One more opportunity in early-stage cervical cancer: the role of photodynamic therapy in managing positive surgical margins

Abstract

Objective

To evaluate recurrence of squamous intraepithelial lesions (SILs) and human papillomavirus (HPV) infection after photodynamic therapy (PDT) in patients with early-stage cervical cancer (CC) and positive surgical margins.

Methods

We retrospectively analyzed 46 patients aged 25 to 52 years with stage IA–IB invasive CC treated with PDT. Chlorin e6-based photosensitizers were used to irradiate both the cervical canal and surface with standardized doses. Patients were stratified by residual tumor status (R_1-2 vs. R₀/SIL⁺). Outcomes were assessed by HPV testing, cytology and pelvic magnetic resonance imaging. The primary endpoint was relapse-free survival (RFS) with complete response (CR) defined by HPV negativity and absence of cytological or radiological abnormalities.

Results

At 12 months, all patients achieved CR with complete HPV clearance and no residual lesions. At 48 months, overall RFS rate was 74.0% (95% confidence interval [CI]=49.5–87.9). SILs recurrence occurred in 3.7% of patients. Outcomes were slightly better in the R_1–2 group than in the R₀/SIL⁺ group without significant differences. Four patients (8.7%) subsequently had vaginal deliveries. In multivariable analysis, older age was associated with higher relapse risk (hazard ratio [HR]=1.27; 95% CI=1–1.6; p=0.047) as was a greater number of lifetime sexual partners (HR=1.08; 95% CI=1.01–1.15; p=0.019).

Conclusion

PDT demonstrates promising efficacy as a minimally invasive, fertility-preserving treatment for early-stage CC with positive surgical margins. The high rate of HPV eradication and durable RFS support its evaluation as an adjunct or alternative to repeat surgery in selected patients.

Synopsis

This study presented a novel strategy of early-stage cervical cancer (CC) with positive margins after surgery. Photodynamic therapy might be used as a primary fertility-preserving treatment of the early-stage invasive CC.

INTRODUCTION

Cervical cancer (CC) remains a major global health problem and is the fourth most common malignancy among women worldwide, with an incidence that continues to rise despite advancements in prevention and treatment [1]. Alarmingly, CC also ranks fourth in mortality among female cancers globally, underscoring its devastating impact on women’s health [1]. Persistent infection with high-risk human papillomavirus (HPV) types, such as HPV16 and HPV18, is the primary cause of CC, accounting for approximately 70% of cases worldwide [2]. HPV infection drives the progression of squamous intraepithelial lesions (SILs) by integrating viral DNA into the host genome, disrupting cell cycle regulation through the action of viral oncoproteins E6 and E7 [3]. These oncoproteins inhibit tumor suppressors such as p53 and Rb, leading to uncontrolled cellular proliferation and accumulation of genetic damage [4,5].

The burden of HPV-associated cervical lesions highlights the need for effective strategies not only to prevent infection but also to manage pre-cancerous and cancerous conditions. In response, the World Health Organization launched a global strategy to eliminate CC as a public health problem [6]. This ambitious initiative emphasizes 3 key targets: vaccination against HPV, effective screening programs, and ensuring timely and effective treatment for women diagnosed with CC or pre-cancerous lesions. Current international guidelines, such as those of the National Comprehensive Cancer Network (NCCN) and European Society of Gynaecological Oncology (ESGO), recommend surgical management as the primary treatment modality for early-stage invasive CC [7]. Standard approaches include conization, simple or radical trachelectomy and hysterectomy depending on stage, tumor size and fertility preservation goals. For women with positive surgical margins after conization or loop electrosurgical excision procedure (LEEP) the prevailing recommendations is either repeat excision or more radical surgery. However, these conventional strategies have limitations. Positive surgical margins are associated with higher recurrence risk largely due to persistent HPV infection and residual dysplastic epithelium [8,9]. Repeat surgery can compromise cervical integrity leading to obstetric complications such as cervical insufficiency or preterm birth [10]. Consequently, there is a clinical need for less invasive, fertility-preserving alternatives that can effectively eradicate both neoplastic tissue and persistent HPV.

Among the emerging treatment modalities, photodynamic therapy (PDT) is a minimally invasive, targeted treatment that uses a photosensitizing agent (PS) activated by light of specific wavelength to generate reactive oxygen species including selective destruction of dysplastic and malignant cells [11,12,13]. In gynecologic oncology, PDT has demonstrated potential for treating HPV-associated cervical intraepithelial neoplasia (CIN) [14,15,16] and early-stage CC [17,18] with reported high rates of complete response (CR) and HPV eradication [19]. Unlike conventional excisional procedures, PDT preserve the structural integrity of the cervix and may reduce obstetric risks making it an attractive option for women desiring future fertility.

