Increasing Adherence to Prophylactic Swallowing Exercises During Head and Neck Radiotherapy: The Multicenter, Randomized Controlled PRESTO-Trial.

BACKGROUND: Prophylactic swallowing exercises (PSE) during radiotherapy can significantly reduce dysphagia after radiotherapy in head and neck cancer (HNC). However, its positive effects are hampered by low adherence rates during the burdensome therapy period. Hence, the main goal of this multicenter randomized controlled trial (RCT) was to investigate the effect of 3 different service-delivery modes on actual patients' adherence. METHODS: A total of 148 oropharyngeal cancer patients treated with primary (chemo)radiotherapy were randomly assigned to a 4 weeks PSE program, either diary-supported (paper group; n = 49), app-supported (app group; n = 49) or therapist-supported (therapist group; n = 50). Participants practiced 5 days/week, daily alternating tongue strengthening exercises with chin tuck against resistance exercises. Adherence was measured as the percentage of completed exercise repetitions per week (%reps). Statistical analysis was performed by means of SPSSv27, using Linear Mixed-effects Models with post hoc pairwise testing and Bonferroni-Holm correction. RESULTS: Adherence and evolution of adherence over time was significantly different between the three groups (p < .001). Adherence rates decreased in all three groups during the 4 training weeks (p < .001). During all 4 weeks, the therapist group achieved the highest adherence rates, whilst the app group showed the lowest adherence rates. CONCLUSIONS: PSE adherence decreased during the first 4 radiotherapy weeks regardless of group, but with a significant difference between groups. The therapist group achieved the highest adherence rates with a rather limited decline, therefore, increasing the face-to-face contact with a speech-language therapist can overcome the well-known problem of low adherence to PSE in this population. TRIAL REGISTRATION: Trial registration: ISRCTN, ISRCTN98243550. Registered December 21, 2018 - retrospectively registered, https://www.isrctn.com/ISRCTN98243550?q=gwen%20van%20nuffelen&filters=&sort=&offset=1&totalResults=2&page=1&pageSize=10&searchType=basic-search .

Study protocol for a randomized controlled trial: prophylactic swallowing exercises in head-and-neck cancer patients treated with (chemo)radiotherapy (PRESTO trial).

BACKGROUND: Dysphagia is a common and serious complication after (chemo)radiotherapy (CRT) for head-and-neck cancer (HNC) patients. Prophylactic swallowing exercises (PSE) can have a significantly positive effect on post-treatment swallowing function. However, low adherence rates are a key issue in undermining this positive effect. This current randomized trial will investigate the effect of adherence-improving measures on patients' swallowing function, adherence and quality of life (QOL). METHODS: This ongoing trial will explore the difference in adherence and swallowing-related outcome variables during and after PSE in HNC patients performing the same therapy schedule, receiving different delivery methods. One hundred and fifty patients treated in various hospitals will be divided into three groups. Group 1 performs PSE at home, group 2 practices at home with continuous counseling through an app and group 3 receives face-to-face therapy by a speech and language pathologist. The exercises consist of tongue-strengthening exercises and chin-tuck against resistance with effortful swallow. The Iowa Oral Performance Instrument and the Swallowing Exercise Aid are used for practicing. Patients are evaluated before, during and after treatment by means of strength measurements, swallowing and QOL questionnaires. DISCUSSION: Since low adherence rates undermine the positive impact of PSE on post-treatment swallowing function, there is need to develop an efficient PSE protocol maximizing adherence rates. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN98243550. Registered retrospectively on 21 December 2018.

Randomized clinical trial on reduction of radiotherapy dose to the elective neck in head and neck squamous cell carcinoma; update of the long-term tumor outcome.

BACKGROUND AND PURPOSE: A multicenter prospective randomized controlled trial was performed to investigate whether dose reduction to the elective nodal volume (PTVelect) in head and neck carcinoma reduces radiation-induced dysphagia, primary endpoint, without compromising tumor control, secondary endpoint. Here, we report on the long-term follow-up of the secondary endpoint (NCT01812486). MATERIALS AND METHODS: Two hundred patients treated with primary (chemo)radiotherapy (RT) were randomized (1:1) between the standard arm, irradiation to PTVelect up to an equivalent dose (EQD2) of 50 Gy and the experimental arm, irradiation to PTVelect up to EQD2 of 40 Gy. The primary tumor and involved nodes were treated according to the standard of care, EQD2 70 Gy (PTVhigh). Regional recurrences (RR) were projected on the initial RT planning-CT to identify the recurrence localization. RESULTS: The 5-year (5Y) RR was 14.0% (CI95% 7.9; 21.8) in the 40 Gy arm versus 7.5% (CI95% 3.3; 14.0) in the 50 Gy arm (p = 0.10). Majority of RR in the 40 Gy arm (9/13) were projected in PTVhigh and 2 RR were seen outside the treated RT volume. Only 2 RR occurred in PTVelect irradiated up to 40 Gy which was the same number as RR occurring in the 50 Gy PTVelect. The 5Y-overall survival (OS) was 56.5% (CI95% 45.7; 65.9) in the 40 Gy arm versus 49.6% (CI95% 39.0; 59.2) in the 50 Gy arm (p = 0.56). CONCLUSION: At 5-years, no statistically significant differences regarding OS, local recurrence, RR nor distant metastases were observed between both treatment arms. This study is underpowered to undoubtedly demonstrate non-inferiority. However, since in both arms only two RR in the PTVelect were observed, reducing the dose to PTVelect appears safe and should be further investigated.

