Clinical evidence on a Coriolus versicolor-based vaginal gel for HPV-related cervical disease: a narrative review

Introduction

Background

Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide. Its global prevalence has been estimated at 11.7%, but it varies widely across countries, reflecting disparities in health care coverage, particularly regarding HPV vaccination, which remains suboptimal in many regions despite extensive evidence supporting the efficacy and safety of HPV vaccines (1). The regions with the highest prevalence are Sub-Saharan Africa (24.0%), Eastern Europe (21.4%), and Latin America (16.1%) (2). High-risk HPV infection is a necessary, though not sufficient cause of cervical cancer, which remains one of the leading causes of cancer-related morbidity and mortality among women. Globally, it ranks as the fourth most common and deadly cancer in women, accounting for approximately 8% of cancer-related deaths in this population (3-5).

HPV has a tropism for human skin and mucous membranes, and its infectious potential depends on several factors that enable interaction with host cells. These include disruption of the epithelial barrier (e.g., microtraumas) and evasion of the host immune system (by inhibiting interferon signaling and interfering with antigen presentation). These mechanisms can, in turn, be facilitated or promoted by conditions such as vaginal microbiota imbalances or structural alterations of the cervical epithelium, for example, due to atrophy or ectropion. Once inside the epithelium, HPV activates its molecular machinery to replicate, which can lead to cellular dysplasia and, if the infection is persistent, may contribute to the development of cervical cancer over time (3,6).

Given the importance of immune modulation in controlling HPV infection and progression, interest has grown in alternative therapies that enhance host defense mechanisms. In recent years, medicinal mushrooms have gained attention not only for their nutritional benefits, but also as a source of pharmaceuticals and as complementary treatments alongside conventional chemotherapy or radiation therapy, either to boost effectiveness or to minimize side effects (7,8). One of the most extensively investigated medicinal mushrooms in recent decades is Coriolus versicolor, known by its scientific name as Trametes versicolor, or by its common name in the Western world—Turkey Tail (9). Its medicinal use in traditional Chinese medicine dates back over 2,000 years, valued for its general health-promoting properties, such as enhancing endurance and promoting longevity (10,11). In both China and Japan, traditional medicine practices include preparations as dried powdered tea made from the fungus.

Evidence on the direct effect of the polysaccharides on gene expression in cancer cells was introduced since 1985 (12). This was followed by results showing inhibition of carcinogenesis in rat models in 1990 (13). Since then, the direct anticancer effects of T. versicolor polysaccharides have been confirmed through various experimental models, including in vitro studies, in vivo research, and clinical trials (7). A meta-analysis published in 2012, including 13 clinical trials in cancer patients, concluded that the use of T. versicolor results in a significant survival advantage compared with standard conventional anti-cancer treatment alone, specifically in breast, gastric, and colorectal cancer (14).

Rationale and knowledge gap

The current standard of care for preinvasive cervical disease, endorsed by all major national guidelines, is a two-tiered approach. Low-grade squamous intraepithelial lesions (LSILs) are typically monitored over time due to their high rate of spontaneous regression and resolution, up to 90% within two years. In contrast, high-grade squamous intraepithelial lesions (HSILs) require prompt treatment because of a higher risk of persistence or progression. Treatment most often involves excisional procedures such as large loop excision of the transformation zone (LLETZ) or conization, or, less frequently, ablative therapies such as cryotherapy or thermal ablation (15-18).

In the context of managing HPV-related low-grade lesions, where surveillance is commonly recommended, topical treatments have emerged as potential alternatives to accelerate the well-known natural regression promoted by immune mechanisms, or even to prevent progression (19,20). Considering the pathophysiological mechanisms involved in HPV infection and dysplastic or oncogenic transformation, a multicomponent vaginal gel has been developed. Its main active ingredient is an extract of T. versicolor, which acts as an immune-boosting agent. The formulation also includes hyaluronic acid niosomes, beta-glucan niosomes, Centella asiatica phytosomes, Azadirachta indica (neem) extract, and Aloe vera. Together, these components target contributing factors such as disruption of the epithelial barrier, imbalances in the vaginal microbiota, and structural alterations of the cervical epithelium (3,21-27). This product is marketed under the brand names Papilocare^® and Palomacare^®. Details regarding the scientific rationale for including each active component are provided in Table 1 and Figure 1.

