Neurofibrosarcoma

  • Dana-Farber/Brigham and Women's Cancer Care

    Neurofibrosarcoma is a malignant tumor that develops in the cells surrounding peripheral nerves. This condition is also known as peripheral nerve sheath tumor. Learn about neurofibrosarcoma and find information on how we support and care for people with neurofibrosarcoma before, during, and after treatment.

Treatment                                    

When you come to the Center for Sarcoma and Bone Oncology, you'll meet with members of our team who have expertise in caring for patients with sarcoma.

Patients with sarcoma often require a combination of surgery, chemotherapy, and radiation therapy. We recognize that a team approach is the best way to manage these complicated cases.

This means pathologists, medical oncologists, radiologists, surgeons and other health care professionals who specialize in sarcoma may be involved in decisions about your care.

Our group is also dedicated to clinical research to develop innovative treatment strategies for soft tissue and bone malignancies.

We will work with you to find other support services within Dana-Farber, including nutrition, complementary therapies, spiritual support, financial help, survivorship, and resources for families and young adults.

Our specialists see patients with all sarcomas and a variety of mesenchymal tumors, including: 

  • Alveolar soft part sarcoma
  • Angiosarcoma
  • Chondrosarcoma
  • Desmoid tumor
  • Desmoplastic small cell tumor
  • Epithelioid sarcoma
  • Ewings sarcoma
  • Extraskeletal mesenchymal chondrosarcoma
  • Extraskeletal osteosarcoma
  • Fibrous histiocytoma of bone
  • Fibrosarcoma
  • Gastrointestinal stromal tumor (GIST)
  • Kaposi's sarcoma
  • Leiomyosarcoma
  • Liposarcoma
  • Malignant fibrous histiocytoma (MFH)
  • Malignant mesenchymoma
  • Malignant primative neuroectodermal tumor (PNET)
  • Myofibroblastic sarcoma
  • Myxofibrosarcoma
  • Neurofibrosarcoma
  • Osteoganic sarcoma
  • Osteosarcoma
  • PEComa
  • Rhabdomyosarcoma
  • Malignant schwannoma
  • Spindle cell sarcoma
  • Synovial sarcoma

Contact us 

If you have never been seen before at Dana-Farber/Brigham and Women's Cancer Center, please call 877-442-3324 or use this online form to make an appointment.

If you need to schedule a follow-up appointment or for other questions, you’ll find your clinician’s contact information here  

Learn more about the Center for Sarcoma and Bone Oncology 

Information for: Patients | Healthcare Professionals

General Information About Adult Soft Tissue Sarcoma

Adult soft tissue sarcoma is a disease in which malignant (cancer) cells form in the soft tissues of the body.

The soft tissues of the body include the muscles, tendons (bands of fiber that connect muscles to bones), fat, blood vessels, lymph vessels, nerves, and tissues around joints. Adult soft tissue sarcomas can form almost anywhere in the body, but are most common in the head, neck, arms, legs, trunk, and abdomen.

There are many types of soft tissue sarcoma. The cells of each type of sarcoma look different under a microscope, based on the type of soft tissue in which the cancer began.

See the following PDQ summaries for more information on soft tissue sarcomas:

  • Childhood Soft Tissue Sarcoma Treatment
  • Ewing Sarcoma Family of Tumors Treatment
  • Gastrointestinal Stromal Tumors Treatment
  • Kaposi Sarcoma Treatment
  • Uterine Sarcoma Treatment

Having certain inherited disorders can increase the risk of adult soft tissue sarcoma.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for soft tissue sarcoma include the following inheriteddisorders:

  • Retinoblastoma.
  • Neurofibromatosis type 1 (NF1; von Recklinghausen disease).
  • Tuberous sclerosis (Bourneville disease).
  • Familial adenomatous polyposis (FAP; Gardner syndrome).
  • Li-Fraumeni syndrome.
  • Werner syndrome (adult progeria).
  • Nevoid basal cell carcinoma syndrome (Gorlin syndrome).

Other risk factors for soft tissue sarcoma include the following:

  • Past treatment with radiation therapy for certain cancers.
  • Being exposed to certain chemicals, such as Thorotrast (thorium dioxide), vinyl chloride, or arsenic.
  • Having swelling (lymphedema) in the arms or legs for a long time.

A sign of adult soft tissue sarcoma is a lump or swelling in soft tissue of the body.

A sarcoma may appear as a painless lump under the skin, often on an arm or a leg. Sarcomas that begin in the abdomen may not cause signs or symptoms until they get very big. As the sarcoma grows bigger and presses on nearby organs, nerves, muscles, or blood vessels, signs and symptoms may include:

  • Pain.
  • Trouble breathing.

Other conditions may cause the same signs and symptoms. Check with your doctor if you have any of these problems.

Adult soft tissue sarcoma is diagnosed with a biopsy.

If your doctor thinks you may have a soft tissue sarcoma, a biopsy will be done. The type of biopsy will be based on the size of the tumor and where it is in the body. There are three types of biopsy that may be used:

  • Incisional biopsy: The removal of part of a lump or a sample of tissue.
  • Core biopsy: The removal of tissue using a wide needle.
  • Excisional biopsy: The removal of an entire lump or area of tissue that doesn’t look normal.

Samples will be taken from the primary tumor, lymph nodes, and other suspicious areas. A pathologist views the tissue under a microscope to look for cancer cells and to find out the grade of the tumor. The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the cells are dividing. High-grade tumors usually grow and spread more quickly than low-grade tumors.

Because soft tissue sarcoma can be hard to diagnose, patients should ask to have tissue samples checked by a pathologist who has experience in diagnosing soft tissue sarcoma.

The following tests may be done on the tissue that was removed:

  • Immunohistochemistry: A test that uses antibodies to check for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the tissue to light up under a microscope. This type of test may be used to tell the difference between different types of cancer.
  • Light and electron microscopy: A laboratory test in which cells in a sample of tissue are viewed under regular and high-powered microscopes to look for certain changes in the cells.
  • Cytogenetic analysis: A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
  • FISH (fluorescence in situ hybridization): A laboratory test used to look at genes or chromosomes in cells and tissues. Pieces of DNA that contain a fluorescent dye are made in the laboratory and added to cells or tissues on a glass slide. When these pieces of DNA attach to certain genes or areas of chromosomes on the slide, they light up when viewed under a microscope with a special light.
  • Flow cytometry: A laboratory test that measures the number of cells in a sample, the percentage of live cells in a sample, and certain characteristics of cells, such as size, shape, and the presence of tumor markers on the cell surface. The cells are stained with a light-sensitive dye, placed in a fluid, and passed in a stream before a laser or other type of light. The measurements are based on how the light-sensitive dye reacts to the light.

Certain factors affect treatment options and prognosis (chance of recovery).

The treatment options and prognosis (chance of recovery) depend on the following:

  • The type of soft tissue sarcoma.
  • The size, grade, and stage of the tumor.
  • How fast the cancer cells are growing and dividing.
  • Where the tumor is in the body.
  • Whether all of the tumor is removed by surgery.
  • The patient's age and general health.
  • Whether the cancer has recurred (come back).

Stages of Adult Soft Tissue Sarcoma

After adult soft tissue sarcoma has been diagnosed, tests are done to find out if cancer cells have spread within the soft tissue or to other parts of the body.

The process used to find out if cancer has spread within the soft tissue or to other parts of the body is called staging. Staging of soft tissue sarcoma is also based on the grade and size of the tumor, whether it is superficial (close to the skin's surface) or deep, and whether it has spread to the lymph nodes or other parts of the body. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment.

The following tests and procedures may be used in the staging process:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it.
  • Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
    • The number of red blood cells, white blood cells, and platelets.
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the blood sample made up of red blood cells.
     
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside of the body, such as the lung and abdomen, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactiveglucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.

The results of these tests are viewed together with the results of the tumor biopsy to find out the stage of the soft tissue sarcoma before treatment is given. Sometimes chemotherapy or radiation therapy is given as the initial treatment and afterwards the soft tissue sarcoma is staged again.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if soft tissue sarcoma spreads to the lung, the cancer cells in the lung are actually soft tissue sarcoma cells. The disease is metastatic soft tissue sarcoma, not lung cancer.

The following stages are used for adult soft tissue sarcoma:

Tumor size compared to everyday objects; shows various measurements of a tumor compared to a pea, peanut, walnut, and lime  
Pea, peanut, walnut, and lime show tumor sizes.

Stage I

Stage I is divided into stages IA and IB:

  • In stage IA, the tumor is low-grade (likely to grow and spread slowly) and 5 centimeters or smaller. It may be either superficial (in subcutaneoustissue with no spread into connective tissue or muscle below) or deep (in the muscle and may be in connective or subcutaneous tissue).
  • In stage IB, the tumor is low-grade (likely to grow and spread slowly) and larger than 5 centimeters. It may be either superficial (in subcutaneoustissue with no spread into connective tissue or muscle below) or deep (in the muscle and may be in connective or subcutaneous tissue).

