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Management of Primary CNS Lymphoma (PCNSL)
1. Management of
Primary CNS Lymphoma
Presenter: Dr. Narayan Adhikari
Junior Resident
Moderator: Dr. Ahitagni Biswas
Department of Radiation Oncology
Dr. B. R. Ambedker Institute Rotary Cancer Hospital
AIIMS, New Delhi
4. Epidemiology
1% of all
intracranial tumours
4% of all
intracranial tumours
Sarkar C, Sharma MC, Deb P, Singh R, Santosh V, Shankar SK. Primary central nervous system lymphoma--a hospital based study of
incidence and clinicopathological features from India (1980-2003). J Neurooncol. 2005;71(2):199-204
Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ. Age, gender, and racial differences in incidence and survival in primary
CNS lymphoma. Br J Cancer. 2011;105(9):1414-1418
10. Stereotactic biopsy followed by histopathological
examination
Diagnosis
• 95% DLBCL
• Molecular subtypes
Germinal center, Activated
B cell and Type 3
• Overlapping state of
differentiation
• EBV associated in
immunocompromised
Histopathological findings in primary CNS lymphoma. (A) Hematoxylin and eosin stain demonstrates a population of mitotically active medium-to-large-sized
lymphoid cells with large vesicular nuclei and prominent nucleoli mixed with small mature lymphocytes with a distinct propensity to cluster around medium-sized
vessels. (B) Immunohistochemistry using a monoclonal anti-CD20 antibody reveals clusters of highly pleomorphic B lymphocytes. (C) Immunohistochemistry using
an anti-CD3 antibody highlights the dense T-cell infiltrate within B-cell PCNSL. Tumor cells are indicated by black arrows. (D) The large fraction of mitotically active
cells within the tumor can be visualized by immunohistochemistry with the Ki-67 antibody
11. Workup
Central review of
pathology
Immunophenotyping
EBV-LMP-1
Bone Marrow Biopsy+
Aspirate
CSF cytology+
Biochemistry
History and Clinical
examination
Ophthalmic examination
(Slit lamp and indirect
ophthalmoscopy)
Neuropsychological
evaluation
Complete blood counts
Liver function Tests,
Kidney Function Tests,
Electrolytes
Serum LDH
HIV serology and viral
markers
Contrast enhanced MRI
brain
CECT neck+ chest+
abdomen
Ultrasonography of testis
in male
Abrey LE, et al: Report of an international workshop to standardize baseline evaluation and response
criteria for primary central nervous system lymphoma. J Clin Oncol 23:5034-5043, 2005
12. • Age ≤60 vs >60 years
• PS 0-1 vs ≥2
• Serum LDH (normal vs elevated)
• CSF protein (normal vs elevated)
• Deep regions (no vs yes)
Prognostic Factors
Ferreri AJ et al: Prognostic scoring system for primary CNS lymphomas: The
International Extranodal Lymphoma Study Group experience. J Clin Oncol 21:266-
272, 2003
Score OS at 2 years
0 or 1 80%
2 or 3 48%
4 or 5 15%
13. • Exclusion of Systemic disease
• Extension of the disease to eyes, CSF
• Treatment feasibility in view of patient
characteristics
• Prognostic factors
• Recurrence
Therapeutic Decision
14. • The optimal treatment strategy is controversial
• High dose methotrexate based polychemotherapy
is the mainstay of treatment
• Role of radiation has been argued upon but it is
recommended in young patients
• The role of rituximab is investigational
Treatment
16. • Inj Methotrexate 2.5 gm/m 2 IV on weeks 1, 3, 5, 7 and 9
• Inj Vincristine 1.4 mg/m 2 IV on weeks 1, 3, 5, 7, 9
• Cap Procarbazine 100 mg/m 2 /day per oral for 7 days on
weeks 1, 5, 9
• Inj Methotrexate 12 mg intrathecal on weeks 2, 4, 6, 8, 10
• Tab Leucovorin 20 mg per oral every 6 h for 12 doses on
weeks 1, 3, 5, 7 and 9 following high dose methotrexate
• Tab Dexamethasone per oral tapering dose for 7 days (16,
12, 8, 6, 4, 2 mg on weeks 1-6)
• Whole brain radiotherapy (WBRT) 45 Gray in 25 fractions
over 5 weeks (weeks 11-15)
• Inj Cytarabine 3 gm/m 2 /day IV for 2 days on weeks 16
and 19
DeAngelis Protocol
18. • Whole Brain is treated due to
multifocal and infiltrative nature
of tumour
• Left and right opposed lateral
fields with 6-10mv photons
• Anterior temporal lobe, cribiform
plate, posterior aspect of eyes
included
• Divergence beam to lens reduced
by placing isocenter anteriorly
between the lateral canthi or if
anterior fields are made coplanar
• Inferior field edge in lower
border of C2 vertebrae
• If ocular involvement both globes
included for a portion of
treatment to receive a dose of
30-36 Gy
• No role of CSI except for
palliation in case of spinal
involvement
Radiation Therapy
19. • Acute Adverse Effects- alopecia, erythema and dry
desquamation of the scalp. Some experience
fatigue, headache and inflammation of the external
auditory canal or middle ear
• Patients requiring treatment of the eye are likely to
experience conjunctival irritation and dry eye.
