MEANS TO REDUCE RADIOTHERAPY-RELATED TOXICITY FOR HEAD AND NECK SQUAMOUS CELL CARCINOMA

Head and neck cancers include malignancies originating in the oral cavity, nasopharynx, oropharynx, hypopharynx and larynx. In Belgium, more than 90 % of head and neck cancers are squamous cell carcinomas (HNSCC), and more than 2500 patients were diagnosed with HNSCC in the year 2016. (Belgium Cancer Registry) The use of alcohol and tobacco, with a substantial synergistic effect, induces most HNSCC except for oropharyngeal (OPC) and nasopharyngeal cancer. These HNSCC subsites often have a viral aetiology, Human Papillomavirus (HPV) and Epstein Barr virus, respectively. In the Western world, the incidence of HPV positive OPC is rapidly increasing.

The treatment of HNSCC depends mainly on the tumour subsite, tumour size, lymph node involvement and the presence of distant metastases, summarised in the TNM classification. Most early-stage HNSCC can be cured by surgery or radiotherapy (RT), which have similar locoregional control rates. The selection of treatment modality in early disease depends on patient characteristics, the expected post-treatment organ functionality and cosmesis. Unfortunately, the majority of patients with HNSCC have locally advanced disease at diagnosis and should, therefore, be treated with chemoradiotherapy (CRT) or with radical surgery followed by adjuvant (C)RT. Thus, RT is one of the cornerstones of the treatment of HNSCC. Since RT damages both normal and neoplastic cells, the clinical challenge in radical RT is to attain a high therapeutic ratio, which is the highest probability of cure with the least toxicity to surrounding healthy structures.

Technical evolutions have made it possible to design high precision three dimensional (3D) conformal and intensity-modulated radiotherapy (IMRT) in which the high dose region is better sculpted around the target volumes, which made it possible to spare the healthy organs at risk (OAR) better. IMRT has become the prefered RT technique in the treatment of HNSCC since the randomised controlled PARSPORT trial has shown the ability and advantage of sparing the parotid salivary glands with IMRT. Despite the improved RT dose distribution on the OAR, acute and late toxicity such as dysphagia, remains a major problem. The risk of dysphagia is correlated with the dose to the swallowing muscles. With the current standard RT dose and fractionation, it is difficult to lower the dose on the swallowing muscles because of the proximity of the target volumes (tumour, nodes and elective neck). Therefore, the current RT procedure and protocol should be optimised in order to reduce treatment-related toxicity.

We hypothesised that dose-de-escalation to the elective nodal neck (PTVelect) could lower the RT related toxicity such as dysphagia and lead to better QoL without compromising the oncological outcome. Therefore, a multicentre randomised controlled trial was set up comparing a lower dose to the PTVelect, EQD2 40 Gy, against the standard dose, EQD2 50 Gy. In previous publications, the dosimetric comparison, the effect on acute and late toxicity and the two-year tumour outcome were published showing a significant reduction in dose on several swallowing structures resulting in a substantial reduction in grade ≥3 dysphagia three months after radiotherapy.  At later time points, only a trend toward less dysphagia was found. Regarding survival and tumour control, no statistically significant differences were found at two years. We assessed the long term oncological outcome with a special interest in the regional recurrence rate in the PTVelect and investigated the differences in QoL between the 40 Gy and 50 Gy arm.

Since in this prospective randomised trial reduction of the dose to PTVelect did not result in a clear benefit in terms of decrease in late dysphagia, other factors may contribute to the development of severe dysphagia. We examined the role of patient and treatment characteristics on dysphagia scored on swallowing videofluoroscopy (VFS) as well as patient and physician scored dysphagia. Next, we evaluated if an existing prediction model for dysphagia, the total dysphagia risk score (TDRS), was also valid in our patient cohort.

Besides efforts to reduce the treatment-related toxicity, we should also strive to tailor the treatment to the individual risk profile of the patient. Presently, all patients treated with curative RT receive a standard high dose of 70 Gy (in 35 fractions of 2 Gy), even though some tumours are more radiosensitive than others. The difference in radiosensitivity and prognosis is particularly proven in OPC. In general, HPV positive OPC have a better prognosis than HPV negative OPC. Treatment intensification, e.g. by dose escalation or hypoxia modification, may improve the oncological outcome for patients with poor prognosis while for others with excellent prognosis who might be overtreated, dose reduction could prevent long term toxicity. Good prognostic models are needed to individualise the patients’ treatment. At the moment, these models are mostly based on the TNM classification in combination with patient characteristics such as smoking. We examined the prognostic impact of a few models and the new TNM classification in our patient population. Although the new TNM classification (8th edition) provides better OS stratification than the 7th  edition, we are convinced that in the future genetic and radiologic information must be integrated to better select patients for de-escalation or escalation of the treatment. First, we examined the prognostic value of a 15-gene hypoxia classifier in OPC. Next, the role of diffusion-weighted (DW) MRI in OPC was investigated. We compared the DW-MRI first-order histogram and radiomic features between HPV positive and negative OPC.

Thus, the objectives of this research project are twofold. The first aim is to reduce the treatment-related toxicity in HNSCC with particular focus on dysphagia. The second aim is to predict the prognosis for patients with OPC to tailor the treatment to the individual risk profile.