{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:01:33Z","timestamp":1790402493011,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,31]],"date-time":"2021-10-31T00:00:00Z","timestamp":1635638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background. Isolated limb perfusion (ILP) is a locoregional procedure indicated by the unresectable melanoma of the limbs. Its complexity and highly demanding multidisciplinary approach means that it is a technique only implemented in a few referral centers around the globe. This report aims to examine its potential role in the era of targeted therapies and immunotherapy by conducting a systematic review of the literature on ILP. Methods. PubMed, Embase and Cochrane Library were searched. The eligibility criteria included publications from 2000\u20132020 providing valid data o effectiveness, survival or toxicity. Studies in which the perfusion methodology was not clearly described, letters to the editor, non-systematic reviews and studies that applied outdated clinical guidelines were excluded. To rule out studies of a low methodological quality and assess the risk of bias, the following aspects were also required: a detailed description of the applied ILP regimen, the clinical context, follow-up periods, analyzed clinical endpoints, and the number of analyzed ILPs. The disagreements were resolved by consensus. The results are presented in tables and figures. Results. Twenty-seven studies including 2637 ILPs were selected. The median overall response rate was 85%, with a median complete response rate of 58.5%. The median overall survival was 38 months, with a 5-year overall survival of 35%. The toxicity was generally mild according to Wieberdink toxicity criteria. Discussion. ILP still offer a high efficacy in selected patients. The main limitation of our review is the heterogeneity and age of most of the articles, as well as the absence of clinical trials comparing ILP with other procedures, making it difficult to transfer its results to the current era. Conclusions. ILP is still an effective and safe procedure for selected patients with unresectable melanoma of the limbs. In the era of targeted therapies and immunotherapy, ILP remains an acceptable and reasonable palliative treatment alternative, especially to avoid limb amputations. The ongoing clinical trials combining systemic therapies and ILP will provide more valuable information in the future to clarify the potential synergism of both strategies.<\/jats:p>","DOI":"10.3390\/cancers13215485","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T22:21:08Z","timestamp":1635805268000},"page":"5485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Role of Isolated Limb Perfusion in the Era of Targeted Therapies and Immunotherapy in Melanoma. A Systematic Review of The Literature"],"prefix":"10.3390","volume":"13","author":[{"given":"Lourdes","family":"Sevilla-Ortega","sequence":"first","affiliation":[{"name":"Clinical Oncology Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Ferr\u00e1ndiz-Pulido","sequence":"additional","affiliation":[{"name":"Dermatology Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Palaz\u00f3n-Carri\u00f3n","sequence":"additional","affiliation":[{"name":"Clinical Oncology Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda del Carmen","family":"\u00c1lamo de la Gala","sequence":"additional","affiliation":[{"name":"Clinical Oncology Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"de Toro-Salas","sequence":"additional","affiliation":[{"name":"Clinical Oncology Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Garnacho-Montero","sequence":"additional","affiliation":[{"name":"Intensive Care Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Antonio","family":"Marcos-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Pharmacy Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Agudo Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Radiopharmacy Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Araji-Tiliani","sequence":"additional","affiliation":[{"name":"Cardiovascular Surgery Department, Heart Area, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Cinta","family":"Calvo-Mor\u00f3n","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Miguel","family":"Barquero-Aroca","sequence":"additional","affiliation":[{"name":"Cardiovascular Surgery Department, Heart Area, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio Ram\u00f3n","family":"Fern\u00e1ndez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Anesthesiology and Reanimation Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Mar\u00eda","family":"Jaime-Borrego","sequence":"additional","affiliation":[{"name":"Cardiovascular Surgery Department, Heart Area, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Santos-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Cardiovascular Surgery Department, Heart Area, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Moreno-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Dermatology Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5333-0535","authenticated-orcid":false,"given":"Luis","family":"de la Cruz-Merino","sequence":"additional","affiliation":[{"name":"Clinical Oncology Department, Universitary Hospital Virgen Macarena, 41003 Seville, Spain"},{"name":"Medicine Department, Universidad de Sevilla, 41003 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,31]]},"reference":[{"key":"ref_1","unstructured":"(2021, May 10). GLOBOCAN. Available online: https:\/\/gco.iarc.fr\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1245\/ASO.2005.05.025","article-title":"Predictors and Natural History of In-Transit Melanoma After Sentinel Lymphadenectomy","volume":"12","author":"Pawlik","year":"2005","journal-title":"Ann. Surg. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101672","DOI":"10.1016\/j.ejon.2019.101672","article-title":"Patient experiences with isolated limb perfusion for malignant melanoma \u2014A qualitative study","volume":"43","author":"Ekenberg","year":"2019","journal-title":"Eur. J. Oncol. Nurs."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1097\/00000658-195810000-00009","article-title":"Chemotherapy of Cancer","volume":"148","author":"Creech","year":"1958","journal-title":"Ann. Surg."},{"key":"ref_5","first-page":"157","article-title":"Regional perfusion treatment with melphalan for melanoma in a limb: An evaluation of drug kinetics","volume":"14","author":"Benckhuijsen","year":"1988","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1001\/jama.1959.03000210033008","article-title":"Treatment of malignant melanoma by isolation perfusion technique","volume":"169","author":"Creech","year":"1959","journal-title":"J. Am. Med. Assoc."},{"key":"ref_7","first-page":"305","article-title":"Hyperthermic perfusion with chemotherapy for cancers of the extremities","volume":"129","author":"Stehlin","year":"1969","journal-title":"Surg. Gynecol. Obs."},{"key":"ref_8","first-page":"1357","article-title":"The success of TNF alpha in isolated limb perfusion for irresectable extremity soft tissue sarcomas, melanoma and carcinomas: Observations in patients and preclinical perfusion models","volume":"23","author":"Eggermont","year":"1996","journal-title":"Gan Kagaku Ryoho."},{"key":"ref_9","first-page":"51","article-title":"Isolated limb infusion (ILI) with melphalan for recurrent limb melanoma","volume":"6","author":"Thompson","year":"1993","journal-title":"Reg. Cancer Treat"},{"key":"ref_10","first-page":"21","article-title":"Isolated perfusion of the limb with high-dose tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and melphalan for melanoma stage III. Results of a multi-centre pilot study","volume":"1","author":"Eggermont","year":"1994","journal-title":"Melanoma Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/1097-0142(19940115)73:2<483::AID-CNCR2820730238>3.0.CO;2-S","article-title":"Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gamma-interferon, and melphalan","volume":"73","author":"Vaglini","year":"1994","journal-title":"Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1200\/JCO.1996.14.2.479","article-title":"Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: Results of a tumor necrosis factor dose-escalation study","volume":"14","author":"Fraker","year":"1996","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1097\/00008390-199910000-00009","article-title":"Isolated limb perfusion with tumour necrosis factor-\u03b1 and melphalan with or without interferon-\u03b3; for the treatment of in-transit melanoma metastases: A multicentre randomized phase II study","volume":"9","author":"Eggermont","year":"1999","journal-title":"Melanoma Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/jnci\/92.3.205","article-title":"New guidelines to evaluate the response to treatment in solid tumors. European Organization for Re- search and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada","volume":"92","author":"Therasse","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ejca.2016.03.081","article-title":"RECIST 1.1-Update and clarification: From the RECIST committee","volume":"62","author":"Schwartz","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/0277-5379(82)90235-8","article-title":"Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions","volume":"18","author":"Wieberdink","year":"1982","journal-title":"Eur. J. Cancer Clin. Oncol."},{"key":"ref_17","unstructured":"National Cancer Institute (2003). Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE), DCTD. NCI, NIH, DHHS."},{"key":"ref_18","unstructured":"(2021, May 10). Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE). Publised: 28 May 2009 (v4.03: 14 June 2010) by National Cancer Institute, Available online: http:\/\/evs.nci.nih.gov\/ftp1\/CTCAE\/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf."},{"key":"ref_19","unstructured":"(2021, May 10). Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE). Publised: 27 November 2017 by National Cancer Institute, Available online: https:\/\/ctep.cancer.gov\/protocoldevelopment\/electronic_applications\/docs\/CTCAE_v5_Quick_Reference_5x7.pdf."},{"key":"ref_20","unstructured":"World Health Organisation (1979). WHO Handbook for Reporting Results of Cancer Treatment, World Health Organisation."