R. Michelle Sarin, MD Mentor: Jeffrey Fowler, MD Close vulvar cancer margins are not strongly associated with recurrence or survival R. Michelle Sarin, MD Mentor: Jeffrey Fowler, MD

objectives To examine the relationship between margin status and recurrence rate and survival in local vulvar cancer

background Vulvar cancer is 4% of female genital cancers Staging is both clinical and surgical- pathological Therapy is predominantly surgical: excise with goal margin 1 cm Margin status postulated as a significant prognostic factor If pathology margins < 8 mm, consider re- excision vs adjuvant therapy based on other risk factors Local recurrence rate is about 20- 35% Overall 5 year survival is about 72% Localized disease 5 year survival 86% In 2015, NCI estimates about 5000 new cases, 1100 deaths

Margin status Surgery is the preferred primary treatment for early vulvar cancer 1 cm “wet” margin (8 mm pathology margins) is ideal Surgery around urethra, clitoris or anus can lead to significant morbidity Heaps et al 1990: Surgical margin most powerful predictor of local recurrence and a margin of <8 mm associated with 50% chance of recurrence Nooij et al 2016: Meta-analysis: Pooled risk ratio for local recurrence with margin < 8 mm was 1.88 (95% CI 0.99-3.5) Cohort study: Margin < 8 mm did not increase risk of local recurrence, HR 1.09 (95% CI 0.32-4.35) (8 mm pathologic margins based on small studies and mostly consensus based evidence) Heaps: Study of surgical-pathologic variables predictiv of local recurrence. 135 pts of all stages, but majority stage 1 and 2. 21 pts with recurrence after primary radical resection. 91 margin > 8 mm, no recurrences Metaanalysis: 10 cohort studies comparing local recurrence rates in those with close surgical margins to those without. 4 studies showed increased risk, 6 did not. Pooled random effects analsysi of 1278 patients; pooled risk ration 1.88 Cohort study: one institution in Netherlands, median followup 42 months. 148 patients, strict definition of local recurrence

Further specific staging of Stage III and IV lesions based on number and size of nodes Changed in 2009; many studies on vulvar cancer use old staging Both tumor size and grade correlated with rate of nodal metastasis Stage I and II 5 year survival 90%; however nodal status important; if pos, 40-50% survival

methods Retrospective cohort study from 2 institutions All patients underwent definitive surgery for stage I or II vulvar carcinoma Charts reviewed for demographic factors, tumor clinical and pathologic characteristics, dates of recurrence and death Close surgical margins defined as < 8 mm Wilcoxon rank-sum, Fisher’s exact test were used for age, race, BMI, tumor size comparison Hazard ratios calculated for recurrence free survival and overall survival Age adjusted Kaplan Meier curves generated for recurrence free and overall survival •Retrospective cohort study from two institutions on patients undergoing definitive surgery for stages I and II vulvar cancer •All patients were reviewed for surgicopathologic data, recurrence and death •Close surgical margins were defined as ≤8 mm. •Comparisons of pre or peri-operative characteristics between those with and without close surgical margins were made by Fisher’s exact test or the Wilcoxon rank-sum test •The risk of recurrence or death was estimated through Cox proportional hazards models

methods Inclusion criteria: Age over 18 Primary surgery for early stage vulvar cancer +/- lymph node assessment Any histology type Exclusion criteria: Lymph node involvement Neoadjuvant therapy Synchronous primary tumors

Results: patient characteristics Margin ≤ 8 mm (n = 101) Margin > 8 mm (n = 22) P value Age, median 62.3 61.1 0.3 Race Black 6 (5.9%) 2 (9.1%) 0.6 White 95 (94.1%) 20 (90.9%) BMI <18-24.9 25 (25.3%) 5 (22.7%) 1 25-29.9 22 (22.2%) >30 52 (52.5%) 12 (54.5%) Lymph node assessment 73 (72.3%) 18 (81.8%) 0.07 Table 1: Patient characteristics

Results: tumor characteristics Mention: tried to find characteristics that should make us more concerned about one patient than another. IE LVSI, grade, size, etc Table 2: Tumor characteristics

