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GYNAECOLOGY
Post-colposcopy Management
of ASC-US and LSIL Pap Tests
(PALS Trial): Pilot RCT
D1X XLana Saciragic, MD;D1,
2X X * D3X XGregg Nelson, MD, PhD;D1,
4X X * D5X XHelene Chiarella-Redfern, MD;D6X2X
3
1
ire A. Duggan, MDD12X4X
D7X XNorma Kanarek, PhD;D8X X D9X XJill Nation, MD;D10X X D1X XMa
1
Section of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Calgary, Tom Baker Cancer Centre,
Calgary, AB
2
Cumming School of Medicine, Health Sciences Centre, University of Calgary, AB
3
Department of Environmental Health and Engineering, Johns Hopkins School of Public Health, Baltimore, MD
4
Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Foothills Medical
Centre, Calgary, AB
ABSTRACT
Objective: Evidence supporting optimal follow-up of women with
atypical squamous cells of undetermined significance (ASC-US) or
low-grade squamous intraepithelial lesion cytology found to have
low-grade disease or normal findings at initial colposcopy is weak.
Surveillance options include continued colposcopy, discharge with
Pap testing, or HPV testing at 12 months. This study was a pilot
RCT comparing these three follow-up policies. The objectives were
to determine the feasibility of an RCT and to compare the incidence
of greater than or equal to high-grade squamous intraepithelial
lesion ( ≥ HSIL) in each of the follow-up policies.
Methods: A total of 133 women referred with ASC-US or low-grade
squamous intraepithelial lesion cytology between June and August
2012 underwent initial colposcopy where incident ≥ HSIL histology
was ruled out. Of these women, 125 were randomized to
colposcopic surveillance, Pap testing, or HPV testing. Patients with
high-risk results at any point were treated according to standard of
care. Patient recruitment and adherence to follow-up were
calculated using descriptive statistics. Accuracy of the three followup arms was calculated (Canadian Task Force Classification: IC).
Results: Recruitment rates were 80%, and adherence to protocol was
85% to 100%. Nine of 125 (7.2%) patients overall were found to
have ≥ HSIL histology at exit: one of 43 in the reference colposcopy
group, and six of 41 and three of 41 in Pap and HPV arms,
respectively. One early cancer was detected in the HPV arm.
Sensitivity and specificity (CI) for each arm, respectively, were as
KEY WORDS: Colposcopy, Papanicolaou test, HPV, low-grade
abnormalities, uterine cervical neoplasm, cervical intraepithelial
neoplasia
Corresponding author: Dr. Gregg Nelson, Section of Gynecologic
Oncology, Department of Obstetrics & Gynecology, University of
Calgary, Tom Baker Cancer Centre, Calgary, AB.
gregg.nelson@albertahealthservices.ca
Competing interests: See Acknowledgements.
Received on June 25, 2018
Accepted on August 13, 2018
follows: colposcopy N/A, 100% (88.1%−100%); Pap, 100% (47.8%
−100%) and 85.7% (63.7%−97%); and HPV, 66.7% (9.4%−99.2%)
and 68% (46.5%−85.1%).
Conclusion: This pilot study demonstrated the operational and safety
feasibility of an RCT in this patient population. Validation of clinical
findings is necessary.
* Dr. Saciragic and Dr. Nelson are joint first authors.
Résumé
Objectif : Nous avons peu de données fiables appuyant le suivi
optimal des femmes présentant une atypie des cellules
malpighiennes de signification indéterminée (ASCUS) ou une
lésion malpighienne intra-épithéliale de bas grade histologique
(LSIL) à la cytologie chez qui on a trouvé une maladie de bas
grade ou des résultats normaux à la première colposcopie. Les
options de suivi comprennent la poursuite du suivi
colposcopique, le congé avec test Pap ou le dépistage du VPH
après 12 mois. Cette étude était un ECR pilote comparant ces
trois politiques de suivi. Les objectifs étaient de déterminer la
faisabilité d'un ECR et de comparer l'incidence de lésions
malpighiennes intra-épithéliales de haut grade ou de grade
supérieur (≥HSIL) associée à chacune de ces politiques.
