Chinese expert consensus on the hematoporphyrin derivative (HpD) photodynamic therapy in cervical high-grade squamous intraepithelial lesion (2025)

Photosensitisers

Photosensitisers, which are key agents in PDT, can be categorised into several types, including porphyrins, chlorins, bacteriochlorins and phthalocyanines. Internationally recognised anticancer photosensitisers include Photofrin, Photolon, Photogem, Foscan and Photosense, and so on. In China, there are currently four types of photosensitisers available on the market: hematoporphyrin derivative (HpD; trade name: HiPorfin) injection is the only systemic photosensitiser that has undergone formal clinical trials and received approval for oncological indications from the Chinese State Food and Drug Administration (SFDA),15 while other foreign systemic photosensitisers have not yet been approved in China. According to the drug instructions, it is used for treating precancerous lesions, malignant tumours and nevus flammeus; aminolevulinic acid hydrochloride topical powder, used for treating condyloma acuminatum; verteporfin powder for injection, prescribed for wet age-related macular degeneration; Hemoporfin for injection, also used for treating nevus flammeus. Additionally, photosensitisers such as Suftalan zinc and hematoporphyrin ether ester are currently undergoing clinical trials in China. This consensus serves as a clinical guideline for the use of HpD as a photosensitiser in the PDT of cervical HSIL.

Comparison of HpD-PDT and other systemic PDT

Huang et al16 treated 30 cases of CIN I-II with HpD-PDT (3 mg/kg), achieving a cure rate of 90% and an HPV eradication rate of 64.3% at 3 months after PDT. One patient (1/30, 3.3%) experienced moderate skin phototoxicity, characterised by heat and swelling on the face and hands, which was resolved with treatment using an oral antihistamine. Another patient (1/30, 3.3%) had severe skin phototoxicity, presenting with blisters on the face and hands, and was treated with both an oral antihistamine and steroids. Moderate pigmentation developed following the skin phototoxicity but resolved within 6 months. Park et al17 reported on 19 patients with cervical HSIL and 3 patients with early-stage invasive cervical carcinoma treated with Photofrin-PDT, resulting in complete response rates of 91% for HSIL and 67% for early-stage invasive cervical cancer. No significant photosensitiser-related side effects were observed in any of the cases after PDT. Istomin et al18 applied Photolon-PDT to 112 patients with cervical HSIL, observing a complete response rate of 92.8% and an HPV eradication rate of 53.4% at 3 months after PDT. Mild skin phototoxicity was observed only on the first day following the Photolon injection. Choi et al19 treated 59 patients with CIN II and III using Photogem-PDT, noting a complete remission rate of 98.1% at a 1-year follow-up and HPV eradication rates of 89.8% and 87.0% at 3 and 12 months, respectively. Among 29 patients who planned to get pregnant, 18 patients achieved 25 pregnancies, including 6 abortion, 1 ectopic pregnancy, 1 preterm pregnancy, 15 term pregnancies and 2 ongoing pregnancies. No fetal loss occurred due to cervical incompetence. Toxicity was predominantly mild cutaneous photosensitivity, with grade 1–2 photosensitivity observed in seven patients, all of whom recovered within 2 weeks without any treatment. One patient experienced grade 3 photosensitivity, which improved shortly after receiving steroids and antihistamines. In a study by the same team,11 21 patients with stage IA–IIA cervical cancer underwent LEEP/cold-knife conization combined with Photogem-PDT. During a follow-up period ranging from 6 to 114 months, only one patient experienced a relapse (4.7 %), and there were no deaths. In thirteen patients who wished to become pregnant, 10 achieved 11 pregnancies, which included 1 ectopic pregnancy, 2 early abortions, 1 late abortion and 7 pregnancies that reached the third trimester. No PDT-related photosensitivity was observed in any of the patients. Gilyadova et al20 treated 45 cases of cervical HSIL with chlorine E6-PDT and 49 cases with conization. The complete regression rates were 86.7% for the chlorine E6-PDT group and 67.3% for the conization group after 6 weeks of treatment. After 12 months, the HPV negative conversion rates were 100.0% in the PDT group and 67.3% in the conization group. In one case in the PDT group, a delayed-type allergic reaction was observed, which was alleviated by intravenous infusion of dexamethasone. Patients were advised to use ultraviolet A (UVA)/ultraviolet B (UVB) sun protection factor (SPF) 50 for 14 days following PDT. Lee et al21 administered Photogem-PDT therapy to 22 patients with cervical HSIL and performed conization on 25 patients, finding cure rates of 95.5% for the PDT group and 100.0% for the conization group. One patient developed photosensitivity due to inadequate light avoidance for 4–5 weeks and was treated with steroids and antihistamines. Liu et al22 23 used PDT with Hiporfin on 41 patients with cervical HSIL (CIN II: 22, CIN III: 19). The median follow-up time was 23 months. The photosensitiser dose is 2 mg/kg. The irradiation dose in the cervical canal was 100–120 J/cm², while the dose on the cervical surface was 150 J/cm². Complete response rates for CIN II were 95.5% and 100% at 6-month and 12-month follow-up, respectively. Meanwhile, the complete response rate was 78.9% and 84.2% in the CIN III group, respectively, at 6 months and 12 months. All cervical canal lesions were completely resolved without any cervical adhesions. The HPV eradication rates were 73.2% at 6 months and 92.7% at 12 months after PDT, with no recurrences observed during the long-term follow-up period. Four patients who planned to get pregnant all delivered at term, with prenatal examinations showing no abnormalities, and the children’s physical growth showed no significant issues. Eight patients (8/41, 19.5%) experienced mild photoallergic symptoms, including mild oedema and a burning sensation in the exposed areas, due to a lack of sunblock education. After receiving guidance, the allergic symptoms resolved with loratadine and ice within 7–10 days. Mild lower abdominal pain was reported in six patients (6/41, 14.6%) during PDT, and in three patients (3/41, 7.3%) after PDT.

