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- Title
A Prospective Phase Ii Trial Of Response Adapted Whole Brain Radiotherapy After High Dose Methotrexate Based Chemotherapy In Patients With Newly Diagnosed Primary Central Nervous System Lymphoma.
- Authors
Adhikari, Narayan; Biswas, Ahitagni; Gogia, Ajay; Sahoo, Ranjit Kumar; Garg, Ajay; Nehra, Asima; Sharma, M. C.; Bhasker, Suman; Kumar, Lalit; Chander, Subhash
- Abstract
Introduction: The treatment of primary CNS lymphoma(PCNSL) comprises high dose Methotrexate(HDMTX) based chemotherapy followed by whole brain radiotherapy(WBRT). The major drawback of this treatment approach is long term neurotoxicity that may lead to poor quality of life, dementia and death. We intended to assess the feasibility of response adapted WBRT after HDMTX based chemotherapy in patients with PCNSL in the Indian setting. Materials and Methods: We screened 32 patients and enrolled 22 eligible patients with PCNSL (age 18-80 years, ECOG PS 0-3, HIV seronegative, biopsy proven PCNSL, no significant end-organ dysfunction) attending our institute from 2015 to 2017 in a prospective phase II trial. The patients underwent 5 two-weekly cycles of MPV induction chemotherapy with Methotrexate 3.5g/ m2 IV D1 with Leucovorin rescue for 3 days, Vincristine 1.4mg/ m2(capped at 2mg) IV D1, Procarbazine 100mg/m2 P.O. D1-7 in odd number cycles. Rituximab 375mg/m2 IV D1 q2weeks was added in 14 patients as per patient-preference and affordability. Patients with complete response(CR) to induction chemotherapy were given reduced dose WBRT 23.4Gy/13fractions/2.5 weeks while those with partial response(PR), stable or progressive disease(SD or PD) were given standard dose WBRT 45Gy/25fractions/5 weeks. Thereafter 2 cycles of consolidation chemotherapy with Cytarabine 3g/m2/day, IV D1 and D2 were given 1 month apart. The primary endpoints of the study were assessment of response rate and progression free survival (PFS). The secondary endpoints of the study were assessment of overall survival (OS), toxicity profile of treatment, molecular subtype of lymphoma, EBV status (by immunohistochemistry for EBV LMP-1) and serial changes in quality of life (EORTC-QLQ-C30 and BN 20 module) and neuropsychological parameters. Results: The median age at diagnosis was 51.5 years (range: 31-67 years) and the male: female ratio was 13:9. The ECOG PS was 3, 2 and 1 in 13(59.09%), 5(22.73%) and 4(18.18%) patients respectively. Out of 19 patients who completed HDMTX based induction chemotherapy, 10 (52.63%) patients achieved CR, 8 (42.11%) patients had PR and 1 patient had PD. Two patients on RMPV regimen died due to chemotherapy related toxicities. Induction chemotherapy was otherwise well tolerated with severe (grade3/4) toxicities being mostly haematological- anaemia in 1 patient, neutropenia in 8(36.36%) patients and thrombocytopenia in 1 patient. Nine patients received reduced dose and 9 received standard dose WBRT. In our study, WBRT was excellently tolerated with no reported grade 3/4 toxicity. Consolidation chemotherapy with high dose Cytarabine was given in 15(68.18%) patients. Grade3/4 neutropenia was observed in 3(20%) patients during consolidation chemotherapy. After a median follow-up period of 11.25 months (mean 12.41 months), 4 patients had disease progression and 8 patients had died, the causes being disease progression in 2, chemotherapy related toxicity in 2 and non-cancer related in 3 patients. The estimated median OS was 19 months. The median PFS had not been reached. The actuarial rates of PFS were 94.1% and 50.2%, disease free survival were 86.4% and 61.4% and OS were 68.2% and 48.5%, respectively at 1 and 2 years. Three patients in reduced dose WBRT arm had recurrence and 2 of them died of progressive disease, whereas there was no recurrence or disease related death in standard dose WBRT arm. On univariate analysis of OS, use of RT (p value<0.0001), use of consolidation Ara-C (p value 0.026) and negative CSF cytology (p value 0.0076) led to significantly improved outcome. On multivariate analysis of OS, only CSF cytology retained prognostic significance with p value of 0.021 and hazard ratio (HR) of 6.71. On univariate analysis of PFS, age?50 years and use of standard dose WBRT (45Gy) led to significantly improved outcome (p value 0.03 and 0.02 respectively). The overall response rates to induction chemotherapy with and without Rituximab were not significantly different (90.9% versus 100%; p value 0.409). There was no significant difference in treatment outcome according to the molecular subtype of PCNSL (germinal centre and activated B cell DLBCL in 3 and 13 patients respectively). In our study immunohistochemistry for EBV LMP-1 was negative in all assessed specimens (N=19). Serial neuropsychological assessments revealed marked improvement in general cognition and other domains (e.g. verbal fluency and motor speed) after induction chemotherapy, which persisted for 6 months after completion of primary treatment and then stabilised. The mean EORTC Global Health Status/Qol score declined from 58.3 at baseline to 41.67 after induction chemotherapy and then increased to 66.67 at 6 and 12 months after completion of treatment (p value 0.748). . Conclusion: In patients with newly diagnosed PCNSL, reduced dose WBRT after complete response to HDMTX based chemotherapy may lead to suboptimal clinical outcome due to higher risk of recurrence, progression and early death. Addition of Rituximab to MPV regimen, does not enhance the response rate or significantly impact the survival outcome but increases the acute toxicity. Whole brain radiotherapy in both reduced and standard dose, does not appear to have short term neuropsychological and quality of life detriment. However longer follow up is required to make definitive conclusions.
- Subjects
CENTRAL nervous system; PROGRESSION-free survival; CANCER chemotherapy; METHOTREXATE; ODD numbers
- Publication
Journal of Cancer Research & Therapeutics, 2017, Vol 13, pS169
- ISSN
0973-1482
- Publication type
Article