Schwannomas are usually benign and slowly growing nerve sheet tumors that arise from the Schwann cells lining of peripheral nerves. They are most commonly located in the intradural extramedullary space and therefore affect mainly cranial or spinal nerves (1). Vestibular schwannomas (also known as acoustic neuromas) that commonly arise from the vestibular portion of the eighth cranial nerve account for most schwannomas. The overall incidence is approximately 1 in 100,000 persons per year in Western countries (2). While sporadic schwannomas are rare, they occur frequently in patients with neurofibromatosis. Bilateral vestibular schwannomas in children with neurofibromatosis put them at risk for complete deafness (3–6).

In the past decades, the most effective treatment for progressive cranial nerve schwannomas has been complete surgical resection. While local control rates were excellent, injuries of the affected or adjacent cranial nerves make the treatment of cranial nerve schwannomas a major challenge. A large surgical trial reports in vestibular schwannoma a functional hearing deterioration in up to 60.5% after surgical resection. So, cranial nerve injuries cause a relatively high morbidity compared to the excellent oncologic prognosis (7, 8). Due to the slow progression of schwannomas, the “watch and wait strategy” can be a legitimate treatment option for selected patients (9). Therapy sequelae like hearing impairment and tinnitus, vertigo and gait disturbances, facial nerve palsy, facial pain or hypesthesia, swallowing difficulties, or others also impair the quality of life. Therefore, treatment decision needs to be made carefully, and research on nerve-saving techniques is necessary.

A promising new technique was developed with stereotactic radiosurgery. Even if large prospective data are still lacking, stereotactic radiosurgery (SRS) seems to be superior regarding the risk of cranial nerve damage in schwannomas smaller than 3 cm with excellent local control rates compared to surgical resection and is therefore taken into consideration in the European Association of Neuro-Oncology (EANO) guidelines (9).

But concerns about the induction of malignant transformation of schwannomas or secondary malignancy induction after stereotactic radiosurgery still exist, even if there is no evidence for these concerns in literature, neither for stereotactic radiosurgery nor for particle beam radiotherapy (10–13). Proton beam radiotherapy (PRT) is a promising approach to better spare healthy surrounding tissue and therefore might contribute to the reduction of side effects in patients unsuitable for SRS due to the advanced tumor stage.

The major concern with proton beam radiotherapy is the risk of radiation-induced contrast enhancements (RICE), as known from, e.g., glioma trials (14, 15). RICE are defined by new brain lesions outside the tumor volume related to cerebral irradiation that are usually contrast-enhancing and not caused by the tumor. These RICE are usually transient blood-brain barrier disruptions and rarely real necrosis.

To date, there are only scarce data on PRT for schwannomas. One study investigated efficacy and toxicity rates in 94 patients who underwent fractionated PRT for vestibular schwannoma. These data demonstrated excellent local control rates and a dose-dependent risk for hearing deterioration of 36% to 56% with doses from 50.4 to 54 Gy, while the risk for damage of other cranial nerves was 5% (16). A case series supported the fact that fractionated PRT for vestibular schwannoma is well tolerated and provides good local control (17). A retrospective cohort study investigated proton (!) beam stereotactic radiosurgery and reported a 5-year tumor control rate of 95% and a dose dependency for facial neuropathy (18). No data at all exist on PRT for other schwannomas except for vestibular schwannomas.

This study investigates the effectiveness and toxicity of fractionated proton beam radiotherapy for cranial nerve schwannomas that were unsuitable for SRS. Is excellent tumor control achievable without major sequelae?

This study investigates the effectiveness and toxicity of fractionated proton beam radiotherapy for cranial nerve schwannomas.

As expected, most cranial nerve schwannomas affected the vestibulocochlear nerve, and therefore, most patients presenting to our clinic suffered from hearing impairment, tinnitus, or vertigo. Nevertheless, cranial nerve schwannomas originating from the trigeminal nerve, the glossopharyngeal nerve, and the vagal nerve were also found, mainly associated to neurofibromatosis type 2 as supported by literature data (24). Most patients sought for treatment due to clinical symptoms or a documented schwannoma progression under monitoring.

Proton beam radiotherapy for cranial nerve schwannoma was shown to be effective. No schwannoma progression was observed, and therefore, 100% effectivity can be reported for the follow-up period of 3.5 years in median. These effectivity rates for proton beam radiotherapy are very promising. However, further prolongation of the follow-up period is needed. The only data available on PRT in vestibular schwannoma include 95 patients treated from March 1991 to March 2008 at Loma Linda University Medical Center. Fractionated proton radiotherapy at daily doses of 1.8 Gy and a total dose ranging between 59.6 Gy (RBE) and 50.4 Gy (RBE) was employed, depending on hearing function. Local control rates for the median follow-up time of 64 months were 95–92%, depending on the applied dose. Cranial nerve injuries occurred in two patients. Hearing preservation was maintained in 44–64% of the patients, depending on the applied dose. The overall patient cohort was divided into three groups with graduated dose concepts (16).

