Complete Response After Stereotactic Body Radiation Therapy With Concurrent Immunotherapy for Vaginal Melanoma

IntroductionMucosal melanomas represent 1.3% of all melanomas. Of those, 18% arise within the female genital tract (FGT).1Chang AE Karnell LH Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society.Cancer. 1998; 83: 1664-1678Google Scholar,2Patrick RJ Fenske NA Messina JL. Primary mucosal melanoma.J Am Acad Dermatol. 2007; 56: 828-834Google Scholar Unique molecular profiles were identified for vulvar and vaginal melanomas (VM) compared with nongynecologic melanomas, suggesting mucosal melanomas (MM) of the FGT represent a distinct melanoma subtype.3Hou JY Baptiste C Hombalegowdaet RB et al.Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma.Cancer. 2017; 123: 1333-1344Google Scholar Vaginal melanomas are particularly rare, making up only 19.8% of FGT melanomas compared with vulvar primaries (76.7%).4McLaughlin CC Wu X-C Jemal A Martin HJ Roche LM Chen VW. Incidence of noncutaneous melanomas in the U.S.Cancer. 2005; 103: 1000-1007Google Scholar Although no formal staging system exists for VM, clinical staging from cutaneous melanomas has been adapted as follows: localized (stage I), lymph node involvement (stage II), disseminated disease (stage III).5Ballantyne AJ. Malignant melanoma of the skin of the head and neck. An analysis of 405 cases.Am J Surg. 1970; 120: 425-431Google Scholar Tumor size and lymph node involvement have been correlated with survival in vaginal melanoma.2Patrick RJ Fenske NA Messina JL. Primary mucosal melanoma.J Am Acad Dermatol. 2007; 56: 828-834Google Scholar,6Buchanan DJ Schlaerth J Kurosaki T. Primary vaginal melanoma: Thirteen-year disease-free survival after wide local excision and review of recent literature.Am J Obstet Gynecol. 1998; 178: 1177-1184Google Scholar, 7Reid GC Schmidt RW Roberts JA Hopkins MP Barrett RJ Morley GW. Primary melanoma of the vagina: A clinicopathologic analysis.Obstet Gynecol. 1989; 74: 190-199Google Scholar, 8Frumovitz M Etchepareborda M Sun CC et al.Primary malignant melanoma of the vagina.Obstet Gynecol. 2010; 116: 1358-1365Google Scholar Unfortunately, VM has a poor overall prognosis, with 5-year overall survival rates of 5% to 25%.9Bonner JA Perez-Tamayo C Reid GC Roberts JA Morley GW. The management of vaginal melanoma.Cancer. 1988; 62: 2066-2072Google Scholar,10Piura B Rabinovich A Yanai-Inbar I. Primary malignant melanoma of the vagina: Case report and review of literature.Eur J Gynaecol Oncol. 2002; 23: 195-198Google Scholar These poor outcomes are attributed to occult location, often multifocal disease with surrounding atypia, advanced disease in close proximity to critical anatomic pelvic structures, and rich submucosal lymphovascular channels with predilection for nodal spread.2Patrick RJ Fenske NA Messina JL. Primary mucosal melanoma.J Am Acad Dermatol. 2007; 56: 828-834Google Scholar,11Lotem M Anteby S Peretz T Ingber A Avinoach I Prus D. Mucosal melanoma of the female genital tract is a multifocal disorder.Gynecol Oncol. 2003; 88: 45-50Google ScholarGiven the rarity of VM and paucity of data, optimal management remains in question.6Buchanan DJ Schlaerth J Kurosaki T. Primary vaginal melanoma: Thirteen-year disease-free survival after wide local excision and review of recent literature.Am J Obstet Gynecol. 1998; 178: 1177-1184Google Scholar,12Leitao Jr, MM Cheng X Hamilton AL et al.Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas.Int J Gynecol Cancer. 2014; 24: S117-S122Google Scholar Retrospective analyses combined with data extrapolated from cutaneous or other MM guide current recommendations regarding surgical, systemic, and radiation therapies (RTs). Primary surgical resection via wide local excision with negative margins is preferred, though the survival benefit of surgery has been debated.6Buchanan DJ Schlaerth J Kurosaki T. Primary vaginal melanoma: Thirteen-year disease-free survival after wide local excision and review of recent literature.Am J Obstet Gynecol. 1998; 178: 1177-1184Google Scholar,13Petru E Nagele F Czerwenka K et al.Primary malignant melanoma of the vagina: Long-term remission following radiation therapy.Gynecol Oncol. 