Prediction of Residual Disease by Circulating DNA Detection After Potentiated Radiotherapy for Locally Advanced Head and Neck Cancer

Study Overview
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Brief Summary
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Sixty percent of newly diagnosed head and neck squamous cell carcinomas (HNSCCs) are at a locally advanced (LA) stage. Depending on tumor site, stage, and resectability, locoregional failure rates can range from 35% to 65%. The persistence of residual disease at the end of treatment is a major prognostic element but is not always reliably assessed by current imaging techniques. Up to 40-50% of patients have residual adenomegaly and only 30% have viable disease when further adenectomy is performed. Sensitive and reproducible detection of residual disease after treatment is a major challenge in this patient category. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) guided surveillance, with a negative predictive value of 95-97%, has proven to be non-inferior to cervical curage in HNSCCs with residual adenomegaly. Cervical curage is now indicated only if the response assessed by PET-CT is incomplete. Nevertheless, the ability of PET-CT to predict treatment failure is unsatisfactory due to a high frequency of false positives, because of inflammatory changes, with a positive predictive value of about 20-50%. Circulating tumor DNA (ctDNA) may provide a more reliable assessment of response to potentiated radiotherapy. Liquid biopsy monitoring of response in patients treated with potentiated radiation therapy for locally advanced HNSCCs a has been shown to be feasible. In 85% of patients, ctDNA is detectable and correlates significantly with tumor volume and response to treatment. In addition, one study showed that post-radiotherapy analysis of circulating HPV16 viral DNA (cvDNA) in patients with HPV16-related HNSCCs complemented PET-CT and helped guide management decisions. HPV16 cvDNA and PET-CT have similar negative predictive values, whereas the positive predictive value is higher for HPV16 cvDNA (100% versus 50%). Nevertheless, current data are insufficient to allow routine use of this marker. This is a multicenter, single arm, open study for patients with a locally advanced head and neck cancer for which a potentiated radiotherapy is indicated.

Official Title
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Prediction of Residual Disease by Circulating DNA Detection After Potentiated Radiotherapy for Locally Advanced Head and Neck Cancer

Conditions
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Locally Advanced Head and Neck Carcinoma

Intervention / Treatment
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* Biological: Blood sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years and ≤ 80 years Histologically confirmed, never treated squamous cell carcinoma with lymph node involvement Stage III (N1), stage IVa (minimum N1) or IVb, resectable but not operated or unresectable, with indication for potentiated radiotherapy Oral cavity, oropharynx, hypopharynx or larynx, cervical adenopathies without primary Availability of FFPE samples prior to treatment initiation Detection of circulating DNA in the initial blood sample Detection of tumor-specific variants in FFPE and leukocytes Obtaining informed consent from the patient Affiliation to the French social security system Exclusion Criteria: Tumor of the nasopharynx, sinuses, nasal cavity, salivary glands or thyroid cancer Treatment by exclusive radiotherapy Contraindication to cervical lymph node dissection Metastatic disease (stage IVc) Previous treatment for head and neck cancer History of other cancer in the last 3 years (except carcinoma in situ, basal cell skin carcinoma, localized prostate cancer Gleason 6) Pregnant or breastfeeding woman Patient under guardianship or curators Psychological disorder (cognitive disorders, vigilance disorders, etc.) or social reasons (deprivation of liberty by judicial or administrative decision) or geographical reasons that could compromise the medical follow-up of the trial or compliance with the treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: Biological samples of patients included in the study (i.e., patients treated with potentiated radiotherapy for a locally advanced head and neck cancer) will be analysed (Next generation sequencing (NGS)): At inclusion : a FFPE block + a blood sample to identify tumor specific variants (tcDNA and cvDNA) 3 months after radiotherapy in case of incomplete response (PET-CT) : a blood sample to search if the tumor specific variants identified before the treatment are found Patients with incomplete response after 3 months potentiated radiotherapy will undergone a salvage adenectomy. The main objective is to assess the ability of circulating DNA to predict residual disease during salvage adenectomy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interventional<br> | Biological: Blood sample<br>* The intervention consist in a blood sample that will be taken twice : at the inclusion (before treatment) 3 months after the potentiated radiotherapy in case of incomplete response (PET-CT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of patients with incomplete cervical lymph node response on PET-CT after radiation therapy potentiated having circulating DNA (cDNA) | Presence/absence of circulating DNA after treatment versus presence/absence of residual disease | 3 months after potentiated radiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cDNA detection rate among patients with residual adenomegaly after treatment | The detection of cDNA and response on CT-Scan will be compared | at three-months after potentiated radiotherapy. | 
| Assessment of the prognostic value of cDNA detection 3 months after the end of potentiated radiotherapy for patients with residual adenomegaly | Evaluated by overall and progression-free survival | at three-months after potentiated radiotherapy. | 
| Assessment of the prognosis value of the presence of residual adenomegaly | Evaluated by overall and progression-free survival | At month 27 | 
| Rate of concordance of mutational profiles and Human papillomavirus-high risk (HPV-HR) genotypes between the primary tumor and cDNAs at diagnosis | evaluated the mutational profiles from FFPE block and the inclusion blood sample | Inclusion | 
| Rate of concordance between p16 immunohistochemistry and HPV-HR genotyping on the primary tumor |  | Inclusion | 
| Test of the concordance between real-time polymerase chain reaction (PCR) and NGS on formalin-fixed paraffin-embedded (FFPE) for simultaneous detection and genotyping of HPV-HR at diagnosis |  | Inclusion | 
| Number of patients with ctDNA and cvDNA detection at diagnosis and the clinical, paraclinical and pathological features of the cancer |  | Through study completion, an average of 66 months | 
| Evaluation of interobserver reproducibility of the interpretation of SUVmax measurements of residual cervical adenomegaly. | A centralized review of the PET-CT will be done by the sponsor to evaluate the reproducibility of the interpretation of SUVmax measurements of residual cervixal adenomegaly (pathological/benign/equivocal) | 3 months after potentiated radiotherapy |