NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Vulvar cancer is a rare gynecologic malignancy. However, based on data from the SEER database, 5-year survival rates range from 86% for localized disease (stages I–II), to 57% for regional or locally advanced disease (stages III–IVA), and finally to 17% for patients with distant metastasis (stage IVB).1 Vulvar cancer can arise through human papilloma virus (HPV)–dependent and HPV-independent pathways, the latter of which is more common in older women.2
Studies of the SEER database and the National Cancer Database have shown that treatment approaches/modalities vary considerably with sociodemographic factors such as race/ethnicity, age, and nonprivate insurance, particularly for patients with advanced disease.3,4
Ninety percent of vulvar cancers are of squamous cell carcinoma (SCC) histology.2 Risk factors for the development of vulvar neoplasia include increasing age, infection with HPV, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages.5 Although vulvar SCC is the most common type of vulvar cancer, rarer histologies exist and include melanoma, extramammary Paget disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma.6
The International Society for the Study of Vulvovaginal Disease (ISSVD) has revised the terminology used to characterize vulvar lesions in recent years. In 2004, vulvar intraepithelial neoplasia (VIN) terminology was refined to include 2 types of lesions, usual-type VIN and differentiated VIN.7 Usual-type VIN was linked to persistent infection with carcinogenic strains of HPV; differentiated VIN was commonly associated with vulvar dermatologic conditions such as lichen sclerosus. In 2015, the ISSVD updated the description to 3 classes of vulvar lesions: (1) low-grade squamous intraepithelial lesion (LSIL) due to flat condyloma or HPV effect; (2) high-grade squamous intraepithelial lesions (HSIL; formerly usual-type VIN); and (3) differentiated VIN.8
NCCN Clinical Practice Guidelines in Oncology: Vulvar Cancer, Version 1.2017
Version 1.2017, 10-04-16 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 1; 10.6004/jnccn.2017.0008
NCCN Clinical Practice Guidelines in Oncology: Vulvar Cancer, Version 1.2017
Version 1.2017, 10-04-16 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 1; 10.6004/jnccn.2017.0008
NCCN Clinical Practice Guidelines in Oncology: Vulvar Cancer, Version 1.2017
Version 1.2017, 10-04-16 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 1; 10.6004/jnccn.2017.0008
NCCN Clinical Practice Guidelines in Oncology: Vulvar Cancer, Version 1.2017
Version 1.2017, 10-04-16 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 1; 10.6004/jnccn.2017.0008
NCCN Clinical Practice Guidelines in Oncology: Vulvar Cancer, Version 1.2017
Version 1.2017, 10-04-16 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 1; 10.6004/jnccn.2017.0008
NCCN Clinical Practice Guidelines in Oncology: Vulvar Cancer, Version 1.2017
Version 1.2017, 10-04-16 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 1; 10.6004/jnccn.2017.0008
NCCN Clinical Practice Guidelines in Oncology: Vulvar Cancer, Version 1.2017
Version 1.2017, 10-04-16 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 1; 10.6004/jnccn.2017.0008
Estimates of the percentage of vulvar cancers attributable to HPV infection range from conservative estimates of 30% to up to 69%.9–11 However, HPV infection is detected in 80% to 90% of HSIL. Historically, VIN has been diagnosed in younger women (median age, 45–50 years) and vulvar cancers are diagnosed in older women (median age, 65–70 years).12,13 Because a large majority of HPV-related vulvar cancers are caused by the HPV-16 and -18 strains, vaccination with currently available HPV vaccines may reduce the burden of HPV-related vulvar cancers in the future.9,12
Squamous cell vulvar cancers are typically treated with primary surgery, with the potential integration of radiation (RT) and/or chemotherapy based on pathology and extent of disease.14 Due to the high rates of morbidity with surgical treatment, the field has shifted from radical approaches to more conservative surgery with the addition of RT or chemoradiation.15 Because the data are limited, trials are ongoing to identify optimal approaches for neoadjuvant and adjuvant therapy, which may include systemic therapy, RT, or chemoradiation.16–19 For patients with inoperable or extensive disease, trials have examined neoadjuvant chemoradiation to improve operability rates.17
By definition, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. Many exceptions to the rule were discussed among panel members during the guideline development process. Recommendations in the NCCN Guidelines are category 2A unless otherwise noted.
Diagnosis and Workup
Currently, these NCCN Guidelines focus on the diagnosis, evaluation, and treatment of vulvar SCC. At this time, the guidelines do not address the evaluation and management of rare, non-SCC histologies. For the purposes of this discussion, vulvar SCC will generally be referred to as “vulvar cancer.”
These guidelines utilize the FIGO and AJCC TNM staging systems, which closely align for the staging of vulvar cancer. The FIGO system was updated in 200920,21; the 8th edition of the AJCC Cancer Staging Manual was released in 2016.22 In the updated FIGO system, major changes include the combination of the former stage I and II, subclassification based on the number and size of involved lymph nodes, and shifting away from the focus on bilateral lymph node involvement.20 The impact of this revised classification system has been examined.23–25
The presentation of vulvar cancer can be widely varied. Most vulvar cancers are located in the labia majora, but other possible sites include the labia minora, clitoris, mons, or perineum. In patients with HPV-negative tumors, vulvar cancer often presents as a single mass or ulcer on the labia majora or minora. In HPV-positive tumors, multifocal lesions and concurrent cervical neoplasia are more common.12,13,26 Although many cases may be asymptomatic, pruritus and pain/irritation is a common symptom; vulvar bleeding or discharge may also occur. Most patients present with early-stage (ie, localized) disease.1
Diagnosis is made via a biopsy of the suspicious areas followed by pathologic review. The College of American Pathologists protocol for vulvar carcinoma is a useful guide (available at: http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/WebContent/pdf/cp-vulva-16protocol-3200.pdf). This protocol was revised in January 2016, and it reflects recent updates in the AJCC/FIGO staging.
Workup includes history and physical examination, CBC, and liver and renal function tests. In additional to vulva examination, evaluation of the vagina and cervix, including cytologic smears, should be emphasized due to the multifocal nature of squamous cell intraepithelial neoplasia. CT, PET/CT, and MRI may be used to delineate the extent of tumor and/or for treatment planning.27–31 Examination under anesthesia with cystoscopy or proctoscopy should be considered as indicated. Appropriate patients should receive smoking cessation counseling and HPV testing.
Prognostic Factors
Historically, en bloc vulvectomy with wide margins was combined with complete inguinofemoral lymphadenectomy to treat vulvar SCC. Although effective in promoting survival, this approach was associated with serious short- and long-term morbidity (eg, wound complications, lymphedema, decreased sexual function, adverse impacts on body image). The emergence of data on important prognostic factors in vulvar cancer has informed the evolution of surgical staging and primary treatment.26 Based on a retrospective review of 586 patients enrolled in Gynecologic Oncology Group (GOG) trials through 1984, independent predictors of survival included the presence and number of involved lymph nodes and primary tumor size.32 Lymph node metastasis is considered the most important prognostic factor and determinant of treatment in vulvar cancer,33,34 and extracapsular extension has been linked to poorer prognosis.35–38 Additional factors shown to be predictive of recurrence and/or survival include depth of invasion, tumor thickness, and presence of lymphovascular space invasion (LVSI).12,32,39–42
These important prognostic data have guided the shift towards more conservative primary tumor resection and regional lymph node management for early-stage disease.43 The preferred surgical approach evolved towards vulvar conservation with separate incisions for lymph node dissection in patients who were clinically node-negative.26,44 Current surgical approaches involve tailored primary tumor resection and lymph node evaluation based on individual patient characteristics.45,46 Data suggest that survival is not negatively impacted by less radical surgical approaches for early-stage cancers.46
Surgical Staging
The AJCC and FIGO systems stage vulvar cancer according to extent of primary tumor (T), lymph node status (N), and distant metastasis (M). Clinical staging alone provides inadequate evaluation of lymph node involvement. Because lymph node metastasis is a primary prognostic factor in vulvar cancer survival,33,46 these systems use a hybrid surgical and clinical/pathologic approach for more accurate evaluation of nodal status. Complete staging using the existing system requires primary tumor resection and inguinofemoral lymphadenectomy. However, common practice has increasingly included the use of sentinel lymph node (SLN) biopsy in lieu of complete lymph node dissection, as well as diagnostic imaging to determine extent of disease.47,48
Primary Tumor Resection: Depending on the size and extent of the primary tumor, radical local excision or modified radical vulvectomy may be required. No prospective data are available to compare outcomes between these resection techniques; however, retrospective data suggest no difference exists for recurrence and/or survival.49–51 Both surgical approaches involve resection of approximately a 1- to 2-cm margin of grossly normal tissue and to the deep fascia or a minimum of 1 cm of tissue depth.