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4196","DOI":"10.1200\/JCO.2005.05.5152","article-title":"Randomized Multicenter Trial of Hyperthermic Isolated Limb Perfusion With Melphalan Alone Compared With Melphalan Plus Tumor Necrosis Factor: American College of Surgeons Oncology Group Trial Z0020","volume":"24","author":"Cornett","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1245\/s10434-007-9791-z","article-title":"TNF-Based Isolated Limb Perfusion Followed by Consolidation Biotherapy with Systemic Low-dose Interferon Alpha 2b in Patients with In-transit Melanoma Metastases: A Pilot Trial","volume":"15","author":"Rossi","year":"2008","journal-title":"Ann. Surg. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/jso.23168","article-title":"Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity melanoma","volume":"107","author":"Papadia","year":"2013","journal-title":"J. Surg. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1245\/ASO.2005.03.060","article-title":"Efficacy of Repeat Isolated Limb Perfusions With Tumor Necrosis Factor \u03b1 and Melphalan for Multiple In-Transit Metastases in Patients with Prior Isolated Limb Perfusion Failure","volume":"12","author":"Brunstein","year":"2005","journal-title":"Ann. Surg. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.ejso.2005.10.009","article-title":"Repeat isolated limb perfusion with TNF\u03b1 and melphalan for recurrent limb melanoma after failure of previous perfusion","volume":"32","author":"Noorda","year":"2006","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1097\/CMR.0000000000000177","article-title":"Repeated isolated limb perfusion in melanoma patients with recurrent in-transit metastases","volume":"25","author":"Deroose","year":"2015","journal-title":"Melanoma Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1245\/s10434-018-07143-4","article-title":"Response and Toxicity of Repeated Isolated Limb Perfusion (re-ILP) for Patients With In-Transit Metastases of Malignant Melanoma","volume":"26","author":"Belgrano","year":"2019","journal-title":"Ann. Surg. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1200\/JCO.2009.23.7511","article-title":"Analysis of Factors Influencing Outcome in Patients With In-Transit Malignant Melanoma Undergoing Isolated Limb Perfusion Using Modern Treatment Parameters","volume":"28","author":"Jr","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1245\/s10434-018-6459-9","article-title":"The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion","volume":"25","author":"Katsarelias","year":"2018","journal-title":"Ann. Surg. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1245\/s10434-017-5803-9","article-title":"Isolated Limb Perfusion for Melanoma is Safe and Effective in Elderly Patients","volume":"24","author":"Madu","year":"2017","journal-title":"Ann. Surg. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/jso.23552","article-title":"Isolated limb perfusion for in-transit melanoma metastases: Melphalan or TNF-melphalan perfusion?","volume":"109","author":"Hoekstra","year":"2014","journal-title":"J. Surg. Oncol."},{"key":"ref_32","first-page":"A4741","article-title":"Tumour response after hyperthermic isolated limb perfusion for locally advanced melanoma","volume":"61","author":"Paulsen","year":"2014","journal-title":"Dan. Med. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"551","DOI":"10.3109\/02656736.2013.802374","article-title":"Long-term follow-up of 163 consecutive patients treated with isolated limb perfusion for in-transit metastases of malignant melanoma","volume":"29","author":"Olofsson","year":"2013","journal-title":"Int. J. Hyperth."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1245\/s10434-011-2030-7","article-title":"20 Years Experience of TNF-Based Isolated Limb Perfusion for In-Transit Melanoma Metastases: TNF Dose Matters","volume":"19","author":"Deroose","year":"2012","journal-title":"Ann. Surg. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1002\/bjs.7621","article-title":"Long-term outcome of isolated limb perfusion with tumour necrosis factor-\u03b1 for patients with melanoma in-transit metastases","volume":"98","author":"Deroose","year":"2011","journal-title":"BJS"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/jso.21949","article-title":"Results of isolated lower limb perfusion for loco-regional advanced\/recurrent melanoma using borderline true hyperthermia plus additional bolus of melphalan. A critical analysis of homogeneous cases","volume":"104","author":"Pace","year":"2011","journal-title":"J. Surg. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.1245\/s10434-010-1104-2","article-title":"Long-Term Results of Melphalan-Based Isolated Limb Perfusion With or Without Low-Dose TNF for In-Transit Melanoma Metastases","volume":"17","author":"Rossi","year":"2010","journal-title":"Ann. Surg. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3109\/02656730903236086","article-title":"Long-term outcome of hyperthermic isolated limb perfusion (HILP) in the treatment of locoregionally metastasised malignant melanoma of the extremities","volume":"26","author":"Boesch","year":"2010","journal-title":"Int. J. Hyperth."