Skip to main content
Top
Published in: Clinical and Translational Oncology 9/2019

01-09-2019 | Soft Tissue Sarcoma | Research Article

Neoadjuvant isolated limb perfusion in newly diagnosed untreated patients with locally advanced soft tissue sarcomas of the extremities: the Gustave Roussy experience

Authors: T. Assi, A. Cavalcanti, A. Le Cesne, M. Faron, J. F. Honart, A. Hadiji, O. Camuzard, T. Ibrahim, C. LePéchoux, O. Mir, S. Dumont, P. Terrier, J. Adam, C. Honoré

Published in: Clinical and Translational Oncology | Issue 9/2019

Login to get access

Abstract

Background

Limb-sparing surgery in locally advanced soft tissue sarcomas (LA STS) is challenging. The aim of this study is to evaluate upfront isolated limb perfusion (ILP) in untreated patients with LA STS.

Methods

All consecutive patients with LA STS of the limbs deemed borderline or unresectable and treated with upfront ILP as induction treatment between 2003 and 2016 were included. Demographic, clinical and long-term characteristics were obtained and retrospectively analyzed.

Results

41 patients (pts), with a median age of 51 years [range 21–76], were identified (lower limb 68%, upper limb 32%). Liposarcoma and undifferentiated pleomorphic sarcoma were the most common subtypes (27% and 22%, respectively). Acute toxicities, using Wieberdink classification, were grade II (35 pts, 85%), grade III (2 pts, 5%) and no grade IV–V. Local control rate was 98%. 32 pts had limb-sparing surgery (78%). 1 pt had an early amputation due to progressive disease after ILP. 8 pts were not operated (four had RT alone, one had distant metastases, two had a complete response and one died 3 months after ILP of a pulmonary embolism). 36 pts (84%) received postoperative RT. After a median follow-up of 43 months, 18 pts (47%) relapsed. Median disease-free survival (DFS) was 6.7 years. The median overall survival (OS) was not reached. The 1-year, 5-year and 10-year DFS and OS rates were, respectively, 75%, 50% and 45%, and 90%, 63% and 55%.

