Abstract
Background
Tumor necrosis factor (TNF)-α–based hyperthermic isolated limb perfusion (HILP) is one of the most active available approaches for locally advanced soft tissue sarcomas (STS) of the limbs. The aim of this study was to investigate the anticancer activity of a novel drug regimen including doxorubicin (DXR) and low-dose TNF-α.
Methods
HILP with low-dose TNF-α (1 mg) and DXR (8.5 mg/L of limb volume) was given to 21 patients with limb-threatening STS: 14 had primary and 7 had recurrent STS, most of which were high grade (grade 1, n = 3; grade 2, n = 6; grade 3, n = 12). Resection of the tumor remnant was performed 6 to 8 weeks after HILP. TNF-α concentrations in plasma and perfusate were measured throughout perfusion.
Results
A major tumor response was observed at histology and clinical evaluation in 90% and 62% of patients, respectively. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 71% and 81% of cases, respectively. Fourteen patients had moderate regional toxicity, which was resolved in all cases. One patient had severe limb toxicity, which did not require amputation. Systemic side effects were minimal, and there were no postoperative deaths. The perfusate/plasma area under the curve ratio for TNF-α was 56.
Conclusions
HILP with low-dose TNF-α and DXR seems to be an active neoadjuvant drug regimen against limb-threatening STS. This therapeutic approach can achieve high limb-sparing surgery rates with acceptable local and negligible systemic toxicity.
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References
HJ Hoekstra HS Koops J Oldhoff (1994) ArticleTitleSoft tissue sarcoma of the extremity Eur J Surg Oncol 20 3–6 Occurrence Handle1:STN:280:ByuC2sfjvVM%3D Occurrence Handle8131865
DA Potter J Glenn T Kinsella (1985) ArticleTitlePatterns of recurrence in patients with high-grade soft-tissue sarcomas J Clin Oncol 3 353–66
SJ Ham HJ Hoekstra H Schraffordt Koops WH Eisma J Oldhoff (1993) ArticleTitleThe interscapulothoracic amputation in the treatment of malignant diseases of the upper extremity with a review of the literature Eur J Surg Oncol 19 543–8 Occurrence Handle1:STN:280:ByuD1MvpsFI%3D Occurrence Handle8270041
SJ Ham HJ Hoekstra WH Eisma H Schraffordt Koops J Oldhoff (1993) ArticleTitleThe Tikhoff-Linberg procedure in the treatment of sarcomas of the shoulder girdle J Surg Oncol 53 71–7 Occurrence Handle1:STN:280:ByyB2svos1A%3D Occurrence Handle8501909
DJ Beech RE Pollock (1995) ArticleTitleSurgical management of primary soft tissue sarcoma Hematol Oncol Clin North Am 9 707–18 Occurrence Handle1:STN:280:BymD3MrgvV0%3D Occurrence Handle7490236
A Stotter (1992) ArticleTitleComparison of amputation with limb-sparing operations for adult soft tissue sarcoma of the extremity Ann Surg 216 615–6 Occurrence Handle1:STN:280:ByyD2svitVU%3D Occurrence Handle1444656
CR Rossi S Mocellin P Pilati M Foletto D Nitti M Lise (2003) ArticleTitleTNFalpha-based isolated perfusion for limb-threatening soft tissue sarcomas: state of the art and future trends J Immunother 26 291–300 Occurrence Handle10.1097/00002371-200307000-00001 Occurrence Handle1:CAS:528:DC%2BD3sXmt1Onu7k%3D Occurrence Handle12843791
AM Eggermont JH Wilt Particlede TL ten Hagen (2003) ArticleTitleCurrent uses of isolated limb perfusion in the clinic and a model system for new strategies Lancet Oncol 4 429–37 Occurrence Handle10.1016/S1470-2045(03)01141-0 Occurrence Handle12850194