1998; 70: 23-26Google Scholar Advanced tumor size, multifocal disease, and proximity to bladder, urethra, rectum, and anus increase the technical challenge of achieving R0 surgical margin. Extensive radical surgery to achieve wider margins has not improved survival, and recommendations for pelvic and/or inguinal staging are lacking.12Leitao Jr, MM Cheng X Hamilton AL et al.Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas.Int J Gynecol Cancer. 2014; 24: S117-S122Google Scholar,14Schiavone MB Broach V Shoushtari AN et al.Combined immunotherapy and radiation for treatment of mucosal melanomas of the lower genital tract.Gynecol Oncol Rep. 2016; 16: 42-46Google Scholar,15Leitao Jr., MM Management of vulvar and vaginal melanomas: current and future strategies.Am Soc Clin Oncol Educ Book. 2014; 34: e277-e281Google Scholar Despite aggressive multimodality therapy including primarily surgical management with or without adjuvant RT, outcomes remain poor for VM with high rates of distant recurrence.1Chang AE Karnell LH Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society.Cancer. 1998; 83: 1664-1678Google Scholar,8Frumovitz M Etchepareborda M Sun CC et al.Primary malignant melanoma of the vagina.Obstet Gynecol. 2010; 116: 1358-1365Google Scholar,9Bonner JA Perez-Tamayo C Reid GC Roberts JA Morley GW. The management of vaginal melanoma.Cancer. 1988; 62: 2066-2072Google Scholar,15Leitao Jr., MM Management of vulvar and vaginal melanomas: current and future strategies.Am Soc Clin Oncol Educ Book. 2014; 34: e277-e281Google Scholar, 16Gökaslan H Sişmanoğlu A Pekin T Kaya H Ceyhan N. Primary malignant melanoma of the vagina: A case report and review of the current treatment options.Eur J Obstet Gynecol Reprod Biol. 2005; 121: 243-248Google Scholar, 17Garbe C Peris K Hauschild A et al.Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guidelineࣧupdate 2016.Eur J Cancer. 2016; 63: 201-217Google Scholar Immunotherapy (IO) shows promise in treating MM with objective response rates of ∼20% and ∼75% of responders with some degree of durable response.18Yentz S Lao CD. Immunotherapy for mucosal melanoma.Ann Transl Med. 2019; 7: S118Google Scholar, 19Hamid O Robert C Ribas A et al.Antitumour activity of pembrolizumab in advanced mucosal melanoma: A post-hoc analysis of KEYNOTE-001, 002, 006.Br J Cancer. 2018; 119: 670-674Google Scholar, 20Moya-Plana A Herrera Gómez RG Rossoni C et al.Evaluation of the efficacy of immunotherapy for non-resectable mucosal melanoma.Cancer Immunol Immunother. 2019; 68: 1171-1178Google Scholar Therefore, treatment selection is challenging given the need to balance the morbidity of local therapies with the propensity for distant metastatic disease and overall poor outcomes.Within this context, improvements in both local and systemic therapy are needed. We present 2 cases of vaginal melanoma treated at different comprehensive cancer centers using a multimodality approach of IO and stereotactic body radiation therapy (SBRT) with or without surgical debulking, and review current management controversies.Case PresentationCase 1A 56-year-old G3 P3 woman with no significant past medical history presented with vaginal pressure and postcoital bleeding. Physical examination at presentation showed a 2 cm mass protruding at the anterior vaginal wall just proximal to the introitus.Biopsy revealed ulcerated melanoma, invasive to a depth of at least 3.1 mm, at least Clark level IV (BRAF and KIT negative) without perineural invasion or lymphovascular invasion. Staging magnetic resonance imaging (MRI) of the pelvis demonstrated a large mass at the vaginal introitus, extending superiorly along the right and left vaginal fornices, and abutting the posterior urethra without intervening fat plane (Fig 1A and 1B). Positron emission tomography (PET)/computed tomography (CT) demonstrated an fluorodeoxyglucose-avid vaginal mass with superior extension to the cervix (Fig 1C). PET/CT and brain MRI were both negative for lymph node involvement and distant metastatic disease.After multidisciplinary