Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 16  |  Issue : 1  |  Page : 13--17

Evolution of the treatment of primary central nervous system lymphoma in a Regional Cancer Center of South India: Impact of high-dose methotrexate on treatment outcome


AH Rudresha, Tamojit Chaudhuri, KC Lakshmaiah, Govind Babu, KN Lokesh, LK Rajeev 
 Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Correspondence Address:
Tamojit Chaudhuri
Room No: 207, PG Hostel for Men, Kidwai Memorial Institute of Oncology, Bengaluru . 560 029, Karnataka
India

Abstract

Objective: Primary central nervous system lymphoma (PCNSL) is a rare form of aggressive extranodal non-Hodgkin lymphoma. This study attempts to delineate the clinicopathological and radiological profile of PCNSL cases at our center. Materials and Methods: All the pathologically confirmed PCNSL cases between January 2007 and July 2016 were analyzed retrospectively. The influence of potential prognostic parameters and therapeutic strategies on survival was investigated by log-rank test and Cox regression analysis. Results: Of the 53 PCNSL patients, 34 (64%) patients were males. Median age at diagnosis was 44 years (range 22–65 years). The most common location in the brain was the cerebral hemispheres in 32 patients (60%), and 16 patients (30%) had multiple intracranial lesions. Histologically, all patients were diffuse large B-cell lymphomas, except one case of anaplastic large-cell lymphoma. The median survival of the patients received whole-brain radiation alone ( n = 6), standard CHOP chemotherapy + radiation ( n = 14), and DeAngelis protocol ( n = 31) was 8 months, 13 months, and 23 months, respectively. Among the 31 patients treated with DeAngelis protocol, Memorial Sloan Kettering Cancer Center Class 1 ( n = 23) and Class 2 ( n = 8) patients had a median overall survival (OS) of 25 months and 13 months, respectively. The incidence of treatment-related neurotoxicity was significantly higher with DeAngelis protocol, in comparison to CHOP + whole-brain radiation therapy (26% vs. 14%, P < 0.05). Conclusion: None of the potential prognostic factors had a statistically significant influence on OS in our patients. High-dose methotrexate-based chemotherapy combined with radiation was the only factor, which had a significant impact on survival (log-rank P = 0.000) but at the cost of increased neurotoxicity.



How to cite this article:
Rudresha A H, Chaudhuri T, Lakshmaiah K C, Babu G, Lokesh K N, Rajeev L K. Evolution of the treatment of primary central nervous system lymphoma in a Regional Cancer Center of South India: Impact of high-dose methotrexate on treatment outcome.J Can Res Ther 2020;16:13-17


How to cite this URL:
Rudresha A H, Chaudhuri T, Lakshmaiah K C, Babu G, Lokesh K N, Rajeev L K. Evolution of the treatment of primary central nervous system lymphoma in a Regional Cancer Center of South India: Impact of high-dose methotrexate on treatment outcome. J Can Res Ther [serial online] 2020 [cited 2020 May 30 ];16:13-17
Available from: http://www.cancerjournal.net/text.asp?2020/16/1/13/204843


Full Text



 Introduction



Primary central nervous system lymphoma (PCNSL) represents a rare subtype of aggressive extranodal non-Hodgkin lymphoma (NHL) restricted to the craniospinal axis (brain parenchyma, spinal cord, eyes, cranial nerves, and/or meninges), without evidence of a systemic lymphoma at the time of diagnosis.[1] Ocular involvement can occur in 10%–15% of patients, and leptomeningeal disease is documented in 20%–30% of cases.[2] It represents 0.8%–6.6% of all primary CNS tumors and about 5% of all extranodal NHLs.[3] More than 90% of PCNSL are of diffuse large B-cell lymphoma (DLBCL) histology, with Burkitt's lymphoma, indolent Bcls, and T-cell histologies rarely reported.[4],[5] The only known risk factor for PCNSL is congenital or acquired immunodeficiency. In the recent era of highly active antiretroviral therapy (HAART), a significant reduction in the incidence of immunodeficiency-associated PCNSL has occurred, correlating with a decline in the proportion of HIV-infected individuals with CD4+ cell counts <50/mm3.[6] The fact that unlike the western countries, the association of PCNSL with HIV/AIDS in India is very low in spite of substantial prevalence of HIV/AIDS cases, suggests that there is geographic variation in the risk factors.[7] Historically, PCNSL has been considered to be associated with a significantly worse prognosis than systemic lymphomas of the same histology, despite of multimodality treatment. With high-dose methotrexate-based chemotherapy, with or without whole-brain radiotherapy, a median survival of 51 months has been reported.[8] It remains unclear whether the dismal outcome of PCNSL patients compared with patients with systemic DLBCL is attributable to the immune-privileged CNS location or reflects a specific aggressive intrinsic biologic behavior.