O Creech E Krementz R Ryan (1958) ArticleTitleChemotherapy of cancer: regional perfusion utilizing an extracorporeal circuit Ann Surg 148 616–32 Occurrence Handle13583933
ET Krementz RD Carter CM Sutherland I Hutton (1977) ArticleTitleChemotherapy of sarcomas of the limbs by regional perfusion Ann Surg 185 555–64 Occurrence Handle1:STN:280:CSiC1c%2Fls1A%3D Occurrence Handle266397
HI Robins F d’Oleire M Kutz et al. (1995) ArticleTitleCytotoxic interactions of tumor necrosis factor, melphalan and 41.8 degrees C hyperthermia Cancer Lett 89 55–62 Occurrence Handle1:CAS:528:DyaK2MXjs1Crs74%3D Occurrence Handle7882302
TS Herman (1983) ArticleTitleTemperature dependence of adriamycin, cis-diamminedichloroplatinum, bleomycin, and 1,3-bis(2-chloroethyl)-1-nitrosourea cytotoxicity in vitro Cancer Res 43 517–20 Occurrence Handle1:CAS:528:DyaL3sXhtVSrtL8%3D Occurrence Handle6184147
D Lienard P Ewalenko JJ Delmotte N Renard FJ Lejeune (1992) ArticleTitleHigh-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma J Clin Oncol 10 52–60 Occurrence Handle1:STN:280:By2D1M3gslQ%3D Occurrence Handle1727926
AM Eggermont H Schraffordt Koops D Lienard et al. (1996) ArticleTitleIsolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial J Clin Oncol 14 2653–65 Occurrence Handle1:CAS:528:DyaK28XmsFCgtr0%3D Occurrence Handle8874324
AM Eggermont H Schraffordt Koops JM Klausner et al. (1996) ArticleTitleIsolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience Ann Surg 224 756–64 Occurrence Handle10.1097/00000658-199612000-00011 Occurrence Handle1:STN:280:ByiC383pvVU%3D Occurrence Handle8968230
M Gutman M Inbar D Lev-Shlush et al. (1997) ArticleTitleHigh dose tumor necrosis factor-alpha and melphalan administered via isolated limb perfusion for advanced limb soft tissue sarcoma results in a >90% response rate and limb preservation Cancer 79 1129–37
M Vaglini F Belli M Ammatuna et al. (1994) ArticleTitleTreatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gamma-interferon, and melphalan Cancer 73 483–92 Occurrence Handle1:STN:280:ByuC38zisFA%3D Occurrence Handle8293417
P Eggimann R Chiolero PG Chassot D Lienard J Gerain F Lejeune (1995) ArticleTitleSystemic and hemodynamic effects of recombinant tumor necrosis factor alpha in isolation perfusion of the limbs Chest 107 1074–82 Occurrence Handle1:STN:280:ByqB38%2Fgs1I%3D Occurrence Handle7705119
F Villani M Galimberti G Mazzola et al. (1995) ArticleTitlePulmonary toxicity of alpha tumor necrosis factor in patients treated by isolation perfusion J Chemother 7 452–4 Occurrence Handle1:CAS:528:DyaK28XjsFOl Occurrence Handle8596131
BC Vrouenraets BB Kroon AC Ogilvie et al. (1999) ArticleTitleAbsence of severe systemic toxicity after leakage-controlled isolated limb perfusion with tumor necrosis factor-alpha and melphalan Ann Surg Oncol 6 405–12 Occurrence Handle10.1007/s10434-999-0405-9 Occurrence Handle1:STN:280:DyaK1Mzgs1GgsA%3D%3D Occurrence Handle10379864
WC Barker MP Andrich HR Alexander DL Fraker (1995) ArticleTitleContinuous intraoperative external monitoring of perfusate leak using iodine-131 human serum albumin during isolated perfusion of the liver and limbs Eur J Nucl Med 22 1242–8 Occurrence Handle10.1007/BF00801607 Occurrence Handle1:CAS:528:DyaK28XktVSgsA%3D%3D Occurrence Handle8575471
