Intraoperative HPV Testing Evaluation

Recurrence Clinical Trial

Official title:

Intraoperative HPV Testing Evaluation: Multicenter Prospective Cohort Study

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04190472
• Other study ID #: IOP VPH IOP Protocol
• Status: Not yet recruiting
• Start date: June 1, 2020
• Est. completion date: June 1, 2024

Study information

• Verified date: April 2020
• Source: Hospital Universitari Vall d'Hebron Research Institute
• Contact: Jordi Rabasa Antonijuan, PhD
• Phone: 93 489 3066
• Email: jordi2546[@]hotmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

High-grade intraepithelial lesion/cervical intraepithelial neoplasia grade 2-3 is a premalignant cervical lesion caused by persistent high-risk human papillomavirus infection. Human papillomavirus test is a very sensitive risk marker of cervical cancer and it has been incorporated in the follow-up after high-grade intraepithelial lesion treatment. Papillomavirus test performed intraoperatively could be a beneficial approach to anticipate treatment failure, allow for early management and consequently a reduction in costs. The aim of this study is to evaluate if the IOP-HPV test has non-inferior diagnostic utility of HSIL/CIN2-3 recurrence at 24 months as the HPV test performed 6 months after treatment.

Description:

Background:

High-Grade Intraepithelial Lesion/Cervical Intraepithelial Neoplasia grade 2-3 (HSIL/CIN2-3) is a premalignant cervical lesion caused by persistent high-risk Human papillomavirus (HPV) infection [1]. It is estimated that approximately 54,000 women in Spain are annually diagnosed with HSIL/CIN2-3, which represents a significant economic burden for the national health system [2]. Electrosurgical excision procedure (LEEP) is the standard treatment of HSIL/CIN2-3 [3,4]. In Spain, current national guidelines recommend control after LEEP at 6, and 24 months [5,6,7]. The HPV test is a sensitive marker of cervical cancer risk and it has been incorporated, with cytology, in the follow-up of squamous cervical intraepithelial lesion after a LEEP [8,9,10].

We recently showed that an HPV test performed intraoperatively (IOP-HPV) has a strong association with recurrent disease as well as a good diagnostic recurrence efficiency at 12 months, similar than the test performed at 6 months. Thus, IOP-HPV test could be feasible and useful to identify treatment failure earlier than conventional strategies [11]. These results are similar to those previously observed by other authors [12].

However, one of the limitations of previous studies was the sample size of patients to achieve greater statistical power and perform a non-inferiority study.

The aim of this study is to evaluate if the IOP-HPV test has non-inferior diagnostic utility of HSIL/CIN2-3 recurrence at 24 months as the HPV test performed 6 months after LEEP.

Material and methods

This is a multicenter prospective cohort study that will include patients diagnosed with HSIL/CIN2-3. This study will be carried out at the Hospital Vall d'Hebron in Barcelona (organizing center) and other National centers from June 2020 to June 2024. All patients will undergo a HPV test 3 months prior to treatment and will be followed for a period of 24 months.

Cytology samples will be interpreted by an experienced pathologist following the Bethesda System [13]. HPV test will be performed using the commercially available Hybrid Capture 2 (HC2) system. If this is positive, it will be followed by the CLART-HPV2 test, a PCR technique that will allow the detection of 35 HPV genotypes.

Colposcopy will be performed using a colposcope Olympus 500 after preparing the cervix with 5% acetic acid and lugol solution. Colposcopy findings will be described following the criteria of the International Federation for Cervical Pathology and Colposcopy (IFCPC) [14].

Prior to LEEP, the abnormal area will be delimited by acetic acid and iodinated lugol, a colposcopy will be performed prior to the application of 1 ml of 2% mepivacaine to each quadrant of the cervix.

The entire pathological area will be removed next to the transformation zone (TZ), followed by selective coagulation of the surgical bed by diathermic coagulation ball. Immediately after the LEEP, a cervical sample will be taken for the IOP-HPV test. At the end of the procedure an ECC will be performed using a Novak curette.

The cervical specimen will be processed in a standardized way: after staining with ink the surfaces (or the margins) of the piece, a paraffin block will be obtained from which a minimum of 12 sections, of the 4 quadrants will be examined. A margin will be considered affected if the lesion reaches the margin or is within 1mm.

After surgery, the follow-up will be performed according to the National Guidelines Recommendations5,6,7. Visits will be scheduled according to the margin status of the LEEP specimen: If the margins are negative, the patient will be reviewed at 6, 12 and 24 months with cytology, HPV test and colposcopy. If they are positive, a visit will be added 4 months after the procedure where an additional cervical cytology will be taken.

Patients with abnormal cytology (LSIL+) or abnormal colposcopy will undergo a CGB. When the TZ is not completely visible or no colposcopic abnormalities are identified, an ECC with Novak curette will also be performed.

High-grade recurrence will be considered either when the CGB confirmes HSIL/CIN2-3 or when the ECC shows HSIL.The criteria to perform a second treatment will be the histological confirmation of HSIL/CIN2-3 during the follow-up.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1553
• Est. completion date: June 1, 2024
• Est. primary completion date: June 1, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 25 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of HSIL/CIN2-3 by colposcopy guided biopsy (CGB) or endocervical curettage (ECC) in the 3 months prior to LEEP and/or confirmation of HSIL/CIN2-3 in the pathologic study of the surgical specimen

Exclusion Criteria:

• Patients with acquired or congenital immunosuppression

• Patients undergoing chronic immunosuppressive treatments, prior treatment with LEEP

• Patients in whom HSIL/CIN2-3 was not histologically confirmed.

