Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03466710 |
| Other study ID # |
HREBA.CC-16-0632_REN1 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 2012 |
| Est. completion date |
August 2012 |
Study information
| Verified date |
November 2017 |
| Source |
University of Calgary |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
There is weak evidence supporting optimal follow-up of women with ASC-US or LSIL cytology
found to have low grade disease or normal findings at initial colposcopy. Surveillance
options include continued colposcopy, discharge with Pap testing, or HPV testing at 12
months. The investigators performed a pilot randomized controlled trial (RCT) comparing these
3 follow-up policies. Study objectives are to determine the feasibility of an RCT and to
compare the incidence of >/=HSIL in each of the arms by intention to treat principle.
Description:
1. BACKGROUND In 2010 the estimated age standardized incidence and mortality rates for cancer
of the uterine cervix in Canada were 7 and 2 per 100,000 women respectively. Squamous cell
carcinoma is the most frequent type and arises from a premalignant squamous dysplasia called
cervical intraepithelial neoplasia (CIN). There are 3 grades of CIN from I to III in order of
increasing severity. A systematic review of 73 studies on the natural history of CIN,
determined nearly 89% of CIN I regressed to normal or a benign lesion or persisted unchanged,
and progression to CIN III occurred in 11% and to cancer in 1%. In contrast, CIN III and II
had a greater malignant potential as 12% and 5% respectively progressed to cancer. The low
incidence and mortality rates of cervical cancer are largely attributed to the availability
of screening for CIN with the Pap test (Papanicolaou stained cervical smear) and the
colposcopic management of cytologic abnormalities. While rates have plateaued in recent
years, decreases are expected with additional improvements in Pap test performance and
pre-colposcopy management of cytologic abnormalities. Changes to the post-colposcopy
management of cytologic abnormalities could also improve the rates, but rigorous
investigation of potential changes is lacking.
1.1 Management and outcome of cytological abnormalities The Bethesda System (TBS) is the
recommended Pap test reporting terminology in Canada. TBS 2001 classifies results as negative
for intraepithelial lesion or malignancy (NILM), or an epithelial cell abnormality. The
latter includes 1) atypical squamous cells of undetermined significance (ASC-US), 2) atypical
glandular cells (AGC), 3) low grade squamous intraepithelial lesion (LSIL), 4) atypical
squamous cells, cannot exclude HSIL (ASC-H), 5) high-grade SIL (HSIL), 6) adenocarcinoma in
situ (AIS), and 7) malignant.
Management of cytological abnormalities may involve colposcopic examination. The colposcope
magnifies the cervix and allows directed biopsy of any visualized mucosal abnormality
(impression). A repeat Pap test and tissue sampling of the endocervical canal (endocervical
curettage; ECC) can also be carried out. CIN II, III and cancer diagnosed at the first
colposcopy exam are considered to be incident disease undersampled by the referral Pap test
(incident >/=CIN II) 3. CIN II or higher detected within the subsequent 24 months is
categorized as progressive disease. Some investigators however, also consider it incident
disease that escaped earlier colposcopic detection and refer to incidentally detected and
progressive CIN II or higher as cumulative CIN II (CIN 2+).
Approximately 1% of cytological results in the United States is an HSIL, 4.4 % is an ASCUS
(atypical squamous cells of undetermined significance to include ASC-US and ASC-H) and 1.6%
an LSIL. Canadian data is somewhat similar (Calgary Laboratory Services unpublished quality
assurance data), Since upwards of 60-80% of HSIL is a CIN II/III colposcopic examination and
treatment is appropriate so as to prevent cervical cancer. Uncertainty and controversy in
regard to the outcome of ASC-US and LSIL existed until the completion of the ALTS (ASCUS and
Low Grade Triage Study) randomized clinical trial. The trial determined 13% of the combined
ASCUS and LSIL cohorts had an incident >/=CIN II and an additional 8% progressed to CIN
II/III. These results underscored the importance of managing low grade cytological
abnormalities to prevent cervical cancer.
1.2 Pre-colposcopy management of ASC-US and LSIL Current management of ASC-US and LSIL in
Canada is guided by the Clinical Practice Guidelines of the Society of Obstetricians and
Gynecologists of Canada (SOGC) and the 2001 and 2006 guidelines of the American Society for
Colposcopy and Cervical Pathology (ASCCP). Management options include referral to colposcopy
after a single or double test result of ASC-US or LSIL or a single ASC-US result testing
positive for HPV (Human Papilloma Virus) DNA (deoxyribonucleic acid). Management in Canada is
mostly based on repeat Pap testing since HPV testing is not routinely available in every
jurisdiction. For example, in Alberta, 2 years of repeat Pap testing carried out at 6-month
intervals is the standard for an ASC-US or LSIL detected during routine screening and
referral to colposcopy occurs when follow up Pap tests show persistence or progression.
