De-escalation of Radiation Dose in HPV-associated OPC Utilising FMISO PET (DE-RADIATE) (DE-RADIATE)

De-escalation of Radiation Dose in HPV-associated Oropharyngeal Squamous Cell Carcinoma Utilising FMISO PET and Magnetic Resonance Imaging as Non-Invasive Biomarkers of Hypoxia (DE-RADIATE)

The goal of this prospective clinical trial is to determine if HPV-associated oropharyngeal squamous cell carcinoma that is non-hypoxic on FMISO PET can be successfully treated with a lower dose of radiation therapy.

The main questions it aims to answer are:

1. What is the pathologic complete response rate in patients selected for radiation dose de-escalation and neck dissection?
2. What is the correlation between MRI and FMISO PET assessment of hypoxia before and during RT?
3. What are the acute and late toxicities in patients selected for radiation dose de-escalation?
4. What are the quality of life scores in patients selected for radiation dose de-escalation?
5. What are the local, regional and distant failure rates of patients selected for radiation dose de-escalation?

Patients with cT1-2N1-2b (AJCC 7th edition) oropharyngeal tumours will undergo surgical resection of the primary tumour. Following this, they will be allocated to standard radiation therapy (70Gy with concurrent cisplatin chemotherapy) or de-escalation radiation therapy (30Gy with concurrent cisplatin chemotherapy) based on the results of FMISO PET. Patients with non-hypoxic tumours at baseline OR after two weeks of radiation therapy will be allocated to the de-escalated group. 3-4 months after completion of radiation therapy, all patients in the de-escalated group will undergo mandatory neck dissection to assess pathologic response.

Researchers will assess the pathologic response rate after surgery in the de-escalation group. They will also compare the outcomes (oncological outcomes and quality of life) between the group receiving the standard treatment (70Gy) and the group receiving de-escalated radiation therapy (30Gy).

Study Overview

• Status: Not yet recruiting
• Conditions: HPV Positive Oropharyngeal Squamous Cell Carcinoma
• Intervention / Treatment: Radiation: Standard of care; Radiation: De-escalation

Detailed Description

This study is designed to evaluate the role of FMISO PET in selecting patients for de-escalated RT. Patients with cT1-2N-1-2b HPV+ OPC or cTxN1-2 CUP, who are suitable for surgical management of the primary (if applicable) and/or RT to the primary and ipsilateral neck will be included. All patients will undergo surgical resection or core biopsy of the primary site if applicable (negative margins and robotic surgery not mandated) or EUA and tonsillectomy (CUP) and FNA or core biopsy of the cervical lymph node (all patients). Patients will be eligible for inclusion if histopathology is consistent with HPV-associated squamous cell carcinoma or CUP, with p16 positivity (IHC) and HPV positivity (PCR).

Patients enrolled will undergo FMISO PET/CT (after surgery to the primary or EUA/biopsy of suspected primary site) to assess for tumour hypoxia, which will stratify patients into two groups. Determination for the presence or absence of hypoxia will be made on the basis of visual inspection and in accordance with well-established tumour-muscle activity ratio (>1.2) on the late static 18F-FMISO PET by 1 nuclear medicine physician. FMISO PET will be repeat after 5-10 fractions of RT (1-2 weeks of treatment) with the same assessment for hypoxia.

Absence of pre-treatment hypoxia or intra-treatment resolution of hypoxia on FMISO PET will be deemed as an indicator of radiosensitivity and qualify a patient for de-escalation (i.e., to total dose 30Gy). The remainder of patients (i.e., with evidence of tumour hypoxia at the FMISO PET performed after 5-10 fractions of RT) will continue to standard of care RT to a total dose of 70Gy.

Additional MRI images (including T1, T2 and dynamic contract-enhanced and oxygen enhanced sequences) before and during RT (at the same time as 18F FMISO PET). These will not change the patient's management.

