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Primary CNS Lymphoma

Primary CNS Lymphoma. Andy Freeman, MD University of Louisville Dept of Radiation Oncology Multimodality Conference August 19, 2010. Outline. Background Pathology Radiological Findings Diagnosis/Presentation Historical Perspective Current Treatment Practices Literature Review

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Primary CNS Lymphoma

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  1. Primary CNS Lymphoma Andy Freeman, MD University of Louisville Dept of Radiation Oncology Multimodality Conference August 19, 2010

  2. Outline • Background • Pathology • Radiological Findings • Diagnosis/Presentation • Historical Perspective • Current Treatment Practices • Literature Review • Conclusion

  3. Primary CNS Lymphoma (PCNSL) • Lymphomatous involvement of CNS without evidence of systemic disease • 20% - CNS involvement in systemic lymphoma • Stage IE • Rare disease • 4% all intracranial neoplasms

  4. PCNSL • Demographics • Median Age – 60 • Frequency increases with advancing age • Predisposing Factors • Immunodeficiency • 15% have antecedent flu like syndrome • Demyelinating disease

  5. Molecular Biology and Pathogenesis • CNS typically lacks lymphoid aggregates • Events leading to infiltration yet to be identified • Aberration in normal systemic lymphocytes with specific affinity for CNS • Neoplastic systemic lymphocytes irradicated by normal immune response

  6. Pathology • Similar to systemic NHL • 80-85% aggressive, diffuse large cell • Virtually all have B Cell origin • Centroblastic in origin • + BCL-6, MUM1, BCL-2 • - CD138 • Reactive perivascular T-cell infiltrates (RPVI) • T Cell Origin rare with similar outcomes

  7. Clinical Presentation • Intracranial Lesion • Most common by far • Solitary of multiple • Diffuse Leptomeningial • Rare without concommitant intracranial lesion • If present, should look for systemic lymphoma • Vitreous/Uveal • Can precede intracranial lesion by up to 7 mo • Intradural Cord Lesion • < 1%; discrete nodules • Nerve Seeking Lymphoma

  8. Natural History • 75% supratentorial • Generally periventricular • 75% solitary lesion • Poorly demarcated with infiltration into surrounding edematous tissues • No cysts, hemorrhage, or necrosis • Spread along CSF pathways • 10-25% neuroaxis spread during disease course • 15-25% Eye involvement; can be presenting symptom • <10% Systemic Spread

  9. Diagnosis • Radiographic Evaluation • Solitary • Non-hemorrhagic • Periventricular • Isodense to Hyperdense on CT • Isointense to Hypointense on MRI; enhancing • Serial imaging used to monitor for recurrence • PET/MRS

  10. Diagnosis cont… • CSF Analysis • Should be performed on all except those at risk for herniation • Elevated protein, lymphoid predominance • Malignant cells in 30% • Sufficient for diagnosis if positive • Histopath • Stereotactic bx • Steroid use avoided before bx

  11. Staging CT C/A/P – only for those with “B” Symptoms Neuroaxis evaluation if clinically indicated Slit lamp evaluation HIV testing

  12. Outcomes Untreated – 1.5 mo Surgery Alone – 4 mo XRT alone – 10-18 mo Combined modality – 44 mo

  13. Treatment Strategies • Surgery • Limited to biopsy only • Extensive resection usually impractical • Used in those with pending herniation • Steroids • More sensitive than systemic lymphomas • Response rates >70% • High relapse • Do not use before histologic diagnosis • Can use mannitol if needed

  14. Treatment Strategies Only two RCTs performed for PCNSL Most strategies are derived from prospective and retrospective series

  15. Treatment Strategies • Historical • XRT alone • Coming of Age • Addition of systemic therapy • Modern Treatment • Eliminate XRT?

  16. XRT Alone:A Historical perspective • Prospective, non-randomized Phase II trial looking at boost dosing • No chemo • N=41, 1983-87 • 40Gy + 20 Gy reduced field boost • Median Survival 12.2 mo/ 28% 2y OS • Prognostic factors – age and PS • <60 23.1 mo vs >60 7.6 mo • 61% intracranial recurrence • Almost all within original site of disease • No difference as compared to historical data RTOG 8315: Int J Radiat Oncol Biol Phys 1992; 23:9

  17. Role of XRT to be re-examined Chemo/XRT Drug Regimen Sequencing Do we need XRT at all?

  18. RTOG 88-06 Phase I/II Trial Efficacy and Safety of 2/3 cycles CHOD chemotherapy with large volume XRT of 41.4 Gy + 18 Gy Bst N = 52 Comparison to RTOG 83-15 results Schultz et al. JCO. 1996. 14(2):556-64

  19. Why did this regimen fail? CHOP is standard chemo regimen for systemic NHL with great response rate and improved overall survival. Answer may lie with intact BBB None of the drugs in the CHOP regimen readily penetrate in tact BBB

  20. Defining the role of Chemotherapy • Most trials adopting systemic lymphoma like treatment strategy • Only trials including Methotrexate (MTX) based chemo show improved survival • 2 y OS 60-65% • Role of XRT, intrathecal MTX, and MTX dose yet to be defined • Cognitive Side Effects Ferreri et al. Annals of Oncology. 2000. 11:927-37