Figure 1 Composition of the Papilocare^® vaginal gel and proposed mechanisms of action. Schematic representation of the key bioactive components included in the Papilocare^® formulation, along with their proposed biological effects. Each ingredient is associated with a specific mechanism—such as immunomodulation, antioxidant activity, epithelial repair, or microbiota support—intended to contribute to cervical epithelial healing and HPV-related lesion management. Source: authors’ own elaboration. This figure is an original creation by the authors. HPV, human papillomavirus.

Objective

The aim of this review is to critically assess the available clinical and preclinical evidence supporting the use of this multicomponent vaginal gel as a therapeutic strategy for HPV-related cervical pathology, and to identify existing limitations in the current body of evidence and highlight areas requiring further research to establish its safety, efficacy, and potential role within standard clinical practice. This review focused exclusively on clinical efficacy outcomes; safety, psychological, and other patient-reported measures were not specifically analyzed. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-100/rc).

Methods

Data included

Although we acknowledge that it is not an official scientific source, the “scientific evidence” section of the manufacturer’s website was consulted to ensure a comprehensive assessment, alongside a broad and structured literature search (28). According to Papilocare^® vaginal gel manufacturer, there are four studies that prove the efficacy of this product and support its use for HPV infection treatment: two prospective non-controlled interventional studies, one randomized clinical trial, and one retrospective observational study (Table 2). To broaden the scope of this review and explore whether previous findings had been independently corroborated, a structured search strategy was developed for MEDLINE, Embase, and Scopus, covering the period from inception to May 2025. The search terms included “Coriolus versicolor” [All Fields] OR “Trametes versicolor” [Supplementary Concept] OR “VPS Coriolus versicolor extract” [Supplementary Concept] OR “polysaccharide-K” [Supplementary Concept] OR “Papilocare” [All Fields] AND “HPV” [All Fields] OR “Human Papillomavirus Viruses” [Mesh] OR “Papillomavirus Infections” [Mesh] AND “Uterine Cervical Dysplasia” [Mesh] OR “Cervical lesion*” [All Fields] OR “Cervical dysplasia” [All Fields] OR “Squamous Intraepithelial Lesions” [Mesh] OR “LSIL” [All Fields] OR “Atypical Squamous Cells of the Cervix” [Mesh] OR “ASCUS” [All Fields] AND “Vaginal gel” [All Fields] OR “Topical Treatment” [All Fields] OR “Administration, Topical” [Mesh] OR “Administration, Intravaginal” [Mesh] OR “Vaginal Application” [All Fields] OR “Vaginal Creams, Foams, and Jellies” [Mesh]. Different combinations of these entries were used to broaden the search. No language restrictions were applied. Additionally, studies registered in ClinicalTrials.gov referring to the topic were reviewed, and a complementary search on Google Scholar was conducted. Narrative reviews and meta-analyses were excluded. A manual search using a reference-tracking strategy of included studies was also performed. Additionally, unpublished conference abstracts identified during the search were screened but interpreted with caution given their non-peer-reviewed nature (Table 3).

Results

Published research

In 2017, a pilot study was conducted to assess the clinical benefits of a T. versicolor-based vaginal gel on epithelization of cervical lesions, its impact on vaginal microbiota and vaginal health in asymptomatic healthy women. It was an open-label, non-comparative, prospective study, conducted in two clinics in Spain, including 21 asymptomatic women, with a normal Pap smear. The HPV status was not informed. Participants were treated with the vaginal gel for 12 days. The results showed an improvement in the epithelization of the cervix (mean epithelialization score 4.42 after therapy vs. 3.09 at baseline, P<0.001), and an improvement in vaginal health index (mean score 22.3 at end of treatment vs. 19.0 at baseline, P=0.007). Of note, it should be underscored that the duration of application was short (12 days only), and there was no control group (21).

Based on the gathered evidence, the EPICERVIX pilot study was conducted, partially replicating the previous one, but including 21 HPV-positive patients without cervical preinvasive disease (normal Pap smear and colposcopy) from a single center in Madrid. These patients underwent a 21-day regimen of the T. versicolor-based vaginal gel. The evaluated outcomes were cervical epithelialization and characterization of the vaginal microbiota. The authors reported a statistically significant improvement in cervical epithelialization (median epithelialization score of 5 compared to 4, post- vs. pre-treatment; P<0.01). Of note, the EPICERVIX implemented microbiota analysis and found a statistically significant improvement in the vaginal microbiota, with a higher proportion of the phylum Firmicutes, to which Lactobacillus spp. belongs (P<0.01). It is worth noting that no outcomes related to HPV persistence or clearance were assessed in this study (29).

