Squamous cell carcinoma of the vulva: Medical therapy and prognosis

INTRODUCTION — Vulvar cancer is the fourth most commonly occurring gynecologic cancer in the United States. Most vulvar cancers are squamous cell carcinoma (SCC).

This topic discusses the medical treatment and prognosis of patients with vulvar SCC, both for those who are receiving adjuvant therapy after surgical treatment and for those who are not surgical candidates. The staging and surgical management of vulvar cancer is discussed elsewhere. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment".)

The clinical presentation, diagnosis, and pathology of vulvar cancer; the techniques for radical vulvectomy and radiation therapy; and the management of other histologies are also reviewed separately.

●(See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment".)

●(See "Radical vulvectomy".)

●(See "Radiation therapy techniques in cancer treatment".)

●(See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment", section on 'Treatment'.)

PATIENT SELECTION — Decisions regarding which patients are managed with surgery and adjuvant therapy versus those who are treated nonsurgically takes into account both the stage of the disease (table 1), as well as the patient's baseline health. The patient should be evaluated for the ability to tolerate surgery and adjuvant therapy. A complete history and physical examination and appropriate laboratory testing are performed. Pretreatment evaluation and staging of vulvar cancer are discussed in detail elsewhere. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment", section on 'Pretreatment evaluation' and "Squamous cell carcinoma of the vulva: Staging and surgical treatment", section on 'Staging and surgical treatment'.)

For most medically fit patients without evidence of distant disease, the standard approach to treatment is surgery, with adjuvant therapy as appropriate. (See 'Adjuvant therapy for surgically resectable disease' below.)

However, for some patients, surgery and adjuvant treatment are not feasible. For example, for some patients with locally advanced disease, removal of the primary tumor and lymph nodes may not be possible if nodes are fixed to the femoral vessels or other pelvic organs. For other patients, surgery may not be possible if removal of the primary tumor requires removal or compromise of a critical midline structure, such as the urethra or anus. Additionally, medically frail patients may not be able to tolerate surgery and adjuvant treatment. Finally, those with distant metastatic disease should be treated with medical treatment only. The approach to such patients is discussed below. (See 'Disease that cannot be managed surgically' below.)

ADJUVANT THERAPY FOR SURGICALLY RESECTABLE DISEASE — For patients who undergo a surgical resection of disease, risk of recurrence may be decreased with adjuvant therapy, though data are limited. We base our decisions for adjuvant therapy on the results of surgical staging. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment", section on 'Staging and surgical treatment'.)

Node-negative disease — Not all patients with early-stage disease require adjuvant therapy. However, data are limited in regards to which patients with early-stage (I or II) vulvar cancer are most likely to benefit. Our approach to the patient with resected vulvar cancer that is node negative based on the results of lymphadenectomy is to administer adjuvant radiation therapy (RT, to the primary only) for tumors that are >4 cm or have positive or close margins (≤8 mm) [1,2], consistent with guidelines from the National Comprehensive Cancer Network (NCCN) [3]. Some experts alternatively opt for re-excision or close surveillance in patients with close margins instead of vulvar radiation in order to avoid the toxicities of vulvar radiation, such as the risk of acute and late skin toxicity including fibrosis and possibly vaginal stenosis. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment", section on 'Treatment of positive or narrow margins'.)

In a retrospective study of 257 patients with primary squamous vulvar cancer, 192 of whom had negative and 65 of whom had close or positive margins, the five-year overall survival rate among those with close or positive margins was 29 percent in patients not receiving RT and 68 percent in those receiving RT [2]. Those with close or positive margins who received RT experienced similar overall survival rates as patients with negative margins (68 versus 66 percent). Among patients with negative surgical margins, RT was not associated with an overall survival benefit.

Technique of RT delivery is discussed below. (See 'Radiation technique' below.)

Node-positive disease

Benefit of adjuvant treatment — Some form of adjuvant treatment (either RT or chemoradiation) is indicated for patients with nodal involvement [4-6], although there is some controversy in regards to its use in the setting of micrometastatic disease to a single lymph node. The choice between adjuvant RT and chemoradiation depends on the risk features of the disease and health status of the patient. In general, our approach is to utilize adjuvant RT alone in patients with one nodal micrometastasis and chemoradiation for those with any macroscopic nodal disease or with micrometastatic nodal disease involving two or more lymph nodes.