Stage II

Stage II is divided into stages IIA and IIB:

  • In stage IIA, the tumor is mid-grade (somewhat likely to grow and spread quickly) or high-grade (likely to grow and spread quickly) and 5 centimeters or smaller. It may be either superficial (in subcutaneoustissue with no spread into connective tissue or muscle below) or deep (in the muscle and may be in connective or subcutaneous tissue).
  • In stage IIB, the tumor is mid-grade (somewhat likely to grow and spread quickly) and larger than 5 centimeters. It may be either superficial (in subcutaneoustissue with no spread into connective tissue or muscle below) or deep (in the muscle and may be in connective or subcutaneous tissue).

Stage III

In stage III, the tumor is either:

  • high-grade (likely to grow and spread quickly), larger than 5 centimeters, and either superficial (in subcutaneoustissue with no spread into connective tissue or muscle below) or deep (in the muscle and may be in connective or subcutaneous tissue); or
  • any grade, any size, and has spread to nearby lymph nodes.

Stage III cancer that has spread to the lymph nodes is advanced stage III.

Stage IV

In stage IV, the tumor is any grade, any size, and may have spread to nearby lymph nodes. Cancer has spread to distant parts of the body, such as the lungs.

Recurrent Adult Soft Tissue Sarcoma

Recurrent adult soft tissue sarcoma is cancer that has recurred (come back) after it has been treated. The cancer may come back in the same soft tissue or in other parts of the body.

Treatment Option Overview

There are different types of treatment for patients with adult soft tissue sarcoma.

Different types of treatments are available for patients with adult soft tissue sarcoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Three types of standard treatment are used:

Surgery

Surgery is the most common treatment for adult soft tissue sarcoma. For some soft-tissue sarcomas, removal of the tumor in surgery may be the only treatment needed. The following surgical procedures may be used:

  • Mohs microsurgery: A procedure in which the tumor is cut from the skin in thin layers. During surgery, the edges of the tumor and each layer of tumor removed are viewed through a microscope to check for cancer cells. Layers continue to be removed until no more cancer cells are seen. This type of surgery removes as little normal tissue as possible and is often used where appearance is important, such as on the skin.
    Mohs surgery; drawing shows a visible lesion on the skin. The pullout shows a block of skin with cancer in the epidermis (outer layer of the skin) and the dermis (inner layer of the skin). A visible lesion is shown on the skin’s surface. Four numbered blocks show the removal of thin layers of the skin one at a time until all the cancer is removed. 
    Mohs surgery. A surgical procedure to remove a visible lesion on the skin in several steps. First, a thin layer of cancerous tissue is removed. Then, a second thin layer of tissue is removed and viewed under a microscope to check for cancer cells. More layers are removed one at a time until the tissue viewed under a microscope shows no remaining cancer. This type of surgery is used to remove as little normal tissue as possible.
  • Wide local excision: Removal of the tumor along with some normal tissue around it. For tumors of the head, neck, abdomen, and trunk, as little normal tissue as possible is removed.
  • Limb-sparing surgery: Removal of the tumor in an arm or leg without amputation, so the use and appearance of the limb is saved. Radiation therapy or chemotherapy may be given first to shrink the tumor. The tumor is then removed in a wide local excision. Tissue and bone that are removed may be replaced with a graft using tissue and bone taken from another part of the patient's body, or with an implant such as artificial bone.
  • Amputation: Surgery to remove part or all of a limb or appendage, such as an arm or leg. Amputation is rarely used to treat soft tissue sarcoma of the arm or leg.
  • Lymphadenectomy: A surgical procedure in which lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer. This procedure is also called a lymph node dissection.

Radiation therapy or chemotherapy may be given before or after surgery to remove the tumor. When given before surgery, radiation therapy or chemotherapy will make the tumor smaller and reduce the amount of tissue that needs to be removed during surgery. Treatment given before surgery is called neoadjuvant therapy. When given after surgery, radiation therapy or chemotherapy will kill any remaining cancer cells. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

See Drugs Approved for Adult and Childhood Soft Tissue Sarcoma for more information.

New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.

Regional chemotherapy

Clinical trials are studying ways to improve the effect of chemotherapy on tumor cells, including the following:

  • Regionalhyperthermia therapy: A treatment in which tissue around the tumor is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to chemotherapy.
  • Isolated limb perfusion: A procedure that sends chemotherapy directly to an arm or leg in which the cancer has formed. The flow of blood to and from the limb is temporarily stopped with a tourniquet, and anticancer drugs are put directly into the blood of the limb. This sends a high dose of drugs to the tumor.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Treatment Options for Adult Soft Tissue Sarcoma

Stage I Adult Soft Tissue Sarcoma

Treatment of stage Isoft tissue sarcoma may include the following:

  • Surgery to remove the tumor, such as Mohs microsurgery for small sarcomas of the skin, wide local excision, or limb-sparing surgery.
  • Radiation therapy before and/or after surgery.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I adult soft tissue sarcoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage II Adult Soft Tissue Sarcoma and Stage III Adult Soft Tissue Sarcoma That Has Not Spread to Lymph Nodes

Treatment of stage II adult soft tissue sarcoma and stage III adult soft tissue sarcoma that has not spread to lymph nodes may include the following:

  • Surgery to remove the tumor, such as wide local excision or limb-sparing surgery.
  • Radiation therapy before or after surgery.
  • Radiation therapy or chemotherapy before limb-sparing surgery. Radiation therapy may also be given after surgery.
  • High-dose radiation therapy for tumors that cannot be removed by surgery.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II adult soft tissue sarcoma and stage III adult soft tissue sarcoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage III Adult Soft Tissue Sarcoma That Has Spread to Lymph Nodes (Advanced)

Treatment of stage III adult soft tissue sarcoma that has spread to lymph nodes (advanced) may include the following:

  • Surgery (wide local excision) with lymphadenectomy. Radiation therapy may also be given after surgery.
  • A clinical trial of surgery followed by chemotherapy.
  • A clinical trial of regionalhyperthermia therapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III adult soft tissue sarcoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage IV Adult Soft Tissue Sarcoma

Treatment of stage IV adult soft tissue sarcoma may include the following:

  • Chemotherapy.
  • Surgery to remove cancer that has spread to the lungs.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV adult soft tissue sarcoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Treatment Options for Recurrent Adult Soft Tissue Sarcoma

Treatment of recurrent adult soft tissue sarcoma may include the following:

  • Surgery (wide local excision) followed by radiation therapy.
  • Surgery (amputation; rarely done).
  • Surgery to remove cancer that has recurred in the lungs.
  • Chemotherapy.
  • A clinical trial of isolated limb perfusion.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult soft tissue sarcoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

To Learn More About Adult Soft Tissue Sarcoma

For more information from the National Cancer Institute about soft tissue sarcomas, see the following:

For general cancer information and other resources from the National Cancer Institute, see the following:


This information is provided by the National Cancer Institute.

This information was last updated on May 2, 2014.


General Information About Adult Soft Tissue Sarcoma

Incidence and Mortality

Estimated new cases and deaths from soft tissue sarcoma in the United States in 2014:[1]

  • New cases: 12,020.
  • Deaths: 4,740.

Soft tissue sarcomas are malignant tumors that arise in any of the mesodermal tissues of the extremities (50%), trunk and retroperitoneum (40%), or head and neck (10%). The reported international incidence rates range from 1.8 to 5 per 100,000 per year.[2]

Risk Factors and Genetic Factors

The risk of sporadic soft tissue sarcomas is increased by prior radiation therapy and, in the case of lymphangiosarcoma, by chronic lymphedema. The chemicals Thorotrast, vinyl chloride, and arsenic are also established carcinogens for hepatic angiosarcomas.[3][4][5]

Soft tissue sarcomas occur with greater frequency in patients with the following inherited syndromes:[3][4][5]

  • Nevoid basal cell carcinoma syndrome (Gorlin syndrome: PTC gene mutation).
  • Gardner syndrome (APC mutation).
  • Li-Fraumeni syndrome (p53 mutation).
  • Tuberous sclerosis (Bourneville disease: TSC1 or TSC2 mutation).
  • von Recklinghausen disease (neurofibromatosis type 1: NF1 mutation).
  • Werner syndrome (adult progeria: WRN mutation).

Diagnosis

Soft tissue sarcomas may be heterogeneous, so adequate tissue should be obtained via either core-needle or incisional biopsy for microscopic examination to determine histologic type and tumor grade. Careful planning of the initial biopsy is important to avoid compromising subsequent curative resection. Since the selection of treatment is determined by the grade of the tumor, it is essential to have a careful review of the biopsy tissue by a pathologist who is experienced in diagnosing sarcomas. Complete staging and treatment planning by a multidisciplinary team of cancer specialists is required to determine the optimal treatment for patients with this disease.

There is evidence that at least some favorable clinical outcomes may be associated with referral to a specialized sarcoma treatment center. In a population-based consecutive series of 375 soft tissue sarcoma patients in Sweden, local recurrence rates of resected tumors were higher in patients who were not referred to the specialized center: in 35 of 78 (45%) patients not referred; in 24 of 102 (24%) patients referred after initial surgery or incisional biopsy; and in 36 of 195 (18%) patients referred prior to any surgical procedure (P = .0001 for the difference between those never referred vs. those referred prior to any surgical procedure).[6][Level of evidence: 3iDii] However, there were no statistically significant differences in death from sarcoma between the groups of patients.

