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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Soft Tissue Sarcoma

Version 2.2021 — April 28, 2021

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NCCN Guidelines for Patients

available at www.nccn.org/patients

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

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Table of Contents

Discussion

ξ Bone marrow

transplantation

‡ Hematology/

Hematologic oncology

Þ Internal medicine

† Medical oncology

τ Orthopedics/Orthopedic

oncology

≠ Pathology

¥ Patient advocacy

€ Pediatric oncology

§ Radiotherapy/Radiation

oncology

¶ Surgery/Surgical

oncology

* Discussion writing

committee member

*Margaret von Mehren, MD/Chair †

Fox Chase Cancer Center

*John M. Kane, III, MD/Vice-Chair ¶

Roswell Park Comprehensive

Cancer Center

Marilyn M. Bui, MD, PhD ≠

Mott Cancer Center

Edwin Choy, MD, PhD †

Massachusetts General Hospital

Cancer Center

Mary Connelly, LSW ¥

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

Sarah Dry, MD ≠

UCLA Jonsson Comprehensive

Cancer Center

Kristen N. Ganjoo, MD †

Stanford Cancer Institute

Suzanne George, MD †

Dana-Farber/Brigham and

Women’s Cancer Center

Ricardo J. Gonzalez, MD ¶

Mott Cancer Center

Martin J. Heslin, MD ¶

O'Neal Comprehensive

Cancer Center at UAB

Jade Homsi, MD †

UT Southwestern Simmons Comprehensive

Cancer Center

Vicki Keedy, MD, MSCI †

Vanderbilt-Ingram Cancer Center

Ciara M. Kelly, MD †

Memorial Sloan Kettering Cancer Center

Edward Kim MD §

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

David Liebner, MD Þ †

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

Martin McCarter, MD ¶

University of Colorado Cancer Center

Sean V. McGarry, MD ¶ τ

Fred & Pamela Buffett Cancer Center

Christian Meyer, MD, PhD †

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

Alberto S. Pappo, MD €

St. Jude Children’s Research Hospital/

University of Tennessee Health Science Center

Amanda M. Parkes, MD ‡ †

University of Wisconsin

Carbone Cancer Center

I. Benjamin Paz, MD ¶

City of Hope National Medical Center

Ivy A. Petersen, MD §

Mayo Clinic Cancer Center

Matthew Poppe, MD §

Huntsman Cancer Institute

at the University of Utah

Richard F. Riedel, MD †

Duke Cancer Institute

Brian Rubin, MD, PhD ≠

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer Center

and Cleveland Clinic Taussig Cancer Institute

Scott Schuetze, MD, PhD †

University of Michigan

Rogel Cancer Center

Jacob Shabason, MD §

Abramson Cancer Center

at the University of Pennsylvania

Jason K. Sicklick, MD

UC San Diego Moores Cancer Center

Matthew B. Spraker, MD, PhD §

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine

Melissa Zimel, MD τ ¶

UCSF Helen Diller Family

Comprehensive Cancer Center

NCCN

Mary Anne Bergman

Giby V. George, MD

NCCN Guidelines Panel Disclosures

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NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

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Discussion

The NCCN Guidelines

are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual

clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network

(NCCN

) makes no representations

or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN

Guidelines are copyrighted by National Comprehensive Cancer Network

NCCN Soft Tissue Sarcoma Panel Members

Summary of the Guidelines Updates

Soft Tissue Sarcoma

• Extremity/Body Wall, Head/Neck (EXTSARC-1)

• Retroperitoneal/Intra-Abdominal (RETSARC-1)

• Desmoid Tumors (Aggressive Fibromatosis) (DESM-1)

• Rhabdomyosarcoma (RMS-1)

Principles of Imaging (SARC-A)

Principles of Pathologic Assessment of Sarcoma Specimens (SARC-B)

Principles of Ancillary Techniques Useful in the Diagnosis of Sarcomas (SARC-C)

Principles of Surgery (SARC-D)

Principles of Radiation Therapy for Soft Tissue Sarcoma (SARC-E)

Systemic Therapy Agents and Regimens with Activity in Soft Tissue Sarcoma (SARC-F)

Staging (ST-1)

Bone Sarcomas - See the NCCN Guidelines for Bone Cancer

Gastrointestional Stromal Tumors - See the NCCN Guidelines for Gastrointestinal Stromal Tumors

Uterine Sarcomas - See the NCCN Guidelines for Uterine Neoplasms

Dermatobrosarcoma Protuberans - See the NCCN Guidelines for Dermatobrosarcoma Protuberans and the

NCCN Guidelines for Soft Tissue Sarcoma (Extremity/Body Wall, Head/Neck, EXTSARC-1 and EXTSARC-5)

Clinical Trials: NCCN believes that

the best management for any patient

with cancer is in a clinical trial.

