Peripheral nerve sheath tumors (PNSTs) and malignant PNSTs (mPNSTs) are neoplasms arising from peripheral nerves and are frequently also described as neurofibroma or schwannoma (PNST), neurofibrosarcoma, neurogenic sarcomas, or malignant schwannomas (mPNST). Both entities are often associated with the genetic disorder neurofibromatosis type 1 (NF-1) (1). PNSTs usually arise from Schwann cells (2) and are typically of benign character but can cause progressive and uncontrolled pain, neurologic deficits, compression/destruction of vital structures, and severe disfigurement (1). mPNST is a rare and highly aggressive soft tissue sarcoma of neural origin with an incidence of 1.46 per 1,000,000 person-years (3). mPNSTs account for approximately 10% of all soft tissue sarcomas and can originate from precursor PNSTs, particularly from plexiform neurofibromas (2, 4–10). An NF-1 disorder is found in approximately 50% of mPNST cases, 10% of all mPNSTs are radiation-induced, and the remaining 40% occur sporadically (6). Tumors of the peripheral nerves tend to present earlier in life (1, 4, 11, 12) than most other sarcomas, and mPNSTs represent one of the most frequent non-rhabdomyosarcomatous soft tissue sarcomas in the pediatric population (4, 13). A multimodal treatment approach including surgery and radiotherapy, with or without chemotherapy, is often administered due to the local aggressiveness and high potential to metastasize (14). Despite aggressive treatment regimens, the outcome for most patients remains poor, with median 5-year survival rates ranging from 15% to 50% (1). Studies have shown an increased radiosensitivity in NF-1 patients, which can lead to increased side effects from irradiation and a higher risk of secondary tumor induction (15, 16). With proton therapy (PT), the dose to organs at risk (OARs) can be reduced, and hence a lower integral dose is achievable. Considering that PNSTs/mPNSTs are often in a critical location (i.e., head or spine) and the young age of patients, PT seems an appropriate treatment strategy for this patient group.

The aim of this study is to report the oncological outcome and toxicity after pencil beam scanning PT (PBSPT) for PNSTs and mPNSTs and to assess the major prognostic factors for these challenging tumors.

In this study, we analyzed the clinical outcome of non-metastatic patients with PNSTs and mPNSTs treated with PBSPT. To the best of our knowledge, this is the first report of the oncological outcome and toxicity rates of mPNST/PNST patients treated with protons using a PBS delivery paradigm. Of note, two retrospective studies and two case reports analyzing mPNSTs treated with carbon ion (C12) particles were published (18–20). Jensen et al., 2015 (18) reported on the outcome and toxicity of 11 patients with unresected or incompletely resected mPNSTs treated with C12 irradiation. Patients with combined photon irradiation received 50 Gy photon intensity-modulated radiation therapy (IMRT) in 25 fractions and a 24 Gy_RBE boost with C12 irradiation in 8 fractions, while patients treated solely with C12 irradiation received 60–66 Gy_RBE in 20–22 fractions. With a median follow-up of 17 months, the authors reported a 2-year LC, progression-free survival, and survival rates of 65%, 56%, and 75%, respectively. Similar results were observed by Vitolo et al., 2019 (19) in their retrospective series of 13 patients with unresected mPNSTs treated with C12 irradiation (median dose of 73.6 Gy_RBE in 16 fractions) and a median follow-up of 24.6 months: reported 2-year LC and survival rates were 63% and 60%, respectively. Compatible with the C12 literature, we report in our cohort consisting mainly of patients with mPNSTs 2-year LC, DC, and OS rates of 73.5%, 61.2%, and 75.5%, respectively ( Figure 1 ). The superior LC rate in our study is possibly due to the fact that in both C12 studies, mainly patients with gross residual tumors were included. While prospective studies examining the impact of irradiation for PNST and mPNSTs are still missing, some larger retrospective series are available. The outcome of the selected studies and the two aforementioned C12 studies is summarized in Table 5 . One of the biggest series was published by Bishop et al., 2018 (22). These authors analyzed 71 mPNSTs treated with external beam radiation therapy (EBRT) either preoperatively with a median dose of 50 Gy or postoperatively with a median dose of 64 Gy. They reported excellent 5-year LC and survival rates of 84% and 66%, respectively ( Table 5 ). However, patients with recurrent and radiation-induced tumors, which are known to have the worse outcome (1, 25–28), were excluded from their analysis. Furthermore, they found positive/uncertain surgical margin status to be adversely associated with local recurrence at 5 years (28% vs. 5% for negative margins, p = 0.02).

In our cohort, univariate analysis revealed no factor to be significantly associated with LF. Patients with FNCLCC Grade 3 mPNSTs were however significantly more likely to develop distant metastases (HR 3.79, 95% CI: 1.32–10.9, p = 0.013; Table 3 ) and to die (HR 3.99, 95% CI: 1.33–12.0, p = 0.014; Table 3 ). For patients with macroscopic or uncertain resection status (R2/RX), a similar circa 4-fold risk increase to develop DFs (HR 3.97, 95% CI: 1.1–14.3, p = 0.035; Table 3 ) and decrease (HR 4.37, 95% CI: 1.19–16, p = 0.026; Table 3 ) was observed. Furthermore, on univariate analysis, a performance status score of ≤80 was negatively associated with DF (p = 0.045), and a trend toward increased DF and worse survival was seen for tumors larger than 5 cm (see Table 3 ). Tumor location seemed to have no impact on outcome in our cohort. These findings are largely in line with the existing literature where higher tumor grade (21, 23, 27, 29–33), incomplete resection (11–13, 23, 26, 27, 29, 31, 34), larger tumor size (11, 12, 21, 25, 27, 30–35), truncal tumors (12, 23, 25, 26, 30) and decreased performance status (36) were shown to be associated with worse prognosis.

