5-aminolevulinic-acid-hexyl-ester and Uterine-Cervical-Neoplasms

High-risk human papilloma virus (HPV)-associated cervical cancer is the fourth most common cancer in women worldwide. Current treatments of high-grade squamous intraepithelial lesion (HSIL) of the cervix are based on invasive surgical interventions, compromising cervical competence and functionality. APRICITY is a multicentre, prospective, double-blind, randomised controlled phase 3 study further evaluating the efficacy and safety of Cevira, an integrated drug-delivery and light-delivery device for hexaminolevulinate photodynamic therapy, which shows promise as a novel, non-invasive outpatient therapy for women with HSIL.. Patients with biopsy-confirmed HSIL histology are invited to participate in the study planned to be conducted at 47 sites in China and 25 sites in Ukraine, Russia and the European Union. The aim is to include at least 384 patients, which will be randomised to either Cevira or placebo group (2:1). All patients will be assessed 3 months after first treatment and a second treatment will be administered in patients who are HPV positive or have at least low-grade squamous intraepithelial lesion. Primary endpoint is the proportion of the responders 6 months after first treatment. Secondary efficacy and safety endpoints will be assessed at 6 months, and data for secondary performance endpoints of the Cevira device will be collected at 3 months and 6 months, in case second treatment was administered. All patients in the Cevira group will be enrolled in an open, long-term extension study for 6 months to collect additional efficacy and safety data (study extension endpoints).. The study was approved by the ethics committee of the Peking Union Medical College Hospital and Hannover Medical University, Germany. Findings will be disseminated through peer review publications and conference presentations.. NCT04484415; clinicaltrials.gov.

Topics: Aminolevulinic Acid; Carcinoma in Situ; Clinical Trials, Phase III as Topic; Female; Humans; Multicenter Studies as Topic; Papillomavirus Infections; Photochemotherapy; Prospective Studies; Randomized Controlled Trials as Topic; Squamous Intraepithelial Lesions; Uterine Cervical Neoplasms

The objective of the study was to investigate the efficacy and safety of hexaminolevulinate (HAL) photodynamic therapy (PDT), a novel therapy for women with cervical intraepithelial neoplasia (CIN)1/2, to define the appropriate population and endpoints for a phase 3 program.. This was a double-blind, randomized, placebo-controlled, dose-finding study that included a total of 262 women with biopsy-confirmed CIN 1/2 based on local pathology. Patients received 1 or 2 topical treatments of HAL hydrochloride 0.2%, 1%, 5%, and placebo ointment and were evaluated for response after 3-6 months based on biopsy, Papanicolaou test, and oncogenic human papillomavirus (HPV) test. All efficacy analyses were performed on blinded central histology review to avoid interreader variability. Adverse events, blood biochemistry, and vital signs were assessed after 3 months.. There were no statistically significant differences between placebo and either the CIN 1 or combined CIN 1/2 populations. A clear dose effect with a statistically significant response in the HAL 5% group of 95% (18/19 patients) compared to 57% (12/21 patients) in the placebo group (P < .001) was observed at 3 months in women with CIN 2, including an encouraging 83% (5/6 patients) clearance of HPV 16/18 compared to 33% (2/6 patients) in the placebo group at 6 months. The treatment was easy to use and well accepted by patients and gynecologists. Only local self-limiting adverse reactions including discharge, discomfort, and spotting were reported.. HAL PDT is a novel therapy that shows promise in the treatment of CIN 2 including clearance of oncogenic HPV, but not of CIN 1. The positive risk/benefit balance makes HAL PDT a tissue-preserving alternative in women of childbearing age who wish to preserve the cervix. Confirmatory studies are planned.

Topics: Administration, Topical; Adolescent; Adult; Aminolevulinic Acid; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Intention to Treat Analysis; Middle Aged; Photochemotherapy; Photosensitizing Agents; Treatment Outcome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Young Adult

Cervical intraepithelial neoplasia (CIN) 1-3 is the precursor of invasive cervical cancer and associated with human papillomavirus infection. Standard treatment is surgical and may be associated with subsequent pregnancy complications. Photodynamic therapy (PDT) of CIN may be an interesting alternative.. Patients were treated by PDT using hexaminolevulinate (HAL) and methylaminolevulinate in six dose and light groups and two incubation periods in a double-blind setting. Follow-up examinations were performed after 3, 6, and 12 months with histology, cytology, and HPV testing.. We included eight patients with CIN1, 23 with CIN2, and 36 with CIN3. Treatment was well tolerated. HAL 40 mM with 3-hour application turned out to be the most-effective group with 67% (10/15) complete response rate. The combined complete and partial response for patients with CIN2 was 83% (20/24).. PDT with CIN may be a safe and effective procedure for CIN treatment.

