Radiation Oncology/Vulva

Epidemiology

 * Rare tumor, estimated 3500 patients per year in the US. Incidence ~1/100,000 accounting for 3-4% of GYN malignancies
 * Higher incidence in age >70
 * Clinical presentation is usually due to symptoms: pruritus, spotting or bleeding, pain, and discharge
 * ~70% arise in labia majora/minora
 * ~20% are locally advanced
 * Follow predictable lymphatic drainage: superficial inguinofemoral, deep inguinofemoral, external illiac
 * Likelihood of LN+ depends on size and depth of primary, it ranges from 5%-60%
 * In GOG experience, 24% of patients who had clinically negative LNs were pathologically positive. If the lymph nodes were clinically suspicious, 76% were pathologically positive
 * Hematogenous dissemination occurs late
 * 15% of patients have a second primary tumor in the cervix, vagina, or anus

Staging
AJCC 7th Edition (2009)
 * Is based on revised FIGO staging (2009)
 * FIGO 2009 PMID 19329116 -- "Revised FIGO staging for carcinoma of the vulva."
 * see also: Revised FIGO Staging (2009)(PDF) (clarifies some errors in AJCC Manual)

Primary Tumor:
 * Tis - in situ
 * T1
 * T1a (FIGO IA) - &le; 2 cm in size and <= 1mm depth of stromal invasion
 * T1b (FIGO IB) - > 2 cm in size, or any size with >1mm depth of stromal invasion
 * T2 (FIGO II) - extension to adjacent perineal structures (lower/distal 1/3 urethra, lower/distal 1/3 vagina, or anal involvement)
 * T3 (FIGO IVA) - extension to any of the following: upper/proximal 2/3 of urethra, upper/proximal 2/3 of vagina, bladder mucosa, rectal mucosa, or fixed to pelvic bone

Regional Lymph Nodes:
 * Regional nodes: include femoral and inguinal nodes. Involvement of iliac nodes is Stage IVB.


 * N0 - none
 * N1 (FIGO IIIA)
 * N1a - 1-2 LN mets, each < 5 mm
 * N1b - 1 LN met &ge; 5 mm
 * N2
 * N2a (FIGO IIIB) - 3 or more LN, each < 5 mm each
 * N2b (FIGO IIIB) - 2 or more LN &ge; 5 mm
 * N2c (FIGO IIIC) - LN with extracapsular spread
 * N3 (FIGO IVA) - fixed or ulcerated LN

Distant Metastases:
 * M0 - none
 * M1 (FIGO IVB) - yes (includes pelvic LN met)

Stage Grouping:
 * IA - T1a N0 (FIGO IA)
 * IB - T1b N0 (FIGO IB)
 * II - T2 N0 (FIGO II)
 * IIIA - T1-2 N1 (FIGO IIIA)
 * IIIB - T1-2 N2a-b (FIGO IIIB)
 * IIIC - T1-2 N2c (FIGO IIIC)
 * IVA - T3 or N3 (FIGO IVA)
 * IVB - M1 (FIGO IVB)

Changes from 5th edition:
 * Now includes number and size of lymph nodes and presence of extracapsular spread
 * Stage III is subdivided into IIIA/B/C

Older staging systems
AJCC 5th Edition (2002) FIGO stage: (AJCC difference in parentheses) Surgical staging implemented in 1989.
 * I
 * IA - 2 cm or less in size, and <= 1mm depth of stromal invasion
 * IB - 2 cm or less in size, >1mm depth of stromal invasion


 * II - > 2cm in size
 * III(T3) - spread to lower urethra, vagina, or anus
 * III(N1) - unilateral lymph node metastasis
 * IVA(T4) - invades upper urethra, bladder mucosa, rectal mucosa, or fixed to pubic bone
 * IVA(N2) - bilateral lymph node metastases
 * IVB - distant mets (including pelvic nodes)

Older staging systems: An older version included N2 (same as now) and N3 nodes (pelvic LN mets).