The PALOMA study (NCT04002154), conducted between 2016 and 2018, was a Spanish multicenter, open-label, randomized controlled clinical trial that evaluated the efficacy of a T. versicolor-based vaginal gel in repairing cervical mucosal lesions in HPV-positive patients with low-grade Pap smear alterations and consistent colposcopy findings. A total of 59 patients receiving treatment were compared to 32 patients who did not receive treatment. No statistically significant difference was found in HPV clearance at 6 months (59.6% in the treatment arm vs. 41.9% in the no-treatment arm; P=0.118). Similarly, there was no significant difference in the clearance of high-risk HPV (62.5% in the treatment group vs. 40.0% in the no-treatment group; P=0.076) (30). The latter was concordant with a previous poster publication evaluating a subpopulation of high-risk HPV-16/18 and 31 by the authors (32). Nevertheless, the authors state a significant difference in clearance when comparing the most intensive scheme of vaginal application with the control group, but partial and complete clearance were not discriminated, conferring a risk of bias. In this randomized trial, no biopsies were performed, according to the authors, because all patients were diagnosed with LSIL, and current guidelines do not recommend histological evaluation in such cases. The authors also argued that biopsies themselves could alter the natural history of these lesions (30).

Published in 2023, PAPILOBS trial (NCT04199260) aimed to prospectively evaluate the results of using Papilocare^® in repairing low-grade cervical lesions (31). In this observational, Spanish, multicentric, prospective, non-comparative clinical study performed between 2018 and 2021, women were included if they had a HPV-positive test; cervical atypical squamous cells of undetermined significance (ASCUS) or LSIL cytology result coupled with colposcopy image showing similar level of cervical dysplasia. Participants were treated with Papilocare^®, one cannula each day for 21 days during the first month, followed by one cannula each alternate day during the subsequent 5 months, and could be continued until 12 months if there was altered cytology/colposcopy and/or HPV persistency. Overall, 192 and 201 accounted for the total and safety samples (patients who used Papilocare at least once), respectively. After 6 months of treatment, 67.0% [95% confidence interval (CI): 60.4–73.7%] of the participants had their cervical lesions repaired. After 6 months of treatment, HPV test results showed 58.7% (95% CI: 51.7–65.8%) clearance. For those who continued treatment for no clearance, 52.1% (95% CI: 38–66.2%) achieved HPV negative test results at 12 months. For women over 40 years, HPV clearance was 61.1% (95% CI: 49.9–72.4%) and 57.9% (95% CI: 35.7–80.1%) at 6 and 12 months, respectively. One of the major criticism points in that study is that HPV clearance endpoint was defined as “disappearance of at least one baseline strain together with normal cytology findings and concordant colposcopy observations”. Importantly, biopsy assessment was available only for 26 patients at visit 2 (6 months), and 13 for visit 3 (12 months). Of those, 76.9% and 69.3%, respectively, did not show changes in the biopsy results vs. baseline.

Following the publication of the PALOMA trial (30), the authors conducted a post-hoc analysis in a subgroup of the study population, including only patients older than 40 years, 41 of the original 91 participants. The rationale provided for selecting this subgroup was that physiological and immunological changes associated with aging may contribute to the persistence of high-risk HPV infection. Additionally, the incidence of cervical cancer peaks in women between 35 and 45 years and again in those over 55 years. The main outcomes were the normalization of cytology with concordant colposcopic findings, and HPV clearance at 6 months. The authors reported a statistically significant higher proportion of patients achieving cytology normalization in the vaginal gel group compared to the control group, except in the high-risk HPV-16/18/31 subpopulation, where significance was not achieved. However, no statistically significant difference was observed regarding HPV clearance (33).

