Chordomas are rare primary bone tumors that originate from remnants of the notochord. Chordomas are low grade histologically, but their aggressive behavior means that few patients can be cured by surgery alone   . Postoperative radiotherapy is standard therapy, but the radiation dose for a skull base chordomais limited by normal tissue around the tumor, such as the brainstem, optic chiasm and temporal lobe. This limits of conventional radiotherapy considered about 50 Gy in 25 fractions, which is insufficient and results in a poor local control rate of 50% or less  .
Proton beam therapy (PBT) can deliver a high dose to a tumor without critical late toxicity for surrounding normal tissue    . We have reported early clinical results in 13 cases of clivalchordomas treated by PBT, in which >70 GyE was delivered and the 5-year local control rate exceeded 50%  . Other studies have also shown good local control after high dose PBT   . We found that hyperfractionated high-dose PBT (78.4 GyE in 56 fractions, 2 fractions per day) for skull base chordoma gave a 5-year local control rate of 70% to 80% in adults  . But the information of safety and effectiveness of PBT for pediatric skull base chordoma is still insufficient.
Here, we describe treatment of pediatric skull base chordoma using the same PBT protocol as that used for adult patients.
2. Material and Methods
From January 2011 to December 2015, a total of 6 patients with newly-diagnosed chordoma received postoperative PBT at our institute. The patients comprised 5 males and 1 female, and had a median age of 9 years old (range: 5 to 13 years old). One had received partial resection, 4 had undergone subtotal, and one had undergone gross total resection (This patient had multiple relapse) before PBT. None had metastasis at the time of PBT. The characteristics of the patients are shown in Table 1. Institutional Review Boards approved the study at our hospital.
2.2. Treatment Methods
We have been treating patients with a hyperfractionation scheme (2 fractions per day). The fractional and total doses were escalated to 1.40 CGE (56 fractions) and 78.40 CGE, respectively. For treatment planning, computed tomography (CT) was performed in slices of 5 mm or less in the treatment position. Proton beam therapy was basically performed for partial resection or subtotal resection cases. At first, 39.2 GyE in 28 fractions was irradiated to tumor bed and surgical pathway as possible. From 40.6 to 58.8 GyE, tumor bed and surgical pathway close tumor bed was irradiated. At this timing, the dose of optic chiasm (50% or less) and brain stem (90% or less at the surface) was reduced. From 60.2 to 78.4 GyE, only tumor bed was irradiated. At this timing, the dose of optic chiasm (almost zero) and brain stem (50% or less at the surface) was additionally reduced.
2.3. Follow-Up Procedures and Evaluation Criteria
Acute treatment-related toxicities were assessed weekly during treatment. After completion of PBT, the patients were evaluated by physical examinations, MRI, and blood tests every 6 months for the first 5 years and every 12 months the reafter. Acute and late treatment-related toxicities were assessed using the National Cancer Institute Common Criteria ver.3.0 and the RTOG/EORTC late radiation morbidity scoring scheme.
The period between surgery and PBT was 34 to 129 days (median 56 days), and PBT was completed in 41 to 46 days (median 43 days). At the time of analysis, all patients were alive and median follow-up period was 27 months (range: 21 - 71 months). All tumors were well controlled.
Acute toxicity was generally acceptable, with only grade 1 and 2 events. 3 patients had growth hormone abnormalityas late toxicities. 2 of 3 patients were checked by only blood test. And one of three patients needed growth hormone and cortical hormone replacement therapy one year after PBT. This patient received surgery several times before PBT and growth hormone and cortical hormone also began to decrease before PBT.
Acute and late toxicities are summarized in Table 2.
Table 1. Patients and PBT characteristics (n = 6).
Table 2. Acute and Late toxicities of proton beam therapy.
As an illustrative case, an 11-year-old female was diagnosed with a skull base chordoma. Before surgery, the tumor was widely compressing the brain stem (Figure 1(a)). Subtotal resection was performed by a transnasal approach (Figure 1(b)). Postoperative PBT was started 103 days after surgery. A dose of 39.2 GyE in 28 fractions (2 fractions per day) was initially administered to the tumor bed and surgical pathway (Figure 1(c)). The dose was then reduced for irradiation of the optic nerve and brainstem. After reaching 58.8 GyE, the target volume was limited to the tumor bed and a dose up to 78.4 GyE was administered in 56 fractions (Figure 1(d), Figure 1(e)).
Conventional radiotherapy for skull base chordomais limited by the critical organs around the tumor bed  . In contrast, PBT allows irradiation at a high dose of >70 GyE without critical late toxicities   and achieves a good 5-year local control rate of 60% - 100% for pediatric skull base chordoma at a dose of 65 - 74 GyE at 1.8 - 2.0 GyE/Fr    . We have also obtained good local control for adult chordoma using PBT at 78.4 GyE in 56 fractions (2 fractions per day). Pituitary insufficiency is the most common late toxicity in PBT, but the risk of high grade late toxicity is low    . Our patients showed the same tendency, with most late toxicities being of low grade (grade 1 or 2).
