Treatment of Locally Advanced Melanoma by Isolated Limb Infusion with Cytotoxic Drugs

OverviewIn 2016, an estimated 76,380 patients will be diagnosed with and approximately 10,130 patients will die of melanoma in the United States.1 However, these figures for new cases may represent a substantial underestimate, as many superficial and in situ melanomas treated in the outpatient setting are not reported. The incidence of melanoma continues to increase dramatically, at an overall rate of 33% for men and 23% women from 2002 to 2006.2 Melanoma is increasing in men more rapidly than any other malignancy, and in women more rapidly than any other malignancy except lung cancer. AbstractThis selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and highdose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted reassessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections. J Natl Compr Canc Netw 2016;14(4):450-473 NCCN Categories of Evidence and ConsensusCategory 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.All recommendations are category 2A unless otherwise noted.Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Please NoteThe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines ® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network ® (NCCN ® ) makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way. The full NCCN Guidelines for Melanoma are not printed in this issue of JNCCN but can be accessed online at NCCN.org.© National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. Disclosures for the NCCN Melanoma ...

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“…163 This approach should only be performed in centers with the expertise to manage both the procedure and the potential complications.…”

Section: Regional Therapy: Isolated Limb Perfusion and Infusionmentioning

confidence: 99%

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology

Coit¹,

Thompson²,

Algazi³

et al. 2016

J Natl Compr Canc Netw

218

167

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“…Melphalan is one such compound that may benefit from a therapeutic approach that takes the “ion trapping” hypothesis into consideration. Melphalan is used in isolated limb perfusion and infusion models both pre-clincally and clinically for the treatment of melanoma 43, 44 . Isolation of the limb temporarily halts blood circulation to the extremity resulting in local hypoxia and acidosis.…”

Section: Low Ph and Physiological Drug Resistancementioning

confidence: 99%

Drug Resistance and Cellular Adaptation to Tumor Acidic pH Microenvironment

et al. 2011

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Despite advances in developing novel therapeutic strategies, a major factor underlying cancer related death remains resistance to therapy. In addition to biochemical resistance, mediated by xenobiotic transporters or binding site mutations, resistance can be physiological; emerging as a consequence of the tumor’s physical microenvironment. This review focuses on extracellular acidosis, an end result of high glycolytic flux and poor vascular perfusion. Low extracellular pH, pHe, forms a physiological drug barrier described by an “ion trapping” phenomenon. We describe how the acid-outside plasmalemmal pH gradient negatively impacts drug efficacy of weak base chemotherapies but is better suited for weakly acidic therapeutics. We will also explore the physiologic changes tumor cells undergo in response to extracellular acidosis which contribute to drug resistance including reduced apoptotic potential, genetic alterations, and elevated activity of a multidrug transporter, p-glycoprotein, pGP. Since low pHe is a hallmark of solid tumors, therapeutic strategies designed to overcome or exploit this condition can be developed.

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“…ILP/ILI can result in response rates of 30–60% in melanoma patients [ 9 – 11 ]. However, randomized clinical trials comparing ILP/ILI with other treatment modalities are lacking.…”

Section: Introductionmentioning

confidence: 99%

Use Patterns and Costs of Isolated Limb Perfusion and Infusion in the Treatment of Regional Metastatic Melanoma: A Retrospective Database Analysis

Zhao

Barber

et al. 2016

Adv Ther

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IntroductionIsolated limb perfusion and infusion (ILP/ILI) are therapies for regional metastatic melanoma that allow high doses of anticancer drugs to be delivered directly into the circulation of an affected limb, thereby minimizing systemic drug toxicity. This procedure can lead to high response rates and is recommended in patients with Stage III unresectable metastatic melanoma. However, limited information is available on patterns of use and costs. This study examined patterns of ILP/ILI use and associated costs in patients with melanoma in the United States (US).MethodsRetrospective, observational study, using administrative claims data from the MarketScan® databases, was performed in patients with a diagnosis of melanoma (ICD-9-CM: 172.xx, V10.82) who underwent ILP/ILI (CPT-4: 36823) between January 1, 2002 and March 31, 2013. Patient characteristics, use patterns, length of hospital stay, and costs (per 2014 US $) of ILP/ILI were assessed.ResultsOne hundred and thirteen patients met the study criteria and were included in the analysis. Mean age was 61.4 years (standard deviation [SD] 13.8) and 38.9% of patients were male; the mean baseline Charlson Comorbidity Index was 0.19; 34.5% of patients were Medicare beneficiaries. The majority of patients (87.6%) had melanoma of the lower limb, 11.5% of the upper limb, and 0.9% of both limbs; 60.2% had lymph node metastasis and 56.6% had skin metastasis. Four patients (3.5%) underwent multiple ILP/ILI. The mean (±SD) length of hospital stay was 5.6 (±3.5) days and the mean (±SD) cost was US$36,758 (±27,124) per ILP/ILI procedure.ConclusionsIsolated limb perfusion and infusion in patients with melanoma were associated with long hospital stays and high costs. These results provide useful source data for the economic evaluation of treatment options for regional metastatic melanoma.FundingThis study was funded by Amgen, Inc.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-016-0283-z) contains supplementary material, which is available to authorized users.

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Treatment of Locally Advanced Melanoma by Isolated Limb Infusion with Cytotoxic Drugs

Cited by 15 publications

References 44 publications

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology

Drug Resistance and Cellular Adaptation to Tumor Acidic pH Microenvironment

Use Patterns and Costs of Isolated Limb Perfusion and Infusion in the Treatment of Regional Metastatic Melanoma: A Retrospective Database Analysis

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