1.3 Colposcopy management of ASC-US and LSIL Mucosal abnormalities of the cervix are biopsied
and additional treatment is based on the histopathological results. Repeating the Pap test at
colposcopy is of minimal value in the added detection of CIN II/III/cancer, and is not
routinely performed. An ECC is recommended to sample disease in the endocervical canal.
ASC-US and LSIL tests with incident >/=CIN II are treated with ablation or excision, whereas
those with
1.4 Post-colposcopy management of ASC-US and LSIL The post colposcopy management of women
referred with ASC-US or LSIL and who do not have incident >/=CIN II is still uncertain.
Management algorithms are available from the ASCCP despite the absence of strong evidence to
support all of the recommendations. Amongst those with
Post-colposcopy management of ASC-US and LSIL in Canada is very variable and likely reflects
the lack of strong evidence supporting the existing guidelines. Based on 102 survey responses
from 252 Canadian colposcopists, 43% recommended discharge from colposcopy for ASC-US/LSIL
negative for CIN, while 53% recommended repeat colposcopy. For ASCUS/LSIL positive for CIN I,
13% recommended discharge to Pap test follow-up, 65% recommended repeat colposcopy, and 16%
recommended treatment. The number of follow up colposcopy exams was variable but there was at
least one at 6 months and more often a second at 12 months. The survey highlighted a greater
reliance on colposcopy as a standard of follow up care and a reluctance to discharge women
for follow up with routine Pap tests performed in the primary care setting. Notably, no
participant reported utilizing HPV DNA testing. The high (48%) level of survey participation
and individual participant's comments attested to the community's interest in scientifically
evaluating the best post-colposcopy management strategy for this clinical scenario.
1.4 Post-colposcopy management of ASC-US and LSIL negative for incident CIN II/III The ALTS
trial was principally designed to assess the pre-colposcopy management of women with ASCUS or
LSIL. Later, some of the trial data was used to test repeat cytology and HPV testing as
post-colposcopy management options. Repeat colposcopy examination could not be measured as a
management option. HPV testing at 12 months was found to be 92% sensitive for progression to
>/=CIN II amongst those with
2 RESEARCH DESIGN This is a pilot randomized controlled trial performed at the Holy Cross
Colposcopy Clinic of the Calgary Health Zone for the purpose of testing a randomized clinical
trial which will be designed to test above-stated objectives. The pilot will test the
recruitment, randomization, operational feasibility, and clinical outcomes. The pilot data
will be added to the future full proposal of the clinical trial. Potential additional studies
stemming from the clinical trial will include the evaluation of molecular determinants of
outcome, e.g. persistence of specific HPV types, viral load and viral integration, analyses
of temporal changes in behavioral factors, and cost effectiveness of the 3 arms.
3 RESEARCH METHODOLOGY 3.1 Pilot sample, enrolment and randomization
Usual colposcopic and pathology practices will be applied at the initial exam and a repeat
Pap test will not be performed. After enrolment, baseline data will be extracted by the study
team from the clinic charts, including date of the referral Pap test and result, date of the
colposcopy exam, colposcopy impression, and cervical biopsy and ECC results. Those with
All cervical disease identified at these referrals back to colposcopy will be managed in
accordance with standard protocols.
4 DATA MANAGEMENT AND ANALYSIS 4.1 Data management All data collected by the research team
will be collected in a de-identified fashion in the REDCap Software managed by University of
Calgary. Data discrepancies will be reviewed by an independent third person. Data forms will
be checked prior to data entry, and range and logic checks carried out regularly on entered
data to ensure the quality of the data. Any results that appear to be out of range or do not
comply with the logic checks will be checked with the hospital or clinic case notes and the
woman and her clinician.
4.2 Data analysis Patient demographics and characteristics will be reported using descriptive
statistics, and comparisons between the three arms will be done using the Chi-square test or
Fisher's exact test for categorical variables and the Kruskal-Wallis test for continuous
variables. For the primary outcome, the investigators will report the proportion of high risk
disease along with the 95% confidence intervals, and compared the arms using relative risks
and 95% confidence intervals, with the Colposcopy arm as the reference group. Sensitivity,
specificity, positive predictive value, and negative predictive value will be calculated in
each arm. SAS 9.3 (SAS Institute Inc., Cary, NC, USA) will be used for analyses.
Non-inferiority of repeat Pap and HPV testing follow-up policies strategies, relative to
colposcopy is hypothesized. Inferiority will be defined as the smallest relative disadvantage
in sensitivity that would be of practical clinical interest. Investigators assume this margin
to be less than 1% based on informal discussions with colposcopists in Calgary and in the
absence of relevant publications.
