1. Germinomas: An Evolution in the Use of Radiation
Marka Crittenden M.D. Ph.D.
Resident Department of Radiation Medicine

2. Talk Outline 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

3. 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 15-20%
Malignant-admixture of benign teratoma with one or more malignant germ cell lines

4. 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%

5. 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

6. 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

7. 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

8. 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)

9. Case Presentation MN

10. Case Presentation MN
Laboratory evaluation revealed panhypopituitarism, nml AFP and beta-HCG in both serum and CSF.
Management:
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.

11. 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 cycles of carbo/etoposide plan individualized to receive 4 cycles of carboplatin and etoposide) 7/31/ /10/08. Followed by whole ventricular radiation therapy to 24 Gy with tumor boost to 30 Gy.

12. 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 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%

13. 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%

14. 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.

15. 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.

16. 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

17. 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
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

18. Radiotherapy of localized intracranial germinoma
Patient Classification
Craniospinal radiotherapy
Whole-brain or whole ventricular radiotherapy plus boost
Radiation of primary tumor alone

19. Reduced Volume Irradiation
Whole Brain RT
Whole-ventricular RT
Focal Radiotherapy

20. Reduced Volume Irradiation
Whole Brain RT
Whole-ventricular RT
Focal Radiotherapy

21. 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

22. 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

23. Radiotherapy dose and volume
343 patients received CSI
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
LC 97.5%
8 (2.9%) had isolated spinal relapse
21 (7.6%) overall relapse
Local relapse rate 2.5%
133 focal radiotherapy
LC 93.5%
15 (11.3%) had isolated spinal relapse
31 (23.3%) overall relapse rate
Local relapse rate 6.8%

24. 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.

25. 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)

26. COG ACNS0232 Regimen A Standard Radiotherapy Staging Large Field
Boost Field
Total dose M0
Ventricular
24 Gy
Involved Field
21 Gy
45 Gy
M(+) mod
M(+)
Craniospinal
Involved Field

27. COG ACNS0232 Regimen B Chemotherapy and Radiotherapy Response
Chemotherapy cycles
Staging
Large Field
Boost Field
Total
Dose CR
2 carbo/etop M0 IF
30 Gy
None M+
CSI
21 Gy
9 Gy
M(+) mod
Vent
CR or MRD
4 cis/cyclophos
PR SD PD 4
24 Gy
45 Gy

28. 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.

29. Acknowledgements Department of Radiation Medicine Charles Thomas Jr
Carol Marquez
John Holland
Martin Fuss
Arthur Hung
Sam Wang
Tasha McDonald
Patrick Gagnon
Celine Bicquart