Méthodologie : Au total, 133 femmes aiguillées pour une ASCUS ou
une LSIL à la cytologie entre juin et août 2012 ont subi une première
colposcopie où une histologie de ≥HSIL a été écartée. De ces
femmes, 125 ont été réparties aléatoirement en trois groupes de
suivi : suivi colposcopique, test Pap ou dépistage du VPH. À tout
point de l'essai, les patientes présentant des résultats à risque élevé
ont été traitées conformément aux normes de soins. Le recrutement
des patientes et l'adhésion au suivi ont été calculés au moyen de
statistiques descriptives. L'exactitude des résultats des trois bras de
suivi a été calculée (classification IC du Groupe d’étude canadien).
Résultats : Le taux de recrutement était de 80 %, et le taux d'adhésion
au protocole, de 85 % à 100 %. Au total, 9 des 125 patientes (7,2 %)
avaient une histologie de ≥HSIL à la fin de l’étude : 1 sur 43 dans le
groupe de colposcopie (groupe de référence), et 6 sur 41 et 3 sur 41
dans les bras de test Pap et de dépistage du VPH, respectivement.
Un cancer précoce a été détecté dans le bras de dépistage du VPH.
La sensibilité et la spécificité (IC) de chaque bras, respectivement,
étaient les suivantes : colposcopie, s.o. et 100 % (88,1%–100 %);
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1
GYNAECOLOGY
test Pap, 100% (47,8 %–100 %) et 85,7 % (63,7 %–97 %); et
dépistage du VPH, 66,7 % (9,4 %–99,2 %) et 68 % (46,5 %–
85,1 %).
Conclusion : Cette étude pilote a démontré la faisabilité opérationnelle
et la sûreté d'un ECR dans cette population de patientes. Une
validation des résultats cliniques sera nécessaire.
© 2018 Society of Obstetricians and Gynaecologists of Canada. Published
by Elsevier Inc. All rights reserved.
J Obstet Gynaecol Can 2018;000(000):1−10
https://doi.org/10.1016/j.jogc.2018.08.004
INTRODUCTION
he most common referral cytologic abnormalities
found on colposcopy are atypical squamous cells of
undetermined significance, usually in conjunction with a
positive HPV test or low-grade squamous intraepithelial
lesion.1 A total of 15% to 20% of these patients will have
high-grade dysplasia or carcinoma detected at initial
colposcopy.2 Colposcopic management of these patients is
controversial for several reasons. First, “real-world” sensitivity of colposcopy is thought to be lower than that in clinical trial settings (74% vs. 87%, respectively).3 Second,
women with normal colposcopy or histologic diagnosis of
lower than cervical intraepithelial neoplasia 2 have a 12%
risk of progression to greater than or equal to CIN 3 within
2 years (Figure 1).4 These results underscore the importance of managing low-grade, in addition to high-grade,
cytologic abnormalities to prevent cervical cancer. Third,
no randomized prospective evidence exists.