Based on information available from published conference abstracts and reports presented at papillomavirus and gynecologic oncology meetings, as well as data summarized on the manufacturer’s website, a total of five independent observational clinical studies supporting evidence on Papilocare^® due to the achieved clearance of high-risk HPV, ranging between 48% and 72.5% at 6 months (28). Four of the studies included did not have a comparative arm; two prospective one-cohort studies (Vigo study from the Servizo Galego de Saúde-Hospital Álvaro Cunqueiro at Vigo, Spain, and the Bari study from a Private Italian Center) and two retrospective one-cohort studies (Coruña Study from the Hospital Materno Infantil Teresa Herrera at Coruña, Spain, and Hospitalet Study from the Institut Català d’Oncologia-Hospitalet de Llobregat at Barcelona, Spain) (34-36). None of these studies has a complete manuscript published in a scientific journal, and the available information is on a poster abstract (34-36), except for the Bari study, for which the reference published cannot be retrieved (the Italian journal mentioned has a registered ISSN number but no website is available; information is only available through citation) (37). Nevertheless, our search yielded only one published retrospective observational study with a non-randomized control group (Roma study) (38). It is noteworthy that this article was published before the EPICERVIX (29) and PALOMA (30) trials. In this study, data from 183 high-risk HPV-positive patients, regardless of their Pap smear results, were retrospectively analyzed. Ninety-seven patients received a 21-day T. versicolor-based vaginal gel regimen and were compared to 86 patients who underwent surveillance. The evaluated outcomes were HPV clearance, colposcopic findings, and the proportion of cytologic abnormalities, assessed after 6 months. The authors reported a statistically significant higher rate of HPV-negative test (67% vs. 37.2% in the active and control arms, respectively; P<0.001), with an almost 5-fold higher likelihood to experience viral clearance according to the multivariate analysis [adjusted odds ratio (aOR) 4.81; 95% CI: 2.43–9.53), a significant increase in negative colposcopy findings, and a higher proportion of normal cytology in the active treatment group. In this study no histological outcomes were evaluated (38).

Ongoing research

To provide a comprehensive overview of the current state of evidence, ongoing and preliminary research related to Papilocare^® is also summarized below. These data mainly derive from conference abstracts and isolated case reports, which, although informative and indicative of growing clinical interest, should be interpreted with caution due to their inherent methodological limitations and absence of peer review. Their inclusion aims solely to illustrate the evolving landscape of clinical investigation rather than to establish confirmatory evidence.

Two clinical trials are currently ongoing: a phase II trial (PALOMA 2) and a phase III double-blinded trial (PAPILOCAN). According to ClinicalTrials.gov, both of them have been completed; nevertheless, to date, only abstracts presented as posters and oral presentations at the 2025 European Society of Gynaecological Oncology (ESGO) Congress have been published. The PALOMA 2 trial (39) (NCT04199078) replicates the design of the PALOMA 1 trial, specifically in high-risk HPV positive women with ASCUS/LSIL cytology and concordant colposcopy, but with a 4-arm randomization (consisting of standard, intensive, and very intensive 6-month Papilocare^® treatment and a watchful waiting control group). Results for 109 patients indicated only a statistically significant difference between the intensive regimen and the control group in terms of high-risk HPV clearance (partial clearance was not clarified) and cervical lesion repair, though no biopsy results were taken into account; if the outcome was solely HPV clearance, the very intensive approach was also significant (40). When combining the high-risk HPV population of the PALOMA 1 and 2 trial treated with an intensive 6-month regimen (n=48) vs. control (n=53), a significant increase in HPV clearance was shown, favoring treatment (85.4% vs. 43.4%, P=0.002) (41). The PAPILOCAN clinical trial (NCT04210336) included 200 high-risk HPV-positive patients who were allocated (1:1) to receive Papilocare^® or lactic-acid active control. Administration posology consisted of a 6-month regimen: either once daily for one month followed by every other day for five months in the first 100 patients, or once daily for 3 months followed by every other day for 3 months in the remaining patients. Although the completion date published was January 2023, the authors only present a preliminary analysis of 40 patients, reporting a higher HPV-16/18 clearance rates in the intensive regimen group; however, no statistical analysis was performed to determine whether the difference was significant (42).