Conclusion

Upfront ILP is an efficient and well-tolerated limb-sparing procedure in borderline or unresectable LA STS without hampering OS.
Literature
1.
go back to reference Honore C, Méeus P, Stoeckle E, Bonvalot S. Soft tissue sarcoma in France in 2015: epidemiology, classification and organization of clinical care. J Visc Surg. 2015;152:223–30.CrossRefPubMed Honore C, Méeus P, Stoeckle E, Bonvalot S. Soft tissue sarcoma in France in 2015: epidemiology, classification and organization of clinical care. J Visc Surg. 2015;152:223–30.CrossRefPubMed
2.
go back to reference Stiller CA, Trama A, Serraino D, Rossi S, Navarro C, Chirlaque MD, et al. Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project. Eur J Cancer. 2013;49:684–95.CrossRefPubMed Stiller CA, Trama A, Serraino D, Rossi S, Navarro C, Chirlaque MD, et al. Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project. Eur J Cancer. 2013;49:684–95.CrossRefPubMed
3.
go back to reference Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, et al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017;18:812–22.CrossRefPubMed Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, et al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017;18:812–22.CrossRefPubMed
4.
go back to reference Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P, et al. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol. 2012;30:850–6.CrossRefPubMed Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P, et al. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol. 2012;30:850–6.CrossRefPubMed
5.
go back to reference Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay J-Y, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15:415–23.CrossRefPubMed Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay J-Y, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15:415–23.CrossRefPubMed
6.
go back to reference Lienard D, Ewalenko P, Delmotte J-J, Renard N, Lejeune FJ. High-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. 1992;10:52–60.CrossRefPubMed Lienard D, Ewalenko P, Delmotte J-J, Renard N, Lejeune FJ. High-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. 1992;10:52–60.CrossRefPubMed
7.
go back to reference Lejeune FJ, Pujol N, Lienard D, Mosimann F, Raffoul W, Genton A, et al. Limb salvage by neoadjuvant isolated perfusion with TNFα and melphalan for non-resectable soft tissue sarcoma of the extremities. Eur J Surg Oncol EJSO. 2000;26:669–78.CrossRefPubMed Lejeune FJ, Pujol N, Lienard D, Mosimann F, Raffoul W, Genton A, et al. Limb salvage by neoadjuvant isolated perfusion with TNFα and melphalan for non-resectable soft tissue sarcoma of the extremities. Eur J Surg Oncol EJSO. 2000;26:669–78.CrossRefPubMed
8.
go back to reference Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. World Health Organization Classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. World Health Organization Classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013.
9.
go back to reference Trojani M, Contesso G, Coindre JM, Rouesse J, Bui NB, De Mascarel A, et al. Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer. 1984;33:37–42.CrossRefPubMed Trojani M, Contesso G, Coindre JM, Rouesse J, Bui NB, De Mascarel A, et al. Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer. 1984;33:37–42.CrossRefPubMed
10.
go back to reference Wieberdink J, Benckhuysen C, Braat RP, Van Slooten EA, Olthuis GAA. Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol. 1982;18:905–10.CrossRefPubMed Wieberdink J, Benckhuysen C, Braat RP, Van Slooten EA, Olthuis GAA. Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol. 1982;18:905–10.CrossRefPubMed
11.
go back to reference Eggermont AM, Koops HS, Klausner JM, Kroon BB, Schlag PM, Liénard D, et al. Isolated 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. 1996;224:756.CrossRefPubMedPubMedCentral Eggermont AM, Koops HS, Klausner JM, Kroon BB, Schlag PM, Liénard D, et al. Isolated 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. 1996;224:756.CrossRefPubMedPubMedCentral
12.
go back to reference Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205.CrossRefPubMedPubMedCentral Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205.CrossRefPubMedPubMedCentral
13.
go back to reference Health UD of, Services H. Common terminology criteria for adverse events (CTCAE) version 4.0. Natl Inst Health Natl Cancer Inst. 2009;4. Health UD of, Services H. Common terminology criteria for adverse events (CTCAE) version 4.0. Natl Inst Health Natl Cancer Inst. 2009;4.
14.
go back to reference O’Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359:2235–41.CrossRefPubMed O’Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359:2235–41.CrossRefPubMed
