CNS GCTs are prevalent in children and adolescents in eastern Asia but are generally rare tumors that account for 2-3% of all primary intracranial tumors [12-16]. These tumors are radiosensitive and curable with radiotherapy alone, with a cure rate of 72-100% [17-22]. These tumors may require neurosurgical interventions, such as debulking or pathological confirmation, and cause tumor-related hydrocephalus. These treatment options offer a multidisciplinary approach to CNS GCT treatment. However, for this reason, patients admitted to institutions that do not practice an active multidisciplinary approach may be treated with different treatment protocols depending on the department they are admitted to.
The KSPNO released the KSPNO-G081/G082 protocols in 2009. Since then, the authors have applied this protocol to patients at the SNUBH. The results of a relatively homogenous group of patients who underwent the KSPNO protocol was used to diagnose a consecutive patient, and the patient's multidisciplinary treatment process was shared among departments through outpatient clinics and institutional conferences. In this study, the authors compared and analyzed the KSPNO protocol group and other protocol groups. All of the patients' clinical information was shared among departments through outpatient clinics and institutional conferences, with a multidisciplinary approach. This study is meaningful for verifying the effectiveness and safety of the KSPNO protocol.
In recent decades, radiation doses applied to primary sites exceeded 50 Gy [2,3]. However, the histological identity between CNS germinoma, seminoma of the testis, and dysgerminoma of the ovary suggest the possibility of application at a dose of 25-30 Gy, the therapeutic dose used in these tumors, for CNS germinoma [20]. In addition, Aydin et al. reported CR at autopsy after treatment of CNS pure germinoma with only 16 Gy of radiation[23]. Some studies have suggested that doses can be reduced to less than 36 Gy in whole-ventricular irradiation without preirradiation chemotherapy [24,25].
There was a report that radiotherapy alone was associated with the risk of new CNS germinoma relapse [26]. In addition, CNS germinoma is reported to be have a 10-year OS rate of 90% [1]. Radiation-induced secondary brain tumors and subsequent malignant neoplasms caused by RT are rare, but there are some reported cases [4-7]. In addition, the cumulative risk of brain tumors obtained after 15 years of cranial irradiation has been reported to be 2.7% [5].
CNS germinoma is known to be susceptible to radiation as well as chemotherapy, and platinum-based chemotherapy reduces late complications associated with RT, and allows a reduction in therapeutic radiation doses to 24-30 Gy without reducing the therapeutic effect [1,8-11]. However, some studies have reported treatment failure due to limited irradiation fields for localized germinoma compared to those for the whole ventricle [27-29].
The KSPNO protocol uses neoadjuvant chemotherapy to maintain a curative effect while applying a reduced radiation dose. Recent consensus suggests that at least the whole ventricle should be treated and irradiated to reduce the risk of local relapse of germinoma [1]. As described above, there have been reports on applying chemotherapy and combination therapy to determine whether CSI is necessary according to the treatment response, reduce the final radiation dose and reduce complications related to radiation in the long term [30-34].
Adverse events in the KSPNO protocol group were not significantly different from those in the other protocol groups. In addition, mortality was 0% in the KSPNO protocol group and 5.7% in the remaining subgroups (p = 0.503). These results show that the KSPNO protocol is acceptable in comparison with conventional treatment.
A significant number of germinomas occur in the pineal, sellar, and suprasellar areas. Therefore, it is crucial to reduce nephrotoxicity because patients often experience diabetes insipidus (DI) before treatment. Cisplatin, which was used in the traditional regimen, was replaced with carboplatin in the KSPNO protocol, which may reduce urotoxicity compared to traditional therapy. However, cyclophosphamide also has urotoxic properties, so mesna (sodium 2-mercaptoethanol sulfonate) should be added [31,35]. The results of the current study revealed that this goal was achieved. The adverse events that occurred in the patients in the KSPNO protocol group were mostly blood and lymphatic system problems, and there were no patients with signs and symptoms of urotoxicity. Moreover, there was one patient in a different protocol group with CTCAE grade 3 urotoxicity. A similar result to that in the current study was reported in another study using the KSPNO protocol [31].
Single chemotherapy regimens for NGGCTs, such as radiotherapy alone, show modest or even inferior effectiveness [36,37]. However, combined chemotherapy and RT may provide comparable germinoma control at lower radiation doses and field volumes than those applied in RT alone [38-42]. In addition, one of the critical benefits of chemotherapy for NGGCTs is that it reduces tumor size and vascularity before surgery [1].
The therapeutic effect of CSI is controversial. The benefit of CSI in patients diagnosed with germinoma is reported to be approximately 15% [43]. Relapses along the neuraxis outside the radiation field are rare, and the improvement in the outcomes with CSI was not significantly different [44]. In our study, the mean PFS was longer in the germinoma group (169.68 months) than in the other group (188.54 months) (p = 0.215). In NGGCT, however, the opposite trend (149.0 vs. 107.8 months, p = 0.831) showed that there was no significant difference according to whether CSI was applied.
Our study has some limitations, and this requires cautious interpretation of the results. Since the introduction of the KSPNO-G081/G082 protocols in 2009, 26 pediatric patients have undergone the KSPNO protocol and were included in our study. The KSPNO protocol group (23.4 Gy; range, 5.4-30.6 Gy) was treated with lower doses of whole-ventricle irradiation than the other treatment protocol groups (33.3 Gy; range, 19.8-50.4 Gy), but there were no significant differences in outcomes such as OS and PFS. However, the patients in the KSPNO protocol group were significantly younger than those in the other protocol groups. Moreover, because of the rarity of the disease, the group size may not be enough to elucidate statistical significance. These limitations should be complemented by long-tern follow-up studies with larger sample sizes.