Chemotherapy for Primary CNS Germ Cell Tumors in Children

Treatment of Primary CNS Germinomas

• Biopsy when diagnosis in question: The initial approach is to perform a biopsy +/- CSF diversion procedure only if the diagnosis cannot be made on serum or CSF tumor markers alone.

• 25% relapse with radiotherapy alone: Traditionally, germinomas were treated with radiation alone as they are exquisitely sensitive to it. Germinomas are also very sensitive to chemotherapy; however, 25% of patients relapse if the chemotherapy is not followed with radiation (57).

• Pretreatment with chemotherapy reduces radiation dose: Although germinomas can be cured with radiation alone, the current trend is to treat with chemotherapy first with the expectation that a complete response will be induced. This will allow a reduction in the dose of radiation and thus a reduction in the long-term side effects of radiation. Two to four cycles of carboplatin- and etoposide- based therapy are usual for germinomas. In the absence of dissemination at diagnosis, current trends are toward whole ventricular radiation after a complete response to chemotherapy with or without resection (58, 59, 63).

• Resect residual tumor after chemotherapy: The resection is followed by induction chemotherapy. If the tumor grows or if there is a surgically amenable residual mass with normalization of tumor markers, then resection is considered to remove the likely teratoma component.

SIOP CNS protocol 96 (63)

• Days 1–3 and 43–45: Carboplatin, 600 mg/m²/day IV; etoposide, 100 mg/m²/day IV

• Days 22–27 and 64–69: Etoposide, 100 mg/m²/day IV; ifosfamide, 1800 mg/m²/day IV

Treatment of Malignant CNS Germ Cell Tumors

• Serum and CSF markers diagnostic: Malignant CNS germ cell tumors are diagnosed on the basis of tumor markers in serum and CSF.

• Combined radiation therapy and chemotherapy: Malignant CNS germ cell tumors are more aggressive and require more intense chemotherapy than germinomas (60). They also are highly responsive to chemotherapy; however, a relapse rate of 70% is observed if chemotherapy is not followed by radiation therapy (57). Radiation therapy alone also has a low cure rate. Radiation therapy is usually 36 Gy craniospinal (62); however, present clinical trials are exploring the possibility of whole ventricular radiation in those with localized disease at diagnosis.

• Surgery for residual after chemotherapy: Second-look surgery is considered for growing teratoma syndrome (61) or surgically amenable residual disease prior to radiation.

Induction chemotherapy – four 28-day cycles (64)

• Days 1–5: Cisplatin, 20 mg/m²/day IV

• Days 1–5: Etoposide, 75 mg/m²/ day IV

• Days 1–5: Ifosfamide, 1.2 g/ m²/ day IV

Dose intensification chemotherapy for residual disease

Two cycles with each cycle having a duration of 21 days are used if there has not been a complete response to induction chemotherapy. This regimen is coupled with blood stem cell rescue using bone marrow transplantation (64).

• Days 1–2: Cyclophosphamide, 2 g/m²/day IV

• Days 1–3: Carboplatin, 400 mg/m²/day IV

• Bone marrow rescue: Infusion of >2 x 106 CD 34 stem cells 48–72 hours after completion of chemotherapy

Complications

• Pancytopenia
• Hemorrhagic cystitis
• Ototoxicity
• Nephrotoxicity
• Acute encephalopathy

Outcome

• Germinoma 5-year survival rate near 100%: Localized germinomas treated with multimodality therapy have a 5-year EFS rate of 88% and an OS rate of 96% (63).
• Malignant germ cell tumor 10-year survival rate 77%: Malignant germ cell tumors treated with multimodality therapy have a 10-year PFS rate of 74% and an OS rate of 77% (62).