Progress and challenges in photodynamic therapy for cervical lesions in China

Cervical cancer is the fourth most common malignancy among Chinese women, with approximately 150 700 new cases and 55 700 deaths reported in 2022, accounting for about 22.7% and 16% of the global incidence and mortality rates, respectively.1 Persistent high-risk human papillomavirus (HR-HPV) infection drives the progression of cervical intraepithelial neoplasia (CIN), with 20%–30% of CIN grade 2 (CIN2) or worse cases progressing to invasive carcinoma without intervention.2 Traditional treatments of CIN like loop electrosurgical excision (LEEP) and conisation, while effective, carry risks of cervical stenosis, abortion and preterm birth.3 4 Photodynamic therapy (PDT), a minimally invasive modality that has emerged as a fertility-preserving alternative for cervical low-grade squamous intraepithelial lesion (LSIL) and selected high-grade squamous intraepithelial lesion (HSIL/CIN2). This editorial synthesises current evidence and challenges in PDT’s clinical translation, proposing strategies to bridge the gap between research and practice.

PDT is a unique combined pharmaceutical and instrumental technique, comprising two steps: local or systemic administration of a photosensitiser (the pharmaceutical component) and illumination with a specific light source (the instrumental component). Based on the interaction between the photosensitiser, light and oxygen, PDT uses photodynamic reactions for both disease diagnosis and treatment. In China, 5-aminolevulinic acid (5-ALA) is primarily used as the local photosensitiser for this purpose. ALA is a hydrophilic precursor in heme synthesis that lacks intrinsic photosensitising activity. When administered exogenously, it is selectively absorbed by proliferating cells and converted into protoporphyrin IX. Due to enhanced porphobilinogen deaminase activity and reduced ferrochelatase activity in these cells, protoporphyrin IX accumulates. Upon illumination with specific wavelengths of light, protoporphyrin IX becomes activated, absorbing light energy and transferring it to surrounding oxygen molecules to generate reactive oxygen species such as singlet oxygen and oxygen radicals. This process achieves the goal of eliminating the lesion through the killing of diseased cells, eradication of pathogenic microorganisms, microvascular damage and immune activation.5

ALA-PDT has demonstrated excellent performance in the treatment of CIN, effectively addressing the lesions while fulfilling patients' desires to preserve cervical tissue structure. Clinical studies report that the histological remission rate of ALA-PDT for cervical LSIL (CIN1) ranges from 75% to 96.08% within 3–24 months, with a recurrence rate of 0%–8.9% within 6–12 months.6–8 Compared with carbon dioxide (CO₂) laser therapy, ALA-PDT has more advantages in reducing recurrence and HPV reinfection.6 Based on statistics from several related clinical studies, the histological remission rate of ALA-PDT for cervical HSIL (CIN2/3) ranges from 82.5% to 98.9% in 12 months after treatment, which is comparable to other physical treatments.3 9–11 ALA-PDT is more effective than cryotherapy in the treatment of CIN2 and has a lower incidence of adverse reactions.12 13

In 2022, for the first time globally, a panel of 27 authoritative gynaecological and obstetrical experts from China released the ‘Expert Consensus on the Clinical Application of Aminolevulinic Acid Photodynamic Therapy in Female Lower Genital Tract Diseases,’ available both in Chinese and English.14 This consensus highlights that ALA-PDT has minimal impact on cervical structure, function, pregnancy and childbirth, making it one of the optional methods for women who have fertility requirements or wish to preserve cervical structure and function. It recommends ALA-PDT for the treatment of histological LSIL/CIN 1 or histological HSIL/CIN 2, provided that at least the squamocolumnar junction of the cervix is fully visible under colposcopy and the upper margin of the lesion is visible.

Many published clinical studies have not only confirmed the efficacy of ALA-PDT for CIN but also further explored factors that may affect treatment outcomes. Adverse factors include persistent HR-HPV infection, multiple HPV infections, sleep disorders, advanced age, and smoking.3 These findings suggest that individualised treatment strategies should be developed for different patient populations.

Despite its therapeutic promise, ALA-PDT continues to confront numerous challenges. Although most CIN typically extend to a depth of approximately 2–3 mm, PDT encounters limitations in patients with lesion depths exceeding 3 mm. To address this issue, advancements in light delivery systems are imperative, including the adoption of interstitial light sources and the creation of more potent photosensitisers. Recent research on photosensitisers has concentrated on refining their photophysical properties and therapeutic outcomes through sophisticated molecular design strategies. These innovations can optimise the delivery and activation of photosensitisers, ultimately enhancing the effectiveness of PDT in treating cervical lesions.15 To further address the limitations of PDT penetration depth, researchers are exploring combination therapies, such as integrating ALA-PDT with CO₂ laser treatment. A single CO₂ laser session prior to ALA-PDT can create controlled tissue ablation up to a depth of 4 mm, allowing deeper lesion coverage and enhancing photosensitiser penetration.16 This strategy improves lesion clearance rates and overcomes the depth limitations of ALA-PDT while minimising laser-associated side effects.

In addition to technical challenges, the high cost of PDT remains a major barrier to widespread adoption, particularly in China. The price of 5-ALA, the key photosensitiser used in PDT, is significantly higher than that of conventional treatments such as CO₂ laser therapy and LEEP. Moreover, unlike these traditional methods, which are covered by national medical insurance, ALA-PDT is not reimbursed, making it financially burdensome for patients. This economic limitation severely restricts the large-scale implementation of PDT in clinical practice.

Additionally, the development of low-cost, portable PDT devices is a critical area of research, particularly in resource-limited environments. These devices, often driven by batteries and equipped with LED technology, offer a cost-effective PDT solution for regions lacking adequate medical infrastructure. Preclinical studies have demonstrated their efficacy to be comparable to that of standard laser sources, underscoring their potential for wider application in global health initiatives.17 Appropriate popular science publicity should be carried out to enhance the awareness and acceptance of PDT among patients and healthcare providers.

Despite these challenges, PDT presents encouraging avenues for research and clinical application. For instance, the exploration of combining PDT with other treatment modalities, such as chemotherapy and immunotherapy, aims to bolster its efficacy and counteract resistance mechanisms.18 19 This integration of PDT with other therapeutic approaches may yield synergistic advantages. Recent research has found that photodynamic therapy can regulate CXCR3 and PD-1 to promote CD8+ T cell immune mechanisms, suggesting that photodynamic therapy may emerge as a novel antitumor treatment strategy for inducing T cell immunity in the future.20 21 Presently, clinical trials are underway to investigate the use of PDT in conjunction with immune checkpoint inhibitors in urological cancers.22 Basic and clinical research is conducive to expanding the clinical application indications of PDT beyond CIN.

In summary, PDT in China presents a promising and minimally invasive alternative to conventional treatments for cervical lesions (table 1). Despite recent studies validating its efficacy, PDT still encounters certain challenges. However, with ongoing research and technological breakthroughs, PDT holds the potential to emerge as a pivotal treatment in the management of cervical diseases, offering women an effective and less invasive therapeutic alternative.