T
Two observational studies found conflicting results. A
nested cohort study of ASCUS-LSIL Triage Study
(ALTS) trial patients examined post-colposcopic outcomes in women with cytologic LSIL or HPV-positive
ASC-US and histologic ≤CIN 1.5 This study concluded
that the most efficient test for identifying women with
CIN 2 to 3 after colposcopy may be an HPV test at 12
months; however, it did not consider ongoing
ABBREVIATIONS
ASC-H
atypical squamous cells, cannot exclude high-grade
squamous intraepithelial lesion
ASC-US
atypical squamous cells of undetermined significance
CIN
cervical intraepithelial neoplasia
ECC
endocervical curettage
HSIL
high-grade squamous intraepithelial lesionLSIL,
low-grade squamous intraepithelial lesion
2
colposcopic surveillance as a management strategy. An
ad hoc analysis of the Trial Of Management of Borderline and Other Low-grade Abnormal smears (TOMBOLA) study examining the influence of high-risk HPV
status on risk of progression to ≥ CIN 2 in patients with
histologic CIN 1 at initial colposcopy deemed the combined HPV-16/18 test to be insufficient for management
of this patient population and suggested repeat cytology
within 2 years.6 A 2006 survey of Canadian colposcopists
outlined the heterogeneity in management of this situation and highlighted reliance on colposcopy as a standard
of follow-up care and a reluctance to discharge women
with routine Pap tests performed in the primary care setting.7 Canadian and US societies give management recommendations on the basis of level B evidence.8,9
Ontario colposcopy guidelines suggest triage with HPV
testing, if colposcopy results are negative and satisfactory
and referral cytology is lower than or equal to LSIL.10
Thus, the clinical challenge becomes identifying women
who will eventually have histologic findings that are greater
than or equal to high-grade squamous intraepithelial lesion,
without overtreating those with histologic ≤ LSIL. Ongoing colposcopic follow-up is taxing for the patients and
costly for the health care system. Several studies have
examined the role of clinicopathologic factors in predicting
risk of progression to pre-invasive or invasive disease, with
insignificant results.11,12
METHODS
This was a pilot of a non-blinded RCT conducted in the
gynaecologic oncology colposcopy clinic at the Tom Baker
Cancer Centre in Calgary, Alberta from January 2012
to August 2012 (clinicaltrials.gov registration ID
NCT03466710). Patients were randomly assigned 1:1:1 to
one of three study arms: colposcopy, Pap testing, or HPV
testing.
Eligible participants included women 18 years or older
referred to colposcopy with an LSIL or ASC-US Pap
test, with or without HPV DNA test, according to
Alberta Cervical Cancer Screening Guidelines.13 Women
were ineligible if they had had a previous hysterectomy,
were pregnant or considering pregnancy in the next 18
months, had previous cervical cancer, had undergone
an excisional or ablative procedure of the cervix, were
younger than 18, or were non-Alberta residents.
Patients were approached at the initial colposcopy visit
by one of the principal investigators (G.N.) and invited
to enrol. Randomization was done using an online randomization tool Randomize.net. Random allocation
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Post-colposcopy Management of ASC-US and LSIL Pap Tests (PALS Trial): Pilot RCT
Figure 1. Natural history of cervical dysplasia.
High grade abnormality
Low grade abnormality
Cytology
(Pap tesng)
Normal
ASC-US
Malignancy
HSIL
AGC
AIS
LSIL
to HSIL - 11%
to cancer – 1%
5-12%
treatment
progress
progress
Histology
(Colposcopy)
Normal
LSIL (CIN1)
HSIL (CIN2/3)
Malignancy
Regress/persist
89%
ASC-US: atypical squamous cells of undetermined significance; LSIL: low-grade squamous intraepithelial lesion;
HSIL: high-grade squamous intraepithelial lesion; AGC: atypical glandular cells; AIS: adenocarcinoma in situ; CIN:
cervical intraepithelial neoplasia.
sequence was generated in blocks of six. Study investigators, patients, and statisticians were not blinded to
study arm allocation because this was not possible.
A convenience sample was used for this pilot study to
generate an appropriate sample size for determining the
outlined clinical objectives.
Figure 2. Schematic of the study design. After initial colposcopy, where histologic findings greater than or equal to a highgrade squamous intraepithelial lesion ( ≥ HSIL) were ruled out, patients were randomized to one of three arms; those in the
colposcopy and Pap arm were seen at 6 and 12 months post-randomization and had relevant investigations, whereas
patients in the HPV arm were seen at 12 months post-randomization. Patients who were found to have high-risk findings,
as outlined in the schematic, discontinued the intervention and were referred to standard of care, consisting of colposcopy. All patients had exit colposcopy at 18 months, to assess for histologic ≥ HSIL.
CIN: cervical intraepithelial neoplasia; LSIL: low-grade squamous intraepithelial lesion; ASC-US: atypical
squamous cells of undetermined significance; HPB+ive: HPV positive.
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GYNAECOLOGY
After consent and enrolment, eligible women had an initial
screening colposcopy and cervical biopsy to exclude incident
histologic ≥ HSIL. If none was detected at screening colposcopy, the women were randomized to one of three arms:
colposcopy (considered the standard of care), Pap testing, or
HPV testing (both simulating discharge to community).
