Role of Isolated Limb Perfusion in the Era of Targeted Therapies and Immunotherapy in Melanoma. A Systematic Review of The Literature

Abstract

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 2000–2020 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perfusion methodology was not clearly described, letters to the editor, non-systematic reviews and studies that applied outdated clinical guidelines were excluded.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.

Isolated Limb Perfusion and Immunotherapy in the Treatment of In-Transit Melanoma Metastases: Is It a Real Synergy?

“…This represented a major limitation when reviewing the literature, as the response rate of ITM patients treated with only IT could not be extrapolated from most published studies. In our patients who were treated with ILP alone, treatment response and patient survival were consistent with the literature [7,[10][11][12][13]16,[32][33][34][35][36][37], while DFS could not be compared because such information was often unreported in previous studies. In our series, patients who were treated with ILP + IT showed better treatment response but a similar patient survival compared to the literature data on patients treated with IT [21,22,37].…”

“…Our findings suggested that combining ILP and IT might offer some advantages over ILP alone in terms of OS, DSS and local DFS. Of note, local toxicity was in accordance with the literature [7,16,[32][33][34][35][36][37], with less than one out of ten patients developing grade III or greater toxicity. At the state of the art, researchers usually include ITM patients among those with distant metastases and not as a stand-alone group.…”

“…Before the introduction of systemic therapies, hyperthermic isolated limb perfusion (ILP) was the most effective treatment in case of multiple, bulky, recurrent in-transit disease [4,5]. Several large retrospective studies reported a median overall response rate of 70-90%, a median complete response of 30-70% and low/medium local toxicity [6,7]. This treatment is very effective, repeatable and is well tolerated even by elderly patients [8][9][10][11][12][13][14].…”

The Diagnosis and Management of Cutaneous Metastases from Melanoma

“…Isolated limb perfusion (ILP) is a technique that was first introduced in 1958 by Creech and Krementz, which consists of the administration of chemotherapy agents exclusively to the involved limb, isolated from the systemic circulation [64]. Chemotherapy drugs are administrated throughout a canulated artery and vein using an extracorporeal bypass circuit, therefore permitting a much higher administration of drugs solely to the isolated limb with a concentration that would not be tolerated systemically [65,66]. Authors have reported overall response rates of 65-100% and complete response rates of up to 65% [67].…”

Oncolytic Virus‐Driven Biotherapies from Bench to Bedside

“…[149] ILP is a classic approach in patients with limb-inoperable sarcoma and rapidly recurrent metastatic melanoma. [150] ILP therapy of OVs has become an emerging regimen for the treatment of tumor-bearing limbs owing to effective tumor targeting and high titers of ILP-delivered viruses. [151] The ILP delivery of VSV inhibited the growth of extremity osteosarcoma xenografts more potently than the same virus administered intravenously or intratumorally.…”