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

NCT02215265 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: 2014/VCC/0014
• Study Type: interventional
• Target: 1,269
• Locations: 5 countries
• Sites: 57

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.

Conditions

Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer

Keywords

Human papillomavirus HPV positive oropharyngeal cancer

Outcome Measures

Primary Outcomes (1)

• MDADI/Overall survival co-primary endpoint

  At 12 months following treatment measured using the MD Anderson Dysphagia Inventory (MDADI) score.

Secondary Outcomes (6)

• 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.

• 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.

• 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.

• Disease Free Survival

  6 months intervals

• Locoregional control

  6 months intervals

Study Arms (5)

A: No adjuvant treatment

NO INTERVENTION

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.

B1: Postoperative radiotherapy 60 Gray

ACTIVE COMPARATOR

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

B2: Postoperative radiotherapy 50 Gray

EXPERIMENTAL

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

C1: Postoperative radiotherapy 60 Gray with Cisplatin

ACTIVE COMPARATOR

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

Drug: Cisplatin; Radiation: Postoperative radiotherapy

C2: Postoperative radiotherapy 60 Gray without chemotherapy

EXPERIMENTAL

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

Interventions

Cisplatin DRUG

Chemotherapy

C1: Postoperative radiotherapy 60 Gray with Cisplatin

Postoperative radiotherapy RADIATION

Postoperative radiotherapy (PORT)

B1: Postoperative radiotherapy 60 Gray; B2: Postoperative radiotherapy 50 Gray; C1: Postoperative radiotherapy 60 Gray with Cisplatin; C2: Postoperative radiotherapy 60 Gray without chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Lisette Nixon: lead
• UNICANCER: collaborator
• AdventHealth: collaborator
• University of Leipzig: collaborator
• Princess Alexandra Hospital, Brisbane, Australia: collaborator
• Stanford University: collaborator

Study Sites (57)

Board of Trustees of the Leland Stanford Junior University

Redwood City, California, 94063, United States

Location

Advent Health

Orlando, Florida, 32803, United States

Location

MD Anderson Cancer Centre

Houston, Texas, 77030, United States

Location

Metro South Health

Brisbane, QLD 4113, Australia

Location

Unicancer

Paris, 75013, France

Location

Vivantes Klinikum

Berlin, Germany

Location

Zentrum für Hals-, Nasen- und Ohrenheilkunde

Giessen, Germany

Location

Asklepios Kliniken

Hamburg, Germany

Location

Kath Marienkrankenhaus gGmbH

Hamburg, Germany

Location

Universitaetsklinikum des Saarlandes

Homburg, Germany

Location

Universitat Leipzig

Leipzig, Germany

Location

Ernst von Bergmann Klinikum

Potsdam, Germany

Location

Städtisches Klinikum Solingen

Solingen, 42653, Germany

Location

Universitätsklinikum Ulm

Ulm, Germany

Location

University Hospitals Dorset NHS Foundation

Poole, Dorset, BH15 2JB, United Kingdom

Location

Royal United Hospitals Bath NHS Foundation Trust

Bath, BA1 3NH, United Kingdom

Location

Queen Elizabeth Hospital

Birmingham, B15 2TH, United Kingdom

Location

Royal Blackburn Hospital

Blackburn, BB2 3HH, United Kingdom

Location

Royal Sussex County Hospital

Brighton, BN2 5BE, United Kingdom

Location

University Hospitals Bristol NHS Foundation Trust

Bristol, BS2 8ED, United Kingdom

Location

Cambridge University Hospitals NHS Foundation Trust

Cambridge, CB2 0QQ, United Kingdom

Location

Kent and Canterbury Hospital

Canterbury, United Kingdom

Location

HPV Research Group Section of Pathology Cardiff University ,School of Medicine

Cardiff, CF14 4XN, United Kingdom

Location

Cardiff and Vale University Local Health Board

Cardiff, CF14 4XW, United Kingdom

Location

Centre for Trials Research

Cardiff, CF14 4YS, United Kingdom

Location

Velindre NHS Trust

Cardiff, CF142TL, United Kingdom

Location

Castle Hill Hospital

Cottingham, HU16 5JQ, United Kingdom

Location

Derby Teaching Hospitals NHS Foundation Trust

Derby, DE22 3DT, United Kingdom

Location

Western General Hospital

Edinburgh, EH4 2XU, United Kingdom

Location

Royal Devon University Health Care NHS Foundation Trust

Exeter, United Kingdom

Location

Royal Surrey County Hospital

Guildford, GU2 7XX, United Kingdom

Location

St James University Hospital

Leeds, LS9 7TF, United Kingdom

Location

Liverpool Head and Neck Centre

Liverpool, L3 9TA, United Kingdom

Location

University of Liverpool

Liverpool, L69 3GB, United Kingdom

Location

Cwm Taf Bro Morganwg

Llantrisant, CF72 8XR, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, NW1 2BU, United Kingdom

Location

Guys and St Thomas's NHS Foundation Trust

London, SE1 9RT, United Kingdom

Location

St Georges University Hospital

London, SW17 0QT, United Kingdom

Location

Imperial College Healthcare NHS Trust

London, SW7 2AZ, United Kingdom

Location

Central Manchester University Hospital NHS Foundation Trust

Manchester, M13 9WL, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

The Pennine Acute Hospital Trust

Manchester, OL1 2JH, United Kingdom

Location

The James Cook University Hospital

Middlesbrough, TS4 3BW, United Kingdom

Location

Royal Victoria Infirmary

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Newcastle upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Aneurin Bevan University Health Board

Newport, NP18 3XQ, United Kingdom

Location

Northampton General Hospital

Northampton, United Kingdom

Location

Nottingham City Hospital

Nottingham, United Kingdom

Location

Oxford University Hospitals NHS Foundation Trust

Oxford, OX3 7LD, United Kingdom

Location

University Hospital Plymouth

Plymouth, PL6 8DH, United Kingdom

Location

Queen Alexandra Hospital

Portsmouth, PO6 3LY, United Kingdom

Location

Royal Preston Hospital

Preston, PR2 9HT, United Kingdom

Location

Royal Berkshire Hospital

Reading, RG1 5AN, United Kingdom

Location

University Hospital Southampton

Southampton, SO16 6YD, United Kingdom

Location

Royal Stoke Hospital

Stoke, United Kingdom

Location

City Hospitals Sunderland NHS Foundation Trust

Sunderland, SR4 7TP, United Kingdom

Location

Swansea Bay University Local Health Board

Swansea, SA2 8QA, United Kingdom

Location

Related Publications (2)

• O'Hara JT, Hurt CN, Ingarfield K, Patterson JM, Hutcheson K, Canham JE, Nixon LS, Heiberg CD, Johson S, Evans M, Jones TM. Transoral Laser or Robotic Surgery Outcomes for Oropharyngeal Carcinoma: Secondary Analysis of the PATHOS Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2024 Oct 10;150(11):1002-11. doi: 10.1001/jamaoto.2024.3371. Online ahead of print.

  PMID: 39388196 DERIVED

• 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.

  PMID: 26311526 DERIVED

MeSH Terms

Interventions

Cisplatin

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Officials

• Mererid Evans, MBBch, PhD

  Velindre NHS Trust

  PRINCIPAL INVESTIGATOR

• Terrence Jones, MBBS,MD

  Aintree University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Trial Manager

Study Record Dates

• First Submitted: August 11, 2014
• First Posted: August 13, 2014
• Study Start: October 1, 2015
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): April 1, 2028
• Last Updated: February 19, 2025

Record last verified: 2025-01

Locations

US (3); FR (1); AU (1); GB (43); DE (9)