Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05858021 |
| Other study ID # |
328436 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 3, 2023 |
| Est. completion date |
July 2, 2025 |
Study information
| Verified date |
May 2023 |
| Source |
University of Manchester |
| Contact |
David A Finch, MbChB, BSc |
| Phone |
+44 1772 522031 |
| Email |
davidfinch-2[@]manchester.ac.uk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Anal cancer can be prevented through detection and treatment of a recognised precancerous
lesion, known as anal intra-epithelial neoplasia (AIN), specifically the anal high-grade
squamous intra-epithelial lesion (aHSIL) subtype.
Assessment of changes in disease burden is an important feature in the clinical evaluation of
a treatment. Existing trials in aHSIL have predominantly used disease response outcomes based
on histological and cytological changes to measure the effects of treatment. Several
limitations to this approach have been identified.
Lesion characteristics such as lesion size and number represent potential indicators of
disease response to treatment and might overcome some of the limitations.
We aim to develop a disease measurement instrument capable of describing disease burden such
that it can be used to evaluate disease response to treatment in addition to histological and
cytological based measurements further strengthening the quality of disease response
outcomes.
The disease measurement instrument will be developed over 4 stages:
1. A meeting of AIN experts to determine a longlist of lesion measurement items capable of
capturing disease burden;
2. A series of disease assessments will be undertaken in participants known to have aHSIL
to assess disease burden using the measurement items identified in stage 1;
3. Data analysis to determine the best performing measurement items and comprise a disease
measurement instrument;
4. Pilot-testing of the proposed disease measurement instrument.
Two trained disease assessors (experienced clinicians familiar with the assessment of anal
intraepithelial lesions) will assess disease burden per participant. Disease burden will also
be captured photographically. We will undertake disease assessments on 20-30 participants. By
analysing the results of the clinician assessments and digital analysis of the photographic
representation of disease burden, we will be able to determine the most acceptable, feasible,
reliable and reproducible ways of measuring disease burden and use these to inform a disease
measurement instrument.
Description:
Anal cancer is a Human Papilloma Virus (HPV) related cancer with approximately 1500 new cases
in the UK per year (2016-2018). Although considered an uncommon cancer, incidence rates have
increased threefold in the last 30 years. Initial treatment is chemoradiotherapy, with
surgical options reserved for early-stage disease, incomplete response to chemoradiotherapy
or disease recurrence. Both treatment modalities are associated with substantial short and
long-term side effects. It is estimated that over 90 percent of anal cancer cases in the UK
are preventable thus avoiding the associated morbidity and mortality.
A number of sub-populations are at increased risk of developing anal cancer and therefore
represent potential targets for cancer prevention and early detection strategies. In
addition, a recognised precursor lesion, known as anal intra-epithelial neoplasia (AIN)
presents further opportunity for early detection and prevention. AIN can be further
stratified into benign low-grade (aLSIL) and potentially cancerous high-grade squamous
intra-epithelial lesion (aHSIL). AIN has some similarities to the precursor lesion of
cervical cancer, known as CIN. While the natural history of CIN is well-quantified, and there
is an evidence-based management strategy of screening and treatment of CIN, with reduction in
incidence of cervical cancer, this is so far not the case in AIN.
The recently published 'Treatment in Preventing Anal Cancer in Patients with HIV and Anal
High-Grade Lesions' trial (ANCHOR), a large, multi-centre, phase III randomised-controlled
trial (RCT) of anal HSIL (aHSIL) treatment versus active monitoring without treatment in
people living with HIV (PLWH) showed significantly lower risk of squamous cell carcinoma of
the anus (SCCA) with aHSIL treatment than with active monitoring. The magnitude of the
benefit observed in the treatment arm led to early closure of the trial (on ethical grounds)
and allowed treatment to be offered to those in the active monitoring arm. The likely
consequence of such significant findings will be a shift towards screening and treatment of
aHSIL and an era of AIN treatment trials to determine the optimal approach.
There are multiple treatments for aHSIL 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. The evidence base underpinning such treatments is of poor quality and
the optimal approach cannot be defined.
Assessment of changes in disease burden is an important feature in the clinical evaluation of
a treatment. In the context of anal intra-epithelial lesions, clinical assessment involves
digital anorectal examination combined with either direct ('naked eye') visual inspection of
the anal canal and peri-anus (non HRA), and or visualisation under magnification using a
technique known as high resolution anoscopy (HRA). A diagnosis of aHSIL is confirmed
histologically following biopsy of suspicious lesions.