Functional Staging:
 * Early stage - can treat with primary surgery (WLE, modified radical vulvectomy, radical vulvectomy)
 * Locally advanced stage - unable to resect without ultra-radical (exenterative) surgery

Pathology

 * 85% are squamous cell
 * The others are: melanoma, basaloid (cloacogenic), adenocarcinoma, etc.
 * Tumors may arise in or near areas of premalignant conditions such as lichen sclerosus, erythroplasia of Queyrat, Paget's disease, or Bowen's disease.

Survival
Stage I - 90% at 5 yrs Stage II - 70-75% Stage III - 40-50% Stage IV - 20%

'''Vulvarcancer! nomogram'''
 * Korean KGOG-1010; 2008 PMID 19471576 -- "Validation of a nomogram for predicting outcome of vulvar cancer patients, primarily treated by surgery, in Korean population: multicenter retrospective study through Korean Gynecologic Oncology Group (KGOG-1010)." (Kim MK, J Gynecol Oncol. 2008 Sep;19(3):191-4. Epub 2008 Sep 30.)
 * Validation. 90 cases from 11 institutions. Mean F/U 4 years
 * Outcome: RFS 2-year observed 81% vs calculated 79% (R2 = 0.35), 5-year observed 68% vs calculated 72% (R2 = 0.8). Concordance index 0.79, improved to 0.82 with squamous cell
 * Conclusion: The nomogram provides predictive capacity in Korean patients


 * Creteil, France; 2006 (1978-2001) PMID 16507940 -- "Development and validation of a nomogram for predicting outcome of patients with vulvar cancer." (Rouzier R, Obstet Gynecol. 2006 Mar;107(3):672-7.)
 * Nomogram. 244 patients from Creteil used as a training set; 129 patients from Torino as a validation set
 * Outcome: Covariaes for RFS included age, T-stage, number of LN+, bilateral LN involvement, omission of LND, SM status, LVI status, depth of invasion. Concordance 0.83 in validation set, which was better than FIGO stage (concordance 0.78, SS)
 * Conclusion: Nomogram developed for predicting 2 and 5 year RFS

Surgery

 * Typically the primary treatment option for resectable disease (appropriate for the ~80% of localized disease)
 * Historically, radical vulvectomy was performed. Even after radical vulvectomy (GOG 37), local failure rate was still 9%. With less radical surgery (modified radical vulvectomy, WLE), importance of margin becomes critical
 * Surgical margin is the most important predictor of recurrence, with >1cm margin satisfactory and <8mm margin ~50% recurrence rate based on UCLA data
 * Other factors: size > 4 cm, lymphatic-vascular space invasion
 * Either factor - 20% recurrence. No factors - 9%
 * However, local vulva recurrences are salvageable (unlike LN failures) and do not strongly correlate with overall survival
 * To some, this suggests that adjuvant RT for vulva may not be as critical as for inguinal lymph nodes
 * Please see below for unresectable disease; a GOG Phase II trial of concurrent chemo-RT followed by surgical resection and LND is ongoing
 * ASTRO 2008 refresher: Adjuvant RT to vulva if SM+ or <8mm, or 2+ "Heaps" factors, or if treat LN already then 1+ "Heaps factor"


 * UCLA; 1990 (1957-1985) PMID 2227541 -- "Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva." (Heaps JM, Gynecol Oncol. 1990 Sep;38(3):309-14.)
 * Retrospective. 135 patients, Stage I-IV.
 * Outcome: Recurrence rate SM >=8mm 0% vs. SM <8mm 48% (SS).
 * Predictors for recurrence: depth of invasion (9 mm), tumor thickness (1cm), infiltrative growth, LVI+, increasing keratin, >10 mitoses
 * Conclusion: Surgical margin most powerful predictor of local recurrence