Adjuvant treatment appeared beneficial in a multi-institutional retrospective study [7]. Among those with pathologically involved groin nodes (n = 447), 244 patients received adjuvant therapy consisting mainly of adjuvant RT (84 percent) and adjuvant chemoradiation (14 percent). Compared with those who did not undergo postoperative therapy, adjuvant treatment significantly improved the three-year rate for progression-free survival (40 versus 26 percent, respectively; hazard ratio [HR] 0.67, 95% CI 0.51-0.88). However, there was no significant improvement in the rate of overall survival at three years (57 versus 51 percent).

The GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINS-V-II)/Gynecologic Oncology group (GOG) 270 protocol investigated the safety of complete inguinofemoral lymphadenectomy versus adjuvant RT in early-stage vulvar cancer patients with a sentinel node metastasis ≤2 mm as well as the efficacy, safety, and short- and long-term morbidity of inguinofemoral lymphadenectomy and RT in patients with a sentinel node metastasis >2 mm. This trial is discussed elsewhere. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment", section on 'Sentinel lymph node biopsy'.)

Chemoradiation versus RT alone — Based upon limited data, our preferred approach is to utilize weekly cisplatin 40 mg/m² concurrently with radiation therapy (RT) in such patients. However, in the absence of randomized data suggesting a preferred adjuvant modality, adjuvant RT without chemotherapy is also an acceptable option. For patients who progress after first-line chemotherapy, treatment options mirror those for patients with metastatic cervical cancer. (See "Management of recurrent or metastatic cervical cancer", section on 'Second-line therapy'.)

The benefit of chemoradiation over RT alone was suggested in a study that utilized the United States National Cancer Database (NCDB) and included over 1700 patients with node-positive, resected vulvar cancer (77 percent with up to three nodes involved) who subsequently were treated with adjuvant therapy (RT only or RT and chemotherapy) [8]. On multivariate analysis, the addition of adjuvant chemotherapy was associated with a trend towards a reduction in the risk of death compared with adjuvant RT alone (HR 0.81, 95% CI 0.65-1.01). Most patients receiving chemotherapy in this study initiated it within one week of initiating RT. The addition of chemotherapy to RT does increase the side effect profile, including increased risk of skin toxicity, decreased blood counts, and other side effects typically associated with the use of weekly cisplatin.

Extent of radiation treatment — For patients with involvement of the lymph nodes, treatment should encompass the inguinal, external iliac, internal iliac, and obturator regions bilaterally. Adjuvant groin RT is not indicated for patients without pathologic evidence of groin node involvement. For patients with involved nodes who have undergone excision of the primary vulvar lesion to negative surgical margins, some UpToDate experts limit RT to the pelvic and inguinal lymph nodes bilaterally without treatment to the vulva, which can help to minimize morbidity. Other UpToDate experts generally include the vulva in order to reduce the risk of recurrence, particularly when other risk factors such as close margins, extensive lymphovascular invasion, or satellite, in-transit lesions are present. The rationale for inclusion of the vulva is that RT to treat a vulvar recurrence, should it occur, can be difficult if groin irradiation has been previously delivered, given the difficulty in matching prior radiation fields. Furthermore, one study showed exclusion of the vulva resulted in a 48 percent central recurrence rate [9]. Technique of RT delivery is discussed below. (See 'Radiation technique' below.)

The evidence to support bilateral pelvic and inguinal RT for patients with confirmed nodal involvement comes from a GOG study that compared adjuvant nodal RT (to the inguinal and pelvic nodal regions) with pelvic lymphadenectomy in patients with pathologic node involvement confirmed after bilateral inguinal lymphadenectomy [5]. This study was stopped early because adjuvant RT resulted in improved two-year survival compared with pelvic lymphadenectomy, particularly among patients with clinically identified node involvement (59 versus 31 percent) and those with two or more positive inguinal nodes (63 versus 37 percent). A long-term update of this clinical trial confirmed these data [10].

