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Precision medicine is looking increasingly promising in advanced vulvar squamous cell carcinomas (VSCCs), which make up 90% of vulvar cancers. The emergence of molecular stratification provides opportunities to tailor treatment, including exploration of how molecular characterization affects response to chemotherapy, radiotherapy, and combined modality treatment.

In a review in the , Helen Mackay, MD, of Odette Cancer Centre of Sunnybrook Health Sciences Centre in Toronto, and colleagues focused mostly on the implications of molecular stratification on the basis of human papilloma virus (HPV) and p53 status on the treatment landscape of advanced disease. (The authors were not available for comment, and the answers here are from the text of the report.)

What does the review add to the literature?

VSCC, a rare gynecologic malignancy, has been rising in incidence. Molecular classification on the basis of HPV and p53 status has identified three clinically distinct subtypes, but we still treat all VSCCs the same. Our review focuses on the molecular classification of VSCC, outlines the treatment landscape, and highlights the potential for targeted therapies in advanced VSCC.

Incorporation of HPV and p53 status in locoregional treatment decision-making has the potential to advise (de)escalation strategies. The role of immunotherapy, alone and in combination, requires further exploration, particularly earlier in the course of the disease.

In advanced stages, the potential for targeted therapies in VSCCs include inhibitors of vascular endothelial growth factor, endothelial growth factor receptor, cell cycle, and DNA damage response, particularly in HPV-negative (HPV–) VSCCs.

Targeting the phosphoinositide 3 kinase/mammalian target of rapamycin pathway is attractive in HPV-positive and HPV–/p53 wild-type VSCCs.

Trials incorporating antibody-drug conjugates (for example, trophoblast cell-surface antigen 2, human epidermal growth factor receptor 2) should be considered, and basket trials in perineal squamous cell cancers are warranted. Preclinical models are limited and should be expanded to inform trial design.

What is the current treatment for VSCC patients?

As noted, despite advances in our understanding of this disease, we currently treat all VSCC patients the same. Primary treatment of localized VSCC is surgical, with significant improvements made in recent decades, including wide local excision, which has largely replaced radical vulvectomy for early-stage disease.

Assessment of groin lymph nodes has transitioned from en-bloc resection to separate inguinal incisions and finally to sentinel lymph node biopsy in appropriately selected patients. These modifications have maintained oncologic outcomes while reducing morbidity.

When complete surgical resection is not possible, treatment with combined chemotherapy and radiotherapy is considered -- an approach extrapolated from experience with cervical and anal cancers.

The use of systemic therapy is largely on the basis of small studies and extrapolated from the treatment of cervical cancer. As with other rare cancers, the understanding of disease biology and investigation of new therapeutic strategies has been slow, with limited funding directed toward researching this disease. Hence, vulvar cancer represents an area of high unmet clinical need.

How can eligibility criteria in clinical trials better reflect the real-world needs of vulvar cancer patients?

Consideration and inclusion of vulvar cancer patients in clinical trials on the basis of their molecular, transcriptomic, and immunohistochemistry profiles with data sharing has the potential to better define agents that may contribute to improvements in survival.

The challenges posed by vulvar cancer are compounded by the physical and psychological impact of this disease in what is frequently a frail patient population. More inclusive patient eligibility criteria for clinical trials, including removal of performance status restrictions, are needed to reflect the real-world needs of patients with vulvar cancer.

Involvement of patients, families, and stakeholders in the design of pragmatic clinical trials addressing symptomatic and supportive care with meaningful end points that improve quality of life is essential. A holistic and collaborative effort is required by the clinical and scientific gynecologic oncology community to achieve much needed multidomain improvements in the lives of women diagnosed with this cancer.

What is the main message for practicing oncologists?

Like other rare cancers, vulvar cancer lags behind in the identification and optimization of precision medicine strategies. Molecular-based preclinical models and rationally designed clinical trials, incorporating high-quality translational studies, are urgently required. These trials will require international collaboration to ensure feasibility and improvement of outcomes for women diagnosed with this disease.

Read the review here.