Study to evaluate the feasibility of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients of newly diagnosed primary central nervous system lymphoma

1. Candidate
Dr. Narayan Adhikari
Junior Resident, Department of Radiation Oncology
Dr. B.R. Ambedkar Institute Rotary Cancer Hospital
All India Institute of Medical Sciences (AIIMS)
New Delhi
Study to evaluate
the feasibility of response adapted whole brain
radiotherapy after methotrexate based chemotherapy
in patients of newly diagnosed primary CNS lymphoma

2. Chief Guide
Dr. Ahitagni Biswas
Assistant Professor
Department of Radiation Oncology
Co-guides
Dr. Ranjit Sahoo
Assistant Professor
Department of Medical Oncology
Dr. Suman Bhasker
Additional Professor
Department of Radiation
Oncology
Dr. V. Sreenivas
Professor
Department of Biostatistics
Dr. M.C. Sharma
Professor
Department of Pathology
Dr. Manmohan Singh
Additional Professor
Department of Neurosurgery
Dr. Lalit Kumar
Professor and Head
Department of Medical Oncology
Dr. Ashima Nehra
Associate Professor
Department of Clinical
Neuropsychology
Dr. Ajay Garg
Additional Professor
Department of Neuroradiology
Dr. Subhash Chander
Professor and Head
Department of Radiation Oncology

3. Introduction
• Primary CNS lymphoma(PCNSL)-
• extranodal malignant lymphomas
• arise within the brain, eyes, leptomeninges or spinal cord
• absence of systemic lymphoma
• Modern first line therapy
High dose methotrexate(HDMTX) based chemotherapy in combination with
Whole Brain Radiotherapy(WBRT)
• WBRT
• improved progression free survival
• treatment related neurotoxicity
• Reduction of dose in complete responders to HDMTX
• high response rate
• long term disease control
• minimal neurotoxicity

4. Epidemiology
• In USA, PCNSL : 4% of newly diagnosed primary CNS tumours
• Age adjusted incidence rate : 4 cases per million persons per year
• Slight male predominance of the disease
• Incidence increasing in elderly and immunocompetent, decreasing
in immunocompromised/HIV AIDS patients
• Age at presentation: 45-70 with median age at diagnosis in the
fifth decade in immunocompetent and earlier in
immunocompromised
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

5. Indian Scenario
• PCNSL - about 1% of total intracranial tumours, according to
hospital based studies
• No increase in incidence in past decades
• Slight male predilection
• Age at presentation – a decade earlier than west
• Mostly immunocompetent only, because of earlier deaths in
immunocompromised/HIV AIDS patients
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

6. Pathology
• 95% DLBCL
• Majority being activated B-cell or Type 3, indicating overlapping
state of differentiation
• Mostly EBV associated with PCNSL in immunocompromised
• EBV associated with immunocompetent patients rare and mostly
T-cell or NK-cell origin
Commins DL. Pathology of primary central nervous system lymphoma. Neurosurg Focus. 2006;21(5):1-10

7. Review of literature

8. SN Study N Median
Age
(years)
Chemotherapy WBRT/
Boost
(Gy)
Response PFS OS Neurotoxicity 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 Abrey et
al, 2000
52 65 MTX, Vin,
Pro, 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)
3 RTOG 93-
10, 2002
102 56.5 MTX (IV and
IT), 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
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
4 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)

9. SN Study N Median
Age
(years)
Chemotherapy WBRT/
Boost
(Gy)
Response PFS OS Neurotoxicity Results and
conclusions
5 Shah et al,
2007
30 57 RTX, HDMTX,
Pro,
Vin, Cyt
23.4 vs.
45
ORR 93%,
77% CR
after all t/t
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.
6 Ferreri et
al, 2011
retrospecti
ve
33 55 MTX based Whole
brain:
30-45
Gy,
tumour
bed: 36
to 54
Gy
5 year
OS 54%
Significantly less
neurologic
impairment, as
measured by
MMSE, in
patients treated
with 30 – 36
Gy vs. ≥ 40 Gy ( p
= 0.05)
WBRT doses ≥40
Gy not asso. with
improved disease
control compared
to dose of 30 - 36
Gy (relapse rate,
46% vs. 30%; 5-
year FFS, 51% vs.
50%; p = 0.26)
7 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
8 G-PCNSL-
SG-1, 2010
551
(318
per
proto
col)
63 HDMTX +/- Ifos 45 vs.
None
Median
18.3 m
(RT arm)
vs. 11.9
m (no
RT arm),
p=0.14
Median
32.4 m
(RT
arm) vs.
37.1
(no RT
arm)
Sustained CR:
22/45 in RT arm
(49%)
vs. 9/34 (26%) in
no RT arm
Omission of
WBRT
compromises OS
(non inferiority
margin 0.9,
HR=1.06, 95% CI
0.8-1.4, p=0.71)

