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Vulvar carcinoma requires multimodal approaches, with an increasing focus on new systemic strategies, including immunotherapies.

A lack of high-level clinical data to guide therapeutic strategy makes the treatment of vulvar carcinoma complex. In addition, the disease frequently spreads to neighboring critical structures, such as the vagina or urethra. Moreover, because of insufficient knowledge and lack of specific screening, diagnosis often is made at advanced stages, reducing the possibility of conservative surgical approaches.

Individualized treatment strategies include organ-sparing surgeries, personalized lymph node staging procedures, modern radiotherapy techniques, systemic treatments on the basis of tumor biology, and best supportive care.

A recent review in the by Cyrus Chargari, MD, PhD, of Sorbonne University in Paris, and colleagues discussed the clinical aspects, biology, and modern treatment strategies of vulvar cancer.

The authors were not available for additional comment, and the answers here are from the text of the report.

What does this review add to the literature?

Epidemiologic data show a recent rise in incidence of vulvar carcinoma, attributed to human papillomavirus (HPV). The mainstay of primary treatment is surgery, but multimodal approaches are frequently required for patients with adverse prognosis histopathologic factors. When organ-sparing surgery is not feasible, chemoradiation is indicated. Inability to achieve high locoregional control rates in advanced cases and the morbidity associated with local treatments remain key issues.

Recent clinical data show the benefit of individualized strategies combining organ-sparing surgical strategies, less invasive lymph node staging procedures, and refinement in radiotherapy modalities. There is a sound rationale for testing modern systemic approaches, such as immune checkpoint inhibitors, in selected patients with recurrent and/or metastatic tumors. The role of supportive care and post-treatment rehabilitation strategies is also crucial, although no specific data exist for vulvar carcinoma.

What are recent advances in surgery?

There have been major efforts to decrease the morbidity and psychological consequences associated with surgery, moving from radical vulvectomy to more conservative and personalized approaches on the basis of wide local excisions.

Advances in reconstructive techniques include vulvar flap procedures that improve healing and reduce reoperation rates. Involvement of surgical margins constitutes a strong prognostic factor. are close to 80%, 65%, and 35% for patients with negative (≥1 cm), close (<1 cm), and positive margins, respectively.

What is the proper treatment of lymph nodes?

Lymph node extension is a major adverse prognostic factor, and inguinofemoral relapses are associated with a dismal prognosis. In case of positive sentinel lymph nodes, an additional treatment of the groins is required to achieve regional control.

International guidelines recommend radiation therapy for patients with micrometastases at the sentinel lymph node. Those with macrometastases are treated with inguinal lymphadenectomy (ILND) followed by additional radiation therapy if there are multiple lymph node metastases. A threshold of at least two positive lymph nodes or extracapsular extension are the criteria for adjuvant radiation therapy after ILND.

When is chemoradiation advised?

When conservative surgery is not feasible, upfront chemoradiotherapy is the standard. Intensity-modulated radiation therapy techniques have become the standard because of higher capacity to spare organs at risk and to perform dose escalation. Retrospective data show the possibility to perform a while sparing uninvolved parts of the vulva with interventional radiation therapy (brachytherapy).

What is the rationale for immunotherapy?

There is a strong rationale for the role of immunotherapy for patients with vulvar carcinoma. The role of HPV infection and immune escape mechanisms in oncogenesis has been well demonstrated. Immunity plays a major role in the oncogenetic process from vulvar neoplasia to vulvar carcinoma, and there is a strong rationale for therapeutic immunomodulation. Immunosuppression decreases HPV clearance and increases the risk of vulvar carcinoma.

Among potential strategies for immunotherapy, inhibitors targeting PD-L1 on tumor cells and PD-1 on T cells are particularly promising. PD-L1 and PD-1 immune checkpoint proteins have a crucial role in controlling antitumor immunity, and their interaction reduces antitumor response by downregulating T-cell activity.

Immunotherapy is emerging as a major tool for the treatment of vulvar carcinoma, with a crucial role for biomarkers of response, such as combined positivity score (CPS) or tumor mutational burden (TMB).

The included 18 patients with vulvar carcinoma treated with pembrolizumab, with an overall response rate (ORR) of 6% and an overall survival (OS) rate of 28% at 12 months. PD-L1 expression by CPS was correlated with ORR and progression-free survival in the eight patients with known PD-L1 status.

The tested pembrolizumab in patients with unresectable or metastatic solid tumors progressing after standard treatment. A total of 71 patients with vulvar carcinoma were included -- 12 with TMB-high and 59 with non–TMB-high tumors. The ORR and median OS were 17% and 10.8 months in TMB-high and 3% and 5.3 months in non–TMB-high patients with vulvar carcinoma, respectively.

PD1 inhibitors are proposed in National Comprehensive Cancer Network guidelines as second-line treatment for patients with recurrent or metastatic vulvar carcinoma expressing PD-L1 with a CPS ≥1, microsatellite instability-high tumor, or TMB-high.

What's your main message for practicing oncologists?

Public health programs for prevention, screening, and early diagnosis are required. Research should be strengthened to provide high-quality clinical evidence and improve patients' oncologic and functional outcomes.

Read the study here.