Vulvar Part 2: Advanced

Vulvar Cancer
Written By Sydney Oesch

Episode Notes

  1. Locally advanced vulvar cancer definition

    1. Disease which is unresectable without removing the proximal urethra, bladder, or anus

  2. Historical Treatment

    1. En bloc radical vulvectomy with bilateral inguinofemoral lymphadectomy (IFLND) or pelvic exenteration

  3. Current Treatment

    1. First perform imaging to determine primary treatment

      1. If radiographically negative nodes → chemoRT (EBRT + concurrent platinum therapy) to primary tumor, IFLN, pelvic LN vs INFLND

        1. Decision between the two dependent on patient factors

        2. If IFLND performed and nodes negative → can omit RT

        3. If IFLND not performed → need to do RT

      2. If radiographically suspicious nodes → consider FNA biopsy or perform IFLND

    2. Evaluate response

      1. Clinical complete response → biopsy

      2. If clinical and pathologic complete response → surveillance

      3. If clinically or pathologically positive and resectable → surgical resection

        1. If negative margins → surveillance

        2. If positive margins → surgical resection, EBRT, systemic therapy, and/or best supportive care

      4. If clinically positive and unresectable → EBRT, systemic therapy, and/or best supportive care

  4. Chemoradiation vs Radiation Alone Data

    1. GOG 101, 1998

      1. Phase II study, n = 73

      2. Clinical stage III-IV SCC of vulva

      3. Cisplatin + 5-FU with RT in a “split course” followed by radical surgical excision of residual tumor and b/l IFLND

      4. 7 did not receive surgery after chemoRT

      5. 46.5% had no visible disease

      6. Only 2.8% had residual, unresectable disease

      7. Only 4% were not able to preserve urinary/GI continence with surgery after chemoRT

    2. Montana et al., 2000

      1. Subgroup analysis/follow up of GOG 101

      2. Pts w/ N2, N3, or unresectable nodes

      3. N = 46

        1. 4 did not complete chemoRT, 4 did not undergo surgery

      4. Out of 40 who completed chemoRT, 38 had resectable nodes

      5. Of 37 who underwent IFLND, 15 with pathologically negative specimens

      6. Local control of nodal disease was achieved in 36 of the 37 patients

    3. Han et al., 2000

      1. Case series of 54 patients

      2. Locally-advanced vulvar, chemoRT vs RT alone in primary or adjuvant treatment

      3. OS and PFS significantly improved in group treated w/ chemoRT vs RT in primary setting

      4. Trends favoring chemoRT in adjuvant group but not significant (underpowered, n = 6)

    4. GOG 205, 2012

      1. Efficacy and toxicity of chemoRT in achieving a complete clinical and pathologic response

      2. N = 58, stage III-IV not amenable to surgical resection

      3. Cis-EBRT followed by surgical resection if residual tumor or no further treatment if biopsy-confirmed complete response

        1. IFLND performed if groin nodes unresectable prior to chemoRT

      4. Limitation of GOG 101 - recurrence rates relatively high

        1. RT doses were purposefully lower and treatment break in middle - the “split course” dosing

      5. 69% completed treatment

        1. 37 had complete clinical response, 34 underwent biopsy

        2. Of 34 w/ biopsy, 78% also had complete pathologic response

      6. Takeaway: combo of cisRT at higher dose led to high clinical and pathological response rates that may eliminate the need for further surgical intervention

    5. Natesan et al., 2017

      1. NCDB retrospective analysis

      2. N  = >2000, locally advanced vulvar, received either primary RT or chemoRT vs preop RT or chemoRT followed by surgery

      3. Those who underwent surgery after chemoRT had longer OS than those w/ RT or chemoRT alone

        1. In subgroup analysis of chemoRT alone vs followed by surgery, no difference in OS if radiation dose > 55 Gy

    6. Rao et al., 2017

      1. NCDM retrospective analysis

      2. Pts not candidates for primary surgery; primary chemoRT (n = 999) vs RT alone (n = 353)

      3. ChemoRT group more advanced disease and younger

      4. ChemoRT w/ longer 5-year OS (49.9% vs 27.4%)

  5. Current Data

    1. GOG 279, 2024

      1. Phase II trial to assess safety/toxicity of cisplatin (40 mg/m2) + gemcitabine (50 mg/m2) w/ IMRT to 64 Gy

      2. Inclusion: disease not amenable to resection w/ radical vulvectomy, n = 52

      3. Intervention

        1. Underwent IFLN assessment by IFLND or IF SLNB

        2. IMRT to groin and nodes if nodes positive or if significant involvement of vagina, anorectal, or urethral regions, even if nodes negative

        3. Higher doses RT for high risk nodal features - 3+ positive nodes, extracapsular extension, and/or close/positive surgical margins

