QUantitative Assessment of Swallowing After Radiation (QUASAR)

Study Overview
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Brief Summary
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To use novel methods for quantitative analysis of VFSS (videofluoroscopic swallow study, also known as modified barium swallow) to study and compare dysphagia in patients treated for head and neck carcinoma with concurrent radiation therapy and chemotherapy (cisplatin) or targeted therapy (cetuximab) vs. immunotherapy (pembrolizumab, nivolumab, or durvalumab). Our hypothesis is that pharyngeal constriction will be greater (lower ratio) with concurrent immunotherapy compared to chemotherapy, as measured by the pharyngeal constriction ratio (PCR).

Detailed Description
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The QUASAR study will use a prospective, observational, cross sectional design (See Schema). HNC patients treated with definitive RT and immunotherapy or chemotherapy (cetuximab or cisplatin) will undergo VFSS at 4-6 and 12-24 months post-treatment. Patients enrolled prior to 6 months after finishing therapy will undergo a swallow study during the 4-6 month period AND the 12-24 month period. Patients enrolled after 6 months after finishing therapy will undergo a single swallow study in the 12-24 month period. The primary endpoint of PCR at 12-24 months will be compared between patients treated with immunotherapy versus chemotherapy. All patients with HNC treated with definitive RT and systemic therapy at our institution will be eligible. In particular, we will recruit patients for this study from participants in two ongoing trials investigating the use of concurrent immunotherapy. The KEYCHAIN trial (ClinicalTrials.gov Identifier: NCT03383094) randomizes patients with locally advanced p16+ HNC undergoing definitive RT to concurrent q3 week cisplatin versus concurrent and adjuvant pembrolizumab. NRG-HN004 (ClinicalTrials.gov Identifier: NCT03258554) is a cooperative group trial that compares HNC patients that are not eligible for cisplatin undergoing definitive radiation therapy to concurrent cetuximab versus durvalumab.

Official Title
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QUantitative Assessment of Swallowing After Radiation (QUASAR): A Longitudinal Comparison of Swallowing Function by Systemic Therapy in Head and Neck Cancer Patients

Conditions
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Head and Neck Cancer, Dysphagia, Oropharyngeal Dysphagia, Oropharynx Cancer, Oropharynx Squamous Cell Carcinoma

Intervention / Treatment
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* Radiation: Radiation Therapy
* Drug: Cetuximab
* Drug: Chemotherapy
* Drug: Immunotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-proven, un-resected invasive carcinoma of the head and neck. Treated with definitive RT and concurrent systemic therapy or treated within the past 4-24 months Concurrent systemic therapy with Cisplatin, Cetuximab or immunotherapy. Age ≥ 18 Able to understand and willing to sign a written informed consent. Exclusion Criteria: Prior radiotherapy that would result in overlap of planned radiation therapy fields. Prior systemic chemotherapy, unless as part of the coordinated plan of care for the treatment of the carcinoma (e.g., induction/neoadjuvant chemotherapy is allowed) Planned adjuvant (i.e., following definitive chemoradiotherapy) chemotherapy or surgery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Radiotherapy with chemotherapy<br>Patients treated with definitive RT and chemotherapy (cisplatin) or targeted therapy (cetuximab) | Radiation: Radiation Therapy<br>* Routine radiation dosing (approximately 70 Gy in 35 fractions over 6.5 weeks) to the head and neck for the treatment of head and neck cancer<br>* Other names: RT;Drug: Cetuximab<br>* Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of head and neck cancer<br>* Other names: Erbitux;Drug: Chemotherapy<br>* Cisplatin is a chemotherapy medication used to treat a number of cancers, including head and neck cancer<br>* Other names: Cisplatin;|
| Radiotherapy with immunotherapy<br>Patients treated with definitive RT and immunotherapy (pembrolizumab, nivolumab, or durvalumab) | Radiation: Radiation Therapy<br>* Routine radiation dosing (approximately 70 Gy in 35 fractions over 6.5 weeks) to the head and neck for the treatment of head and neck cancer<br>* Other names: RT;Drug: Immunotherapy<br>* Keytruda or Pembrolizumab is a highly selective humanized monoclonal IgG4 antibody directed against the PD-1 receptor on the cell surface. Opdivo or Nivolumab is a targeted therapy. It is a human programmed death receptor-1 (PD-1) blocking antibody. Imfinzi or Durvalumab is an anti-cancer (antineoplastic) drug. This medication is classified as an Anti-PD-L1 monoclonal antibody.<br>* Other names: Imfinzi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Swallowing function 12-24 months after concurrent radiation and systemic therapy for HNC, as measured by the PCR | will use a two-sample t-test at 0.05 level to compare Pharyngeal Constriction Ratio (PCR) between groups | 12-24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative swallowing function at 4-6 months and 12-24 months by PCR, TPT, PRR and PPWT | To compare swallowing function between systemic therapies with additional quantitative metrics of swallowing dysfunction from the VFSS including TPT, PRR and PPWT. The presence of aspiration or strictures on VFSS will be compared as binary variables between groups using Pearson's Chi squared test. | 4-6 months and 12-24 months | 
| Correlation between quantitative swallowing function and patient reported symptoms using the EAT-10 tool | To compare patient reported assessments of swallowing function with the EAT-10 tool between systemic therapies. To test if there is correlation between the quantitative VFSS metrics and patient reported outcomes on the EAT-10 index, we will calculate Pearson's correlation coefficient and plot the results on a correlation matrix. The Holm step down procedure will be used to adjust for multiple testing to control the family-wise error rate at 0.05 level. | 12-24 months | 
| Correlation between radiation dose and location of swallowing function and quantitative swallowing function | The purpose of this aim is to evaluate the effect of radiation dose on swallowing structures, applying a previously developed space-preserving NTCP approach based on principal component analysis (PCA). Using this approach, dose distributions to the global swallowing apparatus (i.e. pharynx, larynx and esophagus) will be standardized for patients from both arms of Aim 1, using deformable registration to standardize organs and 3-D dose distributions to a common template. Dose distributions will be converted into a dose array and PCA will be applied to the dose array, as previously described. We will then use PC linear regression to identify eigenvectors significantly associated with long term dysphagia (as measured by PCR). | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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head and neck cancer, oropharyngeal dysphagia, radiation therapy, immunotherapy, videofluoroscopic swallow study, modified barium swallow study, oropharynx cancer, oropharynx squamous cell carcinoma