While observational data suggest that RT can be efficacious when limited to the unilateral involved side [11], we prefer to treat patients with pathologically confirmed nodal involvement with bilateral inguinal and pelvic RT until unilateral RT is evaluated in a properly designed prospective trial.

Radiation technique — For patients with vulvar cancer in whom adjuvant RT is recommended, intensity-modulated RT (IMRT) has become standard of care. IMRT is particularly advantageous in this situation, as it may reduce dose to the femoral head and neck, small bowel, rectum, and bladder. In patients receiving chemoradiotherapy, IMRT may also be used to reduce dose to the pelvic bone marrow, which may help reduce the risk of hematologic toxicity. Because dosimetric calculations for tissues at or immediately below the skin are difficult using IMRT, the delivered dose should be confirmed by thermoluminescent dosimeters (TLDs) when this technology is employed. Consensus guidelines have been published describing the use of IMRT [12].

When IMRT is not available, RT may be administered in the supine, frog-legged position using opposed anterior-posterior/posterior-anterior (AP-PA) beams with a supplement dose to the vulva or inguinal nodes as needed. The total dose is between 45 and 50.4 Gy and up to 60 Gy in patients with positive margins. Tissue equivalent bolus is often added to the surface of the vulva to ensure adequate surface dose. A TLD should be placed externally over the vulvar surface and internally within the vulva for the initial fractions to ensure that the dose received matches the treatment plan, as surface dosing can be challenging with the use of megavoltage photons.

Various techniques for encompassing the regional lymph nodes are used, including a modified AP-PA method. The AP field includes the inguinofemoral lymph node chains with careful attention to the three-dimensional soft tissue anatomy. In order to encompass this area, the treatment field is usually expanded laterally while the PA field is kept narrower, just medial to the femoral necks and heads. Electrons, which penetrate tissue only superficially, are used to supplement the dose to the inguinal nodes and spare the femur from unnecessary radiation.

DISEASE THAT CANNOT BE MANAGED SURGICALLY

Unresectable, locally advanced disease — Resection of the primary tumor and inguinofemoral lymphadenectomy may not be possible when nodes are fixed to the femoral vessels or other vital structures. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment", section on 'Staging and surgical treatment'.)

Chemoradiation — For patients with unresectable, locally advanced disease, we prefer chemoradiation to radiation therapy (RT) alone. We utilize weekly cisplatin 40 mg/m² concurrently with radiation and include the vulva, groin, and lymph nodes in our radiation fields. For patients who are not candidates for chemotherapy, we administer primary RT alone. (See 'Chemoradiation versus RT alone' above.)

We prefer to administer single-agent cisplatin plus RT, although the use of concurrent fluorouracil (FU) alone or in combination with cisplatin or mitomycin may also be used [13]. Chemoradiation may allow for total radiation doses that are 10 to 20 percent less than primary RT, and may therefore result in lesser local toxicity. The bilateral inguinofemoral lymph nodes may be included within the treatment target volume for these patients, although prospective data to inform the benefits and risks of doing so are sparse. However, when appropriate radiation techniques are applied and synchronous chemotherapy administered, groin relapses are very rare [14,15]. Management after chemoradiation is discussed below. (See 'Management after chemoradiation' below.)

Appropriate candidates for chemoradiation include patients with:

●Anorectal, urethral, or bladder involvement (in an effort to avoid colostomy and urostomy)

●Disease that is fixed to the bone

●Gross inguinal or femoral node involvement (regardless of whether a debulking lymphadenectomy was performed)

The benefit of chemoradiation is shown in the studies below:

●In Gynecologic Oncology Group (GOG) 101, which included 46 patients with unresectable, node-positive (N2 or N3) vulvar carcinoma, 38 patients were able to undergo surgery after chemoradiation (those who had a complete response underwent surgical biopsy only) [16]. Of 37 who underwent a lymphadenectomy, 15 (40.5 percent) had no evidence of pathologic node involvement. At a median follow-up of 6.5 years, 12 patients (26 percent) were alive without evidence of disease.

