Germinomas are highly radiosensitive and 60 - 90% of patients survive beyond 5 years with this treatment alone.
Germinomas are also sensitive to chemotherapy. However chemotherapy alone is associated with a roughly 50% chance of relapse.
There is ongoing debate about the roles of both these modalities and how they should be combined.
What should be the radiotherapy (RT) treatment volume?
- There is much debate concerning the need for craniospinal RT if staging investigations are negative.
- Many centers recommend whole ventricular RT with a boost to the primary tumor for localized disease if chemotherapy is not given.
- Some North American centers use local RT after systemic chemotherapy for localized germinoma and craniospinal RT only for documented disseminated disease.
- For localized disease at diagnosis after surgery and systemic chemotherapy with a complete response (outside of a study) it is reasonable to recommend local RT:
- CTV (clinical target volume) = GTV (established by MR and planning CT image fusion) plus 1.5 cm
- A 5 mm margin should be added beyond the CTV to define the PTV
- PTV should be covered by the 95% isodose
- 3D conformal RT is general standard of care
- For disseminated disease at diagnosis:
- Intracranial and spinal metastatic disease requires craniospinal axis (CSA) RT
What is the optimum dose?
- There is debate concerning the RT dose.
- For germinomas RT to a dose of 50 Gy or over is probably excessive.
- With adjuvant chemotherapy it is probably safe to reduce the total dose to the primary tumor to 30 - 35 Gy and the craniospinal dose to 21 Gy.
- The appropriate volume and dose of RT for both localized and disseminated newly diagnosed germinoma is the subject of controversy. Therefore a COG study (ACNS0232) was designed to randomize patients between radiotherapy (RT) alone and pre RT-chemotherapy in an attempt to answer these questions.
The COG ACNS0232 study for intracranial germinomas was a clinical trial of:
- Conventional RT alone (Reg A) versus
- Pre-radiotherapy chemotherapy followed by response-based reduced RT (Reg B).
The trial aimed to prospectively document the late effects of both treatment arms.
Patients randomized to Reg B who had localized disease (M0) and had a dramatic response to chemotherapy got a reduction of both volume and dose of involved field RT. Responding patients on Regimen B with disseminated disease (M+) got a reduced dose to the craniospinal RT field and the boost volume of evaluable disease at diagnosis.
All patients on this study needed to have an operative procedure (endoscopic biopsy, stereotactic biopsy or open craniotomy) to be eligible.
Only small tumor samples were usually obtained after biopsies and so a small component of non-germinomatous germ cell tumor could not be completely excluded.
The diagnosis was also confirmed with serum and lumbar CSF tumor markers.
- The AFP had to be within the normal range (serum < 10 and CSF < 2 IU/L).
- The serum and CSF HCG had to be < 50 IU/dL.
These AFP parameters were meant to exclude an embryonal carcinoma or endodermal sinus tumor component. The HCG parameters were consistent with the diagnosis of a pure germinoma.
Regimen A = conventional radiotherapy (RT)
Patients who had isolated pineal or suprasellar disease at diagnosis received 24 Gy to the entire ventricular system and a 21 Gy boost to the primary measurable or presumed (occult multi-focal) tumor(s). Therefore the total dose to the primary tumor on this study was 45 Gy.
Patients with pineal tumors presenting with diabetes insipidus and patients with metastatic disease received 24 Gy to the craniospinal axis and a 21 Gy boost to all measurable disease.
If there was diffuse "sugar coating" of the ventricles and multiple deposits throughout the CSA, then the dose of CSA RT was 30 Gy.
Regimen B = Pre-RT chemotherapy
Patients who experienced a complete response (CR) after 2 cycles of chemotherapy (carboplatin and etoposide) or a CR or minimal residual disease (MRD) after 2 additional cycles of chemotherapy (cisplatin/cyclophosphamide) qualified for a dose and/or volume reduction of RT.
Another protocol originating from University of Michigan called for 2 cycles of chemotherapy in all newly diagnosed intracranial germinoma up front (carboplatin and etoposide) and then re-evaluation.
If there was a CR for non-metastatic disease then the patient proceeded to local RT alone (30.6 Gy in 180 cGy fractions to primary pre-chemotherapy volume with a margin).
In metastatic disease at presentation and there was a CR of all tumor after 2 cycles then the craniospinal axis would receive 19.8 Gy and the primary tumor 30.6 Gy.
In localized disease if there was less than a CR after 2 cycles, then another 2 cycles were given (usual situation) of cisplatinum and cyclophosphamide and then radiation to the primary site. 39.6 Gy to the pre-chemotherapy volume followed by a boost to the post chemotherapy volume to take the total dose to 50.4 Gy to the primary.
In disseminated disease when there was less than a CR the craniospinal axis was given 30.6 Gy and the primary was taken to a total dose of 50.4 Gy using the guidelines in the previous paragraph. Bulky spinal mets were taken to a total dose of 45 Gy.
A review of the controversy regarding appropriate RT fields in germinoma: Radiotherapy of localised intracranial germinoma: time to sever historical ties? SJ Rogers, MA Mosleh-Shirazi, FH Saran.