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.ejso.2005.09.007","article-title":"Hyperthermic isolated limb perfusion (HILP) in malignant melanoma. Experience with 101 patients","volume":"32","author":"Knorr","year":"2006","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1001\/archsurg.140.11.1115","article-title":"Predictors of outcome after hyperthermic isolated limb perfusion: Role of tumor response","volume":"140","author":"Aloia","year":"2005","journal-title":"Arch. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1097\/01.sla.0000146147.89667.ed","article-title":"One Hundred Consecutive Isolated Limb Perfusions With TNF-\u03b1 and Melphalan in Melanoma Patients With Multiple In-Transit Metastases","volume":"240","author":"Brunstein","year":"2004","journal-title":"Ann. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1245\/ASO.2004.03.019","article-title":"Hyperthermic Isolated Limb Perfusion With Low-Dose Tumor Necrosis Factor-\u03b1 and Melphalan for Bulky In-Transit Melanoma Metastases","volume":"11","author":"Rossi","year":"2004","journal-title":"Ann. Surg. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1001\/archsurg.139.11.1237","article-title":"Isolated Limb Perfusion for Unresectable Melanoma of the Extremities","volume":"139","author":"Noorda","year":"2004","journal-title":"Arch. Surg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1245\/ASO.2004.04.032","article-title":"Isolated Limb Perfusion Prolongs the Limb Recurrence-Free Interval After Several Episodes of Excisional Surgery for Locoregional Recurrent Melanoma","volume":"11","author":"Noorda","year":"2004","journal-title":"Ann. Surg. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1007\/BF02574514","article-title":"Safety and Efficacy of Isolated Limb Perfusion in Elderly Melanoma Patients","volume":"9","author":"Noorda","year":"2002","journal-title":"Ann. Surg. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1634\/theoncologist.2009-0325","article-title":"Isolated Limb Perfusion for Malignant Melanoma: Systematic Review on Effectiveness and Safety","volume":"15","author":"Ferrandiz","year":"2010","journal-title":"Oncologist"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1093\/jnci\/95.6.437","article-title":"Effects of Interferon Alpha on Vascular Endothelial Growth Factor Gene Transcription and Tumor Angiogenesis","volume":"95","author":"Scholz","year":"2003","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ejcsup.2006.08.002","article-title":"Electrochemotherapy\u2014An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study","volume":"4","author":"Marty","year":"2006","journal-title":"Eur. J. Cancer Suppl."},{"key":"ref_49","first-page":"8","article-title":"Electrochemotherapy in the treatment of melanoma","volume":"22","author":"Wichtowski","year":"2018","journal-title":"Contemp. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1016\/S0140-6736(17)31601-X","article-title":"Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)","volume":"390","author":"Schachter","year":"2017","journal-title":"Lancet"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","article-title":"Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma","volume":"381","author":"Larkin","year":"2019","journal-title":"New Engl. J. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/S1470-2045(16)30122-X","article-title":"Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): Updated efficacy results from a randomised, double-blind, phase 3 trial","volume":"17","author":"Ascierto","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/S1470-2045(18)30142-6","article-title":"Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF -mutant melanoma (COLUMBUS): A multicentre, open-label, randomised phase 3 trial","volume":"19","author":"Dummer","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1056\/NEJMoa1904059","article-title":"Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma","volume":"381","author":"Robert","year":"2019","journal-title":"New Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Guadagni, S., Fiorentini, G., Clementi, M., Palumbo, G., Palumbo, P., Chiominto, A., Baldoni, S., Masedu, F., Valenti, M., and Di Tommaso, A. (2017). Does Locoregional Chemotherapy Still Matter in the Treatment of Advanced Pelvic Melanoma?. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18112382"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.jss.2017.03.066","article-title":"Melphalan hypoxic perfusion with hemofiltration for melanoma locoregional metastases in the pelvis","volume":"215","author":"Guadagni","year":"2017","journal-title":"J. Surg. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1158\/2326-6066.CIR-17-0356","article-title":"Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade","volume":"6","author":"Ariyan","year":"2018","journal-title":"Cancer Immunol. Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/21\/5485\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:23:54Z","timestamp":1760167434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/21\/5485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,31]]},"references-count":57,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cancers13215485"],"URL":"https:\/\/doi.org\/10.3390\/cancers13215485","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,31]]}}}