Additionally, PDT enhances the immunogenicity of treated lesions by exposing tumor antigens, which may stimulate an anti-tumor immune response and reduce the likelihood of lesion progression or recurrence [20,21,22,23]. These effects make PDT an attractive option for addressing both the oncogenic and viral components of HPV-associated diseases.

Despite these promising attributes, PDT is not currently included in NCCN or ESGO treatment algorithms for early-stage CC. It is role remains undefined due to the limited number of prospective studies and lack of direct comparisons with standard surgical interventions. Therefore, real-world clinical data are needed to better define its efficacy, safety and potential integration into multidisciplinary treatment pathways.

The present study aimed to evaluate the recurrence of SILs and HPV infection after PDT in patients with early-stage CC and positive surgical margins.

MATERIALS AND METHODS

We analyzed all patient data on age, oncological and gynecological anamnesis, vaccination status, clinical manifestation year, diagnosis year, visualization data, cytological and histological investigations, tumor characteristics and previous treatment characteristics.

1. Study population

Forty-six consecutive patients aged 25–52 years old with early-stage (IA–B) invasive CC were included in the retrospective cohort study (Fig. 1). All eligible patients treated with PDT at Moscow medical centers and clinics between 2015–2023 were screened for inclusion and no patients were excluded based on HPV subtype, viral load or prior therapy.

Fig. 1. Flowchart of study design.

CR, complete response; HPV, human papillomavirus; MRI, magnetic resonance imaging; NILM, negative for intraepithelial lesions or malignancy; PDT, photodynamic therapy; PR, partial response; R, residual; SIL, squamous intraepithelial lesion.

The inclusion criteria for the study were: 1) Age ≥18 years; 2) Histologically confirmed invasive CC; 3) Histological types: squamous cell carcinoma (SCC), adenocarcinoma (AC) or adenosquamous cell carcinoma (ASC); 4) Residual tumor (R_1-2) or SILs after incisional or cone biopsy; 5) Surgical margins ≤2 mm after surgical treatment (LEEP or cold knife conization [CKC]); 6) Availability of standardized follow-up period >12 months (pelvic magnetic resonance imaging [MRI] with contrast; HPV testing and cytological exam); and 7) Signed informed consent for PDT and for use of clinical data in research.

The exclusion criteria for the study were: 1) Stage >IB3 invasive CC; 2) Radiologic evidence (pelvic computed tomography or MRI) of non-localized tumor (N⁺ and/or M⁺); 3) Age <18 years or postmenopausal status; 4) Eastern Cooperative Oncology Group performance status ≥3; 5) Follow-up <12 months or missing baseline investigations (pelvic MRI, HPV testing or cytological exam); and 6) Lack of early treatment response: patients who showed no evidence of regression on cytology/MRI at 3 months after PDT were excluded from the final analysis as the primary endpoint was relapse-free survival (RFS) among responders.

2. PDT protocol

PDT was performed following the completion of the menstrual cycle [24]. The PDT protocol consisted of 3 main steps. The first step involved the intravenous administration of PS based on Chlorin E6 over 30 minutes. The PS dose ranged between 1–1.2 mg per kg of body weight. Patients adhered to a post-injection dark mode for 24–48 hours to allow for PS excretion from the body, minimizing exposure to light during this period. PS accumulation in neoplastic tissues and elimination from healthy tissues occurred within 3 hours. The second step was fluorescence diagnostics (Fig. 2C). This step involved assessing PS accumulation and mapping the neoplastic area by LED radiation source (LLC “Polironik”, Moscow, Russia) emitting in the 400 nm range combined with a yellow optical filter which installed on a videocolposcope (Kernel KN-2200A-HD; Kernel Medical Equipment Co., Ltd., Jiangsu, China). A yellow filter was placed in the light path to remove 400 nm light and transmit red wavelengths, thereby enabling the red fluorescence indicative of PS distribution in the target tissue. In the third step target irradiation of the cervical canal (Fig. 2A) and the vaginal portion of the cervix (Fig. 2B) was conducted. The photoirradiation time (T, minutes) was calculated based on established formula (Formula 1). The areas of the cervical canal and cervical surface were determined using Formulas 2 and 3. The target photoirradiation doses (Es) were 334 J/cm² for the cervical canal and 290 J/cm² for the cervical surface. A flexible cylindrical diffuser with 4 cm long working section (l) and 0,1 cm radius (r) was utilized for photoirradiation of the cervical canal. Photoirradiation power (P) is 1 W. The cervical surface was photoirradiated using macrolenses or microlenses for external photoirradiation. The procedure was conducted remotely and perpendicularly to the target area. Diameter of irradiation pole was 2.5 cm (d). P was 1.7 W and delivered 290 J/cm² of Es. We performed the PS photobleaching control immediate after PDT (Fig. 2D).

