Treatment Option Overview
Standard primary treatment for vulvar cancer is surgery. Radiation is usually added to surgery in patients with stage III or IV disease.[1-3] Newer strategies have integrated surgery, radiation therapy, and chemotherapy and tailor the treatment to the extent of clinical and pathologic disease. Patterns of practice in combining these treatments vary.
Since invasive and preinvasive neoplasms of the vulva may be HPV-induced and the carcinogenic effect may be widespread in the vulvar epithelium, patients should be followed regularly for symptoms or signs of recurrence. Because there are few patients with advanced disease (stages III and IV), only limited data are available on treatment efficacy in this setting, and there is no standard chemotherapy regimen for these patients. Physicians should offer eligible patients with stage III or IV disease participation in clinical trials.
Information about ongoing clinical trials is available on the NCI Web site.
Role of Surgery
Until the 1980s, the standard therapeutic approach to therapy for invasive locoregional vulvar carcinomas was radical surgery, including complete en bloc resection of the vulva and regional lymph nodes. Because of the high attendant complication rates, wound healing problems, lymphedema, and functional deficits, the trend since then has been toward more limited surgery, often combined with radiation therapy. (Refer to the Role of Radiation Therapy section of this summary for more information.)
In tumors clinically confined to the vulva or perineum, radical local excision with a margin of at least 1 cm has generally replaced radical vulvectomy; separate incision has replaced en bloc inguinal node dissection; ipsilateral inguinal node dissection has replaced bilateral dissection for laterally localized tumors; and femoral lymph node dissection has been omitted in many cases. However, the different surgical techniques have not been directly compared in randomized controlled trials. In addition, even the nonrandomized studies suffer from lack of uniform staging definitions and clear descriptions of lymph node dissection or ancillary radiation.[Levels of evidence: 3iiiDii, 3iiiDiv] The evidence base is therefore limited.
Another strategy to minimize the morbidity incurred by groin-node dissection in patients with early clinical-stage disease is sentinel node dissection, reserving groin dissection for those with metastases to the sentinel node(s).
In a multicenter case series, 403 patients with primary vulvar squamous cell cancers smaller than 4 cm and clinically negative groin nodes underwent 623 sentinel node dissections using radioactive tracer and blue dye for sentinel node identification. All patients had radical resection of the primary tumor. Node metastases were identified in 26% of sentinel node procedures, and these patients went on to full inguinofemoral lymphadenectomy. The patients with negative sentinel nodes were followed with no further therapy.
Local morbidity was much lower in patients who underwent sentinel node dissection than in patients with positive sentinel nodes who also underwent inguinofemoral lymphadenectomy (wound breakdown 11.7% vs. 34.0%; cellulitis 4.5% vs. 21.3%; chronic lymphedema 1.9% vs. 25.2%, respectively) (P < .0001 for all comparisons). Mean hospital stay was also shorter (8.4 vs. 13.7 days) (P < .0001). After two local recurrences in 17 patients with multifocal primary tumors, the protocol was amended to only allow patients with unifocal tumors into the study. Actuarial groin recurrence for all patients with negative sentinel node dissections at 2 years was 3% (95% confidence interval [CI], 1%–6%) and 2% (95% CI, 1%–5%) for those with unifocal primary tumors.[Level of evidence: 3iiiDiv]
Therefore, sentinel node dissection may be useful when performed by a surgeon experienced in the procedure, and it may avoid the need for full groin node dissection or radiation in patients with clinically nonsuspicious lymph nodes. (Refer to the Role of Radiation Therapy section of this summary for more information.)
Role of Radiation Therapy
Groin lymph node metastases are present in approximately 20% to 35% of patients with tumors clinically confined to the vulva and with clinically negative nodes.[7,8] Lymph node dissection is traditionally part of the primary surgical therapy in all but the smallest tumors. However, a major cause of morbidity after surgery is groin node dissection, which is associated with high rates of wound breakdown, lymphocele formation, and chronic lymphedema. Some investigators recommend radiation therapy as a means to avoid the morbidity of lymph node dissection, but it is not clear whether radiation therapy can achieve the same local control rates or survival rates as lymph node dissection in early stage disease.
A randomized trial to address the radiation therapy issue in patients with clinically localized vulvar cancer has been reported.[8,9] In that study, women with disease clinically confined to the vulva, who did not have groin lymph nodes clinically suspicious for metastases, underwent radical vulvectomy followed by either groin radiation (50 Gy in 2 Gy fractions) or groin dissection (plus groin radiation if nodes were pathologically involved).
