A Phase I/II Clinical Trial of Proton Therapy for Chordomas and Chondrosarcomas

Background/Objectives: Radiation therapy (RT) for chordomas and chondrosarcomas typically requires doses >70 Gy for optimal local tumor control. Proton therapy may afford safer dose escalation to the tumor; however, prospective data on outcomes and toxicity are lacking. Here we report results from a prospective clinical trial of proton beam radiation for the treatment of chordomas and chondrosarcomas.

Materials/Methods: Fifty-five adult patients with pathologically confirmed, nonmetastatic chordoma or chondrosarcoma with an ECOG score ≤2 were enrolled in a single-institution prospective trial of proton therapy from 2010 to 2018. Forty-seven patients received adjuvant RT, five received definitive RT, one received neoadjuvant RT, and one received RT for recurrence; one patient enrolled did not receive RT and was excluded from toxicity and survival analyses. Median dose was 78.3 Gy (cobalt Gray equivalent [CGE]; range, 50.4–79.2 Gy [CGE]) using protons only (n = 21), combination protons/IMRT (n = 33) with double-scatter or pencil beam scanning techniques, or IMRT only (n = 2). Patients were followed with MRI or CT at 3-month intervals. The primary end points were feasibility and ≤20% rate of unexpected acute grade ≥3 toxicity. Secondary end points included cancer-specific outcomes and other toxicities which were scored using CTCAEv4.0. Kaplan–Meier analysis was used to estimate local control, progression-free survival, and overall survival with respect to the date of RT completion. Local control was defined by most recent imaging; progression-free and overall survival were defined by most recent follow-up ([Fig. 1]).

Results: Of the 55 patients (22, male; 33, female) with a median age of 54, 26 had skull base chordomas, 11 had sacral chordomas, 6 had spinal chordomas, 9 had base of skull chondrosarcomas, 1 had sacral chondrosarcoma, and 2 had sinonasal chondrosarcomas. Positive margins or gross disease was noted in 67% of the patients at the time of RT. Median follow-up was 41.2 months, with 51/54 (96%) patients alive at last follow-up. Feasibility end points were met, with only 3/55 (5.5%) patient RT plans failing to meet dosimetric constraints with protons and 4/54 (7.4%) experiencing a delay or treatment break >5 days. Two patients developed distant disease, one with a metastasis in the craniospinal axis, and one with a biopsy-confirmed inguinal lymph node metastasis. Three-year local recurrence-free, progression-free, and overall survival were 88.4% (95% confidence intervals 78.6–98.2%), 83.2% (72.4–94.0%), and 96.0% (90.6–100%), respectively. Among the 3/54 patients who died, one died 3.5 months after completing RT; however, her death was not definitively attributed to treatment. No grade 4 to 5 toxicities were reported. One grade 3 acute toxicity (sensory neuropathy) was recorded. The only two grade 3 late toxicities recorded, osteoradionecrosis and intranasal carotid blowout, occurred in a single patient.

Conclusion: We report favorable feasibility, local tumor control, survival, and toxicity following high-dose proton therapy for chordomas and chondrosarcomas.

No conflict of interest has been declared by the author(s).