Two additional trials were found in addition to the four previously stated studies (30,31,39,42) that were registered in clinical trials. The multi-center, prospective, non-comparative, observational PAPILOBS-GR study (NCT06399341) replicates the PAPILOBS study but is carried out in a Greek population. While the manuscript hasn’t been published despite completion date was more than 2 years ago, available results of a sub-analysis were released in the ESGO 2025 poster abstracts. The authors focus on HPV-16/18 genotypes, showing that the HPV-16/18 and HPV-16 positive patients had respective clearance rates of 69.2% and 59.5% at the conclusion of the trial (43). The PAPILOCARE study (NCT04624568) is a French randomized, controlled, single-blinded, monocentric trial that examined the effects of Papilocare^® for 6 months vs. surveillance in patients with histologic low-grade cervical intraepithelial neoplasia (CIN 1) following ASCUS or LSIL cytology. The results were published in two theses from the University of Tours in 2021 and 2024; however, only the first one’s written paper is accessible in the university repository (44). However, based on the provided data, no conclusions can be reached because only six of the 25 patients enrolled at the time of the defense had been followed for longer than 6 months.

A recent observational prospective non-controlled pilot study assessed the effect of a 6-month regimen Papilocare^® vaginal gel treatment on HPV-dependent low-grade cervical alterations in patients coinfected with human immunodeficiency virus (HIV). Fifteen patients were included. Of nine colposcopy grade 1 abnormal results at baseline, five regressed to normality, and of 11 histologically proven CIN 1, only four showed histologic persistence, as the other seven patients had normal colposcopy, so biopsy was not deemed necessary. Of note, an overall and partial viral clearance of 73.3% and 13.3% was reported, but HPV testing was only performed for four patients at 6 months (45). The results of this study, though promising, are just exploratory, and other studies with a bigger sample size and a different methodological approach are needed.

Combined treatment was explored in a Polish study of cryotherapy and Papilocare^® short cycle (n=34) compared to cryotherapy and vaginally applied Betadine (n=158) in patients with high-risk HPV and ASCUS/LSIL cytology. HPV eradication favored the Betadine group (95.5% vs. 85.2%, P=0.041) (46). However, conclusion of this study cannot be drawn as serious methodological flaws are detected (no randomization, non-balanced groups, no sample size calculated, inadequate statistical analysis described, no biopsies taken, very short vaginal treatment as compared to foundational studies), and it was published in a non-indexed journal, being part of the Beall’s list.

Although Papilocare^® is currently approved for the management of HPV-related low-grade cervical lesions (ASCUS and LSIL), some studies have explored its potential use in higher-grade scenarios as off-label applications. Apart from the low-grade scenario, Papilocare^® has also been evaluated in patients with high-grade lesions. Histologic regression for histologic high-grade cervical intraepithelial neoplasia (CIN 2–3) has been documented in case reports (47-50). C. versicolor-based vaginal gel 6-month regimen performance was assessed in 44 CIN 2 patients in a one-cohort, prospective, single-center, observational trial. The results showed 68.2% regression by biopsy, 11.4% persistence of CIN 2, and 18.2% progression to CIN 3 (51). However, no statistically significant difference was seen when these data were compared to a retrospective CIN 2 cohort (n=117) undergoing surveillance. It is important to note that no full-text manuscript has been published for any of the investigations listed (52).

Critical appraisal of the literature

In order to perform an objective analysis of the currently available literature, each article was analyzed using the appropriate guideline (53-55) according to its methodological design (Table 4). A descriptive analysis of the main methodological concerns is presented below.

Methodological design

Three of the four foundational studies for the use of this product are prospective single-arm studies (21,29,31). This is considered appropriate when ethical or logistical constraints prevent the inclusion of a control group, such as in early-phase evaluations or in settings where no standard treatment exists. According to ICH E10, single-arm trials can be justified particularly in rare diseases or life-threatening conditions where withholding treatment is unethical (56). This design is also accepted by regulatory agencies like the U.S. Food and Drug Administration (FDA) for rare or under-researched conditions. Thus, considering the high prevalence of HPV infection and the long time between the HPV infection and progression to cancer, this would not be the best methodological design for the foundational research (57).

Of the currently available manuscripts on Papilocare^®, only two studies were designed with a control group (30,38), nevertheless, both used “watchful waiting”, meaning no treatment was administered. It has been suggested that in conditions for which no standard treatment exists, the use of a placebo control can strengthen the methodological design of a clinical trial (58). The only registered trial that assigned participants to a placebo control (lactic acid active) with the same schedule of administration as Papilocare^® is the PAPILOCAN study. However, the presented results in the abstracts cannot be sufficiently evaluated while the full text publication is still awaiting (42).