discussions, she initiated combination ipilimumab (3 mg/kg intravenously [IV] every 3 weeks) and nivolumab (1 mg/kg IV every 3 weeks for 4 cycles, then 480 mg IV every 4 weeks until maximum benefit). She had a partial response with symptomatic improvement after initial cycles of combination IO, and after cycle 4, she continued with nivolumab monotherapy. Restaging CT of the chest and MRI of the abdomen and pelvis demonstrated stable vaginal disease and no evidence of metastatic disease.After cycle 8 of nivolumab monotherapy, she underwent anterior vaginectomy for debulking before RT. Multifocal lesions were identified and all visible lesions were debulked. Pathology redemonstrated melanoma with sarcomatoid features.After maximal debulking, she was planned to undergo SBRT. Three gold seeds were placed in the vaginal wall to mark out the proximal and distal extent of gross residual disease and a third seed inserted out of plane with the others for daily setup alignment. She was simulated supine, frog-legged, in an alpha cradle, with full and empty bladder using CT and MRI with contrast. Using the diagnostic MRI presurgery coregistered to the planning CT and MRI, the original extent of gross disease and the residual gross disease was delineated. The clinical target volume (CTV) was the entire length of the vagina, resulting in a nearly 1.0-1.5 cm margin around the gross tumor volume (GTV). A planning target volume (PTV) margin of 0.3 cm was isometrically applied. Total prescription dose was 30 Gy delivered in 5 fractions every other day with cone beam CT (CBCT) for alignment with attention to gold seeds and PTV, though real-time tumor tracking was not used. A volumetric-modulated arc therapy plan using 6X photons with 2 arcs created an acceptable plan meeting all normal structure constraints (Table 1) and excellent target coverage (Fig 1D). Daily setup included full bladder and empty rectum. Full bladder was obtained with 16 oz of fluid intake 1 hour before each treatment. Patient were instructed to have a bowel movement before arrival to treatment. If full rectum or rectal gas was noted on pretreatment CBCT distending rectum >0.5 cm in diameter from empty at simulation, patients were removed from table and asked to evacuate. There was not a need for use of pretreatment enema or rectal tube, but this was available if needed.Table 1Vaginal stereotactic body radiation therapy planning dose constraintsNormal structures and goalsNormal structuresPriorityParameter planning limitSmall bowel1D0.1cc[Gy] ≤ 27D1cc[Gy] ≤ 25Bladder1D0.1cc[Gy] ≤ 35D0.5cc[Gy] ≤ 32V26Gy[cc] ≤ 50V26Gy[%] ≤ 25Rectum1D0.1cc[%] ≤ 38D1cc[Gy] ≤ 36D2cc[Gy] ≤ 35V36Gy[%] ≤ 5V32Gy[%] ≤ 10V20Gy[%] ≤ 50Colon_sigmoidColon1D0.1cc[Gy] ≤ 30D1cc[Gy] ≤ 28Femur_head3V22Gy[%] ≤ 5V22Gy[cc] ≤ 10Skin3D0.1cc[Gy] ≤ 20Urethra3D0.5cc[Gy] ≤ 40 Open table in a new tab She tolerated treatment well without significant side effects. After RT, she developed abdominal cramping and diarrhea for 1 week, which self-resolved. Three weeks after RT, she developed grade 2 radiation perineal dermatitis (National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0), which resolved with Aquaphor (Beiersdorf AG) and Domeboro soaks (Advantice Health). Follow-up MRI obtained 3 months post-RT showed no abnormal soft tissue remaining at the site of previously seen malignancy in the vagina. Physical examination at 8 months post-RT recorded maintained vaginal length and caliber without any mucosal abnormality, discoloration, discharge, or bleeding. PET/CT 6 months post-RT demonstrated no evidence of disease (Fig 2). She completed 15 cycles of nivolumab monotherapy and has been on surveillance with no evidence of disease at last follow-up, now 16 months post-RT. There were no long-term toxicities attributable to radiation noted to date.Fig. 2Case 1: PET/CT before (A) and 3 months post-RT (B) showing complete radiographic response. Abbreviations: PET/CT = positron emission tomography/computed tomography; RT = radiation therapy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Case 2An 80-year-old G2 P2 female with chronic kidney