Prognostic value of a 15-gene hypoxia classifier in oropharyngeal cancer treated with accelerated chemoradiotherapy.

PURPOSE: A 15-gene hypoxia classifier has been developed and validated as a predictive factor for patients with head and neck squamous cell carcinoma treated with radiotherapy and nimorazole. This paper aimed to investigate the role of this hypoxia classifier as a prognostic factor for patients with oropharyngeal cancer (OPC) treated with accelerated chemoradiotherapy. METHODS: P16 and 15-gene hypoxia classifier status, categorising tumours as more or less hypoxic, were determined for 136 OPC patients. Locoregional recurrence rate (LRR) and overall survival (OS) were estimated with cumulative incidence function and Kaplan-Meier method, respectively, stratified according to p16 and hypoxia status. RESULTS: P16-positive patients (34.6%) had significantly better LRR and OS than p16-negative patients. The 5­year LRR of patients with more hypoxic OPC was similar to those with less hypoxic OPC in the overall patient population (27.3% versus 25.1%; p = 0.98; HR = 1.01 [CI95% 0.47;2.17]) and in the p16-negative OPC (36.4% versus 30.1%; p = 0.70; HR = 1.17 [CI95% 0.53;2.56]). No significant OS differences could be observed in neither p16-negative nor p16-positive subgroup with a 5-year OS for p16-negative more hypoxic OPC of 44.2% versus 49.0% in the less hypoxic OPC (p = 0.92; HR 0.97 [CI95% 0.51;1.84]). CONCLUSION: No significant outcome differences were observed between more or less hypoxic tumours, as determined by the 15-gene hypoxia classifier. These results suggest that the 15-gene hypoxia classifier may not have prognostic value in an OPC patient cohort treated with accelerated chemoradiotherapy.

Toxicity Reduction in the Treatment of HPV Positive Oropharyngeal Cancer: Emerging Combined Modality Approaches.

Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) is a distinct clinical entity within the head and neck cancers, with a unique epidemiology and, in general, a favorable prognosis. Because of this favorable prognosis, researchers have considered de-intensifying the current standard treatment of HPV+ OPC in order to reduce acute and late treatment related toxicity without compromising outcome. Current ongoing trials can be divided in three main categories: de-intensification of the chemotherapy by replacing concomitant platinum-based chemotherapy with the EGFR-inhibitor cetuximab, or de-intensification of the radiation dose of either the primary radiotherapy of selected, good-responding patients after induction chemotherapy or of the adjuvant radiotherapy based on pathology features after primary surgery. Despite the good prognosis of the majority of HPV+ OPC patients, a proportion of them still have poor prognosis. This unmet need has led clinical research on new treatment strategies focused on influencing the unique micro-environment of HPV+ OPC with for example immunotherapy. This article summarizes the current understanding regarding the optimal treatment of non-metastatic HPV+ OPC. Ongoing and published clinical trials regarding de-intensification strategies, immunotherapy and proton therapy are described focusing on the rationale and underlying evidence of these emerging treatment strategies. Nevertheless, until the results of the ongoing trials are known, the treatment of HPV+ OPC in clinical practice should remain identical to the treatment of HPV negative OPC.

Patient Selection in Human Papillomavirus Related Oropharyngeal Cancer: The Added Value of Prognostic Models in the New TNM 8th Edition Era.

