Georgia M. Beasley

Current Trends in Regional Therapy for Melanoma: Lessons Learned from 225 Regional Chemotherapy Treatments between 1995 and 2010 at a Single Institution

BACKGROUND Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) are used 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 (which included 62 first-time and 10 second-time) and ILI (which included 126 first-time and 18 second-time) procedures performed in 188 patients. PET/CT was obtained 3 months postregional treatment for 1 year and then every 6 months thereafter. RESULTS Overall response rate (complete response [CR] + partial response) of HILP was 81% (80% CI, 73-87%), and 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, and 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 after repeat HILP (50%, n = 10) compared with 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 of 62) than ILI (0 of 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 of 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 although ILI is effective and well-tolerated, HILP is a more definitive way to control advanced disease.

Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment

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.

A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma.

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.

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

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. Mol Cancer Ther; 9(7); 2090–101. ©2010 AACR.

Prospective Multicenter Phase II Trial of Systemic ADH-1 in Combination With Melphalan via Isolated Limb Infusion in Patients With Advanced Extremity Melanoma

PURPOSE Isolated 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 METHODS Patients 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. RESULTS In 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). CONCLUSION To 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.

Bevacizumab-Induced Alterations in Vascular Permeability and Drug Delivery: A Novel Approach to Augment Regional Chemotherapy for In-Transit Melanoma

Purpose: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). Experimental Design: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evans blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO2 were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. Results: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO2 decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. Conclusions: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma. Clin Cancer Res; 18(12); 3328–39. ©2012 AACR.

Procedure Delegation by Attending Surgeons Performing Concurrent Operations in Academic Medical Centers: Balancing Safety and Efficiency.

A ttending surgeons performing concurrent operations in 2 separate rooms with qualified surgical trainees assigned to the individual rooms constitutes a longstanding common practice in academic medical centers. This practice has been increasingly questioned and at times reflexively changed without full consideration of the relevant issues. Although there are minimal data specifically defining the appropriateness of concurrent workflows in academic medical centers, its common practice suggests an assumption of safety. The purported benefits include time and cost-effectiveness as well as provision of incremental responsibility for surgical trainees. We posit that the practice of concurrent surgery, within the confines of strict adherence to certain guiding principles and a continued critical assessment of surgical outcomes, is a means of delivering safe, ethically sound, high quality, and cost-effective care. The vulnerable anesthetized surgical patient places immense trust in his or her surgeon irrespective of trainee involvement, and accordingly the surgeon has a responsibility for the conduct and outcome of the entire procedure. Trainee involvement requires full disclosure to the patient, and academic medical centers should have trainee involvement noted in the anesthesia and operative informed consent documents. Running 2 rooms requires adherence to all safety checkpoints including surgical timeouts. The attending surgeon must recognize the skill sets of involved trainees, provide appropriate supervision, be immediately available for the entire case, be physically present for all critical parts of the procedure, and document this in the medical record. Medicare policy currently allows the teaching physician to be involved in 2 overlapping surgeries provided he or she is present for the critical portions and documents his or her presence during the key portions of the case. In this regard, trainee involvement falls within the scope of procedural delegation. Procedural delegation to subordinate practitioners is widely accepted across all professional environments, with procedures of lesser complexity entrusted to qualified, albeit perhaps less trained personnel. Indeed, were this practice eliminated (eg, requiring attending surgeon placement of peripheral intravenous or urinary catheters), care could not be delivered. This approach remains both appropriate and efficient so long as the attending pays dutiful attention to the competency of the subordinate practitioners, which include specialtytrained advanced practice providers and trainees. In this circumstance, the trainee should clearly be defined as someone who has not yet achieved his or her final level of education, and not as someone who is untrained. For surgical house staff, trainees are all licensed physicians who often, as is the case of a chief resident or fellow in surgery, have more formal training than most attending physicians in other specialties. A surgical resident has, during each year of his or her

A multicenter prospective evaluation of the clinical utility of F-18 FDG-PET/CT in patients with AJCC stage IIIB or IIIC extremity melanoma