The best treatment approach for this aggressive extranodal NHL is still controversial. In the present study, we aimed to investigate the clinical, pathological, and radiological characteristics of the PCNSL cases at our center and to evaluate the influence of potential prognostic factors and different therapeutic strategies on the treatment outcome.

 Materials and Methods



All consecutive cases diagnosed with PCNSL between January 2007 and July 2016 at our center were investigated retrospectively. All the patients underwent a detailed history and physical examination including a neurological assessment. The localization and number of the CNS lesions were investigated by magnetic resonance imaging (MRI), and the diagnosis of CNS lymphoma was confirmed by microscopic examination and immunohistochemistry of the biopsy specimens (stereotactic or open biopsy). To exclude systemic lymphoma at presentation, all patients underwent iliac crest bone marrow aspiration and biopsy, whole-body contrast-enhanced computed tomography scan, ophthalmoscopic evaluation, and cerebrospinal fluid (CSF) cytology for malignant cells. Ultrasound examination of testes was performed in male patients. Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score[9] was calculated. Patients were treated with either whole-brain radiation therapy (WBRT) alone, or standard CHOP chemotherapy + WBRT, or DeAngelis protocol,[10] or intensive chemoimmunotherapy with methotrexate, temozolomide, and rituximab (MT-R) induction (high-dose) followed by enterprise architecture (EA) consolidation (etoposide and cytarabine).[11] All patients have been observed with follow-up MRI scans and neurologic examinations at regular intervals. Treatment-related neurotoxicity was defined as progressive neurologic or cognitive impairment as documented on serial clinical examinations in the absence of recurrent lymphoma.

Statistical analysis

Duration of overall survival (OS) was calculated from the date of diagnosis until death. The strength of the association between OS and different prognostic variables was investigated by Kaplan–Meier OS curve and log-rank test. These variables included age (≥60 years vs. <60 years), multifocal involvement, deep-site involvement (i.e., the corpus callosum, basal ganglia, periventricular region, brainstem, and cerebellum), CD10 staining, MUM1 staining, subtype (germinal center [GC] vs. non-GC [NGC]), and MSKCC prognostic score. All statistical analyses were performed using SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).

 Results



A total of 53 cases of PCNSL were retrospectively reviewed. Median age at diagnosis was 44 years (range: 22–65 years) with a male/female ratio of 1.78/1 (34:19). Two patients had HIV and Epstein–Barr virus (EBV) positivity. B-symptoms were very uncommon in our series, and only eight patients (15%) had B-symptoms at presentation. The most common presenting symptoms were raised intracranial tension features (headache and vomiting) in 49% ( n = 26), followed by focal neurological deficits (paresthesia/hemiparesis, cranial nerve palsies, and dysarthria) in 30% of patients ( n = 16). Other presenting symptoms included seizures in 9% ( n = 5), visual disturbances in 8% ( n = 4), personality changes in 2% ( n = 1), and gait disturbances in 2% ( n = 1) of patients. The median serum lactate dehydrogenase (LDH) was 224 U/L and was elevated in 17 patients (32%). The most common area of CNS involvement was cerebral hemispheres in 60% ( n = 32), followed by periventricular regions in 21% ( n = 11), thalamus in 9% ( n = 5), cerebellum in 6% ( n = 3), leptomeninges in 2% ( n = 1), and corpus callosum in 2% ( n = 1) of patients. Sixteen patients (30%) had multifocal CNS lesions. As per the MSKCC risk scoring, 38 patients (72%) belonged to Class 1 and the rest were Class 2. The diagnostic procedures employed were stereotactic biopsy in 49% ( n = 26), surgical decompression in 38% ( n = 20), and gross total excision in 13% ( n = 7) of patients. Histologically, all patients were DLBCL, except one patient who had anaplastic large-cell lymphoma (ALCL). Immunohistochemically, 38 patients (71%) had MUM 1 positivity and 41 cases (77%) belonged to NGC subtype. All of the patients with DLBCL histology ( n = 52) were negative for anaplastic lymphoma kinase (ALK) and had a high Ki-67 index (range: 80%–95%; median 90%). The patient with ALCL was positive for ALK and had a Ki-67 index of 70%. All of the cases of NGC subtype were negative for CD10. The median survival of the patients received WBRT alone ( n = 6), standard CHOP chemotherapy + WBRT ( n = 14), and DeAngelis protocol ( n = 31) was 8 months, 13 months, and 23 months [Figure 1], respectively. Among the 31 patients treated with DeAngelis protocol, MSKCC Class 1 ( n = 23) and Class 2 ( n = 8) patients had a median OS of 25 months and 13 months, respectively. The two patients treated with MT-R regimen are still alive. The incidence of treatment-related neurotoxicity was significantly higher with DeAngelis protocol, in comparison to CHOP + WBRT (26% vs. 14%, P < 0.05), and among the 31 patients received DeAngelis protocol, neurotoxicity was significantly higher in the older age group (>60 years) versus the younger age group (60% vs. 19%, P < 0.05).{Figure 1}

