Treatment and prognosis of vulvar cancer
INTRODUCTION Vulvar cancer is the fourth most common gynecologic cancer (following cancer of the uterine corpus, ovary, and cervix) and comprises 5 percent of malignancies of the female genital tract. There will be an estimated 3,870 new cases and 870 deaths from this disease in the United States in 2005. The treatment and prognosis of women with vulvar cancer will be discussed here. The clinical presentation, diagnosis, evaluation, and staging of these patients is reviewed separately. PRETREATMENT EVALUATION Women diagnosed with vulvar cancer should have a thorough physical examination, including a complete pelvic examination and palpation of the lymph nodes in the groin. We perform cervical cytology and colposcopy of the cervix, vagina, and vulva because of the multifocal nature of squamous intraepithelial lesions in these areas. TREATMENT Treatment should be individualized, especially with early stage disease, so as to perform the most conservative procedure intended to cure the disease. The goal is to cure the cancer while minimizing perioperative morbidity and maximizing long-term psychosexual and physical well-being. Squamous cell cancer Surgical extirpation is the primary treatment of early stage vulvar carcinoma. Stage I Conservatism and individualization of surgical therapy characterize the main approach to patients with stage I disease. However, randomized trials comparing radical local excision to radical vulvectomy have not been done.
Stage II Modified radical vulvectomy and inguinofemoral lymphadenectomy are the mainstays of treatment for stage II disease. Unilateral inguinofemoral lymphadenectomy is adequate if the primary lesion is lateral; bilateral inguinofemoral lymphadenectomy is recommended for bilateral and central lesions because of the increased risk of metastases to both or contralateral lymph nodes. As discussed above, clear margins should extend at least 1 cm beyond the lesion (ideally 2 cm) to minimize the risk of a local recurrence. A three incision technique allows for radical excision of the primary lesion and bilateral groin node evaluation while retaining skin over the groin. In one study of 35 women, survival (and disease free interval) was similar in patients undergoing a modified radical vulvectomy and in those who had en bloc radical vulvectomy (90 and 75 percent, respectively). In addition, the three incision technique decreased the incidence of wound breakdown from 50 to 20 percent. An alternative approach is the en bloc resection through a trapezoid or butterfly incision. Adjuvant radiation therapy In retrospective series of women with resected vulvar cancer, adjuvant radiation therapy (RT) appears to benefit those with either positive inguinal lymph nodes or positive/close surgical margins. The benefit of this approach was shown in a trial in which 114 women with invasive squamous cell carcinoma of the vulva and positive groin nodes after radical vulvectomy and bilateral groin lymphadenectomy were randomly assigned to either pelvic RT or further pelvic lymphadenectomy. The two-year survival rate was significantly better in the irradiated group (68 versus 54 percent), a benefit largely due to the markedly reduced rate of inguinal nodal recurrences (5 versus 24 percent). The greatest survival advantage from RT occurred among patients with clinically suspicious or fixed ulcerated groin nodes and two or more positive groin nodes; the benefit of RT for the remaining patients was uncertain. We usually recommend that patients with only one microscopically positive groin node not receive adjuvant RT. Ipsilateral pelvic and groin irradiation are recommended when there are two or more microscopically positive groin nodes, one or more macroscopically involved lymph nodes, or any evidence of extracapsular spread. Patients with close or positive surgical margins may also benefit from postoperative RT. In one nonrandomized series of 62 such patients with invasive vulvar cancer at high risk of recurrence because of positive or close margins, 31 patients received postoperative RT and 31 did not. Compared with the unirradiated patients, local recurrence rates were lower (16 versus 58 percent) and survival was significantly improved in those who received RT. The GOG recently completed a prospective trial to evaluate the role of adjuvant RT in patients with high-risk primary tumors (4.1 cm in diameter, positive margins, or lymphovascular space invasion) with negative groin nodes (GOG 145). While we await these results, it appears reasonable to consider adjuvant RT to patients with high-risk primary tumors with negative nodes. Stage III and IV Advanced vulvar squamous cell carcinoma involving the anus, rectum, rectovaginal septum, or proximal urethra can be resected using radical vulvectomy combined with pelvic exenteration. However, in view of the high morbidity of these procedures, other approaches are often employed.