disease, uveitis, and prior hysterectomy for benign disease presented with significant vaginal bleeding. Outpatient examination showed large fungating vaginal mass filling and nearly prolapsing through the vagina. Biopsy showed malignant melanoma (BRAF mutation negative and KIT mutation negative, variant of uncertain significance in JAK2). MRI pelvis revealed 6.3 × 6.5 × 9.2 cm anterior vaginal mass eroding into the posterior bladder (Fig 3A and 3B). Staging PET/CT showed disease in the vagina, retroperitoneal and pelvic nodes, and lungs, and a caudate liver lesion (Fig 3C).Fig. 3Case 2: Initial diagnostic scans. (A) axial T2-weighted MRI, (B) sagittal T2-weighted MRI, and (C) fused axial PET/CT. Abbreviations: MRI = magnetic resonance imaging; PET/CT = positron emission tomography/computed tomography.View Large Image Figure ViewerDownload Hi-res image Download (PPT)She was initiated on 200 mg flat-dose pembrolizumab every 3 weeks and referred for palliative RT after no significant improvement in her symptoms and worsening of the vaginal lesion after cycle 3. The patient underwent CT and MRI-simulation supine, frog-legged, in a Vac-Lok bag (Civco). Scans were performed with full bladder and empty rectum with magnesium citrate bowel preparation the night before. The GTV was delineated on fused MRI. The entire vaginal length was contoured as CTV and 0.3 cm expansion to make the PTV. The PTV was treated to 30 Gy in 5 fractions using 2 coplanar arcs respecting constraints indicated herein (Table 1). A hotspot of 114% was allowed but was placed in the GTV. Daily setup included full bladder and empty rectum with the same protocol used earlier for patient 1. Verification consisted of orthogonal pair alignment to bone and CBCT shift to match on the GTV. The patient continued on pembrolizumab during SBRT.By fraction 3, the patient noticed significantly decreased odor and bleeding. Two weeks posttreatment, her symptoms included grade 1 dermatitis in the medial thighs and groin and grade 1 diarrhea, which self-resolved. Six weeks posttreatment, restaging PET/CT showed complete metabolic response to all locoregional and distant sites of disease (Fig 4), indicating complete response locally and possible abscopal effect for distant disease. Local response was confirmed by pelvic examination. At 25 months after completion of RT and 29 months since diagnosis, the patient remains without evidence of disease on physical examination and PET/CT scan, and she continues on maintenance flat dose pembrolizumab. The patient has long-term grade 1 vaginal dryness attributable to radiation.Fig. 4Case 2: Follow-up axial fused PET/CT before (A) and after (B) irradiation demonstrating complete response in vaginal disease post SBRT. Air is noted in rectum in posttreatment scan. Abbreviations: PET/CT = positron emission tomography/computed tomography; SBRT = stereotactic body radiation therapy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)DiscussionWe present 2 cases of vaginal melanoma managed with multimodality IO and SBRT with or without surgical debulking. Both patients are alive and recurrence free after RT. The second patient demonstrated a possible abscopal effect where all distant disease regressed after treating the index vaginal lesion even as the patient was progressing on initial immunotherapy. Both women recovered from acute toxicities including grade 1 to 2 dermatitis. Of note, the potential for increased skin toxicity when combining RT and IO for vulvovaginal melanoma has been previously reported.21Mesko S Konecny GE Tumeh PC Kamrava M. Enhanced skin toxicity with concurrent ipilimumab and radiation in vaginal/vulvar melanoma: A case report and literature review.BJR Case Rep. 2017; 320160002Google ScholarMultimodality management for VM remains key given that 80% to 90% of VMs recur with variable patterns of failure depending on up-front management.8Frumovitz M Etchepareborda M Sun CC et al.Primary malignant melanoma of the vagina.Obstet Gynecol. 2010; 116: 1358-1365Google Scholar,9Bonner JA Perez-Tamayo C Reid GC Roberts JA Morley GW. The management of vaginal melanoma.Cancer. 