        4. If complete clinical response → core biopsy to confirm complete pathologic response

        5. If not complete clinical response → radical resection of remaining tumor or additional chemoRT

      4. 81% completed trial therapy

      5. At median f/u of 52 months, 71% had complete clinical response

        1. Of 9 w/ clinically persistent disease, 4 had pathologically negative specimens after resection

        2. 5 remaining patients w/ clinically and pathologically persistent disease died w/i 8 months of finishing therapy

      6. Toxicities similar to GOG 205, despite higher doses of RT

      7. 12 mo PFS: 74%

      8. 24 mo OS: 70%

      9. Takeaway: rates of clinico-pathologic response higher than in prior GOG studies

        1. Unclear whether IMRT, higher dose of radiation, and/or addition of gem led to better response

        2. Authors suggest based on retrospective data that elevating radiation dose to > 64 Gy is important for clinicopathologic response, vs chemo boost/non-platinum agent

  6. Neoadjuvant Chemotherapy Data

    1. No prospective trials

    2. Kuhn et. al, 2024

      1. N = 113, stage II-IV disease

      2. 13 underwent NACT w/ carbo/taxol/bev or cis/taxol/bev

        1. 9 w/ partial pathologic responses, 4 with complete responses

        2. All w/ negative surgical margins

        3. 77% w/ inguinal node involvement, 4 with residual nodal disease

      3. Median f/u 23 mo; 3 of 13 patients w/ recurrence with 1 death

      4. Takeaway: NACT may be efficacious, lead to more negative margins, and improve surgical morbidity; however need larger, prospective trial

    3. Amant et al. - prospective phase II trial investigating primary chemoRT vs NACT followed by surgery for locally advance vulvr

  7. Metastatic Disease

    1. Stage IVB

    2. Systemic therapy offered - data extrapolated from cervical

      1. No prospective trials in this space

      2. Preferred, first-line treatment: cisplatin or carboplatin + paclitaxel +/- bevacizumab (based on GOG 240 and JCOG 0505, respectively)

    3. If limited to pelvic lymph nodes, definitive chemoRT w/ curative intent may be offered

    4. Can also consider EBRT for locoregional control or symptom management

  8. Recurrent Disease

    1. Recurrence is common

    2. Whole body imaging, consider biopsy

    3. 53% of recurrences confined to vulva

    4. 5-year OS: 60% vulvar, 27% inguinal or pelvic, 15% distant, 14% diffuse/multi-site

    5. No standard of care treatment - need to individualized

      1. Vulva + clinically-negative noes: radical excision +/- IFLND, consider adjuvant RT +/- systemic therapy

      2. Large or central: consider exenteration

      3. Locoregional → NACT, chemoRT, or RT alone

      4. Distant or previous EBRT → systemic therapy

        1. 5-year OS is <10% 

    6. Prognosis with nodal recurrences is very poor regardless of offered treatment

  9. Second-Line for Recurrence

    1. Use cis or carbo + taxol +/- bev if not previously used

  10. Targeted Therapy

    1. Pembro can be considered in PD-L1 pos, TMB-H, and/or MSI-H/dMMR tumors

    2. KEYNOTE-158, 2020

      1. N = 101 w/ progressive, unresectable vulvar SCC

      2. ORR 10.9%

        1. ORR increased to 17% in TMB-H

        2. ORR decreased to 3.4% in TMB-L

      3. 84% included were PD-L1 pos

        1. ORR 9.5% in pos vs 29% in neg

        2. Sample size for PD-L1 neg was low

        3. Showed efficacy in both pos and neg; suggests PD-L1 may not be a great marker for response

        4. Prior studies w/ much lower rates of PD-L1 positivity in vulvar cancer (<30%) and PD-L1 positivity associated w/ worse prognosis

          1. Study included previously treated patients (i.e. worse prognostic group)

      4. Median PFS 2.1 mo

      5. Median OS 6.2 mo

        1. Similar to prior studies in advanced vulvar (although most other studies did not include patients with prior treatments)

    3. Checkmate 358, 2019

      1. Use of nivolumab in HPV-pos or HPV-unknown cancers

      2. N = 5 w/ vulvar or vaginal cancer

      3. 12 mo OS: 40%

      4. 6 mo PFS: 40%

    4. DESTINY, 2024

      1. Phase II trial

      2. Investigated trastuzumab-deruxtecan in HER2 positive tumors

      3. N = 1 for vulvar

        1. Results for clinical use extrapolated from uterine and cervical cohorts

    5. Larotrectinib or entrectinib can be used if NTRK fusion found (0.3% of solid tumors)

    6. Cemiplimab can be considered

      1. Data extrapolated from EMPOWER-cervical-1 tril

    7. Erlotinib can be considered

      1. Horowitz et al, 2012

      2. Phase II trial, n = 41 w/ vulvar SCC

      3. ORR 27.5%

        1. Short duration of response: median 28 days

  11. Surveillance

    1. Most recur within 1-2 years but also can occur > 5 years out

    2. H&P every 3-6 mo x 2 years, then 6-12 mo x 3-5 years, then annually

  12. Survivorship

    1. Dilator use education

    2. Vaginal moisturizers/lubricants +/- estrogen creams

    3. Monitor for secondary radiation-induced cancers
      References

References

1. Montana GS, Thomas GM, Moore DH, et al. PII S0360-3016(00)00762-8 PREOPERATIVE CHEMO-RADIATION FOR CARCINOMA OF THE VULVA WITH N2/N3 NODES: A GYNECOLOGIC ONCOLOGY GROUP STUDY Chemo-Radiation, Vulvar Cancer, N2/N3 Nodes.; 2000.