Background: With the growing interest in treatment de-intensification trials for human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC), prognostic models have become essential for patient selection. The aim of this paper is to validate and compare the prognostic ability of the TNM 8th edition and previous published risk group classifications of Ang et al. and Rietbergen et al. and to derive a patient selection classification for de-intensification trials. Materials: Patients with HPV+ OPC treated with curative (chemo)radiotherapy between 2004 and 2017 were classified according to the TNM 8th edition, the model of Ang et al. and of Rietbergen et al. HPV status was determined by p16 immunohistochemistry staining. Overall survival was estimated using the Kaplan-Meier method and groups were compared using the log-rank test. Harrell's C-index was used as measure of discriminative performance. Results: A total of 333 OPC were identified of whom 100 were HPV+. The median follow-up was 63.7 months. The 5-year overall survival (5Y-OS) of stage I, II and III were 91.6, 55.2, and 38.0%. There was a significant difference between stage I vs. II and III. The Harrell's C-index for TNM 8th edition stage was 0.67. Including only HPV+ OPC, the Harrell's C-index for the model of Ang and Rietbergen were both 0.62. We combined the main prognostic factors defining the low risk groups in the three models, stage I, low comorbidity and ≤ 10 pack years, into one new low risk group to identify patients who may benefit from de-intensification trials. Intermediate risk was defined as stage I with high comorbidity or >10 pack years, high risk as stage II-III. The 5Y-OS were 100, 85.7, and 51.3%. The Harrell's C-index for the new classification model was 0.67. Conclusion: Although TNM 8th edition provides better OS stratification than the 7th edition, it is not performant enough for patient selection, neither are the models from Ang et al. and Rietbergen et al. Therefore, we propose a patient selection classification for de-intensification trials based on the new TNM classification 8th edition, comorbidity and smoking pack years. In addition, this study emphasizes the importance of patient selection and personalized treatment for HPV+OPC.

Clinical factors impacting on late dysphagia following radiotherapy in patients with head and neck cancer.

OBJECTIVE: Patient and treatment characteristics of patients with head and neck cancer (HNSCC) were correlated with dysphagia scored on swallowing-videofluoroscopy (VFS) and with patient- and physician-scored dysphagia. METHODS: 63 HNSCC patients treated with radiotherapy (RT) were evaluated at baseline, and 6 and 12 months post-RT. VFS was scored with Penetration Aspiration Scale (PAS) and Swallowing Performance Scale (SPS). Physician- and patient-scored dysphagia were prospectively recorded according to Common Terminology Criteria for Adverse Events scoring system, Radiation Therapy Oncology Group/EORTC scoring system and European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC-QLQ H&N35). RESULTS: Univariable analysis revealed a significant association between tumour-subsite and higher SPS (p = 0.02) and patient-scored dysphagia (p = 0.02) at baseline. At 12 months, tumour-subsite was significantly associated with higher PAS and SPS. Multivariable analysis and pairwise comparison showed that hypopharyngeal cancer and carcinoma of unknown primary  were associated with higher SPS at baseline and at 12 months, respectively (p = 0.03 and p = 0.01). Upfront neck dissection (UFND) was significantly associated with higher SPS and physician-scored dysphagia in univariable analysis at all timepoints. At 12 months, there was also a significant association with higher PAS (p < 0.01) and patient-scored dysphagia (p < 0.01). After multivariable analysis, the association between UFND and higher PAS (p < 0.01) and SPS (p < 0.01) remained significant at 12 months. CONCLUSION: Hypopharyngeal tumours and carcinoma of unknown primary were related to more dysphagia at baseline and at 12 months, respectively. Furthermore, UFND was associated with more severe dysphagia scored by physicians and patients and on VFS at 12 months. Advances in knowledge: This is the first paper reporting a significant link between UFND and late dysphagia scored with VFS. We advocate abandoning UFND and preserving neck dissection as a salvage option post-RT.

Validation of the total dysphagia risk score (TDRS) in head and neck cancer patients in a conventional and a partially accelerated radiotherapy scheme.

BACKGROUND AND PURPOSE: A risk model, the total dysphagia risk score (TDRS), was developed to predict which patients are most at risk to develop grade ⩾2 dysphagia at 6 months following radiotherapy (RT) for head and neck cancer. The purpose of this study was to validate this model at 6 months and to investigate the power at earlier and later time-points. A second aim was to see if this model can be used in a partially accelerated RT regimen. MATERIALS AND METHODS: 164 patients from 3 different centres treated with RT between 2008 and 2014 were included in the current study. Both physician-scored dysphagia and QoL data were prospectively obtained. The TDRS of all patients was correlated with the physician-scored dysphagia and the QoL data. To validate this prediction model, we tested the validity in terms of calibration and discrimination. RESULTS: Partial acceleration had no influence on the TDRS. Regarding physician-scored dysphagia, there was a significant correlation with dysphagia grade ⩾2 at 1, 3, 6 and 9 months. The area-under-the-curve at 1 month was 0.85; at 3 months 0.80; at 6 months 0.85; at 9 months 0.86 and 0.79 at 12 months. Regarding QoL, TDRS correlates with PEG-tube usage at 6 and 12 months. CONCLUSION: We found significant correlations between TDRS and dysphagia grade ⩾2 and PEG-tube usage.