15.
go back to reference Cheng EY, Dusenbery KE, Winters MR, Thompson RC. Soft tissue sarcomas: preoperative versus postoperative radiotherapy. J Surg Oncol. 1996;61:90–9.CrossRefPubMed Cheng EY, Dusenbery KE, Winters MR, Thompson RC. Soft tissue sarcomas: preoperative versus postoperative radiotherapy. J Surg Oncol. 1996;61:90–9.CrossRefPubMed
16.
go back to reference Bickels J, Manusama ER, Gutman M, Eggermont AMM, Kollender Y, Abu-Abid S, et al. Isolated limb perfusion with tumour necrosis factor-α and melphalan for unresectable bone sarcomas of the lower extremity. Eur J Surg Oncol EJSO. 1999;25:509–14.CrossRefPubMed Bickels J, Manusama ER, Gutman M, Eggermont AMM, Kollender Y, Abu-Abid S, et al. Isolated limb perfusion with tumour necrosis factor-α and melphalan for unresectable bone sarcomas of the lower extremity. Eur J Surg Oncol EJSO. 1999;25:509–14.CrossRefPubMed
17.
go back to reference Grabellus F, Kraft C, Sheu S-Y, Ebeling P, Bauer S, Lendemans S, et al. Evaluation of 47 soft tissue sarcoma resection specimens after isolated limb perfusion with TNF-α and melphalan: histologically characterized improved margins correlate with absence of recurrences. Ann Surg Oncol. 2009;16:676–86.CrossRefPubMed Grabellus F, Kraft C, Sheu S-Y, Ebeling P, Bauer S, Lendemans S, et al. Evaluation of 47 soft tissue sarcoma resection specimens after isolated limb perfusion with TNF-α and melphalan: histologically characterized improved margins correlate with absence of recurrences. Ann Surg Oncol. 2009;16:676–86.CrossRefPubMed
18.
go back to reference Hoven-Gondrie ML, Bastiaannet E, van Ginkel RJ, Suurmeijer AJ, Hoekstra HJ. TNF dose reduction and shortening of duration of isolated limb perfusion for locally advanced soft tissue sarcoma of the extremities is safe and effective in terms of long-term patient outcome. J Surg Oncol. 2011;103:648–55.CrossRefPubMed Hoven-Gondrie ML, Bastiaannet E, van Ginkel RJ, Suurmeijer AJ, Hoekstra HJ. TNF dose reduction and shortening of duration of isolated limb perfusion for locally advanced soft tissue sarcoma of the extremities is safe and effective in terms of long-term patient outcome. J Surg Oncol. 2011;103:648–55.CrossRefPubMed
19.
go back to reference Noorda EM, Vrouenraets BC, Nieweg OE, van Coevorden F, van Slooten GW, Kroon BB. Isolated limb perfusion with tumor necrosis factor-α and melphalan for patients with unresectable soft tissue sarcoma of the extremities. Cancer. 2003;98:1483–90.CrossRefPubMed Noorda EM, Vrouenraets BC, Nieweg OE, van Coevorden F, van Slooten GW, Kroon BB. Isolated limb perfusion with tumor necrosis factor-α and melphalan for patients with unresectable soft tissue sarcoma of the extremities. Cancer. 2003;98:1483–90.CrossRefPubMed
20.
go back to reference Trabulsi NH, Patakfalvi L, Nassif MO, Turcotte RE, Nichols A, Meguerditchian AN. Hyperthermic isolated limb perfusion for extremity soft tissue sarcomas: systematic review of clinical efficacy and quality assessment of reported trials. J Surg Oncol. 2012;106:921–8.CrossRefPubMed Trabulsi NH, Patakfalvi L, Nassif MO, Turcotte RE, Nichols A, Meguerditchian AN. Hyperthermic isolated limb perfusion for extremity soft tissue sarcomas: systematic review of clinical efficacy and quality assessment of reported trials. J Surg Oncol. 2012;106:921–8.CrossRefPubMed
21.
go back to reference Jakob J, Tunn P-U, Hayes AJ, Pilz LR, Nowak K, Hohenberger P. Oncological outcome of primary non-metastatic soft tissue sarcoma treated by neoadjuvant isolated limb perfusion and tumor resection. J Surg Oncol. 2014;109:786–90.CrossRefPubMed Jakob J, Tunn P-U, Hayes AJ, Pilz LR, Nowak K, Hohenberger P. Oncological outcome of primary non-metastatic soft tissue sarcoma treated by neoadjuvant isolated limb perfusion and tumor resection. J Surg Oncol. 2014;109:786–90.CrossRefPubMed
22.
go back to reference Deroose JP, Burger JW, van Geel AN, Den Bakker MA, de Jong JS, Eggermont AM, et al. Radiotherapy for soft tissue sarcomas after isolated limb perfusion and surgical resection: essential for local control in all patients? Ann Surg Oncol. 2011;18:321–7.CrossRefPubMed Deroose JP, Burger JW, van Geel AN, Den Bakker MA, de Jong JS, Eggermont AM, et al. Radiotherapy for soft tissue sarcomas after isolated limb perfusion and surgical resection: essential for local control in all patients? Ann Surg Oncol. 2011;18:321–7.CrossRefPubMed
23.
