	Washington University School of Medicine in St. Louis

As melanoma becomes more prevalent and more lethal in the United States,

 a multidisciplinary approach for treating inoperable in-transit metastases has proved to be a viable and valuable option. In-transit metastases involve lymphatic spread of melanoma between the primary tumor to multiple sites within a regional nodal basin.

 Patients with in-transit metastasis are categorized as stage III by the American Joint Committee on Cancer (AJCC),

 and about 2% to 10% of patients initially treated for melanoma in an extremity go on to develop this pattern of disease.

In the minority of cases, limited in-transit metastases can be treated with simple excision. However, most patients have multifocal disease. In these patients, surgical resection is either impossible or would be unacceptably morbid, requiring such extensive surgery that it would render the affected limb nonfunctional.

In patients with in-transit disease confined to an extremity and without evidence of systemic metastases, regional therapy (where the treatment is targeted and limited to the affected extremity) is an effective way to achieve disease control and possible long-term disease-free survival. Isolated limb perfusion and, more recently, isolated limb infusion (ILI) represent regional approaches to treat in-transit metastases.

Both procedures deliver chemotherapy (typically melphalan with or without dactinomycin) to the affected extremity at a concentration that is several orders of magnitude higher than could be achieved with systemic administration. Both techniques involve isolation of the circulation to the affected extremity, followed by a period of chemotherapy administration and subsequent washout. This maximizes the therapeutic efficacy of the chemotherapy while minimizing any systemic exposure and related side effects.

		Recommended Melanoma and Skin Cancer Patient Resources:

			“What You Need to Know about Melanoma and Other Skin Cancers” on the National Cancer Institute website. 

			“Melanoma” page on the National Cancer Institute website. Detailed information about diagnosis, staging, treatment, follow-up, and prevention for patients with melanoma. Includes information about clinical trials in melanoma. 

www.cancer.gov/ cancertopics/types/melanoma

			“Melanoma Skin Cancer” guide on the American Cancer Society website. Detailed information about melanoma, including information about diagnosis, staging, treatment, follow-up, and prevention for patients with melanoma. Includes information about clinical trials in melanoma. 

www.cancer.org/ Cancer/SkinCancer-Melanoma/index

			Skin Cancer Foundation website. Overview of melanoma and other skin cancers. Complementary to the National Cancer Institute and American Cancer Society websites. 

			“Melanoma” on the American Society of Clinical Oncology and Journal of Clinical Oncology website. Latest information about results of clinical trials, new information, new treatments, and news about melanoma. This website can be more technical/ medical than the other websites above, but contains an extensive amount of melanoma information. 

ILI is a minimally invasive regional therapy technique that involves percutaneous access of the artery and vein supplying the affected extremity.

For example, if a patient had isolated metastases to the right lower extremity, the left femoral artery and vein would be accessed, and catheters would be advanced proximally to the aortic and vena cava bifurcations, respectively, and advanced down into the affected right extremity. With the leg heated, a tourniquet is placed above the highest lesion to isolate the circulation to the affected extremity. Chemotherapy is then administered via the catheters into the right extremity and circulated for 30 minutes. The drug is then flushed out, and the tourniquet and catheters are removed.

Patients usually remain in the hospital for 3 to 5 days to monitor the affected extremity. A recent multicenter retrospective study of 128 patients undergoing ILI demonstrated an overall response rate of 64%, with a complete response rate of 31%.

 Thirty- five percent of patients experienced toxicity, and 1 underwent a toxicity-related amputation (0.8%). Relapse- free survival is approximately 12 to 18 months with ILI.

 Importantly, more than half of these patients survive greater than 2 years without evidence of distant metastases.

However, ILI is not curative and no study of regional therapy for advanced extremity melanoma has shown a survival benefit compared with conventional, systemic chemotherapy.

In the era of improved systemic therapies for melanoma (BRAF and MEK inhibitors, anti-CTLA4 and PD-1 therapy, etc), ILI is a therapy that may improve responses even further. The lytic antitumor response generated by ILI, combined with systemic immunotherapy or targeted therapy, may allow for enhanced antigen exposure and an improved antitumor immune response. Trials investigating this hypothesis are currently under way (eg, ClinicalTrials.gov Identifier NCT01323517).

ILI is available at select melanoma programs in the United States. It represents a multidisciplinary effort among surgical and medical oncology, interventional radiology and/or vascular surgery, anesthesia, perfusion services, and the pharmacy to coordinate, plan, and execute the procedure. It is an important tool in the armamentarium of clinicians caring for patients with melanoma and represents a paradigm for evaluating and testing novel therapeutics.

			Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010 [published online July 7, 2010]. 

			Pawlik TM, Ross MI, Johnson MM, et al. Predictors and natural history of in-transit melanoma after sentinel lymphadenectomy [published online June 16, 2005]. 

			Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification [published online November 16, 2009]. 

			Thompson JF, Kam PC, Waugh RC, Harman CR. Isolated limb infusion with cytotoxic agents: a simple alternative to isolated limb perfusion. 

			Beasley GM, Caudle A, Petersen RP, et al [published online March 26, 2009]. A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US. 

. 2009;208(5):706-715; discussion 715-717.

			Klaase JM, Kroon BB, van Geel AN, et al. Prognostic factors for tumor response and limb recurrence-free interval in patients with advanced melanoma of the limbs treated with regional isolated perfusion with melphalan.

			Grünhagen DJ, Brunstein F, Graveland WJ, et al. One hundred consecutive isolated limb perfusions with TNF-α and melphalan in melanoma patients with multiple in-transit metastases. 

 2004;240(6):939-947; discussion 947-948.

			Aloia TA, Grubbs E, Onaitis M, et al. Predictors of outcome after hyperthermic isolated limb perfusion: role of tumor response. 

			Sanki A, Kam PC, Thompson JF. Long-term results of hyperthermic, isolated limb perfusion for melanoma: a reflection of tumor biology. 

			Brady MS, Brown K, Patel A,et al. A phase II trial of isolated limb infusion with melphalan and dactinomycin for regional melanoma and soft tissue sarcoma of the extremity [published online June 21, 2006]. 

			Beasley GM, Riboh JC, Augustine CK, et al. Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma [published online February 22, 2011]. 

			Kroon HM, Moncrieff M, Kam PC, Thompson JF. Outcomes following isolated limb infusion for melanoma: a 14-year experience [published online May 29, 2008]. 

			Raymond AK, Beasley GM, Broadwater G, et al. Current trends in regional therapy for melanoma: lessons learned from 225 regional chemotherapy treatments between 1995 and 2010 at a single institution [published online April 11, 2011]. 

Articles

As melanoma becomes more prevalent and more lethal in the United States, a multidisciplinary approach for treating inoperable in-transit metastases has proved to be a viable and valuable option. 

Ryan C. Fields, MD

Articles

ILI Provides Valuable Option for Inoperable Melanoma Metastases