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The optimal management of vulvar high-grade squamous intraepithelial lesions (vHSILs) is challenging. Surgery is the standard treatment, but recurrences are observed in half of patients. Medical treatment with imiquimod is an effective alternative, but the two modalities have not been compared in a randomised trial. The aim of this study was to compare the clinical effectiveness, histological response, human papillomavirus (HPV) clearance, acceptance, and psychosexual morbidity of primary imiquimod treatment versus surgical treatment in women with vHSIL. This study was a multicentre, randomised, phase 3, non-inferiority clinical trial done by the Austrian Gynaecological Oncology group at six hospitals in Austria. We recruited female patients aged 18–90 years with histologically confirmed vHSIL with visible unifocal or multifocal lesions. Main exclusion criteria were clinical suspicion of invasion, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, and any active treatment for vHSIL within the previous 3 months. Women with known immunodeficiency, who were pregnant, or who were lactating were excluded. Patients were randomly assigned (1:1) by block randomisation to imiquimod or surgery, and stratified by unifocal or multifocal disease. Treatment with imiquimod was self-administered in a slowly escalating dosage scheme up to three times per week for a period of 4–6 months. Surgery consisted of excision or ablation. Patients were assessed with vulvoscopy, vulvar biopsy, HPV tests, and patient-reported outcomes at baseline and after 6 months and 12 months. The primary endpoint was complete clinical response (CCR) at 6 months after local imiquimod treatment or one surgical intervention. Primary analysis was per protocol with a non-inferiority margin of 20%. This trial is registered at ClinicalTrials.gov, NCT01861535. 110 patients with vHSIL (78% with unifocal vHSIL and 22% with multifocal vHSIL) were randomly assigned between June 7, 2013, and Jan 8, 2020. Clinical response to treatment could be assessed in 107 patients (54 in the imiquimod group and 53 in the surgery group), and 98 patients (46 in the imiquimod group and 52 in the surgery group) completed the study per protocol. 37 (80%) of 46 patients using imiquimod had CCR, compared with 41 (79%) of 52 patients after one surgical intervention, showing non-inferiority of the new treatment (difference in proportion –0·016, 95% CI –0·15 to 0·18; p=0·0056). Invasive disease was found in five patients at primary or secondary surgery, but not in patients with per-protocol imiquimod treatment. There was no significant difference in HPV clearance, adverse events, and treatment satisfaction between study groups. Imiquimod is a safe, effective, and well accepted alternative to surgery for women with vHSIL and can be considered as first-line treatment. Austrian Science Fund and Austrian Gynaecological Oncology group.

BackgroundCurrent treatment options for patients with locally advanced vulvar cancer are limited and associated with high morbidity. Therefore, it is important to develop new and safe treatment strategies for this vulnerable patient group.Primary ObjectiveTo compare the efficacy and safety of neoadjuvant chemotherapy followed by surgery with definitive chemoradiation in patients with locally advanced vulvar cancer.Study HypothesisNeoadjuvant chemotherapy followed by surgery is oncologically safe, potentially more effective than primary chemoradiation in establishing long lasting locoregional control, and associated with an improved quality of life.Trial DesignThis study is a multicenter, prospective, phase II randomized controlled trial. Patients will be randomized 1:1 to the standard treatment arm (primary chemoradiation, consisting of a tumor dose of 64.5 Gy in 30 fractions of external beam radiotherapy with weekly cisplatin for 6 weeks) or the experimental treatment arm (neoadjuvant chemotherapy, consisting of carboplatin and paclitaxel in a 3 weekly scheme, followed by surgery).Major Inclusion/Exclusion CriteriaEligible patients must have a histologically confirmed primary or recurrent locally advanced squamous cell carcinoma of the vulva (International Federation of Gynecology and Obstetrics (FIGO) stages Ib–Iva; Lesions larger than 2 cm in size or stromal invasion larger than 1 mm (T1b or higher), any status of lymph node involvement (any N), no distant metastasis including pelvic lymph nodes (M0)) with the size or localization of the tumor requiring treatment through primary chemoradiation or extensive surgery. Patients with documented metastases of the pelvic lymph nodes will be excluded from participation in this study.Primary EndpointLocoregional control at 24 months.Sample Size98 patients will be included in the study.Estimated Dates for Completing Accrual and Presenting ResultsExpected complete accrual in 2028 with presentation of results by 2030.Trial RegistrationClinicalTrials.gov NCT05905315

