Soft Tissue Sarcoma Treatment Protocols
Treatment protocols for soft tissue sarcoma are provided below, including recommendations for low- and high-grade soft tissue sarcomas, for metastatic disease, and for soft tissue sarcomas with special histologies.
See Soft-Tissue Sarcomas: What You Need to Know, a Critical Images slideshow, to help identify and treat some of these malignant tumors of mesenchymal origin.
Re-resection or adjuvant external beam radiation therapy (XRT) is recommended to prevent local recurrence or if margins are < 1 cm or when location complicates resection at the time of recurrence
Radiation therapy is associated with decreased local recurrence but not necessarily with improved overall survival
Definitive radiation therapy is recommended for patients who are not surgical candidates; radiation doses range from 70-80 Gy
Tumors in this stage can be > 5-10 cm and have a high risk of recurrence and potential metastases
For patients with resectable disease, surgery followed by radiation therapy with or without adjuvant chemotherapy or surgery alone is recommended; preoperative radiation therapy, chemotherapy, or chemoradiation prior to surgery are alternatives in select clinical situations
Role of radiation therapy in the locoregional management of soft tissue sarcoma:
benefits of using preoperative therapy are that large tumors adjacent to critical organs may become resectable; a smaller treatment field is needed; and potentially less tumor seeding may occur during resection
The common dose for XRT is 50 Gy
If margins are close (< 1 cm) or positive, consider boost with brachytherapy, intraoperative radiation therapy (IORT), or postoperative XRT/intensity modulated radiation therapy (IMRT) at doses ranging from 10-26 GY 
Common doses: brachytherapy, 45 Gy; XRT, 50 Gy
Consider re-resection if margins are positive
Consider XRT even when negative margins are achieved with re-resection and the patient is older and/or has stage III disease 
When re-resection is not an option, consider postoperative radiation therapy 
benefits include the fact that wound-healing complications of preoperative radiation are avoided by giving radiation after surgery
In metastatic disease, it is important to differentiate between limited and disseminated metastases
Limited metastasis involves only one organ and should be considered for resection for improved disease-free survival (DFS) and overall survival (OS)
Disseminated metastases can be managed with palliative therapy (radiation, chemotherapy, surgery, or supportive care alone)
Initiation of palliative chemotherapy should be based on histology, tumor growth rate, chemosensitivity, and associated symptoms
Several single-agent and combination chemotherapies are used in metastatic disease; compared with single-agent chemotherapies, many combination therapies have higher response rates but greater toxicities and no survival advantage
The decision for combination therapies should be individualized and take age, performance status, and organ function into account
Combination therapies may require prophylactic growth factor support
Refer patients for clinical trials whenever possible
If the patient is asymptomatic and the tumor has a slow growth rate, then observation with close monitoring is a reasonable option
Patients with limited metastatic disease or recurrent disease after primary therapy should be considered for surgery, radiofrequency ablation (RFA), embolization, or radiation therapy with curative intent
There are no clear guidelines for metastatic and recurrent disease, as treatment depends on the disease-free interval, performance status, and histology
In stage IV sarcoma, patients with limited disease should also be considered for resection or other definitive intervention, as this is associated with improved disease-free survival
Consider re-resection for positive or close margins 
Prevention of local recurrence may require additional radiation and/or chemotherapy
Regimens include the following :
Doxorubicin 60 mg/m2 every 3 wk; doses as high as 75 mg/m2 can be given; however, this can be administered as a split dose over 3 d (25 mg/m2/day for 3 d); maximum lifetime dose is 475-600 mg/m2 or
Liposomal pegylated doxorubicin: doses as high as 50 mg/m2 every 4 wk have been used in clinical trials; however, this is associated with significant toxicity; commonly used doses include 30-35 mg/m2 every 4 wk; no maximum lifetime doses or
Ifosfamide 5000 mg/m2 over 24 h plus mesna 5000 mg/m2 over 24 h and an additional 400-600 mg/m2 for 2 h after completion of ifosfamide; repeat every 21 d (European schedule) or
Gemcitabine 1200 mg/m2 IV over 90-120min on days 1 and 8; repeat cycle every 21d or
Dacarbazine 250 mg/m2 IV for 5 d or 800-1000 mg/m2 IV every 3 wk or
Pazopanib 800 mg PO qd (not indicated for liposarcoma outside of a clinical trial; FDA approved as second-line chemotherapy; recommend starting at a low dose of 200 mg for 2 weeks and slowly increasing the dose)
Combination chemotherapy regimens consist of any one of the regimens described below, including doxorubicin, ifosfamide, and mesna; doxorubicin and dacarbazine; mesna, doxorubicin, ifosfamide, and dacarbazine; or gemcitabine and docetaxel.