1988; 62: 2066-2072Google Scholar,22St. Clair CM Wethington SL Eaton AA et al.Vulvar and vaginal melanomaࣧa single institutional experience 1995–2012.in: Presented at: 44th Annual Meeting on Women's Cancer, Los Angeles, CAMarch 2013Google Scholar With resection alone, locoregional and distant failures occurred in 45% and 55% of patients, respectively, whereas the addition of adjuvant RT was found to have 7% locoregional and 73% distant failures.8Frumovitz M Etchepareborda M Sun CC et al.Primary malignant melanoma of the vagina.Obstet Gynecol. 2010; 116: 1358-1365Google Scholar Effective therapies for recurrence are lacking, and evolving efforts focus on improving neoadjuvant and adjuvant therapies.Traditional cytotoxic chemotherapies play a limited role in melanoma treatment.12Leitao Jr, MM Cheng X Hamilton AL et al.Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas.Int J Gynecol Cancer. 2014; 24: S117-S122Google Scholar BRAF mutations are generally less often found in mucosal melanomas compared with cutaneous melanomas. Conversely, KIT mutations are generally more frequent. Neither of the previous patients harbored these mutations, and subsequently they were not candidates for targeted BRAF- or KIT-inhibitors.23Gutiérrez-Castañeda LD Nova JA Tovar-Parra JD. Frequency of mutations in BRAF, NRAS, and KIT in different populations and histological subtypes of melanoma: A systemic review.Melanoma Res. 2020; 30: 62-70Google Scholar Immunotherapy improves overall survival in cutaneous metastatic melanoma.24Hodi FS O'Day SJ McDermott DF et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Google Scholar Pooled analyses demonstrate durable responses of MM to pembrolizumab, ipilimumab, and nivolumab, though lower efficacy in mucosal compared with cutaneous melanomas.19Hamid O Robert C Ribas A et al.Antitumour activity of pembrolizumab in advanced mucosal melanoma: A post-hoc analysis of KEYNOTE-001, 002, 006.Br J Cancer. 2018; 119: 670-674Google Scholar,25SP D'Angelo Larkin J Sosman JA et al.Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: A pooled analysis.J Clin Oncol. 2017; 35: 226-235Google Scholar These pooled analyses do not break down MM by primary site, but several prospective single-center series demonstrate FGT mucosal melanoma response rates of 20% to 28.5% with IO.20Moya-Plana A Herrera Gómez RG Rossoni C et al.Evaluation of the efficacy of immunotherapy for non-resectable mucosal melanoma.Cancer Immunol Immunother. 2019; 68: 1171-1178Google Scholar,26Indini A Di Guardo L Cimminiello C Lorusso D Raspagliesi F Del Vecchio M. Investigating the role of immunotherapy in advanced/recurrent female genital tract melanoma: A preliminary experience.J Gynecol Oncol. 2019; 30: e94Google Scholar Recent results are encouraging with combination IO and RT for these patients.14Schiavone MB Broach V Shoushtari AN et al.Combined immunotherapy and radiation for treatment of mucosal melanomas of the lower genital tract.Gynecol Oncol Rep. 2016; 16: 42-46Google Scholar,27Kim HJ Chang JS Roh MR et al.Effect of radiotherapy combined with pembrolizumab on local tumor control in mucosal melanoma patients.Front Oncol. 2019; 9: 835Google ScholarExact mechanisms of interaction between IO and RT are incompletely characterized, though responses are attributed to potential synergistic immune modulation.28Barker CA Postow MA. Combinations of radiation therapy and immunotherapy for melanoma: A review of clinical outcomes.Int J Radiat Oncol Biol Phys. 2014; 88: 986-997Google Scholar,29Sharabi AB Lim M DeWeese TL Drake CG. Radiation and checkpoint blockade immunotherapy: Radiosensitisation and potential mechanisms of synergy.Lancet Oncol. 2015; 16: e498-e509Google Scholar Melanoma is relatively radioresistant with high intrinsic repair capacity at lower RT doses.30Barranco SC Romsdahl MM Humphrey RM. The radiation response of human malignant melanoma cells grown in vitro.Cancer Res. 1971; 31: 830-833Google Scholar, 31Shi W. Radiation therapy for melanoma.in: Ward WH Farma JM Cutaneous Melanoma: Etiology and Therapy. Codon Publications, Brisbane, Australia2017Google Scholar, 32Strojan P. Role of radiotherapy in melanoma management.Radiol Oncol. 