We report a case of rapidly enlarging metastatic melanoma in 45-year-old White male following primary resection of thin melanoma five years ago. Location and large size of the lesion possessed significant risk of complications from surgery, therefore provided a challenge in treatment options. Neoadjuvant targeted chemotherapy was commenced and resulted in a significant reduction in size of the lesion, which allowed subsequent safe surgical resection with no residual disease on histopathology results. This case provides a good example of successful utilization of neoadjuvant systemic therapy in advanced metastatic melanoma

Alsaadi, D

Gabuniya, N

Geh, J

Khajuria, A

Annals of Medicine and Surgery

English

Spiral - Imperial College Digital Repository

Contents lists available at ScienceDirectAnnals of Medicine and Surgeryjournal homepage: www.elsevier.com/locate/amsuCase report: Neoadjuvant systemic therapy for melanomaNatiya Gabuniyaa,∗, Ankur Khajuriaa,b, Jenny L.C. Geha, Daniah AlsaadicaGuy's and St Thomas NHS Foundation Trust, United Kingdomb Imperial College London, United KingdomcUniversity College London, United KingdomA R T I C L E I N F OKeywords:Case reportAdvanced metastatic melanomaNeoadjuvant systemic therapySkin cancerA B S T R A C TWe report a case of rapidly enlarging metastatic melanoma in 45-year-old White male following primary re-section of thin melanoma five years ago. Location and large size of the lesion possessed significant risk ofcomplications from surgery, therefore provided a challenge in treatment options. Neoadjuvant targeted che-motherapy was commenced and resulted in a significant reduction in size of the lesion, which allowed sub-sequent safe surgical resection with no residual disease on histopathology results. This case provides a goodexample of successful utilization of neoadjuvant systemic therapy in advanced metastatic melanoma.1. IntroductionMelanoma accounts for 4% of all new cancer cases and is the 5thmost common cancer in the UK. Incidence rates are increasing in mostEuropean countries and around the world. Prognosis for high-riskmelanomas remains poor. Although surgical resection remains a keytreatment for stages I-IIIb melanomas, it doesn't improve survival ratesalone and has a minimal role in treating advanced regional and distantmetastatic disease. The therapeutic value of completion lymphade-nectomy following a positive sentinel lymph node biopsy (SLNB) cur-rently remains questionable. New guidance has been published to allowsystemic therapy or observation with close follow up following positivesentinel node biopsy (Melanoma focus and JPRAS publication Peachet al.). Sentinel node biopsy is the most important staging tool for stageIB to II patients. The management of advanced melanoma has improvedsignificantly following introduction of systemic therapies.Neoadjuvant therapy has shown to aid surgical resection and con-trol disease where tumors were previously inoperable. Effectiveness oftreatment can be assessed preoperatively by monitoring tumor responseand postoperatively by examining resected tissue sample. At the mo-ment neoadjuvant therapy for high-risk melanomas can be consideredfor irresectable disease, but lately advances of immunotherapy arebeing incorporated to neoadjuvant phase I and II trials [1]. This clinicalcase report provides a good example of successful resection and out-come following neoadjuvant chemotherapy.2. MethodsRetrospective overview of clinical case of one patient with rapidlyenlarging advanced metastatic melanoma that had a successful outcomefollowing neoadjuvant chemotherapy and subsequent surgical resec-tion. This clinical case is compliant and reported in line with SCARE2018 criteria [2].3. Case reportIn October 2014, a 46-year-old White male presented to clinic withrecent history of rapidly growing, painful swelling in left axilla. He wasreferred by his GP to Melanoma clinic in view that in February 2010 hehad a wide local excision of malignant melanoma on his right upperback with 0.72mm Breslow thickness. Swelling in the axilla has beenpresent for 3 months, and he first noticed it during game of tennis. Onpresentation the patient was systemically well and had no co-morbid-ities, no other past medical history and no family history of melanoma,however he reported occasional prolonged sun exposure during holi-days and mild sun burns in the past. He is a non-smoker and