Participation in clinical trials is

especially encouraged.

To nd clinical trials online at NCCN

Member Institutions, click here:

nccn.org/clinical_trials/member_

institutions.aspx.

NCCN Categories of Evidence and

Consensus: All recommendations

are category 2A unless otherwise

indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

NCCN Guidelines Version 2.2021

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Table of Contents

Discussion

Global change: "Chemotherapy" changed to "Systemic Therapy"

EXTSARC-1

Workup Essential

• Under Useful in Certain Circumstances:

Modied and moved to the 4th sub-bullet: For patients with personal/family history suggestive of other cancer predisposition syndromes, consider

further genetics assessment

Special considerations for unique histologies:

• Link to the NCCN Guidelines for Gastrointestinal Stromal Tumors (GISTs)

This section of the guideline has been pulled out of the Soft Tissue Sarcoma Guidelines and is now its own Guideline

Other soft tissue sarcomas of the extremity/body wall, head/neck:

• For Stage II, III resectable disease, added and select Stage IV (any T, N1, M0).

EXTSARC-2

Footnotes

• "m" is new: In the setting where wide surgical margins may be dicult or morbid, neoadjuvant radiation may be an option.

• "n" is new: It may be appropriate to consider RT prior to re-resection for R2 resections.

EXTSARC-3

For Stage III resectable disease, added or select Stage IV (any T, N1, M0). (Also for EXTSARC-4).

Primary Treatment

• Added or Observation to RT with the following footnotes:

"u": A prospective study demonstrated low rates of local recurrence with surgery alone in carefully selected patients with high-grade tumors less than

<5 cm (Pisters PW, Ann Surg 2007;246:675-81). Consider omission of RT for tumors <5 cm resected with wide margins if a repeat resection would be

feasible with low morbidity in the case of a recurrence.

"z": Resections with wide negative margins may be considered for observation alone if the risk of radiation is unacceptable.

• For Stage II, deleted the following pathway: "Surgery to obtain oncologically appropriate margins."

EXTSARC-4

• "/radical resection" was added after "amputation."

Footnotes

• "bb" modied: Radiation for patients who are not surgical candidates where definitive radiation is planned should receive radiation to an initial larger

volume, akin to what is used for preoperative radiation followed by a boost to the gross tumor with more limited margin. Doses to the initial volume

should be 50 Gy with a boost at least 63 Gy but higher doses in the range of 70–80 Gy can be considered, limited by tolerance of normal structures.

(Kepka L, et al. Int J Radiat Oncol Biol Phys 2005;63:852-859).

UPDATES

Continued

Updates in Version 2.2021 of the NCCN Guidelines for Soft Tissue Sarcoma from Version 1.2021 include:

SARC-F (3 of 9)

• Footnote "k" was added: An FDA-approved biosimilar is an appropriate substitute for bevacizumab. (Also for SARC-F, 4 of 9).

Updates in Version 1.2021 of the NCCN Guidelines for Soft Tissue Sarcoma from Version 2.2020 include:

NCCN Guidelines Version 2.2021

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Discussion

of the cancer (grade, invasiveness); the technical aspects of the operation (R0

resection anticipated as a reasonable possibility) and the comorbidities of the

patient allow for a safe intervention at the judgment of the operating surgeon.

Consider re-resection if technically feasible for low-grade disease or well

dierentiated liposarcoma

RETSARC-5

Footnotes

• This page is new to Retroperitoneal/Intra-Abdominal:

Footnote "s" is new: Consider biopsy if recurrent disease diagnosis is not

clinically denitive.

Footnote "t" is new: If no prior RT for the treatment of the primary sarcoma.

DESM-1 through DESM-5

• Desmoid Tumors (Aggressive Fibromatosis): This section was extensively

revised, rearranged, reformatted, and condensed.

RMS-1

• The Non-pleomorphic arm has been modied: ...and spindle cell/sclerosing

[VGGL2-related fusions or MYOD1 mutation]

• Footnote "c" is new: Referral to centers with expertise in the management of

pediatric cancers is recommended.

SARC-A (1 of 3)

Principles of Imaging

• 4th bullet is new to the page: Cross-sectional imaging should completely

image the lesion from its cephalocaudal extent within the compartment(s)

from which it originates.

• 8th bullet modied: In addition to recommendations below above, these

additional imaging studies should be included to consider as part of the

workup and follow-up, based on for specic histologic subtypes, based upon

unique patterns of recurrence/metastatic disease: are indicated as follows

Pelvic CT imaging for lower-extremity well-dierentiated liposarcoma; SARC-A

(1 of 3) (continued)

Principles of Imaging

For certain histologies with a propensity for nodal metastatic disease,

imaging assessment of the regional lymph node basin may be appropriate

for staging and during follow-up.

