Attributes underlying patient choice of treatment modality for low-grade squamous intraepithelial lesion complicated by high-risk human papillomavirus infection

Abstract Objective To use logistic regression to analyze the attributes underlying patients’ treatment options for low-grade squamous intraepithelial lesion (LSIL) complicated with high-risk human papillomavirus (HR-HPV) infection, and identify the best benefit group of different treatment options. Methods Clinical data of 197 LSIL patients with HR-HPV infection between June 2009 and February 2022 were collected. According to the treatment options chosen by the patients, they were divided into the interferon, photodynamic therapy, follow-up observation, and focused ultrasound (FUS) treatment groups. One-way analysis of variance (ANOVA) and multivariate logistic regression analysis were used to analyze the influencing factors, including age, occupation, education level, maternity history, reason for encounter, route of consultation, annual personal and household income, screening for related risk factors, and identifying the best benefit group of different treatment options. Results One-way ANOVA revealed a statistically significant difference in age, education level, maternity history, reason for encounter, and annual household income (p < 0.05). Multivariate logistic regression analysis was performed on these five factors, indicating that age ≤35 years, high school educational level or higher, and no childbirth history were independent risk factors influencing patients’ choices of FUS treatment. The receiver operating characteristic curve was used to determine the age threshold of 31 years. Conclusion Age, educational level, and maternity history were independent risk factors influencing patients’ choice of treatment modality for LSIL complicated with HR-HPV infection. Age ≤31 years, high school, equivalent, or higher educational level, and no childbirth yielded a higher rate of choosing FUS treatment for LSIL patients with HR-HPV infection.


Introduction
Cervical cancer is one of the major types of cancer of the female reproductive system that poses a serious health threat to women.According to current studies, the necessary cause of cervical precancerous lesions and cervical cancer is persistent infection with high-risk human papillomavirus (HR-HPV).At present, there are various treatment options for low-grade squamous intraepithelial lesion (LSIL) of the cervix complicated by HR-HPV infection, including interferon therapy, photodynamic therapy (PDT), focused ultrasound (FUS) treatment, and follow-up observation treatment.This study aimed to investigate the classification and distribution of the treatment options for LSIL patients with HR-HPV infection, to evaluate the influencing factors underlying treatment choices in patients, and to provide better insight into the refinement of its clinical protocols.

Study design
In this retrospective study, data were obtained from hospital records of 197 patients diagnosed with LSIL complicated by HR-HPV infection in the routine physical examination or outpatient clinic between June 2009 and February 2022 at the First Affiliated Hospital of Chongqing Medical University.All the patients in this study made decisions regarding their treatment modality without their doctors trying to influence it.All enrolled patients were assigned to four groups according to their treatment options: interferon (n ¼ 57), PDT (n ¼ 36), follow-up observation (n ¼ 57), and FUS (n ¼ 47).
Interferon group: recombinant human interferon a2b cream (2,000,000 IU/branch, Anhui Anke Biotechnology Co., Ltd.); recombinant human interferon a2b vaginal suppository (500,000 IU/piece, Changchun Institution of Biological Products Co., Ltd.); and recombinant human interferon a2b gel (1,000,000 IU/branch, Zhaoke Pharmaceutical Co., Ltd.).The above drugs were used in accordance with the manufacturer's instructions and used for at least one course of treatment.
PDT group: subjects were treated with three sessions of 20% 5-aminolevulinic acid photodynamic therapy at intervals of 7-14 days.First, a sterile cotton soaked with freshly prepared 20% 5-ALA thermogel mix (Fudan Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China) was applied to cover the cervical surface and cervical canal for 3 h.Then, a photodynamic therapeutic instrument (LD600c, Wuhan Yage Optic and Electronic Technique Co., Ltd., Wuhan, China) was used as the light source.An optical fiber was inserted into the cervical canal and a cylindrical head was put into the vagina to cover the cervical surface so that the light irradiation at 632.8 nm with a radiant exposure of 100-150 J/cm 2 can be applied to both the cervical surface and the cervical canal.The treatment was performed 40 min each time for a total of three sessions, once per week, but postponed for one week during menstruation.
FUS group: the focused ultrasound equipment (Model-CZF Focused Ultrasound Therapeutic Device for Gynecology) used for treatment was manufactured by Chongqing Haifu Medical Technology Co, Ltd. (Chongqing, China), with a therapeutic power of 3.5-4.5W, working frequency of 10.0 MHz, and impulse of 1000 Hz.Patients were placed in the lithotomy position and a sterile speculum was used to expose the cervix.The cervix was disinfected and an ultrasound coupling gel was applied before treatment.The treatment probe was placed in close contact with the cervix, and a circular scanning was performed from the lesion area to the normal area.The treatment range was needed to exceed the edge of the lesion by $2 mm.The treatment typically lasted for 3-5 min until the lesion presented as a depressed region with modest introversion of the external cervical aperture.All patients included in the study received one FUS treatment.
Inclusion criteria were as follows: (1) HPV DNA test results showing HR-HPV infection; (2) satisfactory colposcopy findings (satisfactory: cervical squamous columnar junction fully visible) and histopathological examination of the suspicious lesions under colposcopy for the diagnosis of LSIL; (3) patients who can understand and complain of their conditions; (4) informed consent to participate in the cohort study; (5) non-pregnant and non-lactating women of reproductive age; and (6) no acute inflammation of the reproductive tract.
Exclusion criteria were as follows: (1) refusal to participate in the cohort study; (2) comorbidities, consisting of other sexually transmitted diseases; (3) severe lesions in tissues, organs, or body systems; (4) unsatisfactory colposcopy or lesions in the cervical canal; (5) uncontrolled diabetes, hyperthyroidism, or hypothyroidism; and (6) severe hematological, coagulation dysfunction, cardiovascular and cerebrovascular, and immune system diseases.