Our results and previous reports indicate that PBT for pediatric chordoma is effective and that the risk of severe late toxicity is low. However, this conclusion is based on follow-up periods of only 5 to 10 years. A recent large study showed that the main cause of death after pediatric cancer treatment changes from cancer-related death to treatment-related death (late toxicity, secondary cancer, etc) 30 years after treatment  . Additionally, the risk of subsequent malignancy
(a) (b) (c) (d) (e)
Figure 1. Treatment course of PBT for skull base chordomain an11-year-old female.
also continues to increase after 40 years old  and at age 55 the cumulative incidence of new malignancy reaches 16.3%. These data indicate that longer follow-up is needed to evaluate the late toxicity of PBT.
PBT for a pediatric tumor is mainly used to reduce late toxicity and secondary cancer   . For pediatric chordoma, the dose of PBT is high and longer survival is likely, which further emphasizes the need for longer follow-up. Although the number of pediatric patients was small, we consider that PBT is safe and effective for pediatric chordoma. Further follow-up is needed to evaluate late toxicities and the risk of secondary cancer.
This research was supported by a grant for Practical Research for Innovative Cancer Control (15ck0106186h0001) from the Japan Agency for Medical Research and Development (AMED), and in part by Grants-in-Aid for Scientific Research (B) (15H04901) and Young Scientists (B) (25861064) from the Ministry of Education, Science, Sports and Culture of Japan.
 Potluri, S., Jefferies, S.J., Jena, R., et al. (2011) Residual Post Operative Tumor Volume Predicts Outcome after High-Dose Radiotherapy for Chordoma and Chondrosarcoma of the Skull Base and Spine. Clinical Oncology, 23, 199-208.
 Mizumoto, M., Okumura, T., Hashimoto, T., et al. (2011) Proton Beam Therapy for Hepatocellular Carcinoma: A Comparison of Three Treatment Protocols. International Journal of Radiation Oncology, Biology, Physics, 81, 1039-1045.
 Mizumoto, M., Yamamoto, T., Ishikawa, E., et al. (2016) Proton Beam Therapy with Concurrent Chemotherapy for Glioblastoma Multiforme: Comparison of Nimustine Hydrochloride and Temozolomide. Journal of Neuro-Oncology, 130, 165-170.
 Oshiro, Y., Okumura, T., Kurishima, K., et al. (2014) High-Dose Concurrent Chemo-Proton Therapy for Stage III NSCLC: Preliminary Results of a Phase II Study. Journal of Radiation Research, 55, 959-965.
 Weber, D.C., Malyapa, R., Albertini, F., et al. (2016) Long Term Outcomes of Patients with Skull-Base Low-Grade Chondrosarcoma and Chordoma Patients Treated with Pencil Beam Scanning Proton Therapy. Radiotherapy and Oncology, 120, 169-174.
 Hayashi, Y., Mizumoto, M., Akutsu, H., et al. (2016) Hyperfractionated High-Dose Proton Beam Radiotherapy for Clival Chordomas after Surgical Removal. The British Journal of Radiology, 89, Article ID: 20151051.
 Rombi, B., Ares, C., Hug, E.B., et al. (2013) Spot-Scanning Proton Radiation Therapy for Pediatric Chordoma and Chondrosarcoma: Clinical Outcome of 26 Patients Treated at Paul Scherrer Institute. International Journal of Radiation Oncology Biology Physics, 86, 578-584.
 Hoch, B.L., Nielsen, G.P., Liebsch, N.J., et al. (2006) Base of Skull Chordomas in Children and Adolescents: A Clinicopathologic Study of 73 Cases. The American Journal of Surgical Pathology, 30, 811-818.
 Habrand, J.L., Schneider, R., Alapetite, C., et al. (2008) Proton Therapy in Pediatric Skull Base and Cervical Canal Low-Grade Bone Malignancies. International Journal of Radiation Oncology Biology Physics, 71, 672-675.
 Hug, E.B., Sweeney, R.A., Nurre, P.M., et al. (2002) Proton Radiotherapy in Management of Pediatric Base of Skull Tumors. International Journal of Radiation Oncology Biology Physics, 52, 1017-1024.
 Rutz, H.P., Weber, D.C., Goitein, G., et al. (2008) Postoperative Spot-Scanning Proton Radiation Therapy for Chordoma and Chondrosarcoma in Children and Adolescents: Initial Experience at Paul Scherrer Institute. International Journal of Radiation Oncology Biology Physics, 71, 220-225.
 Benk, V., Liebsch, N.J., Munzenrider, J.E., et al. (1995) Base of Skull and Cervical Spine Chordomas in Children Treated by High-Dose Irradiation. International Journal of Radiation Oncology Biology Physics, 31, 577-581.
 Armstrong, G.T., Liu, Q., Yasui, Y., et al. (2009) Late Mortality among 5-Year Survivors of Childhood Cancer: A Summary from the Childhood Cancer Survivor Study. Journal of Clinical Oncology, 27, 2328-2338.
 Turcotte, L.M., Whitton, J.A., Friedman, D.L., et al. (2015) Risk of Subsequent Neoplasms during the Fifth and Sixth Decades of Life in the Childhood Cancer Survivor Study Cohort. Journal of Clinical Oncology, 33, 3568-3578.
 Mizumoto, M., Murayama, S., Akimoto, T., et al. (2016) Proton Beam Therapy for Pediatric Malignancies: A Retrospective Observational Multicenter Study in Japan. Cancer Medicine, 5, 1519-1525.