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Soft Tissue Sarcoma from Version 2.2020 include:

Continued

EXTSARC-5

Footnotes

• "cc" is new: For N1M0 patients, please refer to EXTSARC-3 or

EXTSARC-4.

• "ee" modied: Metastasectomy is the historical standard for patients with

oligometastatic disease (primarily lung) and is preferred if feasible; the

ultimate choice of local control modality...(Also for SARC-6A)

EXTSARC-6

• Added (non-lung) to Embolization procedures

EXTSARC-6A

Footnotes

• "hh", modied:Traditionally, the re-irradiation has been done with

postoperative adjuvant brachytherapy but may now be able to be done

as a combination of brachytherapy and IMRT to reduce the risks of

morbidity with re-irradiation.

Brachytherapy, IMRT, and/or proton therapy may be utilized delivered to

reduce the morbidity of re-irradiation.

RETSARC-1

Workup

• Modied the following four bullets:

• For patients with neurobromatosis, see NCCN Guidelines for Central

Nervous System Cancers (PSCT-3)

• For Li-Fraumeni syndrome, see NCCN Guidelines for Genetic/Familial

High-Risk Assessment: Breast, Ovarian, and Pancreatic.

• For hereditary non-polyposis colorectal cancer (HNPCC or Lynch

syndrome), see NCCN Guidelines for Genetic/Familial High Risk

Assessment: Breast, Ovarian, and Pancreatic

• For patients with personal/family history suggestive of other cancer

predisposition syndromes, consider further genetics assessment.

RETSARC-2

Footnote

• Footnote "j" is new: Consider postoperative systemic therapy for

histologies with high risk for metastatic disease and/or high risk for local

recurrence. Systemic therapy not recommended for low-grade tumors.

(Also for RETSARC-5)

RETSARC-3

Postoperative Treatment

• R1/R2 were combined and modied: Consider re-resection if the biology

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

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Updates in Version 1.2021 of the NCCN Guidelines for Soft Tissue Sarcoma from Version 2.2020 include:

UPDATES

SARC-E (1 of 4) (continued)

(Delaney TF, Kepka L, Goldberg SI, et al. Radiation therapy for control of

soft-tissue sarcomas resected with positive margins. Int J Radiat Oncol

Biol Phys 2007;67:1460-1469.)

• The following footnote has been deleted: Data are still limited on the use

of HDR brachytherapy for sarcomas. Until moredata are available, HDR

fraction sizes are recommended to be limited to 3–4 Gy. Nag S, et al. Int J

Radiat Oncol Biol Phys 2001;49:1033-1043.

The following text has been deleted: If using RT boost, consider:

EBRT:

– 16–18 Gy for microscopic residual disease

– 20–26 Gy for gross residual disease

◊ Brachytherapy (low dose-rate):

– 16–18 Gy for microscopic residual disease

– 20–26 Gy for gross disease

◊ Brachytherapy (high dose-rate):

– 14–16 Gy at approximately 3–4 Gy BID for microscopic residual

disease

– 18–24 Gy for gross residual disease

SARC-E 2 of 4

• Postoperative RT following surgery

with clips

EBRT (50 Gy) to larger volume followed by a boost to the tumor bed of

10–20 Gy depending on surgical margins.

The following text has been deleted: Boost dose:

– No boost is indicated after resection with negative margins.

– Negative margins: 10–16 Gy

– Microscopically positive margins: 16–18 Gy

– Gross residual disease: 20–26 Gy

• Denitive RT for unresectable disease is new to the page with new

footnote: Radiation for patients who are not surgical candidates where

definitive radiation is planned should receive radiation to an initial larger

volume, akin to what is used for preoperative radiation followed by a

boost to the gross tumor with more limited margin. Doses to the initial

volume should be 50 Gy with a boost at least 63 Gy but higher doses in

the range of 70–80 Gy can be considered, limited by tolerance of normal

structures. (Kepka L, et al. Int J Radiat Oncol Biol Phys 2005;63:852-859).

SARC-E 3 of 4

• First bullet modied: Preoperative RT (surgery with clips to follow)

• First sub-bullet modied: 50 Gy external beam RT (EBRT)

Continued

SARC-A (3 of 3)

Principles of Imaging

• 2nd bullet is new to the page: Consider PET/CT as a tool to help

dierentiate between well-dierentiated and dedierentiated

liposarcoma and to help determine site for biopsy with the

corresponding reference, Parkes A, Urquiola E, Bhosale P, et al. PET/

CT imaging as a diagnostic tool in distinguishing well-differentiated

versus dedifferentiated liposarcoma. Hindawi Sarcoma 2020;Article ID

8363986.