Results: recurrence Reported local recurrence rate in literature is approximately 20% This study: 36 patients recurred (29%) 28 recurrences local (78%) 20 deaths (16%) All patients who received adjuvant therapy were in close surgical margins group 123 patients were included •101 (82%) with close surgical margins on final pathology •22 (18%) with surgical margins >8 mm •Patients with close margins were similar in age and BMI to those without close margins •The majority of patients were stage I (84%) and had squamous histology (92%) •Most patients

Results: recurrence P = 0.58 5-year DFS was similar (60%vs 61%) Patients with close surgical margins trended towards larger tumors (p-value=0.09) •36 patients recurred (24.4%) and 20 (16.3%) died during follow up •The majority of recurrences were local (n=28) •Close margins were not associated with recurrence or survival (age adjusted hazard ratio (aHR): 1.29, 95% CI 0.52-3.18, p-value=0.58) •5-year RFS was 60% for those with margins ≤ 8 mm and 61% for those with margins >8mm (Figure 1) •Overall survival did not differ significantly by margin status. 5-year OS was 77% for close margins compared to 94% for margins >8 mm (aHR Figure 1: Kaplan Meier curve depicting recurrence free survival

Results: Overall survival P = 0.62 Figure 2: Kaplan Meier curve depicting overall survival

Results: survival Margins Recurrence free survival, HR (95% CI) Overall survival, HR (95% CI)   <1 mm (n =17) 1.3 (0.55-3.05) 1.23 (0.40-3.74) <5 mm (n=74) 0.86 (0.43-1.72) 0.93 (0.36-2.39) <8 mm (n =101) 1.29 (0.52-3.18) 1.38 (0.39-4.86) All patients who received adjuvant therapy (12) were in close surgical margins group 6 RT, 6 chemo+RT Table 3: Association between margin status and survival

conclusions Margin status has classically been used to stratify patients for risk of recurrence and consideration for further therapy We did not find that margin status (<8 mm) was associated with different rates of recurrence or overall survival Even when we analyzed patients with 1 and 5 mm surgical margins, no difference in recurrence or survival Observation (rather than re-excision or adjuvant therapy) may be appropriate for those with completely resected disease Large cohort at single institution Importance: may not need further therapy and And modified to preserve anatomy (ie be accept an with a smaller margin to preserve anatomy) Future directions: evaluating stage 3 and stage 4 patients (we choe stage 1 and 2 because we are often trying to decide whether or not additional therapy needed) Adequate surgical margins are considered to be important in the course of definitive surgical management of T1/T2 vulvar cancer •Close surgical margin status did not impact recurrence or survival in this cohort of patients with clinically apparent early stage vulvar cancer •Even when examining very close surgical margins (1 and 5 mm) the risk of recurrence or survival was not significantly impacted •The majority of cases in our cohort had close surgical margins and our cohort’s recurrence rates are similar to previous studies •These findings provide evidence that observation may be acceptable in patients with close margins and that the extent of the surgical margin may be modified in order to preserve critical anatomy

Future directions Better identification of who is at higher risk of recurrence to tailor further therapy Analysis of patients with positive margins Similar analysis of stage 3 and 4 patients Even when looking at patients who did not receive adjuvant therapy our results were similar (remember that 12 patients in the close margin group received adjuvant therapy) – can just say don’t have to have on slide/may be question   Although (significantly) underpowered our cohort’s recurrence rate in each group was similar to other previously published reports Vulvar cancer recurrence is challenging since the factors that lead to vulvar cancer in one area are present in other regions of vulva and therefore de novo carcinomas are consideration when discussing recurrence

references NCCN Vulvar Cancer Guidelines SEER Cancer Statistics Factsheets: Vulvar Cancer. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/vulva.html Nooij L et al. Tumor-free margins in vulvar squamous cell carcinoma: Does distance really matter? European Journal of Cancer. 65 (2016): 139-149. Heaps J, Fu Y, Montz F, Hacker N and Berek J. Surgical- Pathologic Variables Predictive of Local recurrence in Squamous Cell Carcinoma of the Vulva. Gynecologic Oncology. 38 (1990): 309-314. Schilder J and Stehman F. Invasive Cancer of the Vulva. In: Di Saia, P, ed. Clinical Gynecologic Oncology. 4th ed. Saunders Elsevier; 2012: 219-244.

Thank you! Attending mentor: Dr. Jeffrey Fowler, MD Fellow mentors: Casey Cosgrove, MD and Adam ElNaggar, MD Statistics: Erinn Hade, PhD