Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities
- Thomas F DeLaney, MD
Thomas F DeLaney, MD
- Section Editor — Bone and Soft Tissue Tumors
- Professor of Radiation Oncology
- Harvard Medical School
- David C Harmon, MD
David C Harmon, MD
- Assistant Professor of Medicine
- Harvard Medical School
- Mark C Gebhardt, MD
Mark C Gebhardt, MD
- Frederic W. and Jane M. Ilfeld Professor of Orthopedic Surgery
- Harvard Medical School
- Section Editors
- Robert Maki, MD, PhD
Robert Maki, MD, PhD
- Section Editor — Bone and Soft Tissue Tumors
- Professor of Medicine
- Monter Cancer Center
- Hofstra-Northwell School of Medicine
- Russell S Berman, MD
Russell S Berman, MD
- Section Editor — Skin and Soft Tissue Surgery
- Chief of Surgical Oncology
- New York University Langone Medical Center
- Raphael E Pollock, MD
Raphael E Pollock, MD
- Editor-in-Chief — General Surgery
- Section Editor — Soft Tissue Sarcoma
- Professor of Surgery
- The Ohio State University
Soft tissue sarcomas (STS) are rare malignant tumors that arise from extraskeletal connective tissues, including the peripheral nervous system. They can arise at any body site.
Treatment for locally recurrent and locally advanced, potentially unresectable STS of the extremities will be reviewed here. Issues relating to classification, diagnosis, and staging of STS, local treatment options for localized primary STS of the extremities and chest wall, the use of adjuvant and neoadjuvant chemotherapy for extremity STS, and the treatment of STS in locations other than the extremities and chest wall are discussed separately. (See "Local treatment for primary soft tissue sarcoma of the extremities and chest wall" and "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities" and "Head and neck sarcomas" and "Breast sarcoma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging" and "Clinical features, evaluation, and treatment of retroperitoneal soft tissue sarcoma" and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)
IMPORTANCE OF MULTIDISCIPLINARY EVALUATION AND MANAGEMENT
Because of their rarity and the frequent need for multimodality treatment, evaluation and management of STS should ideally be carried out in a center with expertise in the treatment of sarcomas, including surgical, orthopedic, medical, pediatric, and radiation oncology. The multidisciplinary team approach to the care of STS optimizes treatment planning, minimizes duplication of diagnostic studies, and reduces the time to implementation of the definitive therapeutic protocol, and the expertise gained by dedicated subspecialists improves clinical outcomes.
LOCALLY RECURRENT DISEASE
For patients with a locally recurrent STS, we recommend reresection rather than nonoperative therapy, if possible. Surgery is an important component of successful therapy for these patients. As with primary treatment, the goal is to salvage the limb with a complete resection and wide margins. (See 'Reresection' below.)
For patients who have not been previously irradiated, we recommend external beam radiation therapy (RT) in addition to surgical resection to improve rates of local control. In this setting, we suggest preoperative, rather than postoperative, treatment for most patients. (See 'Adjunctive RT' below.)
- LeVay J, O'Sullivan B, Catton C, et al. Outcome and prognostic factors in soft tissue sarcoma in the adult. Int J Radiat Oncol Biol Phys 1993; 27:1091.
- Karakousis CP, Driscoll DL. Treatment and local control of primary extremity soft tissue sarcomas. J Surg Oncol 1999; 71:155.
- Sadoski C, Suit HD, Rosenberg A, et al. Preoperative radiation, surgical margins, and local control of extremity sarcomas of soft tissues. J Surg Oncol 1993; 52:223.
- Zagars GK, Ballo MT, Pisters PW, et al. Prognostic factors for disease-specific survival after first relapse of soft-tissue sarcoma: analysis of 402 patients with disease relapse after initial conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 2003; 57:739.
- Gronchi A, Miceli R, Fiore M, et al. Extremity soft tissue sarcoma: adding to the prognostic meaning of local failure. Ann Surg Oncol 2007; 14:1583.
- Eilber FC, Rosen G, Nelson SD, et al. High-grade extremity soft tissue sarcomas: factors predictive of local recurrence and its effect on morbidity and mortality. Ann Surg 2003; 237:218.