Vulval intraepithelial neoplasia is a skin disorder affecting the vulva that, if left untreated, can become cancerous. Currently, the standard treatment for patients with vulval intraepithelial neoplasia is surgery, but this approach does not guarantee cure and can be disfiguring, causing physical and psychological problems, particularly in women of reproductive age. We aimed to assess the activity, safety, and feasibility of two topical treatments—cidofovir and imiquimod—as an alternative to surgery in female patients with vulval intraepithelial neoplasia. We recruited female patients (age 16 years or older) from 32 centres to an open-label, randomised, phase 2 trial. Eligibility criteria were biopsy-proven vulval intraepithelial neoplasia grade 3 and at least one lesion that could be measured accurately. We randomly allocated patients to topical treatment with either 1% cidofovir (supplied as a gel in a 10 g tube, to last 6 weeks) or 5% imiquimod (one 250 mg sachet for every application), to be self-applied three times a week for a maximum of 24 weeks. Randomisation (1:1) was done by stratified minimisation via a central computerised system, with stratification by hospital, disease focality, and presentation stage. The primary endpoint was a histologically confirmed complete response at the post-treatment assessment visit 6 weeks after the end of treatment (a maximum of 30 weeks after treatment started). Analysis of the primary endpoint was by intention to treat. Secondary outcomes were toxic effects (to assess safety) and adherence to treatment (to assess feasibility). We present results after all patients had reached the primary endpoint assessment point at 6 weeks; 2-year follow-up of complete responders continues. This trial is registered with Current Controlled Trials, ISRCTN 34420460. Between Oct 21, 2009, and Jan 11, 2013, 180 participants were enrolled to the study; 89 patients were randomly allocated cidofovir and 91 were assigned imiquimod. At the post-treatment assessment visit, a complete response had been achieved by 41 (46%; 90% CI 37·0–55·3) patients allocated cidofovir and by 42 (46%; 37·2–55·3) patients assigned imiquimod. After 6 weeks of treatment, 156 (87%) patients (78 in each group) had adhered to the treatment regimen. Five patients in the cidofovir group and seven in the imiquimod group either withdrew or were lost to follow-up before the first 6-week safety assessment. Adverse events of grade 3 or higher were reported in 31 (37%) of 84 patients allocated cidofovir and 39 (46%) of 84 patients assigned imiquimod; the most frequent grade 3 and 4 events were pain in the vulva, pruritus, fatigue, and headache. Cidofovir and imiquimod were active, safe, and feasible for treatment of vulval intraepithelial neoplasia and warrant further investigation in a phase 3 setting. Both drugs are effective alternatives to surgery for female patients with vulval intraepithelial neoplasia after exclusion of occult invasive disease. Cancer Research UK.