2. Moore DH, Thomas GM, Montana GS, Saxer A, Gallup DG, Olt G. Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys. 1998;42(1):79-85. doi:10.1016/S0360-3016(98)00193-X

3. Moore DH, Ali S, Koh WJ, et al. 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. Gynecol Oncol. 2012;124(3):529-533. doi:10.1016/j.ygyno.2011.11.003

4. Han SC, Kim DH, Higgins SA, Carcangiu ML, Kacinski BM. CHEMORADIATION AS PRIMARY OR ADJUVANT TREATMENT FOR LOCALLY ADVANCED CARCINOMA OF THE VULVA.; 2000.

5. Rao YJ, Chin RI, Hui C, et al. Improved survival with definitive chemoradiation compared to definitive radiation alone in squamous cell carcinoma of the vulva: A review of the National Cancer Database. Gynecol Oncol. 2017;146(3):572-579. doi:10.1016/j.ygyno.2017.06.022

6. van Triest B, Rasing M, van der Velden J, et al. Phase II study of definitive chemoradiation for locally advanced squamous cell cancer of the vulva: An efficacy study. Gynecol Oncol. 2021;163(1):117-124. doi:10.1016/j.ygyno.2021.07.020

7. Kuhn TM, Ahmad S, Recio FO, et al. Neoadjuvant chemotherapy with bevacizumab for locally advanced vulvar cancer. Int J Gynecol Cancer. 2024;0:1-8. doi:10.1136/ijgc-2024-005402

8. Horowitz NS, Deng W, Peterson ; Ivy, et al. Phase II Trial of Cisplatin, Gemcitabine, and Intensity-Modulated Radiation Therapy for Locally Advanced Vulvar Squamous Cell Carcinoma: NRG Oncology/GOG Study 279. Published online 2024:1914-1921. doi:10.1200/JCO.23.02235

9. Amant F, Van Velzen AF, Reyners A, Zijlmans H, Schaake EE, Nooij L. Primary chemoradiation versus neoadjuvant chemotherapy followed by surgery as treatment strategy for locally advanced vulvar carcinoma (VULCANize2). Int J Gynecol Cancer. 2024;0:1-4. doi:10.1136/ijgc-2024-005493

10. Horowitz NS, Olawaiye AB, Borger DR, et al. Phase II trial of erlotinib in women with squamous cell carcinoma of the vulva. Gynecol Oncol. 2012;127(1):141-146. doi:10.1016/J.YGYNO.2012.06.028

11. Witteveen PO, van der Velden J, Vergote I, et al. Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: a study of the EORTC-GCG (European Organisation for Research and Treatment of Cancer--Gynaecological Cancer Group). Ann Oncol. 2009;20(9):1511-1516. doi:10.1093/ANNONC/MDP043

12. Reade CJ, Eiriksson LR, Mackay H. Systemic therapy in squamous cell carcinoma of the vulva: Current status and future directions. Gynecol Oncol. 2014;132(3):780-789. doi:10.1016/j.ygyno.2013.11.025

13. Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-1365. doi:10.1016/S1470-2045(20)30445-9

14. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/ Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. Published online 2019. doi:10.1200/JCO.19

15. Shapira-Frommer R, Mileshkin L, Manzyuk L, et al. Efficacy and safety of pembrolizumab for patients with previously treated advanced vulvar squamous cell carcinoma: Results from the phase 2 KEYNOTE-158 study. Gynecol Oncol. 2022;166:211-218. doi:10.1016/j.ygyno.2022.01.029

16. Naumann RW, Hollebecque A, Meyer T, et al. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol. 2019;37(31):2825-2834. doi:10.1200/JCO.19.00739

17. Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: Results of the NCI-MATCH trial subprotocol H. Journal of Clinical Oncology. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762

18. Wilhite AM, Wu S, Xiu J, et al. A paradigm shift in understanding vulvovaginal melanoma as a distinct tumor type compared with cutaneous melanoma. Gynecol Oncol. 2024;188:13-21. doi:10.1016/j.ygyno.2024.06.002

19. Morton DL, Thompson JF, Cochran AJ, et al. Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma. New England Journal of Medicine. 2014;370(7):599-609. doi:10.1056/NEJMOA1310460/SUPPL_FILE/NEJMOA1310460_DISCLOSURES.PDF

Sydney Oesch
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Vulvar Part 1: Early Stage