Doxorubicin 20-25 mg/m2 IV push on days 1-3 plus
Ifosfamide 2000-3000 mg/m2 IV push bolus 3 h on days 1-3 plus
Mesna 225 mg/m2 IV over 1 h before ifosfamide and at 4 and 8 h after ifosfamide
Repeat every 21-28 d
Doxorubicin and dacarbazine (AD):
Doxorubicin 15 mg/m2/day IV continuous infusion on days 1-4 plus
Dacarbazine 250 mg/m2/day IV continuous infusion on days 1-4
Repeat every 3 wk 
Mesna, doxorubicin, ifosfamide, and dacarbazine:
Mesna 2.5 g/m2/day IV continuous infusion on days 1-4 plus
Doxorubicin 20 mg/m2/day IV continuous infusion on days 1-3 plus
Ifosfamide 2.5 g/m2/day IV continuous infusion on days 1-3 plus
Dacarbazine 300 mg/m2/day IV continuous infusion on days 1-3
Repeat every 3 wk 
Doxorubicin and olaratumab 
Gemcitabine 900 mg/m2 IV over 30-90 min on days 1 and 8 plus docetaxel 75-100 mg/m2 IV over 60 min on day 8; repeat every 21 d; growth factors may be needed
Gemcitabine 900 mg/m2 IV over 30-90 min on days 1 and 8 plus docetaxel 35 mg/m2 IV over 60 min on day 1 and 8; repeat every 21 d; growth factors typically not needed; very well-tolerated schedule
See the list below:
Concurrent chemoradiation typicalliy is mainly used for extremity and trunk soft tissue sarcoma, as use in intra-abdominal/retroperitoneal sites has more significant toxicities.
Doxorubicin can be administered as a flat dose of 30 mg daily for 3 d, with concurrent radiation therapy.
Radiotherapy with ifosfamide is associated with significant toxicities, and full doses are difficult to administer beyond two cycles.
A single trial reported safe administration of gemcitabine at 700 mg/m2 along with 50 Gy over 25 fractions
There are sparse data on oral temozolomide 50 mg/m2 once daily for 7 d with radiation therapy (dose of 50.4 Gy)
Combination chemotherapy regimens (MAID [mesna, doxorubicin, ifosfamide, and dacarbazine]) with concurrent radiation therapy have higher response and prohibitive toxicities and therefore should be performed at centers with adequate experience with these regimens; there are no prospective studies comparing chemoradiation to radiation therapy alone
Consider adjuvant chemotherapy for chemosensitive, extremity/trunk, and high-risk lesions; consider age, performance status, size, grade, location, type of initial surgery, and margin status when discussing initiation of adjuvant therapy
When possible, patients should be referred to an NCCN-designated center and enrolled in clinical trials.
A phase II study randomized patients with leiomyosarcomas to gemcitabine (1200 mg/m2 IV on days 1 and 8; every 21 d) alone or gemcitabine (900 mg/m2 IV over 90 min on days 1 and 8) and docetaxel (100 mg/m2 IV over 90 min on day 8; every 21 d) and reported higher response rates in the dual chemotherapy arm (32% vs 27%), with a 3% complete response (CR) and significantly improved progression-free survival (6.3 vs 3 mo) 
Temozolomide can be administered as a 6-wk, continuous oral schedule at a dose of 75 mg/m2 or BID on a 12-h schedule for 5 d as an oral bolus dose of 200 mg/m2 followed by 9 doses of 90 mg/m2 every 4 wk
Treatment is wide excision and irradiation; however, angiosarcoma is highly aggressive and has a propensity for local recurrence, multifocal spread, and early hematogenous dissemination
Angiosarcomas have a 5-y overall survival rate of 10-30%; radiation-associated angiosarcomas are thought to have worse outcomes
Systemic treatment of angiosarcomas include doxorubicin or ifosfamide, with responses in the range of 10-20%; angiosarcomas are also highly sensitive to taxanes; pegylated-liposomal doxorubicin has also been shown to have activity in this disease 
A phase II clinical trial of 30 patients with unresectable or metastatic angiosarcoma (ANGIOTAX study) demonstrated a 2-mo and 4-mo progression-free survival of 74% and 42%, respectively, with weekly paclitaxel administered at a dose of 80 mg/m2 on days 1, 8, and 15 in a 4-wk cycle; an overall response rate of 19% was observed 
Docetaxel has also been shown to be promising, with 6 out of 9 patients treated achieving major responses 
A phase II trial of sorafenib that included 37 patients with vascular sarcomas achieved one CR, four partial responses (PR), and an overall response rate of 14%; overall median progression-free survival was 3.2 mo; the median OS was 14.3 mo; patients with angiosarcoma had the greatest degree of tumor shrinkage overall of all vascular sarcoma subtypes 
Chemosensitive disease with particular sensitivity to ifosfamide
A case series of 13 patients with synovial sarcoma treated with high-dose ifosfamide showed response in all patients, with four CRs achieved 
A single-institution study of 100 patients treated with doxorubicin and/or ifosfamide showed a median survival of 22 mo; single-agent doxorubicin or ifosfamide achieved responses in 25% of patients treated, but combination therapy achieved a response rate of 58% 
What is the mesna, doxorubicin, ifosfamide, and dacarbazine regimen for the treatment of metastatic soft tissue sarcoma?
NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma. Available at http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Version 1.2019 — December 19, 2018; Accessed: December 26, 2018.
Kraybill WG, Harris J, Spiro IJ, Ettinger DS, DeLaney TF, Blum RH, 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 Feb 1. 24(4):619-25. [Medline].
Grobmyer SR, Maki RG, Demetri GD, Mazumdar M, Riedel E, Brennan MF. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004 Nov. 15(11):1667-72. [Medline].
DeLaney TF, Spiro IJ, Suit HD, Gebhardt MC, Hornicek FJ, Mankin HJ, et al. Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys. 2003 Jul 15. 56(4):1117-27. [Medline].
Pisters PW, Ballo MT, Patel SR. Preoperative chemoradiation treatment strategies for localized sarcoma. Ann Surg Oncol. 2002 Jul. 9(6):535-42. [Medline].
Judson I, Verweij J, Gelderblom H, Hartmann JT, 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 Apr. 15 (4):415-23. [Medline].
Davis AM, O’Sullivan B, Bell RS, Turcotte R, Catton CN, Wunder JS, et al. Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol. 2002 Nov 15. 20(22):4472-7. [Medline].
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 Jun 29. 359(9325):2235-41. [Medline].
Sadoski C, Suit HD, Rosenberg A, Mankin H, Efird J. Preoperative radiation, surgical margins, and local control of extremity sarcomas of soft tissues. J Surg Oncol. 1993 Apr. 52(4):223-30. [Medline].
Cahlon O, Spierer M, Brennan MF, Singer S, Alektiar KM. Long-term outcomes in extremity soft tissue sarcoma after a pathologically negative re-resection and without radiotherapy. Cancer. 2008 Jun 15. 112(12):2774-9. [Medline].
Alektiar KM, Velasco J, Zelefsky MJ, Woodruff JM, Lewis JJ, Brennan MF. Adjuvant radiotherapy for margin-positive high-grade soft tissue sarcoma of the extremity. Int J Radiat Oncol Biol Phys. 2000 Nov 1. 48(4):1051-8. [Medline].
Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet. 1997 Dec 6. 350(9092):1647-54. [Medline].
Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008 Aug 1. 113(3):573-81. [Medline].
Tierney JF, Mosseri V, Stewart LA, Souhami RL, Parmar MK. Adjuvant chemotherapy for soft-tissue sarcoma: review and meta-analysis of the published results of randomised clinical trials. Br J Cancer. 1995 Aug. 72(2):469-75. [Medline].
Brennan MF, Casper ES, Harrison LB, Shiu MH, Gaynor J, Hajdu SI. The role of multimodality therapy in soft-tissue sarcoma. Ann Surg. 1991 Sep. 214(3):328-36; discussion 336-8. [Medline].
Le Cesne A, Blay JY, Judson I, et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol. 2005 Jan 20. 23(3):576-84. [Medline].
Garcia-Carbonero R, Supko JG, Manola J, Seiden MV, Harmon D, Ryan DP, et al. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol. 2004 Apr 15. 22(8):1480-90. [Medline].
Garcia-Carbonero R, Supko JG, Maki RG, Manola J, Ryan DP, Harmon D, et al. Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study. J Clin Oncol. 2005 Aug 20. 23(24):5484-92. [Medline].
Yovine A, Riofrio M, Blay JY, Brain E, Alexandre J, Kahatt C. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol. 2004 Mar 1. 22(5):890-9. [Medline].
Laverdiere C, Kolb EA, Supko JG, Gorlick R, Meyers PA, Maki RG. Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer. 2003 Aug 15. 98(4):832-40. [Medline].
Judson R, et al. A randomized phase III study of trabectedin (T) or dacarbazine (D) for the treatment of patients (pts) with advanced liposarcoma (LPS) or leiomyosarcoma (LMS). Abstract 10503. Presented at American Society of Clinical Oncology (ASCO) 2015 Annual Meeting, Chicago, IL.
Lopez M, Vici P, Di Lauro L, Carpano S. Increasing single epirubicin doses in advanced soft tissue sarcomas. J Clin Oncol. 2002 Mar 1. 20(5):1329-34. [Medline].
