Clinical Management and Current Research in Isolated Limb Perfusion for Sarcoma and Melanoma

Hohenberger, Peter; Kettelhack, Christoph

doi:10.1159/000011842

Cited by 18 publications

(12 citation statements)

References 82 publications

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“…Heat was initiated by passing heated water through the catheter at the onset of surgery (the time of the incision) and was discontinued at the conclusion of surgery (the conclusion of the infusion). A temperature of 43jC was used as the heating surface of the catheter in the hyperthermic isolated limb infusion group so that the majority of the xenograft would be heated to a range between 38jC and 43jC, which is comparable with temperature applied clinically in hyperthermic isolated limb perfusion or infusion (12,13). For normothermic isolated limb infusion, a temperature of 37.5jC was used for the heating surface of the catheter to ensure that the tumor temperature would remain above 35jC without being heated to hyperthermic condition.…”

Section: Methodsmentioning

confidence: 99%

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

Ko¹,

Ueno²,

Yoshimoto³

et al. 2006

Clinical Cancer Research

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Purpose: Previous preclinical studies have shown that regional temozolomide therapy via isolated limb infusion is more effective than melphalan, the current drug of choice for regional chemotherapy for advanced extremity melanoma. The aim of this study was to determine whether hyperthermia could further augment the efficacy of temozolomide, an alkylating agent, against melanoma and improve its therapeutic index in a rat model of isolated limb infusion. Experimental Design: Athymic rats bearing s.c. human melanoma xenografts (DM6) in their hind limbs were randomized to a 15-minute isolated limb infusion procedure with or without temozolomide at room temperature, normothermic (37.5jC), or hyperthermic (43jC) conditions. Results: The concomitant administration of hyperthermia during an infusion with temozolomide led to the greatest increase in tumor growth delay, decreased proliferative index, and increased cell death. Isolated limb infusion treatment with a low dose (350 mg/kg) of temozolomide was ineffective at producing tumor growth delay (P = 0.07). Similarly, temozolomide infusion under normothermia yielded minimal tumor growth delay (P = 0.08). In contrast, the combination of hyperthermia plus temozolomide treatment produced marked tumor growth delay of 10.4 days (P = 0.02) with minimal toxicity. The addition of heat to temozolomide treatment yielded the smallest proliferative index (P = 0.001), while markedly increasing the level of apoptosis 48 hours after isolated limb infusion. Conclusion: This study, the first to examine the interaction between hyperthermia and temozolomide, shows a strong, synergistic antitumor effect when hyperthermia is combined with temozolomide for regional treatment of melanoma confined to an extremity. The mechanism of this synergy seems to be through an augmentation, by hyperthermia, of the antiproliferative and proapoptotic effects of temozolomide. Isolated limb perfusion and isolated limb infusion haveemerged as effective forms of treatment for regionally advanced melanoma confined to an extremity. These procedures address all in-transit lesions confined to an extremity in a single procedure by supplying a regional concentration of chemotherapeutic agents at least 10 times higher than that reached after systemic administration, without the systemic side effects.Hyperthermia is widely used in conjunction with isolated limb perfusion and infusion to improve the response to the regional chemotherapy. This is usually done by heating the perfusate (or infusate) to 39jC to 41jC and by applying external warming blankets to prevent heat loss. Hyperthermic isolated limb perfusion was introduced based on in vitro evidence of a synergistic, cytotoxic interaction between heat and melphalan, the alkylating agent that is the current drug of choice for regional therapy of melanoma (1). Melphalan has been extensively studied for its efficacy in hyperthermic isolated limb perfusion, with response rates in the 80% range with 40% to 80% being complete responders (2, 3).However, a recent,...