Throughout the study, participants who had high-risk results
were referred for colposcopy (Figure 2; online Appendix).
All participants who continued in the study had exit colposcopy 18 months after initial enrolment, where histologic
diagnosis was obtained (biopsy and/or endocervical curettage). This 18-month cut-off was chosen as a point at which
high-grade dysplasia would more likely reflect disease that
was missed at initial assessment (incident disease), rather
than progression during the study period. Results from this
18-month point were considered in the statistical analysis
when comparing the outcomes among the three arms.
Primary outcome of high-grade disease was defined on the
basis of histology obtained from a cervical biopsy or ECC
and reported as ≥ HSIL. The intent of this definition was
to establish a true pathologic diagnosis and to calculate relative risk of progression to ≥ HSIL among the three arms.
No central pathology review was done for the pilot but
would be part of the full RCT. Second exploratory definition of the primary outcome was determined on the basis
of Pap-based cytology reported as follows: atypical squamous cells, cannot exclude HSIL; atypical glandular cells;
HSIL, adenocarcinoma in situ; or malignant. The intent of
this definition was to replicate the real-life scenario in
which high-risk cytology would prompt a referral back to
colposcopy and to therefore be able to determine rates of
re-referral to colposcopy and subsequent patient outcomes.
Similar reasoning was applied to positive HPV results. An
analysis of test validity was done.
Adherence to the protocol was assessed at two points:
throughout the study, and at exit colposcopy. Adherence to
the protocol throughout the study (6- and 12-month points
for the colposcopy and Pap arm, 12-month point for the
HPV arm) was deemed to be satisfactory if the colposcopist performed the test to which the patient was randomized
and did not perform a different test (e.g.. in the Pap arm,
performed a Pap test and did not perform a biopsy or
ECC). Adherence to the protocol at exit colposcopy was
deemed to be satisfactory if the colposcopist obtained a
histologic diagnosis, independent of randomization arm.
Violation of the protocol was considered any procedure or
examination that was not consistent with the protocol.
Patients’ demographics and characteristics were reported
using descriptive statistics, and comparisons among the
three arms was done using the chi-square test or Fisher
exact test for categorical variables and the Kruskal-Wallis
test for continuous variables. Sensitivity and specificity
were calculated in each arm. SAS version 9.3 (SAS Institute, Inc., Cary, NC) was used for all analyses. Ethics
approval was granted from Health Research Ethics Board
of Alberta Cancer Committee (HREBA.CC-16-0632).
RESULTS
Feasibility
Patient recruitment was accomplished as a result of a large
pool of eligible women and high patient participation rate.
In the study colposcopy clinic, 70% of referrals (or 42
patients per month) are for ASC-US and LSIL (unpublished colposcopy quality assurance data). Eighty percent
of patients approached for the study chose to participate.
All five colposcopists participated in the study. Nursing
and administrative support was excellent. However, this
study was human resource intensive in organization, follow-up, and data collection.
Adherence to the protocol is depicted in Table 1. Protocol
violations in the colposcopy arm occurred in the form of
only colposcopic inspection being performed, and no biopsy
or ECC being done if the colposcopic impression was negative; in the Pap arm, the violations were in the form of biopsy
or ECC being done and no cytology; exit colposcopy violations were seen in the Pap and HPV arms whereby colposcopic inspection only, without histology, was performed.
Clinical Outcomes
A total of 133 eligible women were recruited and consented
to participate in the study. The recruitment period was from
January 2012 to August 2012. Of these women, 125 were
Table 1. Adherence to study protocol
Arm
6 months
12 months
Exit colposcopy
Average
Colposcopy
(41/41) 100%
(38/38) 100%
(26/30) 87%
96%
Pap
(32/34) 94%
(27/28) 96%
(23/27) 85%
92%
HPV
N/A
(33/33) 100%
(27/31) 87%
93.5%
4
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Post-colposcopy Management of ASC-US and LSIL Pap Tests (PALS Trial): Pilot RCT
Figure 3. CONSORT (Consolidated Standards of Reporting Trials) flow diagram.