alcoholconsumption was mild.On examination he had a 10 cm firm swelling under left axilla withno obvious surface skin changes. There was no other palpable lym-phadenopathy.An ultrasound and fine needle aspiration (FNA) of the mass, con-firmed metastatic melanoma with a BRAF V600E mutation. He under-went further scanning to identify any other lesions. Results of brain MRIwere normal and PET-CT showed a large FDG avid axillary mass (Fig. 1)https://doi.org/10.1016/j.amsu.2020.05.013Received 26 February 2020; Received in revised form 6 May 2020; Accepted 8 May 2020∗ Corresponding author.E-mail address: natigab@doctors.org.uk (N. Gabuniya).Annals of Medicine and Surgery 55 (2020) 177–1792049-0801/ Crown Copyright © 2020 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).Tlikely to represent a lymph node with no metabolically active primarylesion.Given the size and location of the mass, it was not amenable for safesurgical resection without significant risk of morbidity. It was decidedto commence systemic treatment with the BRAF inhibitor, Dabrafenib.Four month following commencement of systemic therapy therewas a significant reduction in size of the lesion that made it suitable andsafe for surgical resection. Patient was scheduled on the elective list foraxillary node clearance and was operated by Consultant Plastic sur-geon, procedure was uncomplicated and patient was discharged homethe following day. Specimen was sent to histopathology laboratory andsubsequently been reported as no malignancy. This was a completeresponse to Dabrafenib. It was decided to continue with Dabrafenib tocomplete a full year of therapy.Patient was regularly followed up in Oncology and Plastic surgeryclinics and had yearly PET-CT scans (Figs. 2 and 3) that showed nometastatic disease. Overall recovery was smooth and uncomplicated.Following 2 years of remission, the patient re-presented with apalpable infraclavicular lymph node. Lesion was small and amenablefor surgical excision, following surgical procedure patient completed acourse of radiotherapy.Currently, the patient is completing systemic therapy withPembrolizumab without any toxic side effects. He continues to be inremission with negative follow up scans.4. DiscussionNeoadjuvant therapy has proven to aid surgical resection of tumorsand provide better local control. It helps to adopt more specific therapyapproach by monitoring the response of malignancy to therapy pre andpost operatively.Recently established treatments for advanced and metastatic mela-noma with BRAF V600 E targeted therapy and CTLA-4 immunotherapyshowed dramatic and favorable results [3,4]. The current trials areongoing.There are several neoadjuvant therapy trials being conducted thatinclude immunotherapy, anti-CTLA-4 antibody, BRAF and MEK in-hibitors, anti-PD1 antibodies and tamilogene laherparepvec (T-VEC).REDuCTOR trial phase II in Netherlands, is a single center trial thatevaluated the outcome of neoadjuvant therapy in patients with pri-marily unresectable BRAF positive advanced melanoma to aid surgicalresection [5]. This approach is different as reduction in tumor size isnecessary for resection. Primary outcome measure of this trial includesnumber of patient in whom resection was made possible by the therapy.Combi-Neo is a randomized control trial that is comparing dabra-fenib and trametinib therapy prior surgery versus surgical resectionalone in BRAF mutation positive stage III and IV melanoma.(NCT02231775) [6]. Phase II of this trial will evaluate outcome of 1year relapse free survival.Neo Trio study in Melanoma Institute of Australia is evaluatingdifferent therapy combinations with dabrafenib, trametinib and pem-brolizumab in BRAF positive stage III melanoma (NCT 02858921) [7].This aims to evaluate whether 3-drug combination provides better re-duction in size of the advance melanoma tumor and prevents recur-rence post operatively. Outcome of the trial is not yet published.At the moment there are few published data on survival rates ofpatients managed with systemic therapy and surgery but reports arepromising.Response to neoadjuvant chemotherapy may identify responderpopulations in stage III or oligometastatic stage IV melanoma that maybenefit from surgery, and who previously may have been palliated,additionally it can potentially spare surgery for advanced non-re-sponders. Surgical resection following neoadjuvant systemic therapycan serve in evaluating the histological responsiveness to therapy. Thiscan help individualize systemic regimens for patients based on theirFig. 