Post-operative Adjuvant Treatment for HPV-positive Tumours (PATHOS)
- Conditions
- Human Papillomavirus (HPV)-positive Oropharyngeal Cancer
- Interventions
- Radiation: Postoperative radiotherapy
- Registration Number
- NCT02215265
- Lead Sponsor
- Lisette Nixon
- Brief Summary
The main objectives of the PATHOS study are:
To assess whether swallowing function can be improved following transoral resection of HPV-positive OPSCC, by reducing the intensity of adjuvant treatment protocols. The aim is to personalise treatment, based on disease biology (HPV status and pathology findings), to optimise patient outcomes.
To demonstrate the non-inferiority of reducing the intensity of adjuvant treatment protocols in terms of overall survival in the reduced intensity treatment arms.
- Detailed Description
PATHOS is a multicentre, open-label, parallel-group Phase II/III randomised controlled trial (RCT). The phase II target of 242 patients was reached in December 2018 and there was a seamless transition into Phase III. The protocol was amended in September 2018 to incorporate the changes associated with the phase III transition. The amendment included changes to the outcome measures and sample size calculations.
In March 2024, a protocol amendment increasing the target recruitment to Phase III of the study from 1100 to 1269 patients was approved. Patients eligible for the study must have biopsy proven oropharyngeal squamous cell carcinoma (OPSCC) clinically staged T1T3 N0N2b. Their primary tumour, as judged by the local MDT, must be considered resectable via a transoral approach. Having secured informed consent, patients with centrally or locally determined HPV positive tumours will undergo baseline assessment of swallowing function (includes; MDADI score, videofluoroscopy, PSSH\& N, 100 mL water swallow test) and complete QOL questions (EORTC QLQC30 and EORTC QLQH\&N35) prior to surgery.
Transoral Laser Microsurgery, Transoral Robotic Surgery \& Endoscopically assisted Transoral Surgery are all accepted transoral techniques for the study. A lateral oropharyngectomy performed with monopolar cautery (The Huet Procedure) can also be used.
Following surgery and histopathological assessment of the primary tumour and neck dissection surgical specimens, participants will be allocated into study groups based on the presence or absence of pathological risk factors for recurrence as follows:
Group A: Participants with tumours which exhibit no adverse histological features. Participants in this group will not receive any adjuvant treatment as per standard of care.
Group B: Participants with T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes \<61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour. Patients in this group will be randomised to PORT 60Gy in 30# over 6 weeks (Control Arm B1) or PORT 50Gy in 25# over 5 weeks (Test Arm B2).
Group C: Participants with tumours of any T or any N stage, which exhibit the following high-risk pathological features will be included: A histologically normal tissue margin around the primary tumour of \<1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease. Participants in this group will be randomised to POCRT 60Gy in 30# over 6 weeks with concurrent Cisplatin (Control Arm C1) or PORT 60Gy in 30# over 6 weeks without chemotherapy (Test Arm C2).
Participants in groups B and C will be stratified before randomisation by T stage, N stage, smoking history and treating centre.
The same assessments as at baseline will be completed post-operatively prior to treatment and then at four weeks and 6, 12 and 24 months post-treatment. The exception is videofluoroscopy which will be repeated at post-surgery and 12 months only. Videofluroscopies are only performed at UK sites.
Acute and late toxicity will be recorded weekly during treatment and again at 4 weeks and 6, 12 and 24 months post-treatment.
All study assessments, complications relating to surgery and adjuvant treatment, in particular complications which necessitate a delay to the start of adjuvant treatment, will all be recorded on the Case Report Form (CRF).
International sites have been initiated on Electronic Data Capture (EDC) and local UK sites have transitioned to EDC for participants enrolled after implementation. Data entry needs to be completed within four weeks of the study visit. In accordance with the principles of GCP, the PI is responsible for ensuring accuracy, completeness, legibility and timeliness of the data reported to the CTR in the CRFs. The CRF will be checked for missing, illegible or unusual values (range checks) and consistency over time.
