Isolated Limb Infusion Research Articles

Outcomes and Predictive Factors of Isolated Limb Infusion for Patients with In-transit Melanoma in China.

This study was designed to evaluate the efficacy of isolated limb infusion (ILI) treatment in Chinese patients with in-transit melanoma and to identify factors predictive of the outcome. A total of 150 patients with in-transit melanoma who received a single ILI between 2007 and 2016 were identified from a prospectively collected database. All patients had AJCC Stages IIIb, IIIc, and IV disease. Acral lentiginous melanoma (ALM) accounted for 79% of patients, and 59% had a high burden of disease (BOD). The complete response (CR) and partial response (PR) rates were 6 and 35%, respectively. Forty-five percent of patients experienced grade III-IV limb toxicities, but no grade V toxicity was observed. Patients with a low BOD, high limb temperature, high peak creatine phosphokinase (CK) level, and grade III-IV limb toxicity achieved higher response rates. Stage IV disease and high BOD were associated with worse infield progression-free survival (PFS) and overall survival (OS), whereas patients with CR or PR to ILI had better infield PFS and OS. Multivariate analyses showed that disease stage, BOD, and a CR were independent predictors of infield PFS, whereas disease stage and a response to ILI were independent predictors of OS. ILI is well-tolerated but the response rate in Chinese patients was lower than that reported in US and Australian studies. The prevalence of the ALM histological type, advanced disease stages, and a high BOD may be the main reasons for this. A response to ILI, BOD, and disease stage are prognostic factors for survival.

Development and evaluation of an isolated limb infusion model for investigation of drug delivery kinetics to solid tumors by thermosensitive liposomes and hyperthermia

The combined administration of thermosensitive liposomes (TSLs) and hyperthermia (HT) has been increasingly shown to be a powerful tool for the treatment of solid tumors. At present, it is hypothesized that the circulation of TSLs through the vasculature of a heated tumor results in the rapid release of the entrapped drug, followed by its uptake and distribution within the tumor microenvironment. However, simple questions on the transport kinetics of TSLs through the heated tumor and how much drug is retained upon passage of TSLs through the tumor microcirculation have not been investigated in an experimental setting to-date. The present work describes a novel methodology for investigating these parameters by isolated limb infusion (ILI), developed in a rat model of sarcoma. This approach was used to assess the efficacy of Doxorubicin (Dox) delivery by TSL in a heated (42°C) tumor following a single passage of TSL through the tumor vasculature. Analysis of the effluent post-ILI, whole-tumor histological sections, and tissue homogenates revealed that upon a single passage, Dox delivery by TSL at 42°C did not exceed delivery under conventional (i.e. free Dox) or physiological (i.e. TSL at 37°C, or normothermia; NT) conditions. In fact, mathematical modeling demonstrated that at least thirteen passages are required to obtain the intratumoral Dox levels typically achieved using TSL (i.e. ~5%ID/g). Overall, this work investigates TSL-based determinants for achieving efficacious drug delivery using a model of ILI in tumor-bearing rats and the results bear important implications for TSL disposition in vivo.

Isolated Limb Perfusion and Infusion for Extremity Soft Tissue Sarcoma: A Contemporary Systematic Review and Meta-Analysis.

Isolated limb perfusion (ILP) and isolated limb infusion (ILI) have been variably used in recent years for the treatment of locally advanced or marginally resectable extremity soft tissue sarcomas (STSs). We performed a systematic review and meta-analysis of contemporary studies to further characterize treatment patterns and outcomes. PubMed was queried for articles published in or after the year 2000, in the English language, with >10 patients, and with adequate outcome data following ILP/ILI. Descriptive aggregate statistics were performed. Nineteen studies that met the inclusion criteria were identified, with a total of 1288 patients. Weighted mean patient age was 55.9years and 52% were male. The majority underwent ILP (88%) versus 12% for ILI, and chemotherapeutic regimens used were as follows: (1) melphalan with tumor necrosis factor (TNF)-α (78%), (2) melphalan±actinomycin (10%), and (3) other regimens (12%). Most common histologies treated were malignant fibrous histiocytoma (21%), liposarcoma (16%), synovial (11%) and leiomyosarcoma (7%). Aggregate overall response rate (ORR) post-procedure was 73.3%, with 25.8% demonstrating a complete response (CR). Similar unadjusted ORRs were noted in the melphalan treatment groups with and without TNFα (72.0 and 67.0%, respectively; p=0.27). Grade III toxicity was observed in 15.4% of patients, and grade IV/V toxicity was observed in 6.0% of patients. Overall limb salvage rate was 73.8% and median time to local (in-field) progression ranged from 4 to 28months (weighted median 22.1months). ILP and ILI for extremity STS can be safely performed with appreciable response rates and significant limb salvage rates. Further study is needed to identify optimal treatment regimens by histology.