• These acute effects typically resolve within 6 – 8
weeks of completion of WBRT
Radiation Toxicity
20. • Late adverse effects: neurocognitive decline,
sensorineural hearing loss, permanent alopecia
• Those whose eyes are treated- cataracts, chronic
dry eye
• The risk of neurocognitive dysfunction increases
with age, total RT dose and co-administration of
chemotherapy
Radiation Toxicity
22. Review of literature
SN Study N Median
Age
(years)
Chemotherapy WBRT/
Boost
(Gy)
Response PFS OS Neurotoxic
ity
Results and
Conclusions
1 RTOG 83-
15, 1992
41 66 None 40/20 CR=62% NS 48% 1
year,
28% 2
years
NS KPS (p<0.001) and age
(p=0.001) significant
prognostic factors
2 RTOG 88-
06, 1996
54 NS (>60) CHOD (2-3
cycles)
41.4/
18
CR=19%,
PR=48%,
SD=6%,
PD=15%
Median
9.2
months
42% 2
years
1 grade 5
encephalo
malacia
Age (p=0.005 and KPS
(p=0.057) were
significant prognostic
factors, no survival
benefit of adding CHOD
chemotherapy to RT,
compared with RTOG
83-15, p=0.53)
3 Batchelor
et al,
2003
23 60 MTX 8gm/m2,
upto 8 cycles,
maintenance
upto 11 cycles
- CR=52%
PR=22%
12.8
months
>23
months
modest Radiological response of
74% with grade 3
toxicity 8/25 and grade
4 toxicity 4/25
4 Abrey et
al, 2000
52 65 MTX(3.5gm/m
2)
,Vin(1.4mg/m2
),
Pro(100mg/m2
), Cyt
45 vs
none
Objective
response
rate to
induction
chemother
apy=90%
NS Median
60
months
13 In patients >60 yrs, OS
similar with or without
RT, late neurotoxicity
more common in those
who received RT
(p=0.00004), young
patients both OS and
PFS not reached during
publication but they
fared well
23.
24.
25. SN Study N Median
Age
(years)
Chemotherapy WBRT/
Boost
(Gy)
Response PFS OS Neurotoxicity Results and
conclusions
5 RTOG 93-
10, 2002
102 56.5 MTX (IV
2.5gm/m2 and
IT 12mg), Vin,
Pro, Cyt
45 later
amend
ed to
36 in
CR
group
CR=58%,
PR=36% to
chemother
apy
Response
rate=94%
Median
2 years
36.9
months
64% 2
years,
52% 3
years,
32% 5
years
12 (15%) severe
delayed
neurotoxicity, 8
Deaths
HDMTX- high
response rate,
plus RT-
improved survival
compared to
previous studies
of RT alone
6 Bessell et
al, 2002
57 59 CHOD x 1,
BVAM x 2
45 vs.
30.6
CR at the
end of all
t/t 68%
and 77%
NS 36% 5
years
In 1-year
survivors: 0/13
(30.6 Gy);
1/12 (45 Gy and
<60 years old);
6/10 (45 Gy and ≥
60 years old)
In <60 years who
achieved CR, 3-
year OS 92% v
60%, P =.04), 3
year relapse risk
25% vs 83%
(p=0.01)
7 Ferreri et
al, 2009
79 18-75 MTX 3.5g/m2
d1, Cyt 2g/m2
bd d2-3
36-45 CR 18% vs
46%, ORR
40% vs
69% in
MTX only
vs
MTX+Cyt
resp.
4 vs 8
months
(median
failure
free
survival)
10 vs
32
months
NS Combination of
methotrexate
with cytarabine
produces better
CR (0.006) ORR
(p=0.009), with
increased
toxicity
8 RTOG 02-
27, 2013
Phase II
results
53 57.5 HDMTX(3.5g/
m2), TMZ, RTX
36
hyperfr
actiona
ted
ORR
37.7% post
chemo
63.6% 2
years
80.8% 2
years
NS Compared to
RTOG 93-10,
significant
benefit in
OS(0.006) and
PFS (p=0.03)
26. SN Study N Median
Age
(years)
Chemotherapy WBRT/
Boost
(Gy)
Response PFS OS Neurotoxicity Results and
conclusions
9 Rubenstei
n et al
(CALGB50
202),
2013
44 NS MTX (8g/m2),
TMZ(150mg/
m2 day7-11,
odd cycles),
RTX(375mg/m
2, d3), only
CR- consolidtn
with EA
- CR 66% 52 m,
64%,
57%
47% at
1,2 and
4 years
resp.