For gamma knife, a control rate of 98% after a median follow-up period of 5.8 years was reported (25). For the “watch-and-wait” strategy, a meta-analysis demonstrated in median 43% of schwannoma progressions in a similar follow-up period of 3.2 years (26). For surgery, a median of 9% schwannoma progression was demonstrated in a follow-up of 3.1 years (27) with a considerable rate of surgery-associated cranial nerve damage with chances of hearing preservation between 47% and 88% and even death due to surgery-associated complications (28). Therefore, as stated by the EANO Guideline on the Diagnosis and Treatment of Vestibular Schwannoma, radiotherapy is superior to both the “watch-and-wait” strategy regarding efficacy as well as surgery especially regarding toxicity in small tumors (<3 cm) (9). But both the “watch-and-wait” strategy and surgery are valuable for selected patients. Patients without any symptoms or progression may be suitable for the “watch-and-wait” strategy, while very large tumors that have already completely destroyed the nerve and compress the brainstem may be suitable for surgery. For radiotherapy, there are several factors, e.g., dose, fractionation regimes, and treatment techniques, that have to be taken into consideration when deciding about the individually best approach. According to a retrospective comparative analysis of 125 patients in total, hearing preservation rates might be 2.5-fold higher in fractionated radiotherapy than in single fraction stereotactic radiosurgery, but tumor control rates were at least 97% in both groups (29). However, literature demonstrates also data that report similar rates for hearing preservation and local control for both fractionated radiotherapy and single fraction stereotactic radiosurgery, and the dose of single fraction stereotactic radiosurgery was significantly influencing hearing preservation (30). Furthermore, according to literature, it is recommended to use single fraction stereotactic radiosurgery for smaller lesions, while FSRT can be used independently of tumor size and should be preferred in larger tumors (with contact to the brainstem) due to the better adherence to dose constraints with FSRT (30–33). For PRT, fractionated radiotherapy might be less toxic than single fraction stereotactic radiosurgery (16, 18). We cannot directly compare our results to stereotactic radiosurgery as our cohort was defined by unsuitability for stereotactic radiosurgery (T3-T4 tumors). Valid treatment alternatives for our cohort were surgery or fractionated photon radiotherapy. Cranial nerve preservation of the affected cranial nerve in fractionated proton/photon radiotherapy is well known to be superior to surgery. Compared to fractionated photon radiotherapy, fractionated proton radiotherapy spares the adjacent cranial nerves due to steep dose gradients given in proton radiotherapy. This is a dosimetric advantage, and literature is lacking data whether this results in clinically detectable advantages. Since cranial nerve neuromas are mainly located at the skull base often in close proximity to the brain stem or the facial nerve (for acoustic neuroma/vestibular schwannoma), sparing of adjacent structures is critical.

Interestingly, a retrospective analysis found lower tumor control rates in patients with neurofibromatosis type 2 compared to sporadic tumors (29). This was not confirmed by our study using fractionated PRT.

When patients present for radiotherapy, they are usually suffering from schwannoma-associated symptoms that are mainly hearing impairments in vestibular schwannoma. None of our patients reported a new or worsening hearing impairment after PRT despite relevant dose deposition on the inner ear (D_mean in median = 43.8 Gy). Nevertheless, data on hearing function are based on medical history and physical exam so a very mild hearing deterioration might be underestimated in this analysis, since audiometry was not performed on a regular basis but only if symptoms were reported. Nevertheless, the used method is appropriate to detect a hearing deterioration that is in any way relevant to the patients’ daily life. One-fifth of the patients reported any new or worsening mild clinical symptoms associated to the affected cranial nerve in the follow-up period with a worsening tinnitus being the most common observation. Symptoms like tinnitus or vertigo might represent an irritation of the irradiated cranial nerve. Even if some patients (4.4%) reported an improvement of clinical symptoms, this analysis demonstrates that PRT can irritate or slightly impair the function of the affected cranial nerve leading to a mild deterioration of symptoms even if no loss of cranial nerve function was observed.

To sum up the scarce available data, fractionated proton beam radiotherapy for tumors unsuitable for stereotactic radiosurgery is a promising approach that should be further investigated. For detailed assessment of hearing function using repetitive audiometry, a prospective clinical trial is urgently needed. Such a trial is currently conducted at Boston using fractionated proton radiation therapy for vestibular schwannomas and will close recruitment in a couple of months, so results will be pending for multiple years (ClinicalTrials.gov Identifier: NCT01199978).

A special feature of this study is that RICE has been defined as an endpoint, and it was specifically evaluated for its occurrence, clinical presentation, treatment, and time course. Despite all advantageous properties of proton beam radiotherapy presented above, the rate of 16% for RICE needs to be further focused on. Due to close proximity of the irradiated cranial nerve schwannomas to the brain stem, RICE occurred in the vulnerable healthy brain stem tissue ( Figure 2 ). This unfavorable localization was also the reason why RICE treatment was administered liberally, so all of our RICE cases received a short course of corticosteroids. In two (of seven) patients, RICE were mild symptomatic, but corticosteroids relieved symptoms quickly, so none of the patients needed a bevacizumab therapy. Anti-VEGF antibodies like bevacizumab go along with excellent remission rates for RICE and are therefore the treatment of choice in more severe cases of RICE (34, 35). We showed that these lesions occurred after a median of 14 months. In 43%, the lesions regressed during the follow-up period. Due to this observed time course, we recommend a close timeline of follow-up including MRI within the first 2 years. For these 43% of cases, RICE is probably representing a radiation-induced blood-brain barrier disruption and probably not an irreversible radiation necrosis due to its transient nature, as supported by literature (36).