 Discussion



Previously, PCNSL was regarded as the tumor of immunosuppressed individuals. However, after the introduction of HAART, the incidence of PCNSL decreased substantially in these patients. Today, the frequency of PCNSL is much higher in immunocompetent individuals than in immunocompromised ones. However, the exact reason for this rising incidence of PCNSL among the immunocompetent population is still obscure.[12] Moreover, whether the disease has a different course in patients without an underlying immune dysfunction is also still unclear. The role of various immunophenotypic markers in predicting survival outcome for this highly aggressive extranodal NHL is highly debated. Although several implications of EBV, on various types of tumors arising in immunocompromised individuals, are well recognized, its etiological role in PCNSL of immunocompetent patients is still unclear. In the present study, none of our immunocompetent patients had EBV positivity.

Unlike individuals with systemic NHL, patients with PCNSL rarely present with B-symptoms. They classically present with focal neurologic or cognitive deficits, sensory-motor symptoms, and symptoms of raised intracranial pressure.[4],[13],[14] New onset seizures are less common (10%–15%).

Several prognostic classifications were proposed for PCNSL to make practical algorithms and determine the best treatment strategy. The International Extranodal Lymphoma Study Group has noted that several factors are associated with a poor prognosis in PCNSL. Age >60 years, Eastern Cooperative Oncology Group performance status >1, elevated LDH, high CSF protein concentration, and deep brain involvement were independently predictive for poor survival.[15] The Nottingham/Barcelona score includes age, performance status, and extent of brain disease.[16] A more recent staging system has been developed and validated by the Memorial Sloan Kettering (MSKCC) Group.[9] The group studied multiple factors in over 300 patients and found only two factors, age and performance status, were predictive of outcome. These factors were able to differentiate patients into three very different prognostic groups – Class 1: patients <50 years; Class 2: patients ≥50 years, Karnofsky performance status (KPS) ≥70, and Class 3: patients ≥50 years, KPS <70. Patients with Class 1 prognosis experienced a median OS of 8.5 years whereas patients who were Class 3 had a median OS of only 1.1 years.[9]

As per the molecular classification, DLBCL can be categorized into GC and NGC subtypes.[17] The NGC subtype has a relatively poor outcome. According to the several published reports, 66%–93% of the PCNSL cases belonged to the NGC subgroup.[4],[18],[19] However, none of these studies had demonstrated a statistically significant difference in OS and disease-free survival between these two subtypes. In our series, 77% of the cases were of NGC subtype, and there was no significant survival difference between two groups [Table 1].{Table 1}

Results are conflicting regarding the role of Bcl-6 as an independent prognostic variable. Some studies suggested Bcl-6 as a poor prognostic factor,[18] while some demonstrated its association with a more favorable outcome,[20] while others failed to show any impact on survival.[3],[19] Moreover, there was no significant survival difference between Bcl-2 positive and negative groups also, in most of the prior reports.[3],[4]

Several studies suggested that young age at diagnosis (<60 years) represents a favorable prognosis,[4],[21] and on the other hand, multifocal involvement and deep-site involvement of the brain were proposed to have a negative impact on survival.[15],[20],[22] In our study, we failed to demonstrate an association between these parameters and OS [Table 1]. This may be attributed to the relatively low number of cases enrolled in this study.

