported outcomes in PCNSL treatment are with high-dose methotrexate (HD-MTX)-based chemotherapy combined with whole-brain radiation therapy (WBRT). However, despite aggressive therapy, nearly 50% of the patients relapse within 24 months of diagnosis. Furthermore, the application of the HD-MTX-based regimen is complex with severe treatment-related toxicity. , In an attempt to improve treatment outcomes and reduce treatment-related side effects, we treated 14 PCNSL patients with temozolomide concurrent chemoradiotherapy at the outset and then adjuvant chemotherapy for six cycles with temozolomide, nedaplatin, and vincristine (TNV), as part of frontline therapy. In this paper, we discuss the outcomes with this treatment protocol in PCNSL patients.
| » Materials and Methods|| |
The criteria for enrollment included: Pathological confirmation of DLBCL, extensive diagnostic workup to exclude systemic lymphoma,  and informed consent. Exclusion criteria included patients with seropositivity for the human immunodeficiency virus (HIV) and PCNSL. Pretreatment evaluation included contrast-enhanced magnetic resonance imaging (MRI) of the brain and total spine (if clinically indicated), slit lamp examination, and electrocardiogram, and laboratory testing including serum lactate dehydrogenase, a complete blood count, creatinine clearance, and HIV testing. Cerebrospinal fluid (CSF) examination was done for cell count, cytology, flow cytometry, and biochemistry in patients with suspected meningeal involvement. Clinical evaluation included comprehensive neurologic evaluation, lymph node examination, and testicular examination in men.
WBRT with megavoltage photon (6 MV) X-ray was used once the diagnosis was established and was given five times a week at 2 Gy/day until the WBRT dose reached 40 Gy. Local three-dimensional conformal radiotherapy was considered when the tumor did not get a complete response (CR) through a contrast enhanced MRI of the brain and spinal cord. Patients were given concurrent temozolomide (75 mg/m 2 orally) daily during radiotherapy until the end of radiotherapy. Adjuvant chemotherapy was administered four weeks after radiotherapy. The regimen consisted of temozolomide (200 mg/m 2 orally: Days 1-5), nedaplatin (80 mg/m 2 intravenous: Day 1), and vincristine (1.4 mg/m 2 intravenous: Day 1) (TNV regimen). Each cycle was of a duration of four weeks and a maximum of six cycles were applied. Rapid infusion of 20% mannitol (1-2 g/kg) was given during chemotherapy to help open the blood-brain barrier. We did not set a uniform salvage treatment because the end point of the study was progression-free survival (PFS) of the patient.
Contrast MRI was performed to assess treatment response at an interval of three months for two years and thereafter every six months for the next 3-5 years and then annually. The treatment response was reassessed according to the criteria of the International PCNSL Collaborative Group'.  Patients with CR or partial response (PR) or stable disease (SD) were continued on the protocol. CSF examination for cell count, cytology, flow cytometry, and biochemistry was done at the time of each intrathecal treatment. Toxicity was graded according to the classification of the World Health Organization (WHO).
The study primary end point was response to treatment as assessed by MRI following concurrent chemoradiotherapy and adjuvant chemotherapy. Secondary end points were PFS and fewer toxic effects. PFS was defined as the time from initial diagnosis until progression of disease. PFS and median PFS were analyzed using the Kaplan-Meier product limit curve.
| » Results|| |
Fourteen patients (7 men and 7women) with a median age of 55 years (range: 33-68 years) were enrolled from June 2007 to December 2011. Median Karnofsky Performance Scale (KPS) score was 75 (range: 60-90). In all the patients, the histopathology diagnosis was DLBCL. In eight patients, the lesions were multiple and the number of lesions ranged from one to five with a mean of 2 and the location of the lesions was cerebral hemispheric. Only three patients (33.3%) had recurrence in situ and nearby. All the patients completed concurrent chemoradiotherapy. Two patients with positive CSF cytology received intrathecal chemotherapy with cytarabine (50 mg twice a week) till the CSF cytology was negative (8 times and 12 times, respectively). The median number of adjuvant chemotherapy cycles was five. All patients were followed up till October 2012, and the median follow-up was 32 months (range: 7.2-52.5 months) [Table 1] and [Table 2].
