Germinomas: An Evolution in the Use of
Radiation
Marka Crittenden M.D. Ph.D.
Resident Department of Radiation Medicine
Talk Outline
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Overview of Germ Cell tumors
Case Presentation
Traditional Radiation Treatment for Germinoma
Alternate therapeutic Approaches
– Chemotherapy alone (International study)
– Reduced Field Radiation without Chemotherapy
(Royal Marsden Lancet Review)
– Combined Approaches
• COG ACNS 0232
Overview of Germ Cell Tumors
• Rare-2% of pediatric tumors in North America
– Germinoma-60-70%
– “Malignant” subtypes 15-20%
• Embryonal, endodermal sinus, choriocarcinomas
– Teratomas benign, immature and malignant 1520%
• Malignant-admixture of benign teratoma with one or
more malignant germ cell lines
Overview of Germ Cell Tumors
• Anatomy
– occur in diencephalic structures-almost exclusively
midline 3rd ventricle
– Pineal region
• Most Frequent 50-60%
– Suprasellar
• 30-35%
– Rare
• Basal ganglia and thalamic nuclei
– Multifocal – Pineal and suprasellar “multiple midline
germinomas” 20%
Overview of Germ Cell Tumors
• Epidemiology
– Pineal germioma
• Adolescent males
– Suprasellar
• First 2 decades no gender predilection
– Teratomas
• Teratomas-young children
– “Malignant” histiotypes
• Older childrem adolescent and young adults
Overview of Germ Cell Tumors
• Presentation
– Pineal tumors
• Elevated intracranial pressure-compression of sylvian aquaduct
• Parinaud’s syndrome-ocular symptoms of decrease upward gaze,
near-light dissociation, diminished convergence
– Suprasellar
• Diabetes insipidus, precocious or delayed sexual development,
visual deficits
– Serum Markers
• AFP-serum or CSF in embryonal, endodermal sinus or malignant
teratoma-if posistive excludes a pure germinoma
• Β-HCG- 10IU-70IU in 10-20% pure germinomas, >1000IU
choriocarcinoma
Overview of Germ Cell Tumors
• Diagnosis
– Need for biopsy controversial
• Recommended for pineal tumors
• Suprasellar – biopsy considered essential
• If elevated tumor marke-any AFP orβ-HCG more then
100 some consider adequate to diagnose “malignant”
GCT
Case Presentation MN
• CC: Headache
• HPI: 11 year old boy who presented to OSH with
a 1 month history of HA, polyuria, polydypsia and
a several day history of double vision.
• Imaging: MRI revealed a tumor in the pineal and
pituitary region with associated hydrocephalus.
– 2.7 x 2.2 cm (pineal)
– 1.9 x 1.5 x 1.2 cm (suprasellar tumor)
Case Presentation MN
Case Presentation MN
• Laboratory evaluation revealed panhypopituitarism, nml
AFP and beta-HCG in both serum and CSF.
• Management:
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5/9/2008 placement of EVD
5/14/2008 craniotomy with biopsy – non-diagnostic
5/16/08 VP shunt placement
5/29/08 Second craniotomy with biopsy-non-diagnostic
Treatment of panhypopituitarism treated with DDAVP,
hydrocortisone, and levothyroxine
– 6/27/2008 Endoscopic biopsy of third ventricle and pineal
region tumor.
• Findings – small amount of tumor noted to be coating the floor of the
third ventricle as well as a fluffy tumor in the posterior third ventricle.
Biopsies were obtained.
Case Presentation MN
• Pineal Tumor biopsy – Pathology
– Lymphohistiocytic inflammation with rare
embedded OCT 3 / 4 (+) atypical cells. Most
compatible with germinoma.
• Treatment Plan: COG ACNS 0232 4 cycles of
carbo/etoposide plan individualized to receive
4 cycles of carboplatin and etoposide) 7/31/08
- 10/10/08. Followed by whole ventricular
radiation therapy to 24 Gy with tumor boost
to 30 Gy.
Radiation and Germinomas
• Germ Cell Tumors
– 3-5% primary brain tumors in children and young
adults
• 50-60% Germinomas
• Most common in male children ages 10-20 and arise in
midline locations such as pineal and suprasellar regions
• Traditional radiation for primary CNS
Germinoma’s.
– Large Volume/high dose radiotherapy.
• CSI 30-36Gy
• 15 Gy boost to primary tumor.
• 10 year OS >80%
CSI rational
– Sung et al 1978 (pre-CT era)
• 77 patients
• > 10% percent risk of subarachnoid
dissemination
– Haddock et al (Mayo experience)
reported on 25 patients who
received RT to 44 Gy without full
CSI. 36% spine relapses were
reported.
– 5 year survival was still 90%
CSI
• CSI has been the gold standard for patients
even with local disease.
• Harmful effects of CSI on neurocognitive
development extrapolated from the literature
on PNET.
• The aim now becomes focused on limiting
treatment related side effects.
Chemotherapy Alone
• “International protocol” Balcameda et al JCO 1996
– CDDP, VP-16, bleomycin x 4 cycles followed by imaging eval
– CR received 2 further cycles
– Others received 2 cycles intensified by cyclophosphamide
• High initial response rates (78% CR) but 50% of
patients experience disease progression or recurrence.
• Treatment related mortality approximates 10%
• Salvage with reinduction cyclophosphamide and CSI
still results in 76% 2 yr survival.
