Chi_Principles and Practice of Gynecologic Oncology 8e

Chapter 2.6 ■ Therapy for Vulvar Cancer: Radiation, Systemic Therapy, and Treatment of Persistent and Recurrent Disease 21

rather than a therapeutic procedure. In a multivariate analysis of 644 patients with vulvar melanoma, Sugiyama et al (22) reported 5-year disease-specific survival rates of 68%, 29%, and 19% for pa tients with zero, one, and two or more positive LNs, respectively. Lymphadenectomy can be avoided in patients with superficial melanomas ( < 1 mm), for whom the risk of metastatic disease is negligible. SLN identification and biopsy have been increasingly applied to the surgical management of cutaneous malignant mela nomas, and multiple authors assert that for those surgeons who are competent with the technique, SLN mapping and biopsy should be considered a standard practice (20,21). Historically, systemic therapy for high-risk localized or met astatic melanoma was considered strictly palliative; durable responses were rare, and adverse effects were considerable. In terferon α-2b, dacarbazine, temozolomide, and platinum-based cytotoxic therapies have shown activity in patients with small-­ volume tumor burden; however, toxicities are considerable, with limited improvements in survival (20). More recently, with im proved molecular characterization of cutaneous (nonvulvar) melanomas and the development of multiple targeted inhibitors that have dramatically improved survival for this disease, sys temic therapies for high-risk localized as well as metastatic and recurrent melanoma follow the evolving treatment paradigms of nonvulvar malignant melanoma. Examples of such targets with associated inhibitors are B-Raf (vemurafenib), c-Kit (imatinib), and CTLA-4 (ipilimumab) (23). A more involved discussion of systemic therapy for melanoma is beyond the scope of this chapter. For those gynecologic oncologists without considerable experience in the treatment of patients with melanoma, we rec ommend early referral for patients with high-risk localized vulvar or metastatic melanoma to a medical oncologist or gynecologic oncology center that specializes in the systemic care of patients with malignant melanoma. Patients with superficial lesions have an excellent chance for cure after surgical resection; however, patients with deeper lesions, or metastases at the time of diagnosis, have a worse prognosis. These patients are good candidates for investigational trials. Basal Cell Carcinoma Basal cell carcinomas (BCCs) should be removed by excisional biopsy using a minimum surgical margin of 1 cm. Lymphatic or distant spread is exceedingly rare (24). Local recurrence may hap pen, particularly in tumors removed with suboptimal resection margins. Adenocarcinoma Patients presenting with vulvar adenocarcinoma should first un dergo a clinical evaluation to determine whether the lesion in question is a vulvar cancer or a metastasis. Despite the paucity of data regarding the evaluation and treatment of vulvar adeno carcinoma, resection of localized disease with a radical margin is recommended by radical wide excision, and hemivulvectomy or radical vulvectomy seems appropriate (25). Some form of inguinal lymphadenectomy should be included with primary surgical resec tion. RT may have a role in enhancing local control for women with large primary tumors or inguinal metastases. Paget Disease Paget disease is associated with a concurrent underlying invasive adenocarcinoma component in approximately 15% of cases (26). As many as 20% to 30% of these patients will have or will later de velop an adenocarcinoma at another nonvulvar location (27,28), although more recent series suggest a lower incidence of second ary malignancies (29). Observed sites of nonvulvar malignancies developing in patients with extramammary Paget disease include breast, lung, colorectum, gastric area, pancreas, and upper female genital tract. Screening and surveillance for tumors at these sites should be considered in patients with Paget disease.

Paget disease should be resected with at least a 1-cm margin. If underlying invasion is suspected, the deep margins should be ex tended to the perineal fascia. Black et al (30) showed that patients with microscopically positive margins had a significantly higher rate of recurrence; however, with extended follow-up, all patients eventu ally recurred. Others have shown that despite surgical efforts to the contrary, microscopically positive margins are frequent, and disease recurrence is common regardless of margin status. Repeat local exci sion of recurrent disease is usually effective in the absence of invasion (28). Reportedly, topical imiquimod also has activity in extramam mary Paget disease. In several small case series, complete response (CR) rates of as much as 92% have been reported (31,32). There are case reports of Paget disease treated with either adjuvant RT or de finitive RT for medically inoperable or recurrent disease. A Cochrane review in 2019 reported use of RT as primary modality in 14 patients, although radiation treatment regimens and doses were not consis tently reported (33). Some authors have suggested that when Paget disease is treated with RT, a dose of 40 to 50 Gy is recommended for intraepithelial Paget and 55 to 65 Gy for invasive Paget disease (34). R adiation T herapy Early accounts of poor survival rates after primary RT of vulvar car cinomas led some investigators to surmise that RT had a narrow therapeutic role in the curative management of patients with vulvar cancer (35). The use of high doses of radiation alone, delivered with low-energy cobalt-60 photons and en face electron boosts, in patients who were mostly poor surgical candidates resulted in a suboptimal therapeutic benefit between tumor control probability and normal tissue complications (36). More modern-day practices, such as in corporating consecutive daily fractionation, attention to dosimetric planning detail, and appreciation of vulvar and low pelvic radiation tissue tolerance limits, have undoubtedly shown that relatively high doses of radiation can be delivered safely. RT is now accepted as an important element in the multidisciplinary management of patients with vulvar cancer both as adjuvant therapy for early-stage disease and as preoperative or definitive therapy for locally advanced disease. Adjuvant Radiotherapy to the Vulva Standard of care for early-stage vulvar cancer includes surgical resection where possible without causing excess morbidity or dis figurement. Following initial resection of a vulvar primary tumor, various surgicopathologic features are associated with a higher risk of local recurrence, including tumor margins less than 8 mm after tissue fixation (deep or at the skin surface), lymphovascular space invasion (LVSI), and deep tumor penetration (37,38). Avoidance of local recurrence is critical given poor salvage rates, particularly among those with nodal relapse. Although no prospective trials of postoperative vulvar site RT have been completed, adjuvant radiation of the primary tumor bed in selected patients with close/positive margins or multiple other high risk features (LVSI, depth > 1 cm, or size > 4 cm with high-grade histology) does improve vulvar tumor control (39-41). For example, in a retrospective series by Faul et al (40), patients with positive sur gical margins had a significant reduction (33% vs 69%) in the risk of locoregional recurrence, if receiving adjuvant RT. A similar benefit was seen for patients with close surgical margins (5% vs 31%). More recent data indicate a potential dose-response relation ship for patients with close ( ≤ 5 mm) or positive margins, where patients receiving 56 Gy or more had lower rates of vulvar recur rence compared with 50.4 Gy or less (21% vs 34%, P = .046) (41). A large national database study furthermore showed a survival ad vantage for patients with positive margins treated with RT dose of 54 Gy or more, with no benefit to doses above 60 Gy compared with 54.0 to 59.9 Gy (42). In combination, the data suggest that patients with close/positive margins benefit from adjuvant RT to the vulva to reduce risk of relapse. Nonetheless, after RT, the rates of locoregional relapse remain elevated, suggesting that reexcision, when feasible, may be appropriate (40,41).

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