This team24 recently conducted a retrospective analysis of 104 women diagnosed with cervical HSIL. With 1:1 matched case–control, 52 cases (CIN II: 32, CIN III: 20) received Hiporfin-PDT, and 52 cases (CIN II: 32, CIN III: 20) underwent LEEP. PDT group received Hiporfin (2 mg/kg) intravenously and a diode laser at a wavelength of 630 nm. The complete response rates post-PDT at 3–6 months,10–12 months and 24 months were 98.1%, 100.0% and 100.0%, respectively, compared with 98.1%, 100.0% and 100.0% patients after LEEP. HPV clearance rates after PDT at 3–6 months, 10–12 months and 24 months were 76.9%, 88.9% and 95.5%, respectively, compared with 69.2%, 93.5% and 95.8% after LEEP, with no significant difference between the two groups. There were no serious adverse events during or after PDT. Mild photosensitivity was observed in a few patients, and the symptoms improved within 5–7 days with treatment using oral loratadine and ice. Most recently, Liu et al25 conducted a study using PDT with Hiporfin at a dosage of 2 mg/kg on a cohort of 14 patients with HSIL of the cervical canal (CIN II: 9, CIN III: 5). The median follow-up time was 29 months, ranging from 12 to 35 months. Among the participants, 64.3% (9 out of 14) were nulliparous. The treatment achieved a complete response rate of 100% (14 out of 14) for cervical canal involvement at 3–6 months. The HPV eradication rate was 85.7% (12 out of 14) at 12 months. No recurrences were observed during the extended follow-up. Two patients (2/14, 14.3%) developed mild photohypersensitivity symptoms due to inadequate light avoidance, which resolved within 10 days following treatment with loratadine and ice. Mild lower abdominal pain was reported in three patients (3/14, 21.4%) during PDT, and in three patients (3/14, 21.4%) after PDT. Of the six patients who planned to become pregnant, all achieved pregnancies, resulting in one spontaneous abortion, two term pregnancies and three ongoing pregnancies. Importantly, no fetal loss was attributed to cervical incompetence. Qiao et al26 also compared the efficacy of systemic PDT with Hiporfin (1 mg/kg) and LEEP in treating cervical HSIL (CIN II-III) in the Hainan Hospital of the PLA General Hospital, including 31 patients in the systemic PDT group and 31 patients in the LEEP group. Both the systemic PDT and LEEP groups exhibited a complete remission rate of 77.4% at 3–6 months. The HPV clearance rate after systemic PDT was 87.1%, compared with 64.5% after LEEP at 3–6 months, showing a significant difference. Six patients (6/31, 19.4%) in the PDT group experienced mild photosensitivity without drug treatment, and the condition resolved spontaneously within 3–7 days. Three patients (3/31, 9.7%) experienced mild lower abdominal pain during treatment, which subsided after the treatment was suspended. This did not affect subsequent therapy. Additionally, one patient (1/31, 3.2%) developed a fever on the third day after PDT, which was alleviated with oral acetaminophen. One patient (1/31, 3.2%) developed a local bacterial infection at the external os of the cervix due to delayed follow-up. After continuous irrigation with normal saline for 8 days, the infection subsided and no intrauterine infection occurred (table 1). These studies demonstrate that system PDT selectively targets cervical intraepithelial lesions and effectively clears high-risk HPV while preserving the normal structure and function of the cervix. System PDT avoids the side effects associated with cervicectomy.