1. Pre-operative PET scan in 2014.Fig. 2. Post-operative scan PET scan in 2015.Fig. 3. Follow-up post-operative PET scan in 2016.N. Gabuniya, et al. Annals of Medicine and Surgery 55 (2020) 177–179178individual response.Our case provides a good example of favorable outcome of neoad-juvant systemic therapy metastatic melanoma. We have since seen anumber of other patients in whom bulky or highly co-morbid resectionhas been downgraded to a lower risk surgical procedure with the aid ofneo-adjuvant systemic therapies.5. ConclusionIn the last decade establishment of systemic therapies has drama-tically improved survival rates of advanced melanoma. Although sur-gery remains a cornerstone of treatment, recent trials and early reportsof neoadjuvant and adjuvant therapies has proven to play a crucial rolein the management of advanced regional and metastatic melanoma.Neoadjuvant chemotherapy can aid respectability of melanomas toimprove local control and decrease surgical morbidity. Surgery con-tinues to have a useful role in controlling disease in both early and latestages of melanoma. Surgical resection following neoadjuvant systemictherapy can serve in evaluating the histological responsiveness totherapy. In the future this can help individualize systemic regimens forpatients based on their individual response and improve treatmentoutcomes.Provenance and peer reviewNot commissioned, externally peer reviewed.Ethical approvalNot applicable – not a research.Source of fundingFunding is available from Imperial College LondonAuthor contributionDr Natiya Gabuniya – data and results analysis, writing case report,report concept and design.Mr. Ankur Khajuria, Ms. Jenny Geh, Dr Mark Harris – data collec-tion, data analysis.Dr Daniah Alsaadi – help in organizing the report.Registration of research studies1. Name of the registry2. Unique Identifying number or registration ID3. Hyperlink to the registration (must be publicly accessible)GuarantorDr Natiya Gabuniya.Ms Jenny Geh.Mr Ankur Khajuria.Declaration of competing interestNothing to disclose.Appendix A. Supplementary dataSupplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2020.05.013.References[1] M.C.T. van Zeijl, A.J. van den Eertwegh, J.B. Haanen, M.W.J.M. Wouters, (Neo)ad-juvant systemic therapy for melanoma, [Internet], Eur. J. Surg. Oncol. 43 (2017)W.B. Saunders Ltd[cited 2020 Feb 26]. pp. 534–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27453302.[2] R.A. Agha, M.R. Borrelli, R. Farwana, K. Koshy, A.J. Fowler, D.P. Orgill, et al., TheSCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guide-lines, Int. J. Surg. 60 (2018 Dec 1) 132–136.[3] P.B. Chapman, A. Hauschild, C. Robert, J.B. Haanen, P. Ascierto, J. Larkin, et al.,Improved survival with vemurafenib in melanoma with BRAF V600E mutation,[Internet], N. Engl. J. Med. (2011 Jun 30) [cited 2020 Feb 26];364(26):2507–16.Available from: http://www.ncbi.nlm.nih.gov/pubmed/21639808.[4] F.S. Hodi, S.J. O'Day, D.F. McDermott, R.W. Weber, J.A. Sosman, J.B. Haanen, et al.,Improved survival with ipilimumab in patients with metastatic melanoma, N. Engl. J.Med. 363 (8) (2010 Aug 19) 711–723.[5] S.A. Blankenstein, M.W. Rohaan, W.M.C. Klop, B. Van Der Hiel, B.A. Van De Wiel,D.S. Peeper, et al., Neoadjuvant cytoreductive treatment with BRAF/MEK inhibitionof prior unresectable regionally advanced melanoma to allow complete surgical re-section: REDUCTOR trial, J. Clin. Oncol. 37 (15_suppl) (2019 May 20) 9587–9587.[6] R.N. Amaria, P.A. Prieto, M.T. Tetzlaff, A. Reuben, M.C. Andrews, M.I. Ross, et al.,Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care inpatients with high-risk, surgically resectable melanoma: a single-centre, open-label,randomised, phase 2 trial, Lancet Oncol. 19 (2) (2018 Feb 1) 181–193.[7] Neoadjuvant Dabrafenib, Trametinib and/or pembrolizumab in BRAF mutant re-sectable stage III melanoma - full text view - ClinicalTrials.gov, [Internet]. [cited2020 Feb 26]. Available from: https://clinicaltrials.gov/ct2/show/NCT02858921.N. Gabuniya, et al. Annals of Medicine and Surgery 55 (2020) 177–179179

Case report: Neoadjuvant systemic therapy for melanoma

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Case report: Neoadjuvant systemic therapy for melanoma

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