Prognostic Factors

The prognosis for patients with adult soft tissue sarcomas depends on several factors, including:[3][4][5][7]

  • Patient’s age.
  • Size, histologic grade, mitotic activity, and stage of the tumor.

Factors associated with a poorer prognosis include the following:[8]

  • Age older than 60 years.
  • Tumors larger than 5 cm in greatest dimension.
  • High-grade histology with high mitotic activity.

Although low-grade tumors are usually curable by surgery alone, higher-grade sarcomas (as determined by the mitotic index and by the presence of hemorrhage and necrosis) are associated with higher local-treatment failure rates and increased metastatic potential.

Related Summaries

Note: Other PDQ summaries containing information about soft tissue sarcoma include:

  • Childhood Soft Tissue Sarcoma Treatment
  • Ewing Sarcoma Treatment
  • Gastrointestinal Stromal Tumors Treatment
  • Kaposi Sarcoma Treatment
  • Uterine Sarcoma Treatment

References:

  1. American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014.

  2. Wibmer C, Leithner A, Zielonke N, et al.: Increasing incidence rates of soft tissue sarcomas? A population-based epidemiologic study and literature review. Ann Oncol 21 (5): 1106-11, 2010.

  3. Singer S, Nielsen T, Antonescu CR: Molecular biology of soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1522-32.

  4. Singer S, Maki RG, O'Sullivan B: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1533-77.

  5. Malawer MM, Helman LJ, O'Sullivan B: Sarcomas of bone. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1578-1609.

  6. Gustafson P, Dreinhöfer KE, Rydholm A: Soft tissue sarcoma should be treated at a tumor center. A comparison of quality of surgery in 375 patients. Acta Orthop Scand 65 (1): 47-50, 1994.

  7. Coindre JM, Terrier P, Guillou L, et al.: Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer 91 (10): 1914-26, 2001.

  8. Vraa S, Keller J, Nielsen OS, et al.: Prognostic factors in soft tissue sarcomas: the Aarhus experience. Eur J Cancer 34 (12): 1876-82, 1998.

Cellular Classification of Adult Soft Tissue Sarcoma

Soft tissue sarcomas are classified histologically according to the soft tissue cell of origin. Additional studies, including electron microscopy, specialized immunohistochemistry, flow cytometry, cytogenetics, and tissue culture studies may allow identification of particular subtypes within the major histologic categories. For example, S100 antigen suggests neural sheath origin, cytokeratin suggests epithelioid or synovial cell origin, and factor VIII-related antigen suggests endothelial origin. Likewise, some subtypes of sarcomas have characteristic genetic markers, but these markers are not generally used in the routine clinical setting (e.g., t(X;18)(p11;q11) in synovial sarcomas and t(12;16)(q13;p11) in myxoid and round-cell sarcomas).[1][2][3]

The histologic grade reflects the metastatic potential of these tumors more accurately than the classic cellular classification listed below. Pathologists assign a grade based on the number of mitoses per high-powered field, the presence of necrosis, cellular and nuclear morphology, and the degree of cellularity; discordance among expert pathologists regarding tumor grade, and even histologic subtype, can be substantial.[4]

The World Health Organization lists the following cell types in its classification of soft tissue sarcomas:[5][6]

  • Adipocytic tumors.
    • Dedifferentiated liposarcoma.*
    • Myxoid/round cell liposarcoma.
    • Pleomorphic liposarcoma.
  • Fibroblastic/myofibroblastic tumors.
    • Fibrosarcoma.**
    • Myxofibrosarcoma, low grade.
    • Low-grade fibromyxoid sarcoma.
    • Sclerosing epithelioid fibrosarcoma.
  • So-called fibrohistiocytic tumors.
    • Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (MFH) (including pleomorphic, giant cell, myxoid/high-grade myxofibrosarcoma, and inflammatory forms).
  • Smooth muscle tumors.
    • Leiomyosarcoma.
  • Skeletal muscle tumors.
    • Rhabdomyosarcoma (embryonal, alveolar, and pleomorphic forms).
  • Vascular tumors.
    • Epithelioid hemangioendothelioma.
    • Angiosarcoma, deep.***
  • Tumors of peripheral nerves.
    • Malignant peripheral nerve sheath tumor.
  • Chondro-osseous tumors.
    • Extraskeletal chondrosarcoma (mesenchymal and other variants).
    • Extraskeletal osteosarcoma.
  • Tumors of uncertain differentiation.
    • Synovial sarcoma.
    • Epithelioid sarcoma.
    • Alveolar soft part sarcoma.
    • Clear cell sarcoma of soft tissue.
    • Extraskeletal myxoid chondrosarcoma.
    • Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor.
    • Desmoplastic small round cell tumor.
    • Extrarenal rhabdoid tumor.
    • Undifferentiated sarcoma; sarcoma, not otherwise specified (NOS).

*It is recognized that dedifferentiated liposarcoma primarily arises in the context of deep atypical lipomatous tumor/well-differentiated liposarcoma, a sarcoma of intermediate malignancy because of the lack of metastatic capacity. **The category of fibrosarcoma can be inclusive of fibrosarcomatous differentiation in dermatofibrosarcoma protuberans. ***Cutaneous angiosarcoma may be difficult to stage using the AJCC system. (Refer to the PDQ summary on Gastrointestinal stromal tumor [GIST] summary for more information.

References:

  1. Singer S, Nielsen T, Antonescu CR: Molecular biology of soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1522-32.

  2. Singer S, Maki RG, O'Sullivan B: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1533-77.

  3. Malawer MM, Helman LJ, O'Sullivan B: Sarcomas of bone. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1578-1609.

  4. Alvegård TA, Berg NO: Histopathology peer review of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience. J Clin Oncol 7 (12): 1845-51, 1989.

  5. Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-6.

  6. Brodowicz T, Schwameis E, Widder J, et al.: Intensified Adjuvant IFADIC Chemotherapy for Adult Soft Tissue Sarcoma: A Prospective Randomized Feasibility Trial. Sarcoma 4 (4): 151-60, 2000.

Stage Information for Adult Soft Tissue Sarcoma

Staging has an important role in determining the most effective treatment for soft tissue sarcoma. Clinical staging involves magnetic resonance imaging (MRI) or computed tomography (CT) of the primary tumor area and a chest CT to look for metastasis to the lung (the most common site of distant spread). An abdominal CT scan is done in the case of retroperitoneal sarcomas because the liver may be the site of initial clinical metastasis for these tumors.

The stage is determined by the size of the tumor, the histologic grade, and whether there is spread to lymph nodes or distant sites. Intracompartmental or extracompartmental extension of extremity sarcomas is also important for surgical decision making. For complete staging, a thorough review of all biopsy specimens (including those from the primary tumor, lymph nodes, or other suspicious lesions) is essential. CT scan of the chest is recommended for sarcomas larger than 5 cm (T2) or with moderate to poor differentiation (grades 2–4). Nodal involvement is rare, occurring in less than 3% of patients with sarcoma.[1]

Lymph node involvement in soft tissue sarcomas of adulthood is rare but is somewhat more frequent in some subtypes (e.g., rhabdomyosarcoma, vascular sarcomas, clear cell sarcomas, and epithelioid sarcomas) when they are high grade.[2] Because treatment decisions are predicated on pathology staging, patients should be staged before, and again after, any neoadjuvant therapy. The assessment of tumor grade can be affected in either direction, but more frequently decreased because of differential cellular loss related to the neoadjuvant chemotherapy or radiation.[3] Grade, which is based on cellular differentiation, mitotic rate, and extent of necrosis, should be recorded for all soft tissue sarcomas. A three-grade system (G1–G3) is preferred. (See Table 4 below).

The American Joint Committee on Cancer (AJCC) has designated staging by the four criteria of tumor size, nodal status, metastasis, and grade (TNMG).[3] The characteristic molecular markers of some sarcomas are not formally incorporated in the staging system pending further evaluation of their impact on prognosis. Recurrent sarcomas are restaged using the same system as for primary tumors with the specification that the tumor is recurrent.

Definitions of TNM and Grade

Table 1. Primary Tumor (T)a,b

TX

Primary tumor cannot be assessed.

T0

No evidence of primary tumor.

T1

Tumor ≤5 cm in greatest dimension. (Size should be regarded as a continuous variable, and the measurement should be provided.)

T1a

Superficial tumor.b

T1b

Deep tumor.b

T2

Tumor >5 cm in greatest dimension.b

T2a

Superficial tumor.b

T2b

Deep tumor.

aReprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.

bSuperficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia.

Table 2. Regional Lymph Nodes (N)a

NX

Regional lymph nodes cannot be assessed.

N0

No regional lymph node metastasis.

N1b

Regional lymph node metastasis.

aReprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.

bPresence of positive nodes (N1) in M0 tumors is considered Stage III.