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Section: Methodsmentioning

confidence: 99%

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

Ko¹,

Ueno²,

Yoshimoto³

et al. 2006

Clinical Cancer Research

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“…On the basis of the temperature profile created by the heating apparatus, a temperature of 43°C was chosen for the heating surface of the catheter in the hyperthermia treatments. This was chosen to heat the majority of the surface area of the tumor to temperatures between 38°C and 43°C, which is comparable with temperatures applied clinically in hyperthermic isolated limb infusion and hyperthermic isolated limb perfusion (2,26). For the treatments involving heating the tumor to maintain normothermic conditions, a temperature of 37.5°C was used for the heating surface of the catheter.…”

Section: Methodsmentioning

confidence: 99%

“…This was done to ensure that the tumor temperature would remain above 35°C without being heated to hyperthermic conditions. Also, this temperature range was chosen as it resembles that used clinically in isolated limb infusion and isolated limb perfusion under normothermic conditions (2,12). Temperature was monitored in all animals by thermocouples located in the tumor at 1, 3, and 8 mm from the approximate tumor center, as well as from muscle on the opposite unaffected leg.…”

Section: Methodsmentioning

confidence: 99%

“…Isolated limb perfusion is a surgical procedure in which high-dose chemotherapeutic agents are delivered regionally to an extremity in hopes of eliminating in-transit metastases while limiting systemic exposure and toxicity. Currently there are three main indications for isolated limb perfusion: (1) therapeutic isolated limb perfusion for locoregionally advanced melanoma, which presents as locally recurrent melanoma, satellitosis (the presence of small foci of tumor adjacent to a larger primary tumor), or in-transit metastases; (2) therapeutic isolated limb perfusion for locally advanced, unresectable sarcomas of the extremities; and (3) prophylactic isolated limb perfusion as an adjunct to surgical excision of high-risk primary or recurrent melanoma (2). Isolated limb perfusion has the theoretical benefit over surgical resection in that it allows one to treat an entire area at risk of recurrence, and it differs from traditional systemic chemotherapy in that doses 10 times higher than the allowed systemic dose can be used.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Hyperthermia in Regional Alkylating Agent Chemotherapy

Abdel‐Wahab¹,

Grubbs²,

Viglianti

et al. 2004

Clinical Cancer Research

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The role of hyperthermia during regional alkylating agent chemotherapy is controversial. The aim of this study was to determine the exact contribution of hyperthermia to tumor response during isolated limb infusion with L-phenylalanine mustard. Rats bearing rodent fibrosarcoma on the hindlimb underwent isolated limb infusion with saline, saline plus heat, L-phenylalanine mustard, L-phenylalanine mustard under conditions of normothermia, or L-phenylalanine mustard plus hyperthermia. Heat was administered locally using an in-line hot water circulation loop. Treatment with L-phenylalanine mustard at a concentration of 15 or 50 g/mL was ineffective at producing tumor growth delay (P ‫؍‬ 0.24 and 0.41, respectively). Furthermore, thermal enhancement of L-phenylalanine mustard activity was not seen at 15 g/mL. However, administration of high-dose L-phenylalanine mustard, 50 g/mL, with increasing amounts of heat yielded increasing tumor growth delay, increased regressions, and decreased proliferative index. Although L-phenylalanine mustard infusion under normothermia yielded a tumor growth delay of 7.1 days, combination L-phenylalanine mustard ؉ hyperthermia treatment produced tumor growth delay of 27.0 days (P < 0.01; with two of five animals showing a complete response). Four hours after isolated limb infusion, 50.9% of cells in tumor treated with L-phenylalanine mustard ؉ hyperthermia experienced apoptosis, whereas only 18.1, 16, and 4.4% of cells underwent apoptosis after treatment with L-phenylalanine mustard, saline ؉ hyperthermia, or saline. The mean concentration of L-phenylalanine mustard within tumor relative to perfusate following isolated limb infusion was found to be similar among all groups at 0.023, 0.025, and 0.032 in animals undergoing isolated limb infusion with L-phenylalanine mustard, L-phenylalanine mustard ؉ normothermia, and L-phenylalanine mustard ؉ hyperthermia, respectively. These data indicate a synergistic cytotoxic effect of Lphenylalanine mustard ؉ hyperthermia in isolated limb infusion, which is not attributable to enhanced tumor drug uptake.