Topics: Adult; Aminolevulinic Acid; Double-Blind Method; Female; Humans; Papillomavirus Infections; Photochemotherapy; Photosensitizing Agents; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Cervical intraepithelial neoplasia (CIN) is associated with genital human papillomavirus (HPV) infection and represents the precursor of cervical cancer. Established ablative treatment methods may cause substantial complications in following pregnancies including premature delivery and the birth of low-weight babies. Photodynamic therapy (PDT) of CIN using esters of 5-aminolevulinic acid (5-ALA) represents a promising alternative. However, it has not been analyzed yet if the PDT itself leads to sustained damage of the cervical tissue. This study aims at evaluating the effect of hexylaminolevulinate (HAL) and methylaminolevulinate (MAL) PDT on cervical tissue.. Twenty-five patients underwent 1-2 PDT cycles for CIN 1-3 applying topical HAL and MAL. Before and 6 months after PDT, biopsies were obtained from the cervix. Macroscopic changes of the cervix were evaluated. We assessed H&E slides for signs of sustained tissue damage. Furthermore, expression profiles of p16(INK4a), Ki67, Bcl-2, Bax, and CD31 were evaluated.. PDT was performed satisfactory in all patients. No macroscopic changes of the cervix were encountered and histological evaluation revealed no signs of apoptosis, necrosis, irritation, vascular changes and fibroses 6 months after PDT. Ki67 and p16(INK4a) were useful for the prediction of response to PDT. Bcl-2 and Bax showed no significant expression profile changes after PDT and the micro-vessel pattern was not altered.. HAL and MAL PDT do not leave any sustained damage in normal cervical tissue. This is of paramount importance as cervical insufficiency or stenosis may have implications on pregnancy and cervical cancer screening.

Topics: Administration, Topical; Adult; Aminolevulinic Acid; Biomarkers, Tumor; Cohort Studies; Double-Blind Method; Epithelium; Female; Humans; Middle Aged; Photochemotherapy; Photosensitizing Agents; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Young Adult

CIN is a disease of women in their reproductive years, and treatment includes excisional techniques with increased risk of preterm deliveries. Photodynamic therapy (PDT) using topical precursor of photoactive porphyrins may be a non-invasive alternative with minimal side effects. This study assessed the feasibility and response rate of PDT with hexaminolevulinate (HAL) in cervical intraepithelial neoplasia (CIN) and human papillomavirus (HPV) infection.. Twenty four patients with a CIN 2 or 3 or a persistent CIN 1 and a positive high-risk HPV-DNA test were included. Each patient had gynaecologic examination including cervical cytology, HPV DNA testing, colposcopy and biopsy. Ten milliliters of HAL-thermogel (10 mM) were topically applied to the cervix for 3-5 hours, followed by 1,000 seconds of illumination of both ecto- and endocervical canal with red coherent light (wave length 633 nm) using a PDT laser and a special light catheter. Follow-up examinations were carried out after 3 (cytology, colposcopy, HPV DNA testing, and if needed re-PDT) and 6 months.. Seven, 10, and 7 patients had a CIN 1, 2, or 3, respectively. Treatment could be accomplished in all cases and no severe side effects were encountered. Fifteen out of the 24 patients had a complete response (15/24 = 63%) and a HPV remission 6 months after 1-3 treatments. The remission rates were 71%, 50%, and 71% for CIN 1, 2 and 3.. HAL PDT seems to be a non-invasive, repeatable procedure for CIN and cervical HPV infection with minimal side effects which can be easily performed on outpatient basis.

Topics: Adult; Aminolevulinic Acid; Feasibility Studies; Female; Humans; Papillomavirus Infections; Photochemotherapy; Photosensitizing Agents; Treatment Outcome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Young Adult

Effects of photodynamic therapy (PDT) were tested with respect to immune cell stimulation in cervical intraepithelial neoplasia (CIN).. A patient with CIN received hexaminolevulinate (HAL) and subsequent PDT. These data were compared to a placebo PDT patient and a healthy HPV16-vaccinated donor. Isolation of peripheral blood mononuclear cells (PBMC) was performed before PDT and at 4 different time points after PDT. The proliferation of these PBMC was tested by [. These findings suggest a T cell reaction from CIN patients during repeated HAL/PDT treatment. However, further immune cell populations might be involved during PDT.