- Singer S, Corson JM, Gonin R, et al. Prognostic factors predictive of survival and local recurrence for extremity soft tissue sarcoma. Ann Surg 1994; 219:165.
- Lewis JJ, Leung D, Heslin M, et al. Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. J Clin Oncol 1997; 15:646.
- Trovik CS, Gustafson P, Bauer HC, et al. Consequences of local recurrence of soft tissue sarcoma: 205 patients from the Scandinavian Sarcoma Group Register. Acta Orthop Scand 2000; 71:488.
- Ramanathan RC, A'Hern R, Fisher C, Thomas JM. Prognostic index for extremity soft tissue sarcomas with isolated local recurrence. Ann Surg Oncol 2001; 8:278.
- Eilber FC, Brennan MF, Riedel E, et al. Prognostic factors for survival in patients with locally recurrent extremity soft tissue sarcomas. Ann Surg Oncol 2005; 12:228.
- Abatzoglou S, Turcotte RE, Adoubali A, et al. Local recurrence after initial multidisciplinary management of soft tissue sarcoma: is there a way out? Clin Orthop Relat Res 2010; 468:3012.
- Catton C, Davis A, Bell R, et al. Soft tissue sarcoma of the extremity. Limb salvage after failure of combined conservative therapy. Radiother Oncol 1996; 41:209.
- Karakousis CP, Proimakis C, Rao U, et al. Local recurrence and survival in soft-tissue sarcomas. Ann Surg Oncol 1996; 3:255.
- Ueda T, Yoshikawa H, Mori S, et al. Influence of local recurrence on the prognosis of soft-tissue sarcomas. J Bone Joint Surg Br 1997; 79:553.
- Townley WA, Mah E, O'Neill AC, et al. Reconstruction of sarcoma defects following pre-operative radiation: free tissue transfer is safe and reliable. J Plast Reconstr Aesthet Surg 2013; 66:1575.
- Eilber FR, Morton DL, Eckardt J, et al. Limb salvage for skeletal and soft tissue sarcomas. Multidisciplinary preoperative therapy. Cancer 1984; 53:2579.
- Engel CJ, Eilber FR, Rosen G, et al. Preoperative chemotherapy for soft tissue sarcomas of the extremities: the experience at the University of California, Los Angeles. Cancer Treat Res 1993; 67:135.
- Soulen MC, Weissmann JR, Sullivan KL, et al. Intraarterial chemotherapy with limb-sparing resection of large soft-tissue sarcomas of the extremities. J Vasc Interv Radiol 1992; 3:659.
- Wanebo HJ, Temple WJ, Popp MB, et al. Preoperative regional therapy for extremity sarcoma. A tricenter update. Cancer 1995; 75:2299.
- Levine EA, Trippon M, Das Gupta TK. Preoperative multimodality treatment for soft tissue sarcomas. Cancer 1993; 71:3685.
- Rahóty P, Kónya A. Results of preoperative neoadjuvant chemotherapy and surgery in the management of patients with soft tissue sarcoma. Eur J Surg Oncol 1993; 19:641.
- Rossi CR, Vecchiato A, Foletto M, et al. Phase II study on neoadjuvant hyperthermic-antiblastic perfusion with doxorubicin in patients with intermediate or high grade limb sarcomas. Cancer 1994; 73:2140.
- Temple CL, Ross DC, Magi E, et al. Preoperative chemoradiation and flap reconstruction provide high local control and low wound complication rates for patients undergoing limb salvage surgery for upper extremity tumors. J Surg Oncol 2007; 95:135.
- Eilber FR, Giuliano AE, Huth JF, Weisenburger TH, Eckhardt J. Intravenous (IV) vs. intraarterial (IA) Adriamycin, radiation and surgical excision for extremity soft tissue sarcomas: a randomized prospective trial (abstract). Proc Am Soc Clin Oncol 1990; 9:309a.
- DeLaney TF, Spiro IJ, Suit HD, et al. Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2003; 56:1117.
- Pisters PW, Patel SR, Prieto VG, et al. Phase I trial of preoperative doxorubicin-based concurrent chemoradiation and surgical resection for localized extremity and body wall soft tissue sarcomas. J Clin Oncol 2004; 22:3375.
