CC BY
6DOI 10.24412/cl-37136-2023-1-186-188
HIGH-GRADE CERVICAL INTRAEPITHELIAL NEOPLASIA TREATMENT COMPARING PHOTODYNAMIC THERAPY
PROTOCOLS
NATALIA INADA1, CYNTHIA DE CASTRO2, CAROLINA DA SILVA3, LAURA MARCHETTI3, WELINGTON LOMBARDI3 AND VANDERLEI BAGNATO1,4
'Sao Carlos Institute of Physics, University of Sao Paulo, Brazil 2Federal University of Sao Carlos, Department of Morphology and Pathology, Brazil 3Woman Health Ambulatory, University of Araraquara, Brazil 4Hagler Institute for Advanced Studies, Texas A&M University, United States of America
ABSTRACT
Photodynamic therapy (PDT) is a therapeutical modality which offers a minimally invasive alternative for high-grade cervical intraepithelial neoplasia (CIN) treatment. This prospective randomized controlled clinical trial aims to compare two PDT protocols for histopathologically similar high-grade CIN treatment. In protocol 1, only ectocervix is illuminated; in protocol 2, the patients had both the ectocervix and endocervix illuminated simultaneously with LED plus LASER (a cylindrical diffuser fiber was coupled inside the squamocolumnar junction). In both groups was applied 20% MAL overnight (approximately 10 hours) and the irradiance delivered was 120 mW/cm2, for 21 minutes, in a fluency rate of 150J/cm2. Two years of follow-up showed 96% cure for group 1 and 87% for patients treated by protocol 2. No significant difference was observed between the two protocols. However, the number of patients who completed the two-year follow- up is still low and we expect better conclusions with more patients followed.
INTRODUCTION
Cervical cancer is squamous cell carcinoma often caused by Human papillomavirus (HPV) infection and has been the fourth-most common type of cancer and cause of death in women (1). The high-grade intraepithelial neoplasia (CIN) precedes cervical carcinoma and its major cause has been the persistent infection by HPV, and the vast majority of cervical cancer cases are caused by persistent or chronic HPV infection (2). Aminolevulinc acid (ALA) and methyl aminolevulinate (MAL) mediated photodynamic therapy (PDT) has showed be promising treatments for HPV-related diseases, such as condyloma acuminate and high grade CIN (3) (4) (5). AIMS
We conducted a clinical trial designed to evaluate the efficacy and safety of photodynamic therapy (PDT) using a CerCa 150 System® available for the application of intra-canal fiber or no in patients with high grade cervical intraepithelial neoplasia.
METHODS
Patient Enrollment
The present study was approved by the Ethics Human Medical Ethics Committee (CEP 827.010, April 2013 CAAE: 90629218.8.0000.5383) and all patients provided informed written consent to participate. Patients with confirmed diagnosis of cervical intraepithelial neoplasia (CIN) grades 2/3 by histopathology were selected and invited to participate in this study. Thirty-seven patients were treated between April 2016 and October 2018 and monitored for two years. The patient inclusion was random and decided by the clinicians involved in the research, depending on the type of the transformation area and the lesion site: PDT LED ectocervix (1 or 2 session); PDT LED + LASER endocervix group (1 or2 sessions).
All cases (n=37)
Withdraw (1 patient HIV+)
PDT ectocervix (1 or 2 session) (n=21) PDT endocervix (1 or 2 sessions) (n=15)
PDT (1 session)
HPV Colpo Cyto Pap test 1st session | 60 days 1
7 days 1 2nd session LEEP HPV Cyto Follow-up of 24 months Colpo Pap test
PDT (2 sessions)
(a)
Figure (a) Patient selection and study design. PDT: Photodynamic therapy; Cito: oncotic cervical cytology; Colpo: colposcopy;LEEP: loop electrosurgical excision procedure, Pap test: Papanicolau test.
Photodynamic Therapy
When patients were treated two times, the interval between sessions was a week. The methyl aminolevulinic acid (MAL) 20% cream (PDTPharma, Cravinhos, Sao Paulo, Brazil) was administered by the patient in the cervix by 10 hours (overnight). For illumination, the patient in the gynecological position was treated by the equipment CerCa 150 System® (MMOptics, Sao Carlos, Sao Paulo, Brazil). This device has LEDs (light-emitting diodes) emitting at 630 nm and can be anatomically positioned to illumine the entire ectocervix and also a cylindrical light diffuser (MedLight S.A., model RD30) for homogenous light distribution to the endocervical canal. The illumination was performed by delivering 120 mW/cm2 for 21 minutes and fluency rate of 150 J/cm2. Two months after one or two procedures, a conservative Excision of Transformation Zone (ETZ) is performed for histopathological analysis. The viral load test (digene® HC2 HPV DNA, Qiagen) was carried out in two moments: a) before the treatment and b) 60 days after LEEP.
RESULTS
The average age was 38,52±9,79 years to women treated with LED and 33,06±8,84 years to women treated with LED+LASER. LED was applied to 21 women (11 women received one session and 10 women received two sessions) and LED+LASER was applied to 15 women (5 women received one session and 10 women received two sessions).
60 days after treatment, the PDT performed on the ectocervix, LED, showed 52% of positive results in the cytological exams and 19% in the LEEP product. On the other hand, women treated intracanal, LED+LASER, had a 40% positive overall response in cytological exams and 13% in histopathological analysis.
The decrease in viral load, analyzed 60 days after one or two sessions of PDT, showed exactly the same percentage of decrease, comparing the two protocols. No protocol showed complete elimination of the viral load. This result generates an important discussion because this test, despite being recommended and the gold standard, may present flaws that dependon factors such as sample collection and storage.
Table 1: Summary of results from patients treated with photodynamic therapy (PDT) for cervical intraepithelial neoplasia(CIN) 2/3.
LED
Results General Response of PDT (%) Total
Positive Negative
60 days follow up Cytology 52 48 100
Pathology of LEEP 19 71 100
2 years follow up
96 4 (recurrence) 100
LED+LASER
Results General Response of PDT (%) Total
Positive Negative
60 days follow up Cytology 40 60 100
Pathology of LEEP 13 87 100
2 years follow up 86.66 13.33 (recurrence) 100
Considering all lesions with positive responses to PDT with follow-up of two years, there were 96% positive responses (n=20) with PDT in patients treated for LED and 4% recurrences (n=1). The intracanal LED+LASER treatments showed 86.66% (n=13) of positive response and 13.33% of lesion recurrence (n=2). CONCLUSION
This retrospective study was postponed due to the coronavirus (Covid-19) pandemic. We concluded that just illuminating the cervix from the outside (ectocervix) with LEDs promoted a higher cure rate than the protocol that associates LED lighting with LASER (ecto + endocervix). We also concluded that the follow-up of this type of treatment should always belong-term (two years at least). DISCLOSURES IF REQUIRED: The authors declare no conflict of interest. Acknowledgments
This research was funded by Funda^ao de Amparo á Pesquisa do Estado de Sao Paulo (FAPESP 2013/07276-1 and 2014/50857-8), Financiadora de Estudos e Projetos/Ministério da Saúde (FINEP/MS 01.130430.00) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 465360/2014-9).
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