Adjuvant RT

 * Harvard; 2013 (1988-2009) PMID 23747330 -- "Relationship of margin status and radiation dose to recurrence in post-operative vulvar carcinoma." (Viswanathan AN, Gynecol Oncol. 2013 Sep;130(3):545-9. doi: 10.1016/j.ygyno.2013.05.036. Epub 2013 Jun 5.)
 * Retrospective. 205 patients, Stage I-IVA. Slides reviewed, margin scored as negative (&ge; 1 cm) in 34%, close (<1 cm) 56%, or positive 10%. Median F/U 4.1 years
 * Outcome: 4-year vulvar recurrence negative SM 18%, close SM 37% (HR 3.0), positive 77% (HR 7.0). Highest risk of recurrence with margins &le; 5 mm. Adjuvant radiation dose &ge; 56 Gy better
 * Conclusion: Close or positive margins significantly increase vulvar recurrence risk. Radiation dose &ge; 56 Gy may decrease the risk of recurrence


 * U. Pittsburgh, 1997 (1980-94)
 * PMID 9226327, 1997 &mdash; "Adjuvant radiation for vulvar carcinoma: improved local control." Faul CM et al. Int J Radiat Oncol Biol Phys. 1997 May 1;38(2):381-9.
 * Retrospective. 62 pts with close (<8mm) or positive margins, 31 were observed and 31 received RT. RT fields covered the vulva, bilateral groins, and lower pelvis. Mean dose 56 Gy.
 * Mean f/u 3.16 yrs. For pts with positive margins, LRR in 69% (obs) vs 33% (RT). Close margins, 31% vs 5%.


 * U. Minnesota, 1994 (1971-92)
 * PMID 8083101, 1994 &mdash; "Radical vulvectomy with postoperative irradiation for vulvar cancer: therapeutic implications of a central block." Dusenbery KE et al. Int J Radiat Oncol Biol Phys. 1994 Jul 30;29(5):989-98.
 * Retrospective. 27 pts with positive nodes treated with post-op RT. RT was to bilateral groin and pelvic nodes, unilateral groin and pelvis, or unilateral groin only. Midline was blocked in all but 1 pt. Median dose 45 Gy.
 * Recurrences in 63% at a median of 9 months from surgery. Recurrences were under the midline block in 76%.

Unresectable disease

 * GOG 101 (1989-94)
 * Phase II. 96 pts. Two groups: 1) T3 or T4 not resectable by std surgery, and 2) unresectable N2/N3 nodes (see below). Split-course cisplatin/5-FU + RT followed by resection of residual tumor and bilateral inguinal LN dissection. RT dose 4760 cGy (170 cGy/d qd, 170 cGy/fx BID on days 1-4 of each course), given as two courses of 2380 cGy. RT fields were to tumor only if N0-1, or to include groin and lower pelvis (to SI joint) if N2-3.
 * Pts with unresectable primary:
 * PMID 9747823, 1998 &mdash; "Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group." Moore DH et al. Int J Radiat Oncol Biol Phys. 1998 Aug 1;42(1):79-85.
 * 73 pts with unresectable primary (of whom 50 were N0-N1 and 23 were unresectable N2-N3). 48% cCR. 70% of those had pCR. 84% of those with residual disease had negative margins. Of 50 pts who were initially felt to require pelvic exenteration, only 1 had exent. and 2 had colostomy. Only 2 pts had residual unresectable disease.
 * Median f/u 50 months for pts alive. 32.9% had recurrence. 54.9% alive without disease.
 * Pts with unresectable nodes:
 * PMID 11072157, 2000 &mdash; "Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study." Montana GS et al. Int J Radiat Oncol Biol Phys. 2000 Nov 1;48(4):1007-13.
 * 46 pts with unresectable N2/N3 nodes. Became resectable in 38/42 pts. pN0 in 15/37. Primary tumor had pCR in 20/38 pts. 4 pts had CR of primary and had biopsy only.
 * 12 pts alive without disease (median f/u 78 mo). Control of LN disease in 36/37 and control of primary and nodes in 27/38.
 * Conclusion: preoperative treatment is effective. High rate of pCR for the nodes (~40%) and primary (~31%).


 * GOG 185 - ? cisplatin + RT - closed due to poor accrual?