Assessed for eligibility (n=133)
Excluded (n=8)
- Not meeng inclusion criteria (n=5)
Randomized (n=125)
- Declined to parcipate (n=1)
- Incomplete informaon (n=2)
COLPOSCOPY
Allocated to intervenon (n=43)
Allocated to intervenon (n=41)
HPV
Allocated to intervenon (n=41)
- Received intervenon (n=41)
- Received intervenon (n=34)
- Received intervenon (n=33)
PAP
- No intervenon (n=2)
- No intervenon (n=7)
- No intervenon (n=8)
* Moved to different province
* Previous LEEP (n=2)
* Previous LEEP (n=1)
* Declined further parcipaon
* Pregnant (n=2)
* Out of province paent (n=1)
* Did not aend (n=3)
* Did not aend (n=3)
* HPV test not done (n=3)
Lost to follow-up (n=10)
Lost to follow-up (n=6)
Disconnued intervenon (n=1)
Disconnued intervenon (n=2)
- HSIL on ECC (n=1)
- HSIL on bx (n=1)
Lost to follow up (n=1)
Disconnued intervenon as HPV
posive (n=12)
- HSIL on ECC (n=1)
Analyzed (n=30)
Analyzed (n=27)
Analyzed (n=20)
Outcome (n=1)
Outcome (n=3)
Outcome (n=1)
- HSIL on bx (n=1)
- HSIL on bx (n=3)
- HSIL on bx (n=1)
LEEP: loop electrosurgical excision procedure; HSIL: high-grade squamous intraepithelial lesion; ECC: endocervical
curettage; bx: biopsy.
followed prospectively until they were diagnosed with
≥ HSIL, dropped out, were lost to follow-up, or the study
endpoint was reached, whichever came first (Figure 3).
Table 2 depicts pertinent demographic information. Median
patient age was 31. There was a statistically significant difference in smoking among the three groups (P = 0.04), with the
Pap arm having the most smokers. Overall, 29 of 125
(23.2%) patients were referred with ASC-US cytology and 96
of 125 (76.8%) with LSIL cytology.
A total of 125 participants were randomized to one of
three arms: 43 to the colposcopy arm, 41 to the Pap arm,
and 41 to the HPV arm (Table 3). Of these participants, 84
of 125 (67%) patients were eligible for final analysis. Accuracy of the follow-up arms is depicted in Table 3.
Overall incidence of histologically confirmed ≥ HSIL at 18
months of follow-up was 7.2% (nine of 125). Two patients
had HSIL at exit colposcopy, and 4 had HSIL at 12-month
follow-up; 3 patients had HSIL at 6-month follow-up (and
were subsequently excluded from the trial). One patient
(one of 125, 0.8%) with HSIL at exit colposcopy and a negative HPV test result had stage 1A1 squamous cell carcinoma on subsequent loop electrosurgical excision
procedure. Patients were analyzed according to their
assigned group; no crossover occurred.
