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Cancers of the Vulva and Vagina
Incidence and Mortality
Vulvar carcinoma accounted for an estimated 6190 cancer cases and 1200 deaths in the United States in 2018, comprising 0.70% of all cancers in women, 5.6% of gynecological malignancies, 0.42% of cancer deaths in women, and 3.6% of gynecological cancer deaths. The rarity of the disease has made it difficult to evaluate new treatment strategies in prospective randomized trials. Incidence has risen 0.6% each year on average over the past 10 years, and there has been a shift toward younger age at diagnosis. Several decades ago, the incidence of vulvar cancer in women under the age of 50 years was 2%. Currently, over 20% of cases occur in women younger than 50 years. Until 2004, the 5-year disease-specific survival was stable at around 75%. However, since 2004, death rates have been increasing 0.7% per year on average, with the 5-year disease-specific survival dropping to 68%. Based on data from the Surveillance, Epidemiology, and End Results (SEER) database, 5-year survival rates range from 86% for localized disease (stage I/II), 57% for regional or locally advanced disease (stage III/IVA), and to 17% for patients with distant metastasis (stage IVB).
Biological Characteristics
Squamous cell carcinoma is the most common histological type of vulvar cancer, comprising 80% or more of cases. Other histologies include melanoma, basal cell carcinoma, verrucous carcinoma, Bartholin gland adenocarcinoma, sarcoma, and Paget disease. While carcinomas of the vestibular (Bartholin) gland complex may be adenocarcinomas or adenoid cystic carcinomas, 30% to 50% will have squamous histology as they arise in ductal epithelium. The typical distribution of histologies was illustrated in a Dutch cancer registry study from 1989 to 2010, including 5680 women with vulvar cancer: squamous cell carcinoma (81%), basal cell carcinoma (8%), melanoma (6%), and other histological subtypes (5%). Vulvar intraepithelial neoplasia (VIN) is the putative precursor lesion to vulvar squamous cell carcinoma (VSCC). There are two distinct etiological pathways leading to VSCC arising from either (1) VIN of usual type (uVIN) or (2) VIN of differentiated type (dVIN). uVIN is driven by the oncogenic types of human papillomavirus (HPV) and risk factors for HPV persistence, such as cigarette smoking. dVIN is not typically attributable to HPV but rather is more commonly associated with chronic inflammatory vulvar dermatoses, such as lichen sclerosis. While dVIN is less common than uVIN (dVIN comprises 2%-29% of all VIN), it has a higher risk of progression to VSCC (32.8% vs. 5.7%).VSCC arising from dVIN has a worse prognosis even after adjusting for age and stage. Still, only 4% of patients with lichen sclerosis will develop clinically apparent neoplasia.
Staging Evaluation
Tumor size, depth of invasion, pattern of invasion, presence of lymphovascular space invasion, and margin of resection correlate with risk of recurrence at the primary site. Inguinal lymph node metastasis is present at diagnosis in 20% to 30% of patients and is the single most important prognostic factor. Number, size, and extracapsular extension in metastatic groin nodes correlate with risk of regional recurrence, distant dissemination, and survival. Many of these factors are included in the hybrid clinical-pathological International Federation of Obstetrics and Gynecology (FIGO) 2009 staging formalism. Pretreatment evaluation is comprised of patient history and comprehensive physical examination, including inspection, palpation, and measurement of the primary tumor as well as clinical assessment of inguinofemoral lymph nodes. Regional imaging assessments may include dedicated chest imaging, ultrasonography, magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT). Regional imaging may aid in understanding extent of disease, guiding biopsies, and selecting therapeutic modalities. However, regional imaging findings alone do not affect assignment of stage.
Primary Therapy
Except when surgery would compromise functionally important midline structures (e.g., clitoris, urethra, anus), radical local excision is the preferred initial therapy for invasive primary disease. When the location and extent of the primary tumor suggests that surgery will not secure negative margins (≥ 8 mm in fixed tissue), neoadjuvant chemoradiation or definitive chemoradiation may be used. These options may be curative in some patients with locally advanced disease for whom an exenterative procedure would be the only feasible surgical alternative. Late radiation sequelae may be less severe if conservative surgery is feasible following a moderate preoperative dose of chemoradiation as opposed to chemoradiation escalated to radical intensity. The operative approach to groin assessment and the need for other modalities of treatment depend on the results of clinical and radiographic examination as well as the degree of laterality (distance from midline) of the primary tumor. Positive sentinel node biopsy mandates further treatment to the groin by way of complete inguinofemoral lymphadenectomy or radiation ± radiosensitizing chemotherapy. Upfront chemoradiation is typically the treatment of choice for fixed and/or ulcerated groin nodes. For patients with apparent node-negative, small primary tumors (≤ 4 cm), observation in the setting of a negative sentinel lymph node biopsy has proven to be oncologically safe and less morbid than complete inguinofemoral lymphadenectomy. Management options for clinically positive but resectable (e.g., not fixed or ulcerated) groin nodes include lymph node debulking surgery followed by planned adjuvant regional radiation ± radiosensitizing chemotherapy or neoadjuvant chemoradiation followed by planned excision of residual nodal disease.
Adjuvant Therapy
Adjuvant local vulvar and tumor bed irradiation may be administered for risk factors including involved or close surgical margins (< 8 mm), deep invasion (> 5 mm) and/or the presence of lymphovascular invasion. Unilateral or bilateral radiation to the groin and lower pelvic lymph nodes is recommended following surgical resection of positive inguinofemoral nodes, particularly when there are ≥ 2 positive nodes or a metastatic focus with extracapsular extension or macrometastases with inadequate dissection (≥ 20% node positive). Controversy exists over whether the clinical target volume (CTV) should include the primary tumor bed. Generally, when adjuvant radiation is administered for nodal disease, the CTV will include the primary tumor bed. There is no accepted role for adjuvant cytotoxic chemotherapy except when given concurrently with radiation for radiosensitization. Neoadjuvant chemotherapy alone before surgery for locally advanced disease has been associated with less predictable responses than chemoradiation, and complete pathological responses are less common. Therapy with biologics is investigational. Corrected 5-year survival for surgical patients with negative nodes is 70% to 96% depending on the extent of the primary (stages I-II). When groin lymph nodes are positive (stage III), corrected survival is approximately 50%. However, patients with only one microscopic intracapsular metastasis can expect a 5-year actuarial survival of 68% to 94%. Patients with more than two positive nodes or extracapsular extension will be cured in only 25% of cases.
Palliation
The goal of radiotherapy is to provide relief from pain or bleeding. Cytotoxic chemotherapy alone has minimal or no impact on disseminated disease. Early involvement of palliative care services focusing on symptom management and end-of-life planning for terminal disease is valuable.
Incidence
Vaginal cancer accounted for approximately 4810 new cancer cases and 1240 cancer deaths in the United States in 2017, comprising approximately 0.56% of all cancers in women, 4.5% of gynecological malignancies, 0.44% of cancer deaths in women, and 3.9% of gynecological cancer deaths. Seventy percent of patients are age 60 years or older. The precursor lesion, vaginal intraepithelial neoplasia (VAIN), is just as uncommon, and has an estimated annual incidence of 0.2 to 0.3 cases per 100,000 women in the United States.
Pathology and Biological Characteristics
The majority of lesions (80%) are SCCs. The second most common type is melanoma. Sarcomas and lymphomas may be primary in the vagina. Adenocarcinomas are commonly metastatic from other primary sites (uterus, colon, ovary, kidney, breast) with the exception of primary clear cell cancers. True primary adenocarcinomas of the vagina are extremely rare.
Staging Evaluation
As with cervical cancer, FIGO uses clinical staging for vaginal cancer. FIGO staging includes clinical assessment of the pelvis, chest radiograph, and renal evaluation. Depending on the clinical situation, CT, MRI, and PET/CT may be used to assess local and nodal extent of disease, but findings do not alter FIGO stage. Cystoscopy and proctoscopy may be appropriate when primary disease is extensive and involves the anterior vagina or rectovaginal septum. The results of biopsy or fine-needle aspiration of inguinofemoral or other nodes may be included in the clinical staging. Patients with vaginal adenocarcinoma should be assessed for potential primaries arising in other organs. Patients with melanoma require systemic evaluation. Stage distribution from SEER data spanning from 1988 to 2011 is as follows: 37.5% stage I, 36.5% stage II, 18.5% stage III, and 7.5% stage IV.
Primary Therapy for Preinvasive and Invasive Disease
It is safe to manage patients with low-grade VAIN expectantly. Patients with high-grade VAIN may be treated with local excision, laser ablation, topical 5-FU, topical 5% imiquimod, or radiotherapy (RT). One of the largest series of treated VAIN 2-3 (117 women) found no association between treatment type and risk of recurrence. Given this, treatments that maximize patient quality of life, with an emphasis on maintaining a patent vagina, are best. In women with high-grade VAIN, regular surveillance of the entire anogenital tract is important to minimize the risk of subsequent lower genital tract carcinomas. Primary therapy for invasive disease usually consists of external and intracavitary or interstitial RT except in select early cases, which may be treated surgically with local excision or with brachytherapy alone. Frequently, concurrent chemotherapy is administered, extrapolating from the beneficial results proven for patients with cancers of the cervix and anus. Radical surgery, intended as monotherapy, may entail partial or total pelvic exenteration. As such, it is generally reserved for salvage of isolated pelvic recurrence in a radiated field and as primary therapy for patients with vesicovaginal or rectovaginal fistulas at initial diagnosis. Five-year actuarial cancer-free survival in patients treated with RT alone or chemoradiation are similar stage for stage with those for cervical cancer: 85% in stage I, 75% in stage II, and 30% to 50% in stage III disease. Long-term cancer-free survival is rare for patients with stage IVA disease and is generally less than 20%. Patients who experience relapse usually do so within 2 years. Most patients will manifest locoregional persistence or recurrence as a component of the pattern of failure. Distant failure alone without antecedent locoregional failure is seen in less than a third of relapsing patients.
Adjuvant Therapy
Concurrent chemotherapy with RT has been reported with favorable results in a small number of patients, paralleling similar treatment for anal, cervical, and vulvar cancers. Randomized, controlled trials comparing chemoradiation to radiation alone will likely never be performed due to the rarity of the disease.
