PATHOS

A Phase III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV)-positive oropharyngeal cancer.

Background

Oropharyngeal cancer caused by Human Papillomavirus (HPV) infection is increasing in incidence in the UK and other developed countries. It affects younger patients and has a better prognosis than most other head and neck cancers. Patients cured of their disease often have to live for several decades with the side-effects of their treatment which can be permanent and have a major impact on quality of life. The PATHOS study will recruit approximately 1,082 patients from the UK, Europe and internationally over six years. The aim is to tailor treatment for patients with HPV-positive oropharyngeal cancer to reduce side-effects, particularly swallowing problems, which have the major impact on quality of life.

Minimally invasive surgery

For patients enrolled into PATHOS, it will have been decided by local teams that they should undergo surgery to remove the primary tumour in the tonsil, throat or tongue using a laser or robot – these operations are called ‘minimally invasive’ and are carried out through the mouth. A neck dissection will also be carried out to remove the lymph glands in the neck which may also contain cancerous cells. After surgery, the cancer that has been removed will be examined by a pathologist for features that can help predict whether further treatment in the form of radiotherapy and/or chemotherapy is recommended.

Study aim

Around 10% of patients will not require any further treatment after surgery (PATHOS group A). Patients for whom radiotherapy alone is recommended (PATHOS group B), will be randomly allocated to receive either standard dose post-operative radiotherapy (60 Gray in 30 treatments over six weeks) or lower dose radiotherapy (50 Gray in 25 treatments over five weeks). Other patients (PATHOS group C) will be allocated to receive either radiotherapy with chemotherapy (Cisplatin) or radiotherapy alone at the same dose (60 Gray in 30 treatments over six weeks). The patient will be allocated to either group B or C depending on the results received from the pathologist. The aim is to see if long term toxicity, particularly swallowing problems, can be reduced in patients receiving either lower dose radiotherapy (group B) or no chemotherapy (group C), without affecting the chance of cure.

Oropharyngeal cancer

Oropharyngeal cancer is a type of cancer that can affect the throat, tonsils and back of the tongue. Many oropharyngeal cancers are caused by a virus called Human Papillomavirus (HPV), a common virus that we will almost all be affected by during our lives, usually without any illness at all. We don’t understand why HPV causes cancers to develop but the good news is that cancers caused by HPV usually respond well to treatment.

This study aims to identify the best way of treating oropharyngeal cancers that are caused by HPV. At the moment, cancers caused by HPV are treated like any other cancer in the Head and Neck and the survival rate is very good. This study is looking to see if the treatment can be modified to reduce the risk of side-effects caused by the treatment.

Side effects

Side effects are problems that arise directly as a result of treatment. They can happen during treatment or shortly afterwards (acute side-effects) or they can happen months after treatment (late side-effects) and can last for many years, sometimes permanently.

One common side effect of current treatment is a change in the ability to swallow properly, which can be permanent. Some patients (around 1 in 10) will have to use a feeding tube (gastrostomy tube) for many months or even years after treatment has finished. This will obviously have a big impact on their quality of life.

Internationally, there is a move towards trying to reduce the intensity of treatment for HPV-positive head and neck cancers to reduce the chance of side-effects. In Western countries, some doctors are already reducing the amount of radiotherapy and chemotherapy that is given during treatment to try to reduce the chance of side effects. However, no one has collected data in the right way after surgery to be able to know whether or not this is the best thing to do. PATHOS is looking to do this so that we know for sure that swallowing problems after treatment can be reduced without reducing the chance of curing the tumour.

Recruitment

The aim is to recruit 1,082 participants and the main objectives of the phase III study are to demonstrate:

• If swallowing function can be improved following transoral surgery for HPV-positive oropharyngeal cancer, by reducing the intensity of adjuvant treatment protocols.
• That local control and survival outcomes are maintained in patients receiving less intensive adjuvant treatment following transoral surgery.

Study design

PATHOS is a multicentre, open label, parallel group Phase III randomised controlled trial (RCT). Patients eligible for the study must have biopsy proven or suspected oropharyngeal squamous cell carcinoma (OPSCC) clinically staged T1-T3 N0-N2b. Their primary tumour, as judged by the local MDT, must be considered resectable via a transoral approach. After informed consent, HPV-positivity will be confirmed by local testing (central testing for sites unable to test locally) of the diagnostic biopsy specimen. Participants will undergo baseline assessment of swallowing function and QOL, prior to surgery. Surgery to the primary site may be carried out by Transoral Laser Microsurgery (TLM) or Transoral Robotic Surgery (TORS), whilst a standard open approach will be used to facilitate an associated neck dissection.

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.

Participants in Group A (low-risk) will remain on follow-up only. Patients in Groups B & C (medium & high risk) will be randomised depending on their T and N stage, smoking history and treating centre.

Involving the public and patients

We like to involve people at an early stage of the trial development so that they are part of the research team.

The public get involved in research for a variety reasons. Members of the public might have personal knowledge and experience of the research topic or be able to provide a more general perspective.

In the Centre for Trials Research we involve the public by using their skills to help in the design of patient facing documents such as questionnaires, and participant information leaflets. They can also ensure that the methods proposed for the study are acceptable to the potential research participant. They make certain that the research question outcome is important to the public and they can also be a voice for the seldom heard groups.

We like to have at least two research partners assigned to each trial. We invite the research partners to our regular Trial Management Group meetings so that they can contribute and ensure that the research is being conducted in an acceptable and sensitive way to the potential research participants.

This research was funded by the Stand Up To Cancer campaign for Cancer Research UK.