Edmonson JH, Ryan LM, Blum RH, Brooks JS, Shiraki M, Frytak S, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993 Jul. 11(7):1269-75. [Medline].
Antman K, Crowley J, Balcerzak SP, Rivkin SE, Weiss GR, Elias A, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993 Jul. 11(7):1276-85. [Medline].
Elias A, Ryan L, Sulkes A, Collins J, Aisner J, Antman KH. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989 Sep. 7(9):1208-16. [Medline].
Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016 Jul 30. 388 (10043):488-97. [Medline].
Eli Lilly and Company. Lilly Reports Results of Phase 3 Soft Tissue Sarcoma Study of LARTRUVO. PR Newswire. January 19, 2019. Available at https://www.prnewswire.com/news-releases/lilly-reports-results-of-phase-3-soft-tissue-sarcoma-study-of-lartruvo-300780704.html.
Hensley ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002 Jun 15. 20(12):2824-31. [Medline].
Azevedo RGMVD, Fraile N, Saadi Neto E, Lopez RVM, Toloi D, Hoff PM, et al. Tolerability of modified gemcitabine/docetaxel (split-dose) in patients with advanced soft tissue sarcomas. Ann Oncol. 1 October 2016. 27 suppl 6:1409. [Full Text].
Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno SH, Samuels B, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol. 2007 Jul 1. 25(19):2755-63. [Medline].
Talbot SM, Keohan ML, Hesdorffer M, Orrico R, Bagiella E, Troxel AB. A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer. 2003 Nov 1. 98(9):1942-6. [Medline].
Garcia del Muro X, Lopez-Pousa A, Martin J, et al. A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer. Oct 15 2005. 104(8):1706-12.
Judson I, Radford JA, Harris M, Blay JY, van Hoesel Q, le Cesne A. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001 May. 37(7):870-7. [Medline].
Penel N, Bui BN, Bay JO, Cupissol D, Ray-Coquard I, Piperno-Neumann S. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008 Nov 10. 26(32):5269-74. [Medline].
Nagano T, Yamada Y, Ikeda T, Kanki H, Kamo T, Nishigori C. Docetaxel: a therapeutic option in the treatment of cutaneous angiosarcoma: report of 9 patients. Cancer. 2007 Aug 1. 110(3):648-51. [Medline].
Maki RG, D’Adamo DR, Keohan ML, Saulle M, Schuetze SM, Undevia SD, et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol. 2009 Jul 1. 27(19):3133-40. [Medline]. [Full Text].
Agulnik M, Okuno SH, Von Mehren M, et al. An open-label multicenter phase II study of bevacizumab for the treatment of angiosarcoma. J Clin Oncol. 2009. 7:15s:(suppl; abstr 10522).
Rosen G, Forscher C, Lowenbraun S, Eilber F, Eckardt J, Holmes C, et al. Synovial sarcoma. Uniform response of metastases to high dose ifosfamide. Cancer. 1994 May 15. 73(10):2506-11. [Medline].
Spurrell EL, Fisher C, Thomas JM, Judson IR. Prognostic factors in advanced synovial sarcoma: an analysis of 104 patients treated at the Royal Marsden Hospital. Ann Oncol. 2005 Mar. 16(3):437-44. [Medline].
from Memorial Sloan-Kettering – Mrinal M Gounder, MD Attending Physician in Medical Oncology, Sarcoma and Developmental Therapeutics Service, Memorial Sloan-Kettering Cancer Center
Disclosure: Nothing to disclose.
from Memorial Sloan-Kettering – Richard D Carvajal, MD Assistant Member, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Assistant Professor of Medicine, Weill Cornell Medical College
from Memorial Sloan-Kettering – Richard D Carvajal, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Clinical Oncology
Disclosure: Received consulting fee from Novartis for consulting; Received consulting fee from Morphotek for consulting.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee
Disclosure: Nothing to disclose.
Edwin Choy, MD, PhD Assistant Professor of Medicine, Harvard Medical School; Director of Sarcoma Clinical Research, Clinical Director of Sarcoma Oncology, Department of Medicine, Division of Hematology/Oncology, Dana Farber/Harvard Cancer Center, Massachusetts General Hospital
Edwin Choy, MD, PhD is a member of the following medical societies: American Society of Clinical Oncology, Children’s Oncology Group, Connective Tissue Oncology Society, Radiation Therapy Oncology Group, Sarcoma Alliance for Research through Collaboration
Disclosure: Received honoraria from Amgen, Daiichi Sankyo, and EMC Serono for advisory board participation; Received consulting fee from Pfizer for consulting; Received consulting fee from NPS Pharmaceuticals for consulting.
Soft Tissue Sarcoma Treatment Protocols