Efficacy and safety of 5-aminolevulinic acid-mediated photodynamic therapy versus loop electrosurgical excision procedure for cervical high-grade squamous intraepithelial lesions: a prospective non-randomized controlled clinical study

Abstract Background Excisional procedures represent the standard of care for cervical high-grade squamous intraepithelial lesions (HSIL), but they may affect the integrity of the cervix and fertility. This prospective, non-randomized controlled clinical study evaluated the efficacy and safety of 5-aminolevulinic acid-mediated photodynamic therapy (5-ALA PDT) compared with the loop electrosurgical excision procedure (LEEP) and explored the associated immunomodulatory changes in the local cervical microenvironment. Methods Between June 2023 and December 2024, a total of 123 women with cervical HSIL were enrolled. Based on patient preference, 63 participants received 5-ALA PDT and 60 participants underwent LEEP. Follow-up assessments were performed at 3 and 6 months. Cervical cytokine profiling was conducted at both time points, whereas standardized clinical efficacy evaluation, including cytology, HR-HPV DNA testing, HPV E6/E7 mRNA detection, colposcopy, and histopathological assessment, was performed at the 6-month endpoint. Adverse events were graded using CTCAE version 5.0. Firth penalized logistic regression, adjusted marginal absolute risk differences, and generalized estimating equations were used. Results At 6 months, complete histopathological remission was 87.3% after 5-ALA PDT and 95.0% after LEEP ( P = 0.135); HR-HPV clearance was 74.6% and 86.7% ( P = 0.092). After adjustment, LEEP showed higher odds of complete remission (adjusted OR = 18.619, 95% CI 1.573–220.412; P = 0.020), with substantial imprecision; the marginal ARD was 21.9% points (95% bootstrap CI 7.0–35.7). The treatment association for HR-HPV clearance was non-significant (adjusted OR = 3.406, 95% CI 0.778–14.914; P = 0.104; marginal ARD = 16.5% points, 95% bootstrap CI − 2.3 to 36.3). HPV16/18 positivity was associated with lower clearance odds. Seven cytokines showed significant group-by-time interactions after FDR correction, but none was associated with HR-HPV clearance. Neither group had CTCAE Grade ≥ 3 adverse events. Conclusions 5-ALA PDT showed promising short-term histopathological and virological activity in selected patients, and both had favorable short-term safety. LEEP was associated with higher adjusted odds of complete remission, but HR-HPV clearance did not differ significantly. Given non-randomization, baseline imbalance, no prespecified non-inferiority margin, and 6-month follow-up, equivalence or non-inferiority cannot be concluded. Cytokine findings were exploratory. Larger randomized trials should assess longer-term durability, recurrence, reproductive outcomes, and cytokine findings. Trial registration Chinese Clinical Trial Registry, ChiCTR2300071897. The Registration Date: Registered on 29 May 2023.