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

• DOI: 10.1016/j.adro.2021.100839
• Publication Date: 2021-10-28T18:31:41Z
• Authors: Caitlin A. Schone...; Elizabeth M. Jawo...; Steven G. Allen; Karen McLean; Christopher D. Lao; Lynn M. Schuchter; Janos Tanyi; Neil K. Taunk
• Keywords: Mucosal melanoma; Vulvar neoplasm

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