If missing or questionable data are identified, a data query will be raised on a data clarification form and sent to the site for resolution. All answered data queries and corrections should be signed off and dated by a delegated member of staff at the relevant participating site.
The CTR will send reminders for any overdue data. It is the site's responsibility to submit complete and accurate data in a timely manner.
Quality assurance: The clinical trial risk assessment has been used to determine the intensity and focus of central and on-site monitoring activity in the PATHOS trial. Monitoring levels will be employed and are fully documented in the trial monitoring plan. Investigators should agree to allow trial-related monitoring, including audits and regulatory inspections, by providing direct access to source data/documents as required. Patient consent for this will be obtained.
Registration: All sites have transitioned to an electronic database and the registration and randomisation process is completed online. Participants will be randomised using minimisation with a random element. This will ensure balanced treatment allocation by clinically important stratification factors. Randomisation will have an allocation ratio of 1:1.
Statistical analyses:
Primary outcome measure
MDADI/Overall survival co-primary endpoint
Secondary outcome measures
* Swallowing panel including qualitative and quantitative swallowing assessments (100ml Water Swallow Test, Videofluoroscopy, Performance Status Scale-Head \& Neck)
* QOL (using validated EORTC QLQ C30 and HN35 questionnaires, Appendix 6)
* Acute and late toxicity using CTACE version 4.03
* Disease-Free Survival\*
* Locoregional control\*
* Distant Metastases\* \*Determined by clinical follow-up as per standard guidelines (no trial-specific imaging required)
The co-primary endpoint of the Phase III will be MDADI and overall survival (time to event).
We will use linear regression to estimate the treatment arm effect on MDADI at 12 months and will include the randomisation stratification variables and baseline MDADI in the model. Both OS and MDADI endpoints will be used to define study success so no adjustment for multiplicity is planned. A detailed statistical analysis plan will be developed before the analyses are conducted.
The data will be reviewed (approximately six-monthly) by an Independent Data Monitoring Committee (IDMC), consisting of at least two Clinicians (not entering patients into the trial) and an independent Statistician. The IDMC will be asked to recommend whether the accumulated data from the trial, together with results from other relevant trials, justifies continuing recruitment of further patients. A decision to discontinue recruitment, in all patients or selected subgroups, will be made only if the result is likely to convince a broad range of Clinicians including PIs in the trial and the general clinical community. If a decision is made to continue, the IDMC will advise on the frequency of future reviews of the data based on accrual and event rates.
Sub-group statistical analyses:
For swallowing endpoints, subgroup analysis by T stage and tumour subsite (tonsil, soft palate, tongue base) and surgery technique will be carried out, as the most likely relevant clinical co-variables affecting swallowing function.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 1269
- Histologically confirmed or suspected squamous cell carcinoma of the oropharynx.
- UICC/AJCC TNM 7th edition stage T1-T3, N0-N2b (or UICC TNM 8th edition stage T1-T3, N0-N1) disease.
- Multidisciplinary team (MDT) decision to treat with primary transoral resection and neck dissection.
- Patients considered fit for surgery and adjuvant radiotherapy
- Aged 18 or over.
- Written informed consent provided.
- Known HPV negative squamous cell carcinomas of the head and neck: A negative result for p16 Immunohistochemistry automatically excludes a patient from the trial. If initial p16 testing is positive but High Risk HPV (HR HPV) In-Situ Hybridization (ISH)/Polymerase Chain Reaction (PCR) does not demonstrate the presence of HR HPV DNA, the patient will also be excluded. Patients who are p16+ may complete swallowing assessments, excluding videofluoroscopy, and surgery whilst HR HPV DNA status is being determined (with recourse to central concordance testing, if appropriate, for UK centres). HPV positivity, as determined by p16 and the demonstration of HR HPV DNA is essential before patients undergo videofluoroscopy or randomisation.
- T4 and/or T1-T3 tumours where transoral surgery is considered not feasible.
- UICC/AJCC TNM 7th edition N2c-N3 nodal disease (or UICC/AJCC TNM 8th edition N2-N3 nodal disease).
- Patients for whom transoral surgery and neck dissection is not considered the primary treatment modality.
- Current smokers with clinically staged N2b disease (including smokers up to 6 months before diagnosis), even if HPV-positive. Vaping is permitted and should be considered as non-smoking status.
- Any pre-existing medical condition likely to impair swallowing function and/ or a history of pre-existing swallowing dysfunction prior to index oropharyngeal cancer.
- Patients with distant metastatic disease as determined by routine pre-operative staging radiological investigations e.g., CT thorax and upper abdomen or PET-CT.
- Patients with a history of malignancy in the last 5 years, except basal cell carcinoma of the skin or carcinoma in-situ of the cervix.
- Women who are pregnant or breastfeeding and fertile women who will not be using contraception during the trial.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description C1: Postoperative radiotherapy 60 Gray with Cisplatin Postoperative radiotherapy Arm C1: postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks with concurrent Cisplatin chemotherapy (POCRT). Cisplatin may be given 3 weekly (100mg/m2 week 1 and week 4 of radiotherapy) or weekly (40mg/m2 weekly during radiotherapy), according to local practice. Group C: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: A histologically normal tissue margin around the primary tumour of \<1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease B2: Postoperative radiotherapy 50 Gray Postoperative radiotherapy Arm B2: Postoperative radiotherapy (PORT) at a dose 50 Gray in 25 fractions over 5 weeks. Group B: Patients with: T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes \<61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour. B1: Postoperative radiotherapy 60 Gray Postoperative radiotherapy Arm B1: postoperative radiotherapy (PORT) at a dose of 60 Gray (Gy) in 30 fractions over 6 weeks. Group B: Patients with: T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes \<61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour. C2: Postoperative radiotherapy 60 Gray without chemotherapy Postoperative radiotherapy Arm C2: Postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks without chemotherapy (Test Arm C2). Group C: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: A histologically normal tissue margin around the primary tumour of \<1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease C1: Postoperative radiotherapy 60 Gray with Cisplatin Cisplatin Arm C1: postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks with concurrent Cisplatin chemotherapy (POCRT). Cisplatin may be given 3 weekly (100mg/m2 week 1 and week 4 of radiotherapy) or weekly (40mg/m2 weekly during radiotherapy), according to local practice. Group C: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: A histologically normal tissue margin around the primary tumour of \<1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease
- Primary Outcome Measures
Name Time Method MDADI/Overall survival co-primary endpoint At 12 months following treatment measured using the MD Anderson Dysphagia Inventory (MDADI) score.
- Secondary Outcome Measures
Name Time Method Swallowing panel including qualitative and quantitative swallowing assessments Baseline; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks) post treatment; 6 months (+/- 4 weeks) post treatment; 12 months (+/- 4 weeks) post treatment; 24 months (+/- 8 weeks) post treatment. Water swallow test
Disease Free Survival 6 months intervals Determined by clinical follow up as per standard guidelines
QOL (using validated EORTC QLQ C30 and HN35 questionnaires) Baseline; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks) post treatment; 6 months (+/- 4 weeks) post treatment; 12 months (+/- 4 weeks) post treatment; 24 months (+/- 8 weeks) post treatment. Quality of Life (QOL) questions.
