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Peripheral nerve sheath tumors (PNSTs) commonly arise from peripheral nerve roots and grow locally destructive. Malignant PNSTs (mPNSTs) represent aggressive sarcomas of neural origin that can originate from PNSTs. Radiation therapy is commonly used as part of the required multimodal treatment. However, both entities tend to occur early in life and are associated with the mutation neurofibromatosis type 1 (NF-1), which is known to cause increased radiosensitivity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk (OARs) and the integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We aimed to report the oncological outcome and toxicity rates of patients with (m)PNSTs treated with PBSPT.

We retrospectively reviewed 36 patients who received PBSPT (median dose, 64 GyRBE) with curative intent for (m)PNSTs between 1999 and 2020 at our institute. Twenty eight (78%) and 8 (22%) patients were treated at diagnosis and for tumor recurrence/progression, respectively. Of the latter patients, one was treated 42 months prior to PBSPT with photon radiotherapy. Median age was 32 years (range, 3 – 75) and 25 (69%) patients were male. mPNST and PNST was diagnosed in 31 (86%) and 5 (14%) patients, respectively. Underlying NF-1 disease was found in 8 (22%) patients. Acute and late toxicities were recorded according to CTCAE v4.1. Overall survival (OS), local control (LC) and distant control (DC) were estimated using the Kaplan-Meier method.

With a median follow-up time of 31 months (range, 4 – 194), 13 (36%) patients died with uncontrolled disease, 8 (22%) experienced local failure (LF) and 14 (39%) presented with distant failure after PBSPT. Estimated 2-year OS, LC and DC was 75.5%, 73.5% and 61.2%, respectively. Higher FNCLCC grade and R2/RX resection status was associated with impaired survival: 2-year survival rate for patients with FNCLCC grade 3 vs. grade ≤2 tumors was 67.5% vs. 78.7% (p=0.009), while patients with R2/RX and R0/R1 resection status had 2-year survival rates of 59.8% and 93.3% (p=0.015), respectively. Grade 3 acute toxicity (dermatitis, mucositis, pain in extremity) was observed in 5 (14%) patients. Late grade 3 cataract and osteonecrosis was both observed in 1 (3%) patient, 34 and 194 months after PBSPT, respectively. Two-year late grade >3 toxicity rate was 0%. There was no late grade >3 toxicity or radiation-induced secondary cancer.

To our knowledge, this is the first study to analyze the outcome of (m)PNSTs treated with proton therapy. In our cohort, consisting mainly of patients with mPNSTs, we report excellent oncological outcome and low toxicity rates after PBSPT.