Sample size

In the pilot study by Palacios et al. (21), as well as in the EPICERVIX study (29), no sample size estimation was performed, according to the authors, due to the “exploratory nature” of the trials. Additionally, in the “validation” study by Criscuolo et al. (38), no sample size calculation was conducted either, as it was also considered a pilot study. In contrast, sample size estimation was appropriately reported in both the PALOMA trial and the PAPILOBS study (30,31). Nevertheless, in the PALOMA trial, sample size was determined by an expert board, arguing that the lack of published data justified it, although the natural history of HPV infection, its oncogenic potential and the regression, latency, persistence and progression pathways are well known (16,18,59). In turn, in the PAPILOBS study, appropriately reported a sample size calculation consistent with its observational, single-arm design. However, given that the calculation was based solely on the expected proportion of lesion repair (80%) without consideration for potential subgroup analyses, its statistical power to explore heterogeneity or to allow comparisons across patient subsets remains limited (31).

Of note, only the PALOMA and PAPILOBS trials reported a calculated sample size. Both studies also showed notable attrition rates, 32.1% in PALOMA (30) and 27.0% in PAPILOBS (31), which should be acknowledged when interpreting and generalizing their results. Although transparent reporting of patient loss is commendable, attrition exceeding 20% may still affect the internal validity of a study and should be carefully considered in the interpretation of outcomes (60). In comparison, the EPICERVIX pilot study reported a lower attrition rate of 9.5%, with epithelialization outcomes missing in 2 of the 21 participants (29).

Intervention

There is significant heterogeneity in the interventions used across studies. This could be explained by the fact that Papilocare^® is a medical device, and such variability may reflect real-world differences in medical practice. In the pilot study by Palacios et al. (21), a 12-day regimen was applied. In the EPICERVIX study, a 21-day regimen was evaluated (29). On the other hand, in the only randomized controlled trial currently available, the PALOMA trial, two different treatment regimens were assessed: scheme A included daily application for 21 days followed by 7 days off, then alternate-day use for up to 5 months; scheme B followed the same initial cycle for 3 months, followed by alternate-day use for an additional 3 months (30). Finally, in the PAPILOBS study, a 21-day regimen during the first month was followed by alternate-day use for 5 months, with a second 6-month treatment cycle prescribed when needed (31). This represents one of the major methodological flaws in the current body of evidence regarding the use of this product, as it severely compromises its external validity and makes the design of validation studies particularly challenging due to the lack of a standardized dosing regimen.

Outcomes

The selection of outcomes during the design of a randomized controlled trial is a critical step in achieving high internal validity. There are six key principles that guide the appropriate selection of a primary outcome: the outcome should be affected by the intervention, it should be meaningful to the target audience, clinically relevant to patients, measurable in an efficient and reliable manner, and, when possible, assessed using a well-understood continuous scale (61,62).

The two pre-PALOMA pilot foundational studies (21,29) selected “vaginal health evaluation” as their main outcome, based on a subjective assessment of the vaginal mucosa using an unvalidated score derived from colposcopic criteria. However, a well-validated tool for evaluating vaginal mucosal status, the vaginal maturation index, has been available since 1999 (63). This index relies on histological assessment of vaginal samples and has been widely used in clinical trials for urogenital syndrome in menopause (64). Thus, the outcome used in these studies does not meet the appropriateness criteria mentioned earlier, as it is neither meaningful to the target audience nor clinically relevant to patients, and it is not measured efficiently or reliably (61).

In the two remaining foundational studies, the PALOMA and PAPILOBS trials (30,31), cytology was used as the main outcome, despite its well-known limited accuracy in diagnosing cervical dysplasia. Its operational characteristics include a sensitivity of 55.5%, specificity of 75%, positive predictive value of 88.2%, and negative predictive value of 33.3% (65). Histological assessment, which is undoubtedly the gold standard, was not performed in the PALOMA trial. In that study, the primary endpoint was the rate of cervical lesion repair after 6 months of treatment, defined as normalized cytology and concordant colposcopic findings. This endpoint was met, with a significantly higher proportion of patients in the treatment group showing both normal Pap smear results and concordant colposcopic observations compared to the control group (84.9% vs. 64.5%; P=0.031). However, as cervical biopsies were not included, the reliability of the results is compromised. Additionally, colposcopy was performed in an unblinded manner, introducing a high risk of bias (30). Concordantly, in the PAPILOBS study, biopsies were performed in less than one-third of patients during follow-up (31).

