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The placebo group was administered a vitamin tablet (Centrum) orally, once a day

The experimental group 1 was administered BH4 orally, with a dose of 2mg/kg.d (If the drug dose is within the range of 51-150mg, the drug dose will be 100mg), once per day

The experimental group 2 was administered BH4 orally, with a dose of 5 mg/kg.d (If the drug dose is within the range of 151-250mg, the drug dose will be 200mg, two times a day; If the drug dose is within the range of 251-350mg, the drug dose will be 300mg, three times a day)

The experimental group1 was administered BH4 orally with a dose of 2 mg/kg.d, once per day, and the experimental group 2 was administered BH4 orally witha dose of 5 mg/kg.d, two times a day (If the drug dose is within the range of 151-250mg, the drug dose is 200mg) or three times a day (If the drug dose is within the range of 251-350mg, the drug dose is 300mg). The oral administration of pills was started on the same day of the first radiation treatment, and ended three months after the treatment ended.

Tetrahydrobiopterin

Rutie YIN, Dr

Kemin LI, Dr

Shuyu ZHANG, Dr

This present study envisaged a single-center, prospective, open-label, placebo and randomized controlled phase II clinical study to assess the efficacy and Safety of Tetrahydrobiopterin in Treating Radiation Enteritis in Gynecological Cancer Patients.

Radiotherapy is one of the most effective treatments for pelvic malignancies. About 35\~61% of the patients with pelvic cancer receive pelvic radiotherapy. Although radiotherapy significantly prolongs the survival time of the patients, it induces an injury to the normal tissues that may damage the pelvic and abdominal organs, with rectal damage as the most common and persistent adverse effect. Radiation proctitis refers to the rectal damage as a result of radiotherapy for the treatment of pelvic cancer such as cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, rectal cancer, and bladder cancer. According to the time of onset and changing course of the disease, it can be divided into acute radiation-induced proctitis (ARP) and chronic radiation-induced proctitis (CRP), usually taking three months as a threshold. More than 75% of the patients receiving pelvic radiotherapy develop ARP, and 5%-20% of the patients develop CRP. In fact, the incidence of CRP is highly likely to be underestimated, since not every patient with symptoms goes for a clinical intervention. Studies have shown that 81% of the patients receiving pelvic radiotherapy developed gastrointestinal symptoms, but only 55% consulted the healthcare professionals. Approximately 90 % of the CRP patients exhibited permanent bowel habit changes, and 50% of the patients developed various gastrointestinal symptoms affecting their quality of life. Radiation enteritis seriously affects the treatment process of the patients, worsens the prognosis, and impairs the quality of life. The current common treatments for radiation enteritis are psychological intervention, anti-inflammatory drugs, antibiotics, probiotics to rebalance the gut microbiome, antioxidants, antidiarrheal agents, and surgical treatment, if necessary. However, the overall treatment effect does not yield satisfactory results. It is particularly important to find safe and effective preventive and treatment measures for the radiation enteritis to improve the prognosis of patients, and improve the quality of life.

Free radicals produced by the indirect action of ionizing radiation are considered to be one of the main causes of radiation enteritis. Tetrahydrobiopterin (BH4), also known as Sapropterin, is an important cofactor of the nitric oxide synthase (NOS) enzyme. Under normal physiological conditions, guanosine triphosphate cyclohydrolase 1 (GCH1) is the key enzyme for the synthesis of BH4. Reduction in GCH1 activity lowers the production of BH4, causes NOS uncoupling, and leads to an elevated level of oxygen free radicals (reactive oxygen species, ROS). Studies have shown that GCH1 over expression can restore BH4 level and NO products in irradiated skin cells, reverse and inhibit the NOS uncoupling caused by ionizing radiation, thereby eliminating the ionizing radiation-induced ROS, reducing DNA damage, and postponing the cell apoptosis and cell aging. In animal experiments, BH4 administration significantly reduced the occurrence of acute radiation enteritis.

This present study envisaged a single-center, prospective, open-label, placebo and randomized controlled phase II clinical study. The research subjects included the patients, who received radical radiotherapy and chemotherapy, and patients who needed supplementary radiotherapy due to prognostic risk factors for treating pathologically diagnosed gynecological malignancies (including cervical cancer, endometrial cancer, and vulvar cancer), with no pathological type restrictions.