Safety and Efficacy of Isolated Limb Infusion Chemotherapy for Advanced Locoregional Melanoma in Elderly Patients: An Australian Multicenter Study.

Isolated limb infusion (ILI) offers a minimally invasive treatment option for locally advanced extremity melanoma. The aim of the current study was to evaluate the safety and efficacy of ILI in elderly patients in an Australian multicenter setting. The results of 316 first ILI procedures, performed between 1992 and 2008 in five Australian institutions, were identified and analyzed, with the main focus on elderly patients (≥75years of age). All institutions used the same protocol: melphalan was circulated in the isolated limb for 20-30min (±actinomycin D), and toxicity, responses, and survival were recorded. Characteristics of patients aged ≥75years (n=148) were similar to those aged <75years (n=168), except that older patients had more melanoma deposits (median 4 vs. 5; p=0.035) and lower limb volumes (5.4 vs. 6.5L; p=0.001). Median drug circulation times were lower in the older group (21 vs. 24min; p=0.04), and older patients experienced less limb toxicity (grade III/IV in 22 and 37% of patients, respectively; p=0.003). A complete response (CR) was seen in 27% of patients aged ≥75years and in 38% of patients aged <75years (p=0.06), while overall response rates were 72 and 77%, respectively (p=0.30). No difference in survival was seen (p=0.69). The ILI technique proved safe and effective in elderly patients. When present, toxicity was localized, and lower compared with younger patients, possibly due to shorter drug circulation times. CR rates were higher in younger patients, although not significantly, while overall response and survival were equal. Optimization of perioperative factors in elderly patients may allow response rates to be raised further, while maintaining low toxicity.

Isolated Limb Infusion as a Limb Salvage Strategy for Locally Advanced Extremity Sarcoma

Treatment-resistant, locally advanced soft tissue sarcomas often require amputation for complete tumor extirpation. Isolated limb infusion (ILI) selectively delivers high-dose chemotherapy to the extremity in an attempt to achieve limb salvage. The aim of this study was to report perioperative and oncologic outcomes after ILI in patients with extremity soft tissue sarcomas. From 1994 to 2016, 77 patients underwent 84 ILIs at a total of 5 institutions. Melphalan and actinomycin D were circulated for 30 minutes after complete tourniquet occlusion of the limb, then actively washed out to prevent systemic exposure. The procedure was performed in an upper extremity on 19 patients (21 infusions) and in a lower extremity on 58 patients (63 infusions). The 3-month overall response rate (ORR) for the entire cohort was 58%, and there was a statistically significant difference (p= 0.03) between upper (37%) and lower extremity (66%) ORR. With median follow-up of 20.6 months (range 0.6 to 146.1 months), the overall limb salvage rate was 77.9%. For those who underwent amputation due to progression of disease, the median time to amputation was 4.5 months. With a median follow-up of 20.6 months, the median overall survival for the entire cohort was 44.3 months. The distant metastatic-free survival was longer for responders than nonresponders (p= 0.01), though the disease-specific survival was not different for the same groups (p= 0.2). Isolated limb infusion for extremity soft tissue sarcoma results in an objective response for half of the patients who are otherwise facing amputation, and offers prolonged limb salvage for the vast majority of patients. The procedure is well tolerated without serious complications.

Isolated Limb Infusion in a Pregnant Patient with Sarcoma of the Upper Extremity: A Case Report with Literature Review

Isolated Limb Infusion in a Pregnant Patient with Sarcoma of the Upper Extremity: A Case Report with Literature Review

112. Safety and efficacy of isolated limb infusion in elderly patients with advanced locoregional melanoma: An Australian multicenter experience

112. Safety and efficacy of isolated limb infusion in elderly patients with advanced locoregional melanoma: An Australian multicenter experience

111. Isolated limb perfusion versus isolated limb infusion: A systematic review of outcomes and morbidity

111. Isolated limb perfusion versus isolated limb infusion: A systematic review of outcomes and morbidity

Intralesional PV-10 for in-transit melanoma-A single-center experience.