Objective/Background:There is a high risk of relapse in stage IIIB/IIIC melanoma. The utility of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose positron emission tomography integrated with computed tomography (FDG-PET/CT) in these patients to evaluate response to treatment or for surveillance after treatment is currently not well defined. Methods:Prospective data from 2 centers identified 97 patients with stage IIIB/IIIC extremity melanoma undergoing isolated limb infusion (ILI) who had whole body FDG-PET/CT scans before and every 3 months after treatment. Clinical response was determined at 3 months by Response Evaluation Criteria In Solid Tumors. Results:Complete response (CR) after ILI occurred in 33% (32/97) of patients. FDG-PET/CT accurately identified 59% of patients who were CRs (19/32), whereas 41% (13/32) had residual metabolic activity in the extremity that was histologically negative for melanoma. The 3-year disease-free rate was 62.2% (95% CI: 40.1%–96.4%) for those patients who were CRs by both clinical/pathologic examination and FDG-PET/CT (n = 19) compared to only 29.4% (95% CI: 9.9%–87.2%) of those CRs who still had residual FDG-PET/CT activity (n = 13). FDG-PET/CT was utilized for surveillance of disease recurrence outside the regional field of treatment. Fifty-two percent (51/97) of patients developed disease outside the extremity at a median time of 212 days from pre-ILI FDG-PET/CT. In 47% (29/62) of these cases, the recurrence was resected. Conclusions:Although FDG-PET/CT does not appear to accurately identify patients who appear to be CRs to ILI, it does appear to identify a subgroup of patients whose regional progression-free survival is markedly worse. However, FDG-PET/CT appears to be an excellent method for surveillance in stage IIIB/IIIC patients after ILI with ability to identify surgically resectable recurrent disease in these high-risk patients.

Limb Preservation With Isolated Limb Infusion for Locally Advanced Nonmelanoma Cutaneous and Soft-Tissue Malignant Neoplasms

OBJECTIVE To demonstrate the efficacy of isolated limb infusion (ILI) in limb preservation for patients with locally advanced soft-tissue sarcomas and nonmelanoma cutaneous malignant neoplasms. BACKGROUND Locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms, including soft-tissue sarcomas of the extremities, can pose significant treatment challenges. We report our experience, including responses and limb preservation rates, using ILI in cutaneous and soft-tissue malignant neoplasms. METHODS We identified 22 patients with cutaneous and soft-tissue malignant neoplasms who underwent 26 ILIs with melphalan and dactinomycin from January 1, 2004, through December 31, 2009, from 5 institutions. Outcome measures included limb preservation and in-field response rates. Regional toxic effects were measured using the Wieberdink scale and serum creatinine phosphokinase levels. RESULTS The median age was 70 years (range, 19-92 years), and 12 patients (55%) were women. Fourteen patients (64%) had sarcomas, 7 (32%) had Merkel cell carcinoma, and 1 (5%) had squamous cell carcinoma. The median length of stay was 5.5 days (interquartile range, 4-8 days). Twenty-five of the 26 ILIs (96%) resulted in Wieberdink grade III or less toxicity, and 1 patient (4%) developed grade IV toxicity. The median serum creatinine phosphokinase level was 127 U/L for upper extremity ILIs and 93 U/L for lower extremity ILIs. Nineteen of 22 patients (86%) underwent successful limb preservation. The 3-month in-field response rate was 79% (21% complete and 58% partial), and the median follow-up was 8.6 months (range, 1-63 months). Five patients underwent resection of disease after an ILI, of whom 80% are disease free at a median of 8.6 months. CONCLUSIONS Isolated limb infusion provides an attractive alternative therapy for regional disease control and limb preservation in patients with limb-threatening cutaneous and soft-tissue malignant neoplasms. Short-term response rates appear encouraging, yet durability of response is unknown.

Future directions in regional treatment strategies for melanoma and sarcoma

Hyperthermic isolated limb perfusion (HILP) with melphalan and more recently isolated limb infusion (ILI) with melphalan +/− dactinomycin are common treatment modalities for both in-transit melanoma of the extremity and advanced extremity sarcoma. In order to further optimize treatment, future research should focus on selection of appropriate patients, verification of a technique that produces consistent results while maintaining acceptable toxicity, and development of novel strategies and agents. Development of these novel agents and strategies has potential to not only improve the efficacy of regional chemotherapy but may also help guide future strategies for systemic treatment.