2010; 44: 1-12Google Scholar With a low α/β ratio, hypofractionation with dose-escalation offers a theoretical advantage and improved local control of metastatic melanoma compared with conventional fractionation.33Stinauer MA Kavanagh BD Schefter TE et al.Stereotactic body radiation therapy for melanoma and renal cell carcinoma: Impact of single fraction equivalent dose on local control.Radiat Oncol. 2011; 6: 34Google Scholar Enhanced immunogenicity of SBRT is likely multifactorial, including cytoreductive effects in combination with release of tumor-associated antigens and modulation of the host immune system and tumor microenvironment.27Kim HJ Chang JS Roh MR et al.Effect of radiotherapy combined with pembrolizumab on local tumor control in mucosal melanoma patients.Front Oncol. 2019; 9: 835Google Scholar,34Luke JJ Lemons JM Karrison TG et al.Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors.J Clin Oncol. 2018; 36: 1611-1618Google Scholar, 35Postow MA Knox SJ Goldman DA et al.A prospective, phase 1 trial of nivolumab, ipilimumab, and radiotherapy in patients with advanced melanoma.Clin Cancer Res. 2020; 26: 3193-3201Google Scholar, 36Twyman-Saint Victor C Rech AJ Maity A et al.Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.Nature. 2015; 520: 373-377Google Scholar, 37Cushman TR Gomez D Kumar R et al.Combining radiation plus immunotherapy to improve systemic immune response.J Thorac Dis. 2018; 10: S468-S479Google ScholarWhen considering focal RT, heterogeneity exists in RT regimens with variable target and nodal coverage, sequencing, external beam versus brachytherapy, treatment technique, dosing, fractionation, and image guidance.9Bonner JA Perez-Tamayo C Reid GC Roberts JA Morley GW. The management of vaginal melanoma.Cancer. 1988; 62: 2066-2072Google Scholar,13Petru E Nagele F Czerwenka K et al.Primary malignant melanoma of the vagina: Long-term remission following radiation therapy.Gynecol Oncol. 1998; 70: 23-26Google Scholar,14Schiavone MB Broach V Shoushtari AN et al.Combined immunotherapy and radiation for treatment of mucosal melanomas of the lower genital tract.Gynecol Oncol Rep. 2016; 16: 42-46Google Scholar,38McGuire SE Frank SJ Eifel PJ. Treatment of recurrent vaginal melanoma with external beam radiation therapy and palladium-103 brachytherapy.Brachytherapy. 2008; 7: 359-363Google Scholar In the series by Schiavone et al, both neoadjuvant SBRT and conventionally fractionated RT were used.14Schiavone MB Broach V Shoushtari AN et al.Combined immunotherapy and radiation for treatment of mucosal melanomas of the lower genital tract.Gynecol Oncol Rep. 2016; 16: 42-46Google Scholar McGuire et al reported complete local remission following salvage external beam and interstitial brachytherapy boost.38McGuire SE Frank SJ Eifel PJ. Treatment of recurrent vaginal melanoma with external beam radiation therapy and palladium-103 brachytherapy.Brachytherapy. 2008; 7: 359-363Google Scholar In addition to conventionally fractionated approaches, when considering elective coverage of pelvic or inguinal lymph nodes, we note the safety and precedence for hypofractionated RT in the setting of short-course neoadjuvant RT for rectal cancer.39Ngan SY Burmeister B Fisher RJ et al.Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04.J Clin Oncol. 2012; 30: 3827-3833Google Scholar The incidence of occult nodal involvement is not well known, and risks of pelvic or inguinal coverage should be considered in the context of potential benefit.Technical considerations for SBRT in both cases include the coregistration of pelvic MRI simulation with contrast both preimmunotherapy and postimmunotherapy to delineate initial and residual disease extent. Given the high conformality of SBRT in combination with volumetric and maximum dose constraints of the bladder and rectum (Table 1), both patients were treated with full bladders and empty rectums (similar to prostate SBRT). Based on our experience, a daily empty rectum was the most critical variable to overcome. CTV included the entire length of the