Chi_Principles and Practice of Gynecologic Oncology 8e

26 SECTION 2 ■ Vulvar Cancer

m 2 , q21d) + vinorelbine (25 mg/m 2 , d1, d8) in 16 chemotherapy-naïve patients; 15 patients were evaluable for response, and ORR was 40%, with 4 CRs, 2 PRs, and 5 patients with stable disease. Median progression-free survival (PFS) was 10 months, with a median OS of 19 months. Toxicity was considered manageable, with nausea/­ vomiting and leukopenia the primary grade 3 and 4 toxicities (90). In HPV-negative vulvar SCC, high levels of EGFR expression are associated with advanced disease and worse outcome, which led to interest in the use of EGFR tyrosine kinase inhibitors (TKIs) in patients with advanced and recurrent vulvar cancer (91-93). A phase II prospective GOG trial using erlotinib in 41 patients with advanced or recurrent vulvar cancer described PRs in 28% and sta ble disease (SD) in 40% of patients. Unfortunately, responses were not durable, and grade 3 and 4 toxicities (diarrhea, dehydration, and renal failure) were notable (91). Extrapolating from cervical cancer data showing the benefit of bevacizumab, an anti–vascular endothelial growth factor (VEGF) agent, this agent has been used in combination with cisplatin and paclitaxel for recurrent/metastatic vulvar squamous cell cancer as well (94). Patients with vulvar melanoma harboring KIT mutations may benefit from KIT or MAPK targeted agents (95). The use of immunotherapy in vulvar cancer is an evolving area of research. A phase II study on the single-agent nivolumab for pa tients positive for HPV has shown promising results (96), and on going studies are investigating the use of pembrolizumab (97,98). R eferences 1. Heller DS, Day T, Allbritton JI, et al. Diagnostic criteria for differenti ated vulvar intraepithelial neoplasia and vulvar aberrant maturation. J Low Genit Tract Dis . 2021;25(1):57-70. 2. Tristram A, Hurt CN, Madden T, et al. Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT(3)VIN): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol . 2014;15:1361-1368. 3. Krupp PJ, Bohm JW. 5-fluorouracil topical treatment of in situ vulvar cancer. A preliminary report. Obstet Gynecol . 1978;51(6):702-706. 4. Klapdor R, Wölber L, Hanker L, et al. Predictive factors for lymph node metastases in vulvar cancer. An analysis of the AGO-CaRE-1 multi center study. Gynecol Oncol . 2019;154(3):565-570. 5. Yoder BJ, Rufforny I, Massoll NA, Wilkinson EJ. Stage 1A vulvar squa mous cell carcinoma: an analysis of tumor invasive characteristics and risk. Am J Surg Pathol . 2008;32:765-772. 6. Homesley HD, Bundy BN, Sedlis A, et al. Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study). Gynecol Oncol . 1993;49:279-283. 7. Chafe W, Richards A, Morgan L, et al. Unrecognized invasive carcinoma in vulvar intraepithelial neoplasia (VIN). Gynecol Oncol . 1988;31(1):154-165. 8. Modesitt SC, Waters AB, Walton L, et al. Vulvar intraepithelial neo plasia III: occult cancer and the impact of margin status on recurrence. Ob stet Gynecol . 1998;92(6):962-966. 9. Burke TW, Levenback CF, Coleman RC. Surgical therapy of T1 and T2 vulvar carcinoma—further experience with radical wide excision and selective inguinal lymphadenectomy. Gynecol Oncol . 1995;57(2):215-220. 10. de Mooij Y, Burger MP, Schilthuis MS, et al. Partial urethral resection in the surgical treatment of vulvar cancer does not have a significant impact on urinary continence. A confirmation of an authority-based opinion. Int J Gynecol Cancer . 2007;17(1):294-297. 11. Moore DH, Ali S, Koh WJ, et al. A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: a Gynecologic Oncology Group study. Gynecol Oncol . 2012;124(3):529-533. 12. Kunos C, Simpkins F, Gibbons H, et al. Radiation therapy compared with pelvic node resection for node-positive vulvar cancer: a randomized controlled trial. Obstet Gynecol . 2009;114(3):537-546. 13. te Grootenhuis NC, van der Zee AG, van Doorn HC, et al. Sentinel nodes in vulvar cancer: long-term follow-up of the GROningen INterna tional Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I. Gynecol Oncol . 2016;140(1):8-14. 14. Oonk MHM, Slomovitz B, Baldwin PJW, et al. Radiotherapy versus inguinofemoral lymphadenectomy as treatment for vulvar cancer patients with micrometastases in the sentinel node: results of GROINSS-V II. J Clin Oncol . 2021;39(32):3623-3632.