Data collection
The general clinical data of patients were extracted from the medical records regarding age, occupation, education level, maternity history, reason for encounter, route of consultation, annual personal and household income, treatment options (including interferon therapy, PDT, FUS, and followup observation treatment), HR-HPV types among the patients, time of diagnosis, and treatment efficacy (follow-up).

Statistical analysis
All the data were processed using SPSS version 26.0.Count data were presented as percentages (%), and the v 2 inspections were used for comparative analysis between the groups.Measurement data were expressed as mean ± standard deviation if they followed a normal distribution, and an independent t-test was used for comparative analysis between the groups.One-way analysis of variance (ANOVA) was used to analyze the factors affecting the treatment options chosen by LSIL patients with HR-HPV infection.A multivariate logistic regression model was used to analyze the significant correlations between age, occupation, education level, maternity history, reason for encounter, route of consultation, personal income, household income, and treatment options chosen by the patients.Fisher's exact test was used to analyze treatment efficacy.All statistical tests were two-sided.A p-value <0.05 was considered to be statistically significant, while a p-value <0.01 was considered to be highly statistically significant.

Observed indicators
All the patients were followed up after six months with HPV testing and ThinPrep cytologic test (TCT), and the samplings were performed by a qualified cervical specialist.Colposcopy was performed for patients with TCT results !atypical squamous cells of undetermined significance (ASC-US) with HR-HPV positivity and TCT results !LSIL with or without HR-HPV positivity, and the suspected lesion area was sampled for histopathological examination under colposcopy guidance.Effective was defined as cytological results showing normal or downgraded cervical cells and histological results with no cervical intraepithelial lesions.Effective rate ¼ number of effective cases/total cases Â 100%.The HR-HPV-negative rate of patients was also determined.

One-way ANOVA
One-way ANOVA was used to assess the factors that affected the treatment choice decisions of LSIL patients with HR-HPV infection.The results suggested that age, education level, maternity history, reason for encounter, and annual household income correlated with the patients' choice of treatment modality and statistically significant differences (p < 0.05), as detailed in Table 1.

Multivariate logistic regression analysis
The influencing factors that were statistically significant in the one-way ANOVA were included in the multivariate logistic regression analysis; the assigned values are detailed in Table 2.The results of the multivariate logistic analysis showed that age 35 years, no childbirth, and high school education level or more were independent factors influencing patients' choice of FUS treatment (Table 3).

Analysis of the efficacy for LSIL patients with HR-HPV infection
The analysis of LSIL patients with HR-HPV infection six months after receiving treatment showed that the efficacy of FUS treatment was higher than that of interferon therapy and follow-up observation treatment, and the difference was statistically significant (p < 0.05).The efficacy of FUS treatment was not less than that of PDT, as shown in Table 4.

Current status of treatment choices of patients with LSIL infection lasting two years or more
The current status of treatment of patients with LSIL infection lasting two years or more (95 cases) with follow-up observation (17 cases), and treatment (78 cases) are detailed in Table 5.

Discussion
Cervical cancer is one of the most common malignant tumors in women worldwide.The mortality and incidence rates of cervical cancer are at a high level of female malignant tumors in China with a decreased average onset age, which poses a great health threat to women [1][2][3][4][5][6][7][8][9].Regarding the occurrence and development of cervical cancer, a large number of studies have shown that persistent HPV infection is the main cause, among which HR-HPV invasion is the most significant precipitating factor for cervical cancer [10][11][12][13][14][15][16].Currently, the main treatment options for LSIL complicated by HR-HPV infection are interferon therapy [17,18], PDT [19,20], FUS [21,22], and follow-up observation [23] treatment.However, it is important to clarify the classification and distribution of each treatment decision chosen by patients after diagnosis in clinical settings, and further explore the relevant factors influencing patients' choices of different treatment modalities, which may provide a theoretical basis for optimizing the clinical protocols, relieving the doctorpatient relationship, and improving treatment outcomes.
In this study, we retrospectively analyzed the clinical data of 197 patients with LSIL and HR-HPV infections in our hospital.Our results showed that the treatment options chosen by the patients mainly included interferon therapy, PDT, FUS, and follow-up observation treatment.The patients were divided into interferon therapy, PDT, follow-up observation, and FUS groups, according to the final treatment option, and one-way ANOVA was performed.The results showed statistically significant differences (p < 0.05) in age, educational level, maternity history, reason for encounter, and annual household income.Multivariate logistic regression analysis of these five factors showed that age 35 years, high school education level or higher, and no childbirth were independent risk factors influencing patients' choices for FUS treatment.
In this study, fertility requirement was an important factor influencing the patients' choice of treatment modality.For patients with reproductive requirements, the demands of the disease are not only clinical treatment but also the protection of reproductive function and relief of their psychological burden.In this study, lack of childbirth was an independent risk factor influencing patients' choice of FUS treatment.A possible reason for this is that FUS can completely destroy the lesion tissue while treating subsurface lesions without damaging either the surface tissue or off-target tissue [24][25][26].Focus ultrasound is characterized by precise in vivo localization and energy deposition within the lesion, which can produce thermal, mechanical, and cavitation effects on the lesion, thereby causing immediate coagulative necrosis of the lesion tissue, while keeping the skin intact.For patients with fertility requirements, FUS treatment is recommended because of its low recurrence rate, high curative rate, and minimal trauma to patients after treatment.Most importantly, FUS can avoid the destruction of surrounding normal tissues by first destroying the diseased tissues without scarring, which preserves the physiological shape and elasticity of the cervix and does not affect fertility [21,27].Duan et al. [28] reported that 243 patients who delivered after cervical high-intensity focused ultrasound (HIFU) treatment had no significant differences in preterm delivery, low birth weight, and perinatal mortality compared with those who delivered in the obstetrics department of this hospital during the same period.There was no significant efficacy in cervical HIFU treatment on patients' pregnancy and its outcome.There were no statistical differences in the rates of premature rupture of membranes, preterm delivery, or low-birth-weight infants.Additionally, photodynamic therapy can also achieve good results without affecting fertility.Nonetheless, many patients are more inclined to choose HIFU for two reasons.First, the cost of PDT in Chongqing is currently $20,000-30,000 RMB, while that of HIFU is $2000-4000 RMB, suggesting that HIFU is more cost-effective.Second, PDT requires 2-3 sessions, while HIFU requires only one treatment.However, the health economics of HIFU and PDT requires further investigation.
In this study, educational level was an independent risk factor influencing patients' choice of FUS treatment.Possible reasons are as follows: (1) the level of education is an important reflection of an individual's cognitive ability, awareness of rights, consumption level, and health status [29]; the higher the educational level, the higher the requirements and expectations for the quality of health care (curative rate, treatment environment, doctor-patient communication, etc.), which  directly influences the treatment choices of patients with higher educational level; (2) the degree of education also reflects an individual's awareness and understanding of medical knowledge at a certain level; and the lower the education level, the weaker the reserve of relevant knowledge, the more inclined to the traditional choice of medical modality, and the lack of understanding and acceptance of the new non-invasive treatment technology, such as FUS.
In this study, age 31 years was an independent risk factor influencing the patients' choice of FUS treatment.Possible reasons are as follows: (1) related studies have shown that the average age of first childbearing in China is 26.9 years, the average age of second childbearing is 30.2 years, and the average age of third childbearing and above does not vary significantly [30]; this also directly reflects that the most important reason for patients to choose FUS treatment is 'having childbearing requirements'; (2) with the popularization of national higher educational level, age is also related to the education level.The education level of patients aged 31 years was relatively high, which is also an important reason for their choice of FUS treatment.
In summary, the main treatment options for LSIL complicated by HPV infection are currently interferon therapy, PDT, FUS, and follow-up observation treatment, in which age, education level, and maternal history are independent risk factors affecting patients' choices of different treatment modalities.Overall, when the age is 31 years, the educational level is more than or equal to high school, and there is no childbirth.The rate of choosing FUS treatment for LSIL patients with HR-HPV infection is higher.Patients with LSIL infection lasting !2 years are more likely to receive treatment instead of the follow-up observation recommended by the 2019 ASCCP guidelines, which may be related to the patient's annual personal income.Only by clarifying the classification and distribution of patients' treatment choices after clinical diagnosis and understanding the relevant factors that affect their choices of different treatment options can we improve their physical and mental health and quality of life, relieve the doctor-patient relationship, and increase patients' treatment compliance and treatment efficacy.

Ethical approval
All experimental procedures and protocols were approved by the Medical Research Ethics Committee of Chongqing Medical University and were performed in accordance with the relevant guidelines and regulations.

Figure 1 .
Figure 1.Receiver operating characteristic curve for age.

Table 1 .
One-way ANOVA of attributes underlying patient choice of treatment modality for LSIL complicated with HR-HPV infection.

Table 3 .
Multivariate logistic regression analysis of factors affecting the choices of treatment modality for LSIL complicated with HR-HPV infection.

Table 4 .
Efficacy analysis at six months after treatment in LSIL patients with HR-HPV infection.Values are given as n (%) unless otherwise stated.

Table 5 .
Current status of treatment of patients with LSIL infection lasting two years or more (n ¼ 95).The 2019 American Society for Colposcopy and Cervical Pathology (ASCCP) Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors (hereinafter referred to as the 2019 ASCCP guidelines): Management of LSIL persisting for two years or more: (a) follow-up observation (recommended); (b) treatment (optional).