Patients with tonsillar cancer treated with a combination of surgery and adjuvant radiotherapy have a good prognosis in general, especially if the tumour is p16 positive. In a study done by the KROG (Korean Radiation Oncology Group), where p16 status was unknown in the majority of patients, the 5-year DFS for the bilateral nodal radiotherapy group was 94.2% [10]. In a recent study by Ferris RL et al. [11] reporting results of a phase II study of postoperative radiotherapy in p16 positive oropharyngeal cancer, the two-year progression-free survival was 94.9% for the 5 Gy arm and 96% for the 60 Gy arm. With such a high percentage of long-term survival, late toxicity is a crucial factor that must be considered. Therefore, in tonsillar cancer, ways to de-escalate the intensity of treatment are strongly sought after. The most frequently discussed options are dose de-escalation, chemotherapy omission and unilateral adjuvant radiotherapy. Proton radiotherapy is another possibility for de-escalation of treatment intensity.

Proton radiotherapy has dosimetric advantages in the head and neck area. Several dosimetric studies have been published for oropharyngeal carcinoma. Holliday et al. [7] compared IMPT with IMRT and found that IMPT leads to lower mean doses to many OARs, including the anterior and posteriorsections of the oral cavity, middle and inferior pharyngeal constrictor muscles and oesophagus. Apinorasetsethkul et al. [12] compared proton radiotherapy and volumetric modulated arc therapy (VMAT) for oropharyngeal cancer and found that protons offered improved sparing of the oral cavity, contralateral parotid gland, and contralateral submandibular gland. However, sparing of the parotid glands is highly dependent on the arrangement of the fields for PBS.

The integral dose and potential induction of secondary malignancies also plays a role, considering the relatively young age of patients with tonsillar cancer and their long-life expectancy. Jain et al. [13] compared the risk of secondary malignancies after IMPT or IMRT for oropharyngeal cancer using an organ equivalent dose model for the linear-exponential dose-response curve. They found that at a median age of 54 years at the time of treatment, with an average life expectancy of an additional 27 years, 4 excess secondary malignancies per 100 patients could be avoided by treating them with IMPT versus IMRT.

A particular disadvantage of proton radiotherapy is its higher sensitivity to the accuracy of performance and reproducibility of target volumes. In the postoperative setting in patients with tonsillar cancer, i.e., in a group of patients in a good condition enabling surgery, where the tumour has been removed, problems with changes to the target volume, and the need for adaptive radiotherapy with frequent replanning, are eliminated. Higher sensitivity to set-up errors can be addressed by the robust optimization of treatment plans to be more resistant to set-up errors. The feasibility and applicability of this technique in oropharyngeal cancer has been demonstrated by Hague et al. [14]. Our approach to robustness assessment is described in the section concerning treatment planning. In principle, it is not feasible to create fully robust plans without a pro and con evaluation. Using a standardised treatment approach, all treatment plans we used had the same level of robustness. Before the actual treatment technique was introduced into clinical practice, robust evaluation was performed for typical setup.

Treatment results are generally excellent in HPV16 positive oropharyngeal tumors [15, 16]. To this point, our group of patients did not deviate in any way, and the overall survival and relapse-free survival parameters are comparable to other research outcomes. During our follow-up period, metastasis occurred in one patient (97.9%). Similar studies using photon radiotherapy reported an 8% metastasis rate [17] and 7% in a study utilising only unilateral lymph node irradiation [18].

The toxicity of the treatment was mild, but we observed more pronounced cutaneous toxicity with subsequent subcutaneous fibrosis in patients treated at the beginning of the study period. The problem of skin toxicity has been described, for example, in the case of breast cancer [19]. This was due to an approach to planning that did not sufficiently take into account the skin as a critical planning authority. After tightening the parameters for skin as an OAR, this problem was significantly reduced.

Our rates for other acute toxicities such as oral mucositis and weight loss were comparable and, in some cases, better than in photon-based studies. Developing oral mucositis during radiotherapy can be very painful, and can lead to difficulties with eating, leading to malnutrition [20]. Kim et al. [10] reported oral mucositis grades 1, 2 and 3 in 24.3%, 47.1% and 18.6% of their bilaterally irradiated patients, respectively. Chin et al. [17] observed mucositis grades of 1, 2 and 3 in 10.0%, 50.0%, 32.0% of their patients, respectively. While these studies had more patients with no mucositis (10.0% and 8.0%, respectively), we report considerably less patients with grade 3 mucositis. Our study also revealed markedly lower rates of higher-grade weight loss compared to the 38%, 16%, 8%, 38% of photon-treated patients with grades 0, 1, 2 and 3 [17]. The low percentage of tube feeding required was noteworthy. In a photon-based study with 59 patients receiving bilateral IMRT, PEG was used acutely in 39% of patients and long-term in 20% [17]. Additionally, we had markedly lower rates of late dysphagia compared to the 30% of patients that developed grades 1–3 in another study [10].

Proton radiotherapy could achieve maximum potential in unilateral radiotherapy in the adjuvant treatment of HPV16 positive tonsillar cancer. However, this approach is not yet standard, particularly due to fear of a risk of progression to the contralateral nodes. For example, Kim et al. [2] demonstrated the importance of contralateral radiotherapy for N2b stages of the disease (AJCC 7th edition). However, a higher proportion of contralateral relapses did not translate into overall survival. The main advantage of proton radiotherapy in this context is zero dose to the contralateral side of the neck when the ipsilateral area is irradiated. The contralateral side remains therefore intact, and any other procedures, including surgery and subsequent radiotherapy, can be performed as in treatment-naive patients.