Toxicity and morbidity of isolated limb perfusion

Vrouenraets, B. C.; Klaase, Joost M.; Nieweg, Omgo E.; Kroon, Bin B. R.

doi:10.1002/(sici)1098-2388(199804/05)14:3<224::aid-ssu6>3.0.co;2-a

Cited by 70 publications

(27 citation statements)

References 37 publications

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“…24 The encountered acute regional tissue toxicity after TNF␣-ILP was comparable to data on toxicity reported in the literature, with some erythema and edema in 71% of patients. 25 Three major ILP-related complications occurred, including arterial thrombosis in two patients and one ILP-related death due to fulminant Clostridial infection. Long-term morbidity was seen in several patients.…”

Section: Discussionmentioning

confidence: 99%

Isolated limb perfusion with tumor necrosis factor‐α and melphalan for patients with unresectable soft tissue sarcoma of the extremities

Noorda

Vrouenraets

Nieweg

et al. 2003

Cancer

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BACKGROUNDSince 1992, isolated limb perfusion (ILP) with tumor necrosis factor‐α (TNFα) and melphalan has been used for the treatment of patients with unresectable soft tissue sarcomas of the extremities. The authors retrospectively studied the results of limb salvage surgery using TNFα‐ILP at their institution.METHODSFrom 1992 to 2001, 49 patients (mean age, 51 years; range, 14–85 years) underwent ILP for unresectable soft tissue sarcomas of the extremities. All patients received melphalan and TNFα (four patients also received interferon‐γ). The median follow‐up was 26 months (range, from 2 days to 103 months).RESULTSIn 1 patient (2%) who died 2 days after undergoing ILP, response and acute limb toxicity could not be assessed. One patient (2%) attained a clinical complete response (2%), 23 patients (47%) attained a clinical partial response, 17 patients (35%) demonstrated no change, and 7 patients (14%) had tumor progression. Thirty‐one patients (63%) underwent tumor resection. Histologic material also was available from eight amputations and three punctures/biopsies. Pathologic response was complete in 4 patients (8%), partial in 14 patients (29%), and no change was observed in 24 patients (49%). Final response, based on both clinical and pathologic assessment in which pathology was decisive, was complete in 4 patients (8%) and partial in 27 patients (55%), resulting in a final overall response rate of 63%. Local control with preservation of the limb was attained in 28 patients (57%). Four of 32 patients (13%) who had been rendered tumor free by ILP with or without undergoing resection and radiation therapy, developed a local recurrence. The 5‐year disease specific survival rate was 48% for the 49 patients. Acute limb toxicity after ILP was a mild Grade 1–2 reaction in 35 patients (71%) patients, a Grade 3 reaction in 12 patients (25%), and a Grade 4 reaction in 1 patient (2%). Three major ILP‐related complications were encountered, including arterial thrombosis in two patients and a fulminant Clostridial infection leading to death in one patient. There were no severe cardiovascular reactions after ILP.CONCLUSIONSIn patients with unresectable soft tissue sarcomas of the limbs who underwent ILP with TNFα and melphalan followed by resection of the tumor remnant when possible, a 63% overall tumor response rate and a 57% local control rate with limb preservation was achieved. Cancer 2003;98:1483–90. © 2003 American Cancer Society.DOI 10.1002/cncr.11648

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Section: Discussionmentioning

confidence: 99%

Isolated limb perfusion with tumor necrosis factor‐α and melphalan for patients with unresectable soft tissue sarcoma of the extremities

Noorda

Vrouenraets

Nieweg

et al. 2003

Cancer

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“…Nashan, J. Hübner Relevant types of lymphedemas in melanoma are due to obstruction of lymph drainage by the tumor or secondarily as a result of treatment [685] such as e.g.  surgery, especially lymph node dissection [686],  radiation therapy [687],  isolated limb perfusion [688]. If left untreated, chronic persistent lymphedema may develop.…”

Section: Lymphedemamentioning

confidence: 99%

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

Pflugfelder

Kochs

Blum

et al. 2013

J Deutsche Derma Gesell

180

148

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“…In addition, f1% to 3% of patients suffered complications leading to amputation, 10% to 15% developed compartment syndrome, 30% to 40% developed lymphedema, and 5% to 8% develop long-term neuropathy (30,31). The lack of response durability, the large number of partial responders, and the moderate limb toxicity associated with melphalanbased treatment has led to the exploration of novel approaches to optimizing regional therapy (32 -34).…”

Section: Vessels (20)mentioning

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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Toxicity and morbidity of isolated limb perfusion

Cited by 70 publications

References 37 publications

Isolated limb perfusion with tumor necrosis factor‐α and melphalan for patients with unresectable soft tissue sarcoma of the extremities

Isolated limb perfusion with tumor necrosis factor‐α and melphalan for patients with unresectable soft tissue sarcoma of the extremities

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

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

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