All patients will undergo routine FDG-PET/CT scan three months after RT (as part of standard of care). Patients in the de-escalation arm will undergo mandatory ipsilateral neck dissection within 3-4 months of completing RT to assess for pathologic response. Patients will be followed up for a minimum of five years post treatment.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Carol Kwong; Phone Number: 9463 1300; Email: carolyn.kwong@health.nsw.gov.au

Study Locations

• Australia
  • New South Wales
    • Saint Leonards, New South Wales, Australia, 2065
      • Northern Sydney Cancer Centre, Royal North Shore Hospital
      • Contact: Carol Kwong; Phone Number: 9463 1300; Email: carolyn.kwong@health.nsw.gov.au
      • Principal Investigator: Anna Lawless
      • Principal Investigator: Sarah Bergamin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18 years
• Histologically confirmed cT1-2N1-2b oropharyngeal squamous cell carcinoma or cTxN1-2 carcinoma of unknown primary
• p16 positive (70% nuclear and cytoplasmic staining) and HPV positive (genotyping via PCR) tumours of the tonsil, base of tongue, glossotonsillar sulcus, or unknown primary site (suspected mucosal origin).
• No contraindications to radiotherapy, platinum-based chemotherapy or surgery
• No contraindications to PET/CT or MRI
• Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 (KPS > 70%)
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Women lactating, pregnant or of childbearing potential who are not willing to avoid pregnancy during the study
• Patients with a history of severe renal disease(s) (eGFR <20) than cannot tolerate gadolinium chelate contrast agents.)
• ECOG ≥ 3
• Previous high dose radiation therapy to the head or neck
• Patients unwilling or unable to have PET/CT or MRI
• Geographically remote patients unable to agree to imaging schedule
• Patients with a history of psychological illness or condition such as to interfere with the patient's ability to understand the requirements of the study.
• Patients with significant cardiac or pulmonary disease including cardiac arrythmias or Chronic Obstructive Pulmonary Disease (COPD) that are unable to tolerate high flow O2 for oxygen contrast.
• Patients taking carbonic anhydrase inhibitors (acetazolamide)
• History of glaucoma
• Any implant, foreign body, 3T MRI incompatible device, or other contraindication to MRI imaging

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care; Standard of care treatment for patients undergoing definitive chemoradiation for oropharyngeal squamous cell carcinoma	Radiation: Standard of care; Radiation therapy (70Gy) with concurrent platinum-based chemotherapy to oropharynx + neck
Experimental: De-escalation; De-escalated radiation therapy for patients undergoing surgery to the primary site followed by chemoradiation to the primary site and neck for oropharyngeal squamous cell carcinoma	Radiation: De-escalation; Surgical resection of primary oropharyngeal tumour followed by de-escalated radiation therapy (30Gy) with concurrent platinum-based chemotherapy to oropharynx + neck, followed by surgical neck dissection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response	Pathologic complete response in surgical neck dissection	4 months after completion of radiation therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between MRI and FMISO PET assessment of hypoxia	Correlation between MRI and FMISO PET assessment of hypoxia at baseline and during radiation therapy	Baseline and after 2 weeks of radiation therapy
Quality of Life of patients undergoing de-escalation radiation therapy	Quality of Life - Global (assessment by EORTC QLQ-30)	Baseline, then 3 months post completion of treatment, then 3-monthly post to 2 years, then 6-monthly to 5 years
Quality of Life of patients undergoing de-escalation radiation therapy	Quality of Life - Head & Neck Specific (assessment by EORTC HN-35)	Baseline, then 3 months post completion of treatment, then 3-monthly post to 2 years, then 6-monthly to 5 years
Local control	Failure rate at primary site (oropharynx) (calculated from date of commencing RT)	3-monthly to 2 years, 6-monthly to 5 years
Regional control	Failure rate in neck (calculated from date of commencing RT)	3-monthly to 2 years, 6-monthly to 5 years
Distant metastases	Number of participants with radiologically confirmed distant metastases (calculated from date of commencing RT)	3-monthly to 2 years, 6-monthly to 5 years
Acute toxicities	Acute toxicities of radiation therapy +/- chemotherapy (assessed by CTCAE V 5.0)	From date of commencement of RT, measured weekly during RT, fortnightly post treatment (up to 3 months post treatment)
Late toxicities	Acute toxicities of radiation therapy +/- chemotherapy (assessed by CTCAE V 5.0)	Commencing from 3 months post treatment and measured 3-monthly to 2 years, then 6-monthly to 5 years

Collaborators and Investigators

• Sponsor: Royal North Shore Hospital
• Investigators: Principal Investigator: Anna Lawless, Royal North Shore Hospital; Principal Investigator: Sarah Bergamin, Royal North Shore Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2031

Study Registration Dates

• First Submitted: March 1, 2024
• First Submitted That Met QC Criteria: March 6, 2024
• First Posted (Actual): March 12, 2024

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Hypoxia; Radiation therapy; De-escalation; FMISO PET
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck
• Other Study ID Numbers: 2023/ETH02441

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No