Two separate series administered cisplatin and 5-fluorouracil (5-FU) during the first and last weeks of radiotherapy to women with advanced vulvar cancer. The complete clinical response rates were 64 and 67 percent, respectively .Subsequent surgery was carried out in some but not all cases. in one report of 14 women, there was only one recurrence among the nine women with a complete clinical response (follow-up ranging from 7 to 81 months) despite the fact that surgery was not performed in any. In the second, four patients underwent potentially curative surgery at the completion of treatment; at 37 months median follow-up, all four and six others not undergoing surgery were alive and disease-free. These data raise questions regarding the role of surgery in women with a clinically complete response to chemoradiotherapy. In a second series, twelve women with locoregionally advanced vulvar cancer were treated with prolonged continuous infusion 5-FU and cisplatin in conjunction with RT. Of the eight patients who underwent vulvar resection six weeks following chemoradiotherapy, four had no residual tumor in the resected specimen; all remained recurrence-free up to 37 months postoperatively as did a single patients with a complete clinical response to chemoradiotherapy who did not undergo surgery. Overall six of the twelve patients were recurrence-free from 17 to 37 months following therapy. Others have evaluated the efficacy of mitomycin and 5-FU, which is the standard regimen used for patients undergoing concurrent chemoradiotherapy for squamous cell cancer of the anus. One series included 31 women with locally advanced vulvar squamous cell cancer who received two preoperative courses of mitomycin C and 5-FU concurrent with RT, followed by radical surgery two weeks later. Five of nine patients (55 percent) with biopsy proven inguinal lymph node metastases had no tumor in the surgical specimen; with a median follow-up of 34 months; 32 percent of patients recurred. The potential toxicity of this approach has been emphasized by others. In the larger report, 58 patients with either advanced primary (n = 41) or recurrent (n = 17) disease received preoperative external radiotherapy (54 Gy) with concurrent 5-FU and mitomycin C. Wide local excision and inguinal lymphadenectomy were planned after treatment. Eighty-nine percent of patients completed chemoradiotherapy and 72 percent underwent surgery. Early severe toxicity was recorded in three patients, and three deaths occurred shortly after treatment. Objective responses were observed in 80 percent and complete pathologic response of both primary and inguinal disease was confirmed in 13 patients (31 percent). Survival was not reported. Another GOG trial treated 73 women with clinical stage III-IV squamous cell vulvar carcinoma with planned split course RT concurrent with cisplatin/5-FU, and followed by surgical excision of the residual primary tumor plus bilateral inguinal-femoral lymph node dissection. Seven patients did not undergo a post-treatment surgical procedure. Following chemoradiotherapy, 33 of 71 (47 percent) patients had no visible vulvar cancer at the time of planned surgery, while only 2 of 71 (3 percent) had residual unresectable disease. Urinary and/or gastrointestinal continence was preserved in all but three patients. Survival data were not reported. The GOG has recently completed another prospective trial evaluating chemoradiation in patients with positive groin nodes (GOG 185). Patients received either inguinofemoral RT alone or in combination with weekly cisplatin (40 mg/m2) for 6 weeks. While we await the results from this trial, the use of chemoradiation in the management of vulvar carcinoma with positive groin nodes should be individualized.
In one report, 21 women with locally advanced vulvar cancer received two to three cycles of cisplatin 100 mg/m2 on day 1), bleomycin (15 mg on days 1, 8), and methotrexate (300 mg/m2 on day 8) (PBM chemotherapy) followed by resection in operable patients. There were two objective responses in the primary site, and 14 in inguinal nodes. The operability rate was 90 percent, but the three year survival rate was only 24 percent and 68 percent of the operated patients recurred from 3 to 17 months from the end of treatment. In a second series, 25 patients with locally advanced, inoperable vulvar squamous cell cancer received up to three courses of bleomycin (5 mg IM on days 1 to 5 during week 1, then on days 1 and 4 during weeks 2 through 6), lomustine (40 mg orally on days 5 through 7 during week 1 only), and methotrexate (15 mg orally on day 1 and 4 of week 1, then 15 mg once weekly during weeks 2 through 6), with cycles repeated every seven weeks. The objective response rate was 56 percent (two complete and 12 partial responses). Treatment-related toxicity was predominantly hematologic, with mild bleomycin-related pulmonary toxicity. The operability rate was 40 percent, and 32 percent of patients were still alive at one year. The median duration of progression-free and overall survival was 4.8 and 7.8 months, respectively. Verrucous carcinoma Radical local excision is usually