residual vagina, given the multifocal nature of disease and that even higher doses subject the distal vagina to toxicity. A PTV margin of 3 mm was used with alpha cradle or Vac-Lok and with daily CBCT.Considering the rarity of vaginal melanomas, their poor outcomes, and limited evidence with treatment variability, we encourage multidisciplinary management discussions. The incorporation of IO, surgery, and ultrahypofractionated RT appears safe and effective in this case report. Further high-quality prospectively collected evidence is needed to guide recommendations for optimal RT approaches, particularly when combined with IO.ConclusionsStereotactic body radiation therapy with concurrent immunotherapy with or without surgical debulking was a safe and effective treatment option for local therapy for vaginal melanoma while on systemic therapy. In this rare disease entity, multidisciplinary discussions should consider this approach in select patients with good performance status and localized disease. Patients with vaginal melanoma should also be encouraged to enroll on clinical trials. IntroductionMucosal melanomas represent 1.3% of all melanomas. Of those, 18% arise within the female genital tract (FGT).1Chang AE Karnell LH Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society.Cancer. 1998; 83: 1664-1678Google Scholar,2Patrick RJ Fenske NA Messina JL. Primary mucosal melanoma.J Am Acad Dermatol. 2007; 56: 828-834Google Scholar Unique molecular profiles were identified for vulvar and vaginal melanomas (VM) compared with nongynecologic melanomas, suggesting mucosal melanomas (MM) of the FGT represent a distinct melanoma subtype.3Hou JY Baptiste C Hombalegowdaet RB et al.Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma.Cancer. 2017; 123: 1333-1344Google Scholar Vaginal melanomas are particularly rare, making up only 19.8% of FGT melanomas compared with vulvar primaries (76.7%).4McLaughlin CC Wu X-C Jemal A Martin HJ Roche LM Chen VW. Incidence of noncutaneous melanomas in the U.S.Cancer. 2005; 103: 1000-1007Google Scholar Although no formal staging system exists for VM, clinical staging from cutaneous melanomas has been adapted as follows: localized (stage I), lymph node involvement (stage II), disseminated disease (stage III).5Ballantyne AJ. Malignant melanoma of the skin of the head and neck. An analysis of 405 cases.Am J Surg. 1970; 120: 425-431Google Scholar Tumor size and lymph node involvement have been correlated with survival in vaginal melanoma.2Patrick RJ Fenske NA Messina JL. Primary mucosal melanoma.J Am Acad Dermatol. 2007; 56: 828-834Google Scholar,6Buchanan DJ Schlaerth J Kurosaki T. Primary vaginal melanoma: Thirteen-year disease-free survival after wide local excision and review of recent literature.Am J Obstet Gynecol. 1998; 178: 1177-1184Google Scholar, 7Reid GC Schmidt RW Roberts JA Hopkins MP Barrett RJ Morley GW. Primary melanoma of the vagina: A clinicopathologic analysis.Obstet Gynecol. 1989; 74: 190-199Google Scholar, 8Frumovitz M Etchepareborda M Sun CC et al.Primary malignant melanoma of the vagina.Obstet Gynecol. 2010; 116: 1358-1365Google Scholar Unfortunately, VM has a poor overall prognosis, with 5-year overall survival rates of 5% to 25%.9Bonner JA Perez-Tamayo C Reid GC Roberts JA Morley GW. The management of vaginal melanoma.Cancer. 1988; 62: 2066-2072Google Scholar,10Piura B Rabinovich A Yanai-Inbar I. Primary malignant melanoma of the vagina: Case report and review of literature.Eur J Gynaecol Oncol. 2002; 23: 195-198Google Scholar These poor outcomes are attributed to occult location, often multifocal disease with surrounding atypia, advanced disease in close proximity to critical anatomic pelvic structures, and rich submucosal lymphovascular channels with predilection for nodal spread.2Patrick RJ Fenske NA Messina JL. Primary mucosal melanoma.J Am Acad Dermatol. 2007; 56: 828-834Google Scholar,11Lotem M Anteby S Peretz T Ingber A Avinoach I Prus D. Mucosal melanoma of the female genital tract is a multifocal disorder.Gynecol Oncol. 