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“…12,13 Intra-arterial infusion techniques have been developed for a number of other organs and a variety of drugs, and promising results have been achieved. 14 Finally, isolated limb perfusion 15 has been shown to be effective for treatment of melanoma 16 with the drug melphalan, for example.…”

Section: Introductionmentioning

confidence: 99%

Fluoropyrimidine chemotherapy in a rat model: comparison of fluorouracil metabolite profiles determined by high‐field ¹⁹F‐NMR spectroscopy of tissues ex vivo with therapy response and toxicity for locoregional vs systemic infusion protocols

et al. 2004

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A Sprague-Dawley rat model with DS sarcoma transplanted in the thigh was used to compare transcatheter locoregional i.a. and systemic i.v. administration of 5-fluorouracil (FU) at 12 dose-rate schedules: 25, 50 and 100 mg/kg; bolus, 1, 5 and 24 h infusions. In experiment A tumor (62/67 animals) as well as liver and kidney (56/67 animals) were excised 1 h after a single bolus or 1 h infusion or at the end of 5 and 24 h infusions. (19)F-NMR spectroscopy at 11.7 T was used to quantitate FU and its metabolites in ca. 1 g of tissue at 4 degrees C. In experiment B analogous FU treatments were repeated for 5 days (rats 80+11 controls). Tumor volumes vs time, various blood parameters and survival times were recorded, and a log growth rate parameter log GR, a response index RI, and a toxicity index TI were calculated. The i.a. vs i.v. ratios for tumor concentrations of FU and total anabolites (F-Nucl) were >1 for nearly all treatments and increased with infusion time at the higher doses. F-Nucl in tumor correlated linearly with total fluorine concentration (Tot. F range 30-1100 nmol/g) over all treatments (r=0.92, slope=0.45, p<0.0001). For non-bolus i.v. treatments [FU+F-Nucl] decreased linearly with decreasing FU dose rate (r(2)=0.74, zero intercept), while i.a. treatments showed non-linear behavior. For non-bolus treatments the mean log GR per treatment group showed a negative correlation (r=-0.87) with log[F-Nucl]. The most effective non-toxic treatments were 25 mg/kg over 5 or 24 h; the i.a. route was superior to i.v. on the basis of [FU+F-Nucl], RI, the reduction in log GR, and Kaplan-Meier survival statistics. For liver and kidney Tot. F (>83% FU catabolites) reached ca. 3-4 and 6-7 micromol/g, respectively, at the highest dose rates for either route; F-Nucl were detected only for Tot. F>500 nmol/g and increased exponentially as Tot. F increased (toxic treatments). The concentrations of the main catabolite (alpha-fluoro-beta-alanine, FBAL) in tumor did not correlate with Tot. F but rather with FBAL levels in kidney (r=0.90, all treatments), indicating that uptake of liver-derived FBAL from the circulation is the major source of FBAL in tumor.

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Clinical Management and Current Research in Isolated Limb Perfusion for Sarcoma and Melanoma

Cited by 18 publications

References 82 publications

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

The Role of Hyperthermia in Regional Alkylating Agent Chemotherapy

Fluoropyrimidine chemotherapy in a rat model: comparison of fluorouracil metabolite profiles determined by high‐field ¹⁹F‐NMR spectroscopy of tissues ex vivo with therapy response and toxicity for locoregional vs systemic infusion protocols

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Clinical Management and Current Research in Isolated Limb Perfusion for Sarcoma and Melanoma

Cited by 18 publications

References 82 publications

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

The Role of Hyperthermia in Regional Alkylating Agent Chemotherapy

Fluoropyrimidine chemotherapy in a rat model: comparison of fluorouracil metabolite profiles determined by high‐field 19F‐NMR spectroscopy of tissues ex vivo with therapy response and toxicity for locoregional vs systemic infusion protocols

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Fluoropyrimidine chemotherapy in a rat model: comparison of fluorouracil metabolite profiles determined by high‐field ¹⁹F‐NMR spectroscopy of tissues ex vivo with therapy response and toxicity for locoregional vs systemic infusion protocols