Patients with in-transit melanoma metastasis have longer median survival than patients with distant metastatic disease. Furthermore, local disease control is an important endpoint for symptom management. The treatment of unresectable loco-regional recurrence or in-transit disease has been historically managed with a combination of treatments including surgery, radiotherapy, isolated limb infusion or perfusion as well as systemic therapies. Intralesional PV-10 has been used at Peter MacCallum Cancer Centre since 2010, and the current report presents a retrospective analysis of patient outcomes, reporting the response rates, durability of responses, and observed toxicities. Records were analyzed retrieving details of 19 patients treated with PV-10 over a 4-year period from 2010 to 2014. Medical records were reviewed for these patients and data extracted. Nineteen patients with in-transit melanoma were treated with intralesional PV-10 between 2010 and 2014. Disease control (complete or partial response or disease stability) was achieved in 68% of patients with 26% having a complete response. This was achieved with minimal associated toxicity. PV-10 is an effective, durable, well-tolerated treatment tool with an acceptable side effect profile for the management of unresectable in-transit melanoma. J. Surg. Oncol. 2016;114:380-384. © 2016 Wiley Periodicals, Inc.

Clinical Response and Regional Toxicity Following Isolated Limb Infusion Compared with Isolated Limb Perfusion for In-Transit Melanoma.

Isolated limb perfusion (ILP) and infusion (ILI) are therapeutic modalities for the treatment of in transit melanoma. A retrospective review of all patients undergoing first-time ILI or ILP for in-transit melanoma metastases between 2007 and 2015 was performed. Demographic and clinical characteristics included age, sex, nodal status at the time of ILI/ILP (N-stage), and burden of disease (BOD). Regional toxicity was categorized by the Wieberdink classification. Clinical response was evaluated at 3months after treatment. A total of 203 patients were reviewed (ILI=94, ILP=109). There were no differences in age, sex, or N-stage between groups; however, BOD was higher for the ILI group (high BOD 58 vs. 44%, p=0.04). Regional toxicity was minimal (Grade IV<1% in ILI and 2% in ILP, p=0.40). Overall response rate (ORR) was 53% for ILI versus 80% for ILP (p<0.001). Median overall survival (OS) was 46months for ILI versus 40months for ILP (p=0.31). A high BOD [hazard ratio (HR) 3.02, 95% confidence interval (CI) 1.85-4.93, p<0.001] and N3 disease (HR 1.58, 95% CI 1.01-2.48, p=0.04) were associated with worse OS, whereas there was no difference in OS by procedure (p=0.20). ILP offers an improved ORR, but this does not translate into improved local PFS or OS. Both procedures are well tolerated with minimal regional toxicity.

Australian Multicenter Study of Isolated Limb Infusion for Melanoma.

Isolated limb infusion (ILI) offers a less invasive alternative to isolated limb perfusion (ILP) for the treatment of locally advanced extremity melanoma. In Australia, ILI has essentially completely replaced ILP. The aim of this study was to collect and evaluate the results of ILI in an Australian multicenter setting. The results of 316 first ILI procedures, performed between 1992 and 2008 in five Australian institutions, were collectively analyzed, with all five institutions using the same protocol. Melphalan was circulated in the isolated limb for 20-30min (±actinomycin D). Response was determined using the World Health Organization criteria, and limb toxicity was assessed using the Wieberdink scale. The median patient age was 74years (range 28-100) and 59% of patients were female. Overall response rate was 75% (complete response [CR] 33%; partial response 42%). Stable disease was seen in 18% of patients and progressive disease in 7%. Wieberdink grade III or higher was seen in 30% of the cases. No toxicity-related amputations occurred, and median survival was 44months. In patients with a CR, median survival was 80months (p=0.014). On multivariate analysis, Breslow thickness, lower-limb ILI, and a procedure performed at the Melanoma Institute Australia remained significant predictors for response, although not for survival. This Australian multicenter study of ILI is the largest reported to date. ILI is a useful technique that can be safely and effectively performed across tertiary referral centers for the successful management of advanced extremity melanoma. Increased optimization of perioperative factors might allow response rates to be raised further, while maintaining acceptable toxicity.

Computed Tomography-Based Limb Volume Measurements for Isolated Limb Infusion in Melanoma.