The enrolled cases were randomly divided into three groups ina ratio of 1:1:1. The placebo group was administered a vitamin tablet (Centrum) orally, once a day. The two experimental groups were administered BH4 orally, with a dose of 100 mg, once per day, and a dose of 100 mg, three times a day (morning, noon, and evening). The oral administration of pills was started on the same day of the first radiation treatment, and ended three months after the treatment ended. The degree of injury of the radiation enteritis among the patients was evaluated weekly after the treatment started. It was evaluated one month and three months after the end of treatment, once per three months for two years and once per six months between 2\~5 years after the treatment ended. The degree of ARP and CRP was evaluated according to the radiation morbidity scoring criteria of the Radiation Therapy Oncology Group (RTOG).

Intensity-modulated radiation therapy (IMRT) was adopted, using the conventional split mode,(1.8\~2.0) Gy/day, 5 times/week.The pelvic clinical target volume (CTV) was(45\~50.4)Gy/25\~28 times, and the boost for local lymph nodes metastasis was raised to (60\~70) Gy. Patients with indications for brachytherapy were treated with brachytherapy following the International Commission on Radiation Units \& Measurements (ICRU) Report No. 89. The radical therapy treated or postoperative high-risk patients receiveda concurrent radiotherapy and chemotherapy, usingunrestricted chemotherapy regimen.

A Study for Assessing the Efficacy and Safety of BH4 in Radiation Enteritis

Clinical Professor

Until the end of treatment, The quality of life assessment was performed using QLQ-C30 and QLQ-CX24, before treatment and at 3, 6, 9, and 12 months after treatment. results from multiple questionnaires will be reported.

Follow-up until the patient dies or withdraws from the study

evaluated every week (according to RTOG radiation morbidity scoring criteria)

according to RTOG radiation morbidity scoring criteria

Until the end of treatment, The objective tumor response rate is used as the evaluation standard, which is divided into CR, PR, SD and PD

West China Second University Hospital

Skin and Connective Tissue Diseases

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Wounds and Injuries

Rare Diseases

Dermatitis

Vulvar Neoplasms

Radiodermatitis

Skin Diseases

Radiation Injuries

Vulvar Cancer

A sterile gauze was soaked with BH4 solvent (50 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (100 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (200 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (400 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (600 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (800 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (1000 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

BH4 was applied when skin damage≥ Grade I occurred. A sterile gauze was soaked with BH4 solvent, wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

This study was a single-center prospective phase I clinical study to evaluate the effectiveness and safety of BH4 in the treatment of radiation-induced skin injury during vulvar cancer radiotherapy.

Vulvar Cancer is a type of rare gynecological malignant tumor, accounting to2\~5% of all the female reproductive system malignancies, and mostly occurs in the postmenopausal women. The incidence of vulva cancer is on the rise, especially in the elderly women, with age 75 years and above. It may be related to non-neoplastic epithelial lesions such as lichen sclerosus of the vulva and atypical hyperplasia of the epithelial cells caused by advanced age.

Radiotherapy plays a key role in the treatment of vulvar cancer. High risk factors for postoperative recurrence include positive surgical margin, adjacent surgical margin (\<8 mm), lymphovascular space invasion (LVSI), lymph node metastasis (especially more than two metastatic nodes), and extracapsular invasion of lymph nodes. Patients with high risk factors for postoperative recurrence can benefit from radiotherapy. Radical radiotherapy and chemotherapy could be provided to patients with unresectable locally advanced tumors, including part of stage II (tumor diameter\> 4 cm or tumor invading vagina, urethra, and anus), and to early-stage patients with possible serious postoperative complications or serious complications that do not allow surgery as an option. Due to the dampness of the vulva and the poor tolerance of the skin and mucous membranes to radiation, most patients with vulvar cancer have severe skin damage during radiotherapy, significantly affecting their treatment process, worsening their prognosis, and impairing their quality of life. Seeking safe and effective prevention and treatment measures for radiation-induced skin injury is particularly important to improve the prognosis of patients and improve their quality of life.

