Absence of Severe Systemic Toxicity After Leakage-Controlled Isolated Limb Perfusion With Tumor Necrosis Factor-α and Melphalan

Vrouenraets, B. C.; Kroon, Bin B. R.; Ogilvie, A. C.; Geel, A.N. van; Nieweg, Omgo E.; Swaak, A. J. G.; Eggermont, Alexander M.M.

doi:10.1007/s10434-999-0405-9

Cited by 49 publications

(21 citation statements)

References 27 publications

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“…Application of ILP, with leakage below 5%, allows high local dosages of cytotoxic agents without the systemic side-effects (Benckhuijsen et al, 1988;Buckley et al, 1989;Vrouenraets et al, 1999). This means that local toxicity is the limiting factor.…”

Section: Experimental Therapeuticsmentioning

confidence: 99%

Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

et al. 2002

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Previously we demonstrated that addition of Tumour Necrosis Factor-a to melphalan or doxorubicin in a so-called isolated limb perfusion results in synergistic antitumour responses of sarcomas in both animal models and patients. Yet, 20 to 30% of the treated tumours do not respond. Therefore agents that synergise with tumour necrosis factor alpha must be investigated. Actinomycin D is used in combination with melphalan in isolated limb perfusion in the treatment of patients with melanoma in-transit metastases and is well known to augment tumour cell sensitivity towards tumour necrosis factor alpha in vitro. Both agents are very toxic, which limits their systemic use. Their applicability may therefore be tested in the isolated limb perfusion setting, by which the tumours can be exposed to high concentrations in the absence of systemic exposure. To study the beneficial effect of the combination in vivo, BN-175 soft tissue sarcoma-bearing rats were perfused with various concentrations of actinomycin D and tumour necrosis factor alpha. When used alone the drugs had only little effect on the tumour. Only when actinomycin D and tumour necrosis factor alpha were combined a tumour response was achieved. However, these responses were accompanied by severe, dose limiting, local toxicity such as destruction of the muscle tissue and massive oedema. Our results show that isolated limb perfusion with actinomycin D in combination with tumour necrosis factor alpha leads to a synergistic anti-tumour response but also to idiosyncratic locoregional toxicity to the normal tissues. Actinomycin D, in combination with tumour necrosis factor alpha, should not be explored in the clinical setting because of this. The standard approach in the clinic remains isolated limb perfusion with tumour necrosis factor alpha in combination with melphalan.

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Section: Experimental Therapeuticsmentioning

confidence: 99%

Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

et al. 2002

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“…The perception that TNF-based ILP is a risky endeavor has been demonstrated to be false provided that leakage is monitored and well controlled. 13 But even in the event of significant leakage, we have demonstrated that with correct fluid management and postoperative care, patients do not develop major or life-threatening complications. 14 Therefore we do not think it is reasonable to consider age a limiting factor for patients to undergo a TNF-based ILP.…”

mentioning

confidence: 96%

Fifty Tumor Necrosis Factor?Based Isolated Limb Perfusions for Limb Salvage in Patients Older Than 75 Years With Limb-Threatening Soft Tissue Sarcomas and Other Extremity Tumors

et al. 2003

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Background: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan is highly effective in treating limb-threatening soft tissue sarcoma (STS) and other bulky tumors. Because of fear of TNF-associated toxicity, ILP with TNF is not offered to older patients in some cancer centers, although especially in older patients, every attempt to avoid an amputation that may end their independence must be considered.Methods: Out of 306 TNF-based ILPs, 50 ILPs were performed for limb salvage in 43 patients Ͼ75 years old (range, 75-91 years): 29 STS and 14 melanoma patients.Results: In the STS patients, a response rate of 76% and a limb-salvage rate of 76% were achieved; in the melanoma patients, a 100% response rate and a 93% limb-salvage rate were achieved. Local toxicity was mild. The three postoperative deaths that occurred in the total series of 306 TNF-based ILPs in Rotterdam (Ͻ1%) occurred in patients Ͼ75 years old after leakage-free perfusions and were not related to TNF but to extremely high-risk profiles in these three patients.Conclusions: Older patients should not be withheld a TNF-based ILP for limb salvage, because the procedure is safe and highly effective in these patients.

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“…[19][20][21] However, the use of TNF has been limited secondary to the serious toxicity of TNF in the systemic circulation. 22 Some investigators have devised strategies to mitigate the problems associated with the systemic release of soluble TNF through techniques such as hypothermic isolated limb perfusion of cells transduced in situ, 23,24 physically linking soluble TNF to the tumor-cell membrane, 25 using TNF in the form of a fusion molecule, 26,27 or by driving expression of TNF in transduced cells with weak, tissue-specific or radiation-inducible promoters. [27][28][29][30] In addition, others have used vectors encoding a truncated TNF that lacks the TACE cleavage site.…”

Section: Discussionmentioning

confidence: 99%

Chimeric form of tumor necrosis factor-α has enhanced surface expression and antitumor activity

et al. 2008

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Tumor necrosis factor (TNF)-a is a type-II transmembrane protein that is cleaved by TNF-a-converting enzyme (TACE/ADAM-17) to release soluble TNF, a cytokine with potent antitumor properties whose use in clinical applications is limited by its severe systemic toxicity. We found that human cells transfected with vectors encoding TNF without the TACE cleavage site (DTACE-TNF) still released functional cytokine at substantial levels that varied between transfected cell lines of different tissue types. Vectors encoding membrane-associated domains of CD154, another TNF-family protein, conjoined with the carboxyl-terminal domain of TNF, directed higher-level surface expression of a functional TNF that, in contrast to DTACE-TNF, was resistant to cleavage in all cell types. Furthermore, adenovirus vectors encoding CD154-TNF had significantly greater in vivo biological activity in inducing regression of established, syngeneic tumors in mice than adenovirus vectors encoding TNF, and lacked toxicity associated with soluble TNF. As such, CD154-TNF is a novel TNF that appears superior for treatment of tumors in which high-level local expression of TNF is desired.

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Absence of Severe Systemic Toxicity After Leakage-Controlled Isolated Limb Perfusion With Tumor Necrosis Factor-α and Melphalan

Abstract: Systemic toxicity after ILP with TNF-alpha is minimal and does not differ from that after ILP with melphalan alone when leakage is adequately controlled.

Cited by 49 publications

References 27 publications

Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

Fifty Tumor Necrosis Factor?Based Isolated Limb Perfusions for Limb Salvage in Patients Older Than 75 Years With Limb-Threatening Soft Tissue Sarcomas and Other Extremity Tumors

Chimeric form of tumor necrosis factor-α has enhanced surface expression and antitumor activity

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