Evaluation Of Efficacy And Safety Of Topical Photodynamic Therapy In CINⅡ

Background and ObjectiveCervical cancer is one of the most common malignant tumors in gynecology.High-grade intraepithelial neoplasia of the cervix(HSIL,CIN2/CIN3)is a precancerous lesion of cervical cancer.Human papillomavirus(HR-HPV)infection has been confirmed to be an important factor in the development of cervical cancer,HPV can be detected in 70%of cervical intraepithelial neoplasia(CIN)tissue,it can inactivate p53 and pRb proteins through E6 and E7 proteins,resulting in the proliferation of cervical epithelial cells.With the prevalence of HPV infection,the detection rate of cervical precancerous lesions in young women has increased greatly,and more and more patients with precancerous lesions have fertility requirements.Current treatments for high-grade intraepithelial neoplasia include Loop electrosurgical excision procedure.Cold Knife Conization,and laser conization,with a cure rate of 90 to 98%.However,these treatments also increase the risk of pregnancy-related complications(including cervical insufficiency,premature rupture of membranes,and preterm delivery).Therapies that are effective and preserve fertility for CINⅡ/Ⅲ in the cervix are urgently needed.Photodynamic therapy(PDT)is a highly selective minimally invasive treatment technology,which uses a specific photosensitizer to selectively concentrate on the tissues with abnormal growth and active hyperplasia.With the participation of light source and oxygen,the target tissues are affected and destroyed to exert the therapeutic effect.Compared with traditional treatment methods,PDT has the advantages of less trauma,low toxicity,high selectivity,wide application range and less resistance to drugs.Multiple studies have shown that PDT is effective in treating CIN and clearing HPV infection,and can preserve organ integrity,providing hope for CIN patients who have fertility requirements.Studies have shown that systematic application of photosensitizers has a higher efficiency,but a higher incidence of photosensitization.Local administration can avoid systemic side effects.Aminolevulinic acid(ALA),a second generation photosensitizer,is activated by conversion to protoporphyrin Ⅸ and can be metabolized in rapidly growing cells within 1-2 days to avoid long-term skin photosensitivity.Topical application of 5-ALA PDT has been reported in a wide range of cutaneous malignancies.Topical application of 5-ALA treatment cervical CIN less research and has been controversial.We noticed that some of the studies in the past for photodynamic therapy in the treatment of CINⅡ can demonstrate the effectiveness and security of photodynamic therapy for CINⅡ,to a certain extent.But PDT need long treatment cycle,CINⅡ natural outcome rate is higher,especially in patients under the age of 25 years fading rate can reach more than 60%.So good treatment effect attributed to PDT or attributed to CINⅡ natural outcome remains to be consideration.2019 ASCCP guidelines adopted conservative hierarchical management for CINⅡ,CINⅡunder 25 years old preferred observation.But CINⅡ which continued for more than 2 years recommended treatment,because of lower rates of regression and higher rates of progression,In order to more accurately explore the curative effect of photodynamic therapy for CINⅡ in younger patients,we choose CINⅡ which followed up for 2 years and still did not get regression in patients under 25 years old.This study will explore from the following three aspects:1.To observe the clinical efficacy and safety of 5-ALA-PDT for CINⅡ and high-risk HPV infection.2.Screening the influencing factors of the treatment effect of CINⅡ with topical 5-AlA-PDT.3.To preliminarily explore the efficacy and feasibility of combined photodynamic therapy and surgery for refractory patients.Materials and MethodsThe subjects of this study were 50 patients who were young and worried about the potential impact of treatment on future fertility in the early stage and were selected for observation after full communication.After 2 years of follow-up,no regression was obtained.All patients were treated in the First Affiliated Hospital of Zhengzhou University from September 2018 to September 2019.Collects all patients with clinical data,including:age,HPV testing.results of parting,liquid based cytology test(TCT),treatment and prognosis,and so on.According to the treatment methods,they were divided into PDT group(25 cases)and operation group(25 cases).PDT group:5-ALA-PDT,all patients were placed in the lithotomy position,and the vagina and cervix were cleaned with sterile saline.All patients were evaluated by colposcopy prior to each treatment.Then the freshly prepared 20%ALA thermal gel(Shanghai Fudan Zhangjiang Biomedical Co.,Ltd.)soaked on thin cotton cloth was