Vulvar Cancer Flashcards

Question

Lymph node dissection is traditionally part of the primary surgical therapy in all but the smallest tumors. However, a major cause of morbidity after surgery is groin node dissection, which is associated with high rates of wound breakdown, lymphocele formation, and chronic lymphedema.

Answer 1

Lymph node dissection is traditionally part of the primary surgical therapy in all but the smallest tumors. However, a major cause of morbidity after surgery is groin node dissection, which is associated with high rates of wound breakdown, lymphocele formation, and chronic lymphedema.

Answer 2

A randomized trial to address the radiation therapy issue in patients with clinically localized vulvar cancer has been reported. [8,9] In that study, women with disease clinically confined to the vulva, who did not have groin lymph nodes clinically suspicious for metastases, underwent radical vulvectomy followed by either groin radiation (50 Gy in 2 Gy fractions) or groin dissection (plus groin radiation if nodes were pathologically involved). **Although the planned accrual was 300 patients, the study was stopped after 58 women were randomly assigned to it because of worse outcomes in the radiation therapy arm.** Five (18.5%) of 27 women in the radiation therapy arm and 0 of 25 women in the surgery arm had a groin recurrence, but this difference was not statistically significant (relative risk [RR], 10.21; 95% CI, 0.59-175.78). There were ten deaths in the radiation therapy arm versus three deaths in the groin dissection study arm (RR, 4.31; 95% CI, 1.03-18.15). Disease-specific mortality was not statistically significantly different between the two arms; however, there were eight versus two vulvar cancer-related deaths (including one related to groin dissection), in the radiation therapy arm and groin dissection arm, respectively (RR, 3.70; 95% CI, 0.87-15.80).[8,9][Level of evidence 1 iiA] There were fewer cases of lymphedema in the radiation therapy arm (0 vs. 7) and shorter hospital stays. The dose penetration of the radiation (3 cm for full dose) has been criticized as inadequate.[8] In summary, the trial was stopped prematurely, and little can be said about the relative efficacy of the two treatment approaches.[8]

Answer 3

Pelvic radiation has been compared to pelvic node dissection in the setting of documented groin node-positive disease. Patients with clinical stage I to stage IV primary squamous cell carcinoma of the vulva in whom groin nodal metastases were found at radical vulvectomy and bilateral groin node dissection were randomly assigned during the surgical procedure to receive either ipsilateral pelvic node resection or pelvic radiation (45 Gy-50 Gy at 1.8 Gy-2.0 Gy per fraction).[10] Because of a perceived emerging benefit of radiation, the planned accrual of 152 was stopped after 114 patients were randomly assigned. However, the apparent benefit of radiation was subsequently attenuated with further follow-up. After a median follow-up of 74 months, the 6-year overall survival (OS) rate was 51% in the radiation arm versus 41% in the pelvic node dissection arm (hazard ratio [HR], 0.61; 95% CI, 0.3-1.3; P = .18). Vulvar cancer-specific mortality was statistically significantly lower in the radiation study arm (29% vs. 51% in the pelvic node resection arm) (HR, 0.49; 95% CI, 0.28-0.87; P = .015) However, there were 14 intercurrent deaths in the radiation therapy arm versus two deaths in the pelvic dissection study arm. Late chronic lymphedema was similar in the radiation therapy and pelvic dissection groups arms (16% vs. 22%), respectively.[10][Level of evidence: 1 liB] **Radical radiation therapy can be used for patients unable to tolerate surgery or deemed unsuitable for surgery because of site or extent of disease.**

Answer 4

1. There is no standard chemotherapy for vulvar cancer, and reports describing the use of this modality in the setting of metastatic or recurrent disease are anecdotal. 2. Extrapolating from regimens used for anal or cervical squamous cell cancers, chemotherapy has been studied in combination with radiation in the neoadjuvant setting or as primary therapy in advanced disease. 3. Chemotherapy regimens have included various combinations of **5-fluorouracil (5-FU), cisplatin, mitomycin-C, or bleomycin.[**5] There is no clear evidence of improvement in survival or palliation. Given the advanced age and comorbidity of many patients with advanced or recurrent vulvar cancer, patient tolerance is a major consideration in the use of these agents.

