ILI was found to be a well-tolerated alternative to HILP. While ILI does not appear to be as effective as HILP, it does seem to be associated with less morbidity.

No abstract

Background Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) are utilized to manage advanced extremity melanoma but no consensus exists as to which treatment is preferable and how to monitor patients post-treatment. Study Design Using a prospectively-maintained database, we reviewed our experience with melphalan based HILP (that included 62 first time and 10 second time) and ILI (that included 126 first time and 18 second time) procedures performed in 188 patients. PET/CT was obtained 3 months post regional treatment for one year and then every 6 months thereafter. Results The overall response rate (complete response (CR) + partial response (PR)) of HILP was 81% (80% CI: 73-87%) while the overall response rate from ILI was 43% (80% CI: 37-49%) for first time procedures only. HILP had a CR rate of 55% with a median duration of 32 months, while ILI had a CR rate of 30% with median duration of 24 months. Patients who experienced a regional recurrence after initial regional treatment were more likely to achieve a CR following repeat HILP (50%, n = 10) compared to repeat ILI (28%, n = 18). Although the spectrum of toxicity was similar for ILI and HILP, the likelihood of rare catastrophic complication of limb loss was greater with HILP (2/62) than ILI (0/122). PET/CT was effective for surveillance after regional therapy to identify regional nodal and pulmonary disease that was not clinically evident, but often amenable to surgical resection (25/49, 51% of cases). In contrast, PET/CT was not effective at predicting complete response to treatment with an accuracy of only 50%. Conclusions In the largest single institution regional therapy series reported to date, we found that while ILI is effective, and well-tolerated, HILP is a more definitive way to control advanced disease.

Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.

PurposeIsolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity.Patients and MethodsPatients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.ResultsIn all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one).ConclusionTo the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.

BACKGROUND: Isolated limb infusion with melphalan is a well‐tolerated treatment for patients with in‐transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH‐1 is a cyclic pentapeptide that disrupts N‐cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH‐1 in combination with melphalan via isolated limb infusion in patients with in‐transit extremity melanoma was performed. METHODS: Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH‐1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N‐cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors. RESULTS: Sixteen patients have been treated with no observed dose‐limiting toxicities. Common treatment‐related grade 1 or 2 toxicities included skin/dermatologic (n = 14) and pain (n = 12). Grade 3 toxicities included shortness of breath (n = 1), hypertension (n = 1), serologic toxicities (n = 4), and 1 grade 4 creatine phosphokinase elevation. In‐field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH‐1 concentrations at each dose and minimal variability in melphalan drug levels. CONCLUSIONS: Systemic ADH‐1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well‐tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N‐cadherin may be a new strategy for overcoming melanoma chemoresistance. Cancer 2009. © 2009 American Cancer Society.

Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 μmol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.

No abstract