Despite advances in cross-sectional imaging, chemotherapeutic dosing for isolated limb infusion (ILI) in melanoma is currently calculated through cumbersome and potentially imprecise manual measurements. The primary objective of this study was to examine the feasibility of using computed tomography (CT) to calculate limb volume, its concordance with manual measurement, and its ability to predict clinical response and toxicity in patients undergoing ILI. A retrospective analysis of all patients undergoing lower extremity ILI at Duke University Medical Center between 2003 and 2014 was performed. Data pertaining to manually measured limb volume, chemotherapeutic dosing, and patient outcome was obtained. CT-based measurements of limb volume were performed in all patients for whom imaging was available and subsequently compared with manually measured values. CT data were sufficient for measurement in 73 patients. The mean measurement time was 4.61±2.13min. Although average CT-based measurements were 1.20 L higher in the case of lower limbs, they correlated well with those obtained manually (r (2)=0.90). Unlike manual measurement, patients with complete responses to chemotherapy had smaller limb volumes than those with disease progression as measured by CT (9.3 vs. 10.7L; p=.038). Patients suffering grade 3 and 4 toxicities also had statistically lower limb volumes as measured by CT than those who did not (p<.05). CT-based limb volume measurement is feasible for chemotherapy dosing in patients undergoing ILI for melanoma and has predictive value with respect to clinical response and toxicity.

B06 - Isolated limb infusion chemotherapy with or without hemofiltration for recurrent limb melanoma

B06 - Isolated limb infusion chemotherapy with or without hemofiltration for recurrent limb melanoma

The Role of Regional Therapies for in-Transit Melanoma in the Era of Improved Systemic Options.

The incidence of melanoma has been increasing at a rapid rate, with 4%–11% of all melanoma recurrences presenting as in-transit disease. Treatments for in-transit melanoma of the extremity are varied and include surgical excision, lesional injection, regional techniques and systemic therapies. Excision to clear margins is preferred; however, in cases of widespread disease, this may not be practical. Historically, intralesional therapies were generally not curative and were often used for palliation or as adjuncts to other therapies, but recent advances in oncolytic viruses may change this paradigm. Radiation as a regional therapy can be quite locally toxic and is typically relegated to disease control and symptom relief in patients with limited treatment options. Regional therapies such as isolated limb perfusion and isolated limb infusion are older therapies, but offer the ability to treat bulky disease for curative intent with a high response rate. These techniques have their associated toxicities and can be technically challenging. Historically, systemic therapy with chemotherapies and biochemotherapies were relatively ineffective and highly toxic. With the advent of novel immunotherapeutic and targeted small molecule agents for the treatment of metastatic melanoma, the armamentarium against in-transit disease has expanded. Given the multitude of options, many different combinations and sequences of therapies can be offered to patients with in-transit extremity melanoma in the contemporary era. Reported response and survival rates of the varied treatments may offer valuable information regarding treatment decisions for patients with in-transit melanoma and provide rationale for these decisions.

Perfusion and infusion for melanoma in-transit metastases in the era of effective systemic therapy.

The management of melanoma in-transit metastases (IT-mets) is challenging. For many years, the absence of effective systemic therapy has prompted physicians to focus on regional therapies for melanoma confined to the limb. The introduction of isolated limb perfusion (ILP) and isolated limb infusion (ILI) has enabled effective delivery of cytotoxic drugs in an isolated circuit, so as to overcome systemic toxicity and maximize local response. Both techniques have evolved over years and both tumor necrosis factor (TNF)-alpha-based ILP and ILI have distinct indications. The development of new systemic treatment options for patients with melanoma in the past decade has shed a new light on melanoma therapy. The present manuscript focuses on the modern role of ILI and ILP in the treatment of patients with melanoma with in-transit metastases in the era of effective systemic therapy. The response and control rates of ILI/ILP are still superior to rates achieved with systemic agents. The extent of disease in patients with stage III disease, however, warrants effective systemic treatment to prolong survival. There is great potential in combining rapid response therapy such as ILI/ILP with systemic agents for sustainable response. Trial results are eagerly awaited.