2003; 88: 45-50Google ScholarGiven the rarity of VM and paucity of data, optimal management remains in question.6Buchanan DJ Schlaerth J Kurosaki T. Primary vaginal melanoma: Thirteen-year disease-free survival after wide local excision and review of recent literature.Am J Obstet Gynecol. 1998; 178: 1177-1184Google Scholar,12Leitao Jr, MM Cheng X Hamilton AL et al.Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas.Int J Gynecol Cancer. 2014; 24: S117-S122Google Scholar Retrospective analyses combined with data extrapolated from cutaneous or other MM guide current recommendations regarding surgical, systemic, and radiation therapies (RTs). Primary surgical resection via wide local excision with negative margins is preferred, though the survival benefit of surgery has been debated.6Buchanan DJ Schlaerth J Kurosaki T. Primary vaginal melanoma: Thirteen-year disease-free survival after wide local excision and review of recent literature.Am J Obstet Gynecol. 1998; 178: 1177-1184Google Scholar,13Petru E Nagele F Czerwenka K et al.Primary malignant melanoma of the vagina: Long-term remission following radiation therapy.Gynecol Oncol. 1998; 70: 23-26Google Scholar Advanced tumor size, multifocal disease, and proximity to bladder, urethra, rectum, and anus increase the technical challenge of achieving R0 surgical margin. Extensive radical surgery to achieve wider margins has not improved survival, and recommendations for pelvic and/or inguinal staging are lacking.12Leitao Jr, MM Cheng X Hamilton AL et al.Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas.Int J Gynecol Cancer. 2014; 24: S117-S122Google Scholar,14Schiavone MB Broach V Shoushtari AN et al.Combined immunotherapy and radiation for treatment of mucosal melanomas of the lower genital tract.Gynecol Oncol Rep. 2016; 16: 42-46Google Scholar,15Leitao Jr., MM Management of vulvar and vaginal melanomas: current and future strategies.Am Soc Clin Oncol Educ Book. 2014; 34: e277-e281Google Scholar Despite aggressive multimodality therapy including primarily surgical management with or without adjuvant RT, outcomes remain poor for VM with high rates of distant recurrence.1Chang AE Karnell LH Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society.Cancer. 1998; 83: 1664-1678Google Scholar,8Frumovitz M Etchepareborda M Sun CC et al.Primary malignant melanoma of the vagina.Obstet Gynecol. 2010; 116: 1358-1365Google Scholar,9Bonner JA Perez-Tamayo C Reid GC Roberts JA Morley GW. The management of vaginal melanoma.Cancer. 1988; 62: 2066-2072Google Scholar,15Leitao Jr., MM Management of vulvar and vaginal melanomas: current and future strategies.Am Soc Clin Oncol Educ Book. 2014; 34: e277-e281Google Scholar, 16Gökaslan H Sişmanoğlu A Pekin T Kaya H Ceyhan N. Primary malignant melanoma of the vagina: A case report and review of the current treatment options.Eur J Obstet Gynecol Reprod Biol. 2005; 121: 243-248Google Scholar, 17Garbe C Peris K Hauschild A et al.Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guidelineࣧupdate 2016.Eur J Cancer. 2016; 63: 201-217Google Scholar Immunotherapy (IO) shows promise in treating MM with objective response rates of ∼20% and ∼75% of responders with some degree of durable response.18Yentz S Lao CD. Immunotherapy for mucosal melanoma.Ann Transl Med. 2019; 7: S118Google Scholar, 19Hamid O Robert C Ribas A et al.Antitumour activity of pembrolizumab in advanced mucosal melanoma: A post-hoc analysis of KEYNOTE-001, 002, 006.Br J Cancer. 2018; 119: 670-674Google Scholar, 20Moya-Plana A Herrera Gómez RG Rossoni C et al.Evaluation of the efficacy of immunotherapy for non-resectable mucosal melanoma.Cancer Immunol Immunother. 2019; 68: 1171-1178Google Scholar Therefore, treatment selection is challenging given the need to balance the morbidity of local therapies with the propensity for distant metastatic disease and overall poor outcomes.Within this context, improvements in both local and systemic therapy are needed. We present 2 cases of vaginal melanoma treated at different comprehensive cancer centers using a multimodality approach of IO and stereotactic body radiation therapy (SBRT) with or without surgical debulking, and review current management controversies.