HpD-PDT compared to topical PDT

PDT using topically applied photosensitisers, such as 5-aminolevulinic acid (5-ALA) and hexaminolevulinate (HAL), does not require sunlight avoidance. Due to the limited permeability of the drugs and the restricted depth of necrosis that can be achieved,18 multiple treatment sessions are often necessary, and it frequently requires combination with carbon dioxide (CO₂) laser therapy.27 Additionally, treatment of the cervical canal has been found to be inadequate.28 29 Chinese experts recommend ALA-PDT for treating HSIL/CIN II, emphasising that the cervical squamocolumnar junction or the upper edge of the lesion should be visible.30 This implies that 5-ALA PDT is not suitable for treating HSIL/CIN III, type 3 cervical transformation zones, or HSIL located in the cervical canal. However, HpD-PDT may compensate for the limitations of ALA-PDT and has been shown to be highly effective in treating HSIL/CIN III, including HSIL located in the cervical canal.22–25 The purpose of comparison is not to diminish one approach while elevating another, but rather to highlight the scope of application for different methods. This helps clinicians make informed decisions and allows patients to make better choices.

It is worth mentioning that HpD-PDT has its limitations. According to the expanded phase III clinical trial report on HpD, PDT was used to treat and diagnose 428 malignant tumours and 69 precancerous benign cases. It was recommended that patients avoided direct exposure to fluorescent lamps and took protective measures against light when going out for at least 1 month. The report recommended that patients should take antilight precautions when going outside for at least 1 month. In eight cases, failure to adhere to these light avoidance guidelines resulted in skin photosensitivity reactions, including redness, swelling and itching in the exposed areas (face and hands). These symptoms subsided after several days of symptomatic treatment. Patients should practice ultraviolet (UV) protection for the first 1 month following treatment.14 31 32 It is recommended that the patient undergo a light sensitivity test. The patient’s hand should be placed in a paper bag with a 2 cm diameter hole and exposed to sunlight for 10 min. If swelling, redness or blisters develop within 24 hours, the patient should continue to avoid light until retesting is performed 2 weeks later. If no reaction occurs within 24 hours, the patient can gradually resume exposure to sunlight.31 32 However, the patient’s indoor activities, such as using a telephone or computer, are not affected.22–25 33 34 The suggested dose is 5 mg/kg. However, this dosage results in prolonged metabolism time, requiring patients to avoid light exposure for an extended period. Inadequate light protection can lead to photosensitivity reactions and more severe symptoms. Long-term results of endoscopic retrograde cholangiopancreatography (ERCP)-directed or percutaneous transhepatic cholangioscopy (PTCS)-directed PDT for unresectable hilar cholangiocarcinoma and Chinese expert consensuses on respiratory tumours and oesophageal cancer indicate that a dosage of 2 mg/kg does not compromise the therapeutic effect and can significantly reduce the severity of adverse reactions. This conclusion is supported by the dosage used in foreign photosensitisers and our domestic preliminary clinical studies.22–25 31–35 Patients typically need to stay in the hospital for 3–4 days. Outpatient treatment is also available if the hospital has the necessary facilities.

