Owing to the low incidence of vulvar squamous cell carcinoma, it is challenging to study the prognostic impact of postoperative radiotherapy on patients with vulvar squamous cell carcinoma using large randomized controlled trials (Mahner et al. 2015). In recent years, oncologic radiotherapy techniques have developed rapidly. Their role in treating patients with vulvar cancer has received increasing attention (Rao et al. 2017a); however, the effect of postoperative radiotherapy on the survival of patients with squamous cell carcinoma of the vulva is unclear. To obtain data with strong relevance to current clinical practice, this study used clinically relevant data from the SEER database of patients with vulvar cancer from 2010 to 2015. A retrospective analysis revealed a significant survival benefit of postoperative radiotherapy for patients with vulvar squamous cell carcinoma.
Several previous studies have reported the role of radiotherapy in treating patients with vulvar cancer
(Raspagliesi et al. 2006). Ignatov T et al. recruited 257 patients with squamous cell carcinoma of the vulva, divided the enrolled patients into lymph node metastasis positive and negative groups, and found that adjuvant radiotherapy improved the prognosis of lymph node-positive patients (Ignatov et al. 2016). Meanwhile, Macit Arvas et al. studied 107 postoperative vulvar cancer patients with long-term follow-up. They found that postoperative radiotherapy improved the 5-year overall survival rate of patients with positive surgical margins from 29–67.6%, and mortality was significantly reduced in patients with vulvar cancer who received postoperative radiotherapy (Arvas et al. 2018). In a recent clinical study, adjuvant radiation therapy significantly reduced the risk of local recurrence in patients with HPV-positive vulvar cancer compared with patients with HPV-negative vulvar squamous cell carcinoma, significantly improved overall survival, and enhanced the quality of life of patients (Woelber et al. 2022).
The above study analyzed the effects of postoperative radiotherapy on survival outcomes or disease recurrence in patients with vulvar cancer from the perspective of different subgroups of the population. The present study utilizes the multicenter, large sample platform of the SEER database. It uses PSM to balance the clinical characteristics of the two samples, which can be closer to a randomized controlled study and make the results more reliable. According to the inclusion criteria, 3629 patients with vulvar squamous cell carcinoma were enrolled in this study. The effect of postoperative radiotherapy on OS and DSS was analyzed by 1:1 PSM matching according to whether they received postoperative radiotherapy. The results showed that postoperative radiotherapy significantly improved OS and DSS in patients with vulvar squamous cell carcinoma, which is consistent with previously reported findings, suggesting that radiotherapy can be an important complementary treatment for patients with vulvar squamous cell carcinoma after surgery.
Concerning prognostic factors of vulvar cancer, VULCAN retrospectively analyzed the clinicopathological characteristics and prognosis of 1727 patients with vulvar cancer (Zapardiel et al. 2020). Multivariate analysis suggested that tumor stage, tumor size, and lymph node status were independent prognostic factors affecting patients' OS. In addition, the French Society of Radiation Oncology clearly states that the main factors affecting the postoperative prognosis of patients with vulvar cancer include lymph node involvement, tumor stage, and patient age (Chargari et al. 2022). Our cohort was analyzed by multivariate COX regression after PSM analysis, and lymph node surgery was also an independent factor affecting patients' OS and DSS; however, postoperative radiotherapy was not an independent influencing factor in patients with vulvar squamous cell carcinoma.
To further clarify the subgroup population of vulvar cancer benefiting from postoperative radiotherapy and to guide personalized clinical treatment, we conducted a subgroup survival analysis, which showed that among patients receiving radiotherapy, patients with Grade III, IV, AJCC stage III, N1, lymph node metastasis, large tumor diameter, and those receiving chemotherapy had significantly improved OS. A recent study analyzing factors associated with overall survival and disease recurrence in patients with vulvar cancer pointed out that the size of the primary lesion is a vital reference indicator of overall survival (Salani et al. 2017). Tumor diameter is closely related to lymph node metastasis. When the lesion diameter was less than 2 cm, the lymph node metastasis rate was about 23%, while when the lesion diameter was more significant than 2 cm, the lymph node metastasis rate was as high as 47% (Viswanathan et al. 2013). Adjuvant radiotherapy has been shown to significantly prolong the overall survival of patients with advanced disease (Chargari et al. 2022; Miljanović-Špika et al. 2021). In a retrospective analysis of 54 vulvar cancers by S C Han 1 et al, adjuvant radiotherapy was found to significantly improve disease-specific survival (P = 0.03) and overall survival (P = 0.04) in patients with locally advanced vulvar cancer(Han et al. 2000). In this study, survival analysis of the PSM-matched cohort showed a significant improvement in overall survival after postoperative radiotherapy in patients with advanced (stage III, IV, M1) vulvar cancer, which may be associated with better control of disease recurrence with adjuvant radiotherapy.
It has been confirmed that lymph node status, including whether the lymph nodes are metastatic and the number of positive lymph nodes, affects the recurrence of vulvar cancer and the prognosis of patients (Te Grootenhuis et al. 2016; Van der Zee et al. 2008). Meanwhile, the International Federation of Obstetrics and Gynecology guidelines recommend adjuvant radiotherapy as a necessary treatment for lymph node-positive vulvar cancer patients. For patients with lymph node-positive vulvar cancer, adjuvant radiotherapy was associated with a lower risk of local recurrence (25.5% vs. 15.8%) (Woelber et al. 2022). A recent AGO-CaRE 1 study found that adjuvant radiotherapy significantly improved progression-free survival in lymph node-positive vulvar cancer (Mahner et al. 2015).
A study using the National Cancer Database to assess the prognostic impact of radiotherapy on patients with vulvar cancer noted that radiotherapy was significantly associated with higher overall survival than radiotherapy alone (Rao et al. 2017b). A subgroup survival analysis revealed that patients who received radiotherapy were substantially more likely to survive than those who received postoperative radiotherapy alone. This may be related to the fact that some chemotherapeutic drugs such as fluorouracil and cisplatin (Moore et al. 2012), in addition to their anti-tumor effects, also act as radiosensitizers, resulting in a 15%-20% reduction in the dose of radiotherapy, thus reducing the incidence of acute local radiotherapy reactions in patients and improving their tolerability (Blake 2003; Olawaiye et al. 2021; van Triest et al. 2021).
Whether the degree of pathological differentiation of squamous cells affects the prognosis of patients with vulvar cancer treated with postoperative radiotherapy is poorly reported. Further studies are needed to elucidate the mechanisms involved.
Our study has some limitations: first, it is a retrospective study with some selection bias, and PSM minimized the influence of confounding factors on the results. Secondly, the SEER database does not contain indicators of specific radiotherapy methods, radiotherapy sites, and radiotherapy regimens, which also affect patient prognosis.
In conclusion, analysis of vulvar cancer data from the SEER database showed that postoperative radiotherapy improved overall and disease-specific survival in patients with vulvar squamous cell carcinoma. Age, tumor size, and lymph node surgery are independent prognostic factors that affect the survival of patients with vulvar cancer. Postoperative radiotherapy improves survival outcomes in patients with Grade III, IV, AJCC stage III, N1, lymph node metastases, large tumor diameter, and those receiving chemotherapy.