 * GOG 205 (2003-?) -- Phase II
 * 58 pts. Unresectable T3 or T4, any N. RT (1.8 x 32 = 57.6 Gy) with weekly cisplatin, followed by resection of residual disease.
 * 2012 PMID 22079361 -- "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." (Moore DH, Gynecol Oncol. 2012 Mar;124(3):529-33.)
 * 40 of 58 pts (69%) completed study treatment. cCR in 64% (37/58); of those having CR, 29 had pCR (29/37; 78% of those in cCR. 29/58; 50% of total)
 * Conclusion: "This combination of radiation therapy plus weekly cisplatin successfully yielded high complete clinical and pathologic response rates with acceptable toxicity."
 * Comment: the 64% cCR rate is an increase from the ~48% seen in GOG 101. pCR of 50% is an increase from the 31% in GOG 101.

Management of the lymph nodes

 * Metachronous (after primary treatment) groin node metastases are primary predictor of treatment failure and death
 * Therefore, management of lymph nodes is critically important in vulvar cancer
 * Initial surgery should include histologic assessment of inguinal nodes if the primary has >1mm stromal invasion
 * For lateralized T1a lesions (<1 mm stromal invasion), likelihood of LN involvement is <5%
 * If depth of invasion 2mm - 8% risk, 3 mm - 17% risk, overall 24% risk
 * Clinical tumor size correlates with occult metastases in patients with clinically negative lymph node involvement as follows: 0 to 1 cm = 7.7%; 1.1 to 2 cm = 23.9%; 2.1 to 3 cm = 31%; 3.1 to 5 cm = 36.4%. (from Gonzalez Bosquet, PMID 12957253)
 * At least 10-12 lymph nodes should be removed from bilateral inguinal-femoral dissection for optimal assessment
 * Predictors of lymph node metastasis: tumor thickness, grade, capillary space invasion, depth of invasion, location of tumor, tumor size
 * Approximately 70-75% of patients with clinically negative inguinal groins will have pathologically negative inguinal lymph nodes
 * In the clinically negative patients, GOG 88 showed that bilateral groin LND is superior to poorly done prophylactic RT (0% failures vs 20% failures), as that RT was prescribed to 3 cm and was not CT planned
 * The Dutch have shown that SLND is feasible, and failure rate after SLN- is ~2-3%
 * Number of involved groin lymph nodes strongly correlates with survival; and there is a benefit to adjuvant inguinal/pelvic RT. GOG 37 showed benefit for all patients with LN+, though on subset analysis the benefit was not significant for patients with a single positive LN. Retrospective SEER data suggests that these patients benefit as well, especially if they have inadequate inguinal/femoral LND (<12 lymph nodes removed)
 * Based on GOG data, ~25% of patients with pathologic ipsilateral groin disease will also have contralateral disease
 * PET thus far appears to have <70% sensitivity for assessing contralateral groin LN
 * Therefore, contralateral groin requires assessment/management in ipsilateral groin LN+ patients
 * Based on GOG data, ~28% of patients with groin LN + disease will also have pelvic LN+ disease
 * There is no Phase III data for use of chemotherapy. In GOG 37, the 2-year OS for inguinal LN+ was 68%, but the 2-year OS for pelvic LN+ was only 23%. Extrapolated data from other organs might argue for concurrent chemo-RT
 * ASTRO 2008 refresher: Adjuvant RT if 2+ LN involved, single grossly involved LN with ECE (old N2/N3 disease), or 1 LN+ but inadequate dissection (<5 on that side). Consider adjuvant chemo-RT if 3+ LN involved or ECE. Prophylactic groin RT reasonable with appropriate treatment techniques

Anatomic considerations

 * Torino, Italy; 2002 PMID 12210022 -- "Rationale and definition of the lateral extension of the inguinal lymphadenectomy for vulvar cancer derived from an embryological and anatomical study." (Micheletti L, J Surg Oncol. 2002 Sep;81(1):19-24.)
 * Embryological and anatomic study to determine lateral extension of groin lymphadenectomy in vulvar cancer. 3 human fetuses, 1 patient dissected
 * Outcome: Most lateral superficial inguinal lymph node does not rise above medial margin of the sartorius muscle, nor far lateral to where superficial circumflex iliac vessels cross the inguinal ligament
 * Conclusion: Lateral surgical landmark established