10. Discussion
• In patients with a CR to chemotherapy, escalating the WBRT dose above 36 Gy
does not improve oncologic outcomes but does increase neurotoxicity(1)
• Dose reduction in patients with CR to induction chemotherapy associated with
high response rates, long-term disease control, and minimal neurotoxicity(2)
• Incidence of cognitive dysfunction in PCNSL underestimated due to absence of
neuropsychological evaluation, use of insensitive tests, inadequacy of tests like
MMSE to address all the cognitive domains(3)
1. Ferreri AJM, Verona C, Politi LS, et al. Consolidation radiotherapy in primary central nervous system lymphomas: impact on outcome
of different fields and doses in patients in complete remission after upfront chemotherapy. Int J Radiat Oncol Biol Phys.
2011;80(1):169-175
2. Morris PG, Correa DD, Yahalom J, et al. Rituximab, Methotrexate, Procarbazine, and Vincristine Followed by Consolidation Reduced-
Dose Whole-Brain Radiotherapy and Cytarabine in Newly Diagnosed Primary CNS Lymphoma: Final Results and Long-Term Outcome. J
Clin Oncol. 2013;31(31):3971-3979
3. 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

11. Rationale of Study
• Reduced dose WBRT in PCNSL patients with CR to chemotherapy
proven better in terms of neurocognitive outcome without
compromise in disease control in western studies, no such studies
in Indian context
• Correlation between EBV positivity, molecular subtyping with
treatment outcome may open further doors of research for
personalised treatment
• No such study with detailed neurocognitive tests and quality of
life assessment using test batteries designed for Indian
population

12. Aims and Objectives
• To evaluate the feasibility of response adapted WBRT in PCNSL
patients after methotrexate based chemotherapy
• To assess Epstein-Barr Virus (EBV) positivity and molecular
subtyping and their correlation with treatment outcome
• To assess the toxicity profile, neurocognitive effects of treatment
and serial changes in quality of life

13. Materials and Methods
• Study design: two-arm phase II trial
• Study population: Newly diagnosed immunocompetent patients
of primary CNS lymphoma
• Place of Study: Institute Rotary Cancer Hospital, All India Institute
of Medical Sciences, New Delhi
• Sample size: 20

14. Patient inclusion criteria
• Age: 18-65 years
• Patients of either sex
• Performance status (PS): ECOG 0-3
• Biopsy proven primary CNS lymphoma
• Immunocompetent status (HIV sero-negative)
• Baseline investigations should be within acceptable limits
• Informed Consent

15. • Performance status ECOG 4
• Immunocompromised status
• Any prior oncologic treatment with surgery, chemotherapy or
radiotherapy
• Presence of systemic lymphoma involvement outside CNS and
any other synchronous malignancies
• Any comorbidity which compromises chemo-radiotherapy
treatment schedules
Patient exclusion criteria

16. Study Design

17. 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 x 2 years
Neuropsychological & QoL assessment 6 & 12 months post T/t completion

18. End points
Primary endpoint
•Response rate
•Progression free survival (PFS)
Secondary endpoint
•Overall survival (OS)
•Toxicity profile
•Neuropsychological effects of treatment
•EBV positivity rate, molecular subtypes & correlation with
treatment outcome

19. Investigations
• HMG, LFT, KFT
• SLDH
• HIV serology
• CMRI brain
• Stereotactic biopsy + EBV LMP-1 + molecular subtyping
• Ophthalmic examination (Slit lamp)
• CSF cytology + chemistry
• CECT neck+ chest+ abdomen
• Bone marrow aspirate + biopsy
• Neuropsychological & QoL assessment