Table 3. Distant Metastasis (M)a

M0

No distant metastasis.

M1

Distant metastasis.

aReprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.

Table 4. Anatomic Stage/Prognostic Groupsa

Stage IA

T1a

N0

M0

G1, GX

T1b

N0

M0

G1, GX

Stage IB

T2a

N0

M0

G1, GX

T2b

N0

M0

G1, GX

Stage IIA

T1a

N0

M0

G2, G3

T1b

N0

M0

G2, G3

Stage IIB

T2a

N0

M0

G2

T2b

N0

M0

G2

Stage III

T2a, T2b

N0

M0

G3

Any T

N1

M0

Any G

Stage IV

Any T

Any N

M1

Any G

aReprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.

Neurovascular and bone invasion are indicators of poor prognosis, but they are not incorporated into the formal staging system.

References:

  1. Fong Y, Coit DG, Woodruff JM, et al.: Lymph node metastasis from soft tissue sarcoma in adults. Analysis of data from a prospective database of 1772 sarcoma patients. Ann Surg 217 (1): 72-7, 1993.

  2. Mazeron JJ, Suit HD: Lymph nodes as sites of metastases from sarcomas of soft tissue. Cancer 60 (8): 1800-8, 1987.

  3. Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-6.

Treatment Option Overview

Multimodality Approach

In most cases, a combined modality approach of preoperative radiation therapy (preRX) or postoperative radiation therapy (PORT) is used, rather than the radical surgical procedures, such as amputation, that were used in the past. It may even be possible to use surgery without PORT in selected cases. For example, a case series was reported from a specialized sarcoma treatment referral center in which 74 selected patients with primary extremity and trunk tumors 5 cm or less in size were found to have no histologic involvement of the surgical margins. The patients were observed without radiation therapy, and the estimated local recurrence rate after 10 years was 11%.[1][Level of evidence: 3iiiDiv] The role of chemotherapy is not as well defined as is the role for radiation therapy. Because of the evolving nature of the treatment options for this disease, patients should be offered the option of clinical trials when available. Information about ongoing clinical trials is available from the NCI Web site.

Role of Surgery

Surgical resection is the mainstay of therapy for soft tissue sarcomas. When feasible, wide-margin function–sparing surgical excision is the cornerstone of effective treatment for extremity tumors. This may be facilitated by soft tissue reconstructive surgery, which generally permits wider margins than those obtained when the surgical plan involves direct closure of the excision site.[2] Cutting into the tumor mass or shelling out the gross tumor along the plane of the pseudocapsule of compressed tumor cells and reactive tissue that often surrounds soft tissue sarcomas are associated with an elevated risk of local recurrence. Even high-grade soft tissue sarcomas of the extremities can usually be effectively treated while preserving the limb with combined-modality treatment consisting of preRX or PORT to reduce local recurrence. (Refer to the Role of Radiation Therapy section of this summary for more information.)

Only one small, single-institution randomized trial has directly compared amputation to limb-sparing surgery for soft tissue sarcomas of the extremities.[3] In a 2:1 randomization ratio, 27 patients with high-grade extremity sarcomas were assigned to a wide excision plus PORT (45 Gy–50 Gy to the wide local excision area, and a total of 60 Gy–70 Gy to the tumor bed over 6–7 weeks), and 16 were assigned to amputation at or above the joint proximal to the tumor. Both groups received adjuvant chemotherapy (i.e., doxorubicin, cyclophosphamide, and high-dose methotrexate). At 63 months, with a median follow-up of 56 months, there were four local recurrences in the 27 patients who underwent limb-sparing surgery and no recurrences in the 16 patients who underwent amputation P2 = .12. Overall survival (OS) rates were not statistically significantly different (actuarial 5-year survival rate, 83% vs. 88%, P2 = .99).[3][Level of evidence: 1iiA]

Local control of high-grade soft tissue sarcomas of the trunk and the head and neck can be achieved with surgery in combination with radiation therapy.[4] It may be possible to use surgery without PORT in selected cases. For example, a case series was reported from a specialized sarcoma treatment referral center in which 74 selected patients with primary extremity and trunk tumors 5 cm or less in size were found to have no histologic involvement of the surgical margins.[1] They were observed without radiation therapy, and the estimated local recurrence rate after 10 years was 11%.[1][Level of evidence: 3iiiDiv] The role of chemotherapy is not as well defined as is the role of radiation therapy. Because of the evolving nature of the treatment options for this disease, patients should be offered the option of clinical trials when available.

Effective treatment of retroperitoneal sarcomas requires removal of all gross disease while sparing adjacent viscera not invaded by tumor. The prognosis for patients with high-grade retroperitoneal sarcomas is less favorable than for patients with tumors at other sites, partly because of the difficulty in completely resecting these tumors and the dose-limiting toxicity of high-dose radiation therapy on visceral organs.[5][6][7][8]

In the setting of distant metastasis, surgery may be associated with long-term disease-free survival in patients with pulmonary metastasis and optimal underlying disease biology (i.e., patients with a limited number of metastases and slow nodule growth) who have undergone or are undergoing complete resection of the primary tumor.[9][10][11] It is not clear to what degree the favorable outcomes are attributable to the efficacy of surgery or the careful selection of patients based on factors that are associated with less-virulent disease.

Role of Radiation Therapy

Radiation plays an important role in limb-sparing therapy. Pre- and postoperative external-beam radiation therapies (EBRT), as well as brachytherapy, have been shown to decrease the risk of local recurrence. They have not been shown to increase OS but are used to avoid amputation for all but the most locally advanced tumors or for limbs seriously compromised by vascular disease, where acceptable functional preservation is not possible. In the case of EBRT, irradiation of the entire limb circumference is avoided to preserve vascular and nerve structures that are critical to function and preservation of the limb.

PORT has been tested in a single-institution randomized trial of 141 patients with extremity sarcomas who were treated with limb-sparing surgery. Patients with high-grade tumors (n = 91) also received adjuvant chemotherapy (i.e., five 28-day cycles of doxorubicin and cyclophosphamide). All patients were randomly assigned to receive radiation (45 Gy to a wide field, plus a tumor-bed boost of 18 Gy over 6–7 weeks), concurrent with chemotherapy in the case of high-grade tumors versus no radiation.[12] At up to 12 years of follow-up, there was one local recurrence in the 70 patients randomly assigned to receive radiation versus 17 recurrences in the 71 control patients (P = .0001), with similar reduction in risk of local recurrence for both high- and low-grade tumors. However, there was no difference in OS between the radiation and control groups.[12][Level of evidence: 1iiDiii] Global quality of life was similar in the two groups, but the radiation therapy group had substantially worse functional deficits resulting from reduced strength and joint motion as well as increased edema.

To limit acute toxicity with preRX, smaller fields and lower doses are generally given than is the case with PORT. PreRX has been directly compared with PORT for extremity soft tissue sarcomas in a multicenter randomized trial.[13][14][15] Designed to include 266 patients, the trial was stopped early after 190 patients had been accrued because of an increase in wound complications in the preRX group. The scheduled radiation in the preRX group was a wide field of 50 Gy in 2 Gy fractions (first phase of the trial) with an additional 16 Gy to 20 Gy to the tumor bed and a 2-cm margin (second phase of the trial) only if tumor cells were found at the surgical margins.

Patients in the PORT group were scheduled to receive radiation during both phases of the trial. The wound-complication rates were 35% versus 17% in the preRX and PORT groups, respectively (P = .01). In addition, limb function at 6 weeks after surgery was worse in the preRX group (P = .01).[13] At 5 years, the two groups had similar local control rates (93% vs. 92%) and OS (73% vs. 67%, P = .48).[14] Of the 129 patients evaluated for limb function at 21 to 27 months after surgery (n = 73 for preRX and n = 56 for PORT), limb function was similar in both groups, but there was a statistical trend for less fibrosis in the preRX group (P = .07).[15]

Brachytherapy has also been investigated as an adjuvant therapy for soft tissue sarcomas. Although it has possible advantages of convenience and less radiation to normal surrounding tissue relative to EBRT, the two treatment strategies have not been directly compared in terms of efficacy or morbidity. However, adjuvant brachytherapy has been compared to surgery without radiation.