High Ki-67 index is a poor prognostic factor in systemic DLBCL, but none of the studies till date showed any significant survival difference between high and low Ki-67 groups.[18],[20] In our series, the median Ki-67 index (90%) was too high, to be divided into high and low subgroups.

The historical mainstay of therapy in PCNSL was previously WBRT alone.[23] Because of the limited long-term efficacy of WBRT alone, there has been considerable interest in combining chemotherapy with WBRT to improve response and survival. CHOP-based chemotherapies have been studied[24] but have not offered additional survival benefit to radiation used alone, presumably because of the lack of penetration to the CNS. Subsequent research has centered on the role of systemic methotrexate at doses known to penetrate into the CNS preceding WBRT, which culminated in a radiation therapy oncology group multicenter phase II study of combined modality therapy (CMT) in PCNSL.[10] In this study, overall response rate (ORR) reached 94% including 58% complete responses (CRs), and the median progression-free survival (PFS) was 25 months with 37 months of median OS. Recently, MSKCC has published long-term follow-up of their experience with CMT.[8] Median OS was 51 months for the entire cohort, and for the patients under 60 years, median PFS and OS had not been reached after 115 months of follow-up. In patients ≥60 years, median OS was only 29 months along with increased neurotoxicity. In an attempt to reduce the toxicity of CMT, the use of chemotherapy alone has been studied. In one multicenter phase II study of high-dose methotrexate (single agent 8 g/m2)-based therapy, ORR was 74%, but median PFS was only 13 months.[25] Final results of the cancer and leukemia group B 50,202 trial have been published recently.[11] This study has evaluated the efficacy of dose-intensive chemotherapeutic induction (MT-R) and consolidation EA strategy in 44 newly diagnosed patients with PCNSL. The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with a median follow-up of 4.9 years. Patients >60 years of age responded similarly as younger patients. This study showed first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. However, the optimal methotrexate-based regimen is still unclear in the literature. In our study, the median survival of the patients treated with high-dose methotrexate-based chemotherapy combined with WBRT (DeAngelis protocol) was significantly better than those who treated with WBRT alone (log-rank P = 0.000) or with standard CHOP chemotherapy + WBRT (log-rank P = 0.000).

One of the most significant issues influencing the development of new therapeutic strategies for PCNSL is concern about the treatment-related neurotoxicity. This area has been understudied and often underreported.[26] In our series, 26% of patients (8 of 31) in the DeAngelis arm and 14% of patients (2 of 14) in the CHOP + WBRT arm developed neurotoxicity. Among the 31 patients received DeAngelis protocol, neurotoxicity was significantly higher in the patients aged >60 years (3 of 5) versus the younger patients (5 of 26) (60% vs. 19%, P < 0.05).