adequate. Suspicious lymph nodes should be biopsied; if positive, then inguinofemoral lymphadenectomy is indicated. RT is contraindicated because it can induce anaplastic transformation and increase the likelihood of metastases. Recurrences are treated surgically. Sarcomas Wide local excision is the standard approach to treatment of most vulvar sarcomas. Lymphatic metastases are uncommon. Rhabdomyosarcomas, which typically occur in children, are an exception. These are treated with primary chemotherapy followed by surgery as needed. Vulvar Paget's disease Treatment consists of wide local excision or vulvectomy, depending upon the extent of disease. Twelve to 58 percent of women experience a local recurrence, which may occur despite negative surgical margins, presumably because of multicentricity and microscopic extension of disease beyond the clinically visible margins. Greater depth of invasion and lymphovascular involvement are poor prognostic markers. Treatment with Moh's micrographic surgery (ie, microscopically controlled systematic excision of cancerous tissue) may be associated with a lower recurrence rate, particularly for recurrent tumors. In one report of 25 patients with 27 lesions of extramammary Paget's disease, a margin of 5 cm of normal appearing skin from the visible tumor margin was needed to obtain microscopically clear margins in 97 percent of cases. The roles of RT and chemotherapy (topical and systemic) in the treatment of vulvar Paget's disease are not well-defined, but may be an option for some patients. Long-term follow-up is indicated because of the high risk of recurrence, the possibility of recurrence years after initial therapy, and the increased risk of noncontiguous carcinoma. The vulva should be inspected annually with a low threshold for biopsy and screening and surveillance for tumors at other sites (breast, lung, colorectum, gastric, pancreas, and ovary) should be considered. We adhere to routine recommendations for mammography and colonoscopy screening. (See "Screening for breast cancer" and see "Screening for colorectal cancer"). Bartholin gland The traditional approach to therapy is radical vulvectomy with bilateral groin and pelvic node dissection. Less radical excisions, such as hemivulvectomy or radical wide excision with ipsilateral inguinal lymphadenectomy, also appear to be effective. The lesions are typically deep within the vulva so extensive deep dissection is generally required. Postoperative RT can reduce the incidence of local recurrence (in one series, from 27 to 7 percent). If ipsilateral groin nodes are involved, pelvic and bilateral groin radiation may decrease the frequency of regional recurrence. Primary chemoradiotherapy or brachytherapy may allow sparing of rectal function in women with primary carcinoma of the Bartholin gland. Basal cell Basal cell carcinomas are locally aggressive but rarely metastasize. Therefore, radical local excision without lymph node dissection is adequate. PROGNOSIS Survival rates by disease stage according to the latest FIGO (International Federation of Gynecology and Obstetrics) statistics are shown. 5 Year survival: Stage I = 86.5%, Stage II = 67.7%, Stage III = 40.3%. Stage IV = 21.7% FOLLOW UP After receiving primary treatment, follow-up should include twice yearly gynecologic examination with visual inspection and palpation of the vulva, skin bridge, and inguinal nodes. Vulvar colposcopy and biopsy are indicated if abnormalities are noted. Almost 10 percent of patients in one series had a vulvar recurrence 5 years after diagnosis, thus demonstrating the need for long-term follow-up. Sexual dysfunction and alterations in body image are common after treatment and should be addressed during follow-up visits. Overview Vulvar tumor recurrences are classified as local, inguinal, or distant. The distribution of recurrences can be illustrated by data from s series of 502 patients, 187 (37 percent) of whom recurred following primary surgical management:
Treatment and outcome � Local perineal recurrences can be treated successfully by reexcision in up to 75 percent of cases. In contrast, inguinal recurrences are less commonly cured by radical resection. In the previously mentioned series, the five-year survival rates according to site of recurrence were:
RT may be added to surgery or chemotherapy, or used as a sole modality in patients with recurrent vulvar cancer. In one series of 26 women with recurrent squamous cell cancer, 16 were treated with surgery plus RT, and the remainder received RT with or without chemotherapy [35]. The five-year survival rates for women with vulvar-confined recurrence, and those with recurrence extending beyond the vulva were 46 and 0 percent, respectively. Salvage cytotoxic chemotherapy protocols can be considered for patients with distant metastases. The most active agents are those with substantial activity against squamous cell tumors at other sites, and include cisplatin, methotrexate, bleomycin, mitomycin C, and cyclophosphamide. Overall, the response rates are low and the duration of response is usually short.
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