Estimat
ed 75%,
70%
and
65% at
1,2 and
4 years
resp.
NS High Bcl6
expression
correlated with
shorter survival,
patient above 60
did as well as
younger patients
10 Ferreri et
al, 2011
retrospecti
ve
33 55 MTX based Whole
brain:
30-45
Gy,
tumour
bed: 36
to 54
Gy
5 year
failure
free
survival
51%
5 year
OS 54%
Significantly less
neurologic
impairment, as
measured by
MMSE, in
patients treated
with 30 – 36
Gy vs. ≥ 40 Gy
WBRT( p = 0.05)
WBRT doses ≥40
Gy not asso. with
improved disease
control compared
to dose of 30 - 36
Gy, 5-year FFS,
51% vs. 50%; p =
0.26), WB and
tumour bed RT
doesnot have
impact on
survival
11 Omuro et
al, 2011
64 47 (all
<60,
young),
median
KPS 70
MTX (3 g/m2),
CCNU, pro,
methylpred
and IT MTX,
cyt, and
methylpred
CR-5
more
cycles
of CT,
<CR, 27
WBRT,
29 HDC
with SC
rescue
ORR after
induction
chemo 87%
(CR 54%,
PR33%)
12 m 63 m 5 (none treated
with chemo only)
Deferring WBRT
in chemosensitiv
pts compromises
PFS not OS. As
objective is cure
in this age group,
omitting WBRT
may not be best
strategy
27.
28. • 280 receiving HDMTX (>1gm/m2) from 19 prospective series
• No difference in OS between mono CHT and combination
CHT (p=0.38)
• MTX ≥3gm/m2 (p=0.04), thiotepa (p=0.03) and intrathecal
CHT (p=0.03) improved survival and nitrosoureas (p=0.01)
correlated with worse survival
• In multivariate analysis, limited to patient receiving ≥ 3
gm/m2 MTX, only the addition of cytarabine improved OS
• A RT dose ≥ 40 Gy to the whole brain or tumor bed did not
improve OS
• RT delay had no negative impact on survival
• Similar findings were reported in another restrospective
analysis by Ferrari et al on 370 patients
Findings
29.
30. • 81 patients analysed, 54 HDMTX only, 27 HDMTX+R
• CR- 36% vs 73% (p=0.0145)
• Median PFS 4.5 months vs 26.7 months (p=0.003)
• Median OS 16.3 months vs not reached (p=0.01)
• A retrospective study by Gregory et al in 120
patients published in Neuro Oncol showed addition
of rituximab is associated with increased OS.
• Care must be given to chances of Hepatitis B
reactivation in HBsAg positive patients when given
Rituximab
Findings
36. Limitations
• Poor protocol adherence
• 40% excluded from primary analysis
• Low statistical power (60%)
• Low accrual period
• Suboptimal chemotherapy use
• Inclusion of small centers with low experience in treating PCNSL
• Lack of quality assurance
• Insufficient neuropsychological evaluation
• Dr. Lisa DeAngelis pointed out that competing risks analysis,
adjusting for the effect of relapse, demonstrates that approximately
24% of patients develop neurotoxicity at 5 years after WBRT, while
the risk of PCNSL recurrence is twice the risk of neurotoxicity, so
WBRT cannot be safely excluded from upfront management.
37.
38.
39.
40.
41.
42.
43.
44. Study N Median
Age
(years)
Chemotherapy WBRT/
Boost
(Gy)
Response PFS OS Neurotoxicity Results and
conclusions
Shah et al,
2007
30 57 RTX, HDMTX,
Pro,
Vin, Cyt
23.4 vs.
45
ORR 93% 2 year
PFS 57%,
median
PFS= 40
months
2 year
OS 67%
None In CR patients
with rdWBRT, 2
year PFS and 2
year OS 79% and
89% resp.
45.
46. Study N Median
Age
(years)
Chemotherapy WBRT/
Boost
(Gy)
Response PFS OS Neurotoxicity Results and
conclusions
Morris et
al, 2013
52 60 RTX, HDMTX,
Pro,
Vin, Cyt
23.4 vs.