A Santoro T Tursz H Mouridsen et al. (1995) ArticleTitleDoxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group J Clin Oncol 13 1537–45 Occurrence Handle1:STN:280:ByqA38ros1w%3D Occurrence Handle7602342
CR Rossi M Foletto F Di Filippo et al. (1999) ArticleTitleSoft tissue limb sarcomas: Italian clinical trials with hyperthermic antiblastic perfusion Cancer 86 1742–9 Occurrence Handle10.1002/(SICI)1097-0142(19991101)86:9<1742::AID-CNCR16>3.0.CO;2-G Occurrence Handle1:STN:280:DC%2BD3c%2Fhs1ejsA%3D%3D Occurrence Handle10547547
F Di Filippo CR Rossi M Vaglini et al. (1999) ArticleTitleHyperthermic antiblastic perfusion with alpha tumor necrosis factor and doxorubicin for the treatment of soft tissue limb sarcoma in candidates for amputation: results of a phase I study J Immunother 22 407–14 Occurrence Handle1:CAS:528:DyaK1MXntlakt7k%3D Occurrence Handle10546156
CR Rossi A Vecchiato M Foletto et al. (1994) ArticleTitlePhase II study on neoadjuvant hyperthermic-antiblastic perfusion with doxorubicin in patients with intermediate or high grade limb sarcomas Cancer 73 2140–6 Occurrence Handle1:STN:280:ByuB3cjpslA%3D Occurrence Handle8156518
D Casara D Rubello P Pilati et al. (2004) ArticleTitleOptimized procedure of real-time systemic leakage monitoring during isolated limb perfusion using a hand held gamma probe and 99m Tc-HSA Nucl Med Commun 25 61–6 Occurrence Handle10.1097/00006231-200401000-00009 Occurrence Handle1:STN:280:DC%2BD2c7mslertQ%3D%3D Occurrence Handle15061266
J Wieberdink C Benckhuysen RP Braat EA van Slooten GA Olthuis (1982) ArticleTitleDosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions Eur J Cancer Clin Oncol 18 905–10 Occurrence Handle10.1016/0277-5379(82)90235-8 Occurrence Handle1:STN:280:BiyC3s7nslc%3D Occurrence Handle6891640
TR Fleming (1982) ArticleTitleOne-sample multiple testing procedure for phase II clinical trials Biometrics 38 143–51 Occurrence Handle1:STN:280:Bi2B3cnptlY%3D Occurrence Handle7082756
AM Eggermont TL ten Hagen (2001) ArticleTitleIsolated limb perfusion for extremity soft-tissue sarcomas, in-transit metastases, and other unresectable tumors: credits, debits, and future perspectives Curr Oncol Rep 3 359–67 Occurrence Handle1:STN:280:DC%2BD3MzhvFOktA%3D%3D Occurrence Handle11389822
FJ Lejeune N Pujol D Lienard et al. (2000) ArticleTitleLimb salvage by neoadjuvant isolated perfusion with TNFalpha and melphalan for non-resectable soft tissue sarcoma of the extremities Eur J Surg Oncol 26 669–78 Occurrence Handle10.1053/ejso.2000.0979 Occurrence Handle1:STN:280:DC%2BD3M%2Fms1Squw%3D%3D Occurrence Handle11078614
D Lev-Chelouche S Abu-Abeid Y Kollander et al. (1999) ArticleTitleMultifocal soft tissue sarcoma: limb salvage following hyperthermic isolated limb perfusion with high-dose tumor necrosis factor and melphalan J Surg Oncol 70 185–9 Occurrence Handle10.1002/(SICI)1096-9098(199903)70:3<185::AID-JSO8>3.0.CO;2-# Occurrence Handle1:STN:280:DyaK1M3gtVCksQ%3D%3D Occurrence Handle10102350
BE Plaat WM Molenaar MF Mastik et al. (1999) ArticleTitleHyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan in patients with locally advanced soft tissue sarcomas: treatment response and clinical outcome related to changes in proliferation and apoptosis Clin Cancer Res 5 1650–7 Occurrence Handle1:CAS:528:DyaK1MXltVCqsbs%3D Occurrence Handle10430064