Topics: Aminolevulinic Acid; CD4-CD8 Ratio; Cell Cycle; Female; Human papillomavirus 16; Humans; Leukocytes, Mononuclear; Papillomavirus Vaccines; Photochemotherapy; Photosensitizing Agents; T-Lymphocytes; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Photodynamic therapy has a great potential in the treatment of cervical cancer. The aim of this study was to develop bioadhesive pellets containing hexylaminolevulinate (HAL), a precursor of the photoactive substance PpIX, with a fast release for vaginal drug delivery. Pellets were produced by extrusion/spheronization, and Carbopol(®) 934 was used to obtain bioadhesive properties. A 2(2)-factorial design with center point investigating the HAL content (1 and 10%, w/w) and Carbopol(®) 934 content (1 and 8%, w/w) was set up. The most suitable formulations were mechanically stable and showed bioadhesive properties toward vaginal tissue. The drug load was released within 20 min in phosphate buffer pH 4 and 6.8 in the in vitro dissolution test. The stability of HAL in the pellet formulations varied, but the most stable formulation showed 96-97% HAL remaining in the formulation after 6-7 weeks of storage at accelerated temperature conditions (40 °C). The investigated formulations seem promising for vaginal delivery of HAL.

Topics: Acrylates; Adhesiveness; Aminolevulinic Acid; Animals; Cattle; Drug Delivery Systems; Drug Stability; Drug Storage; Excipients; Female; Mucous Membrane; Photochemotherapy; Photosensitizing Agents; Solubility; Temperature; Uterine Cervical Neoplasms; Vagina

Standard treatments of high-grade Cervical intraepithelial neoplasia (CIN) are conisation procedures. Theses methods have proven effectiveness but are associated with an increased risk of subsequent pregnancy complications. Recently, photodynamic therapy (PDT) of CIN using hexylaminolevulinate (HAL) may represent an alternative treatment without the risk of cervical insufficiency or scaring. This study aims to evaluate the economical aspect of CIN treatment including associated pregnancy complications by comparing both methods.. We developed model treatment pathways for both conisation procedures and PDT using HAL. Thereafter, we calculated total costs for both treatment pathways including necessary re-treatments or alternative treatments. The estimated impact of conisation-related cervical insufficiency, prematurity, perinatal morbidity and life-long disability were determined. The total additional costs per conisation due to perinatal morbidity were calculated.. The total cost of treatment for CIN with a conisation procedure alone was 1,473 €, whereas the PDT procedure alone accounted for 1,386 €, based of assumptions of a 50% re-PDT rate, a 70% response rate and costs of 500 € for the PDT intervention itself. We computed 71, 144 and 545 newborns born prematurely due to conisation procedures <28, between 28 and <32 and between 32 and <37 weeks of gestation, leading to 18, 24 and 65 cases of severe, moderate and mild life-long disability. The attributable additional amount of maternofetal morbidity discounted by 3% for 7 years was 573 € per conisation. The total costs for a conisation therefore added up to 2,046 €, the total costs per treatment with PDT given the above-mentioned assumptions were 1,558 €.. For Germany, PDT has the potential to be a cost-effective treatment for high-grade CIN compared to conisation procedure. Most important, the increased perinatal morbidity, perinatal mortality and associated costs after conisation procedures are significant and may be reduced by the implementation of PDT in CIN treatment.

Topics: Aminolevulinic Acid; Cervix Uteri; Conization; Cost-Benefit Analysis; Female; Germany; Health Care Costs; Humans; Infant, Newborn; Models, Biological; Models, Economic; Photochemotherapy; Photosensitizing Agents; Pregnancy; Pregnancy Complications; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Photodynamic therapy has the potential of a minimal invasive outpatient procedure for CIN patients at reproductive ages. The purpose of this study was to examine the pharmacokinetics and selectivity of porphyrin synthesis after topical application of hexaminolevulinate (HAL) in patients with cervical intraepithelial neoplasia (CIN).. Twenty-four women with CIN 1-3 received 4 mmol/L or 10 mmol/L HAL dissolved in thermolabile pluronic F 127 gel topically 5-720 minutes before surgical conization. The microscopic fluorescence pattern was quantified by ex vivo fluorescence spectroscopy at a wavelength of 635 nm and semiquantitatively by digital image analysis from cryosections.. With 4 and 10 mmol/L HAL, porphyrin fluorescence intensity increased over time, reaching a peak after 180-540 minutes application intervals in CIN and normal epithelium. However, the peak was much more pronounced in CIN than in normal tissues. The fluorescence intensity with 10 mmol/L was significantly higher than that with 4 mmol/L in CIN tissues (P < .05). Maximum intensity could generally be detected in the lower layer of the epithelium.. HAL seems to be a promising molecule for fluorescence diagnosis. For further treatment studies, we recommend application of 10 mmol/L HAL 300-540 minutes before photodynamic therapy in CIN.

Topics: Administration, Topical; Adult; Aminolevulinic Acid; Carbon Radioisotopes; Female; Fluorescence; Humans; Middle Aged; Photochemotherapy; Porphyrins; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms