germinomas: an evolution in the use of radiation

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

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

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


• 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%


• 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


• 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• 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.


• 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

• 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


• 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

DVH BrainWB and WV include dose to 24 Gy followed by a 16 Gy focal boostFocal RT single 40Gy treatment plan


• 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

– 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%

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 Boost Field Total dose

M0 Ventricular 24 Gy Involved Field 21 Gy 45 Gy

M(+) mod Ventricular 24 Gy Involved Field 21 Gy

M(+) Craniospinal 24 Gy Involved Field 21 Gy

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 30 Gy

M+ CSI 21 Gy IF 9 Gy 30 Gy

M(+) mod Vent 21 Gy IF 9 Gy 30 Gy

CR or MRD 4 cis/cyclophos M0 IF 30 Gy None 30 Gy



PR SD PD 4 M0 Vent 24 Gy IF 21 Gy 45 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– Charles Thomas Jr – Carol Marquez– John Holland– Martin Fuss– Arthur Hung– Sam Wang– Tasha McDonald– Patrick Gagnon– Celine Bicquart

germinomas: an evolution in the use of radiation

Documents

pineal region tumor

tumor boost

fluffy tumor

malignant teratoma

malignant subtypes

pure germinomas

pure germinomahcg

ventricular radiation