45
CR 60%
Objective
response
rate 95%
Median
3.3 years
(7.7
years for
CR/23.4
Gy)
Median
6.6
years
(not
reached
for
CR/23.4
Gy)
None, except
decreased motor
speed
(CR/23.4 Gy)
R-MPV with
rdWBRT in CR is
associated with
high response
rates, long-term
disease control,
and minimal
neurotoxicity
47. HDC+ASCT
Study
Soussain et al
Soussain et al
Brevet et al
Colombat et al
Abrey et al
Montemurro et al
Cheng et al
Illerhaus et al
Illerhaus et al
araC indicates cytarabine; BCNU, carmustine; BEAM, carmustine, etoposide, cytarabine, and melphalan; Bu, busulfan; Cy, cyclophosphamide;
IFO, ifosfamide; MBVP(regimen), methotrexate, carmustine, etoposide, and methylprednisolone; OS, overall survival; TRM, treatment-related
mortality; TT, thiotepa; VP16, etoposide; and WBRT,whole-brain irradiation.
*Only for patients not achieving a complete remission.
†One patient received the treatment as salvage therapy
48. • Systemic high dose
methotrexate based
chemotherapy + Local therapy
• Local therapy either
intravitreal chemotherapy
with methotrexate or
rituximab or ocular radiation
upto 40 Gy
Primary Intraocular Lymphoma
49.
50. Domain Test Description
Attention/Executive (Digits Forward
And Backward; WAIS-III)
Auditory attention
Trail Making Test (Parts A and B) Psychomotor speed (A); sequencing (B)-alternate
form available
(flexibility index = B-A)
Brief Test of Attention Auditory working memory
Verbal memory Hopkins Verbal Learning Test—Revised 12-word list:
Three learning/recall trials
Delayed recall
Recognition (discrimination index)
Six alternate forms
Motor Grooved Pegboard Test Motor speed and dexterity (dominant and
nondominant hand)
Quality of life EORTC-QLQ 30 30-item self-report scale (physical, social,
emotional, cognitive status)
BCM 20 20-item self-report scale (tumor and treatment-
related symptoms)
Premorbid IQ Estimation Barona Index Weighted composite score on the basis of age,
gender, race, residence, education, and occupation
Neurocognitive assessment
Correa DD, Maron L, Harder H, et al. Cognitive functions in primary central nervous system lymphoma: literature review and assessment
guidelines. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2007;18(7):1145-1151
51. • CR- complete disappearance and not receiving
corticosteroids in last 2 weeks, no ocular lymphoma,
negative CSF in previously positive patients
• CRu- Meets criteria of CR but continues to require
corticosteroids
• PR- at least 50% decrease in contrast enhancing lesion,
decrease in vitreal cell count, retina/optic nerve
infiltration, CSF may show malignant disease
• SD- not meeting criteria of CR, CRu, PR, PD
• PD- >25% increase in CE lesions, new site, increase in
vitreal cell count
Response Criteria
Abrey LE, Batchelor TT, Ferreri AJ, et al. Report of an international workshop to standardize baseline
evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 2005; 23:5034
52. • Leptomeningeal disease- MTX 12mg weekly
intrathecally or through ommaya reserviour
• Older patients- dose adjustment, RT may be
deffered till progression, proper monitoring of
kidney functions
• In HIV positive: MTX based chemotherapy with anti
retroviral therapy with or without radiation
Special scenarios
53.
54. • Retreatment with methotrexate (ie, 3 to 8 g/m2 ) or
methotrexate based combination chemotherapy if there has
been a prior complete remission with this agent
• Alternative chemotherapy regimens (eg, topotecan,
cytarabine, temozolomide, thiotepa, pemetrexed including
high dose chemotherapy followed by autologous
hematopoietic cell transplantation (HCT)
• Whole brain radiation therapy in previously nonirradiated
patients, stereotactic radiotherapy may be an option for
patients who have received whole brain radiation
Treatment of refractory or
relapsed disease
57. Conclusions
• High dose methotrexate based chemotherapy with
consolidation cytarabine is the mainstay of treatment
• WBRT should be included in the treatment especially in
young patients (<60 years), response adapted approach may
be beneficial
• Rituximab may be tried in upfront management or can be
reserved for recurrence
• Local therapy is recommended for Intraocular lymphoma, or
leptomeningeal involvement along with systemic therapy
• Targeted therapies are investigational
58. Immuno-competent patients of newly diagnosed primary CNS lymphoma
Five 14-day cycles of induction chemotherapy with
methotrexate, procarbazine, and vincristine (MVP)
Investigations
Response Assessment
Neuropsychological & QoL assessment
Complete Response
Partial Response/Stable
Disease/Progressive disease
Reduced dose WBRT
23.4Gy/13#/2.5 weeks
Standard dose WBRT
45Gy/25#/5 weeks
Consolidation Chemotherapy
Inj cytarabine (Ara-C), 2 cycles 1 month apart
Response assessment-CMRI brain every 3 months
Neuropsychological & QoL assessment 6 monthly post T/t completion