Isolated limb infusion: Efficacy, toxicity and an evolution in the management of in-transit melanoma

Background Isolated limb infusion (ILI) delivers low-flow chemotherapy via percutaneous catheters to treat melanoma in-transit metastases. Objective To describe the experience of two regional referral centres with ILI. Methods A retrospective review of patients who underwent ILI between 2002 and 2012 was performed. Outcomes were measured using the WHO criteria for response, the Wieberdink toxicity score and long-term limb function using the Toronto Extremity Salvage Score (TESS). Results Fifty-two patients (mean age 66 years [range 27 to 90 years], female sex 65%, and lower [treated] limb in 86%) with 54 ILIs were reviewed. Wieberdink toxicity score was ≥3 in 21 (39%) procedures. Median follow-up was 18 months (range one to 117 months). Initial complete response (CR) was 29%, partial response 27%, stable disease 18% and progressive disease 27%. Predictors of better initial response were low disease burden and previous treatment. One or more treatments after ILI were common (65%). At 12 months, 19% of ILI patients had died from melanoma but 44% of surviving patients experienced limb CR. At 24 months, 57% of surviving patients experienced limb CR. The quality of life in the surviving, contactable patients according to the Toronto Extremity Salvage Score was 89%. Conclusion Even if ILI does not result in CR for melanoma intransit metastases. it may slow disease progression as a single therapy, but more frequently in combination with other modalities.

Abstract No. 421 - Isolated limb infusion: an interventional oncology opportunity

Abstract No. 421 - Isolated limb infusion: an interventional oncology opportunity

Targeting N-cadherin Increases Vascular Permeability and Differentially Activates AKT in Melanoma

We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma. N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects. Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis. Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ. ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.

Isolated limb infusion: Efficacy, toxicity and an evolution in the management of in-transit melanoma.

Isolated limb infusion (ILI) delivers low-flow chemotherapy via percutaneous catheters to treat melanoma in-transit metastases. To describe the experience of two regional referral centres with ILI. A retrospective review of patients who underwent ILI between 2002 and 2012 was performed. Outcomes were measured using the WHO criteria for response, the Wieberdink toxicity score and long-term limb function using the Toronto Extremity Salvage Score (TESS). Fifty-two patients (mean age 66 years [range 27 to 90 years], female sex 65%, and lower [treated] limb in 86%) with 54 ILIs were reviewed. Wieberdink toxicity score was ≥3 in 21 (39%) procedures. Median follow-up was 18 months (range one to 117 months). Initial complete response (CR) was 29%, partial response 27%, stable disease 18% and progressive disease 27%. Predictors of better initial response were low disease burden and previous treatment. One or more treatments after ILI were common (65%). At 12 months, 19% of ILI patients had died from melanoma but 44% of surviving patients experienced limb CR. At 24 months, 57% of surviving patients experienced limb CR. The quality of life in the surviving, contactable patients according to the Toronto Extremity Salvage Score was 89%. Even if ILI does not result in CR for melanoma intransit metastases. it may slow disease progression as a single therapy, but more frequently in combination with other modalities.

Isolated limb infusion chemotherapy with or without hemofiltration for recurrent limb melanoma.

To better define the efficacy and the safety of intra-arterial infusion performed with or without hemofiltration for recurrent limb melanoma. Patients with the following characteristics were included in the study: recurrent limb melanoma not indicated for surgical resection, measurable disease in the extremity, > 18 years, performances status (Eastern Cooperative Oncology Group ) was 0-1 and life expectancy of at least 6 mo. Twenty nine consecutive patients were enrolled in the study. Patients underwent fluoroscopic placement of angiographic arterial and venous catheters to infuse the drug in the artery [isolated limb infusion (ILI)], and to stop the out flow (venous). Melphalan was rapidly infused into the isolated limb via the arterial catheter after the inflation of venous balloon catheter. Then the circulation of the limb was completely blocked with a pneumatic cuff at the root of the limb. Haemofiltration (HF) was available only in the main center, and was performed with an extracorporeal perfusion system, in order to reduce high systemic toxic peaks of drug. Thirty seven ILI were done in 29 cases (31 ILI-HF and 6 ILI) between 2001 and 2014 at Ancona and Pesaro Hospitals, Italy. Clinical outcomes were monitored 30 d after treatment. Eleven patients (38%) received infusion of melphalan alone, 7 (24%) melphalan associated to mitomicin C and 7 (24%) melphalan associated to cisplatin, the remaining 4 were treated with cisplatin, melphalan and epirubicin or cisplatin and mitomicin C. The overall response rate was 66%, in particular, 3 patients (10%) were complete responders and 16 (56%) were partial responders; whereas 7 patients (24%) had stable disease, and 3 (10%) showed progressive disease. Limb toxicity was assessed adopting Wieberdink scale, with evidence of 90% of low grade (I and II) toxicity. ILI-HF and ILI are effective and safe treatments for recurrent non-resectable limb melanoma. They present evidence of favorable clinical benefit and is effective in delaying progression.