- Toma S, Canavese G, Grimaldi A, et al. Concomitant chemo-radiotherapy in the treatment of locally advanced and/or metastatic soft tissue sarcomas: experience of the National Cancer Institute of Genoa. Oncol Rep 2003; 10:641.
- Mack LA, Crowe PJ, Yang JL, et al. Preoperative chemoradiotherapy (modified Eilber protocol) provides maximum local control and minimal morbidity in patients with soft tissue sarcoma. Ann Surg Oncol 2005; 12:646.
- Cormier JN, Patel SR, Herzog CE, et al. Concurrent ifosfamide-based chemotherapy and irradiation. Analysis of treatment-related toxicity in 43 patients with sarcoma. Cancer 2001; 92:1550.
- Eckert F, Matuschek C, Mueller AC, et al. Definitive radiotherapy and single-agent radiosensitizing ifosfamide in patients with localized, irresectable soft tissue sarcoma: a retrospective analysis. Radiat Oncol 2010; 5:55.
- Pisters PW, Ballo MT, Bekele N, et al. Phase I trial using toxicity severity weights for dose finding of gemcitabine combined with radiation therapy and subsequent surgery for patients with extremity and trunk soft tissue sarcomas (abstract). J Clin Oncol 2004; 22:820s.
- Jakob J, Wenz F, Dinter DJ, et al. Preoperative intensity-modulated radiotherapy combined with temozolomide for locally advanced soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 2009; 75:810.
- Kraybill WG, Harris J, Spiro IJ, et al. Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol 2006; 24:619.
- Kraybill WG, Harris J, Spiro IJ, et al. Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. Cancer 2010; 116:4613.
- Wang D, Zhang Q, Eisenberg BL, et al. Significant Reduction of Late Toxicities in Patients With Extremity Sarcoma Treated With Image-Guided Radiation Therapy to a Reduced Target Volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial. J Clin Oncol 2015; 33:2231.
- Palassini E, Ferrari S, Verderio P, et al. Feasibility of Preoperative Chemotherapy With or Without Radiation Therapy in Localized Soft Tissue Sarcomas of Limbs and Superficial Trunk in the Italian Sarcoma Group/Grupo Español de Investigación en Sarcomas Randomized Clinical Trial: Three Versus Five Cycles of Full-Dose Epirubicin Plus Ifosfamide. J Clin Oncol 2015; 33:3628.
- Tuma RS. Sometimes size doesn't matter: reevaluating RECIST and tumor response rate endpoints. J Natl Cancer Inst 2006; 98:1272.
- Canter RJ, Martinez SR, Tamurian RM, et al. Radiographic and histologic response to neoadjuvant radiotherapy in patients with soft tissue sarcoma. Ann Surg Oncol 2010; 17:2578.
- Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205.
- Therasse P, Le Cesne A, Van Glabbeke M, et al. RECIST vs. WHO: prospective comparison of response criteria in an EORTC phase II clinical trial investigating ET-743 in advanced soft tissue sarcoma. Eur J Cancer 2005; 41:1426.
- Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228.
- Eilber FC, Rosen G, Eckardt J, et al. Treatment-induced pathologic necrosis: a predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas. J Clin Oncol 2001; 19:3203.
- Lucas DR, Kshirsagar MP, Biermann JS, et al. Histologic alterations from neoadjuvant chemotherapy in high-grade extremity soft tissue sarcoma: clinicopathological correlation. Oncologist 2008; 13:451.
- Evilevitch V, Weber WA, Tap WD, et al. Reduction of glucose metabolic activity is more accurate than change in size at predicting histopathologic response to neoadjuvant therapy in high-grade soft-tissue sarcomas. Clin Cancer Res 2008; 14:715.
- Benz MR, Czernin J, Allen-Auerbach MS, et al. FDG-PET/CT imaging predicts histopathologic treatment responses after the initial cycle of neoadjuvant chemotherapy in high-grade soft-tissue sarcomas. Clin Cancer Res 2009; 15:2856.
- Indelicato DJ, Meadows K, Gibbs CP Jr, et al. Effectiveness and morbidity associated with reirradiation in conservative salvage management of recurrent soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 2009; 73:267.
