1. Malignant vulval melanoma cases
Claire Newton
Consultant Gynaecological Oncologist
UH Bristol
On behalf of SWAGGER

2. Collaboration of cases from SWAGGER
Retrospective review
Last 10 years from 01/01/2007
32 cases
2 excluded as very little data
Median age 75 yrs old (range yrs old)
Median follow up time 28.2 months (range months)
Median overall survival 27.4 months

3. STAGE Tumour stage (TNM) Patients TNM stage FIGO stage
Patients FIGO staging
T1a
T1b
<1mm thickness without ulceration and mitoses < 1/mm 2
<1mm thickness With ulceration or mitoses ≥ 1/mm 2 2 1 1A 1B 11 T2
T2a
T2b
1.01–2mm thickness without ulceration
1.01–2mm thickness with ulceration T3
T3a
T3b
2.01-4mm thickness without ulceration
2.01-4mm thickness with ulceration 3 3a 3b T4
T4a
T4b
>4.01mm thickness without ulceration
>4.01mm thickness without ulceration 4 6 4a 4b
unknown 7 9

4. Primary Treatment Treatment WLE/ Radical Vulvectomy 22 (73%)
(3 palliative)
External beam radiotherapy
2 (6.7%)
(2 palliative)
Dacarbazine
1 (3.3%)
Palliative
4 (13.3%)
Unknown
1 (3.3%)
Only 1 patient had groin node dissection (unilateral, involved) – she recurred 4 years later with widespread mets
2 further patients had palpable/enlarged nodes but refused further treatment

5. Outcomes 30 patients: 7 (23%) are alive (1 with disease)
Median survival 27.4 months
Other casues
unknown
Melanoma
Total
Died 2 1
20 (66.7%)
23 (77%)
Recurrences -
10 (33%) 10
Progressive disease

6. Recurrences No. months after diagnosis (Mean 23.2 months)
Where recurrence
No. days died from diagnosis
7.5
groin
21.8
21.4
33.6
29.8
Vulva (71.7 mths groin)
74.7
5.8
lung
11.2
11.6
brain
18.8
48.6
widespread
54.8
6.9
19.5
29.7 -
32.5
47.9
84.1
113.3

7. Literature Review Series of 87 patients from Royal Marsden:
-The median survival of patients diagnosed before 2005 was 26 months, and from 2005 onwards 31 months (p=0.31).
-Median age of diagnosis was 60 years.
-86 (98.6%) patients had initial surgical management,
-11% of these women had adjuvant chemotherapy, radiotherapy or both.
-The median time between diagnosis and first recurrence was 9 months.
-Overall 1 and 5 year survival was 84% and 26%.

8. Prognostic variables From 1308 vulval melanoma patients:
Nodal metastasis increased:
- in the presence of lymphovascular space invasion (LVSI)
(56% vs 25%, P < 0.001)
-high mitotic rate (<1/mm2, 17%; 1-10/mm2, 31%; >11/mm2, 42%; P = 0.028).
On multivariate analysis factors associated with worse survival:
-nodal positivity (LVSI, presence of ulceration, high mitotic rate)
-Breslow depth
-AJCC stage predicted survival.

9. Groin node involvement
From 1308 vulvar melanoma patients increasing tumor thickness and presence of ulceration (a, no ulceration; b, ulceration present) significantly affected the rate of nodal metastasis (p<0.001)1
stage
% Groin lymph node involvement
Survival (months)
T1a
T1b 11 35
(27%)
T2a
T2b 7 23
(28%)
T3a
T3b 22 34
(21%)
T4a
T4b 18 51
(6.6%)

10. Groin node dissection
Elective lymphadenectomy is not therapeutic in melanoma – 10 yr survival in an RCT with 740 patients stage I-II were randomised to lymphadenectomy vs clinical observation. 10 year survival showed no difference2
The Multicenter Selective Lymphadenectomy Trial I (MSLT-I) noted a disease-free survival advantage of SLN mapping with completion lymphadenectomy for node- positive cases compared with groin observation alone.3,4
Additionally, the 5-year survival was 72% in the SLN-positive patients who underwent completion lymphadenectomy compared with 52% in the observation arm patients who underwent a lymphadenectomy at the time of recurrence.4
American society of clinical oncology and society of surgical oncology guidelines recommend SLN biopsy in Breslow thickness 1-4mm (stage 2-3) although melanoma focus have draft guidelines not advocating use of SLN biopsy outside of a trial.

11. Adjuvant therapy Lack of consensus
Interferon α – improved recurrence free survival but not overall survival in an RCT of 642 patients5
A randomized, phase II trial recently reported that adjuvant temozolomide with dose-dense cisplatin resulted in a highly significant improvement in OS compared with high-dose IFN-α-2b (p = 0.009) or observation in stage II/III mucosal melanomas (p < 0.001).6 The median OS was 48.7 months in the chemotherapy arm compared with 21.2 months in the observation arm.6

12. Advanced/metastatic/recurrent disease
Dacarbazine
high-dose interleukin-2 (IL-2)
In a randomized trial, the response rate for dacarbazine was 9% and 12% for temozolomide (p = 0.4). The median OS was 7.7 months and 6.4 months, respectively (p = 0.2).7
Ipilimumab- an anti-cytotoxic T-lymphocyte antigen (CTLA) agent that leads to T-cell stimulation, was the first agent to result in an OS improvement of 2 and 4 months in both chemotherapy-naive and previously treated melanoma, respectively8
Vemurafenib (B-raf enzyme inhibitor) in melanomas harboring a BRAF V600E mutation resulted in a dramatic improvement in progression-free survival (PFS) compared with dacarbazine in a phase III trial.9 The median PFS was 5.3 months for vemurafenib compared with 1.6 months for dacarbazine (hazard ratio [HR] = 0.26l; 95% CI, 0.2 to 0.33).9

13. Future developments
Novel targets include: BRAF mutation in 7.6%-26%, C-KIT mutation in %, NRAS mutation in %, and TP53 mutation in 7.6% of the malignant vulvar melanoma cases

14. References
1. Orr B.C.; Boisen M.M.; Courtney-Brooks M.; Sukumvanich P.; Berger J.; Taylor S.E.; Kelley J.L. Role of lymphadenectomy in vulvar melanoma. Gynecologic Oncology; Jun 2017; vol. 145 ; p. 214 (conference abstract)
2. Balch CM1, Soong S, Ross MI, Urist MM, Karakousis CP, Temple WJ, Mihm MC, Barnhill RL, Jewell WR, Wanebo HJ, Harrison R. Long-term results of a multi- institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol. 2000 Mar;7(2):87-97
3. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:
4. Wong SL, Balch CM, Hurley P, et al. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol. 2012;30:

15. References
5. Kirkwood JM1, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M, Blum RH. High- and low-dose interferon alfa- 2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000 Jun;18(12):
6. Lian B, Si L, Cui C, et al. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013;19:
7. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18:

16. References
8. Robert C, Thomas L, Bodarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:
9. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med ;364:

17. Any Questions?