Related Conditions & MeSH terms

• HSIL, High Grade Squamous Intraepithelial Lesions
• Recurrence
• Squamous Intraepithelial Lesions of the Cervix

Intervention

Diagnostic Test:
• IOP HPV test
Immediately after the LEEP, a cervical sample was taken for the IOP-HPV test

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Hospital Universitari Vall d'Hebron Research Institute

References & Publications (13)

Arbyn M, Paraskevaidis E, Martin-Hirsch P, Prendiville W, Dillner J. Clinical utility of HPV-DNA detection: triage of minor cervical lesions, follow-up of women treated for high-grade CIN: an update of pooled evidence. Gynecol Oncol. 2005 Dec;99(3 Suppl 1):S7-11. Epub 2005 Sep 9. — View Citation

Bornstein J, Bentley J, Bösze P, Girardi F, Haefner H, Menton M, Perrotta M, Prendiville W, Russell P, Sideri M, Strander B, Tatti S, Torne A, Walker P. 2011 colposcopic terminology of the International Federation for Cervical Pathology and Colposcopy. Obstet Gynecol. 2012 Jul;120(1):166-72. — View Citation

Castellsagué X, Rémy V, Puig-Tintoré LM, de la Cuesta RS, Gonzalez-Rojas N, Cohet C. Epidemiology and costs of screening and management of precancerous lesions of the cervix in Spain. J Low Genit Tract Dis. 2009 Jan;13(1):38-45. doi: 10.1097/LGT.0b013e318182cd89. — View Citation

Fuste P, Bellosillo B, Santamaria X, Mancebo G, Mariñoso L, Alameda F, Espinet B, Sole F, Serrano S, Carreras R. HPV determination in the control after LEEP due to CIN II-III: prospective study and predictive model. Int J Gynecol Pathol. 2009 Mar;28(2):120-6. doi: 10.1097/PGP.0b013e3181891459. — View Citation

Jeong NH, Lee NW, Kim HJ, Kim T, Lee KW. High-risk human papillomavirus testing for monitoring patients treated for high-grade cervical intraepithelial neoplasia. J Obstet Gynaecol Res. 2009 Aug;35(4):706-11. doi: 10.1111/j.1447-0756.2008.00989.x. — View Citation

Kang WD, Oh MJ, Kim SM, Nam JH, Park CS, Choi HS. Significance of human papillomavirus genotyping with high-grade cervical intraepithelial neoplasia treated by a loop electrosurgical excision procedure. Am J Obstet Gynecol. 2010 Jul;203(1):72.e1-6. doi: 10.1016/j.ajog.2010.01.063. Epub 2010 Apr 24. — View Citation

Kocken M, Helmerhorst TJ, Berkhof J, Louwers JA, Nobbenhuis MA, Bais AG, Hogewoning CJ, Zaal A, Verheijen RH, Snijders PJ, Meijer CJ. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol. 2011 May;12(5):441-50. doi: 10.1016/S1470-2045(11)70078-X. — View Citation

Kocken M, Uijterwaal MH, de Vries AL, Berkhof J, Ket JC, Helmerhorst TJ, Meijer CJ. High-risk human papillomavirus testing versus cytology in predicting post-treatment disease in women treated for high-grade cervical disease: a systematic review and meta-analysis. Gynecol Oncol. 2012 May;125(2):500-7. doi: 10.1016/j.ygyno.2012.01.015. Epub 2012 Jan 18. Review. — View Citation

Paraskevaidis E, Kalantaridou SN, Paschopoulos M, Zikopoulos K, Diakomanolis E, Dalkalitsis N, Makrydimas G, Pappa L, Malamou-Mitsi V, Agnantis NJ. Factors affecting outcome after incomplete excision of cervical intraepithelial neoplasia. Eur J Gynaecol Oncol. 2003;24(6):541-3. — View Citation

Pinto AP, Crum CP. Natural history of cervical neoplasia: defining progression and its consequence. Clin Obstet Gynecol. 2000 Jun;43(2):352-62. Review. — View Citation

Rabasa J, Bradbury M, Sanchez-Iglesias JL, Guerrero D, Forcada C, Alcalde A, Pérez-Benavente A, Cabrera S, Ramon-Cajal S, Hernandez J, Dinares C, García A, Centeno C, Gil-Moreno A. Evaluation of the intraoperative human papillomavirus test as a marker of early cure at 12 months after electrosurgical excision procedure in women with cervical high-grade squamous intraepithelial lesion: a prospective cohort study. BJOG. 2020 Jan;127(1):99-105. doi: 10.1111/1471-0528.15932. Epub 2019 Sep 25. — View Citation

Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, Raab S, Sherman M, Wilbur D, Wright T Jr, Young N; Forum Group Members; Bethesda 2001 Workshop. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002 Apr 24;287(16):2114-9. Review. — View Citation

Torné A, Fusté P, Rodríguez-Carunchio L, Alonso I, del Pino M, Nonell R, Cardona M, Rodríguez A, Castillo P, Pahisa J, Balasch J, Ramírez J, Ordi J. Intraoperative post-conisation human papillomavirus testing for early detection of treatment failure in patients with cervical intraepithelial neoplasia: a pilot study. BJOG. 2013 Mar;120(4):392-9. doi: 10.1111/1471-0528.12072. Epub 2012 Nov 27. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Intraoperatory HPV testing evaluation: non- inferior study of diagnostic utility of HSIL/CIN2-3 recurrence as 6-months HPV test.	Evaluate if the IOP-HPV test has non-inferior diagnostic utility of HSIL/CIN2-3 recurrence at 24 months as the HPV test performed 6 months after LEEP.	24 months of follow-up after LEEP

External Links

•   Guía de cribado del cáncer de cuello de útero en España, 2014. Editado por Asociación Española de Patología Cervical y Colposcopia ISBN: 978-84-608-36551.