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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

Background Unresectable or metastatic vulvar cancer has relatively poor outcomes despite chemotherapy-sensitized radiation therapy and combination cytotoxic therapy. Despite the virus-associated and immunogenic nature of this disease, novel immunotherapy options that exploit this advantage are currently lacking. Platinum agents such as cisplatin have been shown to prime dendritic cells for T-cell costimulation, promote downregulation of inhibitory checkpoint molecules, and sensitize tumor cells to cytotoxic T-cell killing. Radiation therapy has also been shown to promote immunogenetic cell death as monotherapy and in combination with cisplatin. In combination with pembrolizumab, cisplatin-sensitized radiation is hypothesized to increase overall response rates and recurrence-free survival in patients with vulvar cancer, via induction of an anti-tumor inflammatory response. Methods We propose a single-arm phase II clinical trial of pembrolizumab combined with cisplatin-sensitized radiation therapy for women with unresectable, locally advanced, or metastatic vulvar cancer. The first three patients with locally advanced or unresectable disease will receive cycle 1 of pembrolizumab followed by a break and resumption of pembrolizumab at cycle 4 and as part of a safety cohort. All other patients, including the fourth patient with locally advanced/unresectable disease, will receive weekly cisplatin and pembrolizumab every 3 weeks, concurrently with daily radiation therapy. Following the completion of Cis-RT, patients will continue pembrolizumab maintenance for a total of 12 cycles. Archived tissue will be used for HPV status, MSI status, PD-L1, and TIL stratification post hoc. Imaging will be performed at baseline and every 3 cycles (21-day cycles) as per standard-of-care. Laboratory analysis will occur on the first day of each cycle. Discussion The combination of cisplatin-sensitized radiation and immune checkpoint blockade has not been evaluated in the upfront setting for vulvar cancer. In this rare malignancy, there are limited interventional clinical trials. This trial is designed to be as accessible as possible by allowing patients to receive cisplatin and radiation locally according to accepted standard-of-care while receiving pembrolizumab and adverse event monitoring at a centralized site. A robust suite of translational correlative studies has also been built into the trial to evaluate tumor-directed immune activation. Trial registration NCT04430699

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.

Background Each year, 45,000 women worldwide develop vulvar cancer, often occurred from vulvar high-grade squamous intraepithelial lesions (vHSIL), a precancerous stage associated with high- risk human papillomavirus (HPV). Recurrent vHSIL, experienced by over 30% of patients despite treatment, conducting in significant physical and psychosocial challenges. With no established method to reduce recurrence, our study investigates the potential of adjuvant HPV vaccination during treatment. We aim to determine whether nonavalent HPV vaccination can effectively prevent vHSIL recurrence in women treated for vulvar HSIL. Methods This is a randomized, double-blind, placebo-controlled study protocol involving 498 women diagnosed with vHSIL. Participants will be randomized to receive either the nonavalent HPV vaccine or a placebo in addition to standard treatment. The primary outcome is the recurrence of vHSIL within 24 months following treatment. Secondary endpoints are treatment effectiveness, immune response, cost-effectiveness, and quality of life. Long-term follow-up examines vaccine effect after 5 and 10 years, along with the occurrence of vulvar malignancies. Relative risk between vaccinated and placebo groups will be evaluated, employing intention-to-treat principles. Discussion This study is designed to investigate the potential benefits of HPV vaccination in managing vHSIL. Results from the trial will provide evidence on the vaccine’s impact on recurrence rates, treatment outcomes, and long-term prevention of vulvar malignancies. Trial registration ClinicalTrials.gov. Identifier: NCT06052696. Registered 12 January 2023, https://clinicaltrials.gov/study/NCT06052696 .

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.

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.

The main objective of this study was to describe the clinical, pathological and treatment characteristics of patients with vulvar cancer who had surgery and or radiotherapy at Steve Biko Academic Hospital. The absolute and relative disease burden, trends over the time period were also analyzed. This was a retrospective study that described women with vulvar cancer who presented to the Gynaecology Oncology and Radiation Oncology departments of the hospital between January 2012 and December 2022. Their clinical, pathology and radiotherapy treatment records were reviewed for this study. 317 vulvar cancer cases between 2012 and 2022 were included in the analysis. The average age was 45.1±12.7. Forty percent of the participants were younger than 40 years. More than 75% of them were women living with HIV and were all on antiretroviral treatment. The average age of those who were HIV positive was 20 years lower than their HIV negative counterparts, p <0.0001. Their mean haemoglobin (Hb) at presentation was 10.7g/dL. Squamous cell carcinoma was the most common histological type in 96.5% of cases. Sixty four percent of the cases presented in advanced stage. About 48% of those who had primary radiation received curative doses. The median time to completion of radiotherapy treatment was higher among those who received primary radiotherapy as compared to those who received adjuvant treatment, 51.5 vs 46 days, p 0.039. The annual average age decreased from 56 years to as low as 40 years, a mean difference of 16 years, p 0.012. It is striking that vulvar cancer is no longer a disease of elderly women. Its incidence is now high among women below 50 years. The study also showed an upward trend in the number of vulvar cancer cases in contrast to the declining average age at diagnosis. There is need for more vulvo-perineal surveillance of HIV positive women to detect early stage of vulvar cancers.