go back to reference Deroose JP, Eggermont AM, van Geel AN, Burger JW, den Bakker MA, de Wilt JH, et al. Long-term results of tumor necrosis factor α–and melphalan-based isolated limb perfusion in locally advanced extremity soft tissue sarcomas. J Clin Oncol. 2011;29:4036–44.CrossRefPubMed Deroose JP, Eggermont AM, van Geel AN, Burger JW, den Bakker MA, de Wilt JH, et al. Long-term results of tumor necrosis factor α–and melphalan-based isolated limb perfusion in locally advanced extremity soft tissue sarcomas. J Clin Oncol. 2011;29:4036–44.CrossRefPubMed
24.
go back to reference Neuwirth MG, Song Y, Sinnamon AJ, Fraker DL, Zager JS, Karakousis GC. isolated limb perfusion and infusion for extremity soft tissue sarcoma: a contemporary systematic review and meta-analysis. Ann Surg Oncol. 2017;24:3803–10.CrossRefPubMed Neuwirth MG, Song Y, Sinnamon AJ, Fraker DL, Zager JS, Karakousis GC. isolated limb perfusion and infusion for extremity soft tissue sarcoma: a contemporary systematic review and meta-analysis. Ann Surg Oncol. 2017;24:3803–10.CrossRefPubMed
25.
go back to reference Bonvalot S, Rimareix F, Causeret S, Le Péchoux C, Boulet B, Terrier P, et al. Hyperthermic isolated limb perfusion in locally advanced soft tissue sarcoma and progressive desmoid-type fibromatosis with TNF 1 mg and melphalan (T1-M HILP) is safe and efficient. Ann Surg Oncol. 2009;16:3350–7.CrossRefPubMed Bonvalot S, Rimareix F, Causeret S, Le Péchoux C, Boulet B, Terrier P, et al. Hyperthermic isolated limb perfusion in locally advanced soft tissue sarcoma and progressive desmoid-type fibromatosis with TNF 1 mg and melphalan (T1-M HILP) is safe and efficient. Ann Surg Oncol. 2009;16:3350–7.CrossRefPubMed
26.
go back to reference Pennacchioli E, Deraco M, Mariani L, Fiore M, Mussi C, Collini P, et al. Advanced extremity soft tissue sarcoma: prognostic effect of isolated limb perfusion in a series of 88 patients treated at a single institution. Ann Surg Oncol. 2007;14:553–9.CrossRefPubMed Pennacchioli E, Deraco M, Mariani L, Fiore M, Mussi C, Collini P, et al. Advanced extremity soft tissue sarcoma: prognostic effect of isolated limb perfusion in a series of 88 patients treated at a single institution. Ann Surg Oncol. 2007;14:553–9.CrossRefPubMed
27.
go back to reference Gutman M, Inbar M, Lev-Shlush D, Abu-Abid S, Mozes M, Chaitchik S, et al. High dose tumor necrosis factor-α and melphalan administered via isolated limb perfusion for advanced limb soft tissue sarcoma results in a > 90% response rate and limb preservation. Cancer. 1997;79:1129–37.CrossRefPubMed Gutman M, Inbar M, Lev-Shlush D, Abu-Abid S, Mozes M, Chaitchik S, et al. High dose tumor necrosis factor-α and melphalan administered via isolated limb perfusion for advanced limb soft tissue sarcoma results in a > 90% response rate and limb preservation. Cancer. 1997;79:1129–37.CrossRefPubMed
28.
go back to reference Cherix S, Speiser M, Matter M, Raffoul W, Liénard D, Theumann N, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for non-resectable soft tissue sarcomas: long-term results on efficacy and limb salvage in a selected group of patients. J Surg Oncol. 2008;98:148–55.CrossRefPubMed Cherix S, Speiser M, Matter M, Raffoul W, Liénard D, Theumann N, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for non-resectable soft tissue sarcomas: long-term results on efficacy and limb salvage in a selected group of patients. J Surg Oncol. 2008;98:148–55.CrossRefPubMed
29.
go back to reference Grunhagen DJ, de Wilt JH, Graveland WJ, van Geel AN, Eggermont AM. The palliative value of tumor necrosis factor α-based isolated limb perfusion in patients with metastatic sarcoma and melanoma. Cancer. 2006;106:156–62.CrossRefPubMed Grunhagen DJ, de Wilt JH, Graveland WJ, van Geel AN, Eggermont AM. The palliative value of tumor necrosis factor α-based isolated limb perfusion in patients with metastatic sarcoma and melanoma. Cancer. 2006;106:156–62.CrossRefPubMed
30.
go back to reference Kattan MW, Leung DH, Brennan MF. Postoperative nomogram for 12-year sarcoma-specific death. J Clin Oncol. 2002;20:791–6.CrossRefPubMed Kattan MW, Leung DH, Brennan MF. Postoperative nomogram for 12-year sarcoma-specific death. J Clin Oncol. 2002;20:791–6.CrossRefPubMed
Metadata
Title
Neoadjuvant isolated limb perfusion in newly diagnosed untreated patients with locally advanced soft tissue sarcomas of the extremities: the Gustave Roussy experience
Authors
T. Assi
A. Cavalcanti
A. Le Cesne
M. Faron
J. F. Honart
A. Hadiji
O. Camuzard
T. Ibrahim
C. LePéchoux
O. Mir
S. Dumont
P. Terrier
J. Adam
C. Honoré
Publication date
01-09-2019
Publisher
Springer International Publishing
Published in
Clinical and Translational Oncology / Issue 9/2019
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-019-02034-w

Other articles of this Issue 9/2019

Clinical and Translational Oncology 9/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine