Post-operative Adjuvant Treatment for HPV-positive Tumours (PATHOS) (PATHOS)

A Phase III Trial of Risk-stratified, Reduced Intensity Adjuvant Treatment in Patients Undergoing Transoral Surgery for Human Papillomavirus (HPV)-positive Oropharyngeal Cancer

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Human Papillomavirus (HPV)-positive Oropharyngeal Cancer
• Intervention / Treatment: Radiation: Postoperative radiotherapy; Drug: Cisplatin

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.

• Study Type: Interventional
• Enrollment (Estimated): 1269
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Brisbane, Australia, QLD 4113
    • Metro South Health
• France
  • Paris, France, 75013
    • UNICANCER
• Germany
  • Berlin, Germany
    • Vivantes Klinikum
  • Giessen, Germany
    • Zentrum für Hals-, Nasen- und Ohrenheilkunde
  • Hamburg, Germany
    • ASKLEPIOS Kliniken
  • Hamburg, Germany
    • Kath Marienkrankenhaus gGmbH
  • Homburg, Germany
    • Universitaetsklinikum des Saarlandes
  • Leipzig, Germany
    • Universität Leipzig
  • Potsdam, Germany
    • Ernst von Bergmann Klinikum
  • Solingen, Germany, 42653
    • Städtisches Klinikum Solingen
  • Ulm, Germany
    • Universitätsklinikum Ulm
• United Kingdom
  • Bath, United Kingdom, BA1 3NH
    • Royal United Hospitals Bath NHS Foundation Trust
  • Birmingham, United Kingdom, B15 2TH
    • Queen Elizabeth Hospital
  • Blackburn, United Kingdom, BB2 3HH
    • Royal Blackburn Hospital
  • Brighton, United Kingdom, BN2 5BE
    • Royal Sussex County Hospital
  • Bristol, United Kingdom, BS2 8ED
    • University Hospitals Bristol NHS Foundation Trust
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospitals NHS Foundation Trust
  • Canterbury, United Kingdom
    • Kent and Canterbury Hospital
  • Cardiff, United Kingdom, CF14 4XW
    • Cardiff and Vale University Local Health Board
  • Cardiff, United Kingdom, CF14 4XN
    • HPV Research Group Section of Pathology Cardiff University ,School of Medicine
  • Cardiff, United Kingdom, CF14 4YS
    • Centre for Trials Research
  • Cardiff, United Kingdom, CF142TL
    • Velindre NHS Trust
  • Cottingham, United Kingdom, HU16 5JQ
    • Castle Hill Hospital
  • Derby, United Kingdom, DE22 3DT
    • Derby Teaching Hospitals NHS Foundation Trust
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital
  • Exeter, United Kingdom
    • Royal Devon University Health Care NHS Foundation Trust
  • Guildford, United Kingdom, GU2 7XX
    • Royal Surrey County Hospital
  • Leeds, United Kingdom, LS9 7TF
    • St James University Hospital
  • Liverpool, United Kingdom, L3 9TA
    • Liverpool Head and Neck Centre
  • Liverpool, United Kingdom, L69 3GB
    • University of Liverpool
  • Llantrisant, United Kingdom, CF72 8XR
    • Cwm Taf Bro Morganwg
  • London, United Kingdom, NW1 2BU
    • University College London Hospitals NHS Foundation Trust
  • London, United Kingdom, SW17 0QT
    • St Georges University Hospital
  • London, United Kingdom, SE1 9RT
    • Guys and St Thomas's NHS Foundation Trust
  • London, United Kingdom, SW7 2AZ
    • Imperial College Healthcare NHS Trust
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Manchester, United Kingdom, M13 9WL
    • Central Manchester University Hospital NHS Foundation Trust
  • Manchester, United Kingdom, OL1 2JH
    • The Pennine Acute Hospital Trust
  • Middlesbrough, United Kingdom, TS4 3BW
    • The James Cook University Hospital
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • Royal Victoria Infirmary
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Newcastle upon Tyne Hospitals NHS Foundation Trust
  • Newport, United Kingdom, NP18 3XQ
    • Aneurin Bevan University Health Board
  • Northampton, United Kingdom
    • Northampton General Hospital
  • Nottingham, United Kingdom
    • Nottingham City Hospital
  • Oxford, United Kingdom, OX3 7LD
    • Oxford University Hospitals NHS Foundation Trust
  • Plymouth, United Kingdom, PL6 8DH
    • University Hospital Plymouth
  • Portsmouth, United Kingdom, PO6 3LY
    • Queen Alexandra Hospital
  • Preston, United Kingdom, PR2 9HT
    • Royal Preston Hospital
  • Reading, United Kingdom, RG1 5AN
    • Royal Berkshire Hospital
  • Southampton, United Kingdom, SO16 6YD
    • University Hospital Southampton
  • Stoke, United Kingdom
    • Royal Stoke Hospital
  • Sunderland, United Kingdom, SR4 7TP
    • City Hospitals Sunderland NHS Foundation Trust
  • Swansea, United Kingdom, SA2 8QA
    • Swansea Bay University Local Health Board
  • Dorset
    • Poole, Dorset, United Kingdom, BH15 2JB
      • University Hospitals Dorset NHS Foundation
• United States
  • California
    • Redwood City, California, United States, 94063
      • Board of Trustees of the Leland Stanford Junior University
  • Florida
    • Orlando, Florida, United States, 32803
      • Advent Health
  • Texas
    • Houston, Texas, United States, 77030
      • Md Anderson Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: A: No adjuvant treatment; Group A Patients with tumours which exhibit no adverse histological features. Patients in this group will not receive any adjuvant treatment as per standard of care.
Active Comparator: B1: Postoperative radiotherapy 60 Gray; 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.	Radiation: Postoperative radiotherapy; Postoperative radiotherapy (PORT)
Experimental: B2: Postoperative radiotherapy 50 Gray; 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.	Radiation: Postoperative radiotherapy; Postoperative radiotherapy (PORT)
Active Comparator: C1: Postoperative radiotherapy 60 Gray with 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	Radiation: Postoperative radiotherapy; Postoperative radiotherapy (PORT); Drug: Cisplatin; Chemotherapy
Experimental: C2: Postoperative radiotherapy 60 Gray without chemotherapy; 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	Radiation: Postoperative radiotherapy; Postoperative radiotherapy (PORT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
MDADI/Overall survival co-primary endpoint	At 12 months following treatment measured using the MD Anderson Dysphagia Inventory (MDADI) score.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Swallowing panel including qualitative and quantitative swallowing assessments	Water swallow test	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.
QOL (using validated EORTC QLQ C30 and HN35 questionnaires)	Quality of Life (QOL) questions.	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.
Acute and late toxicity using CTACE version 4.03	Toxicity assessment	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.
Disease Free Survival	Determined by clinical follow up as per standard guidelines	6 months intervals
Locoregional control	Determined by clinical follow up as per standard guidelines	6 months intervals
Distant Metastases	Determined by clinical follow up as per standard guidelines	6 months intervals

Collaborators and Investigators

• Sponsor: Lisette Nixon
• Collaborators: Stanford University; University of Leipzig; AdventHealth; UNICANCER; Princess Alexandra Hospital, Brisbane, Australia
• Investigators: Principal Investigator: Mererid Evans, MBBch, PhD, Velindre NHS Trust; Principal Investigator: Terrence Jones, MBBS,MD, Aintree University Hospital

Publications and helpful links

General Publications

• Owadally W, Hurt C, Timmins H, Parsons E, Townsend S, Patterson J, Hutcheson K, Powell N, Beasley M, Palaniappan N, Robinson M, Jones TM, Evans M. PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer. BMC Cancer. 2015 Aug 27;15:602. doi: 10.1186/s12885-015-1598-x.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: August 11, 2014
• First Submitted That Met QC Criteria: August 12, 2014
• First Posted (Estimated): August 13, 2014

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 14, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Human papillomavirus HPV positive oropharyngeal cancer
• Additional Relevant MeSH Terms: Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Oropharyngeal Neoplasms; Antineoplastic Agents; Cisplatin
• Other Study ID Numbers: 2014/VCC/0014

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No