An exploratory post hoc analysis of the incidence of
histologic ≥ HSIL was examined in the Pap and HPV
arms to determine rates of re-referral to colposcopy at
the 12- and the 18-month point (Table 4). Rate of rereferral to colposcopy using a follow-up Pap strategy
was 17% (seven of 41); 57% (four of seven) of these
participants subsequently required clinically meaningful
excisional or ablative procedures. Using the HPV strategy, there was a 27% (11 of 41) re-referral rate, with
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GYNAECOLOGY
Table 2. Demographics
Factors
Colposcopy
(n = 43)
PAP
(n = 41)
HPV testing
(n = 41)
Gravidity
P valuea
0.118
G0
27 (62.8%)
31 (77.5%)
23 (56.1%)
G1 or more
16 (37.2%)
9 (22.5%)
18 (43.9%)
0
1
0
P0
28 (65.1%)
34 (85.0%)
27 (67.5%)
P1 or more
15 (34.9%)
6 (15.0%)
13 (32.5%)
0
1
1
No
38 (88.4%)
38 (95.0%)
36 (87.8%)
Yes
5 (11.6%)
2 (5.0%)
5 (12.2%)
0
1
0
No
9 (20.9%)
15 (37.5%)
7 (17.1%)
Yes
34 (79.1%)
25 (62.5%)
34 (82.9%)
0
1
0
No
32 (74.4%)
38 (95.0%)
34 (82.9%)
Yes
11 (25.6%)
2 (5.0%)
7 (17.1%)
0
1
0
No
34 (79.1%)
32 (82.1%)
33 (82.5%)
Yes
9 (20.9%)
7 (18.0%)
7 (17.5%)
0
2
1
No
32 (74.4%)
25 (61.0%)
25 (61.0%)
Yes
11 (25.6%)
16 (39.0%)
16 (39.0%)
Unknown/missing
Parity
0.091
Unknown/missing
Immunocompromised
Unknown/missing
0.552
Contraception
0.079
Unknown/missing
Current smoker
Unknown/missing
0.038
History of HPV vaccine
Unknown/missing
0.909
Any comorbidities
0.323
STI
0.583
No
29 (67.4%)
24 (61.5%)
29 (72.5%)
Yes
14 (32.6%)
15 (38.5%)
11 (27.5%)
0
2
1
ASC-US
10 (23.3%)
12 (29.3%)
7 (17.1%)
LSIL
33 (76.7%)
29 (70.7%)
34 (82.9%)
Unknown or missing
Referral Pap results
0.564
HPV status at trial entry
0.813
Positive
5 (11.6%)
3 (7.3%)
5 (12.2%)
Negative
0 (0.0%)
1 (2.4%)
0 (0.0%)
Unknown
Median (IQR) days between referral Pap and
first colposcopy
38 (88.3%)
37 (90.2%)
36 (87.8%)
47 (IQR 24)
Range 27 to 310
47 (IQR 26)
Range 23 to 190 (missing = 1)
44 (IQR 22)
Range 15 to 147 (missing = 1)
0.868
STI: sexually transmitted infection; ASC-US: typical squamous cells of undetermined significance; LSIL: low-grade squamous intraepithelial lesion; IQR: interquartile
range.
a
Chi-square test for categorical data, and Kruskal-Wallis test for continuous data; tests exclude unknown or missing.
6
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Post-colposcopy Management of ASC-US and LSIL Pap Tests (PALS Trial): Pilot RCT
Table 3. Study outcomes
Patient population
Colposcopy arm
Pap arm
HPV arm
Total
Randomized
43
41
41
125
Exclusions
13
15
13
41
6 months
3
7
—
10
12 months
0
5
9
14
18 months
0
0
2
2
Total
3
12
11
26
5
2
—
7
Lost to follow up at:
Protocol violations at:
6 months
12 months
5
0
—
5
18 months
0
1
2
3
Total
10
3
2
15
0 (35)
4 (28)
—
True positive
—
3
—
False positive
—
1
—
0 (30)
4 (19)
10
—
2
2
Results
Follow up test positive (negative)
6 months
12 months
True positive
—
2
8
1 (29)
0 (18)
1 (17)
66
Completed study per protocol
30
26
28
84
Test positive and exited study
0
8
10
18
Exit colposcopy performed
30
18
18
66
False positive
Exit colposcopy positive (negative)
18% (two of 11) having a clinically meaningful result.
No harm was detected or reported at any point during
the trial.
DISCUSSION
The Post-colposcopy Management of ASC-US and LSIL
Pap Tests (PALS) trial is the first prospective study
designed to assess the feasibility of a multicentre RCT
exploring the optimal follow-up policy for patients referred
to colposcopy with ASC-US or LSIL cytology and who do
not have incident histologic ≥ HSIL. Our experience suggests that such a study is feasible from an operational point
of view, provided availability of appropriate support personnel. We saw an 80% recruitment rate, which is larger
than that reported in the general literature, in the absence
of colposcopy-specific data.14 Similarly, a dropout rate
of 33% in our study was in line with reported colposcopy
follow-up rates.15−17 Adherence of 85% to 100% to
study protocol suggests clarity and understanding of the
study design and offers a pragmatic view reflective of
“real-world” practices. Furthermore, protocol violations
consisted of erring on the side of appropriate and safe
practice. The majority of protocol violations occurred in
the colposcopy arm and consisted of a visual inspection
only, without any histology. Histologic sampling would
need to be addressed in a non-pilot RCT to ensure
patients’ safety. We estimate that approximately 1250
patients would be needed for a randomized trial (online
Appendix); this could be accomplished by collaborating
with colposcopic institutions across the country.