An initial scoping exercise of AIN trial literature identified 5 RCTs evaluating AIN
treatments. Outcomes assessing disease response to treatment (complete response, partial
response, recurrence) typically involve before and after treatment evaluation of one or a
combination of HRA guided biopsy and assessment of histology and or assessment of cytological
changes[5, 6]. Assessments related to either lesion specific (index lesion) changes or
overall disease changes (index lesion and potential metachronous lesions). None of the trials
assessed treatment response by any other measure of change in disease burden. Two of the
studies did utilise alternative measures of disease burden though this was not for the
purpose of assessing treatment response, for example, number of index lesions and sum of the
greatest diameters as potential predictors of disease clearance and lesion size (≤50% or ≥50%
of the anal canal or perianal region) for stratification purposes. Neither paper reported the
technique used to undertake these measurements.
There are a number of potential issues with approaches that rely on histological and
cytological outcomes. Histological and cytological outcomes simply confirm the presence or
absence of aHSIL; or downstaging of disease to aLSIL, in instances where all aHSIL resolves
or at the least is downgraded to LSIL treatment benefit can be inferred, there are however
instances where treatment benefits may be inferred in the setting of persisting aHSIL. Lesion
size is well known to correlate with disease severity in the cervix. Similarly in the ANCHOR
trial, a larger lesion size was associated with an increased risk of progression to cancer.
Therefore, even in the presence of persisting aHSIL, by reducing lesion size a treatment may
infer benefit through reduced disease burden. Attempts have been made to address this issue
in two (NCT02059499 and NCT04055142) of three phase 3 RCT's currently recruiting or in
development identified following a search of an international clinical trials register. These
trials intend to incorporate 'number of quadrants' and 'number of octants' affected by
disease in the outcomes respectively. This approach however might not be an accurate
reflection of disease response, for instance, in situations where there are multiple lesions
across multiple octants, the size of lesion and number of lesions may change but the spread
of disease in terms of number of octants occupied remain unchanged; or in situations whereby
octants containing multiple lesions, some of which but not all downgrade to aLSIL, will score
the same as octants containing aHSIL lesions, none of which have downgraded.
A further problem is the reliance on HRA to guide assessment, HRA requires specialist
equipment and is a skilled procedure. Assessors need to be experienced in subtle lesion
characteristics, as such skilled assessors are few and far between. A consequence of a lack
of trained HRA assessors opens the potential for bias with investigators administering trial
interventions also being those that are undertaking the disease assessment, the same problem
is noted in a trial utilising high resolution vulvoscopy for the related condition, vulval
intraepithelial neoplasia. A lack of trained HRA assessors could also represent a limiting
factor for future large-scale trials. Establishing a method of disease assessment that can be
undertaken with photographic representation of disease and is suitable for use in non HRA
settings offer potential solutions to such problems.
An acceptable, feasible, reliable and reproducible method of disease measurement would add
further granularity to outcomes relating to disease assessment. It could be utilised in aHSIL
treatment trials to improve the quality of disease response outcomes and in clinical practice
as a modality for communicating disease extent or evaluating response to treatment.
We aim to develop a disease measurement instrument capable of describing disease burden such
that it can be used to evaluate disease response to treatment in addition to histological and
cytological based measurements further strengthening the quality of disease response
outcomes. To account for variations in diagnostic practice, the approach will be applicable
to both a HRA and non HRA setting. We are unaware of any previous systematic review or
comprehensive methodological work in this clinical area.
A meeting of AIN experts will be conducted to determine a longlist of lesion measurement
items capable of capturing disease burden. A series of disease assessments will be undertaken
in participants known to have aHSIL to assess disease burden using the longlist measurement
items. Disease assessments will be scheduled to coincide with the participants routine
disease assessment undertaken as part of the participants 'usual' clinical care for aHSIL.
Disease burden for each participant will be captured diagrammatically using location and
lesion descriptors recommended by consensus based international guidance for the detection of
anal cancer precursor lesions. Disease burden for each participant will also be captured
photographically. This detail will be captured initially via non HRA approach (usual care)
with the addition of HRA once this approach is established. Described lesions will be
correlated with histology from biopsies taken as part of routine clinical practice to confirm
the presence of aHSIL in the lesions described.
Two trained disease assessors (experienced clinicians familiar with the assessment of anal
intraepithelial lesions) will assess disease burden per participant. Disease burden will also
be captured photographically. We will undertake disease assessments on 20-30 participants to
obtain an acceptable confidence interval around the estimate of reliability for each
measurement item and to ensure variation in the spread of disease patterns for aHSIL is
captured. By analysing the results of the clinician assessments and digital analysis of the
photographic representation of disease burden, we will be able to determine the best
performing measurement items which can be used to inform a disease measurement instrument.
To ensure the disease measurement instrument is relevant (for example, adequacy of
photographic representation of disease, the measurement items used), a study advisory group
comprising experts in aHSIL assessment and management will be assembled to oversee the study.