H Schraffordt Koops AM Eggermont D Lienard et al. (1998) ArticleTitleHyperthermic isolated limb perfusion for the treatment of soft tissue sarcomas Semin Surg Oncol 14 210–4 Occurrence Handle10.1002/(SICI)1098-2388(199804/05)14:3<210::AID-SSU4>3.0.CO;2-B Occurrence Handle1:STN:280:DyaK1c3gvVersQ%3D%3D Occurrence Handle9548603
S Hill WJ Fawcett J Sheldon N Soni T Williams JM Thomas (1993) ArticleTitleLow-dose tumour necrosis factor alpha and melphalan in hyperthermic isolated limb perfusion Br J Surg 80 995–7 Occurrence Handle1:STN:280:ByuD3crmt1Y%3D Occurrence Handle8402100
RB Alexander WG Nelson DS Coffey (1987) ArticleTitleSynergistic enhancement by tumor necrosis factor of in vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II Cancer Res 47 2403–6 Occurrence Handle1:CAS:528:DyaL2sXktlaktro%3D Occurrence Handle2436763
N Watanabe Y Niitsu N Yamauchi et al. (1988) ArticleTitleSynergistic cytotoxicity of recombinant human TNF and various anti-cancer drugs Immunopharmacol Immunotoxicol 10 117–27 Occurrence Handle1:CAS:528:DyaL1cXhsl2ks7k%3D Occurrence Handle2452179
N Watanabe Y Niitsu H Umeno et al. (1988) ArticleTitleSynergistic cytotoxic and antitumor effects of recombinant human tumor necrosis factor and hyperthermia Cancer Res 48 650–3 Occurrence Handle1:STN:280:BieD1c%2FgvFA%3D Occurrence Handle3335027
MF Dubois C Ferrieux P Lebon (1989) ArticleTitleSynergistic cytotoxic effects of recombinant human tumor necrosis factor, interferons, and heat-stress Cancer Res 49 5618–22 Occurrence Handle1:CAS:528:DyaL1MXmtlSnt7k%3D Occurrence Handle2477147
AH Veen Particlevan der JH de Wilt AM Eggermont ST van Tiel AL Seynhaeve TL ten Hagen (2000) ArticleTitleTNF-alpha augments intratumoural concentrations of doxorubicin in TNF-alpha-based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects Br J Cancer 82 973–80 Occurrence Handle10.1054/bjoc.1999.1027 Occurrence Handle10732774
M Santinami M Deraco A Azzarelli et al. (1996) ArticleTitleTreatment of recurrent sarcoma of the extremities by isolated limb perfusion using tumor necrosis factor alpha and melphalan Tumori 82 579–84 Occurrence Handle1:CAS:528:DyaK2sXisFWqs7s%3D Occurrence Handle9061068
AM Eggermont H Schraffordt Koops JM Klausner et al. (1997) ArticleTitleIsolation limb perfusion with tumor necrosis factor alpha and chemotherapy for advanced extremity soft tissue sarcomas Semin Oncol 24 547–55 Occurrence Handle1:STN:280:DyaK1c%2FgtlSjtA%3D%3D Occurrence Handle9344321
MG Rosenblum NJ Donato JU Gutterman (1988) ArticleTitleCharacterization of human recombinant tumor necrosis factor-alpha antiproliferative effects on human cells in culture Lymphokine Res 7 107–17 Occurrence Handle1:CAS:528:DyaL1cXkslWktLY%3D Occurrence Handle2457138
JF Buell E Reed KB Lee et al. (1997) ArticleTitleSynergistic effect and possible mechanisms of tumor necrosis factor and cisplatin cytotoxicity under moderate hyperthermia against gastric cancer cells Ann Surg Oncol 4 141–8 Occurrence Handle1:STN:280:ByiB3sbhs1c%3D Occurrence Handle9084851
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Rossi, C.R., Mocellin, S., Pilati, P. et al. Hyperthermic Isolated Perfusion With Low-Dose Tumor Necrosis Factor α and Doxorubicin for the Treatment of Limb-Threatening Soft Tissue Sarcomas. Ann Surg Oncol 12, 398–405 (2005). https://doi.org/10.1245/ASO.2005.12.038
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DOI: https://doi.org/10.1245/ASO.2005.12.038