Controversies in management of low grade glioma

1. Healing rays for low
grade glioma – what’s
the contention?
Dr Bala Vellayappan MBBS, FRANZCR, MCI
Consultant Radiation Oncologist and Research Director
National University Cancer Institute, Singapore
Assistant Professor, YLLSoM NUS

2. Outline
• Demystifying radiation therapy in 5 minutes
• Rapid review of practice changing RT trials
• Alternative approaches
• Where do we go from here?

3. What is radiotherapy and how does it work?
• Linear accelerator
• >60 year history
• Beams are shaped to
conform to the tumour

4. Rationale for RT
• Gliomas are diffuse.
Tumour cells can be found
far beyond the gross
disease
• The ray reaches further
than the scalpel.
• Early trials have shown RT
to improve survival c.f to
observation and adjuvant
chemotherapy.
A = Observation
B = BCNU chemotherapy
C = Radiotherapy
D = BCNU + Radiotherapy
Sahm Arch Neuro 2012 p 523
Walker NEJM 1980

5. Rationale for fractionation
• Exploits differential repair
capacity between tumour
and normal cells
• Because gliomas are diffuse,
a portion of “normal” brain
parenchyma needs to be
irradiated -->fractionation
allows for tissue repair in
between sessions
• 50Gy in 25 fractions = 20 Gy
in 1 fraction

6. Evolution of RT delivery..
Conventional (before 2005) Intensity modulated radiotherapy
(standard of care currently)

7. The process..
1 to 1.5 cm

8. Dilemma in glioma
• RT is harmful and can be dispensed with..?
Glioma : principles and practice of
neuro-oncology
Karim et al 1991

9. What’s the scientific rationale for early
treatment?

10. Early studies showed RT to improve
neurocognition..?!
Brown JCO 2003 p2519

11. Side effects of RT
• Multifactorial
• Patient factors – age, comorbidities
• Treatment factors – RT dose, fractionation, use of concurrent
chemotherapy
• Tumour factors – volume of initial tumour (related to volume of RT),
location of tumour (?next to critical structures)
• Acute (<3m) : lethargy, alopecia
• Sub-acute (3-6m ) : somnolence
• Late (>6m) : risk of radiation necrosis, risk of cognitive changes, risk of 2nd
malignancy, pituitary dysfunction, ?vascular effects

12. Side effects of RT
• Multifactorial
• Patient factors – age, comorbidities
• Treatment factors – RT dose, fractionation, use of concurrent
chemotherapy
• Tumour factors – volume of initial tumour (related to volume of RT),
location of tumour (?next to critical structures)
• Acute (<3m) : lethargy, alopecia
• Sub-acute (3-6m ) : somnolence
• Late (>6m) : risk of radiation necrosis, risk of cognitive changes, risk of 2nd
malignancy, pituitary dysfunction, ?vascular effects. Tumour recurrence

13. Not all parts of the brain are equal
• Dose to hippocampus is related
to the neurocognitive decline
• dose to >40% bilat hippocampi
>7.3Gy associated with
impairment in word recall
Gondi 2012 IJROBP 487

14. What do the international
guidelines recommend?

15. NCCN 2019

16. Practice changing RCTs
• Grade 2 : Early RT vs delayed RT (EORTC non-believers)
• Grade 2 : Role for dose-escalation (EORTC, RTOG believers)
• Grade 2 : High-risk LGG : RT vs chemoRT (RTOG 9802)
• Grade 2 : chemo alone (RTOG 0424)
• Grade 3: RT vs chemoRT ( RTOG 9402, EORTC)
• Grade 2/3 1p19q codeleted (CODEL) : RT vs chemoRT
• Grade 3 1p19q non-codeleted (CATNON) : 2x2 (RT alone, RT + PCV, RT
+ TMZ)
• Grade 3 : chemo alone (NOA-4)

17. Believers trials
EORTC
N=379
45 vs 59.4 Gy
No diff in OS
NCCTG/RTOG/ECOG
N=203
50.4 vs 64.8Gy
No diff in OS
Shaw JCO 2002 p2267 Karim IJROBP 1996 p 549

18. Non-believers. Upfront vs salvage
Van Den Bent Lancet 2005 p 985
Resected
supratentorial
LGG
N= 311
ECOG 0-2
1986 – 1997
R
Surgery +
upfront RT 54Gy
Surgery
observation.
RT,chemo for
salvage
HR 0.59 (0.45 –
0.77) p<0.0001
Median PFS 5.3 v
3.4 y
HR 0.97 (0.71 –
1.34) p=0.87
Median OS 7.4 v
7.2 y
Better seizure
control with early
RT

19. Is this 30 year old trial still valid?
• Pre-MRI era
• Post-op CT not required.
• Followup schedule not close enough (q4m for 2y, then annually --with CT)
• On progression, majority of observation group was salvaged (90%), but
only 2/3 of RT group were salvaged.
• Within observation group, 1/3 could not receive salvage RT (missed the
boat)
• No QoL/neurocog data –observation group may have had worse QoL and
neurocog (because of progression, or more anti-epileptics??)
• Details of RT volume not apparent : observation group may have required a
larger RT volume due to progression

