Prophylactic cranial irradiation

1. Prophylactic Cranial Irradiation
Dr. Shreya Singh
JR-III
Department of Radiation Oncology
IMS, BHU

2. Introduction
• Technique used to combat the occurrence of
brain metastasis in highly aggressive cancers with
tendency to metastasize to brain
• PCI is intended as preemptive treatment in
patients with no known current intracranial tumor,
but with high likelihood for harboring occult
microscopic disease and eventual occurrence

3. No demonstrable evidence of CNS disease
Imaging
CSF Studies

4. Rationale For PCI
Blood Brain Barrier

5. Rationale for PCI
• Brain is a sanctuary site
• Poor penetrance for
chemotherapy
• High incidence of CNS
metastasis

6. Indications
• Small cell lung cancer
• Leukemia
Controversial-
o NSCLC
o Extra-pulmonary small cell cancer
o Uncommon – Testicular lymphoma

7. Brain Metastases in SCLC
• 10% patients have brain mets at diagnosis
• During the course of treatment – 50 to 80%
• MRI will detect brain metastases in 10 to
15% of neurologically asymptomatic
patients
• Sequelae –
o Decreases survival
o Serious impairment of QoL
o Potentially devastating impact on
neurocognitive function
Hirch, Cancer,1962
Hochstenbag, J Neurooncology 2000

8. Modified VALSG Staging System

9. PCI in LS-SCLC
• Arrigada et al,→ Prospective randomised study
• Auperin et al, → Meta-analysis – 987 patients
PCI Observation
2 year rate of brain
mets
40% 67%
Fraction died due
to brain mets alone
19% 45%
PCI Observation
3 year rate of brain
mets
33.3% 58.6%
Increase in OS 20.7% 15.3%

10. PCI in LS-SCLC
• Auperin Meta Analysis –
o Landmark study
o Higher dose better control
o Early initiation better than late initiation
o All age groups showed benefit
o Caveat- CR assessed by Chest X-Ray only

11. PCI in ES-SCLC

12. PCI in ES-SCLC
• Landmark trial by EORTC
• Studied the role of PCI in ES-SCLC
• 286 patients who responded to chemotherapy
Slotman et al, NEJM, 2007

13. PCI in ES-SCLC
Control PCI
Risk of brain mets 40% 15%
1 year survival rate 13% 27%
Slotman et al, NEJM, 2007
CAVEAT :
NO BRAIN IMAGING DONE
PRIOR TO PCI

14. PCI in ES-SCLC
• Japanese Group- Randomized 224 patients
• PCI vs no PCI
Takahashi, 2017, Lancet Oncology

15. PCI in ES-SCLC
• Takahashi et al showed no improvement in OS
despite significant decline in incidence of
brain mets
• Following this study, NCCN has introduced
MRI surveillance (3 monthly) as an alternative
to PCI in ES-SCLC

16. PCI in NSCLC?

17. Extra Pulmonary Small Cell Carcinoma
• 2.5% to 4% of all small cell cancers
• 6.4% cases develop brain mets
• Management of EPSCC is modeled on SCLS as no prospective
data exists for this uncommon disease
Naidoo JTO, 2013
• Conclusion :
Brain metastases were uncommon in EPSCC compared with
small-cell lung carcinoma. PCI is thus probably not warranted in
this disease.

18. PCI Doses
• 720 patients
• 25 Gy in 10 # vs 36 Gy in 18 #
Le Pechoux et al, 2009, Lancet Oncology
Do higher doses offer better control ??

19. PCI Doses
RESULT:
No significant reduction in incidence of brain metastases in higher dose arm
There was significant increase in chronic neurotoxicity at the end of 1 year
PCI at 25 Gy should
remain standard of care
for LS-SCLC
Le Pechoux et al, 2009, Lancet Oncology

20. Disease Local Control OS Eviidence
SCLC
LS Yes Yes Indicated
ES Yes Yes PCI vs MRI
surveillance
NSCLC Yes No Not indicated
EPSCC NA NA Not indicated

21. Leukemia
Evans, Cancer, 1970

22. Leukemia
• Risk of CNS involvement at diagnosis is low i.e. 3% to 7%
• In absence of CNS directed prophylactic therapy, >50% of
adult patients with leukemia will develop CNS relapse
• CNS prophylaxis can be achieved by
o Radiation (cranial or craniospinal)
o Intrathecal chemotherapy
o High dose systemic chemotherapy, or combinations of
these

23. AML
• CNS relapse is unusual i.e. 5% to 10 %
• Role of Cranial prophylaxis not well defined for AML
• Some studies show no difference in relapse rate with cranial
irradiation
• High WBC at diagnosis ,monocytic variant – common causes
for CNS relapse
• CNS relapse – poor prognosis