Answer 5

Chemotherapy regimens have included various combinations of 1. 5-fluorouracil (5-FU) 2. cisplatin 3. mitomycin-C 4. bleomycin. 5. There is no clear evidence of improvement in survival or palliation. Given the advanced age and comorbidity of many patients with advanced or recurrent vulvar cancer, patient tolerance is a major consideration in the use of these agents.

Answer 6

1. In the four studies using 5-FU + cisplatin or 5-FU + mitomycin-C, the operability rate after chemoradiation ranged from 63% to 92%. 2. In the one study using bleomycin, the operability rate was only 20%. In summary, there is evidence that neoadjuvant chemoradiation with 5-FU plus either cisplatin or mitomycin-C may convert patients to more operable status, but the evidence base is limited by study design. In addition to a paucity of randomized trials, interpretation of these studies is complicated by the lack of a standard definition of

Answer 7

**Systemic treatment for operable patients There is also limited evidence regarding the use of neoadjuvant chemoradiation in advanced operable cases of vulvar cancer, but the available data do not suggest an advantage to this approach**. A systematic review found only one randomized trial that addressed this issue, and it was published only in abstract form.[4,21] In that trial, 68 patients with advanced vulvar cancer (T2 \>4 cm, T3, any case with positive lymph nodes) were randomly assigned to receive preoperative neoadjuvant radiation therapy (50 Gy) concomitantly with 5-FU plus mitomycin-C versus primary surgery. Neoadjuvant therapy-related serious toxicity was high (13 of 24 patients; 10 patients had wound diastasis). After a mean follow-up of 42 months, the 5-year OS rates in the neoadjuvant and primary surgery groups were 30% and 49%, respectively (RR of death, 1.39; 95% CI, 0.94-2.06; P = .19).[4,21] [Level of evidence 1 iiA]

Answer 8

High-grade WIN is usually managed with active therapy because of a higher risk for progression to invasive disease.[2] Estimates of progression rates are imprecise. A systematic literature review that included 88 untreated patients with VIN 3 reported a 9% progression rate (8 of 88 patients) to invasive vulvar cancer during 12 to 96 months of observation. In the same review, the spontaneous regression rate was 1.2%, all of which occurred in women younger than 35 years.[3] However, in a single-center study, 10 of 63 **(16%) untreated women with VIN 2 or VIN 3 progressed to invasive cancer after a mean of 3.9 years.**[4]

Answer 9

Simple vulvectomy yields a 5-year survival rate of essentially 100% but is seldom indicated. There are no reliable data comparing the efficacy and safety of the various surgical approaches.

Answer 10

**No difference** A systematic literature review identified only a single randomized trial comparing any of the surgical approaches.[2] In that trial, 30 women with high-grade VIN were randomly assigned to receive carbon dioxide (CO2) laser ablation versus ultrasound surgical aspiration (USA).[6] There were no statistically significant differences in disease recurrence, painful dysuria or burning, adhesions, or eschar formation between the two treatments after 1 year of follow-up. Scarring was observed in 5 of 16 women treated with laser ablation and 0 of 14 women treated with USA (P \< .01 ), but consequences of the scarring on sexual function or quality of life were not reported.[6][Level of evidence 1 iiDii] The trial was too small to draw reliable conclusions about the relative efficacy of these surgical techniques. The remainder of the surgical literature is derived from case series and is prone to important study biases.[Level of evidence 3iiiD]

Answer 11

About 4% of patients treated for VIN subsequently develop invasive cancer.[8,9]

Answer 12

More recently, among women with high-grade VIN, substantial response rates and acceptable tolerability were reported for topical imiquimod 5%, an immune-response modifier with activity in HPV 6/11-associated vulvar condylomata. Three randomized placebo-controlled trials (including a total of 104 patients) with clinical response as their primary endpoints.[Level of evidence: 1 iDiv] have been reported in either peer-reviewed-journal or abstract format.[14-17] The results of these trials were summarized in a systematic review.[11] At 5 to 6 months, the complete and partial response rates in patients were 36 of 62 and 18 of 62 in the combined imiquimod arms versus 0 of 42 and 1 of 42 in the combined placebo arms (relative risk [RR], 11.95; 95% confidence interval [CI], 3.21-44.51 ). In the only trial reporting progression to cancer (at 12 months), there was no difference in progression rate, but the trial was severely underpowered because only 3 of the total 52 women included developed invasive disease by 12 months.[16] The only trial reporting quality of life [16] showed no difference between imiquimod and placebo. Local side effects of imiquimod included pain, edema, erythema, and a single case of erosion. However, no patients had to discontinue treatment as a result of

Answer 13

Standard treatment options: 1. Separate excision of focal lesions.[3] 2. Wide local excision.[3] 3. CO2 laser surgery and vaporization.[2,6] A disadvantage of vaporization is that it does not provide tissue for histologic examination to confirm complete removal of the lesion and the absence of invasive disease. 4. Ultrasonic surgical aspiration (USA).[2,6] 5. Superficial skinning vulvectomy with or without grafting.[3] 6. Topical imiquimod for patients wishing to avoid

Answer 14

1. A wide (1 cm margin) excision (without lymph node dissection) for microinvasive lesions (\<1 mm invasion) with no associated severe vulvar dystrophy. For all other stage ! lesions, if well lateralized, without diffuse severe dystrophy, and with clinically negative nodes, a radical local excision with complete unilateral lymphadenectomy.[1] Candidates for this procedure should have lesions 2 cm or smaller in diameter with 5 mm or less invasion, no capillary lymphatic space invasion, and clinically uninvolved nodes.[2,3] 2. Radical local excision with ipsilateral or bilateral inguinal and femoral node dissection. In tumor clinically confined to the vulva or perineum, radical local excision with a margin of at least 1 cm has generally replaced radical vulvectomy; separate incision has replaced en bloc inguinal node dissection, ipsilateral inguinal node dissection has replaced bilateral dissection for laterally localized tumors; and femoral lymph node dissection has been omitted in many cases.[4-7] 3. Radical local excision and sentinel node dissection, reserving groin dissection for those with metastasis to the sentinel node(s).[8] 4. Some investigators recommend radical excision and groin nodal radiation therapy as a means to avoid the morbidity of lymph node dissection. However, it is not clear whether radiation therapy can achieve the same local control rates or survival rates as lymph node dissection in early-stage disease. A randomized trial to address this issue in patients with clinically localized vulvar disease was stopped early as a result of early emergence of worse outcomes in the radiation therapy arm.[9,10] (Refer to the Role of Radiation Therapy section of this summary for more information.) 5. Radical radiation therapy for patients unable to tolerate surgery or deemed unsuitable for surgery because of site or

Answer 15

Radical local excision with bilateral inguinal node and femoral node dissection with a resection margin of at least 1 cm.[1] Radical local excision with a margin of at least 1 cm has generally replaced radical vulvectomy, and separate incision has replaced en bloc inguinal node dissection.[2] Large T2 tumors may require modified radical or radical vulvectomy.[3] Adjuvant local radiation therapy may be indicated for surgical margins smaller than 8 mm, capillary-lymphatic space invasion, and thickness greater than 5 mm.[4,5] 2. Radical excision and sentinel node dissection, reserving groin dissection for those with metastasis to the sentinel node(s).[6] 3. Some investigators recommend radical excision and groin nodal radiation therapy as a means to avoid the morbidity of lymph node dissection. However, radiation therapy may not achieve the same local control rates or survival rates as lymph node dissection in early-stage disease. A randomized trial to address this issue in patients with clinically localized vulvar disease was stopped early as a result of early emergence of worse outcomes in the radiation therapy group.[7,8] (Refer to the Role of Radiation Therapy section in this summary for more information.) 4. For those few patients unable to tolerate radical surgery or deemed unsuitable for surgery because of site or extent of disease, radical radiation therapy may be associated with favorable survival.[9-12]

Answer 16

Modified radical or radical vulvectomy with inguinal and femoral lymphadenectomy is the standard therapy.[1] Nodal involvement is a key determinant of survival. 1. Modified radical or radical vulvectomy with inguinal and femoral node dissection. Radiation therapy to the pelvis and groin is given if inguinal nodes are positive. 2. Radical vulvectomy with inguinal and femoral node dissection followed by radiation therapy in patients with large primary lesions and narrow margins. Localized adjuvant radiation therapy consisting of 45 Gy to 50 Gy may also be indicated when there is capillary-lymphatic space invasion and a thickness of greater than 5 mm, particularly if the nodes are involved.[1] Radiation therapy to the pelvis and groin is usually given if two or more groin nodes are involved.[2,3] 3. Preoperative neoadjuvant radiation therapy or chemoradiation may be used to improve operability and even decrease the extent of surgery required.[4-10] 4. For the few patients unable to tolerate radical surgery or deemed unsuitable for surgery because of site or extent of disease, radical radiation therapy may be associated with long-term survival.[11,12] Some physicians prefer to add concurrent 5-FU or 5-FU and cisplatin.[1,13]

Answer 17

Standard treatment options: 1. Radical vulvectomy and pelvic exenteration. 2. Surgery followed by radiation therapy for large resected lesions with narrow margins. Localized adjuvant radiation therapy consisting of 45 Gy to 50 Gy may also be indicated when there is capillary-lymphatic space invasion and thickness greater than 5 mm.[1] Radiation therapy to the pelvis and groin is given if two or more groin nodes are involved.[2,3] 3. Neoadjuvant radiation therapy or chemoradiation of large primary lesions to improve operability, followed by radical surgery.[4-10] 4. For those patients unable to tolerate radical vulvectomy or who are deemed unsuitable for surgery because of site or extent of disease, radical radiation therapy may be associated with long-term survival.[11,12] When radiation therapy is used for primary definitive treatment of vulvar cancer, some physicians prefer to add concurrent 5-FU or 5-FU and cisplatin.[1,13-17]

Answer 18

Localized adjuvant radiation therapy consisting of 45 Gy to 50 Gy may also be indicated when there is **capillary-lymphatic space invasion** and **thickness greater than 5 mm**.[1] Radiation therapy to the pelvis and groin is given if t**wo or more groin nodes are involved**

Answer 19

For those patients unable to tolerate radical vulvectomy or who are deemed unsuitable for surgery because of site or extent of disease, radical radiation therapy may be associated with long-term survival.[11,12] When radiation therapy is used for primary definitive treatment of vulvar cancer, some physicians prefer to add concurrent 5-FU or 5-FU and cisplatin.[

Answer 20

**There is no standard treatment approach in the management of metastatic vulvar cancer**. Local therapy must be individualized depending on the extent of local and metastatic disease. There is no standard chemotherapy for metastatic disease, and reports describing the use of this modality are anecdotal.[17] However, by largely extrapolating from regimens used for anal or cervical cancer, chemotherapy has been studied. Regimens have included various combinations of **5-fluorouracil, cisplatin, mitomycin-C, or bleomycin**.[6,17,18] Given the advanced age and comorbidity of many patients with advanced or recurrent vulvar cancer, patient tolerance is a major consideration in the use of these agents. Physicians should offer eligible patients participation in clinical trials.

Answer 21

Recurrent Vulvar Cancer Treatment and outcome depend on the site and extent of recurrence.[1] Radical excision of localized recurrence may be considered if technically feasible.[2] Palliative radiation therapy is used for some patients. Radiation therapy with or without chemotherapy may be associated with substantial disease-free periods in some patients with a small local recurrence.[3-5] When local recurrence occurs more than 2 years after primary treatment, a combination of radiation therapy and surgery may result in a 5-year survival rate of greater than 50%.[6,7] There is no standard treatment approach in the management of metastatic vulvar cancer. There is no standard chemotherapy, and reports describing the use of this modality are anecdotal.[8] However, by largely extrapolating from regimens used for anal or cervical cancer, chemotherapy has been used, but with no clear evidence of improvement in survival or palliation. Regimens have included various combinations of 5-fluorouracil, cisplatin, mitomycin-C, or bleomycin.[8,9] Given the advanced age and comorbidity of many patients with advanced or recurrent vulvar cancer, patient tolerance is a major consideration in the use of these agents. Physicians should offer eligible patients participation in clinical trials. Information about ongoing clinical trials is available from the NCI website. Standard treatment options: 1. Wide local excision with or without radiation in those patients with local recurrence. 2. Radical vulvectomy and pelvic exenteration in patients with local recurrence. 3. Synchronous radiation and cytotoxic chemotherapy with or without surgery.[4]