In a single-institution trial, 164 patients with sarcomas of the extremity or superficial trunk were randomly assigned during surgery, if all gross tumor could be excised, to receive an iridium-192 implant (delivering 42 Gy–45 Gy over 4–6 days; 78 patients) or to a control arm of no radiation (86 patients).[16][17] Some of the patients with high-grade tumors received adjuvant doxorubicin-based chemotherapy if they were thought to be at a high risk for metastasis (34 patients in each study arm). With a median follow-up of 76 months, the 5-year actuarial local recurrence rates were 18% and 31% in the brachytherapy and control arms, respectively (P = .04). This difference was limited to patients with high-grade tumors. There was no discernible difference in sarcoma-specific survival rates between the brachytherapy and control arms (84% and 81%, respectively; P = .65), and there was no difference in the high tumor-grade group.[16][Level of evidence: 1iiDiii] The rates of clinically important wound complications (e.g., need for operative revision or repeated seroma drainage, wound separation, large hematomas, or purulent infection) were 24% and 14% in the radiation and control arms, respectively (P = .13); wound reoperation rates were 10% and 0%, respectively (P = .006).[17]

Intensity-modulated radiation therapy (IMRT) has been used to deliver preRX or PORT to patients with extremity soft tissue sarcomas in an effort to spare the femur, joints, and selected other normal tissues from the full prescription dose and to maintain local control while potentially reducing radiation therapy-related morbidity. Initial single-institution reports suggest that high rates of local control with some reduction in morbidity are possible with this technique.[18][19]

In some tumors of the extremities or trunk, surgery alone can be performed without the use of radiation. Evidence for this approach is limited to single-institution, relatively small, case series [1][20][21] or analysis of outcomes in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) tumor registry.[22] However, these comparisons suffer from low statistical power and differential evaluability rates that could have introduced bias.[1] Patient selection factors may vary among surgeons. In general, this approach is considered in patients with low-grade tumors of the extremity or superficial trunk that are less than or equal to 5 cm in diameter (T1) and have microscopically negative surgical margins; long-term local tumor control is about 90% in such patients.[23]

On occasion, surgical excision cannot be performed in the initial management of soft tissue sarcomas because the morbidity would be unacceptable or nearby critical organs make complete resection impossible. In such circumstances, radiation has been used as the primary therapy.[24] However, this must be considered a treatment of last resort. Experience is limited to retrospective case series from single centers.[24][Level of evidence: 3iiiDiv]

Role of Adjuvant or Neoadjuvant Chemotherapy for Clinically Localized Tumors

The role of adjuvant chemotherapy is not completely clear. The investigation of its use falls into two categories or generations—pre- and postifosfamide regimens. In discussions with a patient, any potential benefits should be considered in the context of the short- and long-term toxicities of the chemotherapy.

First-generation trials (preifosfamide)

Several prospective, randomized trials were unable to determine conclusively whether doxorubicin-based adjuvant chemotherapy benefits adults with resectable soft tissue sarcomas. The majority of these studies accrued small numbers of patients and did not demonstrate a metastasis-free survival or an OS benefit for adjuvant chemotherapy.[4] A small study of adjuvant chemotherapy showed a positive effect on both disease-free survival (DFS) and OS in patients treated with postoperative chemotherapy.[25] There was wide interstudy variability among the reported trials, including differences in therapeutic regimens, drug doses, sample size, tumor site, and histologic grade.

A quantitative meta-analysis of updated data from 1,568 individual patients in 14 trials of doxorubicin-based adjuvant therapy showed an absolute benefit from adjuvant therapy of 6% for local relapse-free interval (95% confidence interval [CI], 1%–10%), 10% for distant relapse-free interval (95% CI, 5%–15%), and 10% for recurrence-free survival (95% CI, 5%–15%). A statistically significant OS benefit at 10 years was not detected: absolute difference 4% (95% CI, -1%–+9%).[26][27][Level of evidence: 1iiDii] However, only a small proportion of patients in this meta-analysis were treated with ifosfamide, an agent with demonstrated activity against soft tissue sarcoma. In addition, a subset analysis suggested that patients with sarcomas of the extremities may have benefited from adjuvant chemotherapy (hazard ratio [HR] for death, 0.8, P = .029), but there was no clear evidence that patients with extremity sarcomas had outcomes that were statistically significantly different from the outcomes of patients with tumors at other sites (P = .58).[27]

Second-generation trials (postifosfamide)

Subsequent chemotherapy trials were performed using anthracycline and ifosfamide combinations in patients who primarily had extremity or truncal soft tissue sarcomas. The data are conflicting, and the issue is still not settled. In a small feasibility study, 59 patients with high-risk soft tissue sarcomas, 58 of whom had an extremity or trunk as the primary site, underwent primary resection plus PORT and were randomly assigned to observation versus a dose-dense regimen of six 14-day courses of ifosfamide, dacarbazine (DTIC), and doxorubicin (IFADIC regimen) with granulocyte colony-stimulating factor (G-CSF) bone marrow support and mesna uroprotection.[28] There were no statistically significant differences in OS or relapse-free survival (RFS), but the study was severely underpowered.

In a second trial performed by the Italian National Council for Research, high-risk patients were treated with local therapy (i.e., wide resection plus preRX or PORT, or amputation as clinically necessary) and were then randomly assigned to observation versus five 21-day cycles of 4-epidoxorubicin (epirubicin) plus ifosfamide (with mesna and G-CSF).[25][29] Based on power calculations, the planned study size was 190 patients, but the trial was stopped after 104 patients had been entered because an interim analysis revealed a statistically significant (P = .001) difference in DFS favoring the chemotherapy arm. By the time of the initial peer-reviewed report of the study, the DFS still favored the chemotherapy group (median DFS of 48 months vs. 16 months), but the P value had risen to .04.[25]

Although there was no difference in metastasis-free survival at the time of the report, there was an improvement in median OS (75 months vs. 46 months, P = .03). However, at the follow-up report (at a median of 89.6 months in a range of 56–119 months), OS differences were no longer statistically significant (58.5% vs. 43.1% [P = .07]). The DFS difference had also lost statistical significance (47.2% vs. 16.0% [P = .09).[29] In summary, the trial was underpowered because it was stopped early, and the early promising results that led to stopping the trial diminished as the trial matured.

In a third, underpowered, single-center trial, 88 patients with high-risk soft tissue sarcomas (64 of whom had extremity or truncal primary tumors) underwent surgery (with or without radiation) and were then randomly assigned to receive four 21-day cycles of chemotherapy (epirubicin [n = 26] or epirubicin plus ifosfamide [n = 19]) versus no adjuvant chemotherapy (n = 43).[30] The trial was closed prematurely because of a slow accrual rate. After a median follow-up of 94 months, the 5-year DFS in the chemotherapy and control arms was 69% versus 44%, respectively (P = .01); the 5-year OS rates were 72% versus 47% (P = .06). All of the benefit associated with chemotherapy appeared restricted to the 19 patients who received epirubicin plus ifosfamide.

In yet another underpowered trial, 137 patients with high-risk soft tissue sarcomas (93% with extremity or truncal primary tumors) who met the eligibility criteria were randomly assigned to undergo surgical resection (with or without radiation) or to receive three preoperative 21-day cycles of doxorubicin plus ifosfamide.[31] This multicenter European Organization for Research and Treatment of Cancer trial (EORTC-62874) was closed because of slow accrual and results that were not promising enough to continue. With a median follow-up of 7.3 years, the 5-year DFS in the surgery alone and chemotherapy plus surgery arms was 52% and 56%, respectively (P = .35); and OS was 64% and 65%, respectively (P = .22).

These last four trials have been combined with the 14 first-generation trials in a trial-level meta-analysis.[32] Of the 18 randomized trials of patients with resectable soft tissue sarcomas, five trials used a combination of doxorubicin (50–90 mg/m2 per cycle) plus ifosfamide (1500–5000 mg/m2 per cycle). The remaining 13 trials used doxorubicin (50–70 mg/m2 per cycle) alone or with other drugs. The absolute risk reduction in local recurrence rates associated with any chemotherapy added to local therapy was 4 percentage points (95% CI, 0%–7%), and it was 5 percentage points (95% CI, 1%–12%) when ifosfamide was combined with doxorubicin. The absolute reduction in overall mortality was 6 percentage points with any chemotherapy (95% CI, 2%–11%; [i.e., a reduction from 46%–40%]), 11 percentage points for doxorubicin plus ifosfamide (95% CI, 3%–19%; [i.e., a reduction from 41%–30%]), and 5 percentage points for doxorubicin without ifosfamide.[32][Level of evidence: 1iiA]

An additional multicenter randomized trial (EORTC-62931 [NCT00002641]), the largest trial reported to date using adjuvant doxorubicin (75 mg/m2) plus ifosfamide (5000 mg/m2), was subsequently published in abstract form and was not included in the above meta-analysis.[33] The results differed from those reported in the meta-analysis.[32] After local therapy, 351 patients were randomly assigned to five 21-day cycles of adjuvant therapy versus observation. The trial was stopped for futility because the 5-year RFS was 52% in both arms. OS was 64% in the chemotherapy arm versus 69% in the observation arm. In a subsequent abstract, the EORTC investigators reported a combined analysis of this trial and their previous trial (EORTC-62771) [34] of adjuvant cyclophosphamide plus doxorubicin plus DTIC (CYVADIC), representing the two largest trials of adjuvant therapy for adult soft tissue sarcoma in the literature.[35] The combined analysis showed no improvement in either RFS or OS associated with adjuvant chemotherapy.[35][Level of evidence: 1iiA]

In summary, the impact of adjuvant chemotherapy on survival is not clear but is likely to be small in absolute magnitude. Therefore, in discussions with a patient, any potential benefits should be considered in the context of the short- and long-term toxicities of the chemotherapy.