Fig. 2. PDT procedure and fluorescence assessment. The target irradiation of the cervical canal (A) and the vaginal portion of the cervix (B). Fluorescence diagnostics before treatment (C) and photosensitizer photobleaching control after PDT (D).

PDT, photodynamic therapy.

$$T=\frac{Es\times S}{60\times P}$$  (Formula 1)

where Es is photoirradiation dose (J/cm²), P is photoirradiation power (W), and S is photoirradiation square (cm²).

$$S_{cc}=6.28\times r\times l$$  (Formula 2)

where r is diffuser radius (working section) and l is diffuser length (cm).

$$S_{cs}=0.785\times d^2$$  (Formula 3)

where d is diameter of photoirradiation pole.

Power density control was conducted using the PDI-01 laser irradiation indictor (LLC «Alcom Medica», Saint Petersburg, Russia). The «LAKHTA-MILON» 662–2 laser apparatus generates light at a wavelength of 662 nm to activate PS. The pre- and post-procedure dark mode protocol included wearing sunglasses, limiting the use of phones and tablets, setting device screens to minimal brightness and maintaining room lighting levels below 50 lux. Additionally, patients are advised to apply sunscreen with a sun protection factor of 50 when necessary.

3. Response criteria

We estimated the CR and partial response (PR) after PDT. CR was HPV negative, negative for intraepithelial lesions or malignancy (NILM) by liquid-based cytology and no signs of tumor by pelvic MRI with contrast. PR was estimated as NILM by liquid-based cytology and no signs of tumor by pelvic MRI with contrast, but HPV positive.

4. Statistical analysis

Quantitative variables were assessed for normality using the Shapiro-Wilk test. Quantitative variables following a normal distribution were described using mean, standard deviations, and the 95% confidence interval (95% CI). Quantitative variables that are not normally distributed were described using median and interquartile range (first quartile to third quartile). Categorical data were described with absolute (n) and relative frequencies (%). The 95% CI for proportions were calculated using the Clopper-Pearson method. The estimation of patient survival function was conducted using the Kaplan-Meier method. Survival curves were compared using the log-rank test. The resulting test statistic follows an approximate χ² distribution with one degree of freedom. Differences were considered statistically significant at p<0.05.

5. Ethical statement

The study was approved by the local ethical committee of the I.M. Sechenov First Moscow State Medical University (protocol Nº15-21/01.09.2021). The trial will be conducted according to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with Good Clinical Practice standards. Informed consent was signed by each patient for PDT and using their data to prepare research articles.

RESULTS

Forty-six patients (mean age 37.7±5.9 years) with early-stage invasive cervical carcinoma were treated by PDT. A single PDT session was administered in 29 patients (63.1%), 2 sessions in 15 patients (32.6%) and 3 sessions in 2 patients (4.3%). The cohort was predominantly composed of HPV16-associated squamous cell carcinomas with indeterminate differentiation. Approximately half of the patients had previously undergone treatment for cervical dysplasia (low-grade SIL/CIN1 or high-grade SIL/CIN2-3). Detailed clinical and demographic characteristics are presented in Table 1.

Table 1. Characteristics of patients with early-stage invasive cervical cancer and comparison R₀/SIL⁺ versus R_1-2 .