Approaches to limiting toxicity
• Lower total radiation dose while maintaining
irradiation volume
• Decrease the volume while maintaining dose
and use chemotherapy as a substitute for
extended-field
• Decrease both volume and dose without the
use of chemotherapy
• Use systemic chemotherapy with both volume
and dose reduction
Radiotherapy of localized intracranial
germinoma
• Rogers et al reported in Lancet Oncology in July of 2005 on a
review of the “modern” literature (published) since 1988 to
compare patterns of disease relapse, and cure rates after CSI,
reduced –volume irradiation and focal radiation alone.
• Most comprehensive review on patterns of relapse after
radiotherapy alone for localized intracranial germinomas.
• Reported on series published after 1988.
– Excluded series
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Recurrent disease
Spinal staging not reported
Radiotherapy volumes were not specified
Relapse pattern was not defined
Chemotherapy was used
Patients without histologic verification
Patients with evidence of spinal dissemination
Radiotherapy of localized intracranial
germinoma
• Patient Classification
– Craniospinal radiotherapy
– Whole-brain or whole ventricular radiotherapy
plus boost
– Radiation of primary tumor alone
Reduced Volume Irradiation
Whole Brain RT
Whole-ventricular RT
Focal Radiotherapy
Reduced Volume Irradiation
Whole Brain RT
Whole-ventricular RT
Focal Radiotherapy
Reduced Volume Irradiation
DVH Brain
WB and WV include dose to 24 Gy followed by a 16 Gy focal boost
Focal RT single 40Gy treatment plan
Radiotherapy of localized intracranial
germinoma
• 788 patients included
– Weighted median age was 13.5 years
– Median follow up 6.4 years
– Median radiation dose to primary tumor 48.6 Gy.
• Relapse rates subdivided into categories based on
first relapse
– Local with or without other sites
– Isolated spinal relapse (what would be prevented by
CSI)
– Other sites inside and outside CNS
Radiotherapy dose and volume
• 343 patients received CSI
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LC achieved in all but one patient (99.7%)
4 (1.2%) had isolated spinal relapses
13 (3.8%) overall relapse over half outside craniospinal axis.
Local relapse rate 0.3%
• 278 patients treated with whole brain or whole ventricular
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LC 97.5%
8 (2.9%) had isolated spinal relapse
21 (7.6%) overall relapse
Local relapse rate 2.5%
• 133 focal radiotherapy
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LC 93.5%
15 (11.3%) had isolated spinal relapse
31 (23.3%) overall relapse rate
Local relapse rate 6.8%
Radiation and Chemotherapy
• SIOP experience reported on chemotherapy + focal radiotherapy
associated with a 10% excess risk of relapse in the ventricular area
when compared to craniospinal radiotherapy
• US phase II study reported on patients with localized or metastatic
germinomas.
– Treated with 4 cycles of etoposide and cisplatin,
– Local disease treated with focal RT to prechemo volume + 2 cm margin
with dose stratification based on response.
– All but one remained in complete remission
• Phase II study reported by Matsutani et al 84% of patient with
localized germinoma’s achieved a CR after induction chemotherapy
– All received 24 Gy to a field including the third and lateral ventricles.
– 12.2% relapse rate at 2.9 years
– 77% were out of field.
COG ACNS0232
• Phase III study comparing radiotherapy alone vs
chemotherapy followed by Response-based
Radiotherapy for Newly diagnosed primary CNS
Germinoma
• Stratification
– Local (M0)
– Occult multifocal (Modified M+) DI, M0 patients on
Regimen B with significant reduction in “normal”
pineal gland or pituitary stalk
– Disseminated (M+) (Patient MN)
COG ACNS0232
• Regimen A
– Standard Radiotherapy
Staging
Large Field
M0
Ventricular
24 Gy
Involved Field
21 Gy
M(+) mod Ventricular
24 Gy
Involved Field
21 Gy
M(+)
24 Gy
Involved Field
21 Gy
Craniospinal
Boost Field
Total dose
45 Gy
COG ACNS0232
• Regimen B
– Chemotherapy and Radiotherapy
Response
Chemotherapy
cycles
Staging
Large
Field
CR
2 carbo/etop
M0
IF
M+
CR or MRD 4 cis/cyclophos
PR SD PD
4
Boost
Field
Total
Dose
30 Gy
None
30 Gy
CSI
21 Gy
IF
9 Gy
30 Gy
M(+) mod
Vent
21 Gy
IF
9 Gy
30 Gy
M0
IF
30 Gy
None
M+
CSI
21 Gy
IF
9 Gy
30 Gy
M(+) mod
Vent
21 Gy
IF
9 Gy
30 Gy
M0
Vent
24 Gy
IF
21 Gy
45 Gy
M+
CSI
24 Gy
IF
21 Gy
45 Gy
M(+) mod
Vent
24 Gy
IF
21 Gy
45 Gy
30 Gy
Implications
• Radiotherapy alone for Germinomas can
achieve high long-term rates >90%
• Reduction in field size without additional
therapy can achieve good local control rates in
localized disease
• Chemotherapy may be able to help reduce
failure rates so patient can receive reduced
dose and field radiation.
Acknowledgements
• Department of Radiation Medicine
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Charles Thomas Jr
Carol Marquez
John Holland
Martin Fuss
Arthur Hung
Sam Wang
Tasha McDonald
Patrick Gagnon
Celine Bicquart