Intensity modulated proton therapy for early-stage glottic cancer: high-precision approach to laryngeal function preservation with exceptional treatment tolerability

The current study reports first clinical results of high-precision proton therapy in patients with early-stage glottic squamous cell carcinoma. IMPT resulted in exceptional overall treatment tolerability with high laryngeal function preservation rates and promising oncological outcome.

The two-year L-PFS and OS were 90.0% and 100%, comparable to previously reported treatment outcomes after MLS or RT in patients with early-stage glottic cancer [3]. Since none of the patients in our study required a gastric feeding tube or tracheostomy, the two-year LE-DFS, an essential outcome parameter for patients with laryngeal cancer [18], was also 90.0%. Further follow-up is necessary to confirm the long-term functional outcome and larynx preservation. Previous studies reported comparable oncological and functional outcome after MLS versus RT in early-stage glottic cancer [5, 6]. In a meta-analysis by Guimarães et al. [8], endoscopic resection showed a tendency to lower overall risk for laryngectomy while definitive RT was favorable with regard to long-term vocal quality in early-stage glottic cancer. However, most of these clinical trials did not reflect current high-precision image-guided RT and dose fractionation regimens, which yield decisive advantages with regard to toxicity [19] and dose escalation [20], compared to 3D-conformal RT. In addition, in patients with non-superficial T1-2N0 glottic cancer or diagnosed field cancerization, requiring more extensive larynx-preserving resection, definitive RT is generally preferred [3].

Previous studies could also demonstrate favorable outcomes with altered fractionation RT. In a prospective study on 180 patients with T1N0 glottic cancer [21], moderate hypofractionation compared to normofractionated RT resulted in a superior 5-year local control rate of 92% versus 77% (p = 0.004). Moderate acceleration (6 versus 5 weekly fractions) can also significantly improve locoregional control in patients with glottic squamous cell carcinoma [22]. Due to its biophysical features, IMPT is well suited for both moderately hypofractionated and accelerated treatment regimens, as performed in a subgroup of patients in the current study. The treatment regimens were rather heterogeneous in the current study, since uncertainties regarding the optimal total dose and fractionation remain. In the reported studies on altered fractionation, both acute and long-term toxicity rates were not significantly changed compared to normofractionation [23]. However, different approaches to toxicity reporting impede the comparison of results. Several studies evaluated only the total toxicity count per patient, e.g. the highest toxicity grade, or only reported high-grade (CTC grade III–IV) toxicities in general. Our results are based on the TAME toxicity reporting system [16], accounting for every grade and event per patient. Nevertheless, the mean number of overall acute and late toxicity events of 5.3 was encouraging and either comparable or favorable to previous studies using IMRT techniques [23]. The most important conclusion regarding toxicity in the current study is also the most obvious—no severe acute or late grade III–IV toxicities were reported. In addition, all patients completed IMPT without interruptions, which is essential for the treatment outcome in patients with glottic cancer [24].

High-precision RT of glottic cancer, e.g. IMPT, yields pronounced dosimetric advantages, in particular for the treatment of head and neck cancer [10]. Several dosimetric comparison studies for laryngeal cancer could verify the advantages of protons [25, 26], e.g. with regard to the carotid arteries, the arytenoid cartilage, the swallowing muscles, the thyroid gland, and the spinal cord. However, a major challenge of IMPT, which is particularly important for glottic cancer, is the high susceptibility to density changes due to anatomical or positional changes during RT. Thus, the increased precision of proton therapy of glottic cancer requires measurements to account for the risk of marginal misses and motion interplay effects. Therefore, prospective clinical trials including on-site image guidance are indispensable for the implementation of IMPT for the treatment of glottic cancer.

In particular in partial laryngeal irradiation of early-stage lateralized glottic cancer, image guidance with daily laryngeal soft tissue matching can increase local control considerably [20]. In addition, the dose to the contralateral vocal cord can be significantly reduced using image-guided IMRT compared to conventional 3D-conformal RT [27], resulting in a distinct decrease of treatment toxicity [19]. The potential clinical benefits of unilateral vocal cord versus complete laryngeal RT are currently evaluated as part of a prospective randomized clinical trial [9]. High-precision IMPT has the potential to improve treatment tolerability in selected patients with early-stage lateralized tumors even further. However, state-of-the-art on-site image-guidance with CT or MRI, which is increasingly availably in particle therapy centers, is required for daily soft-tissue matching, in particular for treatment regimens with altered fractionation. In addition, further radiation therapy innovations with the potential to minimize treatment toxicity while enhancing tumor control in early-stage glottic cancer, e.g. ultra-high dose rate RT [28, 29] or helium ion RT [30,31,32], are currently under development.

Limitations

There are among others the following limitations of this study. First, due to the retrospective nature, the reported toxicity was recorded non-standardized and could therefore be underestimated. Second, the median follow-up interval of 17.0 months was rather short, which creates uncertainties with regard to the results of oncological and functional outcome and long-term toxicity. Third, patients often continued follow-up with their external ENT-specialist in a non-standardized setting. Nonetheless, the current study increases the body of evidence with regard to particle therapy for early-stage laryngeal cancer with direct implications for ongoing and future clinical studies.

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