20. RTOG 9802: does addition of chemo to RT
improve outcomes?
Phase III
N=250 with LGG
Divided into low risk and
high risk groups
High risk = >40y, or less
than gross total
resection (surgeon’s call)
High
risk
group
R
RT alone 54Gy
RT alone 54Gy +
6 cycles PCV
Outcomes
• PFS
• OS
Buckner NEJM 2016 374 p1344

21. Median survival 13.3 YEARS (!!!) vs 7.8 years
Survival difference only apparent after 4 years
Changed our practice towards LGG – best prognosis patients
benefited the most.
Caveat : Does not answer the question of whether we should
observe after surgery

22. RT vs RT/PCV for Anaplastic ODG
RTOG 9402 EORTC 26951
• N= 368
• RT 59.4Gy + 6 PCV vs RT 59.4Gy
alone
• OS better with chemoRT
• N=291
• 4 PCV + 59.4Gy RT vs RT 59.4Gy
alone
• No diff in OS overall, but co-
deleted group had profound
survival benefit with chemoRT
Cairncross JCO 2013 p337 Van den Bent JCO 2013 p 344

23. Phase III Trial of Anaplastic Glioma
Without 1p/19q LOH (CATNON)
1:1:1:1 Randomization, n=751
RT
RT/TMZ
RT--> TMZ
RT/TMZ-->TMZ
Adjuvant TMZ improved OS (5y
OS 44 -->56%)
Benefit of concurrent TMZ
unclear
Lancet 2017 390 p1645

24. RT With Concomitant and Adjuvant Temozolomide Versus RT With Adjuvant PCV
Chemotherapy in Patients With Anaplastic Glioma or Low Grade Glioma (CODEL)
ClinicalTrials.gov Identifier: NCT00887146

25. Summary
• Favourable molecular type
• MRI-defined gross total resection ->close followup reasonable
• Biopsy/STR, or still has significant neurological deficits, older patients : early adjuvant treatment
• Grade 3 : usually early adjuvant treatment
• Exception : IDH – wild type (with other risk factors EGFR amp, +7/-10 or TERT) -->early adjuvant treatment
Courtesy of Lia Halasz, U of Washington,
ASTRO

26. Alternative approaches

27. Can we use chemo alone for Grade 2?
Baumert Lancet oncology 2016
At least one high risk feature :
age >40
progressive disease
>5cm
crossing midline
neuro symptoms
Caveat : given strong survival benefit
from combination approach, we should
not offer monotherapy alone.
ALL or NONE approach
Median PFS 46m RT, 39m TMZ
RT 50.4Gy
ddTMZ x 12

28. Can we use chemo alone for Grade 3?
No diff in OS
whether we start
with chemo first
or RT first ..
But surveillance and early
salvage is important
Molecular subtype NOA-4 overall
survival
RTOG94-02 overall
survival
1p19q co-deleted 9.8 y 14.7y
1p19q non-
codeleted
4.5 y 5.5 y
Wick JCO 2009 p5874

29. Are we obliged to discuss adjuvant RT for all
LGG?
Phase III Trial Inclusion Experimental Standard
EORTC 22845 G2 Delayed RT Immediate RT
RTOG 9802 High-risk LGG (Grade 2) RT + PCV RT alone
RTOG 9402 G3 OD PCV + RT RT alone
EORTC 26951 G3 OD RT + PCV RT alone
NOA-4 G3 Chemo upfront RT upfront
CATNON G3 non-codeleted RT + chemo RT alone
CODEL G2,3 co-deleted RT + chemo RT alone

30. Future direction

31. The role of proton therapy in LGG

32. IDH mutated 1p/19q intact lower grade glioma
following resection: Wait Or Treat? IWOT – A
phase III study
Histologically WHO
grade II (diffuse) or III
(anaplastic)
astrocytoma, IDHmt
without 1p/19q co-
deletion
Phase III, RCT
R
50.4 Gy RT -
-> TMZ x 12
Observation, and
salvage treatment
Primary outcome : next-
intervention free-survival
Secondary outcome : PFS, OS,
HRQoL from seizures
Planned accrual :624 , from >60
sites
EURADCT 2018-003539-31
ClinicalTrials.gov Identifier: NCT03763422

33. Conclusion
• The management of glioma is evolving. Contemporary trials stratifying by mlq
classification are needed.
• LGG remains incurable, aim of treatment is to provide tumour control and
maintain QoL
• Tumour recurrence and cancer therapy (surgery, RT, chemo) can affect
neurocognition and QoL
• There may be a role for close surveillance in LGG who have undergone GTR,
without causing OS detriment --> trigger to initiate treatment is unclear
• The “standard” management should be discussed with patients until we have
good level 1 evidence to do otherwise
• Slant towards earlier treatment in older patients, patients with significant
residual disease, persistent neurological symptoms and IDH-WT (with RF)
• If we decide to give post-op treatment --> combined modality

34. Thank you!
Bala_vellayappan@nuhs.edu.sg