Radiation Oncology Synopsis

PEDS:CNS Germ Cell Tumors and Pineal Tumors

Common Pineal Region Tumors

Distribution varies by age and geography with GCT more common in Japan and Taiwan
Germ Cell Tumors
  • Pure Germinomas
  • Non germinoma germ cell tumors/mixed tumors
32% - 60%
Parenchymal Tumors
  • Pineocytomas
  • primary parenchymal tumors of intermediate differentiation
  • Pineoblastomas
 20%
Others
  • Gliomas
  • Meningiomas
  • Mesenchymal tumors
20%

Germ Cell Tumors

There are two broad categories of germ cell tumors: Gonadal and Extragonadal. Intracranial Germ Cell Tumors are extragonadal as are the other two categories: Sacrococcygeal GCT and retroperitoneal germ cell tumors.

Intracranial Germ Cell Tumors

IC GCT are rare in North America and Europe. They represent only 2% - 4% of all intracranial pediatric tumors. They are more common in Asia, representing up to 11% in Japan and Taiwan. There is a full range of germ cell tumor types reflected in CNS GCT.

Germ cell tumors are typically classified histopathologically into two highly prognostic classes: germanomas and non-germanomatous germ cell tumors (Malignant NGGCT.) NGGCT are germanomas with any malignant component and any tumor that secretes α-FP or high levels of βHCG > 100 IU is considered high.

Pure germinomas carry a much more favorable prognosis than do NGGCT.

Germinomas arise in the midline proximal 3rd ventricular structures. Two thirds are pineal and 1/3 suprasellar.

Around 15% - 20% of germanomas have leptomeningeal spread and up to 50% of the pineoblastomas have CSF dissemination.

The probability of spinal failure with pineal tumors is dependant on the type and nature of the pineal tumors:

Typical presentation of pineal region tumors is Perinaud's Syndrome which is related to pressure on the superior colliculus resulting in a downard gaze and an abnormal pupillary light reflex with normal accomodation. Suprasellar masses usually present with a triad of visual difficulties, diabetes insipidus and precocious/delayed or abnormal sexual development.

Germ cell tumors are the most common arising in the pineal region. These tumors and their relative incidents are:

Tumor Type Relative frequency Characteristics
Pure Germinoma 40% - 60% Predominantly adolsecent males
  • αFP negative
  • May have isolated elevated β-HCG (typ. <15 - 75 IU)
Malignant GCT
  • endodermal sinus tumor
  • choriocarcinoma
  • malignant teratoma
  • immature teratoma
20% - 25%
  • +++αFP
  • +++β-HCG
  • intralesional hemorrhage, often partially calcified
  • Teratomas have moderately elevated AFP,± β-HCG elevation
Pineal parenchymal tumors
  • pineoblastoma
  • pineocytoma
14% Predominantly in young children
Glioma, Astrocytoma, ependymoma 15% Uncommon in children/adolescents

The differential diagnosis for pediatric pineal region tumors includes:

80% of pineal region tumors are GCT.

Workup and Staging

A comprehensive cranial nerve examination is important in the workup of pineal tumors. Suspected GCT should be worked up with a history and physical examination including the CN exam with fundoscopic examination. An MRI of the brain and spine is indicated. Basic labs, and special labs:

If an AFP level is > 10 ng/ml a pure germinoma is excluded. AFP is not elevated in pure germinomas.β-HCG levels do not exclude pure germinomas but highly elevated β-HCG (7ge; 50 ng/ml, it is far less likely to be a pure germinoma.

Histopathology is particularly important. Placental alkaline phosphatase staining confirms the diagnosis of germinoma.

MRI findings include both homogenous and heterogeneous findings. hypointense T1 (dark) and hyperintense on T2 (bright). On CT Calcium may be seen and cysts are seen. There is no way to distinguish GCT from NGGCT by clinical imaging.

Staging

Presently GCT are staged with the Modified Chang (M) staging system as for medulloblastoma.

Treatment and Prognosis

Prognosis

Histology is the most important prognostic indicator in germ cell tumors. The prognosis is far better for pure germinomas than for NGGCT. PFS-5 for germinomas is 90% and for NGGCT it drops to 40% - 70%.

General Treatment Paradigms

Localized pure germinomas can be treated either with radiation alone or with neoadjuvant chemotherapy followed by radiation therapy on an experimental protocol.

Radiation therapy given for defintive treatment to localized pure germinomas include whole ventricular radiation therapy to 24 Gy followed by a boost to the primary tumor of 45 Gy. Surgery is generally not performed for germinomas.

In the case of disseminated germinoma with CSF spread (Chang M+), the craniospinal axis is irradiated to 24 Gy with gross disease treated to 45 Gy.

Chemotherapy is not adequate to replace radiation for pure germinomas. A large CNS GCT study by Balmaceda in 1996 (JCO) treated 45 patinets with pure germinomas with carboplatin/etoposide/belomycin. 84% had a complete response but 48% recurred in 13 months and 10% died of treatment toxicity. > 90% were salvaged by radiation therapy.

ACNS 0232 is currently examining if neoadjuvant chemotherapy can help reduce radiation doses using carboplatin, cisplatin and etoposide as chemotherapy agents in the study.

In the neoadjuvant chemotherapy arms of ACNS 0232 radiation doses in the experimental arm are reduced:

ACNS0232 closed early due to poor accrual.