ObjectiveObesity is associated with worse survival and an increased risk of relapse in several malignancies. The influence of obesity on vulvar cancer recurrence has not been previously described. The primary objective of this study was to evaluate the association between obesity and tumor recurrence in patients with vulvar cancer.MethodsThis is an analysis of the AGO-CaRE-1 study. Patients diagnosed with squamous cell vulvar cancer (stage IB and higher), treated in 29 cancer centers between January 1998 and December 2008, were registered in a centralized database. The cohort was divided into two gropus depending on the body mass index (BMI) (<30 vs ≥30 kg/m²). Descriptive statistics, survival analyses, and multivariate Cox regression analyses were performed in order to evaluate the association between obesity and progression-free and overall survival.ResultsIn 849 (52.4%) of 1618 patients in the database, the BMI was documented. Patients were grouped according to their BMI (<30 vs ≥30 kg/m²). There were 621 patients with a BMI <30 kg/m² and 228 patients with a BMI ≥30 kg/m². Besides age, there was no difference in baseline variables (tumor diameter, depth of infiltration, tumor stage, nodal metastasis, tumor grade). Treatment variables (R0 resection, chemotherapy, radiotherapy, continuation of adjuvant therapy) did not differ between groups. However, patients with BMI ≥30 kg/m² underwent radical vulvectomy more often (61.1% vs 51.8%, p=0.04). During follow-up there was a higher recurrence rate in the group with BMI ≥30 kg/m² (43.4% vs 28.3%, p<0.01) due to an increased rate of local recurrences (33.3% vs 18.5%, p<0.01). There was a significantly shorter time to recurrence in obese patients on univariate analysis (BMI ≥30 kg/m² vs <30 kg/m²: 43.8 months (95% CI 23.3 to 64.3) vs 102.3 months (95% CI 72.6 to 131.9), p=0.001) and on multivariate Cox regression analysis (HR 1.94 (95% CI 1.4 to 2.8), p<0.001).ConclusionsIn this study a BMI ≥30 kg/m² was associated with a shorter time to recurrence in patients with vulvar cancer and this was mainly attributed to a higher risk of local recurrence.

ObjectiveThe incidence of vulvar squamous cell carcinoma has been rising in recent decades. The prognosis of patients with vulvar squamous cell carcinoma was explored, and nomograms were constructed to predict survival rates.MethodsVulvar squamous cell carcinoma patient data were downloaded from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into a training dataset and testing dataset. Univariable and multivariable Cox regression were used to identify risk factors affecting vulvar squamous cell carcinoma overall survival in the training dataset. Cumulative incidence function and Fine–Gray regression were used to analyze cancer specific death in the training dataset. Overall survival and cancer specific death nomograms were constructed and validated in the testing and whole datasets. Receiver operating characteristic and calibration were used to verify the predictive value and clinical applicability of the models.ResultsAge ≥60 years, grade 3, American Joint Committee on Cancer stages III and IV, TNM (tumor, nodes, metastasis) stages T2, T3, N1, and M1 had a negative effect on overall survival in vulvar cancer patients. Surgery (hazard ratio (HR)=0.416, 95% confidence interval (CI) 0.349 to 0.496, p<0.001) and chemotherapy (HR=0.637, 95% CI 0.544 to 0.746, p<0.001) may improve overall survival. Age, tumor grade, American Joint Committee on Cancer stage, T stage, N stage, M stage, surgery, and chemotherapy significantly affected vulvar cancer specific death. For area under the receiver operating characteristic curve, the predictive ability of the nomograms for overall survival and cancer specific death for 1 year (area under the curve (AUC)=0.862), 3 years (AUC=0.832), and 5 years (AUC=0.808) were all >0.800.ConclusionThe nomograms established in our study had an excellent predictive ability for overall survival and cancer specific death in vulvar cancer patients.

The efficacy of local treatment of vulvar intraepithelial neoplasia with imiquimod, an immune-response modifier, was tested in a double-blind, randomized trial. As compared with placebo, imiquimod cream was effective in reducing or eliminating the lesion, relieving symptoms, and clearing the lesion of human papillomavirus. Imiquimod cream was effective in reducing or eliminating vulvar intraepithelial neoplasia, relieving symptoms, and clearing the lesion of human papillomavirus. Surgery, the treatment of choice for vulvar intraepithelial neoplasia, removes all visible lesions, with the aim of relieving symptoms and preventing vulvar cancer. 1 However, there are limitations to surgery. The percentage of lesions with positive surgical margins ranges from 24 to 68%. 2 , 3 Recurrences are common, because surgery does not eliminate human papillomavirus (HPV), the cause of most vulvar intraepithelial neoplasia. 4 , 5 Progression is not influenced by radical excision, 4 , 6 and surgery can mutilate the vulva, thereby causing psychosexual distress. 7 – 10 Thus, alternative treatments are needed. Vulvar intraepithelial neoplasia is caused by HPV, 11 which has prompted the use of imiquimod . . .

