The COrSIcA Study

This 3 year PhD thesis is part funded by the NIHR Manchester Biomedical Research Centre (BRC) 2022 bid ‘North West ’ section, funding clinical research at Lancashire Teaching Hospitals NHS Foundation Trust (Preston).

Undertaking this project is David Finch, ST7 colorectal trainee surgeon within the North West deanery. David is the first student in this component of the BRC programme and will be central to coordinating this collaboration.

COrSIcA brings together clinical researchers (Parkin; Mitchell) at Preston, clinical academic at the MCRC and Manchester BRC (Renehan); methodological expertise in core outcome sets (Fish) and qualitative research (Morris), with research leadership (Martin-Hirsch).

Located between both the Royal Preston Hospital and the Manchester Cancer Research Centre, David will be integrated into the Manchester NIHR BRC Cancer Prevention and Early Detection theme.

Project Background and Aims

Anal squamous cell carcinoma (ASCC) is a HPV- related cancer with approximately 1400 new cases in the UK per year. Incidence rates has increased threefold in the last 30 years. Initial treatment is chemoradiotherapy, associated with substantial short-term and long-term side effects.

There are a number of sub-populations at increased risk of developing ASCC. These include men who and sex with men (MSM) whether they are HIV positive or not, other HIV positive groups, immunosuppressed groups such as transplant patients, and women who have previous vulval, vaginal and cervical cancers.

In addition, there is a recognised precursor lesions, known as anal intra-epithelial neoplasia (AIN), which has some similarities to the precursor lesion of cervical cancer, known as CIN. While the natural history of CIN is will well-quantified, and there is a well-worked out management strategy of screening and treatment of CIN, with reduction in incidence of cervical cancer, this paradigm is not proven for AIN.

AIN is stratified into low grade and high grade squamous intra-epithelial lesion (HSIL). Positive p16 immunohistochemical staining is a useful marker for HSIL.

There are multiple treatments for HSIL broadly categorised as medical (for example, topical imiquimod, 5-FU, and anti-viral agents such as cidofovir) and surgical (laser, infra-red coagulation, electrocautery, and local excision) therapies. Vaccination is a possible third management strategy.

To-date, there are few phase III randomised controlled trials for the treatment of HSIL. Our scoping search identified two – namely the AIDS malignancy consortium ANCHOR trial ( NCT02135419) and TreatAIN (NCT04055142). Both are in HIV positive patients.

Both trials have utilised different primary and secondary outcomes. This hinders evidence synthesis and presents challenges to the selection of optimal outcomes in future trials. The ANCHOR trial developed a trial-specific QoL questionnaire but its generalisability is not

To determine the priority outcomes for all stakeholders and reach agreement on a
standardised COS to be measured and reported in all future trials in all patients with HSIL.

Rationale and Experimental Plan

To-date the limitations of the AIN trials include: limited to select high-risk sub-populations; the outcome measures of invasive cancer does not appear to be included; treatment-related factors e.g. frequency of hospital attendance, are not included; and other morbidities e.g. pain, incontinence, and not listed. Our research group have previously developed a core outcome set (COS) for trials including chemoradiotherapy for non-metastatic ASCC. This was called CORMAC (1) and used COMET methodological principles (

The present COrSIcA proposal will extend this work and develop a COS for patients with HSIL recruited to later phase
intervention trials. A COS will facilitate evidence synthesis in HSIL and ensure future trials utilise outcomes that are relevant to all stakeholders.

Experimental Plan:

There will be four workstreams (WSs). These will be consecutive

PPI A patient and public involvement (PPI) group will be established with patients with experience of squamous intra-epithelial precursor lesions of the anus or family members. The group will help inform the study from design, commenting on patient-focused information (e.g. adverts, and PIS), wording of interview questions, through to dissemination and wider public engagement.

SAG An international study advisory group (SAG) will be assembled to oversee the project, and will include patient representation. We will explore registering this proposal with international professional organisations, such as IANS (International Anal Neoplasia Society).

Additional work within the PhD project will focus on the development of a clinical scoring system to facilitate the objective evaluation of AIN in future trials.