Free radicals generated by the indirect action of ionizing radiation on skin cells are considered to be the primary cause of radiation skin injury. Tetrahydrobiopterin (BH4), also known as Sapropterin, is an important cofactor of the nitric oxide synthase (NOS) enzyme. Under normal physiological conditions, guanosine triphosphate cyclohydrolase 1 (GCH1) is the key enzyme for the synthesis of BH4. Reduced GCH1 activity lowers the production of BH4, causing NOS uncoupling, thereby leading to a raised level of oxygen free radicals (reactive oxygen species, ROS). Studies have shown that GCH1 overexpression restores the BH4 level and NO products in irradiated skin cells, reversed and inhibited the NOS uncoupling caused by ionizing radiation, thereby eliminating the ROS induced by ionizing radiation, reducing DNA damage, and postponing the cell apoptosis and cell aging. In animal experiments, direct injection of BH4 under the skin did not only reduce the degree of acute radiation skin injury, but also promoted the repair of the skin damage, lowered the occurrence of radiation-induced skin fibrosis, and maintained the normal physiological functions of the skin.

This study was a single-center prospective phase I clinical study. The phase I clinical trial included 21 patients. Given satisfactory results, the cases appropriate for the study of drug concentration were expanded to 25, with a total of 45 subjects included eventually. The subjects of the study were pathologically diagnosed vulvar cancer patients, who needed postoperative supplemental radiotherapy, patients who received radical radiotherapy and chemotherapy (unresectable locally advanced tumors, including some stage II with tumor diameter \> 4 cm or tumor invading vagina, urethra, and anus), and early-stage patients with possible serious postoperative complications or serious complications, wherein the option of undergoing a surgery was not appropriate.

Intensity-modulated radiation therapy (IMRT) was employed, using the conventional split mode, (1.8\~2.0) Gy/day, 5 times/week. The vulva and pelvic clinical target volume (CTV) was (45\~50) Gy/25 times. The boost applied for primary visible lesions and metastaticlocal lymph nodes was (60\~70) Gy. The techniques for boost regarding residual tumor and tumor bed area were determined based on the tumor location and the radiation dose limit of the surrounding organs. The electron beam vertical irradiation was applied for tumors located superficially. For residual tumors good for brachytherapy, techniques such as near-distance post-implantation were adopted to give a radiation boost. The specific dose and type of the radiation was determined according to the tumor location, size, treatment response, acute side effects, and whether chemotherapy was accompanied or not. For late-stage, metastatic vulvar cancer patients and those received radical chemotherapy and radiotherapy, systemic chemotherapy was provided, with unrestricted chemotherapy regimens.

The degree of the skin injury during the radiotherapy was assessed according to the radiation morbidity scoring criteria of the Radiation Therapy Oncology Group (RTOG). After the start of radiotherapy, the degree of the damage to the patient's skin was assessed every week. BH4 was applied when skin damage≥ Grade I occurred. A sterile gauze was soaked with BH4 solvent, wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

BH4 gradient: 50, 100, 200, 400, 600, 800, and 1,000 ug/ml.

The degree of the skin injury during the radiotherapy was assessedaccording to the radiation morbidity scoring criteria of the Radiation Therapy Oncology Group (RTOG).After the start of radiotherapy, the degree of the damage to the patient's skin was assessed every week. BH4 was applied when skin damage≥ Grade I occurred. A sterile gauze was soaked with BH4 solvent, wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

BH4 gradient: 50, 100, 200, 400, 600, 800, and 1,000 ug/ml.

A Study for Assessing the Efficacy and Safety of Tetrahydrobiopterin in Radiation-Induced Skin Injury

Follow-up until the death of the patient or withdraw from the clinical study

incidence that was evaluated every week (according to RTOG radiation morbidity scoring criteria)

It was evaluated one month and three months after the end of treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study for Assessing the Efficacy and Safety of BH4 in Radiation Enteritis	NCT05138887	Radiation Enter...	Tetrahydrobiopt...	18 Years -	West China Second University Hospital
A Study for Assessing the Efficacy and Safety of Tetrahydrobiopterin in Radiation-Induced Skin Injury	NCT05114226	Radiation-Induc...	Tetrahydrobiopt...	18 Years -	West China Second University Hospital

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