Relevant experts from the Tumor Photodynamic Therapy Committee of China Anti-Cancer Association, Laser Medicine Branch of the Chinese Medical Association, Chinese Society for Colposcopy and Cervical Pathology of China Healthy BirthScience Association (CSCCP), Fertility Protection Branch of the Chinese Preventive Medicine Association, Laser Medicine Committee of Chinese Optical Society and Fertility Protection Society of China Anti-Cancer Association collaborated to write this consensus. The draft process involved a comprehensive literature review using databases such as PubMed, Embase, Cochrane Library, China National Knowledge Internet (CNKI) and Wanfang Data, and so on, and based on the latest international research developments, Chinese clinical experience, research findings, ‘Laser Medicine in Clinical Diagnosis and Treatment Guidelines’ and ‘Laser Medicine in Clinical Technical Operation Standard’. After several rounds of discussion and revisions by the expert group, a consensus was reached. This consensus is intended to guide gynaecologists, oncologists, nursing and PDT practitioners at all levels in the clinical application of HpD-PDT for the treatment of cervical HSIL.

Indications

Cervical HSIL: CIN II and CIN III, including HSIL in cervical canal.18 25

The exclusion criteria

(1) Suffering from hematoporphyria and diseases aggravated by light or allergic to porphyrins or to any excipients, (2) menstrual period, pregnancy or lactation period, (3) patients with obvious abnormal liver function, coagulation dysfunction and other serious uncontrolled medical complications, (4) acute inflammatory period and activity period of general infectious disease, (5) antithrombotic or antiplatelet agglutination drugs were being used in high doses, (6) patients suffering from immune system diseases and taking immunosuppressive or regulatory drugs at high doses (such as hormone drugs, which could reduce the efficacy of PDT).31 32

UV protection post-treatment

Immediately after intravenous administration of HpD to 1–2 months after PDT, patients must avoid exposing their skin to direct sunlight. When going outdoors during this period, it is essential to use UV protection. If direct sunlight enters the room, draw the curtains to block it. Protection from indoor lighting is not necessary, and patients may use mobile phones and computers without concern. UV protection is not required outdoors when there is no sunlight present, such as before sunrise, after sunset, at night, excluding cloudy days during the day.

Gradual increase in outdoor activity

After the initial 1–2 months post-treatment, patients can gradually increase the duration of their outdoor activities.

Monitoring individual responses

Since individual responses to light can vary, patients should monitor their reaction to sunlight exposure after the 2-month period. If any abnormal reactions occur, the protective measures should be extended for an additional 1–4 weeks. Should discomfort persist, patients are advised to contact their doctor for further guidance.

Timing of treatment

Schedule the treatment within 2 weeks following the patient’s menstruation. Prior to treatment, conduct a complete blood count, blood HCG, urinalysis, coagulation profile, liver and kidney function tests, vaginal discharge analysis and an ECG (figure 1).

Pre-treatment assessment

Perform a colposcopy to reassess the lesion size, determine the exposure area and develop a corresponding treatment plan.