Characteristics		Total patients (n=46)	R0 (<2 mm)/SILs+ (n=20, 43.5%)	R1-2 (n=26, 56.5%)	p-value
Age (yr)		37.7±5.9	39.4±5.5	36.5±6	0.100
Depth of stromal invasion (mm)		2 [1–3]	2 [1–2]	2 [1–4]	0.290
Horizontal spread (mm)		4 [3–6]	3 [2.5–5]	4 [3–6]	0.110
Number of sexual partners		5 [3–10]	5 [4–10]	5 [2–10]	0.460
Main HPV type, viral load (lg/105 cells)		5.4 [4.8–5.9]	5.4 [4.2–5.55]	5.5 [5.45–6.15]	0.400
Pregnancy		37 (80.4)	20 (100.0)	17 (65.4)	0.010
Childbirth		32 (69.6)	17 (85.0)	15 (57.7)	0.170
Acetowhite epithelium		40 (87.0)	17 (85.0)	23 (88.5)	1.000
HPV infection (>6 mo)		12 (26.1)	5 (25.0)	7 (26.9)	1.000
Genital condylomas		11 (23.9)	6 (30.0)	5 (19.2)	0.490
HPV infected					0.035
	Monoinfection	22 (47.8)	14 (70.0)	8 (30.8)
	Polyinfection	7 (15.2)	3 (15.0)	4 (15.4)
	No detected	3 (6.5)	1 (5.0)	2 (7.7)
	Unknown	14 (30.4)	2 (10.0)	12 (46.2)
Main HPV type		(n=29)	(n=17)	(n=12)	0.170
	HPV16	21 (72.4)	14 (82.4)	7 (58.3)
	HPV18	5 (17.2)	1 (5.9)	4 (33.3)
	HPV31	1 (3.4)	0 (0.0)	1 (8.3)
	HPV45	1 (3.4)	1 (5.9)	0 (0.0)
	HPV52	1 (3.4)	1 (5.9)	0 (0.0)
Tumor stage					0.080
	cT1	3 (6.5)	0 (0.0)	3 (11.5)
	pT1a	37 (80.4)	19 (95.0)	18 (69.2)
	pT1b	6 (13.0)	1 (5.0)	5 (19.2)
Morphological type					0.090
	SCC	38 (82.6)	18 (90.0)	20 (76.9)
	AC	5 (10.9)	0 (0.0)	5 (19.2)
	ASC	3 (6.5)	2 (10.0)	1 (3.8)
Grade of tumor differentiation					0.520
	G1	12 (26.1)	7 (35.0)	5 (19.2)
	G2	8 (17.4)	4 (20.0)	4 (15.4)
	G3	2 (4.3)	1 (5.0)	1 (3.8)
	Gx	24 (52.2)	8 (40.0)	16 (61.5)

Values are presented as mean ± standard deviation, median [interquartile range, first quartile to third quartile], or number (%).

AC, adenocarcinoma; ASC, adenosquamous carcinoma; HPV, human papillomavirus; PDT, photodynamic therapy; SCC, squamous cell carcinoma; SIL, squamous intraepithelial lesion.

1. CR and PR in cohort

At 12 months following cervical PDT the entire cohort achieved a CR and defined by confirmation of HPV elimination and absence of atypical cells. Median RFS was not reached for either the CR or PR (Fig. 3A). By 30 months of follow-up, the cumulative incidence of SIL recurrence was 3.7%. The probability of sustaining a CR remained at 100% through 15 months post-PDT, after which RFS declined from 97.8% (95% CI=85.3–99.7) at 15 months to 74.0% (95% CI=49.5–87.9) at 48 months. Notably, 4 patients (8.7%) subsequently delivered vaginally following PDT.

Fig. 3. RFS analysis. (A) CR and PR in cohort. (B) CR in patients with R_1-2 and R₀/SIL⁺. (C) PR in patients with R_1-2 and R₀/SIL⁺.

CR, complete response; PR, partial response; R, residual; RFS, relapse-free survival; SIL, squamous intraepithelial lesion.

2. CR and PR in R_1-2 and R₀/SIL⁺ patients

Patients with the residual-tumor group (R_1-2) or the R₀/SIL⁺ group had no statistically significant differences in baseline characteristics (Table 1). In the RFS probability analysis for patients with CR neither the residual-tumor group (R_1-2) nor the R₀/SIL⁺ group reached median RFS (Fig. 3B). At 12 months of follow-up, a CR was observed both in patients who had previously undergone conservative surgical treatment (LEEP or CKC) and in those treated with primary-tumor PDT. In the R₀/SIL⁺ cohort, the risk of recurrence was 6.2% (95% CI=0.9–36.8) at 15 months, rising to 39.7% (95% CI=13.0–84.2) by 48 months. In the residual-tumor (R_1-2) cohort, recurrence risk was 4.3% (95% CI=0.6–27.1) at 18 months and 15% (95% CI=5.1–39.8) at 33 months. No statistically significant difference in RFS between primary-tumor and residual-change treatments was detected by the log-rank test (χ²=1.06; p=0.300).