●In GOG 205, 58 patients with unresectable vulvar cancer underwent chemoradiation for locally advanced vulvar carcinoma [17]. Of 40 patients who completed chemoradiation, 37 had a complete clinical response. Among these patients, 34 underwent surgical biopsy, of whom 29 had a complete pathologic response (78 percent).

Despite the lack of high-quality data in vulvar cancer, we feel chemoradiation is an appropriate option in selected patients with locally advanced vulvar cancer based on our experience with chemoradiation in cervical cancer and cancers of the anal canal. Chemoradiation compared with radiation alone has led to decreased recurrence rates of anal cancer and has been associated with a survival benefit in cervical cancer. (See "Management of locally advanced cervical cancer", section on 'Primary chemoradiation' and "Treatment of anal cancer", section on 'Initial chemoradiotherapy'.)

There are no prospective trials comparing RT alone to chemoradiation in the treatment of vulvar cancer. However, indirect evidence suggests that chemoradiation may be equivalent to surgery in patients with resectable disease, therefore providing a rationale for its use in patients for whom surgery is not an option. A 2011 systematic review of three studies (one randomized) compared primary surgery with chemoradiation in patients with locally advanced, primary SCC [18]. Compared with primary surgery, the use of chemoradiation alone resulted in no difference in overall mortality (hazard ratio [HR] 1.09, 95% CI 0.37-3.17); however, the wide confidence intervals suggest there are insufficient data to make a definitive conclusion, and all three studies were determined to be at moderate or high risk of bias.

Management after chemoradiation — Following primary treatment for unresected, non-metastatic disease, further management is based on the response to treatment, which is usually assessed by clinical examination, restaging positron emission tomography (PET)/computed tomography (CT) and/or biopsy 6 to 12 weeks after completion of chemoradiation:

●Some patients treated with initial chemoradiation for locoregional disease deemed to be unresectable at initial presentation may experience a complete response. For these patients, we proceed with a biopsy to determine pathologic response.

•If the biopsy confirms a complete response, no further surgery is needed and we initiate careful surveillance. (See 'Post-treatment surveillance' below.)

•If there is evidence of a partial response, we offer surgical excision of residual disease, provided the disease is now resectable and patients are surgical candidates. There are only limited data on whether surgery after chemoradiation influences survival outcomes. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment", section on 'Vulvar excision'.)

●If patients are not surgical candidates, we opt for surveillance only and reserve further medical treatment if disease progression is documented. (See 'Post-treatment surveillance' below.)

●For patients who have persistent or progressive disease despite treatment, we generally proceed with treatment and surveillance mirroring the approach to patients with metastatic disease. (See 'Post-treatment surveillance' below.)

Patients who are medically frail — Patients who are not candidates for any form of surgical excision are treated with primary RT. If primary RT is used, the total dose of radiation should be between 60 and 70 Gy. In general, we do not utilize chemosensitization in frail patients given increased toxicities, including myelosuppression and fatigue. Assessment and management of patients who have completed primary RT is similar to that of patients who completed primary chemoradiation.

The data to support the role of primary RT are limited to single-institution case series [19-22]. The largest series reviewed the outcomes of 76 patients with unstaged vulvar cancer. Treatment with RT alone resulted in 56 and 52 percent rates of local control and disease-free survival at five years [21]. In addition, the activity of primary RT is supported by its use in the preoperative setting for patients who present with advanced vulvar cancer [23,24], in which high rates of tumor shrinkage and complete responses at the time of surgery have been reported.

Distant metastases — For patients who present initially with stage IVB or who have recurrent disease involving the pelvic region, multiple sites, and/or distant metastatic disease, we offer chemotherapy, generally with the combination of carboplatin and paclitaxel and perform restaging exams with CT of the chest, abdomen, and pelvis every three cycles. Addition of PET is optional. For patients with stage IVB disease limited to the pelvic lymph nodes, definitive chemoradiation with curative intent may be considered.

There are no prospective trials of first-line chemotherapy for this population. Therefore, we extrapolate our treatment from the management of metastatic cervical cancer, in which platinum-based treatment is routinely administered in this setting. Our preference is to administer carboplatin plus paclitaxel because this combination was shown to be better tolerated than cisplatin plus paclitaxel in one trial of patients with metastatic cervical cancer [25].

