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

Overview

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.

Interventions

• Biological Blood sample
  The intervention consist in a blood sample that will be taken twice : * at the inclusion (before treatment) * 3 months after the radiochemotherapy in case of incomplete response (PET-CT)

Primary outcome measures

• Rate of patients with incomplete cervical lymph node response on PET-CT after radiochemotherapy having circulating DNA (cDNA) [Time frame: 3 months after potentiated radiotherapy]

Secondary outcome measures (8)

• cDNA detection rate among patients with residual adenomegaly after treatment [Time frame: at three-months after potentiated radiotherapy.]
• Assessment of the prognostic value of cDNA detection 3 months after the end of radiochemotherapy for patients with residual adenomegaly [Time frame: at three-months after potentiated radiotherapy.]
• Assessment of the prognosis value of the presence of residual adenomegaly [Time frame: 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 [Time frame: Inclusion]
• Rate of concordance between p16 immunohistochemistry and HPV-HR genotyping on the primary tumor [Time frame: 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 [Time frame: Inclusion]
• Number of patients with ctDNA and cvDNA detection at diagnosis and the clinical, paraclinical and pathological features of the cancer [Time frame: Through study completion, an average of 66 months]
• Evaluation of interobserver reproducibility of the interpretation of SUVmax measurements of residual cervical adenomegaly. [Time frame: 3 months after potentiated radiotherapy]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years and ≤ 80 years
• Histologically confirmed, never treated squamous cell carcinoma with lymph node involvement
• squamous cell carcinoma p16+or p16-, stage III (N1), IVa or IVb (UICC classification 8th edition), N1 minimum, and oropharyngeal sqamous cell carcinomas p16+ stage I or II, N1 minimum, resectable but not operated or unresectable, with indication for concomitant or sequential radiochemotherapy with induction chemotherapy using Docetaxel, Platinum, 5-Fluorouracil (TPF or modified TPF according to the practices of the investigating centers)
• 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
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

France · 4 centers

• Centre Jean PERRIN — Clermont-Ferrand
• Centre Hospitalier Henri Mondor — Aurillac
• Hôpital de la Croix-Rousse — Lyon
• CHU de Saint-Étienne — Saint-Etienne

Publications

• Ginzac A, Ferreira MC, Cayre A, Bouvet C, Biau J, Molnar I, Saroul N, Pham-Dang N, Durando X, Bernadach M. Prediction of residual disease using circulating DNA detection after potentiated radiotherapy for locally advanced head and neck cancer (NeckTAR): a study protocol for a prospective, multicentre trial. BMC Cancer. 2023 Jul 4;23(1):621. doi: 10.1186/s12885-023-11136-2. PMID 37400806

Identifiers

NCT: NCT05710679 · 2022-A01668-35

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