C hemotherapy Primary Treatment of Advanced Disease Chemotherapy monotherapy is an option for the palliative treat ment of advanced disease. However, patients with advanced vulvar cancers tend to be older, with significant medical comorbidities, making them poor candidates for cytotoxic therapy because of concomitant diseases that increase the likelihood of significant ad verse effects. Furthermore, recurrent vulvar cancer often occurs in the setting of extensive prior surgery and/or RT, making tolerance to cytotoxic therapy poor. Neoadjuvant Chemotherapy In order to reduce the morbidity of subsequent curative intent surgi cal therapy, a number of small studies have been performed to assess the feasibility of neoadjuvant chemotherapy in advanced primary vulvar cancer not initially amenable to surgery or RT. SCC is the only histologic type of vulvar cancer for which there are data assess ing this approach. Geisler et al treated 13 patients with neoadjuvant cisplatin (50 mg/m 2 ) and 5-FU (1,000 mg/m 2 /24 hours) q3w ( n = 10 cisplatin and 5-FU, n = 3 cisplatin only). The combination achieved CRs in 100% of patients (10% CR); 9/10 patients then underwent radical vulvar resection and inguinofemoral lymphadenectomy. In all patients, preservation of anal and urethral sphincter function was achieved; 9/9 patients who completed both neoadjuvant chemother apy and surgery remained alive and free of disease at 49 months (84). In a more recent prospective study of 10 patients with advanced primary vulvar cancer whose only curative option was PE com bined with neoadjuvant chemotherapy, patients were offered ei ther paclitaxel (175 mg/m 2 , d1) + ifosfamide (5 mg/m 2 , d2) + cisplatin (70 mg/m 2 , d1) [TIP], or paclitaxel (175 mg/m 2 , d1) + cisplatin (70 mg/m 2 , d1) [TP] at the discretion of the treating physician (TIP n = 4, TP n = 5). Overall response rate (ORR) was 80%; 9/9 patients underwent radical surgery with inguinofemoral lymph adenectomy, and all were disease-free at completion of primary combined therapy. After a median follow-up of 40 months, 56% of patients were alive and without evidence of disease (NED) (85). A prospective multicenter trial compared four cisplatin-based regimens and one bleomycin-based regimen in 35 patients with ad vanced vulvar cancer; 33 of 35 patients completed chemotherapy, with PRs noted in 30 patients and stable disease noted in 3 patients; 27 patients subsequently underwent radical surgery (25 with in guinofemoral lymphadenectomy). Of 16 patients with clinically ap parent nodes before treatment, 11 were found with residual nodal disease, and they then underwent CRT. At a median of 49 months of follow-up, 24 of 27 patients remained NED (86). Before neoadjuvant therapy is considered a standard approach in advanced patients, further study involving larger numbers of patients and more controlled therapy regimens is recommended. Systemic Treatment of Metastatic and Recurrent Vulvar Cancer Despite the success of curative intent therapies in patients with ad vanced vulvar cancer, a significant proportion of patients will recur (40%-50%), and 5-year OS in this group of patients is less than 10% (62,87). Unfortunately, in view of the rarity of this disease, there is no clear standard for treatment of patients with metastatic or recurrent disease who are not amenable to surgery or RT. As a result, most pa tients are treated with regimens extrapolated from study of chemo therapy in metastatic SCC of the cervix or anus. Accordingly, most patients are treated with cisplatin-based combination regimens, with or without bevacizumab. Additional systemic therapy options under investigation include targeted agents and/or immunotherapy. Early studies in vulvar cancer with single-agent cytotoxic chemo therapies such as piperazinedione, cisplatin (50 mg/m 2 , q21d), and mitoxantrone were disappointing, with no responses noted (88,89). A prospective phase II study evaluated the use of cisplatin (80 mg/

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