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

Purpose/Objective(s)

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. We report results from a prospective clinical trial of proton beam radiation for the treatment of chordomas and chondrosarcomas.

Materials/Methods

Fifty-five patients with pathologically confirmed, non-metastatic chordoma or chondrosarcoma with an ECOG score <=2 were enrolled in a single-institution prospective trial of proton therapy from 2010-2018. Forty-seven patients received adjuvant RT, 5 received definitive RT, 1 received neoadjuvant RT, and 1 received RT for recurrence; 1 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 three-month intervals. The primary endpoints were feasibility and <=20% rate of unexpected acute grade ≥3 toxicity. Secondary endpoints included cancer-specific outcomes and toxicity. Toxicities 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.

Results

Of the 54 patients who were analyzed (22 males, 32 female) with a median age of 54, 26 had skull base chordomas, 10 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 patients at the time of RT. Median follow-up was 72 months, with an Overall survival of 45/54 (83%) patients alive at last follow-up. Local failure-free survival and progression-free survival were 70% and 68% respectively at a median follow up of 69 months. Feasibility endpoints 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. Five patients developed distant disease, 3 with a metastasis in the craniospinal axis, and 1 with a biopsy-confirmed inguinal lymph node metastasis, and 1 with distal iliac and femur metastases. Among the 9/54 patients who died, 4 deaths were not attributed to treatment or recurrence. There were no grade 4 toxicities. One grade 3 acute toxicity (sensory neuropathy) was recorded. The only 2 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.