20. Treatment
• Induction Chemotherapy:
• Five 14-day cycles with methotrexate, procarbazine, and vincristine (MVP)
• Day 1: Inj Methotrexate 3.5 g/m2 IV over 2 hours; Inj Vincristine 1.4 mg/m2 IV push
• Days 1 to 7: Cap Procarbazine 100 mg/m2/day (odd cycles only)
• Hydration, alkalinisation and leucovorin rescue
• Radiotherapy:
• 3-5 weeks after completion of MVP chemotherapy
• In case of complete response on MRI after chemotherapy, WBRT 23.4 Gray/13 fractions/2.5 weeks
• In case of partial response, stable disease or progressive disease, WBRT 45 Gray/25
fractions/5weeks
• Consolidation Chemotherapy:
• After completion of WBRT, two cycles of Inj cytarabine (Ara-C)- 3 gm/m2
/day over 3 hours
(maximum daily dose, 6 gm) for 2 days, 1 month apart

21. Assessments
• Response assessment on CEMRI of brain
• 1 month after completion of five cycles of MVP chemotherapy
• 3 months after completion of WBRT
• Every 3 months for first 2 years after completion of treatment and 6 monthly
thereafter (for follow-up)
• Treatment related acute toxicity assessment using Common
Terminology Criteria for Adverse Events version 4 (CTCAE v4)
• Neurocognitive assessment for neuropsychological functions and
quality of life
• at baseline
• after completion of MVP chemotherapy
• 6 & 12 months after completion of cranial radiotherapy

22. Result Analysis
• Number of patients, % of treatment completion, % EBV positivity,
% of Molecular Subtypes
• Response Rate
• Progression free survival (PFS) - duration of time from date of
diagnosis to the date of clinical or radiological disease
progression
• Overall survival (OS)- duration of time from date of diagnosis to
the date of death or last follow-up
• Patients alive at last follow-up will be censored
• PFS and OS will be evaluated by Kaplan- Meier product limit

23. Statistical Analysis
• Univariate analysis of PFS & OS with respect to EBV status &
molecular subtype by Log Rank test
• Neuropsychological test results to be summarized using
descriptive statistics, and t tests will be used for longitudinal
comparisons

24. SN FUNCTION TEST SOURCE TIME
TAKEN
AVAILABILITY
1 COGNITION PGI – Memory Scale (Attention &
Concentration, Delayed Recall, Immediate
Recall, Simple Memory, New learning ability,
Visual Retention & Recognition)
PGI BBD (Pershad &
Verma 1990)
20 Mins Test Bought by Department of
Clinical Neuropsychology &
Permission given by the author to
Dr. Ashima Nehra (who is a co
guide) to use test for clinical &
research purposes.
2 EXECUTIVE
FUNCTIONS
Controlled Oral Word Association Test
(Verbal Fluency)
NIMHANS Battery
(Rao et al 2004)
2 Mins Test Bought by Department of
Clinical Neuropsychology
Color Trail Making Test A; Color Trail Making
Test B
(Visual Attention & Task Switching)
NIMHANS Battery
(Rao et al 2004)
10 Mins
Stroop Color Word Test
(Reaction Time / Response Inhibition)
NIMHANS Battery
(Rao et al 2004)
15 Mins
3 MOTOR SPEED Digit Symbol Substitution Test (DSST) NIMHANS Battery
(Rao et al 2004)
7 Mins Test Bought by Department of
Clinical Neuropsychology
4 VISUAL
CONSTRUCTION
Nahar and Benson Test (N&BT) PGI BBD (Pershad &
Verma 1990)
5 Mins Permission given by the authors
to Dr. Ashima Nehra (who is a co
guide) to use test for clinical &
research purposes.
5 LANGUAGE Indian Aphasia Battery (IAB) (Speech &
Language: Set B-9) (Naming Subtest)
Nehra et. al. 2013 2 Mins Test developed by Dr. Ashima
Nehra
6 MOOD Brief Mood Introspection Scale (BMIS) John D. Mayer &
Gaschkey.in 1988
5 Mins PUBLIC DOMAIN
7 QUALITY OF LIFE EORTC-QLQ 30 Aaronson et al 10 Mins Permission given by the authors
to Dr. Ahitagni Biswas (who is the
chief guide) to use test for clinical
& research purposes.
BN 20 Taphoorn MJ et al 5 Mins
Total time 81 Mins
Neurocognitive Assessment

25. Ethical Issues
• Subject will have a right to withdraw any time throughout the
study
• Clearance from the Ethics Committee of AIIMS will be taken
• Informed consent from the patient/guardian will be taken

26. Thank you