Purpose Analyzing the large patient cohort of the multicenter AGO-CaRE-1 study, we compared isolated sentinel lymph node dissection (SLND) with radical lymph node dissection (LND) of the groin in relation to recurrence rates and survival. Methods The AGO-CaRE-1 study retrospectively collected data on treatment patterns and follow-up of vulvar cancer patients [International Federation of Gynecology and Obstetrics (FIGO) stage ≥1B] treated at 29 gynecologic cancer centers between 1998 and 2008. This subgroup analysis evaluated the influence of SLND alone on progression-free survival (PFS) and overall survival (OS). Results In 487 (63.1%) of 772 included patients with tumors smaller than 4 cm, an LND was performed and no metastatic lymph nodes were detected (LN0). Another 69/772 (8.9%) women underwent SLND alone, showing a negative SLN (SLN0). Tumors in the LN0 group were larger and showed a deeper invasion (LN0 vs. SLN0 tumor diameter: 20.0 vs. 13.0 mm, p  < 0.001; depth of invasion: 4.0 vs. 3.0 mm, p  = 0.002). After a median follow-up of 33 months (0–156), no significant differences in relation to isolated groin recurrence rates (SLN0 3.0% vs. LN0 3.4%, p  = 0.845) were detected. Similarly, univariate 3-year PFS analysis showed no significant differences between both groups (SLN0 82.7% vs. LN0 77.6%, p  = 0.230). A multivariate Cox regression analysis, including tumor diameter, depth of invasion, age, grading, and lymphovascular space invasion was performed: PFS [hazard ratio (HR) 0.970, 95% confidence interval (CI) 0.517–1.821] and OS (HR 0.695, 95% CI 0.261–1.849) did not differ significantly between both cohorts. Conclusion This subgroup analysis of the large AGO-CaRE-1 study showed similar results for groin LND and SLND alone with regard to recurrence rates and survival in node-negative patients with tumors <4 cm.

Imiquimod is a standard therapy option for vulvar high-grade squamous intraepithelial lesions (vHSIL). In a retrospective study, the pre-existing composition of the immune cell infiltrate was associated with clinical outcome after imiquimod treatment. To validate these findings, an in-depth analysis of the tumor microenvironment was performed on a vHSIL cohort treated with imiquimod in the prospective PITVIN randomized controlled trial (ClinicalTrials.gov identifier: NCT01861535). Pretreatment biopsies of per-protocol patients participating in the PITVIN trial allocated to the imiquimod arm were included (n=38). These were analyzed by multispectral immunofluorescence using two seven-color staining panels for T cell and myeloid cell composition. Samples were scanned with the Vectra imaging microscope. Cell phenotyping was conducted using semi-supervised machine learning. Quick complete response (qCR) (n=27) was defined as absence of clinical lesions at 16 weeks; slow complete response (n=4) as delayed clearance requiring treatment up to 6 months; and non-response (n=7) as persistent histological vHSIL after 6 months, necessitating extended treatment or surgery. Analysis of the tumor immune microenvironment revealed interpatient variability in immune cell infiltration. Immune infiltrate composition in primary and recurrent vHSIL was comparable and this was also reflected by their clinical responsiveness to imiquimod. Higher numbers of intraepithelial CD3+CD8-(CD4+) T helper cells CD4+FoxP3+ regulatory T cells and CD14+ inflammatory myeloid cells and lower numbers of intraepithelial CD33+ immature cells were detected in qCR when compared with other response groups. Importantly, the lesions of complete responders displayed a positive correlation between the numbers of CD4+, CD8+ T cells and CD14+ inflammatory myeloid cells infiltrating the stroma and epithelium, indicative of a coordinated immune response. Slow complete responders displayed increased intraepithelial infiltration of recently activated CD4+PD1+ T cells (p<0.05), but displayed a lower CD14+ and CD68+ myeloid cell infiltration when compared with qCR. The presence of a pre-existing coordinated infiltration of vHSIL lesions with CD4+ T cells, CD8+ T cells and CD14+ inflammatory myeloid cells in patients displaying a CR after imiquimod treatment confirms our previous findings and suggests their use as biomarkers to predict responsiveness, but may also function as biomarkers to reduce or extend treatment duration of imiquimod.