Role of regional hyperthermia

The use of regional hyperthermia to enhance the local effects of systemic chemotherapy in the neoadjuvant and adjuvant setting is under investigation. In a multicenter phase III trial, 341 patients with high-risk (tumor ≥5 cm, grade 2–3, and deep to fascia) soft tissue sarcomas (149 extremity tumors and 192 nonextremity tumors) were randomly allocated to receive four 21-day cycles of chemotherapy (etoposide 125 mg/m2 on days 1 and 4; ifosfamide 1500 mg/m2 on days 1–4; doxorubicin 50 mg/m2 on day 1) with or without regional hyperthermia both before and after local therapy.[36] Approximately 11% of the patients were being treated for recurrent tumors. The regional hyperthermia was designed to produce tumor temperatures of 42°C for 60 minutes and was given on days 1 and 4 of each chemotherapy cycle. After the first four cycles of chemotherapy, definitive surgical excision of the tumor was performed, if possible, followed by radiation therapy, if indicated (i.e., a 52.7 Gy median dose delivered), and then the last four cycles of chemotherapy plus or minus hyperthermia. Three of the nine treatment centers with particular expertise in hyperthermia treated 91% of the patients in the trial.

The median duration of follow-up was 34 months. Local progression occurred in 56 patients in the hyperthermia group and 76 patients in the control group. The relative HR for local progression or death was 0.58 (95% CI, 0.41–0.84), with an absolute difference at 2 years of 15% (76% vs. 61%; 95% CI of the difference 6–26). The decreased risk of local progression or death was seen in both extremity and nonextremity tumors. However, hyperthermia had no effect on distant failure rates nor was there a statistically significant effect on OS (HR, .88, 95% CI, 0.64–1.21; P = .43).[36][Level of evidence: 1iiDiii] There was a higher rate of grade 3 to 4 leucopenia in the hyperthermia group: 77.6% versus 63.5% (P = .005). Since a large proportion of the patients were treated at centers with special expertise, there is no certainty that the finding can be generalized to apply to other settings.

Role of isolated limb perfusion

Isolated limb perfusion is under investigation as a means to deliver high doses of chemotherapy and permit limb salvage in unresectable primary or recurrent extremity soft tissue sarcomas that would otherwise require amputation, in the opinion of the surgeon.[37][38] Common drugs used in the procedure are TNF-alpha, melphalan, and interferon-gamma. Experience is limited to case series with response rates and reported avoidance of amputation as the outcome.[37][38][Level of evidence: 3iiiDiv] The technique requires specialized expertise to avoid severe local and systemic toxicity including systemic effects of TNF-alpha. The technique has not been directly compared to standard approaches with combined systemic and local therapy.

Role of chemotherapy for advanced disease

Doxorubicin is a mainstay of systemic therapy in the management of locally advanced and metastatic soft tissue sarcoma. Pegylated liposomal encapsulated doxorubicin is a formulation of doxorubicin designed to prolong the half-life of circulating doxorubicin and slow the release of active drug.[39] The changed pharmacokinetics result in less myelosuppression and possibly less cardiotoxic effects, but there is a substantial incidence of hypersensitivity-like reactions and hand-foot syndrome. Its clinical activity relative to unencapsulated doxorubicin is not clear.[39][Level of evidence: 3iiiDiv] Other drugs that are thought to have clinical activity as single agents are ifosfamide, epirubicin, gemcitabine, and paclitaxel.[40][41][42][43][Level of Evidence: 3iiiDiv] Their clinical activity relative to single-agent doxorubicin is not clear, and they are not known to have superior activity.

There is controversy about the clinical benefit of adding other drugs to doxorubicin as a single agent. A systematic evidence review and meta-analysis conducted by the Cochrane Collaboration summarized the eight randomized trials reported from 1976 to 1995.[44] No additional randomized trials had been reported or were known to be in progress between 1995 and the 2002 literature search. Single-agent doxorubicin had been compared with a variety of doxorubicin-containing combinations that included vincristine, vindesine, cyclophosphamide, streptozotocin, mitomycin-C, cisplatin, and/or ifosfamide. Combination regimens consistently caused more nausea and hematologic toxicity. However, the better response rates associated with combination therapy were marginal and depended on the statistical model used (fixed effects model ORresp = 1.29; 95% CI, 1.03–1.60, P = .03; random effects model ORresp = 1.26; 95% CI, 0.96–1.67, P = .10) There was no statistically significant difference in the 1- (ORmortality = 0.87; 95% CI, 0.73–1.05, P = .14) or 2-year mortality rates (ORmortality = 0.84; 95% CI, 0.67–1.06, P = .13).

These results were very similar even when the analyses were restricted to the four trials that used DTIC and/or ifosfamide as part of the combination regimen with doxorubicin agents that were postulated to have greater activity than the others tested. A subsequent meta-analysis of all three published randomized trials of chemotherapy regimens that contained ifosfamide versus those that did not came to similar conclusions: tumor response rates were better when the regimen included ifosfamide (RRresp = 1.52; 95% CI, 1.11–2.08), but mortality at 1 year was not (RRmortality = 0.98; 95% CI, 0.85–1.13).[45][Level of evidence: 1iiDiv]. Therefore, response rate was a poor surrogate for OS. Quality-of-life outcomes were not reported in any of the above-mentioned randomized trials, but toxicity was worse when agents were added to doxorubicin.

References:

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  2. Lohman RF, Nabawi AS, Reece GP, et al.: Soft tissue sarcoma of the upper extremity: a 5-year experience at two institutions emphasizing the role of soft tissue flap reconstruction. Cancer 94 (8): 2256-64, 2002.

  3. Rosenberg SA, Tepper J, Glatstein E, et al.: The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196 (3): 305-15, 1982.

  4. O'Byrne K, Steward WP: The role of adjuvant chemotherapy in the treatment of adult soft tissue sarcomas. Crit Rev Oncol Hematol 27 (3): 221-7, 1998.

  5. Singer S, Nielsen T, Antonescu CR: Molecular biology of soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1522-32.

  6. Singer S, Maki RG, O'Sullivan B: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1533-77.

  7. Malawer MM, Helman LJ, O'Sullivan B: Sarcomas of bone. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1578-1609.

  8. Lewis JJ, Leung D, Woodruff JM, et al.: Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg 228 (3): 355-65, 1998.

  9. van Geel AN, Pastorino U, Jauch KW, et al.: Surgical treatment of lung metastases: The European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer 77 (4): 675-82, 1996.

  10. Casson AG, Putnam JB, Natarajan G, et al.: Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 69 (3): 662-8, 1992.

  11. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.

  12. Yang JC, Chang AE, Baker AR, et al.: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16 (1): 197-203, 1998.

  13. O'Sullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359 (9325): 2235-41, 2002.

  14. O'Sullivan B, Davis A, Turcotte R, et al.: Five-year results of a randomized phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma. [Abstract] J Clin Oncol 22 (Suppl 14): A-9007, 819s, 2004.

  15. Davis AM, O'Sullivan B, Turcotte R, et al.: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 75 (1): 48-53, 2005.

  16. Pisters PW, Harrison LB, Leung DH, et al.: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 14 (3): 859-68, 1996.

  17. Alektiar KM, Zelefsky MJ, Brennan MF: Morbidity of adjuvant brachytherapy in soft tissue sarcoma of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys 47 (5): 1273-9, 2000.

  18. Alektiar KM, Brennan MF, Healey JH, et al.: Impact of intensity-modulated radiation therapy on local control in primary soft-tissue sarcoma of the extremity. J Clin Oncol 26 (20): 3440-4, 2008.

  19. Alektiar KM, Brennan MF, Singer S: Local control comparison of adjuvant brachytherapy to intensity-modulated radiotherapy in primary high-grade sarcoma of the extremity. Cancer 117 (14): 3229-34, 2011.

  20. Fabrizio PL, Stafford SL, Pritchard DJ: Extremity soft-tissue sarcomas selectively treated with surgery alone. Int J Radiat Oncol Biol Phys 48 (1): 227-32, 2000.

  21. Rydholm A, Gustafson P, Rööser B, et al.: Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol 9 (10): 1757-65, 1991.

  22. Al-Refaie WB, Habermann EB, Jensen EH, et al.: Surgery alone is adequate treatment for early stage soft tissue sarcoma of the extremity. Br J Surg 97 (5): 707-13, 2010.

  23. Rydholm A: Surgery without radiotherapy in soft tissue sarcoma. Acta Orthop Scand Suppl 273: 117-9, 1997.

  24. Kepka L, DeLaney TF, Suit HD, et al.: Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 63 (3): 852-9, 2005.

  25. Frustaci S, Gherlinzoni F, De Paoli A, et al.: Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol 19 (5): 1238-47, 2001.

  26. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 350 (9092): 1647-54, 1997.

  27. Sarcoma Meta-analysis Collaboration (SMAC): Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults. Cochrane Database Syst Rev (4): CD001419, 2000.

  28. Brodowicz T, Schwameis E, Widder J, et al.: Intensified Adjuvant IFADIC Chemotherapy for Adult Soft Tissue Sarcoma: A Prospective Randomized Feasibility Trial. Sarcoma 4 (4): 151-60, 2000.