The PALS pilot study contributes information to clinical
management. The Pap arm proved to have the highest sensitivity (100%) at 18 months, thus suggesting that serial
testing in a population already identified as being higher
risk will accurately identify women who have the disease,
thereby allowing timely treatment. This finding is consistent with published literature suggesting that Pap testing
for this population of women is safe.6,18 Sensitivity of
100% for the Pap arm in this population is different from
that in the general population, where it has been reported
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GYNAECOLOGY
Table 4. Exploratory post hoc analysis of incidence of high risk diseasea,b
Patient
Referral Pap Screening
colposcopy
6-month
follow-up
12-month follow-up 18-month follow-up
(exit colposcopy)
Final outcome
Pap arm (n = 41)
1
LSIL
Negative
Pap − ASC-H
Bx + ECC− HPV
features
Pap − nil
Discharge to screening
2
LSIL
Negative
Pap − HSIL
Pap − HSIL
Pap − HSIL, bx HSIL
LEEP recommended −
patient declined
3
LSIL
LSIL
Pap − HSIL
Bx − HSIL
N/Ac
Laser vaporization
4
LSIL
LSIL
ECC − HSIL
N/A
N/A
LEEP − HSIL (CIN 3)
5
ASC-US
Negative
Negative
Pap − HSIL
Bx HSIL,
ECC SIL unqualified
LEEP − HSIL (CIN 3)
6
ASC-US
ECC − LSIL
N/Ac
Pap − ASC-H
Bx − LSIL
Ongoing colposcopic follow-up
7
LSIL
Bx − LSIL
Pap − ASC-US
PAP − HSIL
Bx − LSIL
Ongoing colposcopic follow-up
8
LSIL
Negative
N/Ac
HPV positive
Pap ASC-H
LEEP − HSIL (CIN 2)
9
ASC-US,
Bx − LSIL
N/Ac
HPV positive
Pap − HSIL
LEEP − HSIL (CIN 3)
HPV negative
Pap − AGC
LEEP − 1A1 SCC cervix
c
c
HPV arm (n = 41)
10
ASC-US
Negative
c
N/A
LSIL: low-grade squamous intraepithelial lesion; ASC-H: atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion; Bx: biopsy; ECC: endocervical curettage; HSIL: high-grade squamous intraepithelial lesion; LEEP: loop electrosurgical excision procedure; CIN: cervical intraepithelial neoplasia; ASC-US: atypical squamous cells of undetermined significance; SIL: squamous intraepithelial lesion; SCC: squamous cell carcinoma.
a
For colposcopy 2 and 3, only the most clinically worrisome cytology results are displayed because these would have prompted referral back to colposcopy.
b
Bold text represents cytology results in a community that would have prompted repeat referral to colposcopy.
c
N/A because the patient did not have the test.
to be 50% to 60%.19 HPV testing in our study had low
sensitivity and specificity (66.7% and 68%, respectively) for
detection of ≥ HSIL at 18 months; these rates were comparable to those of the TOMBOLA study.6 However, this
differs significantly from the aforementioned nested cohort
study by Guido et al., where sensitivity of the HPV arm
was reported at 92.2%.5 This could be the result of (1)
technical limitations of the HPV test used for our study;
(2) the latent nature of HPV infection, whereby the virus is
causing minor cytologic abnormalities at the 18 month
point; or (3) a lack of pathology review, whereby HPV-positive patients deemed to have LSIL on histology may have
higher-grade disease. Colposcopy performed best in terms
of specificity, thus suggesting that it may still be the best
test to confidently rule out disease, consistent with the
reported literature.20 Indeed, the Ontario guidelines combine follow-up colposcopy and exit HPV testing as a strategy to further risk stratify this population of women.10
This strategy was not explored in our study.
A recently published Norwegian study is the largest cohort
to date to assess outcomes retrospectively.21 The study
included 25 948 women and compared 42- and 78-month
outcomes of histologic CIN 3+ in women in the general
screening population versus women who were referred to
8
colposcopy with an ASC-US/LSIL or ASC-H/HSIL Pap
test, who had normal or CIN 1 histology after initial colposcopy. These investigators found that the results of the first
follow-up cytology were significant at assessing subsequent
risk; women with abnormal first follow-up cytology had a
9.4% cumulative incidence of CIN 3+ at 42 months, versus
1.6% for women with normal follow-up cytology, versus
0.21% for the general population.21 These findings corroborate with our study findings; although the absolute number
of women with ≥ HSIL histology was higher in the Pap
arm, had these women been discharged back to the community after the initially negative colposcopy, they would have
subsequently been re-referred to colposcopy, where preinvasive disease would have been detected and treated. In
the absence of an RCT, these results could serve as interim
guidance for the colposcopist.
The lower referral rate to colposcopy using the follow-up
cytology policy (17%), as compared with HPV policy
(27%), with a greater proportion of patients having clinically meaningful cervical lesions, suggests an economic and
clinical advantage of the Pap arm over HPV and colposcopy. Additional risk stratification on the basis of variables
such as age, smoking status, and history of HPV vaccination should be explored in larger studies and may provide
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Post-colposcopy Management of ASC-US and LSIL Pap Tests (PALS Trial): Pilot RCT
another way to risk stratify this patient population. Cytology and HPV testing, as opposed to ongoing colposcopic
surveillance, have benefits in terms of resource use, patient
anxiety, and adherence to follow-up.15,20,22,23,24,25
Limitations of this trial include a somewhat low incidence of
histologic ≥ HSIL, which precluded sensitivity analysis in the
colposcopy arm. This may be reflective of a convenience
sample chosen for the pilot (the literature reports an incidence
between 4.6% and 11.3%).5,6,18 The nonblinded nature of the
study design and the study setting and statistically significant
difference in smoking status may have biased the results. The
direction of bias is difficult to predict; however, the high rates
of adherence to the study protocol suggest that this bias may
not be large. Furthermore, one third of our patients were lost
to follow-up—it is possible these patients are at higher risk of
developing ≥ HSIL because of noncompliance. Given the
limitations of this study, safety and effectiveness of each follow-up arm should be verified in an RCT, also keeping in
mind cost considerations.
CONCLUSION
The PALS trial demonstrates that an RCT is operationally feasible; adequate patient recruitment can be
achieved by engaging multiple colposcopic centres in
the country. The Society of Canadian Colposcopists has
supported such a trial (unpublished letter communication). It is well understood in epidemiology and prevention science that the better a screening program
performs, the more effort has to be expended to
decrease rates of disease further. Therefore, investing in
research that examines the important question of how
to manage the study population of women who have a
meaningful 12% risk of developing a precancerous
lesion is a worthwhile effort. Confirming our clinical
findings in an RCT is important for health systems
economy and optimizing patient care.
Acknowledgements
Financial support for this project was provided by an unrestricted research grant from the Tom Baker Cancer Centre.
Tom Baker Cancer Centre had no role in study design,
implementation, data analysis, or writing of this manuscript. The funds were used for logistical purchases related
to study implementation (subscription to randomization
tool Randomize.net and stationary). The authors would
like to acknowledge non-financial support provided by
Hologic, which arranged the HPV testing in an external
laboratory of Rob Nicholson, Path QC, Montreal, QC.
Hologic had no role in the analysis or interpretation of the
data. The authors would like to thank Selphee Tang for her
statistical support.
SUPPLEMENTARY DATA
Supplementary data related to this article can be found, at
doi:10.1016/j.jogc.2018.08.004.
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