Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study

Abstract

Purpose: This phase II trial evaluated the effect of neoadjuvant chemotherapy with or without second-look surgery before craniospinal irradiation on response rates and survival outcomes in children with newly diagnosed non-germinomatous germ cell tumors.

Patients and methods: Induction chemotherapy consisted of six cycles of carboplatin/etoposide alternating with ifosfamide/etoposide. Patients demonstrating less than complete response after induction chemotherapy were encouraged to undergo second-look surgery. Patients who did not achieve complete response or partial response after chemotherapy with or without second-look surgery proceeded to high-dose chemotherapy with thiotepa and etoposide and autologous peripheral blood stem-cell rescue before craniospinal irradiation.

Results: The study included 102 patients treated between January 2004 and July 2008. Median age was 12 years, and 76% were male; 53.9% had pineal region masses, and 23.5% had suprasellar lesions. Sixty-nine percent of patients achieved complete response or partial response with neoadjuvant chemotherapy. At 5 years, event-free survival was 84% ± 4% (SE) and overall survival was 93% ± 3%. During the median follow-up of 5.1 years, 16 patients recurred or progressed, with seven deaths after relapse. No deaths were attributed to therapy-related toxicity. Relapse occurred at the site of primary disease in 10 patients, at a distant site in three patients, or both in one patient. In two patients, progression was detected by marker increase alone. Increased serum α-fetoprotein was a negative prognostic variable. Histologic subtype and increase of beta-human chorionic gonadotropin were not significantly correlated with worse outcomes.

Conclusion: Neoadjuvant chemotherapy with or without second-look surgery achieved high response rates contributing to excellent survival outcomes in children with newly diagnosed non-germinomatous germ cell tumors. This regimen should be included as a backbone for further studies.

Fig 1.

CONSORT diagram. CR, complete response; PD, progressive disease; SD, stable disease.

Fig 2.

Treatment schema and dosing. ANC, absolute neutrophil count; CSI, craniospinal irradiation; CR, complete response; G-CSF, granulocyte colony-stimulating factor; IV, intravenous; PBSC, peripheral blood stem cell; PD, progressive disease; PR, partial response; SD, stable disease; SQ, subcutaneous. (*) Strongly recommended but not required.

Fig 3.

Overall survival (OS) and event-free survival (EFS). (A) OS and EFS for all eligible patients. (B) OS and EFS for eligible patients excluding those with gross total resection. (C) OS by histology (blue line, germinoma with > 50 IU/L hCG; gold, embryonal carcinoma; gray, teratoma malignant; red, mixed germ cell tumor [GCT]; black, choriocarcinoma). Of note, patients with increased markers and no histology were coded as having mixed germ cell disease. g, group.

Fig 4.

Event-free survival (EFS) stratified by serum or CSF markers. (A) EFS stratified by serum or CSF beta human chorionic gonadotropin less than 100 IU/L and ≥ 100 IU/L. (B) EFS stratified by serum or CSF beta human chorionic gonadotropin at less than 1,000 IU/L and ≥ 1,000 IU/L. (C) EFS stratified by serum or CSF α-fetoprotein at less than 10 IU/L and ≥ 10 IU/L.

Fig 5.

Overall survival (OS) and event-free survival (EFS) for patients with localized disease who achieved complete response or partial response with induction chemotherapy or second-look surgery.