Lymph node management
Sentinel lymph node mapping:
 * GROINSS-V II; 2021 (2005 - 2016) PMID 34432481 -- "Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node: Results of GROINSS-V II" (Oonk MHM, J Clin Oncol. 2021 Aug 25;JCO2100006. doi: 10.1200/JCO.21.00006)
 * Prospective multicenter Phase II, single arm trial. 1535 patients. Early stage vulvar cancer (<4 cm), negative lymph nodes by imaging, sentinel node assessment. If SNB+, adjuvant RT 50/25
 * Outcome: SN metastasis in 21%. Stopping rule activated, since groin recurrence above threshold. 90% of recurrences wwere in SN mets >2 mm and/or ECE+. Protocol amended if SN macromets (>2 mm), completion IFL dissection, if SN micromets, continued adjuvant RT.
 * Outcome: If SN micromet, 2 year isolated groin recurrence 1.6%. If SN macromet, 2 year isolated groin recurrence 22% if RT only, and 7% if IFL (SS)
 * Toxicity: Less frequent after RT compared with IFL
 * Conclusion: Inguinofemoral RT safe alternative with SN micromets; not sufficient with SN macromets
 * GROINSS-V (2000-2006)
 * Primary Outcome; 2008 PMID 18281661 -- "Sentinel node dissection is safe in the treatment of early-stage vulvar cancer." (Van der Zee AG, J Clin Oncol. 2008 Feb 20;26(6):884-9.)
 * Prospective. 623 groins in 403 patients. T1-2, <4cm, SCC of vulva, clinically negative inguino-femoral LNs. SLN performed. If SLN- by ultrastaging, LND omitted. Median F/U 3 years
 * Outcome: SLN- in 68% patients. If SLN-, 2.3% groin failure rate and 3-year OS 97%
 * Toxicity: lymphedema 2% vs. 25%, recurrent erysipelas 0.4% vs. 16%
 * Conclusion: In early-stage vulvar CA, groin recurrences are low in patients with negative SLN
 * SLN Positivity; 2010 PMID 20537946 -- "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" (Oonk MH, Lancet Oncol. 2010 Jul;11(7):646-52. doi: 10.1016/S1470-2045(10)70104-2. Epub 2010 May 25.)
 * Sentinel node positive in 33% patients; completion inguinofemoral lymphadenectomy in 85%, 10% received RT or 5% no further treatment
 * Outcome: Further non-sentine metastases in 4% with ITC, 10% with micromets (<2 mm), 13% with macromets (2-5 mm), and 48% with macromets (>5 mm). DSS if <2mm 94% vs >2 mm 69% (SS)
 * Conclusion: Risk of non-sentinel node metastases increases with size of sentinel node metastasis


 * GOG 173 (1999-2009) - Phase III trial.
 * 459 eligible pts. Eligible if depth &ge; 1mm, tumor limited to vulva, primary tumor &ge; 2 cm and &le; 6 cm, and inguinal lymph nodes negative by examination; i.e. T1b and N0 (but <=6cm).
 * Performed SLNB followed by completion lymphadenectomy. If tumor within 2 of midline, bilateral SLNB and lymphadenectomies were performed; otherwise, unilateral.
 * 2012 PMID 22753905 -- "Lymphatic Mapping and Sentinel Lymph Node Biopsy in Women With Squamous Cell Carcinoma of the Vulva: A Gynecologic Oncology Group Study." (Levenback CF, J Clin Oncol. 2012 Nov 1;30(31):3786-3791.)
 * 452 pts underwent lymphatic mapping. 772 groin dissections performed (320 bilateral, 132 unilateral). SLN identified in 418 of 452 pts.
 * LN metastases found in 132 of 418 pts (31.6%). SLN positive in 121 of 418 pts; 11 pts with negative SLN but positive LN identified on dissection. Sensitivity of SLNB 91.7%. In pts with tumors < 4 cm, false negative rate is 2%.
 * Conclusion: "Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva." Women with tumors < 4 cm can be counseled that they have a less than a 3% risk of a groin relapse due to a false-negative SLN.