  29. Frustaci S, De Paoli A, Bidoli E, et al.: Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology 65 (Suppl 2): 80-4, 2003.

  30. Petrioli R, Coratti A, Correale P, et al.: Adjuvant epirubicin with or without Ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol 25 (5): 468-73, 2002.

  31. Gortzak E, Azzarelli A, Buesa J, et al.: A randomised phase II study on neo-adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma. Eur J Cancer 37 (9): 1096-103, 2001.

  32. Pervaiz N, Colterjohn N, Farrokhyar F, et al.: A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 113 (3): 573-81, 2008.

  33. Woll PJ, van Glabbeke M, Hohenberger P, et al.: Adjuvant chemotherapy (CT) with doxorubicin and ifosfamide in resected soft tissue sarcoma (STS): Interim analysis of a randomised phase III trial. [Abstract] J Clin Oncol 25 (Suppl 18): A-10008, 2007.

  34. Bramwell V, Rouesse J, Steward W, et al.: Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 12 (6): 1137-49, 1994.

  35. Le Cesne A, Van Glabbeke M, Woll PJ, et al.: The end of adjuvant chemotherapy (adCT) era with doxorubicin-based regimen in resected high-grade soft tissue sarcoma (STS): pooled analysis of the two STBSG-EORTC phase III clinical trials. [Abstract] J Clin Oncol 26 (Suppl 15): A-10525, 2008.

  36. 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 11 (6): 561-70, 2010.

  37. Eggermont AM, de Wilt JH, ten Hagen TL: Current uses of isolated limb perfusion in the clinic and a model system for new strategies. Lancet Oncol 4 (7): 429-37, 2003.

  38. 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 16 (7): 1061-8, 2005.

  39. Grenader T, Goldberg A, Hadas-Halperin I, et al.: Long-term response to pegylated liposomal doxorubicin in patients with metastatic soft tissue sarcomas. Anticancer Drugs 20 (1): 15-20, 2009.

  40. Lorigan P, Verweij J, Papai Z, et al.: Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 25 (21): 3144-50, 2007.

  41. Nielsen OS, Dombernowsky P, Mouridsen H, et al.: High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer 78 (12): 1634-9, 1998.

  42. Maki RG, Wathen JK, Patel SR, 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 25 (19): 2755-63, 2007.

  43. Okuno S, Ryan LM, Edmonson JH, et al.: Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer 97 (8): 1969-73, 2003.

  44. Bramwell VH, Anderson D, Charette ML, et al.: Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma. Cochrane Database Syst Rev (3): CD003293, 2003.

  45. Verma S, Younus J, Stys-Norman D, et al.: Meta-analysis of ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma. Cancer Treat Rev 34 (4): 339-47, 2008.

Stage I Adult Soft Tissue Sarcoma

Refer to the Treatment Option Overview section of this summary for a more detailed discussion of the roles of surgery and radiation therapy.

Low-grade soft tissue sarcomas have little metastatic potential, but they have a propensity to recur locally. Accordingly, surgical excision with negative tissue margins of 1 cm to 2 cm or larger in all directions is the treatment of choice for patients with these early-stage sarcomas.[1][2][3] The Mohs surgical technique may be considered as an alternative to wide surgical excision for the very rare, small, well-differentiated primary sarcomas of the skin when cosmetic results are considered to be important, as margins can be assured with minimal normal tissue removal.[4]

Carefully executed high-dose radiation therapy using a shrinking-field technique may be beneficial for unresectable tumors or for resectable tumors in which a high likelihood of residual disease is thought to be present when margins are judged to be inadequate, and when wider resection would require either an amputation or the removal of a vital organ.[5] Because of the low metastatic potential of these tumors, chemotherapy is usually not given.[6][7]

Standard treatment options:

  1. Surgical excision of tumors no greater than 5 cm in diameter with negative tissue margins in all directions.[8][9][10][11][12]
  2. Surgical excision with preoperative radiation therapy (preRX) or postoperative radiation therapy (PORT). Radiation decreases the risk of local recurrence but has not been shown to increase overall survival.[13][14][15][16]
  3. If the tumor is unresectable, high-dose preRX may be used.[17]
  4. For tumors of the retroperitoneum, trunk, and head and neck, the following are options:
    • Surgical resection with the option of PORT if negative margins cannot be obtained. Wide margins are unusual in these sites, and radiation therapy is usually advocated for trunk and head and neck primary sites.[18]
    • PreRX followed by maximal surgical resection. Radiation therapy may be used in sarcomas of the trunk and head and neck to maximize local control because of the inability to obtain wide surgical margins.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I adult soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Singer S, Nielsen T, Antonescu CR: Molecular biology of soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1522-32.

  2. Singer S, Maki RG, O'Sullivan B: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1533-77.

  3. Malawer MM, Helman LJ, O'Sullivan B: Sarcomas of bone. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1578-1609.

  4. Fish FS: Soft tissue sarcomas in dermatology. Dermatol Surg 22 (3): 268-73, 1996.

  5. Temple WJ, Temple CL, Arthur K, et al.: Prospective cohort study of neoadjuvant treatment in conservative surgery of soft tissue sarcomas. Ann Surg Oncol 4 (7): 586-90, 1997 Oct-Nov.

  6. Sarcoma Meta-analysis Collaboration (SMAC): Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults. Cochrane Database Syst Rev (4): CD001419, 2000.

  7. Pervaiz N, Colterjohn N, Farrokhyar F, et al.: A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 113 (3): 573-81, 2008.

  8. Al-Refaie WB, Habermann EB, Jensen EH, et al.: Surgery alone is adequate treatment for early stage soft tissue sarcoma of the extremity. Br J Surg 97 (5): 707-13, 2010.

  9. Pisters PW, Pollock RE, Lewis VO, et al.: Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg 246 (4): 675-81; discussion 681-2, 2007.

  10. Fabrizio PL, Stafford SL, Pritchard DJ: Extremity soft-tissue sarcomas selectively treated with surgery alone. Int J Radiat Oncol Biol Phys 48 (1): 227-32, 2000.

  11. Rydholm A, Gustafson P, Rööser B, et al.: Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol 9 (10): 1757-65, 1991.

  12. Rydholm A: Surgery without radiotherapy in soft tissue sarcoma. Acta Orthop Scand Suppl 273: 117-9, 1997.

  13. Yang JC, Chang AE, Baker AR, et al.: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16 (1): 197-203, 1998.

  14. O'Sullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359 (9325): 2235-41, 2002.

  15. O'Sullivan B, Davis A, Turcotte R, et al.: Five-year results of a randomized phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma. [Abstract] J Clin Oncol 22 (Suppl 14): A-9007, 819s, 2004.

  16. Davis AM, O'Sullivan B, Turcotte R, et al.: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 75 (1): 48-53, 2005.

  17. Kepka L, DeLaney TF, Suit HD, et al.: Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 63 (3): 852-9, 2005.

  18. Brennan MF, Singer S, Maki RG: Sarcomas of the soft tissue and bone. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Vols. 1 & 2. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2008, pp 1741-1833.

Stage II and Node-Negative Stage III Adult Soft Tissue Sarcoma

Refer to the Treatment Option Overview section of this summary for a more detailed discussion of the roles of surgery, radiation therapy, and chemotherapy.

High-grade localized soft tissue sarcomas have an increased potential for local recurrence and metastasis. For sarcomas of the extremities, local control comparable to that obtained with amputation may be achieved with limb-sparing surgery that involves wide local excision in combination with preoperative radiation therapy (preRX) or postoperative radiation therapy (PORT).

Complete surgical resection is often difficult for sarcomas of the retroperitoneum because of their large size before detection and anatomical location.[1][2] As opposed to soft tissue sarcomas of the extremities, local recurrence is the most common cause of death in patients with retroperitoneal soft tissue sarcomas. Complete surgical resection (i.e., removal of the entire gross tumor) is the most important factor in preventing local recurrence and, in many instances, requires resection of adjacent viscera.

Standard treatment options:

  1. Surgical excision with preRX or PORT. Radiation decreases the risk of local recurrence but has not been shown to increase overall survival.[3][4][5][6][7]
  2. Surgical excision with negative tissue margins in all directions. This approach is generally restricted to low-grade tumors ( ≤5 cm in diameter) of the extremities or superficial trunk with microscopically negative surgical tumor margins.[8][9][10][11][12]
  3. If the tumor is unresectable, high-dose radiation therapy may be used, but poor local control is likely to result.[13]
  4. In some situations, radiation therapy and/or chemotherapy may be used prior to surgery in an attempt to convert a marginally resectable tumor to one that can be adequately resected with limb preservation; this treatment may be followed by PORT.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II adult soft tissue sarcoma and stage III adult soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Heslin MJ, Lewis JJ, Nadler E, et al.: Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol 15 (8): 2832-9, 1997.

  2. Jaques DP, Coit DG, Hajdu SI, et al.: Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum. Ann Surg 212 (1): 51-9, 1990.