- Pearlstone DB, Janjan NA, Feig BW, et al. Re-resection with brachytherapy for locally recurrent soft tissue sarcoma arising in a previously radiated field. Cancer J Sci Am 1999; 5:26.
- Torres MA, Ballo MT, Butler CE, et al. Management of locally recurrent soft-tissue sarcoma after prior surgery and radiation therapy. Int J Radiat Oncol Biol Phys 2007; 67:1124.
- Nori D, Schupak K, Shiu MH, Brennan MF. Role of brachytherapy in recurrent extremity sarcoma in patients treated with prior surgery and irradiation. Int J Radiat Oncol Biol Phys 1991; 20:1229.
- Lans TE, Grünhagen DJ, de Wilt JH, et al. Isolated limb perfusions with tumor necrosis factor and melphalan for locally recurrent soft tissue sarcoma in previously irradiated limbs. Ann Surg Oncol 2005; 12:406.
- Tepper JE, Suit HD. Radiation therapy alone for sarcoma of soft tissue. Cancer 1985; 56:475.
- Kepka L, DeLaney TF, Suit HD, Goldberg SI. Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2005; 63:852.
- Grünhagen DJ, de Wilt JH, van Geel AN, et al. TNF dose reduction in isolated limb perfusion. Eur J Surg Oncol 2005; 31:1011.
- Wieberdink J, Benckhuysen C, Braat RP, et al. 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.
- Gutman M, Inbar M, Lev-Shlush D, et al. High 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 1997; 79:1129.
- Eggermont AM, Schraffordt Koops H, Liénard D, et al. Isolated 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 1996; 14:2653.
- Noorda EM, Vrouenraets BC, Nieweg OE, et al. Isolated limb perfusion with tumor necrosis factor-alpha and melphalan for patients with unresectable soft tissue sarcoma of the extremities. Cancer 2003; 98:1483.
- Grunhagen DJ, de Wilt JH, Graveland WJ, et al. Outcome and prognostic factor analysis of 217 consecutive isolated limb perfusions with tumor necrosis factor-alpha and melphalan for limb-threatening soft tissue sarcoma. Cancer 2006; 106:1776.
- Bonvalot S, Laplanche A, Lejeune F, et al. Limb salvage with isolated perfusion for soft tissue sarcoma: could less TNF-alpha be better? Ann Oncol 2005; 16:1061.
- Eggermont AM, Schraffordt Koops H, Klausner JM, 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.
- Olieman AF, Pras E, van Ginkel RJ, et al. Feasibility and efficacy of external beam radiotherapy after hyperthermic isolated limb perfusion with TNF-alpha and melphalan for limb-saving treatment in locally advanced extremity soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 1998; 40:807.
- Grünhagen DJ, Brunstein F, Graveland WJ, et al. Isolated limb perfusion with tumor necrosis factor and melphalan prevents amputation in patients with multiple sarcomas in arm or leg. Ann Surg Oncol 2005; 12:473.
- Hayes AJ, Neuhaus SJ, Clark MA, Thomas JM. Isolated limb perfusion with melphalan and tumor necrosis factor alpha for advanced melanoma and soft-tissue sarcoma. Ann Surg Oncol 2007; 14:230.
- Bonvalot S, Rimareix F, Causeret S, 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.
- Pennacchioli E, Deraco M, Mariani L, 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.
- van Ginkel RJ, Thijssens KM, Pras E, et al. Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma: three time periods at risk for amputation. Ann Surg Oncol 2007; 14:1499.
- Eggermont AM, Schraffordt Koops H, Klaase JM, et al. Limb salvage by isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced extremity soft tissue sarcomas: results of 270 perfusions in 246 patients (abstract). Proc Am Soc Clin Oncol 1999; 11:535a.
- Lejeune FJ, Pujol N, Liénard D, et al. Limb salvage by neoadjuvant isolated perfusion with TNFalpha and melphalan for non-resectable soft tissue sarcoma of the extremities. Eur J Surg Oncol 2000; 26:669.