Although the planned accrual was 300 patients, the study was stopped after 58 women were randomly assigned to it because of worse outcomes in the radiation therapy arm. Five (18.5%) of 27 women in the radiation therapy arm and 0 of 25 women in the surgery arm had a groin recurrence, but this difference was not statistically significant (relative risk [RR], 10.21; 95% CI, 0.59–175.78). There were ten deaths in the radiation therapy arm versus three deaths in the groin dissection study arm (RR, 4.31; 95% CI, 1.03–18.15). Disease-specific mortality was not statistically significantly different between the two arms; however, there were eight versus two vulvar cancer-related deaths (including one related to groin dissection), in the radiation therapy arm and groin dissection arm, respectively (RR, 3.70; 95% CI, 0.87–15.80).[8,9][Level of evidence 1iiA] There were fewer cases of lymphedema in the radiation therapy arm (0 vs. 7) and shorter hospital stays. The dose penetration of the radiation (3 cm for full dose) has been criticized as inadequate. In summary, the trial was stopped prematurely, and little can be said about the relative efficacy of the two treatment approaches.
Pelvic radiation has been compared to pelvic node dissection in the setting of documented groin node-positive disease. Patients with clinical stage I to stage IV primary squamous cell carcinoma of the vulva in whom groin nodal metastases were found at radical vulvectomy and bilateral groin node dissection were randomly assigned during the surgical procedure to receive either ipsilateral pelvic node resection or pelvic radiation (45 Gy–50 Gy at 1.8 Gy–2.0 Gy per fraction). Because of a perceived emerging benefit of radiation, the planned accrual of 152 was stopped after 114 patients were randomly assigned. However, the apparent benefit of radiation was subsequently attenuated with further follow-up.
After a median follow-up of 74 months, the 6-year overall survival (OS) rate was 51% in the radiation arm versus 41% in the pelvic node dissection arm (hazard ratio [HR], 0.61; 95% CI, 0.3–1.3; P = .18). Vulvar cancer-specific mortality was statistically significantly lower in the radiation study arm (29% vs. 51% in the pelvic node resection arm) (HR, 0.49; 95% CI, 0.28–0.87; P = .015) However, there were 14 intercurrent deaths in the radiation therapy arm versus two deaths in the pelvic dissection study arm. Late chronic lymphedema was similar in the radiation therapy and pelvic dissection groups arms (16% vs. 22%), respectively.[Level of evidence: 1iiB]
Role of Chemotherapy
There is no standard chemotherapy for vulvar cancer, and reports describing the use of this modality in the setting of metastatic or recurrent disease are anecdotal. Extrapolating from regimens used for anal or cervical squamous cell cancers, chemotherapy has been studied in combination with radiation in the neoadjuvant setting or as primary therapy in advanced disease. Chemotherapy regimens have included various combinations of 5-fluorouracil (5-FU), cisplatin, mitomycin-C, or bleomycin. There is no clear evidence of improvement in survival or palliation. Given the advanced age and comorbidity of many patients with advanced or recurrent vulvar cancer, patient tolerance is a major consideration in the use of these agents.
Systemic treatment for inoperable patients
A systematic review of the use of neoadjuvant chemoradiation in patients who were considered inoperable or who would have required extensive surgery, such as pelvic exenteration, colostomy, or urinary diversion revealed no randomized trials. Five nonrandomized studies that met the inclusion criteria of neoadjuvant chemoradiation administered in this population with an intent to permit curative surgery were reviewed.[16-20] The five studies used four different chemoradiation schedules and different radiation therapy dose-fractionation techniques. In the four studies using 5-FU + cisplatin or 5-FU + mitomycin-C, the operability rate after chemoradiation ranged from 63% to 92%.[16-19]
In the one study using bleomycin, the operability rate was only 20%. In summary, there is evidence that neoadjuvant chemoradiation with 5-FU plus either cisplatin or mitomycin-C may convert patients to more operable status, but the evidence base is limited by study design. In addition to a paucity of randomized trials, interpretation of these studies is complicated by the lack of a standard definition of inoperability.[Level of evidence: 3iiiDiv] Treatment-related toxicity is substantial.