  3. Yang JC, Chang AE, Baker AR, et al.: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16 (1): 197-203, 1998.

  4. Rosenberg SA, Tepper J, Glatstein E, et al.: The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196 (3): 305-15, 1982.

  5. O'Sullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359 (9325): 2235-41, 2002.

  6. O'Sullivan B, Davis A, Turcotte R, et al.: Five-year results of a randomized phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma. [Abstract] J Clin Oncol 22 (Suppl 14): A-9007, 819s, 2004.

  7. Davis AM, O'Sullivan B, Turcotte R, et al.: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 75 (1): 48-53, 2005.

  8. Al-Refaie WB, Habermann EB, Jensen EH, et al.: Surgery alone is adequate treatment for early stage soft tissue sarcoma of the extremity. Br J Surg 97 (5): 707-13, 2010.

  9. Pisters PW, Pollock RE, Lewis VO, et al.: Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg 246 (4): 675-81; discussion 681-2, 2007.

  10. Fabrizio PL, Stafford SL, Pritchard DJ: Extremity soft-tissue sarcomas selectively treated with surgery alone. Int J Radiat Oncol Biol Phys 48 (1): 227-32, 2000.

  11. Rydholm A, Gustafson P, Rööser B, et al.: Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol 9 (10): 1757-65, 1991.

  12. Rydholm A: Surgery without radiotherapy in soft tissue sarcoma. Acta Orthop Scand Suppl 273: 117-9, 1997.

  13. Kepka L, DeLaney TF, Suit HD, et al.: Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 63 (3): 852-9, 2005.

Advanced Stage III (N1) Adult Soft Tissue Sarcoma

Refer to the Treatment Option Overview section of this summary for a more detailed discussion of the roles of surgery, radiation therapy, and chemotherapy.

Regional lymph node involvement by soft tissue sarcomas of adulthood is very infrequent. However, sarcoma types that more commonly spread to lymph nodes include high-grade rhabdomyosarcoma, vascular sarcomas, and epithelioid sarcomas.[1]

Standard treatment options:

  1. Surgical resection and lymphadenectomy for patients with clinically positive lymph nodes with or without postoperative radiation.[1]
  2. Adjuvant chemotherapy may be considered but is not known to improve overall survival.[1][2][3][4][5] Clinical trials should be considered if available.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II adult soft tissue sarcoma and stage III adult soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Mazeron JJ, Suit HD: Lymph nodes as sites of metastases from sarcomas of soft tissue. Cancer 60 (8): 1800-8, 1987.

  2. Watson DI, Coventry BJ, Langlois SL, et al.: Soft-tissue sarcoma of the extremity. Experience with limb-sparing surgery. Med J Aust 160 (7): 412-6, 1994.

  3. Cormier JN, Huang X, Xing Y, et al.: Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: chemotherapy-associated outcomes. J Clin Oncol 22 (22): 4567-74, 2004.

  4. O'Byrne K, Steward WP: The role of adjuvant chemotherapy in the treatment of adult soft tissue sarcomas. Crit Rev Oncol Hematol 27 (3): 221-7, 1998.

  5. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 350 (9092): 1647-54, 1997.

Stage IV Adult Soft Tissue Sarcoma

Refer to the Treatment Option Overview section of this summary for a more detailed discussion of the roles of surgery, radiation therapy, and chemotherapy.

In the setting of lung metastasis, resection of metastatic tumors may be associated with long-term disease-free survival in patients selected for optimal underlying disease biology (i.e., patients with a limited number of metastases and slow tumor growth).[1][2][3] It is not clear to what degree the favorable outcomes are attributable to the efficacy of surgery or to careful selection of patients based upon factors that are associated with less-virulent disease.[1][2][3] The value of resection of hepatic metastases is unclear.

As noted in the Treatment Option Overview section above, doxorubicin is the standard systemic therapy in the management of metastatic sarcomas.[4][5] Other drugs that are felt to have clinical activity as single agents are ifosfamide, epirubicin, gemcitabine, and paclitaxel.[6][7][8][9] Their clinical activity relative to single-agent doxorubicin is not clear, and they are not known to have superior activity. There is controversy about whether adding drugs to doxorubicin offers clinical benefit beyond what is achieved by doxorubicin as a single agent. For older patients to avoid severe toxicity, sequential use of single agents may be the preferred strategy for palliation.

Standard treatment options

  1. Chemotherapy.
    • Single-agent chemotherapy, with subsequent single agents for disease regrowth.[4][5][6][8][9][10] Doxorubicin is generally the first-line agent. Ifosfamide also has substantial single-agent activity.
    • Doxorubicin-based combination chemotherapy. A variety of regimens have been used, but none has been proven to increase overall survival compared to doxorubicin alone.[4][5] There is some evidence that the addition of ifosfamide increases response rates (but not survival). Toxicity is increased with the addition of drugs to doxorubicin. No quality-of-life studies have been reported in comparisons of single-agent therapy versus combination therapy.
  2. Resection of pulmonary lesions may be performed if the primary tumor is under control.[1][2][3]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV adult soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. van Geel AN, Pastorino U, Jauch KW, et al.: Surgical treatment of lung metastases: The European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer 77 (4): 675-82, 1996.

  2. Casson AG, Putnam JB, Natarajan G, et al.: Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 69 (3): 662-8, 1992.

  3. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.

  4. Bramwell VH, Anderson D, Charette ML, et al.: Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma. Cochrane Database Syst Rev (3): CD003293, 2003.

  5. Verma S, Younus J, Stys-Norman D, et al.: Meta-analysis of ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma. Cancer Treat Rev 34 (4): 339-47, 2008.

  6. Lorigan P, Verweij J, Papai Z, et al.: Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 25 (21): 3144-50, 2007.

  7. Nielsen OS, Dombernowsky P, Mouridsen H, et al.: High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer 78 (12): 1634-9, 1998.

  8. Maki RG, Wathen JK, Patel SR, 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 25 (19): 2755-63, 2007.

  9. Okuno S, Ryan LM, Edmonson JH, et al.: Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer 97 (8): 1969-73, 2003.

  10. Grenader T, Goldberg A, Hadas-Halperin I, et al.: Long-term response to pegylated liposomal doxorubicin in patients with metastatic soft tissue sarcomas. Anticancer Drugs 20 (1): 15-20, 2009.

Recurrent Adult Soft Tissue Sarcoma

Treatment of patients with recurrent soft tissue sarcoma depends on the type of initial presentation and treatment. Patients who develop a local recurrence often can be treated by local therapy: surgical excision plus radiation therapy after previous minimal therapy or amputation after previous aggressive treatment.[1][2][3][4][5][6][7] Resection of limited pulmonary metastases may be associated with favorable disease-free survival.[8][9][10][Level of evidence: 3iiiDiv] However, the contribution of selection factors, such as low tumor burden, slow tumor growth, and long disease-free interval, to these favorable outcomes is not known.

There is no standard chemotherapy for recurrent soft tissue sarcomas that have progressed after doxorubicin as a single agent or in combination with other agents that have clinical activity, such as ifosfamide, epirubicin, gemcitabine, and paclitaxel. Any of these agents not previously administered to the patient may be used sequentially at the time of recurrence or progression.[11][12][13][14][Level of Evidence: 3iiiDiv] Given that none of these agents has been shown to increase overall survival in this setting, clinical trials are an appropriate option.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Singer S, Nielsen T, Antonescu CR: Molecular biology of soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1522-32.

  2. Singer S, Maki RG, O'Sullivan B: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1533-77.

  3. Malawer MM, Helman LJ, O'Sullivan B: Sarcomas of bone. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1578-1609.

  4. Midis GP, Pollock RE, Chen NP, et al.: Locally recurrent soft tissue sarcoma of the extremities. Surgery 123 (6): 666-71, 1998.

  5. Essner R, Selch M, Eilber FR: Reirradiation for extremity soft tissue sarcomas. Local control and complications. Cancer 67 (11): 2813-7, 1991.

  6. Singer S, Antman K, Corson JM, et al.: Long-term salvageability for patients with locally recurrent soft-tissue sarcomas. Arch Surg 127 (5): 548-53; discussion 553-4, 1992.

  7. Lewis JJ, Leung D, Heslin M, et al.: Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. J Clin Oncol 15 (2): 646-52, 1997.

  8. van Geel AN, Pastorino U, Jauch KW, et al.: Surgical treatment of lung metastases: The European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer 77 (4): 675-82, 1996.

  9. Casson AG, Putnam JB, Natarajan G, et al.: Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 69 (3): 662-8, 1992.

  10. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.

  11. Lorigan P, Verweij J, Papai Z, et al.: Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 25 (21): 3144-50, 2007.

  12. Nielsen OS, Dombernowsky P, Mouridsen H, et al.: High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer 78 (12): 1634-9, 1998.

  13. Maki RG, Wathen JK, Patel SR, 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 25 (19): 2755-63, 2007.

  14. Okuno S, Ryan LM, Edmonson JH, et al.: Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer 97 (8): 1969-73, 2003.


This information is provided by the National Cancer Institute.

This information was last updated on February 28, 2014.

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