Acute and late toxicity using CTACE version 4.03 Weekly during RT and at end of treatment; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks), 6 months (+/- 4 weeks), 12 months (+/- 4 weeks), and 24 months (+/- 8 weeks) post treatment. Toxicity assessment
Locoregional control 6 months intervals Determined by clinical follow up as per standard guidelines
Distant Metastases 6 months intervals Determined by clinical follow up as per standard guidelines
Trial Locations
- Locations (57)
Zentrum für Hals-, Nasen- und Ohrenheilkunde
🇩🇪Giessen, Germany
Kath Marienkrankenhaus gGmbH
🇩🇪Hamburg, Germany
Universitaetsklinikum des Saarlandes
🇩🇪Homburg, Germany
Northampton General Hospital
🇬🇧Northampton, United Kingdom
Royal Stoke Hospital
🇬🇧Stoke, United Kingdom
Board of Trustees of the Leland Stanford Junior University
🇺🇸Redwood City, California, United States
Advent Health
🇺🇸Orlando, Florida, United States
MD Anderson Cancer Centre
🇺🇸Houston, Texas, United States
Metro South Health
🇦🇺Brisbane, Australia
Unicancer
🇫🇷Paris, France
Vivantes Klinikum
🇩🇪Berlin, Germany
Asklepios Kliniken
🇩🇪Hamburg, Germany
Universitat Leipzig
🇩🇪Leipzig, Germany
Ernst von Bergmann Klinikum
🇩🇪Potsdam, Germany
Städtisches Klinikum Solingen
🇩🇪Solingen, Germany
Universitätsklinikum Ulm
🇩🇪Ulm, Germany
University Hospitals Dorset NHS Foundation
🇬🇧Poole, Dorset, United Kingdom
Royal United Hospitals Bath NHS Foundation Trust
🇬🇧Bath, United Kingdom
Queen Elizabeth Hospital
🇬🇧Birmingham, United Kingdom
Royal Blackburn Hospital
🇬🇧Blackburn, United Kingdom
Royal Sussex County Hospital
🇬🇧Brighton, United Kingdom
University Hospitals Bristol NHS Foundation Trust
🇬🇧Bristol, United Kingdom
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
Kent and Canterbury Hospital
🇬🇧Canterbury, United Kingdom
HPV Research Group Section of Pathology Cardiff University ,School of Medicine
🇬🇧Cardiff, United Kingdom
Cardiff and Vale University Local Health Board
🇬🇧Cardiff, United Kingdom
Centre for Trials Research
🇬🇧Cardiff, United Kingdom
Velindre NHS Trust
🇬🇧Cardiff, United Kingdom
Castle Hill Hospital
🇬🇧Cottingham, United Kingdom
Derby Teaching Hospitals NHS Foundation Trust
🇬🇧Derby, United Kingdom
Western General Hospital
🇬🇧Edinburgh, United Kingdom
Royal Devon University Health Care NHS Foundation Trust
🇬🇧Exeter, United Kingdom
Royal Surrey County Hospital
🇬🇧Guildford, United Kingdom
St James University Hospital
🇬🇧Leeds, United Kingdom
Liverpool Head and Neck Centre
🇬🇧Liverpool, United Kingdom
University of Liverpool
🇬🇧Liverpool, United Kingdom
Cwm Taf Bro Morganwg
🇬🇧Llantrisant, United Kingdom
University College London Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
Guys and St Thomas's NHS Foundation Trust
🇬🇧London, United Kingdom
St Georges University Hospital
🇬🇧London, United Kingdom
Imperial College Healthcare NHS Trust
🇬🇧London, United Kingdom
Central Manchester University Hospital NHS Foundation Trust
🇬🇧Manchester, United Kingdom
The Christie NHS Foundation Trust
🇬🇧Manchester, United Kingdom
The Pennine Acute Hospital Trust
🇬🇧Manchester, United Kingdom
The James Cook University Hospital
🇬🇧Middlesbrough, United Kingdom
Royal Victoria Infirmary
🇬🇧Newcastle upon Tyne, United Kingdom
Newcastle upon Tyne Hospitals NHS Foundation Trust
🇬🇧Newcastle upon Tyne, United Kingdom
Aneurin Bevan University Health Board
🇬🇧Newport, United Kingdom
Nottingham City Hospital
🇬🇧Nottingham, United Kingdom
Oxford University Hospitals NHS Foundation Trust
🇬🇧Oxford, United Kingdom
University Hospital Plymouth
🇬🇧Plymouth, United Kingdom
Queen Alexandra Hospital
🇬🇧Portsmouth, United Kingdom
Royal Preston Hospital
🇬🇧Preston, United Kingdom
Royal Berkshire Hospital
🇬🇧Reading, United Kingdom
University Hospital Southampton
🇬🇧Southampton, United Kingdom
City Hospitals Sunderland NHS Foundation Trust
🇬🇧Sunderland, United Kingdom
Swansea Bay University Local Health Board
🇬🇧Swansea, United Kingdom