primary cns lymphoma
Download
Skip this Video
Download Presentation
Primary CNS Lymphoma

Loading in 2 Seconds...

play fullscreen
1 / 51

Primary CNS Lymphoma - PowerPoint PPT Presentation


  • 123 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Primary CNS Lymphoma' - veata


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
primary cns lymphoma

Primary CNS Lymphoma

Andy Freeman, MD

University of Louisville

Dept of Radiation Oncology

Multimodality Conference

August 19, 2010

outline
Outline
  • Background
  • Pathology
  • Radiological Findings
  • Diagnosis/Presentation
  • Historical Perspective
  • Current Treatment Practices
    • Literature Review
  • Conclusion
primary cns lymphoma pcnsl
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
pcnsl
PCNSL
  • Demographics
    • Median Age – 60
    • Frequency increases with advancing age
  • Predisposing Factors
    • Immunodeficiency
    • 15% have antecedent flu like syndrome
    • Demyelinating disease
molecular biology and pathogenesis
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
pathology
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
clinical presentation
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
natural history
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
diagnosis
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
diagnosis cont
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
staging
Staging

CT C/A/P – only for those with “B” Symptoms

Neuroaxis evaluation if clinically indicated

Slit lamp evaluation

HIV testing

outcomes
Outcomes

Untreated – 1.5 mo

Surgery Alone – 4 mo

XRT alone – 10-18 mo

Combined modality – 44 mo

treatment strategies
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
treatment strategies1
Treatment Strategies

Only two RCTs performed for PCNSL

Most strategies are derived from prospective and retrospective series

treatment strategies2
Treatment Strategies
  • Historical
    • XRT alone
  • Coming of Age
    • Addition of systemic therapy
  • Modern Treatment
    • Eliminate XRT?
xrt alone a historical perspective
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

role of xrt to be re examined
Role of XRT to be re-examined

Chemo/XRT

Drug Regimen

Sequencing

Do we need XRT at all?

rtog 88 06
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

why did this regimen fail
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

defining the role of chemotherapy
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

role of mtx
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

nabtt phase ii
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

neuropsychological effects
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

dosing of mtx
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

high dose mtx
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

high dose mtx1
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

european multicenter study
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

european multicenter study1
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
radiation toxicity after hd mtx
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

chemotherapy xrt
Chemotherapy + XRT

Chemotherapy alone has proved to be better than XRT alone

Can Side Effects be tolerable?

rtog 93 10
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.

slide39

Median Survival 50.4 vs 21.8 mo

Median Survival 37 mo

rtog 93 101
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
mskcc
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.

rituximab
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

continued
Continued

2y OS 67%

2y PFS 57%

CR – 44%

RR – 93%

No neurotoxicity observed

mtx rituximab
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.

slide46
TMZ

CR rate 50%

MGMT methylation has been identified

Further investigation warranted

palliation1
Palliation
  • CR achievable with 20-40 Gy
  • Local relapses common---most within a year
  • MTX intolerant
    • TMZ + rituximab
    • Auto transplant
  • Corticosteroids – CR 70%
currently open
Currently Open

MTX + RTX + BBBD

conclusions
Conclusions
  • PCNSL is a persistent and ultimately deadly disease, especially in elderly
  • Therapy should be focused towards improving survival but also avoiding severe side effects
    • Optimal Treatment Unknown
  • Clinical Trials are always recommended
  • MTX based chemo is standard
  • Role of XRT is questionable, especially in elderly
ad