Lymph node dissection:
 * Ottawa; 2007 (1980-2004) PMID 17473950 -- "The definition of optimal inguinal femoral nodal dissection in the management of vulva squamous cell carcinoma." (Le T, Ann Surg Oncol. 2007 Jul;14(7):2128-32. Epub 2007 May 2.)
 * Retrospective. 58 patients with vulvar cancer, radical vulvectomy, and bilateral inguinal/femoral LND. 20th percentile for total LN removed = 10. RT 31%
 * Outcome: Only predictor for time-to-progression was <10 lymph nodes removed
 * Conclusion: Total number of LNs removed is independent prognostic factor, and at least 10 removed from bilateral dissection should be used for optimal evaluation


 * Mayo; 2003 (1955-90) - PMID 12957253 -- "Risk of occult inguinofemoral lymph node metastasis from squamous carcinoma of the vulva." (Gonzalez Bosquet J, Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):419-24.)
 * Retrospective. 226 pts, clinically N0.
 * Lymph node metastases by clinical tumor size: 0 to 1 cm = 7.7%; 1.1 to 2 cm = 23.9%; 2.1 to 3 cm = 31%; 3.1 to 5 cm = 36.4%


 * GOG 74 (1983-89) - superficial inguinal lymphadenectomy
 * 121 evaluable pts. Tumor thickness &le; 5 mm; no vascular invasion, clinically negative LNs.
 * 1992 PMID 1553164 -- "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." (Stehman FB, Obstet Gynecol. 1992 Apr;79(4):490-7.)
 * 19 recurrences. Vulvar recurrence: 8 of 10 pts salvaged. Groin recurrence: 5 of 7 deaths from cancer occurred in pts with first recurrence in the groin.
 * Conclusion: "The number of patients who experienced recurrence in the operated groin is of concern and may be attributable to the decision to leave the femoral nodes intact."


 * GOG 36 (1977-84) - Surgery-pathologic study after lymph node dissection.
 * 588 evaluable pts
 * Superficial tumors (<= 5mm); 1987 - PMID 3578430 &mdash; "Positive groin lymph nodes in superficial squamous cell vulvar cancer. A Gynecologic Oncology Group Study." (Sedlis A, Am J Obstet Gynecol. 1987 May;156(5):1159-64.)
 * Subset of 272 of 588 pts (48.7%) had superficial tumors, defined as <= 5mm thick (N.B.: this is different that the cutoff of 1 mm used for Stage IA vs IB. This study measured the total tumor thickness, not the depth of stromal invasion.)
 * Significant predictors of groin LN metastasis: tumor thickness, grade, capillary-like space involvement, clitoral or perineal location, and clinically suspicious nodes.
 * Conclusion: "The risk of lymph node metastases is best determined by simultaneous evaluation of all risk factors rather than a single factor such as tumor thickness."
 * All patients; 1993 - PMID 8314530 &mdash; "Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study)." (Homesley HD, Gynecol Oncol. 1993 Jun;49(3):279-83.)
 * All 588 pts. Predictors of groin LN metastasis (ranked in order of importance): higher grade, suspicious or fixed/ulcerated LNs, presence of capillary-lymphatic involvement, older age, greater tumor thickness. Tumor size and location were not predictive.
 * Toxicity: Chronic lymphedema 27%, wound breakdown 49%

Adjuvant RT

 * Radiation indicated for: >1 LN+, LN with ECE, margin < 8-10 mm, lymphadenectomy not performed due to comorbid disease, LVSI
 * Patients with fixed or ulcerated nodes should be treated with chemo/RT as per unresectable disease


 * GROINSS-V II (ongoing, opened 2005) - Non-randomized, observational study. In patients with SLN+, adjuvant RT (or chemo-RT, at physician discretion). For pts with SLN-, observation.


