Germinomas: An Evolution in the Use of Radiation

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 sylvianaquaduct • 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, polydypsiaand 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 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.

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 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%

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 reinductioncyclophosphamide 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

27. COG ACNS0232 • Regimen B • Chemotherapy and Radiotherapy

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