308 - Phase I/II Prospective Dose Escalation Trial with Proton-Based Radiation Therapy for Chordomas and Chondrosarcomas of the Skull Base and Cervical Spine: Long-Term Results from Proton Radiation Oncolog

M. Ioakeim-Ioannidou¹, B. Y. Yeap², Z. Soetan³, D. Packard⁴, A. Tejada⁵, R. Hegazy⁶, E. S. R. Todary⁷, J. A. Adams⁸, H. M. Kooy⁹, F. Giap¹⁰, Y. L. E. E. Chen⁸, T. F. DeLaney⁸, M. Goitein¹¹, J. E. Munzenrider¹², E. B. Hug¹³, and S. M. MacDonald⁸; ¹Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, ²Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, ³Massachusetts General Hospital, Boston, MA, ⁴Tufts University School of Medicine, Boston, MA, ⁵Columbia Univeristy Irving Medical Center, NYC, NY, ⁶Childrens Cancer Hospital Egypt, Cairo, Egypt, ⁷Childrens Cancer Hospital Cairo, Cairo, Egypt, ⁸Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, ⁹Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, ¹⁰University of Texas Southwestern, Dallas, TX, ¹¹Harvard Medical School, Boston, MA, ¹²Massachussets General Hospital, Boston, MA, ¹³MedAustron Ion Therapy Center, Wiener Neustadt, Austria

Purpose/Objective(s): To assess the outcomes of skull base and spinal chordomas (CH) and chondrosarcomas (CHS) treated to three radiation dose levels. Materials/

Methods: We designed a prospective Phase I/II dose searching trial in adult patients with CH and CHS of the base of skull (BOS) and cervical spine (CS) assigned to three dose arms: 70 Gy (RBE), 76 Gy (RBE), and 83 Gy (RBE) of fractionated combined proton/photon radiotherapy (RT) with >70% of the dose delivered with protons at a single institution. The primary endpoint was local control with hypothesis of improved tumor control with higher dose. Secondary endpoints included overall survival, cancer-specific survival, progression-free survival, and rates of treatment-related toxicities graded according to CTCAE v5.
Results: Between 1987 and 2007, 381 patients were assigned to three dose arms. Two patients refused assigned treatment; therefore, 379 patients were analyzed: 128 patients were assigned 70 Gy (RBE), 193 to 76 Gy (RBE), and 58 to 83 Gy (RBE). The median follow-up for entire cohort was 27 years (IQR, 22-30). Local failure for the entire cohort was 23% at 5 years, 31% at 10 years and 37% at 20 years. Local failure at 5-, 10-, and 20-years were 20%, 28%, and 38% for the low-dose group, 23%, 32%, and 36% for the intermediate-dose group, and 27%, 34%, and 40% for the high-dose group (p=0.86). Overall survival at 5, 10, and 20 y was 88%, 66%, and 50% for the low-dose group, 87%, 64%, and 47% for the intermediate-dose group, and 82%, 63%, and 35% for the high-dose group (p=0.31). Cancer-specific survival at 5, 10, and 20 y was 91%, 76%, and 70% for the low-dose group, 91%, 75%, and 65% for the intermediate-dose group, and 84%, 69%, and 58% for the high-dose group (p=0.41). Progression-free survival at 5, 10, and 20 y was 74%, 60%, and 42% for the low-dose group, 68%, 51%, and 39% for the intermediate-dose group, and 59%, 44%, and 24% for the high-dose group (p=0.06). All survival outcomes were significantly worse in chordoma patients. There was no statistically significant difference in outcomes between skull base and spinal tumors. Late RT injury = grade 2 was reported in a total of 92 (24%) patients at a similar rate across all dose levels with 27% in the low-dose group, 23% in the intermediate-dose group, and 24% in the high-dose group (p=0.74). 14 (4%) patients suffered a cerebrovascular accident, 13 (3%) patients developed osteoradionecrosis, 13 (3%) patients had brainstem necrosis, and 21 (6%) patients had a symptomatic temporal lobe injury. 8 (2%) patients developed secondary tumors in the previous RT field.
Conclusion: This is the first report of the largest trial of patients with CH and CHS of the skull base and the spine assigned to three different dose arms. Proton-based RT is effective for those tumors with no apparent benefit in dose escalation. Despite high doses, the rates of grade II-V late toxicities were low across all dose arms.