While the applied dose is standard (16), nearly half of our patients received up to six fractions per week, which is due to historical reasons and can therefore be regarded as slight acceleration. We decided at our institution not to proceed the irradiation with six fractions per week for central nervous system tumors as a safety measure. Nevertheless, this was not an influencing factor in the performed exploratory analysis regarding toxicity, RICE, or response of the treatment, but power was lacking. PTV conformity was sufficient in these cases, so inconformity can be excluded as a potential cause for RICE.

Another hypothesis is that the current technique of dose calculation for proton beam radiotherapy underestimates the real regional biological effectiveness as currently heavily discussed in the proton beam radiotherapy community. Interestingly, an RICE localization exactly behind the peak and therefore exactly distally to the target volume is a typical finding (as also depicted in Figure 1 ). The current method of dose prescription in PRT has known weaknesses. This leads to an uncertainty in dose calculation and therefore to underdosed and overdosed areas. Possibly, also an intrinsic difference in radiosensitivity of different brain tissue types might play a role and makes adaptions in proton beam radiotherapy planning necessary. First approaches for a physical risk model to estimate the probability of the occurrence of RICE for low-grade gliomas can be found in the literature (15). To reduce the risk for RICE without compromising the excellent oncologic outcomes, PRT planning needs to be improved further.

In summary, PRT was demonstrated to be effective and yielded high rates of cranial nerve functional preservation. The comparably low cranial nerve toxicity rates are promising, but the follow-up period needs to be further expanded. Also, a longer follow-up is needed. The analysis of RICE in this context is described for the first time. Even if no clinical relevance of RICE occurrence was demonstrated and corticosteroid response was good, it is above our understanding why some patients develop RICE and therefore further research is needed. Patients should undergo MRIs on a regular basis after cranial PRT.

These data demonstrate excellent effectiveness with 100% local control in a median follow-up period of 3.6 years with a promising cranial nerve functional protection rate of 80%. RICE occurred in 16% of the patients after PRT and were not or only mildly symptomatic but made a short course of dexamethasone necessary.

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 Heidelberg University ethics committee, January 2018 (#S-832/2018). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

TE, LK, KH, and JD planned and supervised this analysis. TE performed data extraction and review. TE, RES, and DK performed all statistical analysis. TE reviewed data analysis and drafted the manuscript. All authors contributed patient data and participated in reviewing and improving analysis and manuscript. All authors read and approved the final manuscript.

We acknowledge financial support by Deutsche Forschungsgemeinschaft within the funding program for Open Access Publishing, by the Baden-Württemberg Ministry of Science, Research and the Arts and by Ruprecht-Karls-Universität Heidelberg. TE received funding by Ruprecht-Karls Universität Heidelberg, Herbert Kienzle Foundation, and Else Kröner-Fresenius Foundation.

TE reports grants from Ruprecht-Karls Universität Heidelberg, Herbert Kienzle Foundation, and Else Kröner-Fresenius Foundation and received travel reimbursement from Bristol-Myers Squibb outside the submitted work. JH-R received speaker fees and travel reimbursement from ViewRay Inc, as well as travel reimbursement and grants from IntraOP Medical and Elekta Instrument AB outside the submitted work. RS reports grants from Ruprecht-Karls Universität Heidelberg, during the conduct of the study; personal fees from Accuray Inc., personal fees from AstraZeneca GmbH, personal fees from Bristol Myers Squibb GmbH & Co., personal fees from Novocure GmbH, personal fees from Merck KGaA, personal fees from Takeda GmbH, and grants from Accuray Inc., outside the submitted work. JD reports grants from the Clinical Research Institute (CRI), grants from View Ray Incl., grants from Accuray International, grants from Accuray Incorporated, grants from RaySearch Laboratories AB, grants from Vision RT limited, grants from Merck Serono GmbH, grants from Astellas Pharma GmbH, grants from Astra Zeneca GmbH, grants from Siemens Healthcare GmbH, grants from Solution Akademie GmbH, grants from Eromed PLC Surrey Research Park, grants from Quintiles GmbH, grants from Pharmaceutical Research Associates GmbH, grants from Boehringer Ingelheim Pharma GmbH Co, grants from PTW-Frieburg Dr. Pychlau GmbH, grants from Nanobiotix A.a., grants from IntraOP Medical, outside the submitted work. LK reports grants from Ruprecht-Karls Universität Heidelberg, personal fees from Accuray Inc., and Novocure GmbH outside the submitted work.

The remaining 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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