Current treatment options for patients with locally advanced vulvar cancer are limited and associated with high morbidity. Therefore, it is important to develop new and safe treatment strategies for this vulnerable patient group. To compare the efficacy and safety of neoadjuvant chemotherapy followed by surgery with definitive chemoradiation in patients with locally advanced vulvar cancer. Neoadjuvant chemotherapy followed by surgery is oncologically safe, potentially more effective than primary chemoradiation in establishing long lasting locoregional control, and associated with an improved quality of life. This study is a multicenter, prospective, phase II randomized controlled trial. Patients will be randomized 1:1 to the standard treatment arm (primary chemoradiation, consisting of a tumor dose of 64.5 Gy in 30 fractions of external beam radiotherapy with weekly cisplatin for 6 weeks) or the experimental treatment arm (neoadjuvant chemotherapy, consisting of carboplatin and paclitaxel in a 3 weekly scheme, followed by surgery). Eligible patients must have a histologically confirmed primary or recurrent locally advanced squamous cell carcinoma of the vulva (International Federation of Gynecology and Obstetrics (FIGO) stages Ib-Iva; Lesions larger than 2 cm in size or stromal invasion larger than 1 mm (T1b or higher), any status of lymph node involvement (any N), no distant metastasis including pelvic lymph nodes (M0)) with the size or localization of the tumor requiring treatment through primary chemoradiation or extensive surgery. Patients with documented metastases of the pelvic lymph nodes will be excluded from participation in this study. Locoregional control at 24 months. 98 patients will be included in the study. Expected complete accrual in 2028 with presentation of results by 2030. ClinicalTrials.gov NCT05905315.

Human papillomavirus (HPV), particularly HPV type 16, causes most anal and vulvar high-grade squamous intraepithelial lesions (HSIL), which are precursors to cancer. After initial treatment of HSIL, more than 30% of patients will have disease recurrence, with even higher recurrence among HIV-positive individuals and men who have sex with men. Recurrences can be debilitating and lead to significant morbidity and medical expense. Observational studies suggest a possible therapeutic benefit of the licensed HPV vaccines in reducing recurrent lesions in previously infected persons. To test whether the licensed prophylactic HPV vaccine (Gardasil-9) can reduce the risk of HSIL recurrence by 50% in previously unvaccinated individuals recently treated for anal or vulvar HSIL. This is a trial protocol for a randomized, double-blind, placebo-controlled, proof-of-concept clinical trial. Eligible participants are aged 27 to 69 at study start and have not received prior HPV vaccination, have had anal or vulvar HSIL diagnosed on or after January 1, 2014, and have no evidence of HSIL recurrence at screening. Persons infected with HIV are eligible for the study provided they are receiving antiretroviral therapy. Target enrollment is 345 individuals. The primary outcome is time to histopathologically confirmed recurrence of HSIL. Differences in the risk for recurrence of HSIL will be evaluated using Cox proportional hazard models. Additional analyses include (1) frequency of HSIL recurrence; (2) role of HPV antibodies in deterring recurrence; (3) role of HPV persistence in recurrence, as measured by HPV genotype or HPV-16 variant lineage determined using swab samples collected at months 0, 18, and 36; and (4) incidence of adverse events. The study will be conducted at the University of Washington Virology Research Clinic from 2017 through 2022. Participants will be followed up for up to 36 months in the clinic, and up to 42 months by telephone. Management of persistent or rapidly recurring anogenital HSIL remains challenging. Results from this study will provide evidence on whether incorporating the nonavalent HPV vaccine into routine care can decrease recurrence of anal and vulvar HSIL. ClinicalTrials.gov identifier: NCT03051516.