 * SEER data; 2006 (1988-2001) PMID 16889821 -- "The benefit of adjuvant radiation therapy in single-node-positive squamous cell vulvar carcinoma." (Parthasarathy A, Gynecol Oncol. 2006 Dec;103(3):1095-9. Epub 2006 Aug 4.)
 * Retrospective SEER data. 208 patients with single positive inguinal LN. 92% underwent radical vulvectomy with uni/bilateral LND. Median number LN resected 13. ~50% adjuvant RT.
 * Outcome: 5-year DSS adjuvant RT 77% vs. no RT 61% (SS). 5-year DSS improved if <12 LN removed RT 77% vs. no RT 55% (SS), if >12 LN removed RT 77% vs. no RT 67% (NS)
 * Conclusion: Adjuvant RT may improve DSS in patients with single LN+ who underwent less extensive LND


 * GOG 88 (1986-1990) -- GN-: RT vs bilateral groin dissection
 * Randomized. Stopped prematurely after failures seen only in RT arm. 52/300 patients, radical vulvectomy. T1-T3 (T1 eligible if LVI+ or depth >5mm). Nonsuspicious (clinical N0-N1) inguinal nodes. Arm 1) Bilateral inguinal/femoral LND vs Arm 2) bilateral groin irradiation. RT dose 50 Gy prescribed to 3 cm depth, CT planning not mandated.
 * 1992 PMID 1526880 &mdash; "Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study." (Stehman FB, Int J Radiat Oncol Biol Phys. 1992;24(2):389-96.)
 * Outcome: Groin recurrence RT 18% vs surgery 0% (SS), though 20% found to have positive disease and received ipsilateral inguinal/pelvic RT. OS RT 63% vs. surgery 88%. All recurrences were in-field
 * Conclusion: Radiation of intact groins is inferior to surgical dissection
 * Criticism: Dose to groin was prescribed at 3cm which greatly underdosed the nodes. ~50% patients had BMI >28. (See article by Koh below.) Koh showed that of the 5 pts who failed, all received tumor doses <47 Gy and 3 were underdosed by 30%. Failure rate of 18% is comparable to surgical LN+ rate of 20%, which is comparable to historical GOG data 24%


 * GOG 37 (1977-84) -- GN+: Inguinal/pelvic RT vs pelvic LND
 * Randomized. Closed prematurely for better outcome in RT arm. 114 patients with invasive SCC of vulva, who underwent radical vulvectomy and bilateral inguinal LND, and were found to have positive inguinal lymph nodes (unilateral or bilateral). Arm 1) Ipsilateral pelvic LN dissection vs Arm 2) Bilateral inguinal/pelvic RT. RT AP/PA 45-50 Gy (midplane) to bilateral pelvic nodes and bilateral groins. Superior border L5/S1. No radiation to primary. FIGO clinical staging used (but pathologic confirmation of + LN required for study entry).
 * 1986 PMID 3785783 &mdash; "Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes." (Homesley HD et al. Obstet Gynecol. 1986 Dec;68(6):733-40.)
 * Outcome: 2-yr OS RT 68% vs LND 54% (SS). Local groin failures RT 5% vs surgery 24% (SS). Failure rate in vulva 9% (23% of recurrences). Most recurrences within 2 years
 * Subset analysis: Survival advantage to RT if clinically suspicious/matted nodes or 2+ LN positive. 2-year OS clinically normal nodes (N0-N1) 78% vs. suspicious nodes (N2) 52% vs. matted nodes (N3) 33%. One LN+ 80% vs. 2-3 LN+ 66% vs. 4+ LN+ 27% (SS). If 2+ LN, RT 63% vs. surgery 37% (SS); no difference in only single LN+.
 * Toxicity: No significant difference
 * Conclusion: Adjuvant RT to groin and pelvic lymph nodes after WLE/B inguinal LND is superior to pelvic LN dissection
 * Comment: Benefit of RT was from control of the previously dissected groins (24% -> 5% failure rate)
 * 2009 PMID 19701032 -- "Radiation therapy compared with pelvic node resection for node-positive vulvar cancer: a randomized controlled trial." (Kunos C, Obstet Gynecol. 2009 Sep;114(3):537-46.) Median survivor F/U 6.1 years
 * Outcome: 6-year vulva recurrence RT 9% vs PLND 7% (recall no vulva RT given), groin LN recurrence 5% vs 24%, pelvic LN recurrence 5% vs 2%, DM only 12% vs 11%. 6-year RFS RT 59% vs PLND 48% (HR 0.4, SS). CSS 71% vs 49% (HR 0.5, SS). OS 51% vs 41% (HR 0.6, NS). RT still significantly improved OS for cN2-N3 disease and 2+ groin LN
 * LN disease burden: Significant benefit for RT (HR 3.9) if &ge; 20% ipsilateral LN+. If &ge; 20% LN+, significantly more likely to have contralateral LN+, relapse, and cancer-specific death. 6-year OS for these patients RT 36% vs PLND 13%. Single LN+ in 35% of patients, so inadequate power to estimate benefit
 * Toxicity: chronic lymphedema RT 16% vs PLND 22% (NS)
 * Conclusion: RT significantly reduces local relapses and cancer-related deaths; new indication for adjuvant RT is &ge; 20% ipsilateral LN+