There is some conflicting information in the literature concerning the impact of NF-1 disorder in mPNST patients. The majority of studies report decreased survival for mPNSTs occurring in NF-1-patients (11, 13, 26, 27, 29, 30), while several other studies report similar outcomes for NF-1 associated mPNSTs (12, 25, 31, 34). More recent studies have shown that genetically NF-1 and non-NF-1 mPNSTs seem to be indistinguishable (37, 38), and so far, no determining molecular differences have been identified (31). Most authors, therefore, attribute the observed poorer outcome of NF-1-associated mPNSTs to several accompanying factors known to be associated with worse prognosis, namely, 1) mPNSTs in NF-1 patients tend to be larger in size at the time of diagnosis (13, 26, 30), 2) the tumors are often in a non-extremity location and are therefore less amenable to surgery (11, 39), 3) NF-1 patients are more likely to develop other malignancies that might impair survival (13), and finally, 4) NF-1-associated tumors seem to respond less to chemotherapy (13). In 2013, Kolberg et al. (31) published survival meta-analyses comprising >1,800 mPNSTs comparing the survival of NF-1 and non-NF-1 patients. Indeed, they found that non-NF-1 patients had significantly increased OS (HR 1.38, 95% CI: 1.1–1.72, p = 0.004) and disease-specific survival rates (HR 1.4, 95% CI: 1.13–1.75, p = 0.002). Interestingly, this observed difference in survival is diminishing when only analyzing the patients treated after the year 2000. While disease-specific survival rates remain borderline significantly increased for non-NF-1 patients (HR 1.32, 95% CI: 1.0–1.74, p = 0.05), OS for NF-1 patients treated in the last 2 decades did not differ significantly compared to non-NF-1 patients (HR 1.19, 95% CI: 0.85–1.66, p = 0.3). A similar survival improvement for more recently treated NF-1-associated mPNSTs has been observed by Ingham et al., 2011 (40). Kolberg et al. (2013) considered that increased awareness among NF-1 patients and improved monitoring routines in the last years have led to earlier detection of mPNSTs and, thus, increased survival in NF-1 patients. One might also speculate that in the past, NF-1-associated mPNSTs were treated differently and that nowadays, due to improved and safer treatment modalities, NF-1 patients benefit from the same anticancer treatment as non-NF-1 patients.

In our cohort, NF-1 disorder was not associated with worse oncological outcomes ( Table 3 and Figure 1 ). On the one hand, only 8 (22%) patients had proven NF-1 disorder, which rendered finding a statistical difference for this sub-cohort difficult. On the other hand, 35 (97%) of our patients were treated after the year 2000 and 28 (78%) after the year 2010.

Cells from patients harboring a mutated NF-1 gene are considered to be more radiosensitive. No significant rate of relevant acute or late toxicity was observed in our NF-1 patients. In general, we report very low toxicity rates for our cohort after PBSPT. Late grade ≥2 toxicity rate was observed in 4 (11%) patients. There was no observed late grade 4 or 5 toxicity. These rates are in line with the reported toxicity in the literature, particularly when comparing PBSPT with C12 irradiation ( Table 5 ). Jensen et al. (2015) (18) reported late grade 3 toxicity in 2 (18%) patients, and Vitolo et al. (2019) (19) observed late grade ≥2 toxicity in 2 (15%) patients. No secondary tumor after PBSPT was observed in our cohort, although the follow-up period of our series is short. Kahn et al. (2014) (23) and Sloan et al. (2018) (24) reported in their series secondary tumor rates of 15% and 13%, respectively. However, their cohorts consisted of 50% and 100% NF-1 patients, which highlights the concern of secondary tumors after irradiation for this selected patient group.

Undoubtedly, our study has certain limitations, mainly being retrospective in nature with its inherent biases. A larger sample size and a longer follow-up period would have further increased the clinical validity of this study. The small sample size of 36 patients limited the statistical power to detect associations between outcome and some of the clinical factors examined. Our inability to perform a multivariate analysis also prohibits definitive conclusions regarding the outcome and prognostic factors. Additionally, this study consists of a rather heterogeneous cohort, including patients of any age, any resection status, and any histologic grade as well as five PNST cases. However, PNSTs are known to be a precursor of mPNSTs and are sometimes difficult to distinguish from mPNSTs (2, 10, 41, 42). As such, PNSTs usually require the same multimodal treatment including surgery and irradiation due to their destructive growth.

In our cohort, consisting mainly of patients with mPNSTs, we report 2-year LC and OS rates of 73.5% and 75.5%, respectively. The majority (n = 14, 39%) of patients failed distantly, and FNCLCC grade and resection type were significantly associated with DF. Only 1 (3%) patient presented with high-grade toxicity. No difference in toxicity rates was observed between NF-1 and non-NF-1 patients. Additional PT series are needed to legitimate the administration of protons in these young challenging patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethikkommission Nordwest- und Zentralschweiz (2021-00369). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

NB established the concept and design of the study; acquired, analyzed, and interpreted the data; and drafted the article. DL supported the statistical analysis and critically reviewed the submitted version of the manuscript. AP critically reviewed the submitted version of the manuscript. BB critically reviewed the submitted version of the manuscript. DW established the concept and design of the study, supervised the study, interpreted the data, and critically reviewed the submitted version of the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Open access funding provided by PSI - Paul Scherrer Institute.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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