In the RFS analysis among patients achieving a PR neither the residual-tumor cohort (R_1-2) nor the R₀/SIL⁺ cohort reached median RFS (Fig. 3C). By 12 months of follow-up, CRs were observed both in patients who had previously undergone conservative surgical treatment (LEEP or CKC) and in those receiving primary-tumor PDT. No SIL recurrences were recorded in the R₀/SIL⁺ cohort. In the residual-tumor (R_1-2) cohort, the cumulative recurrence risk was 5.3% (95% CI=0.9–35) at 30 months. Log-rank testing revealed no significant difference in RFS between primary-tumor PDT and treatment of residual changes (χ²=0.59; p=0.440).

3. Multivariate Cox regression analysis

To further delineate prognostic factors associated with RFS following PDT, a Cox proportional hazards regression analysis was undertaken. In the full model with forced entry of all covariates (Table 2), no individual factor demonstrated a statistically significant association with RFS (likelihood ratio test, p=0.638). However, the stepwise selection model (Table 3) based on Akaike Information Criterion yielded a statistically significant improvement in model fit (likelihood ratio test, p=0.026). Within this model, patient age and number of sexual partners emerged as independent predictors of reduced RFS. Advanced age was associated with an increased risk of relapse (hazard ratio [HR]=1.27; 95% CI=1–1.6; p=0.047). Similarly, a higher number of lifetime sexual partners was independently correlated with poorer outcomes (HR=1.08; 95% CI=1.01–1.15; p=0.019). The presence of HPV16 or HPV18 infection exhibited a trend toward higher HRs (HPV16: HR=4.79; 95% CI=0.43–52.96; p=0.202 and HPV18: HR=2.04; 95% CI=0.17–24.16; p=0.572, respectively), although these findings did not reach statistical significance.

Table 2. Cox proportional hazards regression analysis in the full model with forced entry of all covariates.

Factors	Unadjusted		Adjusted
	HR (95% CI)	p-value	HR (95% CI)	p-value
Age	1.16 (1.00–1.35)	0.048*	1.07 (0.94–1.22)	0.290
R0/SIL+	1.87 (0.31–11.21)	0.493	1.33 (0.3–5.96)	0.710
Histological type: ASC	N/A	N/A	0.69 (0.03–17.05)	0.820
Histological type: AC	N/A	N/A	0.62 (0.05–7.97)	0.710
Histological type: SCC	N/A	N/A	1.63 (0.19–13.68)	0.650
Depth of stromal invasion	0.91 (0.55–1.50)	0.720	1.08 (0.73–1.62)	0.690
Horizontal spread	0.72 (0.46–1.15)	0.170	0.94 (0.70–1.26)	0.680
Positive family history of cancer	0.67 (0.11–4.13)	0.660	0.61 (0.13–2.82)	0.520
Age of sexual life onset	0.47 (0.26–0.88)	0.018*	0.89 (0.62–1.28)	0.530
Number of sexual partners	1.09 (1.03–1.17)	0.005*	1.06 (0.98–1.13)	0.140
Multiple HPV	4.09 (0.68–24.71)	0.130	3.39 (0.47–24.56)	0.230
Single HPV	0.44 (0.07–2.81)	0.390	1.00 (0.21–4.68)	1.000
HPV16+	0.81 (0.12–5.28)	0.830	0.92 (0.19–4.48)	0.920
HPV18+	1.16 (0.13–10.65)	0.890	0.80 (0.11–5.95)	0.830

AC, adenocarcinoma; ASC, adenosquamous carcinoma; CI, confidential interval; HPV, human papillomavirus; HR, hazard ratio; N/A, not applicable; SCC, squamous cell carcinoma.

^*p<0.05.

Table 3. Cox proportional hazards regression analysis in the model with stepwise selection.

Factors	Unadjusted		Adjusted
	HR (95% CI)	p-value	HR (95% CI)	p-value
HPV16+	1.2 (0.21–6.94)	0.840	4.79 (0.43–52.96)	0.200
HPV18+	0.94 (0.11–8.20)	0.960	2.04 (0.17–24.16)	0.570
Number of sexual partners	1.07 (1.02–1.13)	0.008*	1.08 (1.01–1.15)	0.019*
Age	1.17 (1.02–1.34)	0.025*	1.27 (1.00–1.60)	0.047*

CI, confidential interval; HPV, human papillomavirus; HR, hazard ratio.

^*p<0.05.