Overall response (CR and PR) was observed in all the patients; 12 (85.7%) patients had CR, whereas two (14.3%) had achieved PR. The disease control rate [CR + PR + stable disease (SD)] was 100%. Of the 12 patients with CR, lesions relapsed in seven (58.3%) patients. The median progression-free survival (PFS) was 21 months (range: 2.9-42.5 + months, [Figure 1]).
|Figure 1: Kaplan‑Meier curve shows progression‑free survival in 14 primary central nervous system lymphoma (PCNSL) patients|
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Adverse events observed during chemotherapy are summarized in [Table 3]. The most common adverse events were hematotoxicity (57.1%) and nausea (42.9%). All the drug adverse side effects could be relieved with appropriate treatment. The other adverse events included fatigue (35.7%), abnormal liver function (35.7%), alopecia (35.7%), peripheral nerve damage (21.4%), and constipation (57.1%). Although standardized neuropsychological evaluation has not been performed, all patients have been followed by neurologists and no neurotoxicity has been observed till date.
| » Discussion|| |
Previous studies have shown that the best outcomes are HD-MTX-based chemotherapy combined with WBRT in patients with PCNSL. However, HD-MTX-based chemotherapy regimen is associated with high rates of adverse drug events and toxicity mortality with complex applications. Regimen without radiotherapy is associated with decreased PFS.  Although a controversial issue, radiotherapy is an important component of various treatment regimens, therefore establishing that more effective chemotherapy regimens with a lower incidence of drug adverse events and long-term remission are necessary.  In view of these limitations, we tried a new regimen, temozolomide-based chemotherapy in combination with radiotherapy.
Temozolomide is an oral alkylating drug with a moderate toxicity profile and can penetrate the intact blood-brain barrier. It was initially developed with the intent to treat malignant melanoma brain metastases and has also been shown to be effective in patients with PCNSL relapse. In a phase II trial assessing the effectiveness of temozolomide in recurrent PCNSL, of the 36 patients, nine patients had a CR and two had a PR.  Although temozolomide is an active chemotherapeutic agent for salvage therapynot all patients benefit and its efficacy is limited.
One of the mechanisms for resistance to temozolomide is high intracellular levels of O 6 -methylguanine-DNA methyltransferase (MGMT) involved in DNA repair processes transferring an alkyl group from DNA to another cysteine residue. Therefore, cells with increased concentrations of MGMT or with a deficiency in mismatch repair may develop resistance to temozolomide. , In vitro studies have shown that cisplatin reduces intracellular MGMT levels and this effect is dependent on the duration of exposure of the cells to the drug.  The effect seems to be due to alkylation of the MGMT gene promoter, whose region is rich in guanine-cytosine sequences with high cisplatin affinity.  Platinum drugs can inhibit MGMT transcription and downregulate the expression of MGMT.  This is the basis for the synergistic effect of temozolomide and platinum drugs. So, nedaplatin was added to our chemotherapy in an attempt to improve upon therapeutic efficacy.
Nedaplatin (cis-diammine-glycoplatinum), a derivative of cisplatin, was developed in 1983 by the Shionogi Pharmaceutical Company in Japan with the aim of developing a drug with similar effectiveness as that of cisplatin but with lesser renal and gastrointestinal toxicity.  The lower incidence of nephrotoxicity as compared to cisplatin is related to renal clearance. Phase II studies conducted in Japan suggest that nedaplatin has a favorable clinical efficacy. Moreover, as nedaplatin does not require adequate hydration, it can be given in an outpatient setting. On the basis of these advantages, nedaplatin has been used clinically in this study as an alternative to cisplatin for patients with PCNSL.  The addition of platinum drugs to temozolomide might overcome the in vivo resistance to temozolomide with unmethylated MGMT promoter.
This is the first report of the use of temozolomide-based chemotherapy combined with concurrent radiotherapy in newly diagnosed PCNSL. Our objective was to assess the efficacy and toxicity of temozolomide-based adjuvant chemotherapy plus concurrent chemoradiotherapy in such patients. The outcomes of this study show that this treatment regimen is feasible and effective with manageable side effects and no treatment-related mortality. The treatment response rate was 100% (12 CRs), median PFS was 21 months, similar to HD-MTX-based regimens in combination with WBRT [Table 4]. Furthermore, acute toxicity compares favorably to other regimens and no delayed neurotoxicity has been documented till date.
|Table 4: Result of studies using MTX‑based protocols with radiation in PCNSL patients|
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| » Conclusion|| |
Outcomes in this study with temozolomide-based chemoradiotherapy in newly diagnosed PCNSL are similar to HD-MTX-based regimens plus WBRT in prolonging the PFS of patients. Furthermore, this agent is relatively well tolerated and is easy to administer in the outpatient setting, unlike HD-MTX, which requires hospitalization. However, low rates of neurotoxicity may perhaps be because patients have not been followed for a time long enough to detect the typical features of radiotherapy-related delayed neurotoxicity. Assessment of MGMT promoter status maybe of use before using temozolomide. However, high cost and the small number of patients are limiting factors. Future studies should evaluate whether MGMT promoter methylation status would affect therapeutic efficacy with a significant difference.  In conclusion, this regimen seems to be well tolerated and modestly effective in patients with newly diagnosed PCNSL.
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[Table 1], [Table 2], [Table 3], [Table 4]
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