- Deroose JP, van Geel AN, Burger JW, et al. Isolated limb perfusion with TNF-alpha and melphalan for distal parts of the limb in soft tissue sarcoma patients. J Surg Oncol 2012; 105:563.
- Olofsson R, Bergh P, Berlin O, et al. Long-term outcome of isolated limb perfusion in advanced soft tissue sarcoma of the extremity. Ann Surg Oncol 2012; 19:1800.
- Di Filippo F, Giacomini P, Rossi CR, et al. Hyperthermic isolated perfusion with tumor necrosis factor-alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcoma: the experience of the Italian Society of Integrated Locoregional Treatment in Oncology (SITILO). In Vivo 2009; 23:363.
- Deroose JP, Eggermont AM, van Geel AN, et al. Long-term results of tumor necrosis factor alpha- and melphalan-based isolated limb perfusion in locally advanced extremity soft tissue sarcomas. J Clin Oncol 2011; 29:4036.
- Trabulsi NH, Patakfalvi L, Nassif MO, et al. 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.
- Jakob J, Hohenberger P. Role of isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan in locally advanced extremity soft tissue sarcoma. Cancer 2016; 122:2624.
- Moncrieff MD, Kroon HM, Kam PC, et al. Isolated limb infusion for advanced soft tissue sarcoma of the extremity. Ann Surg Oncol 2008; 15:2749.
- Hegazy MA, Kotb SZ, Sakr H, et al. Preoperative isolated limb infusion of Doxorubicin and external irradiation for limb-threatening soft tissue sarcomas. Ann Surg Oncol 2007; 14:568.
- Issels RD, Abdel-Rahman S, Wendtner C, et al. Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft-tissue sarcomas (STS) of adults: long-term results of a phase II study. Eur J Cancer 2001; 37:1599.
- Wendtner CM, Abdel-Rahman S, Krych M, et al. Response to neoadjuvant chemotherapy combined with regional hyperthermia predicts long-term survival for adult patients with retroperitoneal and visceral high-risk soft tissue sarcomas. J Clin Oncol 2002; 20:3156.
- Issels RD, Lindner LH, Verweij J, et al. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol 2010; 11:561.
- Schlemmer M, Wendtner CM, Lindner L, et al. Thermochemotherapy in patients with extremity high-risk soft tissue sarcomas (HR-STS). Int J Hyperthermia 2010; 26:127.
- Lagendijk JJ, Van Rhoon GC, Hornsleth SN, et al. ESHO quality assurance guidelines for regional hyperthermia. Int J Hyperthermia 1998; 14:125.
- Krieg AH, Hefti F, Speth BM, et al. Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors. Ann Oncol 2011; 22:458.
- Trovik CS, Bauer HC. Local recurrence of soft tissue sarcoma a risk factor for late metastases. 379 patients followed for 0.5-20 years. Acta Orthop Scand 1994; 65:553.
- Patel SR, Zagars GK, Pisters PW. The follow-up of adult soft-tissue sarcomas. Semin Oncol 2003; 30:413.
- Cheney MD, Giraud C, Goldberg SI, et al. MRI surveillance following treatment of extremity soft tissue sarcoma. J Surg Oncol 2014; 109:593.
- IMPORTANCE OF MULTIDISCIPLINARY EVALUATION AND MANAGEMENT
- LOCALLY RECURRENT DISEASE
- Adjunctive treatment
- - Patients without prior radiation therapy
- Adjunctive RT
- Preoperative chemoradiotherapy
- - Doxorubicin
- - Ifosfamide
- - Gemcitabine and temozolomide
- - Multiagent chemotherapy and RT
- - Response assessment
- - Previously irradiated patients
- Regional chemotherapy approaches
- Chemotherapy with regional hyperthermia
- - Postoperative chemotherapy
- UNRESECTABLE LOCALLY ADVANCED DISEASE
- Radiation therapy and chemoradiotherapy
- Regional chemotherapy
- - Isolated limb perfusion
- - Isolated limb infusion
- Systemic chemotherapy with and without regional hyperthermia
- Palliative chemotherapy
- NCCN guidelines
- POSTTREATMENT SURVEILLANCE
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS
- Local recurrence
- Unresectable locally advanced
- Posttreatment follow-up