For patients who progress after first-line chemotherapy, treatment options also mirror those for patients with metastatic cervical cancer, which is discussed elsewhere. (See "Management of recurrent or metastatic cervical cancer".)

For patients who are not candidates for chemotherapy, RT to areas of symptomatic metastases may provide palliative benefit.

POST-TREATMENT SURVEILLANCE

Surveillance — Patients require long-term follow-up for vulvar cancer. Because vulvar cancer may be a manifestation of "field cancerization," lifetime observation of residual vulvar tissue may be necessary when conservative treatment approaches are employed.

The majority of relapses of vulvar cancer occur in the first year after definitive treatment, but in one series, almost 10 percent of patients had a second malignancy diagnosed ≥5 years after the initial treatment [26,27].

The optimal surveillance strategy has not been established. However, we agree with the guidelines for follow-up from the Society of Gynecologic Oncology (SGO), which include [28]:

●Serial review of symptoms and physical examination of the vulva, skin bridge, and inguinal nodes.

•For early-stage disease (I and II), this should be done every six months for the first two years and then annually.

•For advanced-stage disease (III and IVA), this should be done every three months for the first two years, then every six months for years 3 through 5, and then annually.

●Cervical cytology (or vaginal cytology if the cervix has been removed) annually.

Routine use of imaging studies in the absence of symptoms or exam findings should be avoided. Most salvageable recurrences are easily detected by physical examination. If recurrence is suspected, we proceed with a CT and/or positron emission tomography as well as vulvar colposcopy and biopsy.

Sexual dysfunction and alterations in body image are common after treatment and should be addressed during follow-up visits [29,30]. (See "Overview of sexual dysfunction in female cancer survivors".)

Frequency of recurrences — Vulvar cancer recurrences are classified as local (primary tumor bed or residual vulva), regional (nodal), or distant (hematogenous). The distribution of recurrences was described in one series of 502 patients, 187 (37 percent) of whom recurred following primary (surgical) management [31]:

●Recurrences involved the vulvar or inguinal regions in 53 and 19 percent, respectively.

●Distant recurrences involved the pelvis or beyond the pelvis in 6 and 8 percent, respectively.

●Multiple recurrences were identified in 14 percent.

Management of recurrence — Treatment recommendations for patients with recurrent vulvar cancer take into account patient performance status, prior treatment modalities received, and sites of recurrence [32].

Local recurrence — For patients with an isolated local recurrence, we proceed with re-excision rather than systemic therapy. Local perineal recurrences can often be treated successfully by re-excision, whereas inguinal recurrences have been associated with a much worse prognosis [31,33,34]. For example, in one series the five-year survival rates according to site of recurrence were [31]:

●Vulvar – 60 percent

●Inguinal and pelvic – 27 percent

●Distant – 15 percent

●Multiple – 14 percent

Patients with a local recurrence who are not surgical candidates should be offered local radiation if this has not been previously employed. If prior radiation has been of limited dose, cautious re-irradiation to small target volumes along with concurrent chemotherapy may be a reasonable option in carefully selected patients with manageable late toxicity. For patients without surgical or chemoradiotherapeutic options, systemic chemotherapy, similar to the approach to patients with metastatic disease, may be offered. (See 'Distant metastases' above.)

Distant recurrence — Recurrent metastatic disease is treated in the same manner as an initial presentation of stage IVB. (See 'Distant metastases' above.)

PROGNOSIS — Inguinal and/or femoral node involvement is the most significant prognostic factor for survival in patients with vulvar cancer [31,35]. Reported five-year survival ranges from 70 to 93 percent for patients with negative nodes, to 25 to 41 percent for those with positive nodes [36].

Other prognostic factors include stage (which encompasses size and depth of invasion), capillary lymphatic space invasion, and older age [37,38]. Survival rates by disease stage are available (table 2) [39]. Some data suggest that outcomes are improving over time despite less aggressive surgical procedures, possibly attributable to advances in adjuvant therapy and demographic shifts (younger patients and less advanced disease at presentation) [40,41].