 Conclusion



In the current study, we retrospectively investigated the demographic and clinicopathological features of PCNSL cases together with an analysis of potential prognostic factors and their impact on OS. None of the factors had a statistically significant influence on OS. The treatment of PCNSL with high-dose methotrexate combined with WBRT is an effective therapeutic approach and was the only factor in our study, which had a significant impact on survival but at the cost of increased treatment-related neurotoxicity. However, further prospective studies with large patient number are needed to elucidate prognostic factors as well as optimum treatment regimens including rituximab, particularly in immunocompetent patients with PCNSL.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: Evolving concepts and practical applications. Blood 2011;117:5019-32.
2Ferreri AJ, Blay JY, Reni M, Pasini F, Gubkin A, Tirelli U, et al. Relevance of intraocular involvement in the management of primary central nervous system lymphomas. Ann Oncol 2002;13:531-8.
3Zhang X, Chen QH, Farmer P, Nasim M, Demopoulos A, Devoe C, et al. Central nervous system lymphoma in immunocompetent patients: The North Shore-Long Island Jewish Health System experience. J Clin Neurosci 2013;20:75-9.
4Raoux D, Duband S, Forest F, Trombert B, Chambonnière ML, Dumollard JM, et al. Primary central nervous system lymphoma: Immunohistochemical profile and prognostic significance. Neuropathology 2010;30:232-40.
5Miller DC, Hochberg FH, Harris NL, Gruber ML, Louis DN, Cohen H. Pathology with clinical correlations of primary central nervous system non-Hodgkin's lymphoma. The Massachusetts General Hospital experience 1958-1989. Cancer 1994;74:1383-97.
6Cheung MC, Pantanowitz L, Dezube BJ. AIDS-related malignancies: Emerging challenges in the era of highly active antiretroviral therapy. Oncologist 2005;10:412-26.
7Pasricha S, Gupta A, Gawande J, Trivedi P, Patel D. Primary central nervous system lymphoma: A study of clinicopathological features and trend in Western India. Indian J Cancer 2011;48:199-203.
8Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol 2006;24:4570-4.
9Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W, et al. Primary central nervous system lymphoma: The Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 2006;24:5711-5.
10DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation therapy oncology group study 93-10. J Clin Oncol 2002;20:4643-8.
11Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 2013;31:3061-8.
12Sierra del Rio M, Rousseau A, Soussain C, Ricard D, Hoang-Xuan K. Primary CNS lymphoma in immunocompetent patients. Oncologist 2009;14:526-39.
13Gualco G, Weiss LM, Barber GN, Bacchi CE. Diffuse large B-cell lymphoma involving the central nervous system. Int J Surg Pathol 2011;19:44-50.
14Makhdoomi R, Nayil K, Rayees A, Kirmani A, Ramzan A, Khalil MB, et al. Primary CNS lymphoma in immunocompetent: A review of literature and our experience from Kashmir. Turk Neurosurg 2011;21:39-47.
15Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, et al. Prognostic scoring system for primary CNS lymphomas: The international extranodal lymphoma study group experience. J Clin Oncol 2003;21:266-72.
16Bessell EM, Graus F, Lopez-Guillermo A, Lewis SA, Villa S, Verger E, et al. Primary non-Hodgkin's lymphoma of the CNS treated with CHOD/BVAM or BVAM chemotherapy before radiotherapy: Long-term survival and prognostic factors. Int J Radiat Oncol Biol Phys 2004;59:501-8.
17Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004;103:275-82.
18Hattab EM, Martin SE, Al-Khatib SM, Kupsky WJ, Vance GH, Stohler RA, et al. Most primary central nervous system diffuse large B-cell lymphomas occurring in immunocompetent individuals belong to the nongerminal center subtype: A retrospective analysis of 31 cases. Mod Pathol 2010;23:235-43.
19Camilleri-Broët S, Crinière E, Broët P, Delwail V, Mokhtari K, Moreau A, et al. Auniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: Analysis of 83 cases. Blood 2006;107:190-6.
20Song MK, Chung JS, Joo YD, Lee SM, Oh SY, Shin DH, et al. Clinical importance of Bcl-6-positive non-deep-site involvement in non-HIV-related primary central nervous system diffuse large B-cell lymphoma. J Neurooncol 2011;104:825-31.
21Jahnke K, Korfel A, O'Neill BP, Blay JY, Abrey LE, Martus P, et al. International study on low-grade primary central nervous system lymphoma. Ann Neurol 2006;59:755-62.
22Tomlinson FH, Kurtin PJ, Suman VJ, Scheithauer BW, O'Fallon JR, Kelly PJ, et al. Primary intracerebral malignant lymphoma: A clinicopathological study of 89 patients. J Neurosurg 1995;82:558-66.
23Nelson DF, Martz KL, Bonner H, Nelson JS, Newall J, Kerman HD, et al. Non-Hodgkin's lymphoma of the brain: Can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the radiation therapy oncology group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 1992;23:9-17.
24Mead GM, Bleehen NM, Gregor A, Bullimore J, Shirley D, Rampling RP, et al. Amedical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: Cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. Cancer 2000;89:1359-70.
25Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: A report of NABTT 96-07. J Clin Oncol 2003;21:1044-9.
26Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz M, Pulczynski EJ, Zucca E, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 2005;23:5034-43.