applied to the cervical mucosa and cervical canal for 3 h.The patient’s cervix was irradiated directly with 635nm red light,with an energy density of 100 J/cm2,and the cervical canal was irradiated with a 3 cm long cylindrical optical fiber inserted into the cervical canal.The irradiation time is 30 minutes.They were treated every 10 days until the lesions disappeared completely under colposcope.In the operation group,LEEP or CKC were used.The efficacy and safety of the two groups were compared and analyzed.Medical data were recorded for CINⅡ patients treated with PDT,including age at diagnosis,high-risk HPV type,glandular involvement,associated intracervical lesions,transformed area,atypical vessels,and lesion area.Univariate and multivariate regression analyses were used to screen for risk factors affecting the treatment outcome of PDT.All patients with residual lesions after PDT or surgical monotherapy were tried to use the combined therapy to observe the efficacy and safety of the combined therapy.Results1 General conditions of the patientsA total of 50 patients with cervical CINⅡ lasting more than 2 years were included in this study,including 25 patients in the PDT group and 25 patients in the surgery group.The age range is 19-25,the mean age of patients in the ALA-PDT group was(22.12±0.84)years old,and the mean age of patients in the surgical resection group was(22.23±1.03)years old.The pre-treatment HR-HPV infection rate in the PDT group was 98%(24/25),including 18 cases of HPV16/18 infection,16 cases of unitary HPV infection,and 8 cases of multiple HPV infection.Before treatment,the infection rate of high-risk HPV in the surgery group was 100%,including 17 cases of HPV 16/18 type infection,15 cases of unitary type HPV infection,and 10 cases of multi-type HPV infection.There were no significant differences in the age of patients,the infection rate of high-risk HPV before treatment,and the distribution of HPV subtypes between the two groups(P>0.05).2 Therapeutic effectThe mean frequency of treatment in PDT group was(6.12±0.223),ranging from 2 to 10 times,and the average duration of treatment was 64 days.Twenty-one patients achieved complete remission,with a complete remission rate of 84%.In the 4 patients who did not achieve complete remission,LEEP or CKC was then performed to achieve complete remission.Complete response was achieved in 23 patients in the surgical resection group,with a complete response rate of 92%.Two patients with incomplete response(including 1 positive surgical margin and 1 residual lesion)received PDT and achieved complete response.In this study,there was no progression or recurrence in all patients during follow-up.The HPV clearance rate was 62.5%(15/24)in the PDT group and 72%(18/25)in the surgery group at the follow-up 3 months after surgery.There was no significant difference in the complete response rate and HPV clearance rate between the two treatments.3 Factors influencing the effectUnivariate analysis and multivariate analysis showed that the atypical vascular,type III transformation zone,the lesion area larger than 37mm2,intracervical involvement was an independent factor affecting the efficacy of PDT on CINⅡ.4 Adverse reactions and Reproductive OutcomesNo systemic adverse reactions were reported during or after PDT treatment.The most common reported event was mild self-limiting local discomfort,with increased vaginal discharge in 6 patients,intermittent lower abdominal distention in 1 patient,and vaginal burning in 2 patients,all of which were mild and relieved spontaneously after 3-5 days without special treatment.No bleeding,infection,cervical stenosis and other serious complications;Most of the patients showed increased vaginal secretions after surgery,most of which were relieved after 1 month without special treatment.Severe complications included postoperative bleeding and second hospitalization in 1 case,infection and high fever in 1 case,and cervical canal stenosis combined with dysmenorrhea in 1 case.During the follow-up period,4 women in the PDT group became pregnant after treatment and all had a healthy full-term delivery,while 5 women in the surgical resection group became pregnant,1 had spontaneous abortion,1 had premature delivery,and 3 had a healthy full-term delivery.Conclusion1 The efficacy of ALA-PDT in the treatment of CINⅡ in patients under 25 years old was significant,and there was no significant difference compared with the surgical resection group.2 Atypical blood vessels,type Ⅲ transformation zone,lesion area larger than 37mm2,and cervical canal involvement are the influencing factors for the effect of photodynamic therapy.Patients with these factors are recommended for surgical treatment.3 Patients with refractory CINⅡ who need to preserve fertility can try PDT combined with surgery.