Malignant CNS-GCTs have been classified as germinomas vs. nongerminomatous GCTs or secreting vs. non-secreting tumors. However, such classifications have limitations since biopsy-proven germinomas can have nongerminomatous elements among the unbiopsied sites and non-secreting tumors can also have nongerminomatous components such as immature teratoma with less favorable prognosis (16
). It is well-known that both nongerminonatous and secreting GCTs have worse prognosis. Therefore, we regarded those as high-risk either having nongerminomatous components or having elevated AFP or bHCG ≥50 mIU/mL. Considering that germinomas can secrete small amount of bHCG, a relatively low bHCG level (<50 mIU/mL) was not included in the high-risk criteria.
Our risk-adapted chemotherapy strategy produced very high clinical CR rate when we included those having a radiological remnant tumor into the complete responders provided that it was considered nonevolving. Assessing the response of GCTs is frequently confusing because treated GCTs tend to remain as remnant fibrotic, calcified, cystic or fully differentiated mass but actually containing no viable tumor cells. Therefore, we also regarded those as clinical complete responders who had a small residual lesion with normal tumor marker levels at the end of chemotherapy, provided that the lesion did not show any increase in size without any elevation of tumor markers for more than 2 yr after a completion of irradiation. In fact, 2 of 4 patients in this study who underwent second-look surgery after chemotherapy had no viable tumor cells despite a significantly large residual tumor size after chemotherapy.
Because of the rarity of these tumors and a lack of large prospective studies, the optimal therapeutic strategy for malignant CNS-GCTs remains unsettled. An early study by Rich et al. (5
) suggested that nongerminomatous or secreting tumors were relatively resistant to radiotherapy. After the chemotherapy was introduced as a treatment modality for gonadal GCTs, the efficacy of chemotherapy for CNS-GCTs has been tested by many investigators. In 1995, Itoyama et al. (17
) showed the effectiveness of multidisciplinary treatment including combination chemotherapy in treating AFP-producing CNS-GCTs. In the next year, the International Central Nervous System Germ Cell Tumor Study Group reported the results of an international cooperative trial using chemotherapy without irradiation, which showed 78% of CR rate (84% for germinoma, 78% for nongerminomatous GCTs) (18
). However, 49% of the complete responders in their study eventually relapsed, which implicates the indispensible role of radiotherapy. The importance of radiotherapy was confirmed again in a study, in which patients with secreting CNS-GCTs were treated with chemotherapy alone, but unfortunately 12 of the 13 non-irradiated patients eventually relapsed (19
). On the other hand, a study by Robertson et al. (20
) using 'sandwich' therapy (chemotherapy-radiation-chemotherapy) showed 67% of 4-yr EFS among 18 nongerminomatous GCT patients and they concluded that the multi-modality adjuvant therapy approach appeared to dramatically improve the prognosis of these tumors. More recently, clinical trials using systemic chemotherapy combined with radiotherapy showed clear benefits over the strategy using radiotherapy alone especially for nongerminomatous GCTs. Matsutani et al. (21
) conducted a multiinstitutional phase II study to establish a postsurgical combined chemotherapy and radiotherapy, and concluded that their protocols were effective for patients with germinomas and those with an intermediate prognosis. A multiinstitutional retrospective analysis by Ogawa et al. (22
) reported a higher 5-yr survival rate in chemotherapy group than that in non-chemotherapy group (84% vs. 44%). According to the Children's Oncology Group report in 2007 on the efficacy of pre-radiation chemotherapy with response-based radiation therapy in children with CNS-GCTs, although the number of patients was small (n=26), 3-yr OS was 100% for germinomas and 79% for nongerminomatous GCTs (23
In the current study, authors demonstrated an improvement in the survival rate of our patients using risk-adapted intensive chemotherapy in conjunction with subsequent radiotherapy. Our early treatment outcomes using 4 cycles of PEB regimen prior to radiotherapy had resulted in unsatisfactory outcome, which showed 67% of 5-yr EFS. Therefore we changed the chemotherapy strategy to more intensive risk-adapted cisplatin-based regimens. Although this change in treatment strategy showed excellent survival outcomes (1 relapse occurred among 16 patients), an unexpected high incidence of ototoxicity in high-risk patients who received high-dose cisplatin (200 mg/m2
/cycle, 2 cycles) put us into a major protocol revision. Thereafter, we have been using a carboplatin-based regimen, with which no ototoxicity has occurred. Carboplatin is known to be less nephrotoxic or ototoxic than cisplatin (24
). Considering the high incidence of diabetes insipidus among patients with CNS-GCTs, cisplatin may not be appropriate for those having diabetes insipidus because they should be controlled with strict input/output balance along with adequate hydration and desmopressin replacement, which is often very difficult. Almost a half (45.3%) of our patients had diabetes insipidus before treatment and ototoxicity occurred in 4 of 10 patients who received high-dose cisplatin. Notably, 3 of 5 patients (60%) who received high-dose cisplatin and also had diabetes insipidus ultimately developed ototoxicity. Since our current protocol using carboplatin-based regimen not only gave rise to excellent survival rate but also were more tolerable without ototoxicity, we believe that our current carboplatin-based chemotherapy protocol is highly effective for malignant CNS-GCTs.
One of the major limitations of our study is that the radiation guideline was not consistent. Patients in group 2 and group 3 generally received higher dose of craniospinal irradiation as compared with group 1, although a statistically significant difference was found only between the low-risk patients of group 1 and group 3 when matched with each corresponding risk group (). At any rate, the radiation dose in our cohort was not any higher than usual doses applied in other studies-only 10 patients (18.5%) receiving more than 30 Gy of craniospinal irradiation or more than 50 Gy to the tumor bed (data not shown). Wolden et al. (9
) applied 45 to 54 Gy to the tumor bed with or without craniospinal irradiation, which produced approximately 70% of 5-yr disease-free survival rate, but is still inferior to our results. In a report by Ogawa et al. (22
), the median radiation dose was 50 Gy to the primary site and 30 Gy to the whole brain and whole spine, which is also higher than that used in our patients.
Despite our excellent results for both low-risk and high-risk patients, we cannot conclude that our current strategy is also advantageous for low-risk patients because studies using radiotherapy as a single treatment modality generally have shown excellent outcomes in pure germinoma. However, we believe that further reduction of radiation dose might be possible in selected patients with our current chemotherapy protocols.
Although intensive chemotherapy led to a high incidence of severe myelosuppression and infection, all infectious episodes following risk-adapted intensive chemotherapy were manageable with broad-spectrum antibiotics and G-CSF supports and there were no infection-related major complications. Because of the rarity of CNS-GCTs, nationwide or multicenter clinical trial is required to determine the efficacy of current strategy.
In conclusion, our strategy using short course of risk-adapted intensive systemic chemotherapy prior to radiotherapy shows excellent results even in high-risk patients with malignant CNS-GCTs. However, high-dose cisplatin in high-risk patients causes a high incidence of ototoxicity, especially in the presence of diabetes insipidus, which favors the use of the carboplatin-based regimen in that it has lower toxicity profiles without the expense of efficacy as shown in our study.