Skin test for photosensitiser

Conduct a skin test before intravenous injection of the photosensitiser. Dilute the HpD solution to 0.01 mg/mL and administer a 0.1 mL intradermal injection. Observe the injection site after 15–20 min; the absence of redness, swelling and induration indicates skin test negative.32

Photosensitiser injection

Patients with a negative skin test may receive an intravenous injection of the photosensitiser. Administer porphyrin at a dose of 2 mg/kg in 250 mL of normal saline, infused over 1 hour in a light-protected environment.31 32

Laser treatment procedure

Perform laser irradiation 48–72 hours after injection,36 when the concentration difference between diseased tissue and normal tissue is greatest. Monitor the patient’s vital signs closely during treatment. Operators must be trained in photodynamic dosimetry, laser medical device metrology and gynaecological tumour PDT. Medical personnel should also ensure that protective eyewear is worn during treatment. (1) Optical fiber selection: first, use a column fiber to irradiate the cervical canal. Then, use a flat-cut optical fiber to irradiate the cervical surface lesions (figure 2); (2) laser power measurement: calculate the required laser output power based on the power density and treatment area. Connect the fiber to the laser therapy machine and preset the laser output power. Use an integrating sphere power metre for the column fiber and a power metre for the flat-cut optical fiber to measure the laser power at the fiber’s output end; (3) exposure range and dose: if endocervical curettage is positive or the squamocolumnar junction is not fully visible, irradiate the cervical canal with the column fiber first, ensuring the fiber top is more than 1 cm from the internal cervical opening to prevent adhesion. The laser power density in the cervical canal should be 100 mW/cm², with an irradiation time of 900–1200 s, resulting in an energy irradiation density of 90–120 J/cm². After irradiating the cervical canal, use a flat-cut optical fiber to irradiate the cervical vaginal part, extending 0.5 cm beyond the lesion edge. The laser power density should be 100–150 mW/cm², with an irradiation time of 900–1800 s, and an energy irradiation density of 120–240 J/cm² for the cervical surface.

Photosensitivity reaction management

Patients should be aware that during the light avoidance period, exposure to direct sunlight, firelight or other strong light sources can trigger clinical symptoms of a photosensitivity reaction. The initial signs typically include redness, swelling and mild burning pain in the affected skin areas. Some individuals may develop a rash, while severe cases can lead to blisters, peeling and eventual pigmentation changes. If any of these symptoms occur, it is crucial to immediately protect the skin from further light exposure. Apply cold water compresses to the hot, red and swollen areas to alleviate discomfort. Subsequently, patients should avoid direct sunlight for an additional 2 weeks. For rashes, treatment may include oral antihistamines and the application of topical ointments containing corticosteroids. In cases of significant swelling and blistering, which indicate a serious phototoxic reaction, medical intervention is necessary. Treatment may involve intravenous glucocorticoids and oral antihistamines like loratadine. Patients must continue to avoid sunlight exposure.

Others

(1) Pain: patients may experience a dull pain in the lower abdomen, which is generally tolerable and seldom necessitates the use of painkillers, (2) Fever: to prevent chills during the procedure, patients are advised wear long and thick socks to keep warm. It is common for body temperature to range between 37-38℃ for 1-3 days after treatment, which may be due to heat absorption resulting from necrosis of localized pathological tissue following treatment. If body temperature exceeds 38℃ and is accompanied by significant discomfort, measures to reduce fever should be taken. In the event of an infection, appropriate anti-infection treatment is required, (3) Bleeding: although rare, it is important to carefully monitor the time of light exposure and the energy settings. Abstain from sexual activity for one month following the treatment. If bleeding occurs and exceeds the volume of a normal menstrual period, it should be addressed promptly with local pressure or medication to stop the bleeding, (4) Infection: prior to treatment, ensure thorough disinfection. After treatment, maintain personal hygiene by frequently changing sanitary napkins and underwear. If an infection develops, anti-infection treatment is necessary, (5) Cervical or vaginal wall adhesion: topical use of estrogen after PDT in postmenopausal women can promote wound healing and avoid adhesion accordingly.