Salvage
Radical surgery, usually exenterative, may be appropriate for persistent or locally recurrent disease in a radiated field, but the likelihood of salvage is low.
Palliation
Individualized irradiation may be effective to reduce local symptoms. Chemotherapy, as with vulvar cancer, is generally minimally effective for disseminated disease.
Vulvar Cancer
Vulvar carcinoma is a rare disease. Currently, there are approximately 6000 cases and 1100 disease-related deaths in the United States annually. Heterogeneity in the location and clinical extent of disease at presentation—ranging from in situ or small-volume invasive primary disease to neglected, extensive tumors that locally invade the vagina, urethra, anus, or ischial rami—necessitates individualized treatment planning. The status of regional lymph nodes adds to the complexity. Patient age, the burden of medical comorbidities, and the diversity of patient concerns regarding function and cosmesis further increase the therapeutic challenge.
Appreciation of the broad clinical spectrum of patients afflicted with vulvar cancer and the utility of radiation and chemoradiation has resulted in major changes in disease management over the past several decades. Fortunately, these treatment modifications have reduced morbidity and improved quality of life for women with vulvar cancer. Still, studies of the Surveillance, Epidemiology and End Results (SEER) program database and the National Cancer Database (NCDB) have shown that treatment approaches/modalities vary considerably with sociodemographic factors across practices, particularly for individuals with advanced disease. The first iteration of the National Comprehensive Cancer Network (NCCN) clinical practice guidelines was developed in 2017 by a panel of experts in the field to provide an evidence-based decision-making tool for management of this challenging disease, with the ultimate goal of improving patient care and outcomes. The second iteration was published in early 2018, and online access is free. Recommendations are category 2A unless otherwise noted.
Historically, radical vulvectomy and bilateral inguinofemoral lymph node dissection was the standard approach for the majority of patients, regardless of disease extent. Consequent to the chronic, often debilitating, physical and psychological sequelae of this radical surgery in long-term survivors, questions arose regarding its necessity in patients with limited disease at diagnosis. Unsatisfactory rates of locoregional control in patients with advanced disease as well as high complication rates associated with exenterative surgery stimulated exploration of multimodal therapy. Increasing awareness of the sensitivity of vulvar squamous cell carcinoma (VSCC) to radiation and chemoradiation further improved the treatment of this disease.
Although the optimal therapeutic approach to many scenarios remains to be defined, modifications include conservative surgery for select patients with early disease and multimodality therapy (chemoradiation alone or integrated with less extensive surgery) for those with locally advanced disease. Chemoradiation is increasingly accepted as alternative therapy for patients with disease that would require partial or total exenteration if treated by initial surgery. Preoperative or postoperative adjuvant radiation or chemoradiation is now commonly used to complement conservative surgery in patients with adverse clinical or histopathological features.
Mature published results remain sparse for patients treated according to the newer concepts of integrated multimodality management tailored to the site and extent of disease. Valuable information continues to accumulate from Phase II studies, most of which supports the concept of integrated multimodality therapy. Correct sequencing of treatment modalities, defining the intensity and scope of radiation and the extent of surgery when these complementary modalities are used sequentially, and optimizing the choice and schedule of chemotherapy when combined with radiation represent ongoing challenges in optimizing treatment.
Etiology and Epidemiology
Vulvar intraepithelial neoplasia (VIN) encompasses premalignant squamous lesions of the vulva, which comprise the great majority of vulvar neoplasia. The International Society for the Study of Vulvovaginal Disease (ISSVD) classification includes (1) low-grade squamous intraepithelial lesion (LSIL) of the vulva (including flat condylomata, or human papillomavirus [HPV] effect), (2) high-grade squamous intraepithelial lesion (HSIL) of the vulva (formerly vulvar intraepithelial neoplasia of usual type [uVIN]), and (3) VIN differentiated type (dVIN). The 2015 classification reflects the distinct etiologies, natural histories, and prognoses associated with these 3 types of VIN. LSIL is equivalent to uVIN 1; infection with low-risk HPV types 6 and 11 account for over 90%. Vulvar LSIL lesions are benign manifestations of the skin's reaction to HPV infection; they are typically self-limited and should not be considered neoplastic. HSILs include both uVIN 2 and 3; 90% of cases are attributable to infection with high-oncogenic-risk HPV types 16 (77%-91%), 33 (3%-11%), and 18 (3%-6%). Although the majority of uVINs are associated with high-risk HPV, the rate of HPV positivity in VSCC is considerably lower. In a study of 1709 patients with VSCC, only 28.6% of cases harbored HPV, and the reported rates in the literature vary from 15% to 79%. It is estimated that 20% of VSCCs arise from HSIL, while dVIN is responsible for the remaining 80%.
uVIN tends to occur in young women in the third to fifth decades of life. Risk factors include smoking, number of sexual partners, and immunosuppression. Women with uVIN often have synchronous or metachronous squamous neoplasia of other lower genital tract sites. dVIN typically occurs in postmenopausal women in the sixth to eighth decades of life but can occur in younger patients. dVIN is associated with adjacent lichen sclerosis and/or chronic inflammatory dermatoses. In comparison to uVIN, which is often multifocal, dVIN tends to be unicentric at presentation. There is prospective evidence that earlier detection and proactive management of lichen sclerosis with long-term topical corticosteroid treatment may lead to reduced risk of dVIN or development of VSCC.
VIN recurs in up to 30% of women despite treatment. Cumulative evidence from the literature to date demonstrates that an estimated 2% to 15% progress to VSCC depending on the precursor lesion (uVIN vs. dVIN) and treatment. As previously mentioned, less than 5% of uVIN cases evolve into VSCC on average; the risk is 9% in untreated and 3.3% in treated cases. In contrast, up to one-third of dVIN cases progress to VSCC and progression is often observed to occur more quickly. The American College of Obstetricians and Gynecologists (ACOG) Committee Opinion recommends surveillance at 6- and 12-month intervals following treatment of VIN with a complete response to therapy and no new lesions at follow-up visits.
Early Detection, Treatment and Prevention
With the exception of cancers arising in the Bartholin complex, most vulvar malignancies arise from cutaneous surfaces readily accessible to examination. Ideally, invasive lesions are diagnosed when small and, hence, most easily treated with surgical resection. Unfortunately, most advanced vulvar cancers are a result of patient delay/neglect or physician failure to diagnose. There is little justification for physician failure to perform a thorough pelvic examination when patients present with the classic symptoms of vulvar pruritus, pain, bleeding, and/or a mass. Because of the risk for multifocal disease throughout the lower genital tract and anus, it is necessary to thoroughly evaluate the cervix, vagina, and anus for the presence of synchronous lesions at other sites. Women with lower genital tract dysplasia have an estimated risk of anal intraepithelial neoplasia (AIN) between 12% and 28%, suggesting a role for anoscopy in women with high-grade lower genital tract dysplasia.
Invasive SCC is present at the time of excision in 10% to 22% of women with high-grade VIN on initial biopsy. Excisional techniques affording full-thickness histopathological evaluation, provided that there is minimal loss of functionality and cosmesis, are preferable to ablative techniques (CO 2 laser vaporization, argon beam ablation, ultrasonic surgical aspiration), as there is no tissue for histopathological review following ablation. Wide local excision (defined as excision of an individual lesion with a 1-cm margin) is suggested for most small, unifocal vulvar abnormalities, if necessary under colposcopic guidance. Even if vulvar lesions appear to have a warty appearance and are believed to be benign, confluent warts should undergo biopsy to exclude an underlying diagnosis of SCC. Vulvectomy is reserved for women in whom vulvar carcinoma is suspected and who have lesions that are large and/or multifocal. Conservative treatment with topical therapies (e.g., immunomodulatory agents such as 5% imiquimod cream) aimed at preserving vulvar anatomy can be successful with complete response rates of 50% to 60%. Biopsies to exclude invasive disease are mandatory prior to initiating treatment.
Currently, there are 3 different HPV vaccines approved by the US Food and Drug Administration (FDA): the quadrivalent vaccine, Gardasil, manufactured by Merck; the bivalent vaccine, Cervarix, manufactured by GlaxoSmithKline; and the nonavalent, second-generation vaccine, Gardasil 9, made by Merck. Results from large Phase III trials of HPV-negative women 15 to 26 years old with the quadrivalent vaccine—which is active against HPV types 6, 11, 16, and 18—indicate that the vaccine is close to 100% effective in reducing the risk of HPV 16/18-related genital tract HSIL and of HPV 6/11-related genital warts. The nonavalent vaccine was developed to provide direct protection against the HPV types already covered by the quadrivalent vaccine and the next five HPV types most commonly associated with cervical cancer worldwide: HPV 31, 33, 45, 52, and 58. On the basis of epidemiological studies, the nonavalent vaccine has the potential to prevent 90% of all cervical and vulvovaginal cancers. The vaccine has proven sustained efficacy for prevention of persistent infection and disease related to the 7 most common oncogenic HPV types up to 6 years following the first vaccination visit. Routine vaccination is recommended for boys and girls between the ages of 11 and 12 years by the Centers for Disease Control and Prevention (CDC). Two doses of vaccine are acceptable if the series is started at age 9 years and up to 14 years old; younger adolescents make a stronger immune response than older adolescents. Three doses of HPV vaccine are recommended for teens and young adults who start the series at ages 15 through 26 years and for immunocompromised persons. The recommended 3-dose schedule is 0, 1 to 2, and 6 months.
Treatment of vulvar dermatoses, such as lichen sclerosis, and smoking cessation may also help prevent VIN. A history of smoking tobacco is associated both with VIN and invasive vulvar malignancy. Patients who smoke should be encouraged to quit because the statistical risk of anogenital malignancy associated with former smoking is observed to be substantially less than that associated with current smoking and diminishes with increasing time since cessation of smoking. Additionally, women with vulvar or vaginal cancer appear to have a fourfold increased risk of subsequently developing a second primary cancer of the lung.
Pathology and Pathways of Spread
Pathology
Squamous cancer is the most common malignant lesion of the vulva and constitutes 80% to 90% of vulvar tumors. Clinically important variant histological growth patterns include tumors with “spray-pattern invasion” and verrucous tumors ( Fig. 69.1 ). Spray-pattern invasion is characterized by infiltration of the stroma by single cells or cords of tumor cells adjacent to the more “conventional” SCC cells that instead have well-circumscribed nests and a “pushing” stromal interface. Recognition of spray-pattern invasion should prompt consideration of adjuvant radiotherapy (RT), as these tumors have an increased propensity to spread to regional nodes, even when small, and frequently recur beyond the margins of local excision within dermal lymphatic channels. Sarcomatoid differentiation is seen in a minority of squamous cancers and can be associated with an aggressive course. Verrucous cancers may clinically manifest a warty appearance resembling a cauliflower, with exuberant hyperkeratosis microscopically. Broad, bulbous borders characterize these tumors, which rarely metastasize to regional nodes. Morphological and biological studies on 10 cases of verrucous carcinoma of the vulva suggest that verrucous cancers may actually constitute a discrete clinicopathological subset of VSCC. Recognition of this rare histological variation of VSCC is important because surgery is the most effective treatment, even for large tumors, as high recurrence rates with RT have been observed. In some cases, radiation has been reported to cause anaplastic transformation.
Other histological types of vulvar cancer include malignant melanoma, basal cell carcinoma, Merkel cell tumors, carcinoid, transitional cell carcinomas, adenoid cystic carcinoma, vulvar Paget disease, and a variety of sarcomas. Tumors metastasizing from other sites may also manifest in the vulva.
Pathways of Spread
Vulvar cancer metastasizes by a variety of mechanisms. Modes of spread include direct extension to adjacent structures, lymphatic spread to regional lymph nodes, and hematogenous dissemination. Lymphatic spread to regional lymph nodes is typically by tumor cell embolization. Permeation of local lymphatics is uncommon ( eFig. 69.1 ), but may account for the occasional patient with recurrence in the skin bridge conserved when surgery has employed separate incisions for the primary and groin node dissection. This is rare in the absence of extensive groin node metastases. Hematogenous dissemination typically occurs late in the disease course and is rare in patients without regional lymph node involvement.
The lymphatics of the vulva ( Fig. 69.2 ) consist of a network that covers the entire labia minora, fourchette, prepuce, and distal vagina below the hymenal membrane. Lymphatics coalesce anteriorly, forming larger trunks, which run lateral to the clitoris to the mons veneris, acquiring tributaries from the lymphatics of the labia majora, which run in a parallel fashion anteriorly from the perineal body. At the mons veneris, the vulvar lymphatic trunks diverge laterally to the inguinal nodes. Study of the localization of dye or radiolabeled tracer in regional lymph nodes after focal injection of discrete sites in the vulva and on the perineum reveals that the lymphatic drainage of the perineum, clitoris, and anterior labia minora is often bilateral, whereas the lymph flow from well-lateralized sites (> 2 cm from midline) in the vulva is predominantly to the ipsilateral groin.
The vulvar lymphatics run through the vulva and do not traverse the labiocrural fold. Perineal lymphatics course lateral to the labiocrural fold through the superficial tissues of the upper medial thigh. In the radiation treatment of patients with advanced vulvar cancer that extends to the perineal skin, these lateral channels should be taken into consideration. Advanced vulvar cancer extending up the vagina proximal to the hymenal ring may spread through vaginal lymphatics directly to pelvic nodes.
Primary lymphatic drainage is usually to the superficial inguinal nodes with secondary lymphatic drainage through the cribriform fascia to the femoral nodes, with subsequent tertiary flow under the inguinal ligaments to the external iliac nodes. However, metastases have been reported to the femoral lymph nodes without involvement of the superficial inguinal lymph nodes, especially from carcinomas of the clitoris and Bartholin gland. Sentinel node studies have demonstrated primary lymphatic flow to deep nodes in as many as 15% of cases, and a Gynecological Oncology Group (GOG) study also found an unexpectedly high incidence of ipsilateral groin recurrences secondary to presumed involvement of lymph nodes deep to the cribriform fascia despite prior negative superficial inguinal lymphadenectomy. The actuarial risk of groin recurrence at 5 years was 16% (19 of 119) among a series of patients with vulvar cancer whose groins were treated with lymphadenectomy alone at the M. D. Anderson Cancer Center (MDACC); 111 of 119 had only superficial inguinal node dissections. Of these 119 patients, 117 had groin node specimens negative for metastases. In contrast, groin recurrence after superficial and deep groin dissection retrieving histologically negative nodes is 2% or less.
Clinical assessment of groin node status by palpation is notoriously inaccurate; approximately 20% of groins judged clinically negative harbor occult node metastases, and approximately 20% of groins considered clinically suspicious for metastases are found to contain only reactive or inflammatory nodes. The frequency of inguinofemoral lymph node metastasis is related to the depth of stromal invasion by the primary tumor ( Table 69.1 ). The incidence of occult nodal involvement in clinically nonsuspicious groin nodes treated by complete lymphadenectomy is cross-tabulated by primary tumor size in ( Table 69.2 ).
TABLE 69.1
Incidence of Groin Node Metastasis Correlated With Depth of Invasion for Primary Tumors 2 cm or Smaller
| Depth of Invasion (mm) | Patients ( n ) | Positive Nodes ( n ) | % |
|---|---|---|---|
| ≤ 1 | 120 | 0 | 0 |
| 1.1-2.0 | 121 | 8 | 6.6 |
| 2.1-3.0 | 97 | 8 | 8.2 |
| 3.1-4.0 | 50 | 11 | 22 |
| 4.1-5.0 | 40 | 10 | 25 |
| >5.0 | 32 | 12 | 37.5 |
Pooled data, six series.
TABLE 69.2
Primary Vulvar Tumor Size Versus Nodal Risk
| Primary Tumor (cm) | Clinically Occult Node Metastases (%) |
|---|---|
| 0-1.0 | 3/43 (7) |
| 1.1-2.0 | 14/63 (22.2) |
| 2.1-3.0 | 14/52 (26.9) |
| 3.1-5.0 | 14/41 (34.1) |
| >5.0 | 3/15 (20) |
| Total | 48/214 (22.4) |
Metastases to the contralateral groin in the absence of ipsilateral groin metastases may be seen in up to 15% of patients with advanced primaries. Metastases to contralateral groin nodes in the setting of uninvolved ipsilateral groins have been reported in patients with Bartholin gland primaries and tumors of the anterior labia minora. In the absence of spread to ipsilateral nodes, small (≤ 2-cm diameter), well-lateralized (≥ 2 cm from midline) primary cancers limited to the vulva manifest spread to contralateral groin nodes in less than 1% of patients undergoing bilateral lymphadenectomy. However, 5 patients of 192 pooled patients (2.6%) with T1 lateralized cancers and a negative ipsilateral groin dissection developed contralateral groin recurrence. A hypothetical explanation for this discrepancy is the possibility that resection of unrecognized, micrometastatic disease from the contralateral groin may be therapeutic in a small number of patients. Still, unilateral groin assessment is appropriate for small, well-lateralized tumors given the low risk of metastatic spread to and recurrence in the contralateral groin. The necessity of bilateral groin assessment for laterally ambiguous tumors (tumors within 2 cm of but not involving the midline) was recently called into question by an analysis from the GOG 173 sentinel lymph node (SLN) mapping study. This analysis demonstrated that patients with laterally ambiguous primaries and unilateral drainage on preoperative lymphoscintigraphy (LSG) may safely undergo unilateral groin assessment alone. Patients with midline tumors require bilateral groin assessment irrespective of preoperative LSG results. That being said, the most recent iteration of the NCCN guidelines recommends bilateral groin assessment for tumors located within 2 cm from or crossing the midline.
The overall incidence of pelvic lymph node metastases is 5%. Lymphadenectomy will detect metastatic involvement in pelvic nodes in 15% to 28% of patients with metastases to inguinal nodes. Pelvic node metastasis is extremely rare in the absence of groin node metastases and uncommon in the context of occult, microscopic involvement of a single groin node. The International Federation of Gynecologic and Obstetrics (FIGO) staging system still classifies patients with positive pelvic lymph nodes as 4B, grouping these patients with patients who have hematogenous metastases. However, given that locoregional treatment with definitive or adjuvant RT can be curative for many patients with pelvic lymph node-positive stage IVB vulvar cancer, many feel that pelvic lymph node-positive disease should not be designated as 4B.
Hematogenous spread, usually to lung and bone, is unusual in the absence of known inguinofemoral lymph node involvement and generally occurs late in the course of the disease. The risk strongly correlates with the number of positive groin nodes. In patients with three or more positive lymph nodes, the ultimate risk of hematogenous spread is 66%. In contrast, patients with fewer than three positive lymph nodes have only a 4% risk of hematogenous spread.
Biology and Prognostic Factors
In multivariate analysis, the presence or absence of lymph node involvement remains the single most important prognostic factor in treatment outcomes for locoregional vulvar cancer. For those with negative lymph nodes, the average 5-year survival from 9 large literature series is 91% (range, 83%–100%). For those with involved lymph nodes treated with curative intent, the average 5-year survival is 52% (range, 38%–61%). The extent of lymphatic involvement is prognostic and includes laterality of nodal spread (unilateral or bilateral), volume of tumor in the involved nodes, extracapsular penetration, number of positive nodes, and level of metastatic disease in the nodal chain.
A large proportion of relapses following definitive treatment of stage III disease will occur locally in the vulva. It has been shown that disease-specific survival decreases from 90% to 69% in patients after a local recurrence independent of nodal status. There are a number of primary tumor–related characteristics that independently predict local vulvar relapse. These include tumor size, tumor location, depth and pattern of invasion, margin status, and lymphovascular invasion. A recent systematic review out of the Netherlands, including 22 studies in the published literature through July 2017, evaluated our current knowledge on the incidence of and risk factors for locally recurrent vulvar cancer. Importantly, the cumulative data point to a local recurrence rate of 4% per year without plateauing. The analysis included 4 studies that reported the risk for local recurrence by tumor size and divided tumor size into 2 groups: tumors measuring less than or equal to 4 cm and tumors measuring greater than 4 cm. None of the 4 studies found an effect of tumor size, dichotomized in this way, on the risk of local recurrence. Two studies reported that increasing tumor size (as a continuous variable) did not increase the risk of local recurrence. However, the work of Aragona et al. has shown that there is “a clear cut-off value in tumors ≥ 6 cm, above which survival drops remarkably.” Several retrospective studies have shown that patients with VSCC with clitoral involvement have a worse prognosis than those with disease at other anatomic locations. Clitoral tumors tend to be larger, more deeply invasive, have more lymphovascular invasion, and have a higher risk of groin metastasis.