24. ALL
Role of Radiotherapy in ALL :
• Cranial prophylaxis
• Cranial treatment (all CNS involvement )
• Craniospinal irradiation (overt CNS involvement in adult ALL)

25. ALL
Backbone to modern leukemic treatment consists of following
steps:
• Induction phase
• Early intensification
• Consolidation → CNS preventive therapy
• Delayed intensification
• Maintenance phase - targeted at eliminating residual disease

26. Risk Factors for CNS involvement in
ALL
• T-cell immunophenotype
• High leukemic cell proliferation index
• Mature B-cell subtype
• Elevated LDH levels
• Others –
– Age : <1 year, >10 years
– WBC > 50,000
– Philadelphia chromosome

28. CNS Prophylaxis in ALL
• In most regimens, CNS prophylaxis for patients at lower risk is
achieved with systemic and intrathecal chemotherapy without
cranial irradiation
• Children with high-risk features are at an increased risk of CNS
relapse and, historically, have received prophylactic cranial
irradiation
• Infants younger than age 12 months with 11q23 abnormalities
are at high risk of CNS relapse but because of their young age
are usually treated without cranial irradiation, using
intensified systemic and intrathecal chemotherapy

29. Current Status in ALL

30. • Does not recommend PCI in children / adults with
CNS1 and CNS2
• Cranial RT in :
o CNS 3
o CNS relapse
o Pre HCT (Hematopoietic cell transplant)

31. Dose
• Historically, the standard dose for high-risk ALL cranial prophylaxis
had been 1800 cGy
• Berlin-Frankfurt-Munich (BFM) group used 1200 cGy in patients
with CNS-1 disease with good results
• The standard dose for prophylactic cranial irradiation in those
patients with high-risk disease still treated with irradiation is now
1200 cGy
• For patients with an isolated CNS relapse occurring 18 months or
more after initial diagnosis, a dose of 1800 cGy to the cranial field
has been shown to be effective

32. Dose Overview
BFM-95

33. Timing of PCI
• Earlier initiation of PCI following chemotherapy
• Should not be given together – High neurotoxicity
• SCLC :
– CTRT ends → Start PCI immediately
• ALL :
– IT-MTX /Cytarabine → 2 weeks→ PCI
– Gap can be kept to a minimum of 48-72 hours if
urgent RT is necessary

34. RT Planning Technique
Volumes :
o SCLC
 Entire brain parenchyma
o Leukemia
 Entire subarachnoid space – Intracranial and
extracranial
 Extracranial subarachnoid space - use of high dose
intrathecal MTX
 Radiation ONLY to intracranial component

35. RT Planning Technique
The technique for cranial
irradiation must ensure
coverage of the cranial
meninges as well as other
areas of potential access to
the CNS such as :
 Cribriform plate
 Posterior retina and
posterior globe of eye
 Inferior extent of temporal
meninges

36. RT Planning Technique

37. RT Planning Technique

38. RT Planning Technique

39. RT Planning Technique
• To ensure adequate dose to the meninges, the entire calvaria
is covered and the energy should be 4 MV or 6 MV photons
• Custom blocks can be used to shield normal tissues
• Parallel opposed lateral fields are used
• Immobilisation is critical to ensure precise treatment and
reproducibility and use of immobilisation devices is
recommended when possible

40. RT Planning Technique
• Sedation may be required for younger patients who are
unable to fully co-operate
• Every field should be treated in every sessions
• Daily single dose is administered in 5 sessions per week until
the total dose has been applied
• Angulation of the beam (3-5 deg posterior) - To avoid
ophthalmological complications

41. Recent Advances
• Results extrapolated from studies for brain mets
• Hippocampal Sparing PCI :
o RTOG – 0933
o HA-WBRT resulted in a mean decline of 7% in HVLT-DR scores from
baseline to 4 months, which was significantly lower
o Dutch Study
o No mets in avoidance region
o Decline by ≥ 5 points on HVLT-total recall score in 28% patients
o No significant difference in two arms
• Memantine / Donepezil
o RTOG – 0614
o Less decline in delayed recall at 24 weeks - NS

42. Radiation Induced Brain Injury
• Leads to an acute increase in BBB leakiness and edema
• White matter necrosis often occurs following brain
irradiation
• Brain irradiation leads to an acute burst in apoptotic
cell death
• Structural alterations – demyelination and vasculopathy

43. Toxicity
• Acute :
o Fatigue
o Alopecia
o Pharyngitis
• Chronic :
o Neurocognitive defects
o Endocrine disorder – growth retardation
o Secondary malignancy
o Delayed dentition
o Cataract formation