ObjectiveThe aim of this study was to analyze the prognostic factors related to the recurrence rate and overall survival of vulval melanoma patients by means of a subgroup analysis of the VULvar CANcer study.MethodsThe international multicenter VULvar CANcer study involved 100 international centers, which contributed 2453 vulvar cancer cases. Of the 1727 patients finally included in the study, 42 were suffering from vulvar melanoma (2.4%).ResultsThe mean follow-up for vulval melanoma patients was 44.1±35.7 months. Recurrence rate was 50%, and the mean recurrence-free survival was 43.5±6.6 months. For local recurrences, the mean recurrence-free interval was 63.3±8.6 months; for metastasis, 33.5±3.5 months. The 5-year recurrence-free survival rate was 28.6%. The mean overall survival for vulvar melanomas was 45.9±4 months and the 5-year overall survival rate was 78.6%. The only factor with prognostic significance regarding local recurrence of vulvar melanoma was tumor size (P = 0.003). American Joint Committee on Cancer staging was the only prognostic factor associated with metastatic disease at recurrence (P < 0.001). Finally, age of patient was significantly associated with overall survival (P < 0.001).ConclusionsTumor size and American Joint Committee on Cancer stage were independent prognostic factors associated with local and distant recurrence, respectively. Patients’ age was the only independent prognostic factor associated with overall survival.

Background: Electrochemotherapy (ECT) is a combined treatment method based on electroporation and simultaneous chemotherapy. In cases where radiotherapy has previously been used, surgery is often the only treatment option for vulvar cancer recurrence with potential resection of clitoris, vagina, urethra or anal sphincter. The unique advantage of ECT is its selectivity for cancer cells while sparing the surrounding healthy tissue. The aim of the study was to compare the ECT treatment of vulvar cancer recurrence for non-palliative purposes with surgical treatment. Materials and methods: Eleven patients with single vulvar cancer recurrence were treated with ECT and followed up for 12 months. As a control group, 15 patients with single vulvar cancer recurrence were treated with wide local excision. The following data were collected, analyzed and compared: Age, body mass index, comorbidities, histological type, location and size of vulvar cancer recurrence, treatment history, details of procedures and hospital stay. Results: The probability curves for local tumor control did not differ between the ECT group and the surgical group (p = 0.694). The mean hospital stay and the mean duration of procedure were statistically significantly shorter in the ECT group (p < 0.001). There were no statistically significant differences between the ECT and surgical groups in terms of mean body mass index, associated diseases, previous treatments, presence of lichen sclerosus, p16 status, gradus, anatomical site of the tumor, and type of anesthesia. Conclusion: In this case-control study, treatment of vulvar cancer recurrence with ECT for non-palliative purposes was comparable to surgical treatment in terms of effectiveness. The results need to be confirmed in larger randomized trials.

Background Usual type vulvar intraepithelial neoplasia (uVIN) is caused by HPV, predominantly type 16. Several forms of HPV immunotherapy have been studied, however, clinical results could be improved. A novel intradermal administration route, termed DNA tattooing, is superior in animal models, and was tested for the first time in humans with a HPV16 E7 DNA vaccine (TTFC-E7SH). Methods The trial was designed to test safety, immunogenicity, and clinical response of TTFC-E7SH in twelve HPV16 + uVIN patients. Patients received six vaccinations via DNA tattooing. The first six patients received 0.2 mg TTFC-E7SH and the next six 2 mg TTFC-E7SH. Vaccine-specific T-cell immunity was evaluated by IFNγ-ELISPOT and multiparametric flow cytometry. Results Only grade I-II adverse events were observed upon TTFC-E7SH vaccination. The ELISPOT analysis showed in 4/12 patients a response to the peptide pool containing shuffled E7 peptides. Multiparametric flow cytometry showed low CD4 + and/or CD8 + T-cell responses as measured by increased expression of PD-1 (4/12 in both), CTLA-4 (2/12 and 3/12), CD107a (5/12 and 4/12), or the production of IFNγ (2/12 and 1/12), IL-2 (3/12 and 4/12), TNFα (2/12 and 1/12), and MIP1β (3/12 and 6/12). At 3 months follow-up, no clinical response was observed in any of the twelve vaccinated patients. Conclusion DNA tattoo vaccination was shown to be safe. A low vaccine-induced immune response and no clinical response were observed in uVIN patients after TTFC-E7SH DNA tattoo vaccination. Therefore, a new phase I/II trial with an improved DNA vaccine format is currently in development for patients with uVIN.