Additionally, evidence suggests that patients treated for human papillomavirus (HPV)-associated vulvar cancer have better disease outcomes compared with those treated for tumors not associated with HPV [42,43]. In one retrospective study of 57 patients, HPV prevalence was determined by p16 immunostaining in 37 percent and confirmed in 27 percent by HPV polymerase chain reaction [42]. Patients with p16-positive tumors had higher five-year progression-free survival (PFS; 65 versus 16 percent) and overall survival (65 versus 22 percent), as well as lower local relapse rates (19 versus 75 percent). The association with improved PFS and local relapse rate was maintained after multivariate adjustment for age and stage. Results were similar when analyzed according to HPV DNA status. Similarly, in a retrospective study including over 1600 patients with primary vulvar SCC followed for a median duration of 19 months, those with HPV-dependent disease versus those without HPV-dependent disease (ie, p16 overexpression) had better survival rates (83 versus 70 percent, respectively) [43]. (See "Treatment of human papillomavirus associated oropharyngeal cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vulvar cancer and vaginal cancer".)

SUMMARY AND RECOMMENDATIONS

●Patient selection – For vulvar squamous cell carcinoma, decisions regarding which patients are managed with surgery and adjuvant therapy versus those who are treated nonsurgically takes into account both the stage of the disease (table 1) as well as the patient's ability to tolerate treatment. (See 'Patient selection' above.)

Surgical staging and treatment are discussed in detail elsewhere. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment".)

●Adjuvant therapy for surgically resected disease – For patients who undergo a surgical resection of disease, risk of recurrence may be decreased with adjuvant therapy. We base our decisions for adjuvant therapy on the results of surgical staging.

•For node-negative disease for tumors that are >4 cm or have positive or close margins (≤8 mm), we suggest adjuvant radiation to the vulva (Grade 2C). (See 'Node-negative disease' above.)

•For patients with node-positive disease, we recommend adjuvant radiation to the groin and lymph node regions (Grade 1B). Some experts also treat the vulva to minimize recurrences, while others generally do not, in order to decrease morbidity. A risk-benefit discussion should be undertaken with the patient. For patients with macrometastatic disease or for those with micrometastatic disease to two or more lymph nodes, we add concurrent chemotherapy (Grade 2C). (See 'Benefit of adjuvant treatment' above.)

●Disease that cannot be managed surgically – For patients with unresectable, locally advanced disease, we suggest concurrent chemoradiation to the vulva, groin, and lymph nodes over radiation alone (Grade 2C). (See 'Unresectable, locally advanced disease' above.)

Some patients treated with initial chemoradiation for locoregional disease deemed to be unresectable at initial presentation may experience a response. For these patients, we proceed with a biopsy to determine pathologic response.

•If the biopsy confirms a complete response, no further surgery is needed and we initiate careful surveillance.

•If there is evidence of a partial response, we offer surgical excision of residual disease, provided the disease is now resectable and patients are surgical candidates. If patients are not surgical candidates, we opt for surveillance only and reserve further medical treatment if disease progression is documented.

•Patients who have persistent or progressive disease despite treatment are managed similarly to patients with metastatic disease. (See 'Distant metastases' above.)

●Patients who are medically frail – For patients who are medically frail, options include primary radiation therapy (RT) or referral to palliative care. (See 'Patients who are medically frail' above.)

●Distant metastases – For patients with metastatic disease, we offer initial management with chemotherapy. Our preferred regimen is carboplatin and paclitaxel. (See 'Distant metastases' above.)

●Post-treatment surveillance – Patients require long-term follow-up for vulvar cancer (see 'Post-treatment surveillance' above). Patients should have cervical cytology (or vaginal cytology if the cervix has been removed) annually. Additionally:

•For early-stage disease (I and II), we perform serial review of symptoms and physical examination of the vulva, skin bridge, and inguinal nodes every six months for the first two years and then annually.

•For advanced-stage disease (III and IVA), this should be done every three months for the first two years, then every six months for years 3 through 5, and then annually.

●Recurrent disease – Patients with isolated local recurrence should be treated with local treatments such as surgery or radiation. Those with distant recurrence should be managed like those with initial presentation of metastatic disease. (See 'Distant recurrence' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John C Elkas, MD, JD, and Anthony H Russell, MD, who contributed to an earlier version of this topic review.