  21. Role of MTX • International Phase III Trial • N = 79 • MTX 3.5g +/- Cytarabine q3wk + WBRT • Experimental arm • CR 46 v 18% • Overall Response 69 v 40% • Grade ¾ toxicity 92 v 15% Ferreri et al. Lancet. 2009. 374:1512

  22. NABTT Phase II N=23 MTX 8g/m2 q2wk x 8 cycles If response, maintenance MTX qmo x 11 months Response Rate 74% PFS – 12.8 mo OS - >23 mo Only 1 had decline in MMSE Of the 12 with CR, 5 have survival >6.5 y Batchelor et al. JCO. 2003. 21:1044

  23. Neuropsychological Effects • Multicenter Phase II Trial • MTX 5g/m2 + ARA-C + Vinca Alk + ifos + cyclophosphamide + IT-MTX • Overall response – 71% • Treatment related mortality – 9% • MS 50 mo • 5y OS • <60 – 75% • >60 – 19% Fliessbach et al. Neurology. 2005. 64:1184

  24. Dosing of MTX N=357, retrospective analysis MTX dose <3g/m2 v >3g/m2 CR 64 v 38% Reni et al. 2001. Int J Radiat Oncol Physics. 51:419

  25. Can we limit toxicity by deferring XRT HD MTX Multi-drug regimens

  26. High Dose MTX • NABTT 96-07, prospective • Phase II, single agent HD MTX, deferred XRT • N = 25 • MTX 8g/m2 every 2 weeks for 8 cycles, CR, or progression • Measured by radiological findings • 74% response, majority CR • PFS 12.8 mo, Median survival not reached at 39 mo • 50% Grade III/IV toxicity Batchelor et al. JCO. 2003. 21(6):1044-49

  27. High Dose MTX • German NOA-03 • Prospective multi-center • N=37 of planned 105 • MTX 8g/m2 biweekly, reassessed after 3 and 6 cycles • Closed early at intermediate analysis • 30% CR but 38% had progressive disease • Median survival 25 mo • Leukoencephalopathy 58% Herrlinger et al. Ann Neurology. 2002. 51:247-52 and 2005. 57:843-47

  28. European Multicenter study Retrospective N = 98; XRT alone N = 32; CHT alone N = 36; XRT + CHT N = 197; CHT + XRT HD MTX in 169 with IT-MTX in 109 Ferreri et al. Neurology. 2002; 58: 1513-20

  29. European Multicenter study • CTX with XRT improved OS • MTX containing regimens were superior • Cytarabine improved OS • IT-MTX not associated with improved outcomes • Need for XRT after CR from chemo questioned • 25-35% severe cognitive deficits at 5y

  30. Radiation Toxicity after HD MTX • Immediate complications few if given with steroids • Delayed symptoms (7-40 days) related to myelin synthesis • Long term complications can be months to years • Rapidly progressive dementia • Motor/Autonomic dysfunction including ataxia and incontinence • No defined dose or fraction size determined as of yet • Radiation Necrosis – can be misinterpreted as recurrence Omuro et al. Arch Nerol. 2005. 62:1595

  31. Chemotherapy + XRT Chemotherapy alone has proved to be better than XRT alone Can Side Effects be tolerable?

  32. RTOG 93-10 • Prospective, non-randomized • N = 102 • MTX 2.5g/m2 + Vincristine, Procarbazine, and 12 g IT-MTX for 5 cycles • WBRT to 45 Gy • 50% received hyperfractionated 36 Gy @ 1.2 bid • HD-Cytarabine consolidation DeAngelis et al. JCO. 2002. 20:4643-48.

  33. Median Survival 50.4 vs 21.8 mo Median Survival 37 mo

  34. RTOG 93-10 • 94% response rate to induction chemotherapy • Response did not correlate with survival • PFS 24.0 mo • 50% Grade III/IV toxicity to induction • 15% severe neurological complications

  35. MSKCC • Prospective, non-randomized • N = 52 • MTX 3.5g/m2 , Procarbazine, Vincristine • WBRT to 45 Gy • N = 22 > 65y who deferred XRT • Response rate = 90% • Median Survival = 60mo • Older patients had equivalent survival (32mo) +/- XRT • Neurotoxicity worse with XRT Abrey et al. JCO. 2000. 18:3144-50 and Gavrilovic et al. JCO. 2006. 24(28):4570-74.

  36. Alternative Approaches

  37. Rituximab N= 30 rituximab, MTX (3.5g/m2), procarbazine, and vincristine x 7 cycles induction CR – dose reduced WBRT (23.4 Gy) Others – standard WBRT (45 Gy) Cytarabine consolidation Rituximab CSF levels monitored Shah et al. JCO. 2007. 25:30

  38. Continued 2y OS 67% 2y PFS 57% CR – 44% RR – 93% No neurotoxicity observed

  39. MTX + rituximab N=40 MTX (8g/m2) + RTX x 12 cycles Deferred XRT 80% RR 60% CR MS 33 months Chamberlain et al. Neuro Oncol. 2010. Feb.

  40. TMZ CR rate 50% MGMT methylation has been identified Further investigation warranted

  41. Palliation

  42. Palliation • CR achievable with 20-40 Gy • Local relapses common---most within a year • MTX intolerant • TMZ + rituximab • Auto transplant • Corticosteroids – CR 70%

  43. Current Trials

  44. Currently Open MTX + RTX + BBBD

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