Vulvar cancer is associated with significant risk of local recurrence, and data demonstrate tumor margin status to be a significant prognostic factor.39,42,52 A recent review identified 4-year recurrence-free rates of 82%, 63%, and 37% for patients with negative, close, and positive margins, respectively (P=.005); the highest risk of recurrence was associated with margins ≤5 mm.53 The goal of primary tumor resection is complete removal with 1- to 2-cm margins. In the setting of close (<8 mm) or positive tumor margins, re-resection to obtain adequate margins or adjuvant local RT are options.39,54
The risk-benefit ratio and morbidity of each approach must be weighed and individualized for each patient. Evidence supports improved recurrence rates and survival with re-resection or adjuvant external-beam RT (EBRT) to the primary site.55 However, for close or positive margins involving the urethra, anus, or vagina, re-resection may incur significant morbidity and negatively impact patient quality of life. Re-resection may also be inappropriate for patients with close or positive margins who have inguinal node involvement requiring adjuvant treatment with EBRT with or without chemotherapy.
Lymph Node Evaluation: Because lymph node status is the most important determinant of survival in vulvar cancer, careful evaluation and determination of nodal status is paramount. Lymph node resection is performed through a separate incision from the primary tumor and may entail unilateral or bilateral inguinofemoral lymphadenectomy, or SLN biopsy in select cases. Inguinofemoral lymphadenectomy involves removal of superficial inguinal and deep femoral lymph nodes (ie, superficial to the inguinal ligament, within the proximal femoral triangle, and deep to the cribriform fascia). Further emphasizing the importance of adequate inguinofemoral lymph node (IFLN) evaluation and treatment at initial presentation, it has been widely reported that subsequent groin relapses are rarely amenable to successful secondary treatment.
Lymph node dissection in patients with clinically negative groin nodes is informed by the size and location of the primary tumor. Because the risk of lymph node metastasis is <1% in patients with stage IA disease,45 lymphadenectomy is not required for those with T1A and N0 tumors. However, inguinofemoral lymphadenectomy is recommended for patients with stage IB/II disease because the risk of nodal metastasis is estimated at >8% for stage IB tumors.45 Lymphadenectomy for stage III/IV disease is individualized and integrated with combined modality approaches. For primary vulvar tumors <4 cm in diameter, located ≥2 cm from the vulvar midline, with clinically negative IFLNs, unilateral inguinofemoral lymphadenectomy or SLN biopsy are appropriate.56,57 However, bilateral lymph node evaluation (full dissection or SLN biopsy, if indicated) is recommended for patients with primary tumors that are within 2 cm of, or crossing, the vulvar midline.57
SLN Biopsy: Reported rates of postoperative morbidity with unilateral or bilateral inguinofemoral lymphadenectomy are high. An estimated 20% to 40% of patients have wound complications and 30% to 70% of patients experience lymphedema.15,58 In a summary of 12 retrospective studies of patients with negative groin lymphadenectomy, groin recurrence rates varied from 0% to 5.8%,59 suggesting the potential to safely avoid completion lymphadenectomy in patients with negative SLNs. To investigate this approach, several prospective multicenter trials have evaluated the feasibility, safety, validity, and risk of groin recurrences with SLN biopsy in early-stage vulvar cancer.
The safety of SLN biopsy was examined in a multicenter observational study of 403 women with primary vulvar tumors <4 cm. Inguinofemoral lymphadenectomy was omitted if SLNs were negative on ultrastaging. With a median follow-up period of 35 months (24-month minimum), groin recurrences were detected among 6 of 259 patients (2.3%) with a unifocal primary tumor and negative SLN; the 3-year survival rate was 97%. Short- and long-term morbidity was reduced if the SLN only was removed compared with SLN removal followed by full groin dissection.59
The GROINSS-V observational study was also performed in this cohort, examining 135 of 403 patients with positive SLNs (33%). Investigators examined the relationship between size of SLN metastasis and risk of non-SLN disease among 115 patients who underwent inguinofemoral lymphadenectomy after detection of positive SLNs. 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 >10 mm. Disease-specific survival (DSS) was worse among those with SLN metastases >2 mm versus ≤2 mm (69.5% vs 94.4%; P=.001).60 Patients undergoing SLN biopsy reported less treatment-related morbidity compared with those undergoing IFLN dissection; however, patient-reported quality of life did not differ significantly between groups.61
Long-term follow-up of the GROINSS-V cohort compared outcomes of SLN-positive patients who underwent IFLN dissection with SLN-negative patients (no IFLN dissection). At a median follow-up of 105 months, the data revealed a 5- and 10-year recurrence rate of 24.6% and 36.4% for SLN-negative patients, respectively, and 33.2% and 46.4% for patients with a positive SLN, respectively (P=.03). DSS at 10 years was 91% in the SLN-negative group and 65% in the SLN-positive group (P<.0001).62
In GOG 173, 452 women (with vulva-confined primary tumors 2–6 cm, ≥1-mm invasion, and clinically node-negative) 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).63 A recent systematic review and meta-analysis of the cumulative data on SLN biopsy revealed a per-groin detection rate of 87% when using dual tracers and a false-negative rate of 6.4%. When comparing inguinofemoral lymphadenectomy, superficial inguinofemoral lymphadenectomy, and SLN biopsy, recurrences rates were 1.4%, 6.6%, and 3.4%, respectively.64
The ongoing GROINSS-V-II/GOG 270 study (ClinicalTrials.gov identifier: NCT01500512) is comparing RT of the groin to groin node dissection among patients with SLN metastases.
Panel Recommendations: For appropriate individuals, the panel considers SLN mapping and biopsy of the IFLN basin a reasonable alternative approach to decrease postoperative morbidity while maintaining low groin recurrences with this surgical approach in vulvar cancer.59,60,63
Candidates for SLN biopsy should have clinically/radiologically negative groin nodes, unifocal primary tumor <4 cm, and no history of previous vulvar surgery.60,64 Mapping and biopsy should be performed by a high-volume SLN surgeon using dual tracers (ie, radiocolloid and dye) to ensure the best detection rates.63,64 The NCCN Vulvar Cancer Panel recommends complete inguinofemoral lymphadenectomy if no ipsilateral SLN is detected. If the ipsilateral SLN is positive, completion lymphadenectomy or treatment of the affected groin may be warranted. Additionally, surgical evaluation or treatment of the contralateral groin is indicated.
Primary Treatment
For the purposes of primary treatment, these NCCN Guidelines provide treatment recommendations by clinical stage, separating patients into those with early-stage (stage I/II), locally advanced (stage III/IVA), and distant metastatic disease (stage IVB, beyond the pelvis). Patients with early-stage disease include those with T1 or smaller T2 primary tumors; smaller T2 primary tumors are classified as ≤4 cm with no/minimal involvement of the urethra, vagina, or anus. Patients with locally advanced disease include those with larger T2 or T3 primary tumors for whom visceral-sparing primary surgery is not indicated. Patients with distant metastatic disease may fall within any T or N classification and must have disease beyond the pelvis.
Early-Stage Disease
After careful clinical evaluation and staging, standard primary treatment for earlystage vulvar SCC is conservative individualized tumor excision with IFLN evaluation.44,50,65–68 Clinicians should strive for primary tumor resection with oncologically appropriate margins of 1 to 2 cm if feasible.39,42,52,54 See “Primary Tumor Resection” and “Lymph Node Evaluation” (page 109). Although there are no prospective data comparing radical local incision to radical vulvectomy, existing data from retrospective analyses do not demonstrate a difference in recurrence or survival outcomes.50,51
Surgical dissection and RT have been evaluated for treatment of the groin in early-stage disease. Limited data suggest that primary groin RT results in less morbidity than surgical dissection.14 However, surgical treatment of the groin has been associated with lower groin recurrence rates, therefore, remaining the preferred approach.69 Primary RT may have some benefit for those unable to undergo surgery.70,71
Panel Recommendations: For T1 tumors with ≤1 mm depth of invasion (pT1A), the NCCN Guidelines Panel recommends wide local resection or radical local resection; IFLN evaluation is not required due to the low risk of lymph node metastasis in these patients.45,66,72–75 Patients should be observed following resection. If surgical pathology reveals >1-mm invasion, additional surgery may be indicated.
For patients with T1 or smaller T2 tumors with a depth of invasion >1 mm, primary treatment is dictated by tumor location. Patients with lateralized lesions (>1-mm invasion) located ≥2 cm from the vulvar midline should undergo radical local resection or modified radical vulvectomy accompanied by ipsilateral groin node evaluation.56,57,72 Groin evaluation can be performed through SLN biopsy or ipsilateral IFLN dissection. Dissection should be performed if no SLNs are detected. Adjuvant therapy is informed by primary tumor and nodal surgical pathology. Patients with midline vulvar lesions (>1-mm invasion) should undergo radical local resection or modified radical vulvectomy accompanied by bilateral groin node evaluation consisting of SLN biopsy or ipsilateral IFLN dissection.50,57,72 Groin dissection is required on sides for which SLNs are not detected. Adjuvant therapy is informed by primary tumor and nodal surgical pathology.
Locally Advanced Disease
Historically, locally advanced vulvar cancers were treated primarily with radical surgeries such as en bloc radical vulvectomy with bilateral inguinofemoral lymphadenectomy or pelvic exenteration. These surgeries resulted in some cures, but also led to significant postoperative complications, loss of function, and reduced quality of life.26,76–78 Additionally, complete resection of locally advanced disease may be complicated by tumor fixed to vital organs or vessels, rendering the disease unresectable.79 A shift to multimodality treatment was explored to improve organ preservation and reduce surgical treatment morbidity.80 Preoperative RT was shown in some earlier studies to result in tumor debulking and reduce the extent of surgery required for locally advanced disease.79,81–84 Subsequently, borrowing on experience from advanced cervical and anal cancers, chemotherapy typically has been combined added as a “radiosensitizer” when RT is delivered to patients with advanced disease.
Chemoradiation: Research directly comparing treatment approaches for locally advanced vulvar cancers is limited. Data from small patient cohorts have shown a generally high response rate to chemoradiation among most patients with stage III/IVA disease, as well as the feasibility of resection for residual disease after chemoradiation. After chemoradiation, at least partial tumor responses were noted among a majority in these cohorts,85–89 with several studies revealing complete tumor responses among >60% of the cohort.90–94 Overall survival (OS) after primary chemoradiation was superior to OS after primary RT in a series of 54 patients with locally advanced disease.95
In GOG 101, preoperative chemoradiation was examined in 73 patients with stage III/IV disease.87 The study investigated whether chemoradiation allowed for less radical surgery in patients with T3 tumors and avoidance of pelvic exenteration in those with T4 tumors. Only 3% of patients (2/71) had residual unresectable disease after chemoradiation, and preservation of urinary and/or gastrointestinal continence was possible in 96% of patients (68/71).
Two prospective studies from the GOG more closely examined the benefits of surgery after chemoradiation for patients with locally advanced disease. GOG 101 examined 46 patients with vulvar SCC and N2/N3 nodal involvement.96 Subsequent surgery was performed on 38 patients with resectable disease after chemoradiation with cisplatin/5-FU. Local control of nodal disease was achieved in 36 of 37 patients and for the primary tumor in 29 of 38 patients. More recently, GOG 205 examined the feasibility of surgery after chemoradiation with cisplatin in 58 patients with T3/T4 tumors that were initially unresectable by radical vulvectomy.97 Complete clinical response was noted in 64% of patients (37/58) with complete pathologic response in 78% (29/34) of patients undergoing surgical biopsy. The high pathologic complete response rates have led many to believe that surgery can be avoided in patients with locally advanced tumors who achieve clinical complete responses.
A 2011 Cochrane database review of the existing randomized controlled trial data on 141 women with locally advanced vulvar SCC revealed no difference in OS when comparing primary surgery to primary or neoadjuvant chemoradiation.18 However, the data did not allow for broad conclusions to be drawn regarding treatment-related quality of life and adverse events. An earlier Cochrane database review of 5 nonrandomized trials suggested that patients with unresectable primary disease and those requiring exenteration may benefit from neoadjuvant chemoradiation if disease was rendered resectable or requiring less radical surgery.17
The combination regimen used for radiosensitization was most commonly cisplatin/5-FU,87,88,90,92,93 but also included 5-FU/mitomycin C86,89,94 or single-agent therapy.91,97 The selection of radiosensitizing chemotherapy is often based on an extrapolation of findings from cervical, anal, or head and neck cancer.
Panel Recommendations: Patients with larger T2 or T3 tumors should undergo radiologic imaging if it was not previously performed to examine potential nodal involvement. The panel recommends that all patients with locally advanced disease receive EBRT with concurrent chemotherapy. IFLN dissection may be used to assess nodal metastasis to inform RT treatment planning.
If IFLN dissection is not performed or positive IFLNs are found on dissection, EBRT coverage should include the primary tumor, groin, and pelvis. If no positive nodes are detected following inguinofemoral lymphadenectomy, EBRT with concurrent chemotherapy should be provided with RT coverage of the primary tumor with or without selective coverage of groin lymph nodes.
Patients with radiographically positive nodes (including those with pelvis-confined metastases) should be evaluated for IFLN dissection. If groin node dissection is not performed, fine-needle aspiration of enlarged lymph nodes can be considered. Patients should receive EBRT and concurrent chemotherapy; EBRT coverage should include the primary tumor, groin, and pelvis. Selective groin/pelvis RT coverage can be considered if dissection reveals no positive lymph nodes. Agents recommended by the panel for chemoradiation include cisplatin, 5-FU/cisplatin, and 5-FU/mitomycin-C.16,98
Metastasis Beyond the Pelvis
Data on systemic treatments for vulvar SCC with distant metastasis are extremely limited.99–101 Treatment regimens are often extrapolated from agents that are active against advanced cervical cancer. See “Systemic Therapy for Recurrent/Metastatic Disease” (page 116) for information regarding specific regimens.
Panel Recommendations: Primary treatment options for extra-pelvic metastatic disease include EBRT for control of locoregional disease and symptom control, and/or chemotherapy. Best supportive care is also an alternative in this setting. Agents recommended by the panel for treating advanced recurrent/metastatic disease include cisplatin, carboplatin, paclitaxel (category 2B), and erlotinib (category 2B) as single agents and cisplatin/vinorelbine, cisplatin/paclitaxel, and carboplatin/paclitaxel (category 2B).16
Adjuvant Therapy
Because of the rarity of vulvar cancer, especially advanced disease, prospective randomized trials on adjuvant therapy are extremely limited. Much of the common adjuvant treatment approaches have been drawn from studies describing heterogenous, often individualized, treatment approaches or extrapolated from effective adjuvant therapies for cervical and anal cancers.
Adjuvant RT and Chemoradiation
Although commonly accepted that lymph node involvement is a critical prognostic factor in vulvar SCC, the optimal patient selection criteria and adjuvant therapy regimens to address nodal disease continue to be determined.102 As previously emphasized, it is crucial to prevent metachronous groin relapses, because these often prove refractory to secondary management and are often ultimately fatal.
Early randomized trial data on adjuvant RT was published from GOG 37, which enrolled 114 patients with groin node-positive vulvar cancer after radical vulvectomy and bilateral inguinofemoral lymphadenectomy.103,104 Patients were randomized to receive pelvic node dissection or adjuvant RT to the groin/pelvis. In the adjuvant RT group, 2- and 6-year survival was superior, but the most significant survival benefits were observed among patients with ≥2 positive groin nodes or those with fixed ulcerative groin nodes. Long-term follow-up (median, 74 months) revealed higher rates of disease-related death for those receiving pelvic node resection compared with pelvic/groin RT (51% vs 29%; hazard ratio [HR], 0.49; P=.015).104
There are conflicting data on the benefit of adjuvant RT in patients with a single positive lymph node. Some studies of patients with a single positive lymph node have reported no benefit to adjuvant RT.105,106 However, examination of SEER data from 208 patients with stage III, single node-positive vulvar SCC revealed significant improvements in 5-year DSS with the addition of adjuvant RT compared with those receiving no RT.107 The survival benefit was more pronounced among patients who underwent less extensive lymphadenectomy (≤12 nodes excised).
In a case series of 157 patients, disease-free survival (DFS) at 2 years was 88% in node-negative patients, but 60%, 43%, and 29% in patients with 1, 2, and >2 positive nodes, respectively. The number of involved nodes negatively impacted prognosis in patients receiving no adjuvant RT; however, among patients receiving adjuvant RT to the groin/pelvis, the number of metastatic nodes did not harm prognosis.108
A large multicenter retrospective study reported significant survival benefits in node-positive patients receiving adjuvant RT or chemoradiation (3-year progression-free survival [PFS]: 39.6% vs 25.9%; P=.004; 3-year OS: 57.7% vs 51.4%; P=.17).106 RT coverage most commonly included the groin and pelvis with or without coverage of the vulva, with a smaller subset receiving coverage to the groin with or without vulvar coverage. Again, the benefits of adjuvant RT were the most clear for patients with ≥2 positive lymph nodes. When adjuvant RT is delivered to the lymph nodes, care should be used to avoid excessive blocking of the central pelvic structures.109
Recent examination of data from the National Cancer Database supported the addition of chemotherapy to RT in the adjuvant setting. Among 1,797 patients with node-positive vulvar cancer, 26.3% received adjuvant chemotherapy in addition to RT after primary surgery. Adjuvant chemotherapy increased survival time and reduced mortality risk (44 vs 29.7 months; HR, 0.62; 95% CI, 0.48–0.79; P<.001).110 Based on SEER data, outcomes of adjuvant RT were examined in 519 patients aged ≥66 years who received primary surgery for node-positive vulvar cancer. Adjuvant RT was associated with improved OS over surgery alone in this cohort of older women (HR, 0.71; 95% CI, 0.57–0.88; P=.002) along with a trend toward improved cause-specific survival (HR, 0.79; 95% CI, 0.59–1.05; P=.11).111 Parameters for RT delivery were important among this cohort; 3-year OS and cause-specific survival were significantly improved in patients who received ≥20 fractions (3-year OS: 34% vs 26%; P=.008, and 3-year cause-specific survival: 48% vs 37%; P=.03).
Research has also examined the role of adjuvant RT to the primary tumor site. Studies have indicated that isolated primary site recurrences may be addressed effectively by subsequent surgery, or that late recurrences may actually represent secondary tumors. The benefit of adjuvant RT to the vulva in patients with close/positive surgical margins has also been investigated.112 Among patients with close/positive surgical margins at the primary site, 5-year OS was significantly improved by the addition of adjuvant RT to the primary site (67.6% vs 29%; HR, 0.36; P=.038). Patients receiving adjuvant RT for close/positive margins had a similar 5-year OS to those with negative margins. A retrospective study examined the association of RT dose with vulvar recurrence, revealing a lower risk of recurrence in patients receiving doses of ≥56 Gy compared with those receiving ≤50.4 Gy.53
Panel Recommendations: For patients with early-stage disease (T1) and a depth of invasion ≤1 mm (pT1a), observation is appropriate after primary surgery. For patients with T1b and T2 disease, surgical evaluation of the groin is indicated in addition to primary site surgery. Nodal status is an important determinant of adjuvant therapy recommendations. For patients with a negative SLN or negative IFLNs, observation can be considered.59,113–116 Adjuvant therapy is warranted if the SLN or IFLNs contain metastases. Adjuvant therapy for patients with SLN involvement includes: (1) RT (category 1) with or without concurrent chemotherapy; or (2) completion IFLN dissection followed by EBRT with or without concurrent chemotherapy. Adjuvant therapy for patients who have positive IFLNs detected during groin node dissection includes EBRT (category 1) with or without concurrent chemotherapy. Chemoradiation is strongly recommended for patients with ≥2 positive IFLNS or a single IFLN with >2-mm metastasis.103,106
In additional to nodal status, a number of primary tumor risk factors may influence adjuvant therapy decisions, which include LVSI, close or positive tumor margins, tumor size, depth of invasion, and/or diffuse/spray pattern of invasion. Observation is reasonable in the setting of negative primary tumor margins with no additional risk factors. Treatment should be individualized for patients with primary tumor margins that are positive for noninvasive disease (eg, HSIL). If surgical margins are positive for invasive disease, re-excision should be considered to achieve oncologically appropriate margins. Patients with continued positive margins after re-excision should receive adjuvant EBRT.112 Patients with oncologically appropriate margins after re-excision may be candidates for observation unless additional risk factors warrant adjuvant EBRT. For those with positive margins for invasive disease who are not candidates for re-excision, adjuvant EBRT should be offered.
For patients with locally advanced disease, adjuvant therapy decisions should be made based on clinical evaluation of treatment response after EBRT with concurrent chemotherapy (potentially preceded by IFLN dissection). These NCCN Guidelines provide adjuvant therapy recommendations based on whether patients are clinically negative or positive for residual tumor at the primary site and in the groin. Patients with no clinical evidence of residual tumor after EBRT with concurrent chemotherapy should undergo surveillance. Biopsy of the tumor bed can also be considered to confirm pathologic complete response. Patients with residual tumor should be considered for resection. In the case of positive margins on resection, providers should consider additional surgery, additional EBRT, and/or systemic therapy, or best supportive care. For unresectable residual disease, providers should consider additional EBRT and/or systemic therapy, or best supportive care.
Surveillance
Most recurrences of vulvar cancer occur within the first year, although recurrences beyond 5 years have been observed in a significant subset of patients.117 Accordingly, long-term follow-up is indicated. Definitive data on an optimal surveillance strategy is lacking.118 However, the panel concurs with the updated recommendations from the Society of Gynecologic Oncology for posttreatment surveillance,119 which is based on the patient's risk for recurrence and personal preferences. History and physical examination are recommended every 3 to 6 months for 2 years, every 6 to 12 months for another 3 to 5 years, and then annually (see VULVA-8, page 100). Patients with high-risk disease can be assessed more frequently (eg, every 3 months for the first 2 years) than patients with low-risk disease (eg, every 6 months).
Annual cervical/vaginal cytology tests can be considered as indicated for detection of lower genital tract dysplasia, although its value in detecting recurrent cancers is limited and the likelihood of detecting asymptomatic recurrence is low. Imaging (ie, chest radiography, CT, PET/CT, MRI) and laboratory testing (ie, CBC, blood urea nitrogen, creatinine) are recommended as indicated by suspicious examination findings or symptoms of recurrence.
Patient education regarding symptoms suggestive of recurrence or vulvar dystrophy is recommended, as well as periodic self-examination. Patients should also be counseled on healthy lifestyle, obesity, nutrition, exercise, and sexual health (including vaginal dilator use and lubricants/moisturizers). For information on these and other issues related to survivorship (ie, pain/neuropathy, fear of recurrence, and depression), see the NCCN Guidelines for Survivorship (available at NCCN.org). Smoking cessation and abstinence should be encouraged, see the NCCN Guidelines for Smoking Cessation (available at NCCN.org).
Sexual dysfunction and low body image is unfortunately common among women who have undergone vulvectomy and/or RT of the groin/pelvis.15,120,121 Patients who have received RT for vulvar cancer may experience vaginal stenosis and dryness, and should receive education on important issues regarding sexual health and vaginal health. Providers should inform patients about regular vaginal intercourse and/or vaginal dilator use, and the use of vaginal moisturizers/lubricants (eg, estrogen creams, nonhormonal options). Anecdotal evidence suggests that vaginal dilators may be used to prevent or treat vaginal stenosis. Dilator use can start 2 to 4 weeks after the completion of RT and can be performed indefinitely (https://www.mskcc.org/cancer-care/patient-education/improving-your-vaginal-health-after-radiation-therapy).
If persistent or recurrent disease is suspected, patients should be evaluated using additional imaging studies and biopsy as outlined in the following section.
Treatment for Recurrent Disease
A multicenter case series evaluated the rates and patterns of recurrence among 502 patients, of whom 187 (37%) developed recurrent vulvar SCC. More than 50% of recurrences were vulvar (53.4%), followed by inguinal (18.7%), multisite (14.2%), distant (7.9%), and pelvic (5.7%). Survival rates at 5 years were 60% for vulvar recurrence, 27% for inguinal/pelvic, 15% for distant sites, and 14% for multiple sites.34 Although localized vulvar recurrences can be successfully addressed with subsequent surgery, some studies have suggested a higher risk of cancer-related death.
Given the rarity of primary vulvar cancer, data for treating recurrences are even scarcer and no clear standard of care exists.122 Treatment approaches and patient outcomes depend on site and extent of recurrent disease.122,123 Isolated local recurrences can often be treated successfully with radical local excision,34,124 and RT with or without chemotherapy provided some degree of DFS in several studies.83,84 A retrospective review of patients with locoregional recurrences that were managed with chemoradiation, neoadjuvant chemotherapy, or RT alone showed 5-year DFS and OS rates of approximately 20%; however, those with a single-site recurrence and lesions ≤3 cm who received an RT dose ≥64.8 Gy remained disease-free at 5 years.125 Conversely, another series noted a decline in survival for those with nodal metastases, tumors >3 cm, or high-grade lesions.126 For central/large recurrences, pelvic exenteration has been shown to prolong survival when performed on carefully selected patients.76,77,127 Regardless of treatment approach, prognosis for nodal recurrences was very poor.124,126,128,129
Panel Recommendations
If recurrence is suspected, the NCCN Vulvar Cancer Panel recommends workup for metastatic disease with imaging studies. Biopsy can be considered to confirm distant metastasis. Treatment recommendations for recurrent disease are outlined according to the site of recurrence and previous therapies received.
Vulva-Confined Recurrence
If recurrence is clinically limited to the vulva with clinically negative nodes and the patient did not receive prior RT, the panel recommends surgical and RT treatment pathways. Surgical recommendations include radical excision with unilateral or bilateral IFLN dissection if lymphadenectomy was not previously performed. Pelvic exenteration can be considered for select cases with a central recurrence. Additional therapy is indicated by margin status and nodal status. Observation is appropriate for negative margins and nodes. In patients with positive margins but no evidence of nodal involvement, options include re-excision or EBRT with or without brachytherapy and/or concurrent chemotherapy (category 2B for chemotherapy). EBRT with or without chemotherapy is recommended for patients with negative surgical margins but surgically positive IFLNs. In patients with both positive margins and surgically positive IFLNs, the panel recommends EBRT with or without brachytherapy, concurrent chemotherapy, and/or re-excision as appropriate.
Nonsurgical therapy for recurrence includes EBRT with or without brachytherapy and/or concurrent chemotherapy. Resection can be considered for patients with gross residual tumor. When feasible, resection is also indicated for patients with vulva-confined recurrence who were previously irradiated. After treatment for recurrence, patients should undergo surveillance.
Nodal Recurrence or Distant Metastasis: Chemotherapy, palliative/best supportive care, or clinical trial enrollment is recommended for patients experiencing recurrence who received prior pelvic EBRT and for those with multiple positive pelvic nodes or distant metastasis. Resection followed by systemic therapy can be considered for select cases of isolated groin/pelvic recurrence that were previously irradiated.
If recurrence is limited to the groin and no prior RT was given, then resection of positive nodes followed by EBRT with or without concurrent chemotherapy should be considered. For unresectable nodes, EBRT with or without concurrent chemotherapy is appropriate. All patients should undergo surveillance following treatment for recurrent disease.
Systemic Therapy for Recurrent/Metastatic Disease
No standard chemotherapy regimens exist for treating advanced or recurrent/metastatic disease. Several reports provide anecdotal evidence for various regimens, at times extrapolating from regimens with known activity in advanced cervical and anal cancers, as well as other SCCs. An overview of systemic therapies used to treat vulvar SCC is available in the article by Reade et al16; recommended systemic therapy agents are listed on VULVA-D, page 107.
Cisplatin is a commonly employed radiosensitizing agent in locally advanced vulvar cancer, and is recommended for single-agent or combination chemotherapy for the treatment of metastatic disease.79,130 Cisplatin/vinorelbine was studied in a small case series of patients with recurrent disease, producing a 40% response rate, 10-month PFS, and 19-month OS.131
Carboplatin (category 2A) is an alternative platinum agent active in metastatic cervical cancer that can be used as a single agent or in combination with paclitaxel (category 2B). A small series of 6 patients with advanced or recurrent/metastatic vulvar cancer noted limited clinical benefit of the combination regimen99; however, it has been included in these NCCN Guidelines based on data from patients with advanced or recurrent/metastatic cervical cancer.132
Paclitaxel (category 2B) was modestly active in a phase II trial of 31 women with advanced recurrent/metastatic vulvar cancer, and generated a response rate of 14% and PFS of 2.6 months.100
Erlotinib was studied in a phase II trial that included a cohort of women with metastatic disease. Short-duration responses were observed, with partial responses and stable disease noted in 27.5% and 40% of enrolled patients, respectively.101
Individual Disclosures for the NCCN Vulvar Cancer Panel
References
- 1.↑
SEER Cancer Statistics Factsheets: Vulvar Cancer. Bethesda, MD: National Cancer Institute; Available at: http://seer.cancer.gov/statfacts/html/vulva.html. Accessed April 22, 2016.
- 2.↑
Vulvar Cancer Treatment (PDQ®)–Health Professional Version. Bethesda, MD: 2015. Available at: http://www.cancer.gov/types/vulvar/hp/vulvar-treatment-pdq#section/_1. Accessed August 3, 2015.
- 3.↑
Tergas AI, Tseng JH, Bristow RE. Impact of race and ethnicity on treatment and survival of women with vulvar cancer in the United States. Gynecol Oncol 2013;129:154–158.
- 4.↑
Chase DM, Lin CC, Craig CD et al.. Disparities in vulvar cancer reported by the National Cancer Database: influence of sociodemographic factors. Obstet Gynecol 2015;126:792–802.
- 5.↑
Stroup AM, Harlan LC, Trimble EL. Demographic, clinical, and treatment trends among women diagnosed with vulvar cancer in the United States. Gynecol Oncol 2008;108:577–583.
- 6.↑
Figge DC. Rare vulvar malignancies. In: Greer BE, Berek JS, eds. Current Topics In Obstetrics And Gynecology: Gynecologic Oncology: Treatment Rationale And Techniques. Elsevier; 1991:239–257.
- 7.↑
Sideri M, Jones RW, Wilkinson EJ et al.. Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J Reprod Med 2005;50:807–810.
- 8.↑
Bornstein J, Bogliatto F, Haefner HK et al.. The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) terminology of vulvar squamous intraepithelial lesions. Obstet Gynecol 2016;127:264–268.
- 9.↑
Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer 2008;113:3036–3046.
- 10.
Watson M, Saraiya M, Ahmed F et al.. Using population-based cancer registry data to assess the burden of human papillomavirus-associated cancers in the United States: overview of methods. Cancer 2008;113:2841–2854.
- 11.↑
Gargano JW, Wilkinson EJ, Unger ER et al.. Prevalence of human papillomavirus types in invasive vulvar cancers and vulvar intraepithelial neoplasia 3 in the United States before vaccine introduction. J Low Genit Tract Dis 2012;16:471–479.
- 12.↑
Eifel PJ, Berek JS, Markman MA. Cancer of the cervix, vagina, and vulva. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. Principles and Practice of Oncology, 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:1311–1344.
- 13.↑
Hampl M, Deckers-Figiel S, Hampl JA et al.. New aspects of vulvar cancer: changes in localization and age of onset. Gynecol Oncol 2008;109:340–345.
- 14.↑
van der Velden J, Fons G, Lawrie TA. Primary groin irradiation versus primary groin surgery for early vulvar cancer. Cochrane Database Syst Rev 2011:CD002224.
- 15.↑
Wills A, Obermair A. A review of complications associated with the surgical treatment of vulvar cancer. Gynecol Oncol 2013;131:467–479.
- 16.↑
Reade CJ, Eiriksson LR, Mackay H. Systemic therapy in squamous cell carcinoma of the vulva: current status and future directions. Gynecol Oncol 2014;132:780–789.
- 17.↑
van Doorn HC, Ansink A, Verhaar-Langereis M, Stalpers L. Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev 2006:CD003752.
- 18.↑
Shylasree TS, Bryant A, Howells RE. Chemoradiation for advanced primary vulval cancer. Cochrane Database Syst Rev 2011:CD003752.
- 19.↑
Woelber L, Kock L, Gieseking F et al.. Clinical management of primary vulvar cancer. Eur J Cancer 2011;47:2315–2321.
- 20.↑
Hacker NF. Revised FIGO staging for carcinoma of the vulva. Int J Gynaecol Obstet 2009;105:105–106.
- 21.↑
Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009;105:103–104.
- 22.↑
Amin MB, Edge SB, Greene FL et al.. AJCC Cancer Staging Manual, 8th edition. New York, NY: Springer; 2016.
- 23.↑
Li J, Cai Y, Ke G et al.. Validation of the new FIGO staging system (2009) for vulvar cancer in the Chinese population. Gynecol Oncol 2015;137:274–279.
- 24.
Tabbaa ZM, Gonzalez J, Sznurkowski JJ et al.. Impact of the new FIGO 2009 staging classification for vulvar cancer on prognosis and stage distribution. Gynecol Oncol 2012;127:147–152.
- 25.↑
Tan J, Chetty N, Kondalsamy-Chennakesavan S et al.. Validation of the FIGO 2009 staging system for carcinoma of the vulva. Int J Gynecol Cancer 2012;22:498–502.
- 26.↑
Greer BE, Berek JS. Evolution of the primary treatment of invasive squamous cell carcinoma of the vulva. In: Greer BE, Berek JS, eds. Current Topics In Obstetrics And Gynecology: Gynecologic Oncology: Treatment Rationale And Techniques: Elsevier; 1991:227–238.
- 27.↑
Kataoka MY, Sala E, Baldwin P et al.. The accuracy of magnetic resonance imaging in staging of vulvar cancer: a retrospective multi-centre study. Gynecol Oncol 2010;117:82–87.
- 28.
Cohn DE, Dehdashti F, Gibb RK et al.. Prospective evaluation of positron emission tomography for the detection of groin node metastases from vulvar cancer. Gynecol Oncol 2002;85:179–184.
- 29.
Kamran MW, O'Toole F, Meghen K et al.. Whole-body [18F]fluoro-2-deoxyglucose positron emission tomography scan as combined PET-CT staging prior to planned radical vulvectomy and inguinofemoral lymphadenectomy for squamous vulvar cancer: a correlation with groin node metastasis. Eur J Gynaecol Oncol 2014;35:230–235.
- 30.
Peiro V, Chiva L, Gonzalez A et al.. [Utility of the PET/CT in vulvar cancer management]. Rev Esp Med Nucl Imagen Mol 2014;33:87–92 [in Spanish].
- 31.↑
Robertson NL, Hricak H, Sonoda Y et al.. The impact of FDG-PET/CT in the management of patients with vulvar and vaginal cancer. Gynecol Oncol 2016;140:420–424.
- 32.↑
Homesley HD, Bundy BN, Sedlis A et al.. Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study). Am J Obstet Gynecol 1991;164:997–1003; discussion 1003–1004.
- 33.↑
Burger MP, Hollema H, Emanuels AG et al.. The importance of the groin node status for the survival of T1 and T2 vulval carcinoma patients. Gynecol Oncol 1995;57:327–334.
- 34.↑
Maggino T, Landoni F, Sartori E et al.. Patterns of recurrence in patients with squamous cell carcinoma of the vulva. A multicenter CTF Study. Cancer 2000;89:116–122.
- 35.↑
van der Velden J, van Lindert AC, Lammes FB et al.. Extracapsular growth of lymph node metastases in squamous cell carcinoma of the vulva. The impact on recurrence and survival. Cancer 1995;75:2885–2890.
- 36.
Luchini C, Nottegar A, Solmi M et al.. Prognostic implications of extranodal extension in node-positive squamous cell carcinoma of the vulva: a systematic review and meta-analysis. Surg Oncol 2016;25:60–65.
- 37.
Origoni M, Sideri M, Garsia S et al.. Prognostic value of pathological patterns of lymph node positivity in squamous cell carcinoma of the vulva stage III and IVA FIGO. Gynecol Oncol 1992;45:313–316.
- 38.↑
Raspagliesi F, Hanozet F, Ditto A et al.. Clinical and pathological prognostic factors in squamous cell carcinoma of the vulva. Gynecol Oncol 2006;102:333–337.
- 39.↑
Heaps JM, Fu YS, Montz FJ et al.. Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva. Gynecol Oncol 1990;38:309–314.
- 40.
Homesley HD, Bundy BN, Sedlis A et al.. Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study). Gynecol Oncol 1993;49:279–283.
- 41.
Aragona AM, Cuneo NA, Soderini AH, Alcoba EB. An analysis of reported independent prognostic factors for survival in squamous cell carcinoma of the vulva: is tumor size significance being underrated? Gynecol Oncol 2014;132:643–648.
- 42.↑
Rouzier R, Haddad B, Plantier F et al.. Local relapse in patients treated for squamous cell vulvar carcinoma: incidence and prognostic value. Obstet Gynecol 2002;100:1159–1167.
- 43.↑
Figge DC, Tamimi HK, Greer BE. Lymphatic spread in carcinoma of the vulva. Am J Obstet Gynecol 1985;152:387–394.
- 44.↑
Farias-Eisner R, Cirisano FD, Grouse D et al.. Conservative and individualized surgery for early squamous carcinoma of the vulva: the treatment of choice for stage I and II (T1-2N0-1M0) disease. Gynecol Oncol 1994;53:55–58.
- 46.↑
Landrum LM, Lanneau GS, Skaggs VJ et al.. Gynecologic Oncology Group risk groups for vulvar carcinoma: improvement in survival in the modern era. Gynecol Oncol 2007;106:521–525.
- 47.↑
Kim KW, Shinagare AB, Krajewski KM et al.. Update on imaging of vulvar squamous cell carcinoma. AJR Am J Roentgenol 2013;201:W147–157.
- 48.↑
Slomovitz BM, Coleman RL, Oonk MH et al.. Update on sentinel lymph node biopsy for early-stage vulvar cancer. Gynecol Oncol 2015;138:472–477.
- 49.↑
Magrina JF, Gonzalez-Bosquet J, Weaver AL et al.. Primary squamous cell cancer of the vulva: radical versus modified radical vulvar surgery. Gynecol Oncol 1998;71:116–121.
- 50.↑
Ansink A, van der Velden J. Surgical interventions for early squamous cell carcinoma of the vulva. Cochrane Database Syst Rev 2000:CD002036.
- 51.↑
DeSimone CP, Van Ness JS, Cooper AL et al.. The treatment of lateral T1 and T2 squamous cell carcinomas of the vulva confined to the labium majus or minus. Gynecol Oncol 2007;104:390–395.
- 52.↑
De Hullu JA, Hollema H, Lolkema S et al.. Vulvar carcinoma. The price of less radical surgery. Cancer 2002;95:2331–2338.
- 53.↑
Viswanathan AN, Pinto AP, Schultz D et al.. Relationship of margin status and radiation dose to recurrence in post-operative vulvar carcinoma. Gynecol Oncol 2013;130:545–549.
- 54.↑
Chan JK, Sugiyama V, Pham H et al.. Margin distance and other clinicopathologic prognostic factors in vulvar carcinoma: a multivariate analysis. Gynecol Oncol 2007;104:636–641.
- 55.↑
Faul CM, Mirmow D, Huang Q et al.. Adjuvant radiation for vulvar carcinoma: improved local control. Int J Radiat Oncol Biol Phys 1997;38:381–389.
- 56.↑
Woelber L, Eulenburg C, Grimm D et al.. The risk of contralateral non-sentinel metastasis in patients with primary vulvar cancer and unilaterally positive sentinel node. Ann Surg Oncol 2016;23:2508–2514.
- 57.↑
Coleman RL, Ali S, Levenback CF et al.. Is bilateral lymphadenectomy for midline squamous carcinoma of the vulva always necessary? An analysis from Gynecologic Oncology Group (GOG) 173. Gynecol Oncol 2013;128:155–159.
- 58.↑
DiSaia PJ, Creasman WT, Rich WM. An alternate approach to early cancer of the vulva. Am J Obstet Gynecol 1979;133:825–832.
- 59.↑
Van der Zee AG, Oonk MH, De Hullu JA et al.. Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol 2008;26:884–889.
- 60.↑
Oonk MH, van Hemel BM, Hollema H et al.. Size of sentinel-node metastasis and chances of non-sentinel-node involvement and survival in early stage vulvar cancer: results from GROINSS-V, a multicentre observational study. Lancet Oncol 2010;11:646–652.
- 61.↑
Oonk MH, van Os MA, de Bock GH et al.. A comparison of quality of life between vulvar cancer patients after sentinel lymph node procedure only and inguinofemoral lymphadenectomy. Gynecol Oncol 2009;113:301–305.
- 62.↑
Te Grootenhuis NC, van der Zee AG, van Doorn HC et al.. Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I. Gynecol Oncol 2016;140:8–14.
- 63.↑
Levenback CF, Ali S, Coleman RL et al.. Lymphatic mapping and sentinel lymph node biopsy in women with squamous cell carcinoma of the vulva: a gynecologic oncology group study. J Clin Oncol 2012;30:3786–3791.
- 64.↑
Covens A, Vella ET, Kennedy EB et al.. Sentinel lymph node biopsy in vulvar cancer: systematic review, meta-analysis and guideline recommendations. Gynecol Oncol 2015;137:351–361.
- 65.↑
Hacker NF, Berek JS, Lagasse LD et al.. Individualization of treatment for stage I squamous cell vulvar carcinoma. Obstet Gynecol 1984;63:155–162.
- 66.↑
Burke TW, Levenback C, Coleman RL et al.. Surgical therapy of T1 and T2 vulvar carcinoma: further experience with radical wide excision and selective inguinal lymphadenectomy. Gynecol Oncol 1995;57:215–220.
- 67.
Hacker NF, Van der Velden J. Conservative management of early vulvar cancer. Cancer 1993;71:1673–1677.
- 69.↑
Stehman FB, Bundy BN, Thomas G et al.. Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 1992;24:389–396.
- 70.↑
Hallak S, Ladi L, Sorbe B. Prophylactic inguinal-femoral irradiation as an alternative to primary lymphadenectomy in treatment of vulvar carcinoma. Int J Oncol 2007;31:1077–1085.
- 71.↑
Petereit DG, Mehta MP, Buchler DA, Kinsella TJ. Inguinofemoral radiation of N0,N1 vulvar cancer may be equivalent to lymphadenectomy if proper radiation technique is used. Int J Radiat Oncol Biol Phys 1993;27:963–967.
- 72.↑
Rouzier R, Haddad B, Atallah D et al.. Surgery for vulvar cancer. Clin Obstet Gynecol 2005;48:869–878.
- 73.
Magrina JF, Gonzalez-Bosquet J, Weaver AL et al.. Squamous cell carcinoma of the vulva stage IA: long-term results. Gynecol Oncol 2000;76:24–27.
- 74.
Yoder BJ, Rufforny I, Massoll NA, Wilkinson EJ. Stage IA vulvar squamous cell carcinoma: an analysis of tumor invasive characteristics and risk. Am J Surg Pathol 2008;32:765–772.
- 75.↑
Wilkinson EJ. Superficial invasive carcinoma of the vulva. Clin Obstet Gynecol 1985;28:188–195.
- 76.↑
Forner DM, Lampe B. Exenteration in the treatment of stage III/IV vulvar cancer. Gynecol Oncol 2012;124:87–91.
- 77.↑
Miller B, Morris M, Levenback C et al.. Pelvic exenteration for primary and recurrent vulvar cancer. Gynecol Oncol 1995;58:202–205.
- 78.↑
Hoffman MS, Cavanagh D, Roberts WS et al.. Ultraradical surgery for advanced carcinoma of the vulva: an update. Int J Gynecol Cancer 1993;3:369–372.
- 79.↑
Gadducci A, Cionini L, Romanini A et al.. Old and new perspectives in the management of high-risk, locally advanced or recurrent, and metastatic vulvar cancer. Crit Rev Oncol Hematol 2006;60:227–241.
- 80.↑
Boronow RC. Combined therapy as an alternative to exenteration for locally advanced vulvo-vaginal cancer: rationale and results. Cancer 1982;49:1085–1091.
- 81.↑
Fuh KC, Berek JS. Current management of vulvar cancer. Hematol Oncol Clin North Am 2012;26:45–62.
- 82.
Leiserowitz GS, Russell AH, Kinney WK et al.. Prophylactic chemoradiation of inguinofemoral lymph nodes in patients with locally extensive vulvar cancer. Gynecol Oncol 1997;66:509–514.
- 83.↑
Russell AH, Mesic JB, Scudder SA et al.. Synchronous radiation and cytotoxic chemotherapy for locally advanced or recurrent squamous cancer of the vulva. Gynecol Oncol 1992;47:14–20.
- 84.↑
Thomas G, Dembo A, DePetrillo A et al.. Concurrent radiation and chemotherapy in vulvar carcinoma. Gynecol Oncol 1989;34:263–267.
- 85.↑
Eifel PJ, Morris M, Burke TW et al.. Prolonged continuous infusion cisplatin and 5-fluorouracil with radiation for locally advanced carcinoma of the vulva. Gynecol Oncol 1995;59:51–56.
- 86.↑
Lupi G, Raspagliesi F, Zucali R et al.. Combined preoperative chemoradiotherapy followed by radical surgery in locally advanced vulvar carcinoma. A pilot study. Cancer 1996;77:1472–1478.
- 87.↑
Moore DH, Thomas GM, Montana GS et al.. Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys 1998;42:79–85.
- 88.↑
Geisler JP, Manahan KJ, Buller RE. Neoadjuvant chemotherapy in vulvar cancer: avoiding primary exenteration. Gynecol Oncol 2006;100:53–57.
- 89.↑
Landoni F, Maneo A, Zanetta G et al.. Concurrent preoperative chemotherapy with 5-fluorouracil and mitomycin C and radiotherapy (FUMIR) followed by limited surgery in locally advanced and recurrent vulvar carcinoma. Gynecol Oncol 1996;61:321–327.
- 90.↑
Berek JS, Heaps JM, Fu YS et al.. Concurrent cisplatin and 5-fluorouracil chemotherapy and radiation therapy for advanced-stage squamous carcinoma of the vulva. Gynecol Oncol 1991;42:197–201.
- 91.↑
Koh WJ, Wallace HJ III, Greer BE et al.. Combined radiotherapy and chemotherapy in the management of local-regionally advanced vulvar cancer. Int J Radiat Oncol Biol Phys 1993;26:809–816.
- 92.↑
Cunningham MJ, Goyer RP, Gibbons SK et al.. Primary radiation, cisplatin, and 5-fluorouracil for advanced squamous carcinoma of the vulva. Gynecol Oncol 1997;66:258–261.
- 93.↑
Gerszten K, Selvaraj RN, Kelley J, Faul C. Preoperative chemoradiation for locally advanced carcinoma of the vulva. Gynecol Oncol 2005;99:640–644.
- 94.↑
Tans L, Ansink AC, van Rooij PH et al.. The role of chemo-radiotherapy in the management of locally advanced carcinoma of the vulva: single institutional experience and review of literature. Am J Clin Oncol 2011;34:22–26.
- 95.↑
Han SC, Kim DH, Higgins SA et al.. Chemoradiation as primary or adjuvant treatment for locally advanced carcinoma of the vulva. Int J Radiat Oncol Biol Phys 2000;47:1235–1244.
- 96.↑
Montana GS, Thomas GM, Moore DH et al.. Preoperative chemoradiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 2000;48:1007–1013.
- 97.↑
Moore DH, Ali S, Koh WJ et al.. A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: a gynecologic oncology group study. Gynecol Oncol 2012;124:529–533.
- 98.↑
Chin JY, Hong TS, Ryan DP. Mitomycin in anal cancer: still the standard of care. J Clin Oncol 2012;30:4297–4301.
- 99.↑
Han SN, Vergote I, Amant F. Weekly paclitaxel/carboplatin in the treatment of locally advanced, recurrent, or metastatic vulvar cancer. Int J Gynecol Cancer 2012;22:865–868.
- 100.↑
Witteveen PO, van der Velden J, Vergote I et al.. Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: a study of the EORTC-GCG. Ann Oncol 2009;20:1511–1516.
- 101.↑
Horowitz NS, Olawaiye AB, Borger DR et al.. Phase II trial of erlotinib in women with squamous cell carcinoma of the vulva. Gynecol Oncol 2012;127:141–146.
- 102.↑
Jolly S, Soni P, Gaffney DK et al.. ACR Appropriateness Criteria(R) adjuvant therapy in vulvar cancer. Oncology (Williston Park) 2015;29:867–872.
- 103.↑
Homesley HD, Bundy BN, Sedlis A, Adcock L. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 1986;68:733–740.
- 104.↑
Kunos C, Simpkins F, Gibbons H et al.. Radiation therapy compared with pelvic node resection for node-positive vulvar cancer: a randomized controlled trial. Obstet Gynecol 2009;114:537–546.
- 105.↑
Fons G, Groenen SM, Oonk MH et al.. Adjuvant radiotherapy in patients with vulvar cancer and one intra capsular lymph node metastasis is not beneficial. Gynecol Oncol 2009;114:343–345.
- 106.↑
Mahner S, Jueckstock J, Hilpert F et al.. Adjuvant therapy in lymph node-positive vulvar cancer: the AGO-CaRE-1 study. J Natl Cancer Inst 2015;107:pii: dju426.
- 107.↑
Parthasarathy A, Cheung MK, Osann K et al.. The benefit of adjuvant radiation therapy in single-node-positive squamous cell vulvar carcinoma. Gynecol Oncol 2006;103:1095–1099.
- 108.↑
Woelber L, Eulenburg C, Choschzick M et al.. Prognostic role of lymph node metastases in vulvar cancer and implications for adjuvant treatment. Int J Gynecol Cancer 2012;22:503–508.
- 109.↑
Dusenbery KE, Carlson JW, LaPorte RM et al.. Radical vulvectomy with postoperative irradiation for vulvar cancer: therapeutic implications of a central block. Int J Radiat Oncol Biol Phys 1994;29:989–998.
- 110.↑
Gill BS, Bernard ME, Lin JF et al.. Impact of adjuvant chemotherapy with radiation for node-positive vulvar cancer: a National Cancer Data Base (NCDB) analysis. Gynecol Oncol 2015;137:365–372.
- 111.↑
Swanick CW, Smith GL, Huo J et al.. (P021) Delivery and outcomes of adjuvant radiation therapy in older women with node-positive vulvar cancer. Oncology (Williston Park) 2016;30(Suppl):pii: 216605.
- 112.↑
Ignatov T, Eggemann H, Burger E et al.. Adjuvant radiotherapy for vulvar cancer with close or positive surgical margins. J Cancer Res Clin Oncol 2016;142:489–495.
- 113.↑
van Beekhuizen HJ, Auzin M, van den Einden LC et al.. Lymph node count at inguinofemoral lymphadenectomy and groin recurrences in vulvar cancer. Int J Gynecol Cancer 2014;24:773–778.
- 114.
Bell JG, Lea JS, Reid GC. Complete groin lymphadenectomy with preservation of the fascia lata in the treatment of vulvar carcinoma. Gynecol Oncol 2000;77:314–318.
- 115.
Stehman FB, Bundy BN, Dvoretsky PM, Creasman WT. Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstet Gynecol 1992;79:490–497.
- 116.↑
Kirby TO, Rocconi RP, Numnum TM et al.. Outcomes of stage I/II vulvar cancer patients after negative superficial inguinal lymphadenectomy. Gynecol Oncol 2005;98:309–312.
- 117.↑
Gonzalez Bosquet J, Magrina JF, Gaffey TA et al.. Long-term survival and disease recurrence in patients with primary squamous cell carcinoma of the vulva. Gynecol Oncol 2005;97:828–833.
- 118.↑
Elit L, Reade CJ. Recommendations for follow-up care for gynecologic cancer survivors. Obstet Gynecol 2015;126:1207–1214.
- 119.↑
Salani R, Backes FJ, Fung MF et al.. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol 2011;204:466–478.
- 120.↑
Hazewinkel MH, Laan ET, Sprangers MA et al.. Long-term sexual function in survivors of vulvar cancer: a cross-sectional study. Gynecol Oncol 2012;126:87–92.
- 121.↑
Westin SN, Sun CC, Tung CS et al.. Survivors of gynecologic malignancies: impact of treatment on health and well-being. J Cancer Surviv 2016;10:261–270.
- 122.↑
Mahner S, Prieske K, Grimm D et al.. Systemic treatment of vulvar cancer. Expert Rev Anticancer Ther 2015;15:629–637.
- 124.↑
Piura B, Masotina A, Murdoch J et al.. Recurrent squamous cell carcinoma of the vulva: a study of 73 cases. Gynecol Oncol 1993;48:189–195.
- 125.↑
Raffetto N, Tombolini V, Santarelli M et al.. Radiotherapy alone and chemoirradiation in recurrent squamous cell carcinoma of the vulva. Anticancer Res 2003;23:3105–3108.
- 126.↑
Podratz KC, Symmonds RE, Taylor WF, Williams TJ. Carcinoma of the vulva: analysis of treatment and survival. Obstet Gynecol 1983;61:63–74.
- 127.↑
Chiantera V, Rossi M, De Iaco P et al.. Morbidity after pelvic exenteration for gynecological malignancies: a retrospective multicentric study of 230 patients. Int J Gynecol Cancer 2014;24:156–164.
- 128.↑
Stehman FB, Bundy BN, Ball H, Clarke-Pearson DL. Sites of failure and times to failure in carcinoma of the vulva treated conservatively: a Gynecologic Oncology Group study. Am J Obstet Gynecol 1996;174:1128–1132.
- 129.↑
Hopkins MP, Reid GC, Morley GW. The surgical management of recurrent squamous cell carcinoma of the vulva. Obstet Gynecol 1990;75:1001–1005.
- 130.↑
Bellati F, Angioli R, Manci N et al.. Single agent cisplatin chemotherapy in surgically resected vulvar cancer patients with multiple inguinal lymph node metastases. Gynecol Oncol 2005;96:227–231.
- 131.↑
Cormio G, Loizzi V, Gissi F et al.. Cisplatin and vinorelbine chemotherapy in recurrent vulvar carcinoma. Oncology 2009;77:281–284.
- 132.↑
Kitagawa R, Katsumata N, Shibata T et al.. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol 2015;33:2129–2135.