Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial

Trutnovsky, Gerda; Reich, Olaf; Joura, Elmar A.; Holter, Magdalena; Ciresa-König, Alexandra; Widschwendter, Andreas; Schauer, Christian; Bogner, Gerhard; Jan, Žiga; Boandl, Angelika; Kalteis, Martin Simon; Regauer, Sigrid; Tamussino, Karl

doi:10.1016/s0140-6736(22)00469-x

Cited by 26 publications

(31 citation statements)

References 26 publications

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“…It is noted that the overall HPV prevalence in our cohort (86.4%) is somewhat higher than many studies quoted in the literature, including a systematic review of 2,764 cases of VIN (76.3%) published in 2017 [ 1 ]. However, this systematic review also describes a wide range of prevalence (0%–100%) and a more recent trial in the same population found a prevalence of 89.7% [ 18 ]. The high prevalence rate seen in our study may be due to the application of two HPV detection assays that target different regions of the HPV genome (E6 PCR targets E6 and PapilloCheck targets E1) which is not a common approach in many of the published studies.…”

Section: Discussionmentioning

confidence: 99%

Combined HPV 16 E2 and L1 methylation predict response to treatment with cidofovir and imiquimod in patients with vulval intraepithelial neoplasia

Hurt

Nedjai

Alvarez-Mendoza

et al. 2022

CBM

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BACKGROUND: Topical cidofovir and imiquimod can effectively treat approximately 55% of patients with vulval intraepithelial neoplasia (VIN), thus avoiding the need for surgery. Human papillomavirus (HPV) E⁢2 gene methylation predicts response to treatment but a methylation measurement is only obtainable in approximately 50% of patients. OBJECTIVE: This work aimed to determine if the applicability and predictive power of the E⁢2 methylation assay could be improved by combining it with the components of a host and viral DNA methylation panel (S5) that has been found to predict disease progression in patients with cervical intraepithelial neoplasia. METHODS: HPV E2 methylation and S5 classifier score were measured in fresh tissue samples collected pre-treatment from 132 patients with biopsy-proven VIN grade 3 who participated in a multicentre clinical trial and were randomised to treatment with cidofovir or imiquimod. RESULTS: Combining HPV16 E⁢2 and HPV16 L⁢1 methylation provides a biomarker that is both predictive of response to topical treatment and that can produce a clinically applicable result for all patients. Patients with HPV 16 L⁢1ℎ𝑖𝑔ℎand HPV 16 E⁢2ℎ𝑖𝑔ℎ (36/132 (27.3%)) were more likely to respond to treatment with cidofovir (12/15 (80.0%)) than imiquimod (9/21 (42.9%)) (p= 0.026). Patients with HPV 16 L⁢1𝑙𝑜𝑤or HPV 16 E⁢2𝑙𝑜𝑤 (including those with no HPV/unassessable methylation) were more likely to respond to imiquimod: 23/50 (46.0%) vs 31/46 (67.4%) (p= 0.035). CONCLUSIONS: Combined HPV E⁢2 and L⁢1 methylation is a potential predictive marker in treatment for all patients with VIN. These findings justify validation in a prospective trial.

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Section: Discussionmentioning

confidence: 99%

Combined HPV 16 E2 and L1 methylation predict response to treatment with cidofovir and imiquimod in patients with vulval intraepithelial neoplasia

Hurt

Nedjai

Alvarez-Mendoza

et al. 2022

CBM

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“…Nevertheless, combining these surgical methods with imiquimod does not seem to reduce the risk of recurrence, though it may allow less extensive excisions and anatomical and functional conservation of the vulvar structures [ 118 ]. Studies demonstrated that imiquimod is a secure and efficient method for women with vHSIL, so it can be considered as a first-line treatment, but it demands a good patient compliance due to its relatively long treatment period [ 119 ].…”

Section: Tlr Agonists In Oncologymentioning

confidence: 99%

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies

et al. 2023

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Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLR7 and the closely correlated TLR8 affiliate with toll-like receptors family, are located in endosomes. They recognize single-stranded ribonucleic acid (RNA) molecules and synthetic deoxyribonucleic acid (DNA)/RNA analogs—oligoribonucleotides. TLRs are primarily expressed in hematopoietic cells. There is compiling evidence implying that TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. The latest research shows a positive effect of therapy with TRL agonists on the course of hemato-oncological diseases. Ligands impact activation of antigen-presenting cells which results in production of cytokines, transfer of mentioned cells to the lymphoid tissue and co-stimulatory surface molecules expression required for T-cell activation. Toll-like receptor agonists have already been used in oncology especially in the treatment of dermatological neoplastic lesions. The usage of these substances in the treatment of solid tumors is being investigated. The present review discusses the direct and indirect influence that TLR7/8 agonists, such as imiquimod, imidazoquinolines and resiquimod have on neoplastic cells and their promising role as adjuvants in anticancer vaccines.

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“…Two active trials are investigating Imiquimod combining HPV vaccine (phase II, NCT02864147) or topical Fluorouracil (phase I, NCT03196180) in treating CIN2/3. In vaginal intraepithelial neoplasia (VIN), the results of the phase III trial NCT01861535demonstrated that: Imiquimod is safe and effective in treating VIN and should be considered as a first-line treatment alternative to surgery ( 198 ).In the active phase III trial NCT02059499, single use of Imiquimod is applied in HIV patients who have anal intraepithelial neoplasia.…”

Section: Recent Advances Of Tlr-targeted Tumor Therapiesmentioning

confidence: 99%

Toll-like receptor-targeted anti-tumor therapies: Advances and challenges

Yang

Fotopoulou

et al. 2022

Front. Immunol.

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Toll-like receptors (TLRs) are pattern recognition receptors, originally discovered to stimulate innate immune reactions against microbial infection. TLRs also play essential roles in bridging the innate and adaptive immune system, playing multiple roles in inflammation, autoimmune diseases, and cancer. Thanks to the immune stimulatory potential of TLRs, TLR-targeted strategies in cancer treatment have proved to be able to regulate the tumor microenvironment towards tumoricidal phenotypes. Quantities of pre-clinical studies and clinical trials using TLR-targeted strategies in treating cancer have been initiated, with some drugs already becoming part of standard care. Here we review the structure, ligand, signaling pathways, and expression of TLRs; we then provide an overview of the pre-clinical studies and an updated clinical trial watch targeting each TLR in cancer treatment; and finally, we discuss the challenges and prospects of TLR-targeted therapy.

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Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial

Cited by 26 publications

References 26 publications

Combined HPV 16 E2 and L1 methylation predict response to treatment with cidofovir and imiquimod in patients with vulval intraepithelial neoplasia

Combined HPV 16 E2 and L1 methylation predict response to treatment with cidofovir and imiquimod in patients with vulval intraepithelial neoplasia

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies

Toll-like receptor-targeted anti-tumor therapies: Advances and challenges

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