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. [email protected] 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 %); 000 JOGC 000 2018 Descargado para Anonymous User (n/a) en Universidad Peruana Cayetano Heredia de ClinicalKey.es por Elsevier en noviembre 24, 2018. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados. 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 000 JOGC 000 2018 Descargado para Anonymous User (n/a) en Universidad Peruana Cayetano Heredia de ClinicalKey.es por Elsevier en noviembre 24, 2018. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados. 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. 000 JOGC 000 2018 Descargado para Anonymous User (n/a) en Universidad Peruana Cayetano Heredia de ClinicalKey.es por Elsevier en noviembre 24, 2018. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados. 3 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% 4 000 JOGC 000 2018 Descargado para Anonymous User (n/a) en Universidad Peruana Cayetano Heredia de ClinicalKey.es por Elsevier en noviembre 24, 2018. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados. 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 000 JOGC 000 2018 Descargado para Anonymous User (n/a) en Universidad Peruana Cayetano Heredia de ClinicalKey.es por Elsevier en noviembre 24, 2018. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados. 5 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. 6 000 JOGC 000 2018 Descargado para Anonymous User (n/a) en Universidad Peruana Cayetano Heredia de ClinicalKey.es por Elsevier en noviembre 24, 2018. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados. 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 000 JOGC 000 2018 Descargado para Anonymous User (n/a) en Universidad Peruana Cayetano Heredia de ClinicalKey.es por Elsevier en noviembre 24, 2018. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados. 7 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 000 JOGC 000 2018 Descargado para Anonymous User (n/a) en Universidad Peruana Cayetano Heredia de ClinicalKey.es por Elsevier en noviembre 24, 2018. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados. 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. REFERENCES 1. Jones BA, Davey DD. Quality management in gynecologic cytology using interlaboratory comparison. Arch Pathol Lab Med 2000;124:672–81. 2. 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