Depth of invasion correlates not only with locoregional recurrence but also with the risk of node metastasis. Because most relapses after primary surgical treatment occur in the vulva or groin, to improve outcomes it is necessary to understand how factors predictive of local recurrence and nodal relapse impact overall survival (OS). Although risk probably increases continuously with depth, two datasets suggested that a sharply defined classification into low-risk versus high-risk groups may occur depending on tumor depth (first series—low risk < 5 mm and high risk ≥ 5 mm; second series—low risk < 9 mm, high risk ≥ 9 mm).
Three publications ( Table 69.3 ) have reported a clear association between risk of vulvar recurrence and width of surgical resection margins. When microscopic margins are 8 mm or less in formalin-fixed tissue, local recurrence has been observed in 43 of 145 patients (30%). Allowing for estimated fixation shrinkage artifact between 25% and 45%, this correlates with a margin of at least 1.0 to 1.45 cm in unfixed tissue. A minimal clinical free space of 1 cm of uninvolved normal tissue provides a practical guideline for identifying patients who are highly likely to undergo further excision or postoperative local radiation for inadequate margins if treated by initial surgery. Under such circumstances, preoperative chemoradiation may be preferable to secure better margins and to reduce the scope of subsequent conservative surgery.
TABLE 69.3
Width of Surgical Margin and Risk of Local Recurrence
| Series/Author | Margin < 8 mm | Margin ≥ 8 mm |
|---|---|---|
| Heaps et al. | 21/44 (48%) | 0/91 |
| Chan et al. | 13/61 (21%) | 0/29 |
| de Hullu et al. * | 9/40 (23%) | 0/39 |
| TOTAL | 43/145 (30%) | 0/159 |
Clinical Manifestations, Patient Evaluation, and Staging
Clinical Manifestations
The fact that vulvar cancer is often virally mediated, is associated with preinvasive or invasive cancers in other parts of the lower genital tract, and either recurs or arises de novo in conserved, unexcised vulvar tissues suggests that vulvar cancer may be one manifestation of a multifocal disease or “field cancerization.” Still, only about 5% of vulvar cancers are multifocal at the time of initial diagnosis ( eFig. 69.2 ).
Patients usually present with a vulvar mass or ulcer often following a variable history of pruritus and/or vulvar pain. Depending on the location and size of the lesion, the patient may also complain of dysuria, difficulty with defecation, inability to sit comfortably, bleeding, or discharge. Rarely, patients may present with advanced inguinal node involvement, occasionally with ulcerating masses in the groins or with lower extremity lymphedema resulting from lymphatic obstruction ( eFig. 69.3 ). In rare instances, neglected vulvar cancer may directly extend to, or invade, adjacent bone ( eFig. 69.4 ). Progressive organ destruction by untreated stage IV vulvar cancer may progress to urinary or fecal incontinence due to fistula formation or to incompetence of bladder or anal sphincters ( eFig. 69.5 ).
Patient Evaluation
The diagnosis of vulvar cancer requires biopsy. For lesions smaller than 1 cm, a definitive excisional biopsy—including surrounding skin, underlying dermis, and connective tissue—may be preferable to obtain gross surgical margins of at least 1 cm circumferentially around the lesion. For larger lesions, a wedge biopsy should be performed at the interface between the tumor and normal adjacent skin. When vulvar dystrophy is present and the vulva is more difficult to assess visually, use of a colposcope may assist in identifying abnormal areas for targeted biopsies. The remainder of the lower genital tract and anus should be examined, if necessary, by colposcopy and anoscopy to evaluate for the presence of synchronous preinvasive or invasive cancers.
Clinical evaluation of the groin nodes by palpation is inaccurate. Assessment of groin nodes is particularly compromised in obese patients, when even superficial inguinal nodes lie several centimeters below the skin. Because of the imprecision of clinical assessment and the importance of knowing nodal status for treatment planning, pathological verification of nodal status is vital when feasible.
Staging
In 1988, FIGO introduced a surgical staging system for vulvar cancer that has since undergone several revisions, most recently in 2009 ( Table 69.4 ). Staging systems allow accurate prognostication between centers and countries. Ideally, stage should be assigned before any major therapeutic intervention such as surgery. The 2009 FIGO staging system includes 3 major updates. First, locoregional disease to the lower urethra, vagina, or anus was shifted to stage II, effectively separating these cases from lymph node–positive patients. In addition, larger size, nonmetastatic primary lesions were grouped with smaller lesions into stage I. Lastly, the stage III designation is reserved for cases with positive inguinofemoral nodes and is composed of 3 substages based on the number and extent of lymph node involvement. Thus, the current clinicopathological system defines stage for many patients based, in part, on information derived from surgical treatment of the groin nodes. Because of the strong association between prognosis and the number and size of groin node metastases, the staging system appears to implicitly endorse surgical management of the groin nodes, but this may not be prudent or feasible in all clinical circumstances. In a patient with a locally advanced primary requiring preoperative chemoradiation in an effort to avoid compromise of functionally important midline structures, it may be reasonable to electively include the groins in the irradiated volume provided that they appear clinically and radiographically uninvolved. Without sampling of groin nodes before treatment or subsequent groin dissection following chemoradiation, such patients are reported to have a low probability of groin failure if treatment is carried out with appropriate technique. They are, however, strictly speaking, “unstaged.” The NCCN guidelines provide a framework for pretreatment workup, including considerations with regard to pretreatment imaging.
TABLE 69.4
FIGO 2009 Staging of Cancer of the Vulva
| Stage | Description |
|---|---|
| Stage I | Tumor confined to the vulva |
| IA | Lesions ≤ 2 cm in size, confined to the vulva or perineum and with stromal invasion ≤ 1.0 mm, a no nodal metastasis |
| IB | Lesions > 2 cm in size or with stromal invasion > 1.0 mm, a confined to the vulva or perineum, with negative nodes |
| Stage II | Tumor of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes |
| Stage III | Tumor of any size with or without extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with positive inguinofemoral lymph nodes |
| IIIA | (i) With 1 lymph node metastasis (≥ 5 mm), or (ii) 1-2 lymph node metastasis(es) (< 5 mm) |
| IIIB | (i)With 2 or more lymph node metastases (≥ 5 mm), or (ii) 3 or more lymph node metastases (< 5 mm) |
| IIIC | With positive nodes with extracapsular spread |
| Stage IV | Tumor invades other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures |
| IVA | Tumor invades any of the following: (i) upper urethral or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or (ii) fixed or ulcerated inguinofemoral lymph nodes |
| IVB | Any distant metastasis including pelvic lymph nodes |
FIGO, International Federation of Gynecologic and Obstetrics.
a The depth of invasion is defined as the measurement of the tumor from the epithelial stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion.
For women with primary, unifocal vulvar cancers measuring less than 4 cm in diameter, sentinel nodes may be identified for selective excisional biopsy by injection of blue dye, fluorescent dye, and/or radiocolloid at the primary. It is increasingly clear that use of a blue dye alone is insufficient to identify sentinel nodes. Results are better when a radioactive tracer is used in combination with blue dye, although radiotracer alone appears to be as accurate for other anatomic sites where sentinel node evaluation is performed. Use of indocyanine green fluorescent dye intraoperatively in patients who are lean is currently under investigation. Meta-analysis of published vulvar sentinel node work, in large part derived from the GROINSS-V and GOG 173 multicenter observational studies, reports a 92% sensitivity (by patient and groin) with negative predictive values of 97% (by patient) and 98% (by groin). Since the publication of these data, the sentinel node procedure has been widely accepted as standard of care in early-stage vulvar cancer patients. Candidates for SLN biopsy include patients with negative clinical groin examination and imaging, a primary unifocal tumor size of less than 4 cm, and no previous vulvar surgery that may have impacted lymphatic flow to the groin region.
Pathological ultrastaging of SLNs increases the sensitivity of SLN excisional biopsy for the detection of occult microscopic groin node metastases that otherwise would be missed on routine processing. Ultrastaging includes thin step-sectioning of retrieved nodes with hematoxylin and eosin staining with follow-up cytokeratin immunostaining on negative nodes, with or without additional diagnostic immunostaining. Cytokeratin immunostaining will identify some metastatic deposits in nodes (e.g., isolated tumor cells and micrometastases) otherwise missed by routine hematoxylin and eosin processing. When nodal disease is advanced and initial surgery to the groin area is not planned, histological confirmation of metastatic spread may be obtained by fine-needle core biopsy or aspiration cytology.
Noninvasive imaging with PET/CT, US, or MRI (with diffusion-weighted imaging) may assist in assessing lymph node status, particularly in patients who are larger or obese in whom femoral nodes may be many centimeters below the skin, beyond a depth where node palpation is feasible. Metabolic imaging may sometimes detect metastases in the absence of gross nodal enlargement. Positron emission tomography/computed tomography (PET/CT) may occasionally detect in-transit dermal metastases as well as nodal spread ( eFig. 69.6 ). CT using size criteria alone is less accurate because of the frequency with which groin nodes are nonspecifically enlarged as a result of inflammatory or reactive changes or fat replacement. Small prospective studies have shown PET/CT to have a sensitivity of 50% to 67% and a specificity of 95% to 100% in the detection of metastasis in vulvar cancer with negative and positive predictive values ranging from 57% to 86% and 86% to 100%, respectively. While PET/CT can aid in the assessment of the inguinofemoral nodes, its relative poor sensitivity renders it an unsuitable alternative to histopathological evaluation by surgery or image-guided biopsy when surgery is not feasible. The Sloan Kettering group recently reported that PET/CT significantly influences prognostic impression and patient management in 50% and one-third of cases, respectively.
Although clinically useful in some patients, the results of imaging assessment, unless confirmed histologically, do not alter assignment of FIGO stage. Accurate measurement of the depth of femoral nodes below the anterior skin surface at the level of the femoral artery as it passes under the inguinal ligament is critical in the design and implementation of radiation-based therapy of undissected groins as well as in the context of adjuvant irradiation of the groins after superficial or total inguinal lymph node dissection. Axial (transverse plane) imaging is probably the most precise means of making this measurement.
Primary Therapy
Treatment options include radical vulvectomy as primary surgery, pelvic exenteration (ultraradical surgery), RT (primary or neoadjuvant), concurrent chemoradiation (primary or neoadjuvant), and neoadjuvant chemotherapy followed by surgery. The treatment of patients with vulvar cancer has been in a state of evolution for more than 3 decades. Previously, en bloc radical vulvectomy with bilateral inguinofemoral node dissection with or without bilateral pelvic node dissection was the treatment of choice for all patients with vulvar cancer. Extirpative surgery was associated with substantial acute and chronic postoperative morbidity as well as major psychological sequelae. Inguinofemoral lymphadenectomy alone is associated with a high rate of postoperative morbidity; 20% to 40% of patients are at risk for wound complications and 30% to 70% of women experience lymphedema. Pelvic relaxation, organ prolapse, and urinary incontinence can develop in some patients, particularly when removal of the distal urethra or a portion of the lower vagina is required to achieve surgical clearance. Vaginal introital stenosis can occur, and the absence of the vulvar and venereal fat can have the functional equivalence of shortening effective vaginal depth and removing a protective cushion from the pubic arch, which may contribute to dyspareunia in many patients. Additionally, clitorectomy will profoundly diminish capacity for arousal and climax. Thus, the psychosexual consequences of vulvectomy can be devastating.
The clinical extent of vulvar cancer at the time of diagnosis may be down-trending, possibly consequent to more enlightened attitudes regarding the pathogenesis of the disease and improved access to health care. Among operable patients undergoing radical groin dissection, the frequency of lymph node metastasis fell from approximately 50% in reports from the 1940s and 1950s to approximately 30% in surgical literature from the 1970s and 1980s. As younger, sexually active patients were being diagnosed with preinvasive disease or unifocal disease of minimal volume and depth of invasion, modifications in the surgical approach to vulvar cancer were motivated by concerns about the chronic morbidities of ablative surgery, particularly in patients with disease of limited extent.
The focus of vulvar cancer management has moved toward decreasing the morbidity and mortality of radical vulvectomy in patients with early-stage, prognostically favorable tumors and toward improving results without increasing morbidity in patients with advanced, poor-prognosis disease by using integrated multimodality therapy that includes radiation, chemotherapy, and functionally conservative surgery. The heterogeneity of the disease and affected women requires tailoring the nature and extent of treatment to the location and severity of the cancer, with careful consideration given to the activity, efficacy, and toxicity of each available treatment modality when used alone or in combination.
Decisions regarding management of the primary tumor in the vulva are made on the basis of primary tumor volume, location, and anatomic extent (direct involvement or impingement on functionally important midline structures), taking into consideration the potential impact of both biopsy and definitive surgery on anatomic function and cosmesis. Decisions regarding management of the groin nodes are directed by whether histologically confirmed node metastases are present, their extent (size, number), location, and depth of invasion of the vulvar primary.
Surgical Trends Including Sentinel Node Studies
Radical surgery for vulvar cancer has moved away from the classic radical vulvectomy with en bloc bilateral inguinofemoral lymph node dissection toward less extensive vulvar and groin surgery, particularly in patients with early-stage lesions. Indicators of this trend include (1) the use of separate vulvar and groin incisions (so-called “triple incision”) with preservation of the intervening skin bridges, (2) use of SLN procedures and less comprehensive groin node surgery coupled with adjuvant radiation where indicated, (3) the use of chemoradiation in patients with gross inguinofemoral node metastases, and (4) use of pelvic radiation in lieu of pelvic node dissection in patients with confirmed groin node metastases. The definition of radical vulvar surgery has changed with the realization that the efficacy of radical surgery is best defined by the closest resection margin rather than by achievement of total organ ablation (total vulvectomy).
In patients with limited disease and clinically negative groin nodes or occult groin node metastases, use of separate incisions for the primary and groins is associated with decreased morbidity without compromise of disease-specific survival (DSS) or OS compared with en bloc resection. However, when corrected for other prognostic variables in a multivariate analysis, the type of surgical treatment (triple incision versus en bloc) was an independent predictor for vulvar recurrence but not for inguinal and pelvic relapse. The lack of impact on DSS and OS may be attributed to high salvage rates for isolated vulvar recurrence reported in some clinical series. However, a 2-year actuarial survival after vulvar recurrence has been reported to be as low as 25% and uncontrolled local recurrence was a contributing cause of death in 15 of 16 patients dying from cancer in one series. Risk of recurrence in preserved skin bridges appears related to trapped dermal lymphatic emboli in patients with extensive groin adenopathy and is rare in the absence of groin adenopathy because lymphatic dissemination in vulvar cancer is characteristically embolic rather than permeative. Rather, local recurrence, particularly in node-negative patients, is likely related to “field cancerization” of the vulva due to HPV infection or chronic vulvar dermatoses. Following subtotal vulvectomy, the residual unresected vulvar skin remains at risk for “de novo” vulvar cancers.
Radical excision for invasive tumors extends to the level of the perineal membrane and should have a minimal margin of 1 cm (ideally, 1-2 cm) of clinically uninvolved tissue circumferentially. Although there is some uncertainty about the optimal extent of surgical margin following resection of the vulvar primary, data from three clinical series reveal high local control rates for cases in which the surgical margin was greater than or equal to 8 mm in the fixed state postoperatively (see Table 69.3 ). This suggests that, in the nonfixed state, tumor margins of at least 1 to 2 cm in all dimensions are desirable to achieve high local control rates. Many clinicians endorse a clinical margin of 2 cm for this reason. Implicit is the understanding that radical local excision should include dissection down to the perineal membrane. Although radical local excision/partial vulvectomy is widely accepted in the treatment of small lesions, radical total vulvectomy may still be the best surgical option for patients with multifocal invasive disease, patients with invasive cancer associated with extensive VIN, and patients with cancer associated with symptomatic vulvar dystrophy unresponsive to topical therapies.
Optimal management of the inguinal nodes is essential because outcomes of patients with nodal recurrence have historically been poor, with less than 27% alive at 5 years. For tumors less than or equal to 2 cm in diameter with less than or equal to 1 mm of invasion (stage IA), groin evaluation may be omitted since there is minimal risk of groin node metastasis. Groin evaluation is recommended for stage IB/II tumors. For an isolated primary vulvar tumor that is less than 4 cm, located 2 cm or more from the vulvar midline and in the setting of clinically negative inguinofemoral lymph nodes, ipsilateral inguinofemoral lymphadenectomy or sentinel lymph node biopsy is appropriate unless the ipsilateral groin is involved. In cases of SLN-positive disease, bilateral inguinofemoral lymphadenectomy should be considered.
The move toward more conservative, tailored surgical management has led to changes in the extent of groin dissection and the use of unilateral groin dissection for selected patients. The previous standard radical bilateral superficial and deep inguinofemoral lymph node dissection results in as much as a 50% incidence of acute wound breakdown, lymphangitis, or lymphocyst formation and at least 10% to 25% incidence of chronic lower extremity lymphedema. The surgical morbidity associated with limited superficial groin dissections is less than that with superficial and deep dissections. The rationale for limiting the extent or depth of groin dissection relates to the somewhat orderly sequence of metastatic progression in the groin nodal chain and the observation that involvement of the deep femoral nodes without involvement of the superficial nodes is uncommon. However, the actuarial risk of groin relapse at 5 years was 16% among patients with vulvar cancer treated with superficial groin node dissection alone at the MDACC. Thus, superficial and deep inguinofemoral lymphadenectomy remains the standard of care when SLN biopsy is contraindicated. Data on the diagnostic accuracy of a repeat SLN procedure in cases of local recurrence are lacking. Anatomic study of sentinel node location has shown that sentinel nodes will include deep femoral nodes in as many as 16% of patients. Routine study of sentinel nodes by combined injection of blue dye and radiotracer (technetium-99m sulfur colloid) might further reduce the risk of groin failure by identifying the minority of patients with direct lymphatic pathways to deep nodes. A sentinel groin node identified by blue dye is illustrated in eFig. 69.7 .
In well-selected patients, full-therapeutic groin dissection may be sensibly omitted when SLNs are negative. This is based on several prospective multicenter trials evaluating the feasibility, safety, validity, and risk of groin recurrences with SLN biopsy in early vulvar cancer. The safety of SLN biopsy was examined in a multicenter observational study (GROINSS-V) of 403 women with primary vulvar tumors less than 4 cm. Inguinofemoral lymphadenectomy was omitted if SLNs were negative on ultrastaging. With a median follow-up period of 35 months, groin recurrences were detected among 2.3% of patients with a unifocal primary tumor and negative SLN. Accordingly, the 3-year survival rate was 97%. Long-term follow-up of the GROINNS-V cohort compared outcomes of SLN-positive patients who underwent reflexive inguinofemoral lymphadenectomy with those of SLN-negative patients in whom inguinofemoral lymphadenectomy was omitted. At a median follow-up of 105 months, the data revealed a 5- and 10-year local recurrence rate of 24.6% and 36.4% for SLN-negative patients and 33.2% and 46.4% for patients with positive SLNs. DSS at 10 years was 91% in the SLN-negative group and 65% in the SLN-positive group. Thus, a significant proportion of patients will develop a local recurrence regardless of SLN status; these local recurrences can occur even a long time after primary treatment. In contrast to previous large retrospective studies, DSS was significantly decreased for patients with a local recurrence, particularly those within 2 years of primary treatment—again, regardless of previous SLN status, indicating that earlier implementation of postoperative radiation may decrease local recurrence rates.
In the GROINSS-V study, short-term morbidity was decreased in patients after sentinel node dissection only compared with patients who had a positive sentinel node biopsy who underwent complete inguinofemoral lymphadenectomy ( Table 69.5 ). Acutely, groin wound breakdown was seen in 11.7% and cellulitis was observed in 4.5% of sentinel node biopsy–only patients, compared with 34.0% and 21.3% of patients undergoing complete groin dissection, respectively. Chronic morbidity also was less frequently observed after removal of only the sentinel nodes (see Table 69.5 ). Recurrent erysipelas was seen in 0.4% compared with 16.2% of patients, respectively, and lymphedema of the legs was observed in 1.9% of patients undergoing sentinel node biopsy compared with 25.2% of patients undergoing full groin dissection.
TABLE 69.5
Complications After Sentinel Lymph Node Biopsy Versus Inguinofemoral Dissection Seen in GROINSS-V
| Complications | Sentinel Lymph Node Biopsy (%) | Inguinofemoral Lymph Node Dissection (%) |
|---|---|---|
| Wound breakdown | 11.7 | 34 |
| Cellulitis | 4.5 | 21.3 |
| Recurrent erysipelas | 0.4 | 16.2 |
| Lymphedema | 1.9 | 25.2 |
GROINSS-V, GROningen INternational Study on Sentinel nodes in Vulvar cancer.
A parallel multi-institutional study was conducted by the GOG in the United States (GOG 173) that enrolled 452 eligible patients (women with vulva-confined primary tumors 2-6 cm, at least 1 mm invasion, and clinically node negative) commencing in December 1999. All participants underwent SLN mapping and biopsy followed by inguinofemoral lymphadenectomy. SLNs were identified in 418 women, and 132 women were node positive (including 11 false-negative nodes). SLN biopsy had a sensitivity of 91.7%, negative predictive value of 96.3%, and false-negative predictive value of 3.7% overall (2% for primary tumors < 4 cm).
A separate analysis of all GROINSS-V patients with positive SLNs (33%) who subsequently underwent completion inguinofemoral lymphadenectomy (115 patients) was conducted to assess the association between size of SLN metastasis and risk of metastasis in nonsentinel nodes as well as DSS. Risk of non-SLN involvement increased steadily with the size of SLN metastasis, beginning at 4.2% with detection of isolated tumor cells and increasing to 62.5% with SLN metastases greater than 10 mm ( Table 69.6 ). DSS was worse among those with SLN metastases greater than 2 mm versus less than or equal to 2 mm (69.5% vs. 94.4%).
TABLE 69.6
Risk of Non-Sentinel-Node Metastases by Largest Tumor Burden in the Sentinel Node From GROINSS-V
| Non-SNL Metastases (%) Per Groin a | |
|---|---|
| ITC | 4.2 |
| ≤ 1 mm | 10 |
| > 1-2 mm | 11.1 |
| > 2-5 mm | 13.3 |
| > 5-10 mm | 38.5 |
| > 10 mm | 62.5 |
| Total | 19 |
GROINSS-V, GROningen INternational Study on Sentinel nodes in Vulvar cancer; ITC, isolated tumor cells; SLN, sentinel lymph node.
a Analyzed for groins in which inguinofemoral lymphadenectomy was done following a finding of a positive SLN.
These data became available in the midst of the GROINSS-V2/GOG 270 observational study, which had been accruing patients since 2006. This follow-up observational study to GROINSS-V/GOG 173 was designed to compare RT of the groin to groin dissection among patients with SLN metastases. Eligible patients are limited to those with unifocal squamous cancers confined to the vulva less than 4 cm in diameter without encroachment on the urethra, vagina, or anus and with clinically and radiographically negative groin nodes. Patients who have successful identification of negative sentinel node(s) undergo no further therapy directed to the groins. Patients with positive sentinel node(s) initially would undergo groin radiation or chemoradiation (at individual investigator discretion) as an alternative to conventional completion of a therapeutic superficial and deep inguinofemoral lymphadenectomy. Interim study results showed that groin recurrence in patients with SLN micrometastases was 2.1%; for those with macrometastases, it was 20%. The study design was modified when this interim safety monitoring revealed an unexpectedly high rate of in-field groin failures in patients with macrometastases. The study was reopened in 2011, requiring all patients with nodal metastases exceeding 2 mm in size to undergo full groin node dissection followed by radiation (50–56 Gy) with concurrent chemotherapy ( Fig. 69.3 ). The reasons for the high failure rate in patients with SLN macrometastases was not clear, and the proposed GROINSS-V3 study is exploring addition of concurrent cisplatinum chemotherapy and increasing dose of RT to 56 Gy in patients with macrometastases on SLN without any additional dissection. The goal is to see if regional control can be improved without the additional morbidity of nodal dissection.
The impact of chemoradiation on survival in the adjuvant setting was recently evaluated with a population-based analysis using the NCDB. A total of 1797 patients were treated with external-beam radiotherapy (EBRT) for stage III disease between 1998 and 2011; 473 received ERBT + chemotherapy. Most (78.5%) started chemotherapy within 1 week of EBRT. A majority had 1 to 3 involved lymph nodes (76.6%), with most patients (39.8%) having only 1 involved lymph node at the time of surgery. In a propensity score analysis to correct for underlying selection bias, delivery of adjuvant chemotherapy led to a 38% reduction in risk of death (3-year OS was 46.9% vs. 53.9% in patients receiving chemoradiation). On subset analysis stratifying patients by ratio of positive lymph nodes (≤ 20% and > 20%), both groups retained a similar benefit from adjuvant chemotherapy. Unfortunately, details regarding type of regimen used and number of cycles as well as radiation fields and sites of failure are not available through the NCDB.
Rob et al. published the most detailed study concerning sentinel node anatomical location in vulvar cancer. They divided groin nodes into four regions: the superficial medial group located above and medial to the femoral vein and medial to the saphenous vein; the superficial intermediate group located in the vicinity of, but superior and lateral to, the saphenous and femoral veins; the superficial lateral group located in the outer third of the groin; and the profundum nodes located deep and medially along the femoral vein. Of the 118 SLNs found in 82 groins in this study, 84% were in the superficial medial region or in the superficial intermediate region, and 16% were in the profundum group. Importantly, no SLNs were found in the superficial lateral region. These findings are informative for the determination of radiation target volumes for patients with clinically and radiographically negative groins undergoing elective or prophylactic groin radiation. Covering only tissues overlying and medial to the femoral vessels allows substantial reduction in radiation dose to the femoral necks and metaphyseal regions while ensuring that first echelon nodes are comprehensively included. As insufficiency fractures of the femur constitute a rare but serious complication of groin node irradiation, tailored treatment volumes based on understanding of the relative risk of different node groups within the groin may be a sensible way to help reduce the risk of this major source of delayed treatment morbidity.
When nodal disease is fixed or ulcerating and/or the local tumor burden is large and unlikely to be controlled by either surgery or radiation alone, combined therapy with initial chemoradiation followed by surgery may offer the best chance of local control if the groin nodes become resectable. In rare patients with unresectable groin nodes, local and regional control can sometimes be obtained with high-dose chemoradiation (see eFig. 69.3 ).
Radiotherapy
RT for vulvar cancer was pioneered in Europe in the early 20th century in an era when surgical options for advanced vulvar cancer were limited. As radical surgery became more feasible and surgical results improved consequent to improvements in anesthesia, postoperative nutritional support, blood transfusion, antibiotics, and refinements in reconstructive surgery and wound care, primary RT with its attendant morbidity was largely abandoned. Because of the acute desquamation accompanying radical irradiation of the vulva and the severe late effects of radiation on the vulva in long-term survivors, the use of RT was largely restricted to palliative use and patients with anatomic extent of disease or medical comorbidities precluding operative intervention. With focused hindsight, RT equipment and techniques were primitive in comparison to current technology, and radiation fractionation and total dose were naïve with respect to potential late normal-tissue effects. In addition, the perception that radiation was a poor second choice as a curative modality stemmed, in part, from the low survival rates reported in early series for patients selected for RT who were unsuitable for primary surgery because of poor general medical condition, locally advanced tumors, or both.
In the past 3 decades, the use of RT (alone or in concert with concurrent radio-potentiating chemotherapy) in the treatment of vulvar cancer has increased dramatically. Commonly administered as adjuvant therapy before or following conservative surgery, chemoradiation has also emerged as an alternative treatment for patients whose extent of disease would require exenterative procedures or other extensively deforming surgical interventions. Two important prospective clinical trials of the GOG (GOG 37, GOG 101) helped form the foundation for these changes in management. Additionally, two randomized prospective trials demonstrated the superiority of chemoradiation to RT alone in the treatment of the analogous cancers of the anal canal. Extension of chemoradiation to treat patients with vulvar cancer was a natural extrapolation and has led to publication of a number of single-institution series reporting encouraging results in limited numbers of patients.
Adjuvant Postoperative Radiation
Early randomized trial data on the benefit of adjuvant radiation for patients with groin node–positive disease was published from GOG 37. This study was conducted to determine whether pelvic radiation could improve survival over the standard pelvic node dissection. Ipsilateral pelvic lymphadenectomy ( n = 55) was compared to RT (45-50 Gy, n = 59) administered to the bilateral groins and pelvis (excluding the tumor bed and residual vulva) in 114 patients who were surgically treated and were found to have groin node metastasis. Metastases were detected in pelvic nodes in 15 of 53 patients (28%) undergoing pelvic lymphadenectomy, 9 of whom died within 1 year. With median follow-up in survivors of 74 months, the OS was 51% in irradiated patients at 6 years compared with 41% in patients treated by pelvic node dissection alone. The cancer-related death rate was 51% in patients undergoing pelvic node dissection compared with 29% in patients undergoing RT. The major benefit of RT was in patients with gross node metastasis, extracapsular extension, or metastases to two or more nodes. The major effect of RT was a reduction in groin failures; radiation was associated with a 5% rate of groin relapse compared with a 24% incidence in patients treated with pelvic lymphadenectomy alone. The tumor bed and residual vulvar tissues were not irradiated, and a 12% crude incidence of vulvar recurrence was observed across both treatment arms.
There are conflicting data on the benefit of adjuvant radiation in patients with a single intracapsular groin node metastasis found on complete inguinofemoral lymphadenectomy. The discussion section in the NCCN clinical practice guidelines nicely summarizes the data contributing to this controversy. Some studies, including an analysis from the AGO-CaRE-1 study, in patients with a single positive lymph node have reported no benefit to adjuvant radiation in this particular setting. However, in a case series of 157 patients, disease-free survival (DFS) was 88% in node-negative patients but 60% in patients with 1 positive node. Examination of SEER data from 208 patients with stage III, single node-positive VSCC revealed significant improvements in 5-year DSS with the addition of adjuvant radiation compared with those receiving no radiation. Presently, the NCCN recommends adjuvant therapy if the SLN or inguinofemoral lymph nodes contain metastases. Adjuvant therapy for patients with SLN involvement includes (1) radiation with or without concurrent chemotherapy for patients with micrometastases with no additional dissection; and (2) completion inguinofemoral lymphadenectomy in the case of positive macrometastases in SLN, followed by radiation with or without concurrent chemotherapy. Adjuvant chemoradiation is strongly recommended for patients after inguinofemoral dissection with 2 or more positive inguinofemoral lymph nodes or a single inguinofemoral lymph node with extracapsular extension or inadequate dissection.
The target volume for adjuvant postoperative RT depends on the indications for adjuvant therapy. For patients with negative groin nodes on SLN biopsy or dissection but adverse primary tumor risk factors, RT targeted at the primary tumor site may be appropriate. The most agreed on primary tumor risk factor is a persistent positive margin. The NCCN lists other candidate risk factors (e.g., tumor size, close margin, depth of invasion, lymphovascular invasion, and pattern of invasion) but does not offer specific recommendations given the lack of data for adjuvant radiation to the primary tumor site based on one or combinations of these. Recently, p16 positivity was found to be a favorable prognostic factor for in-field relapse in patients with VSCC treated with vulvectomy and adjuvant radiation (in-field relapse rates 33% vs. 59% at 3 years for p16-positive vs. p16-negative, respectively, p = 0.072). For patients with unilateral node metastases in whom the contralateral groin has been dissected and is uninvolved, there is no consensus whether to treat the contralateral groin and pelvic nodes, although they were routinely treated in the GOG 37 study of adjuvant radiation.
Whether to routinely include the tumor bed and residual vulva in all patients undergoing adjuvant postoperative RT because of node metastasis also remains controversial. Dusenbery et al. reported 27 patients with squamous carcinoma of the vulva and 1 to 15 (average, 4) histologically involved inguinal lymph nodes who were treated after radical vulvectomy and bilateral lymphadenectomy (25 patients), radical vulvectomy and unilateral lymphadenectomy (1 patient), or hemivulvectomy and bilateral lymphadenectomy (1 patient). Postoperative RT was directed at the bilateral groin and pelvic nodes (19 patients), unilateral groin and pelvic nodes (6 patients), or unilateral groin only (1 patient). Twenty-six patients had the midline (primary tumor bed) shielded. Actuarial 5-year OS and DFS estimates were 40% and 35%, respectively. Relapses developed in 63% (17 of 27) of the patients at a median of 9 months from surgery (range, 3 months to 6 years). Central recurrences (under the midline block) were present in 13 of these 17 patients (representing 50% of the patients treated with the midline blocked), as central only (8 patients), central and regional (4 patients), or central and distant (1 patient). This led the authors to conclude that the target volume for adjuvant postoperative RT for patients with node metastases should include the tumor bed.
Some late local recurrences (defined as occurring > 2 years after primary treatment) may actually represent true second primary cancers in conserved vulvar tissue that is predisposed to malignant transformation. This is more recognizable where second lesions develop in residual contralateral vulva following wide local excision of initially well-lateralized lesions. By definition, a “true” local recurrence is disease recurring within 2 cm of the original primary. Whether adjuvant radiation to all of the remaining vulva would reduce or increase the risk of such second primary cancers is unknown. However, morbidity is definitely increased if the entire vulva is included in adjuvant treatment of a localized lesion. Determining which risk factor(s) are associated with early and delayed vulvar recurrence may inform this treatment decision.
Whether adjuvant local radiation can overcome the negative prognostic impact of close or positive margins is unknown. However, the outcomes from an observational study by Faul et al. are suggestive of a therapeutic benefit. Sixty-two patients with invasive vulva carcinoma and either positive or close (< 8 mm) margins of excision were retrospectively studied. Thirty-one patients were treated with adjuvant RT to the vulva and 31 patients were observed after surgery. Local recurrence occurred in 58% of observed patients and 16% of patients treated with adjuvant irradiation. Adjuvant RT appeared to significantly reduce local recurrence rates in both the close-margin and positive-margin groups. On multivariate analysis, adjuvant radiation and margins of excision were significant prognostic predictors for local control. Patients with observed positive margins had a significantly worse 5-year OS than the other groups, and adjuvant RT appeared to significantly improve survival for this group. The 2-year OS after developing local recurrence was only 25%, lower than other reports for salvage therapy, and local recurrence was a significant predictor for death from vulva carcinoma (risk ratio [RR], 3.54).
The optimal pathological margin for reducing the risk of local recurrence remains controversial. In one report, local recurrence was observed in 8 of 21 patients with pathological margins between 5 and 8 mm. In another report, there were 0 recurrences in 18 patients with margins between 5 and 8 mm. Viswanathan et al. examined margin distance and the number of recurrences by millimeter margin increment. Margins greater than or equal to 5 mm were associated with a significantly reduced risk of local recurrence. The most commonly used indication for adjuvant vulvar irradiation is close margins; some use less than 8 mm as the criterion and others less than 5 mm. When other risk factors such as depth of invasion greater than 5 mm or the presence of lymphovascular space invasion are present, this may tip the decision in favor of local radiation. The usual dose of radiation for adjuvant treatment is between 50.4 and 60.0 Gy. In one retrospective study from Harvard, dose escalation to 56 Gy or above reduced the local relapse rate from 35% to 21% in patients with a 0- to 5-mm margin. In an NCDB analysis on adjuvant RT for positive margins, the greatest mortality reduction occurred with cumulative doses greater than 54 Gy. The unadjusted 3-year OS for dose subsets 30.0 to 45.0 Gy, 45.1 to 53.9 Gy, 54.0 to 59.9 Gy, and ≥ 60 Gy was 54.3%, 55.7%, 70.1%, and 65.3%, respectively. Patients with vulvar squamous cell carcinoma and positive surgical margins may derive an OS benefit from adjuvant RT with a seemingly optimal dose in the range of 54.0 to 59.9 Gy.
Preoperative Radiation
In the 1960s, Boronow pioneered the use of preoperative RT followed by more conservative surgery in patients with locally advanced or recurrent vulvovaginal cancers as an alternative to pelvic exenteration. With a total of 48 treated cases (37 primary cases and 11 cases of recurrent disease), he reported a 72% 5-year survival for all 48 cases treated. One patient required a total pelvic exenteration for local failure, and one had a posterior exenteration for local failure. One bladder and one rectum were lost to permanent diversion because of radiation injury. Five of 96 viscera (48 urinary bladders and 48 rectums) were lost and 91 (94.8%) were retained. Three small series totaling 26 patients treated with 30- to 55-Gy preoperative RT reported histologically negative surgical specimens in 13 patients (50%) with only microscopic residual disease in others. These series provide further evidence for the radiation sensitivity of vulvar cancer.
Preoperative/Neoadjuvant Chemoradiation
Several single-institution studies reported encouraging results employing preoperative chemoradiation before conservative resection in locally advanced or locally recurrent vulvar cancer. These reports, along with reported treatment successes using chemoradiation for patients with anal and esophageal cancer, provided much of the foundation for protocol work commencing in 1989 in the GOG. This work centered around two single-arm prospective trials (GOG 101 and GOG 205), which demonstrated 31% to 50% complete pathological response rates using chemoradiation for locally advanced vulvar cancer.
GOG 101 used planned preoperative chemoradiation consisting of 47.6 Gy in once- or twice-daily fractions of 1.7 Gy synchronously with 2 courses of infusional 5-fluorouracil (5-FU) and cisplatin as initial therapy for 71 evaluable patients with extensive squamous cancer of the vulva (1969 FIGO stages III and IV judged not resectable by radical vulvectomy) followed by surgical resection of residual primary tumor plus bilateral inguinofemoral lymph node dissection. The planned 1.5- to 2.5-week treatment interruption was intended to mitigate the severity of acute RT dermatitis that can progress to confluent moist desquamation as well as to permit hematological recovery. Twice-daily RT was employed to synergize radiation and chemotherapy. Following chemoradiation, 33 of 71 (46.5%) patients had no visible vulvar cancer at the time of planned surgery, and 38 of 71 (53.5%) had gross residual cancer at the time of operation. Five of the 38 had positive resection margins and underwent either further RT to the vulva (3 patients), wide local excision and vaginectomy necessitating colostomy (1 patient), or no further therapy (1 patient). Only 2 of 71 (2.8%) had residual unresectable disease. Preservation of fecal and urinary continence was feasible in 96% of patients. The authors concluded that preoperative chemoradiation is feasible and may reduce the need for more radical surgery, including primary pelvic exenteration.
In parallel with the study of preoperative chemoradiation for patients with locally advanced primary vulvar cancer, the GOG studied patients presenting with advanced disease in the inguinofemoral nodes (1969 nodal classification N2/N3), including some patients with matted, fixed, or ulcerated groin nodes not judged resectable by initial surgery. The identical preoperative chemoradiation schedule was employed to treat 46 patients, except that the treatment volume was increased to encompass the groins and pelvic nodes. Following preoperative chemoradiation, the disease in the lymph nodes was judged resectable in 38 of 40 evaluable patients. Two patients who completed chemoradiation did not undergo surgery because of pulmonary metastasis. The operative lymph node specimen was histologically negative in 15 of 37 patients. Nineteen patients developed recurrent or metastatic disease. Local control of the disease in the lymph nodes was achieved in 36 of 37 and in the primary area in 29 of 38 of the patients. Two patients died of treatment-related complications. The authors concluded that resectability and local control of advanced nodal disease may be obtained with a high probability following preoperative chemoradiation in patients with carcinoma of the vulva with extensive groin adenopathy even with this modest dose of radiation (47.6 Gy).
Acute toxicity in GOG 101 was primarily in the irradiated skin, with moist desquamation reported in many patients. Major hematological toxicity was rare, presumably because the volume of irradiated bone marrow was small in patients with clinically negative groins who received radiation only to the vulva and immediately adjacent tissues. When initial RT target volume includes the groins and pelvic nodes because of confirmed node metastasis, hematological and gastrointestinal toxicities can be expected to be significantly more severe.
Because vulvar cancer and level 1 evidence to support optimal treatment approaches are both rare, there is a large variation in management strategies. At many centers, the initial RT volume electively encompasses the groin and lower pelvic nodes bilaterally in all patients with locally extensive primary cancers selected for preoperative or definitive chemoradiation, regardless of whether groin node metastases have been histologically verified. Evaluation for resectability of residual disease is carried out 4 to 6 weeks following completion of preoperative chemoradiation. If resection can be carried out without compromising functionally important midline structures, this is considered preferred management to avoid the chronic sequelae of high-dose RT on the vulva and perineum. Reduced volume boost treatment is administered to unresectable gross residual primary disease. In patients with initially negative groin nodes (clinically and radiographically), electively irradiated groin nodes are not subsequently routinely dissected. At other centers where chemoradiation is selected for the upfront management of a locally extensive vulvar tumor, groin node status will be confirmed histologically by inguinofemoral lymphadenectomy (almost always bilateral) so that patients with negative groins may be spared unnecessary groin irradiation.
In some patients, a complete clinical response may be seen after moderate-dose preoperative radiation. In GOG 101, preoperative chemoradiation resulted in a complete clinical response in 34 of 71 patients evaluable for therapeutic efficacy (48%) and a pathological complete response (pCR) in 70% (22 of 31) of the 34 complete clinical responders undergoing surgery. Possible options for further management of patients with a clinical complete response to preoperative chemoradiation include generous biopsy to confirm pCR ( eFig. 69.8 ), conservative surgery to remove palpable scar tissue and the tumor bed, or a modest dose of consolidation radiation (8.5–9.0 Gy in 5 fractions over 1 week).
In GOG 205 (the successor to GOG 101) with similar patient eligibility requirements, 5-FU was dropped and the more commonly used regimen of concurrent weekly cisplatin at 40 mg/m 2 was adopted. RT was administered once daily in 32 fractions of 1.8 Gy to a total dose of 57.6 Gy, escalating the physical dose 21% from the 47.6 Gy administered in fractions of 1.7 Gy in GOG 101 while dropping the twice-daily fractionation schedule employed on 8 of the 20 treatment days in that study. Primary endpoints were clinical and pCR. Because of these substantial differences in total dose, dose per fraction, and drug regimen, it is difficult to discern which of these factors may have contributed to the higher complete clinical (64%) and pathological (50%) response rates seen in GOG 205 compared with GOG 101 ( Table 69.7 ).
TABLE 69.7
Outcomes With Different Chemoradiation Schedules in GOG 101 and GOG 205
| GOG 101 a | GOG 205 b | |
|---|---|---|
| Evaluable patients | 71 | 58 |
| Clinical Complete response |
34 (48%) | 37 (64%) |
| Pathological complete response |
22 (31%) | 29 (50%) |
GOG, Gynecological Oncology Group.
a 47.6 Gy in 1.7-Gy fractions (twice-daily days 8–20) 5 d/wk plus concurrent 5-fluorouracil.
b 57.6 Gy in 1.8-Gy fractions (once daily), 5 d/wk plus concurrent weekly cisplatin.
Additionally, prechemoradiation groin dissections were done in 34 patients entered in the GOG 205 trial, of whom 19 (56%) had positive nodes, 12 (35%) had negative nodes, and 3 (9%) had unknown nodal status. Pathological complete response at the primary site was observed in 8 of 19 (42%) patients with node-positive disease but also in 9 of 12 (75%) patients with node-negative disease, suggesting the possibility that nodal status and the efficacy of chemoradiation at the primary site may be interrelated clinical factors. Pretreatment histological groin status was not reported for patients treated in GOG 101, although 23 patients were reported to have FIGO 1969 N2/N3 clinical groin assessment. The comparability of patients entered in these sequential trials is not clear. Interestingly, a recently published retrospective series of 73 women with vulvar cancer treated with neoadjuvant or definitive chemoradiation showed that, compared with p16-negative tumors, p16-positive tumors have better clinical (64% vs. 35%) and pathological (54% vs. 31%) complete response rates. Clinical outcomes also appear to be improved, with 2-year vulvar control for p16-positive tumors reported at 76% compared with 50% for p16-negative tumors. In this series, no patients with a p16-positive tumor developed distant metastases compared with 7 with p16-negative tumors.
Preoperative Chemotherapy
Preoperative neoadjuvant chemotherapy (without radiation) has been used in the treatment of locally advanced vulvar cancer ( Table 69.8 ). Advantages may include reduced tumor volume increasing operability, allowance for more effective radiotherapy, and treatment of micrometastatic disease. Response rates have been quite variable and, although complete clinical or pathological responses have been recorded, these are rare. Still, neoadjuvant chemotherapy can produce responses and reduce the extent of surgery in some, but not all, women with locally advanced vulvar cancer. Many patients in these studies were still heavily node positive after neoadjuvant chemotherapy, and distant relapse was a problem. The best results to date have been obtained with regimens containing cisplatin/5-FU and infusional bleomycin. Dose intensity is likely important; 3 to 4 cycles is advised.
TABLE 69.8
Summary of Neoadjuvant Chemotherapy Studies in Locally Advanced Vulvar Cancer
Adapted from Graham K, Burton K. “Unresectable” vulval cancers: is neoadjuvant chemotherapy the way forward? Curr Oncol Rep 2013;15(6): 573-580.
| No. Patients | Regimen(s) | Response Rate (%) | Operability Rate (%) | |
|---|---|---|---|---|
| Durrant et al. | 31 | Bleo/MTX/CCNU | 58 | 26 |
| Benedetti-Panici et al. | 21 | Cis/Bleo/MTX | 76 | 90 |
| Wagenaar et al. | 25 | Bleo/MTX/CCNU | 56 | 32 |
| Geisler et al. | 13 | Cis/5-FU; Cis | 77 | 77 |
| Domingues et al. | 25 | Bleo; Cis/5-FU; Taxol | 40 | 40 |
| Aragona et al. | 35 | Cis/5-FU; Cis/Taxol; Cis/5-FU/Taxol; Cis/Bleo/Vincristine; Bleo |
86 | 77 |
| Raspagliesi et al. | 10 | Cis/Ifos/Taxol; Cis/Taxol | 80 | 90 |
Bleo, Bleomycin; MTX, methotrexate; CCNU, lomustine, Cis, cisplatin; 5-FU, 5-fluorouracil; Ifos, ifosfamide.
Primary Radiation or Chemoradiation
Treatment of primary lesions.
The Cochrane Collaboration analyzed the use of primary as well as neoadjuvant chemoradiation in locally advanced vulvar cancer. There was no statistically significant difference in overall survival between primary chemoradiation and primary surgery. These results were based on two nonrandomized case series with inherent risk of selection bias. A more recent NCDB study examined primary and neoadjuvant chemoradiation for the treatment of locally advanced vulvar cancer and found the two treatment approaches comparable in terms of survival benefit as long as the RT dose for primary treatment exceeds 55 Gy. The 3-year OS rates for primary and neoadjuvant chemoradiation were 56.9% and 58.3%, respectively. These findings suggest that primary RT at sufficient doses, with chemotherapy, may be a comparable approach to chemoradiation followed by surgical resection for women with initially unresectable disease.
Given the complexity of treatment decision-making and the many possible ways of integrating surgery, RT, and chemotherapy, all patients should be managed by a multidisciplinary team. Reports of RT monotherapy using contemporary techniques and dose-fractionation schedules after biopsy are uncommon. Consequent to probable selection biases in choosing patients for such treatment, it is impossible to meaningfully compare outcomes to alternative treatment strategies. While a recent NCDB propensity-match adjusted analysis demonstrated a significant OS advantage—with a 22% reduction in mortality—for patients treated with primary chemoradiation compared with RT alone, patients treated with chemoradiation were more likely to have received treatment later in the study period (2011-2013 vs. 2004-2010). Thus, patients treated with chemoradiation in this study may have benefited from more contemporary radiation techniques than those who received RT alone. It can only be concluded that some patients benefit from locoregional control and prolonged DFS when managed with radiation or chemoradiation alone. Currently, definitive treatment with RT and synchronous radiosensitizing chemotherapy is typically reserved for patients with disease deemed too extensive for functionally conservative surgery or comorbidities that preclude surgery. Unfortunately, heterogeneity in patient selection criteria as well as chemotherapy prescription and RT dose and fractionation schemes makes it difficult to define the optimal regimen for the small numbers of patients selected for this approach. However, as experience continues to accumulate and observational data become more mature, this can be expected to become a better formulated treatment strategy.
The optimal choice of cytotoxic drugs to administer in conjunction with RT in this and other scenarios remains unknown. Whether cisplatin (cis) with 5-FU or mitomycin-C is more or less effective than weekly cisplatin alone remains unclear. In a nonrandomized, retrospective outcomes comparison of cis-FU versus cisplatin chemoradiation used contemporaneously in the treatment of advanced vulvar cancer, there were no differences in the apparent efficacy of these two different concurrent chemoradiation approaches, though side effect profiles differed.
The currently active GOG 279 study ( Fig. 69.4 ) builds on prior efforts by escalating primary RT dose to 64 Gy for patients with locally advanced vulvar cancer unresectable by initial radical vulvectomy and augmenting the radiation potentiating effects of weekly cisplatin 40 mg/m 2 with the addition of weekly gemcitabine 50 mg/m 2 . The primary study endpoint is pCR. This represents an extrapolation from the benefit of the two-drug regimen demonstrated in a prospective randomized trial of preoperative treatment of locally advanced cervical cancer conducted in Mexico City. However, given the high incidence of acute gastrointestinal and hematological toxicities with the two-drug regimen, it has not replaced weekly cisplatin in the standard treatment of locally advanced cervical cancer. Because RT target volumes for patients with vulvar cancer treated on GOG 279 will include less bowel and less bone marrow than conventionally irradiated volumes used in the treatment of cervical cancer, it is hoped that the two-drug regimen will be tolerated in this mainly elderly population. All RT is to be administered by intensity-modulated radiotherapy (IMRT).
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