Systemic treatment for operable patients
There is also limited evidence regarding the use of neoadjuvant chemoradiation in advanced operable cases of vulvar cancer, but the available data do not suggest an advantage to this approach. A systematic review found only one randomized trial that addressed this issue, and it was published only in abstract form.[4,21] In that trial, 68 patients with advanced vulvar cancer (T2 >4 cm, T3, any case with positive lymph nodes) were randomly assigned to receive preoperative neoadjuvant radiation therapy (50 Gy) concomitantly with 5-FU plus mitomycin-C versus primary surgery. Neoadjuvant therapy-related serious toxicity was high (13 of 24 patients; 10 patients had wound diastasis). After a mean follow-up of 42 months, the 5-year OS rates in the neoadjuvant and primary surgery groups were 30% and 49%, respectively (RR of death, 1.39; 95% CI, 0.94–2.06; P = .19).[4,21][Level of evidence 1iiA]
- Hacker NF, Van der Velden J: Conservative management of early vulvar cancer. Cancer 71 (4 Suppl): 1673-7, 1993. [PUBMED Abstract]
- Thomas GM, Dembo AJ, Bryson SC, et al.: Changing concepts in the management of vulvar cancer. Gynecol Oncol 42 (1): 9-21, 1991. [PUBMED Abstract]
- Homesley HD, Bundy BN, Sedlis A, et al.: Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 68 (6): 733-40, 1986. [PUBMED Abstract]
- Shylasree TS, Bryant A, Howells RE: Chemoradiation for advanced primary vulval cancer. Cochrane Database Syst Rev (4): CD003752, 2011. [PUBMED Abstract]
- Eifel PJ, Berek JS, Markman MA: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1311-44.
- Ansink A, van der Velden J: Surgical interventions for early squamous cell carcinoma of the vulva. Cochrane Database Syst Rev (2): CD002036, 2000. [PUBMED Abstract]
- Van der Zee AG, Oonk MH, De Hullu JA, et al.: Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol 26 (6): 884-9, 2008. [PUBMED Abstract]
- Stehman FB, Bundy BN, Thomas G, et al.: Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 24 (2): 389-96, 1992. [PUBMED Abstract]
- van der Velden J, Fons G, Lawrie TA: Primary groin irradiation versus primary groin surgery for early vulvar cancer. Cochrane Database Syst Rev (5): CD002224, 2011. [PUBMED Abstract]
- 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 114 (3): 537-46, 2009. [PUBMED Abstract]
- Petereit DG, Mehta MP, Buchler DA, et al.: Inguinofemoral radiation of N0,N1 vulvar cancer may be equivalent to lymphadenectomy if proper radiation technique is used. Int J Radiat Oncol Biol Phys 27 (4): 963-7, 1993. [PUBMED Abstract]
- Slevin NJ, Pointon RC: Radical radiotherapy for carcinoma of the vulva. Br J Radiol 62 (734): 145-7, 1989. [PUBMED Abstract]
- Perez CA, Grigsby PW, Galakatos A, et al.: Radiation therapy in management of carcinoma of the vulva with emphasis on conservation therapy. Cancer 71 (11): 3707-16, 1993. [PUBMED Abstract]
- Kumar PP, Good RR, Scott JC: Techniques for management of vulvar cancer by irradiation alone. Radiat Med 6 (4): 185-91, 1988 Jul-Aug. [PUBMED Abstract]
- van Doorn HC, Ansink A, Verhaar-Langereis M, et al.: Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev 3: CD003752, 2006. [PUBMED Abstract]
- Eifel PJ, Morris M, Burke TW, et al.: Prolonged continuous infusion cisplatin and 5-fluorouracil with radiation for locally advanced carcinoma of the vulva. Gynecol Oncol 59 (1): 51-6, 1995. [PUBMED Abstract]
- Landoni F, Maneo A, Zanetta G, et al.: Concurrent preoperative chemotherapy with 5-fluorouracil and mitomycin C and radiotherapy (FUMIR) followed by limited surgery in locally advanced and recurrent vulvar carcinoma. Gynecol Oncol 61 (3): 321-7, 1996. [PUBMED Abstract]
- Montana GS, Thomas GM, Moore DH, et al.: Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 48 (4): 1007-13, 2000. [PUBMED Abstract]
- Moore DH, Thomas GM, Montana GS, et al.: Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 79-85, 1998. [PUBMED Abstract]
- Scheiströen M, Tropé C: Combined bleomycin and irradiation in preoperative treatment of advanced squamous cell carcinoma of the vulva. Acta Oncol 32 (6): 657-61, 1993. [PUBMED Abstract]
- Maneo A, Landoni F, Colombo A, et al.: Randomised study between neoadjuvant chemoradiotherapy and primary surgery for the treatment of advanced vulvar cancer. [Abstract] Int J Gynecol Cancer 13 (Suppl 1): A-PL19, 6, 2003.