Surgery

The goal of surgery is to provide tissue diagnosis, and in some cases improve local control. For cases of suspected germ cell tumors without marker elevation, biopsy is considered mandatory. Modern surgical techniques permit stereotactic biopsy for both suprasellar and pineal region tumors with minimal morbidity. Aggressive resection is not advocated either in the US or in Europe, due to higher rates of morbidity and mortality. Delayed surgery after chemotherapy for persistent disease is preferred.

Chemotherapy

Intracranial germ cell tumors are chemosensitive with well documented objective response rates to a number of agents, including:

Objective response rates approach 100%. Carboplatin mostly with etoposide has replaced CDDP for germinomas because carboplatin has fewer long term sequalae. The goal of chemotherapy has not been to improve disease control. The goal has been to improve functional outcomes by decreased radiation doses and/or irradiated volumes.

Balmaceda International Chemotherapy Protocol testing carboplatin, etoposide and bleomycin included pure germinomas and NGGCT. This trial achieved high initial response rates but disease progression or recurrence occured in > 50% in both pure germinomas and NGGCT patients. Chemotherapy related mortality was unacceptable at 10%. Failures occured primarily at the original ventricular site.

For NGGCT radiotherapy has not been adequate with 20% - 40% long term survival rates. Adding platinum based chemotherapy has dramatically improved outcome with short term survival rates in excess of 70% and is now the standard of care for these tumors prior to irradiation.

NGGCT chemotherapy regimens have been tested by the SFOP (French) and ACNS 0122 studies using alternating carboplatin/etoposide and ifosphamide/etoposide. The regimen has been both well tolerated and effective, when coupled with reduced dose radiation therapy..

High Dose chemotherapy with stem cell transplant in relapse has shown promise.

Radiation Therapy

There has been controversy regarding the most appropriate volumes to be treated. Evidence of disseminated (CNS) disease is seen in 10% - 20% of intracranial germinomas. Classical third ventricle disease involving pineal and suprasellar recesses but somtimes showing multiple ependymal nodules along the linings of the ventricles, particularly in the 3rd ventricle but less often in the lateral ventricles. Imaging rarely shows overt spinal seeding. A large portion of clinical series reporting disease control rates higher than 90% have been with more limited radiation volumes and lower doses. Spinal cord failures have been reported to be in the 0% - 10% range in these series irradiated to cranial volumes only.

Radiation volumes limited only to the tumor bed have been associated with significant rates of intracranial or ventricular region relapse in recent series.

It is likely that CSI has a marginal benefit for pure germinomas treated with definitive radiation therapy alone. The potential gain is controversial and must be weighed against the added toxicities. of 24 - 25 Gy to the neuroaxis.

ALL patients with metastatic disease (M+) at diagnosis REQUIRE cranio-spinal radiation to 24 Gy - 30 Gy with radiation alone or 21 Gy - 24 Gy with combined chemotherapy and radiation therapy. Local doses to primary and large metastatic foci remain 45 Gy or 30 Gy cumulative. The reduced dose is in the setting of chemotherapy neoadjuvantly.

Neoadjuvant chemotherapy doses for localized germinoma are likewise reduced: Whole Ventricle Radiation to 19.8 Gy with a boost to 30 Gy to the tumor sites and any gross nodules.

Boost volumes are the enhancing tumor in the pineal region, the infundibular stalk and the 3rd ventricle.

SIOP CNS GCT96 studied reduced volumes without whole ventricle radiation therapy. This study treated M0 patients with Cranio-spinal irradiation to 24 Gy + 16 Gy boost (to 40 Gy) or to 2 cycles of isfosfamide, carboplatin, etoposide (ICE) followed by IFRT only to 40 Gy. The combined modality, limited field arm did worse:

This study indicates that IFRT alone may not be sufficient, even with chemotherapy. Most failure were within the ventricular system.

Rogers' (2005, Lancet) retrospective review of 788 patients revealed that there was greater failure rate in IFRT/focal radiation therapy v. WBRT or WVRT + boost or CSI + Boost, with 23% failing in the focal radiation cohort and 4% - 8% in the larger field cohort. The relapse patterns were mostly isolated spinal column relapses. A Korean study produced similar results.

The German MAKEI 83/86/89 Study demonstrated the feasibility of radiation therapy dose reduction from 50 Gy to 34 Gy.

NGGCT

Chemotherapy is always necessary for NGGCT. The general treatment paradigms for NGGCT is

  1. Induction platinum based chemotherapy for 4 - 6 cycles → CSI radiation therapy to 30 - 36 Gy with a lower dose for CR to chemotherapy, followed by a primary boost to 50.4 - 54 Gy. If there is still residual disease, proceed to surgery.
  2. Maximum safe surgical resection → adjuvant platinum based chemotherapy → restage. If no neuroaxial involvement seen treat with IFRT consolidation. IF M+, CSI to 30 - 36 Gy followed by boost to 50.4 Gy

CHEMOTHERAPY IS ALWAYS INDICATED IN NGGCT.Chemotherapy influences survival.

Pineoblastoma

Pineoblastomas are treated as medulloblastomas: CSI to 36 Gy Gy → boost locally to 54 Gy.

These are histologically similar to medulloblastomas and the prognosis is poorer. These tumors are the PNET of the pineal gland. These patients do poorly and require very aggressive treatment: maximum possible resection → radiation therapy → post-RT chemotherapy.

Pineocytomas

Pineocytomas are treated as low grade gliomas. The recommended treatments are dependent on surgical extent of resection:

Toxicity of Treatment

Long term sequalae of radiation include second malignancies (GBM 5% - 10%), need for hormonal therapy in 69% with RT alone v. 38% with CRT.

AVOID radiation therapy with use of 6MP. 6MP with radiation has been associated with higher rates of secondary high grade glioma development.