Soft Tissue Sarcoma Treatment Protocols 

Updated: Oct 31, 2016
  • Author: from Memorial Sloan-Kettering - Mrinal M Gounder, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
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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.

Treatment recommendations for low-grade soft tissue sarcoma

Stage I:

  • Surgery is the primary treatment for stage I sarcoma; it is considered definitive when margins are >1 cm or if the fascia is still intact [1]

  • 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 improved overall survival

  • Definitive radiation therapy is recommended for patients who are not surgical candidates; radiation doses range from 70-80 Gy

  • Re-resection is associated with improved 5-y disease-free survival (DFS)

Treatment recommendations for high-grade soft tissue sarcoma

Stages II-III:

  • Tumors in this stage can be >8-10 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

  • Patients with unresectable disease should be treated with preoperative radiation therapy, chemotherapy, or chemoradiation with doxorubicin-based regimens [2, 3, 4, 5, 6]

Role of radiation therapy in the locoregional management of soft tissue sarcoma:

Preoperative XRT:

  • Benefits of using preoperative therapy are that large retroperitoneal or inguinal tumors 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

  • Negative aspects of using this therapy include increased wound-healing complications [7, 8]

  • If margins are close (<1 cm) or positive, consider boost with brachytherapy, intraoperative radiation therapy (IORT), or XRT/intensity modulated radiation therapy (IMRT) at doses ranging from 10-26 GY [9]

Postoperative brachytherapy:

  • 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 [10]

  • When re-resection is not an option, consider postoperative radiation therapy [11]

  • Benefits include the fact that wound-healing complications are minimized

Treatment recommendations for metastatic disease

Stage IV:

  • 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 observation or palliative therapy (radiation, chemotherapy, or surgery)

  • Initiation of palliative chemotherapy should be based on histology, tumor growth rate, chemosensitivity, and associated symptoms

  • Adjuvant chemotherapy is not generally considered as first-line therapy [12, 13, 14]

  • Several single-agent and combination chemotherapies are used in metastatic disease; compared with single-agent chemotherapies, 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 growth factor support

  • Refer patients for clinical trials when 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 [15]

  • Prevention of local recurrence may require additional radiation and/or chemotherapy

Single-agent chemotherapy recommendations for metastatic disease

Methotrexate, cisplatin, and taxanes are not considered active in most soft tissue sarcomas; however, important exceptions include osteosarcoma, uterine sarcoma, and angiosarcoma.

Regimens include the following  :

  • Doxorubicin 60 mg/m2 every 3 wk; doses as high as 75 mg/m2 can be given; however, this is best administered as a split dose over 3 d (25 mg/m2/day for 3 d); maximum lifetime dose is 475 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 2000-3000 mg/m2/day IV over 3 h for 3-4 d plus mesna; repeat every 21 d 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

  • Trabectedin 1.5 mg/m2 IV q3wk until disease progression or unacceptable toxicity; premedication require and infuse via central line over 24h [16, 17, 18, 19, 20, 21] or

  • Epirubicin 160 mg/m2 IV bolus every 3 wk with growth factor support [22] 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 recommendations for metastatic disease

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, ifosfamide, and mesna (AIM) [3, 23, 6] :

  • 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 [24]

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 [25]

Doxorubicin and olaratumab [26]

  • Olaratumab 15 mg/kg IV infused over 60 min on days 1 and 8 plus
  • Doxorubicin 75 mg/m 2 on day 1
  • Repeat every 21 d
  • Administer olaratumab in combination with doxorubicin for first 8 cycles
  • After the first 8 cycles, continue with olaratumab every 21 d until disease progression or unacceptable toxicity

Gemcitabine and docetaxel [23, 27] :

  • 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

Chemotherapy considerations

See the list below:

  • Concurrent chemoradiation is only offered for extremity and trunk soft tissue sarcoma, as intra-abdominal/retroperitoneal sites have prohibitive toxicities

  • Doxorubicin is 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 of therapy are difficult to administer beyond two cycles; there is very limited experience with chemoradiation with gemcitabine

  • A single trial reported safe administration of gemcitabine at 700 mg/m2 along with 50 Gy over 25 fractions

  • Similarly, 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

Treatment recommendations for soft tissue sarcomas with special histologies

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 90min 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 (32% vs 27%), with a 3% complete response (CR) and significantly improved progression-free survival (6.3 vs 3 mo) [28]

  • Several phase II trials have demonstrated the activity of temozolomide in sarcoma, with efficacy particularly notable in leiomyosarcoma [29, 30]

  • 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 [31]

  • 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 [32]

  • Docetaxel has also been shown to be promising, with 6 out of 9 patients treated achieving major responses [33]

  • 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 [34]

  • Single-agent bevacizumab can achieve a response rate of 12% and tumor stabilization in 62% [35]

Synovial sarcoma:

  • 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 [36]

  • 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% [37]