Primary site

 * Pittsburgh; 2008 PMID 18455637 -- "Preoperative intensity-modulated radiotherapy and chemotherapy for locally advanced vulvar carcinoma." (Beriwal S, Gynecol Oncol. 2008 May;109(2):291-5.)
 * Retrospective. 18 patients, locally advanced Stage II-IVA cancer. Concurrent 5-FU/cisplatin and IMRT 45 Gy. Surgery 6-8 weeks post-treatment. Median F/U 1.8 years
 * Outcome: cCR 72%, pCR 64%
 * Toxicity: No Grade 3+ acute or late toxicity
 * Conclusion: Well tolerated, with good clinical response


 * Minnesota; 1994 (1971-92) - PMID 8083101 &mdash; "Radical vulvectomy with postoperative irradiation for vulvar cancer: therapeutic implications of a central block." Dusenbery KE et al. Int J Radiat Oncol Biol Phys. 1994 Jul 30;29(5):989-98.
 * Retrospective. 26 pts. 76% of recurrences were under the central block. Recommend tailoring the block to the individual pt.

Inguinal lymph nodes

 * University of Florida; 2004 PMID 15528067 &mdash; "Irradiating the groin nodes without breaking a leg: a comparison of techniques for groin node irradiation." Gilroy JS et al. Med Dosim. 2004 Winter;29(4):258-64.
 * Advocate the use of the "photon through-and-through" (similar fields for AP/PA but using 15 MV PA and 6MV AP) or the "photon thunderbird" (uses smaller field for the PA that spares the femoral head; electron patch over the inguinals to make up for the dose)


 * Taiwan; 1996 PMID 8641909, 1996 &mdash; "Topographic distribution of inguinal lymph nodes metastasis: significance in determination of treatment margin for elective inguinal lymph nodes irradiation of low pelvic tumors." Wang CJ et al. Int J Radiat Oncol Biol Phys. 1996 Apr 1;35(1):133-6.
 * Mapped inguinal mets on a sim film. The gross nodes lie within: 1) Lateral - lateral border of the femoral head, 2) Medial - 3 cm from body's midline, 3) Superior - 1 cm below upper border of femoral head, 4) Inferior - 2.5 cm below the bottom of the ischial tuberosity. 1-2 cm should be added to this region in designing a radiation portal to give adequate margin on the nodes.


 * University of Washington; 1993 PMID 8244831 &mdash; "Femoral vessel depth and the implications for groin node radiation." Koh WJ et al. Int J Radiat Oncol Biol Phys. 1993 Nov 15;27(4):969-74.
 * Measured depth of femoral vessel beneath the skin in 50 pts using CT. Range was 2-18 cm. Mean was 6.1 cm.
 * Importance: had implications for results of GOG study of prophylactic groin irradiation.

Official Guidelines
Link to guidelines page

Reviews

 * PMID 8431907, 1993 &mdash; "Gynecologic Oncology Group randomized trials of combined technique therapy for vulvar cancer." Keys H et al. Cancer. 1993 Feb 15;71(4 Suppl):1691-6.