The other evaluated outcome among studies was HPV clearance (31,38), which—although a surrogate rather than a clinically relevant endpoint—may be reasonable to assess given that persistent HPV infection is the necessary cause of cervical cancer. Nevertheless, the selection of the follow-up time point for this outcome must align with the natural history of the infection. Most randomized trials assess viral clearance at 6 months; however, spontaneous regression frequently occurs up to 24 months in untreated cases (16,66,67). As such, a short follow-up window may lead to an underestimation of true treatment effects or misclassification of natural regression as therapeutic efficacy. According to CONSORT and SPIRIT guidelines, trial protocols should provide a clear rationale for the chosen assessment time points, based on expected clinical trajectories. Failing to do so may compromise the internal validity and interpretability of the findings (62,68).

Furthermore, as established the majority of CIN 1 will resolve naturally in less than 2 years with little chance of progression, supporting the frequently advised surveillance strategy. Justifying treatment because of potential negative emotional and psychological distress in women seems insufficient, as educational strategies widely explaining normal clearance and regression mechanisms can help diminish anxiety, which in turn can also be reduced by extending the testing interval as advised by guidelines (retesting between 12 and 24 months).

Ethical considerations

The T. versicolor-based vaginal gel is classified as a medical device, not as a drug. Although national regulations in some countries, such as Spain (69), do not require institutional review board (IRB) approval for medical device research, it is widely recommended as a good practice. IRB review helps ensure the protection of patients’ rights, improves study quality, and may enhance the external validity of results. The Council for International Organizations of Medical Sciences (CIOMS) and the Declaration of Helsinki of the World Medical Association both emphasize that all research involving human subjects should undergo IRB review, regardless of local regulations (70,71). Neither of the two pilot studies, the one by Palacios et al., nor the EPICERVIX study, underwent IRB review, although the authors disclosed this, claiming that Spanish regulations do not require it (21,29).

The International Standards for Clinical Trial Registries established by the World Health Organization (WHO) (72), as well as the recommendations of the International Committee of Medical Journal Editors (ICMJE) for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals (73), encourage the prospective registration of clinical trials, as a measure to reduce publication bias and the selective reporting of positive results. In Europe, the European Medicines Agency (EMA) regulations mandate prospective registration for pharmaceutical trials (74). The first published pilot study by Palacios et al. (21) was submitted on September 24, 2016, published online on March 16, 2017, but retrospectively registered in the International Standard Randomised Controlled Trial Number (ISRCTN) registry on February 15, 2017. Although retrospective registration is not prohibited, both WHO and ICMJE explicitly recommend registering protocols before the enrollment of the first participant. It is worth noting that, as the evaluated product is classified as a medical device, it is not subject to the mandatory prospective registration requirements established by the EMA for drug trials. Notably, the PALOMA trial and PAPILOBS study were prospectively registered (30,31).

Sponsorship

The 2017 pilot study by Palacios et al. (21) and the EPICERVIX pilot study (29) received logistic support by Procare Health. In the EPICERVIX pilot study, the first three authors disclosed being speakers for Procare Health. The PALOMA trial was industry-sponsored, and nine of the authors disclosed support from the pharmaceutical company funding the project. Although being funded by the pharmaceutical industry does not necessarily imply low methodological quality or biased results, it has been demonstrated that industry-funded research has four times the odds of reporting outcomes favorable to the sponsor compared to studies funded by other sources [odds ratio (OR): 4.05; 95% CI: 2.98–5.51] (62,75-77).

Conclusions

Although there is a scientific rationale for the incorporation of each component in the multi-ingredient T. versicolor-based vaginal gel, the currently available evidence is not sufficient to recommend its routine use for the treatment of HPV infection or LSIL, mainly due to significant methodological flaws, some ethical concerns, and the absence of external validation of the results. The scientific community is encouraged to promote primary and secondary prevention in cervical cancer and to lead well-designed trials to clarify the usefulness of this product in the treatment of HPV infection and LSIL.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at: https://cco.amegroups.com/article/view/10.21037/cco-25-100/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-100/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-100/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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