DISCUSSION

The management of early-stage CC remains a clinical challenge where the balance between oncological safety and fertility preservation is critical. This is important particularly in patients with positive surgical margins. The standard treatment options for early-stage (stages I–IIA) CC are simple or radical hysterectomy with lymph node dissection [7]. Conization or simple trachelectomy are considered the gold standard treatment of for early-stage CC as fertility-preserve option [7,25]. Jorgensen et al. [26] demonstrated no statistical differences between standard surgery and fertility-sparing surgery for early-stage CC in a large 5-year life expectancy. Tamauchi et al. [27] reported a 6% of CC recurrence rate in 67 patients after radical trachelectomy. The main disadvantage of these studies is treatment response estimation by absence of visual tumor. Caruso et al. [28] demonstrated a high 5-year RFS (93.5%) after radical surgery. This excellent result was archived by exclusion patients with high risk factors from analysis. Despite on high effectiveness of surgical treatments [29] many studies demonstrated high frequency of SILs relapse [30,31]. The main factors of disease relapse are HPV persistence and positive margin after surgical treatment [30,31,32,33]. Authors indicate that 40% of relapses after conization are due to HPV persistence. Generally, it occurs in 18 months [34].

In this context, PDT provides a non-invasive alternative that may complement or substitute surgical management in selected cases. One of the first mentioned of PDT in oncogynecology was in Italy in 1995 [35]. They are treated a locoregional recurrences of cervical-endometrial cancers with 66.7%–70.6% of CR. The next study was performed in 1999 (Japan) [36]. The main reason to perform a PDT was fertility-preserve (85% of cases). Authors described a 96.9% of CR after PDT of non-invasive CC. Kim et al. [37] presented results of high effectiveness (CR, 97.1%) of PDT HSIL/CIN3 for a positive resection margin after 1 year. HPV eradication rate was 96.9% after 6 months following PDT. The present study aimed to demonstrate the PDT effectiveness of treatment primary early-stage CC and residual neoplastic changes after surgical treatment in 5-year RFS probability. The better result of PDT was achieved in PR (more than 90%) for both study groups and 100% at 12 months post-PDT. This demonstrates that PDT based on chlorin e6 is highly effective to remove SILs or residual tumors. HPV eradication following PDT was higher than with surgical treatment, as demonstrated in studies with 12-month follow-up by Liu et al. [38], showing rates between 76.5% and 78.6%, and with 6-month follow-up by Song et al. [39], showing a rate of 82.1%. We demonstrated a 74% of HPV relapse-free probability at 48th month after PDT. The fertility outcomes, our cohort included 4 women who subsequently achieved successful vaginal deliveries following PDT. Although encouraging, this number is too small to permit firm conclusions regarding reproductive safety. Therefore, these findings should be interpreted as preliminary observations, consistent with prior reports describing high CR rates and preservation of fertility after PDT in young women with cervical neoplasia [40].

Additionally, our findings offer preliminary support for the reproductive safety of PDT. Four patients successfully delivered vaginally post-treatment, consistent with earlier reports, who observed high CR rates and maintained fertility following PDT in young women with cervical neoplasia [17,36,40]. These observations reinforce PDT’s potential as a fertility-preserving strategy—an increasingly relevant consideration in the era of personalized gynecologic oncology.

Despite the favorable outcomes, several limitations of this study should be acknowledged. First, the retrospective design and the moderate sample size restrict the strength of causal inferences. Second, although all consecutive eligible patients treated at Moscow medical centers and clinics during the study period were screened potential selection bias cannot be fully excluded. Women motivated to preserve fertility may have been more likely to accept PDT and patients who failed to demonstrate early regression within three months were excluded from the final analysis. These factors may have enriched the study population with individuals having more favorable prognostic profiles. Third, the absence of a matched control group limits the ability to control for confounders such as HPV subtype, viral load, prior therapies or patient age. Finally, the follow-up period, although sufficient to assess medium-term outcomes, may not fully capture late recurrences or delayed HPV reactivation. The inclusion of prospective, randomized controlled trials with longer surveillance windows and immunological profiling will be necessary to confirm these findings and elucidate predictors of long-term success.

In conclusion, the data presented herein suggest that PDT is an effective, well-tolerated, and fertility-sparing treatment option for early-stage CC with positive margins. Its dual capacity to eliminate both neoplastic and viral components makes it particularly suited for managing HPV-driven disease. Future research should focus on optimizing treatment parameters, evaluating synergy with immunotherapeutic strategies, and incorporating PDT into evidence-based clinical guidelines for comprehensive CC care.