Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities

Klaase, Joost M.; Kroon, Bin B. R.; Benckhuijsen, C.; Geel, A.N. van; Albus‐Lutter, Ch.; Wieberdink, J

doi:10.1002/1097-0142(19890801)64:3<616::aid-cncr2820640309>3.0.co;2-8

Cited by 98 publications

(28 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, histopathologic observations (Nooijen et al, 1996a) closely resemble observations in patients (Renard et al, 1994;Nooijen et al, 1996b). TNF alone is not active (Posner et al, 1994) and melphalan is only marginally active in soft tissue sarcoma (Kremetz et al, 1977;Klaase et al, 1989), whereas the combination results in very high response rates in this rat model just as in melanoma patients (Liénard et al, 1992;Fraker et al, 1996) or soft tissue sarcoma patients . Here we report on 167 ILPs to determine ways to optimize ILP efficacy for the clinical setting.…”

Section: Discussionsupporting

confidence: 58%

“…Melphalan has been the standard drug for this regional treatment because of low regional toxicity (Thompson and Gianoutsos, 1992). ILPs with melphalan or other cytostatic drugs has also been used in the treatment of patients with extremity soft tissue sarcomas, although with little success (Kremetz et al, 1977;Klaase et al, 1989). Therefore, Liénard et al (1992) pioneered the application of high-dose tumour necrosis factor (TNF)-α and interferon gamma (IFN-γ) with melphalan, which was reported to result in very high complete response rates in melanoma patients.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats

et al. 1999

View full text Add to dashboard Cite

MelphalanMelphalan (Alkeran, 50 mg per vial, Wellcome, Beckenham, UK) was diluted in 10 ml solvent. Further dilutions were made in 0.9% sodium chloride to give a concentration of 1 µg µl -1 . A volume of 40 µl (= 40 µg) was added to the perfusion circuit.Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats Summary An isolated limb perfusion (ILP) model using soft tissue sarcoma-bearing rats was used to study prerequisites for an effective ILP, such as oxygenation of the perfusate, temperature of the limb, duration of the perfusion and concentration of tumour necrosis factor (TNF). Combination of 50 µg TNF and 40 µg melphalan demonstrated synergistic activity leading to a partial and complete response rate of 71%. In comparison to oxygenated ILP, hypoxia was shown to enhance anti-tumour activity of melphalan alone and TNF alone but not of their combined use. Shorter perfusion times decreased anti-tumour responses. At a temperature of 24-26°C, anti-tumour effects were lost, whereas temperatures of 38-39°C or 42-43°C resulted in higher response rates. However, at 42-43°C, local toxicity impaired limb function dramatically. Synergy between TNF and melphalan was lost at a dose of TNF below 10 µg in 5 ml perfusate. We conclude that the combination of TNF and melphalan has strong synergistic anti-tumour effects in our model, just as in the clinical setting. Hypoxia enhanced activity of melphalan and TNF alone but not the efficacy of their combined use. For an optimal ILP, minimal perfusion time of 30 min and minimal temperature of 38°C was mandatory. Moreover, the dose of TNF could be lowered to 10 µg per 5 ml perfusate, which might allow the use of TNF in less leakage-free or less inert perfusion settings.

show abstract

Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 99%

Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats

et al. 1999

View full text Add to dashboard Cite

show abstract

“…2 Before that, no other antisarcoma drugs had lead to the promising results with acceptable toxicity attained with TNF␣ in the isolated circuit. 3 In the first 4patients with unresectable, recurrent STS who were treated with TNF␣ and melphalan, a 100% tumor response rate was reported after ILP. 2 Later results of TNF␣-ILP for patients with unresectable STS of the extremities from other institutions demonstrated overall response rates varying from 79% to 91%.…”

mentioning

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

View full text Add to dashboard Cite

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

show abstract

“…In patients with multiple and/or bulky in-transit melanoma metastases, obtaining local control is a major challenge. In contrast to the inefficacy of ILP with melphalan alone in the management of irresectable extremity STS, with response rates of only 10% to 35%, 3,4 the introduction of tumor necrosis factor-␣ (TNF) in combination with melphalan in ILP has been reported in a European multicenter trial; it resulted in response rates Ͼ80% and limb-salvage rates Ͼ70% in STS. 5,6 These results led to the approval of TNF in Europe.…”

mentioning

confidence: 99%

“…Approximately 18% of the patient population is above the age of 70 years. 4 The incidence of malignant melanoma has more than doubled over the last 20 years. 12 For both men and women, rates increased relatively more in the older age groups.…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities

Cited by 98 publications

References 18 publications

Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats

Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats

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

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

Contact Info

Product

Resources

About