SARC-B

Principles of Pathologic Assessment of Sarcoma Specimens

• 7th sub-bullet, 3rd sub-bullet has been deleted: Type and status of

margins excision

• 8th sub-bullet, is new: Quality of margin (a more limited fascial margin

may be equivalent to a wider soft tissue margin)

• 11th sub-bullet, 1st sub-bullet modied: per 10 HPF added to Mitotic rate

SARC-C (1 of 3)

Principles of Ancillary Techniques Useful in the Diagnosis of Sarcomas

• 3rd sentence modied as follows: Molecular genetic testing has

emerged as an particularly powerful ancillary testing approach...

• The following genes were added to Embryonal RMS: MYOD1, KRAS,

HRAS, TP53, NF1, NRAS, PIK3CA, FBXW7, FGFR4, BCOR

SARC-D

Principles of Surgery

• Biopsy the following bullet is new: For certain histologies with a

propensity for nodal metastatic disease, sentinel node biopsy can

be considered, especially if the presence of occult nodal metastatic

disease would change the multimodality treatment plan.

SARC-E (1 of 4)

Principles of Radiation Therapy for Soft Tissue Sarcoma

• Removed "(surgery with clips to follow)" after preoperative RT 50 Gy

RT (EBRT)

• The following sub-bullet is new to the page: reference was added:

Use of a boost after positive margins is controversial, if elected doses

of additional 14–20 Gy can be considered with fractionated EBRT or

brachytherapy.

NCCN Guidelines Version 2.2021

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Discussion

SARC-F (3 of 9)

• Non-Pleomorphic Rhabdomyosarcoma

Preferred Regimens:

◊ Vincristine, dactinomycin, cyclophosphamide (VAC)

◊ Vincristine, dactinomycin, ifosfamide (VAI-Europe)

For patients with intermediate risk disease, consider maintenance therapy

with vinorelbine and cyclospamide for 6 months, corresponding to

Vincristine, dactinomycin, cyclophosphamide and Vincristine, doxorubicin,

and cyclophosphamide alternating with ifosfamide and etoposide

Other Recommended Regimens:

◊ Modied: Vincristine, doxorubicin, and cyclophosphamide alternating

with ifosfamide and etoposide

◊ Vincristine and dactinomycin

◊ Doxorubicin

◊ High-dose methotrexate

– footnote "l": High-dose methotrexate may be useful for select patients

with CNS or leptomeningeal involvement when RT is not feasible.

◊ Trabectedin

• Angiosarcoma

The following footnote was deleted from Paclitaxel: Casanova M,

Ferrari A, Spreaco F, et al. Vinorelbine in previously treated advanced

childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer

2002;94:3263-3268.

SARC-F (4 of 9)

• Solitary Fibrous Tumor

The following footnote was deleted from Pazopanib: Stacchiotti S, Negri

T, Libertini M, et al. Sunitinib malate in solitary brous tumor(SFT). Ann

Oncol 2012;23:3171-3179.

• Inammatory Myobroblastic Tumor (IMT) with Anaplastic Lymphoma

Kinase (ALK) Translocation

Preferred Regimens:

◊ Brigatinib is new.

SARC-F (5 of 9)

• Undierentiated Pleomorphic Sarcoma (UPS) has been deleted.

Useful in Certain Circumstances

◊ moved to SARC-F (1 of 9)

ST-1

• Updated page to reect the 5th edition of the WHO Classication of Tumors.

Updates in Version 1.2021 of the NCCN Guidelines for Soft Tissue Sarcoma from Version 2.2020 include:

SARC-F (1 of 9)

Systemic Therapy Agents and Regimens with Activity in Soft Tissue Sarcoma

• For this section the references have been extensively revised and

rearranged.

• Neoadjuvant/Adjuvant Therapy/Useful in Certain Circumstances:

Added: Trabectedin (for myxoid liposarcoma)

• First-Line Therapy Advanced/Metastatic/Useful in Certain Circumstances:

MAID (mesna, doxorubicin, ifosfamide, dacarbazine) moved from Preferred

Regimens

• Subsequent Lines of Therapy for Advanced/Metastatic Disease:

Preferred Regimens:

◊ Added, category 2A for other subtypes to Trabectedin

Useful in Certain Circumstances:

◊ Pembrolizumab (for myxobrosarcoma, undierentiated pleomorphic

sarcoma [UPS], cutaneous angiosarcoma, and undierentiated

sarcomas).

SARC-F (2 of 9)

• Extraskeletal Osteosarcoma is new to the page.

Usually treated as soft tissue sarcoma with the following:

◊ Ifosfamide or platinum-based therapy (cisplatin/doxorubicin)

• Desmoid Tumors (Aggressive bromatosis)

Preferred Regimens/Time to response less critical:

◊ Deleted: Tamoxifen ± sulindac

◊ Deleted: Toremifene

Preferred Regimens/Time to response more critical:

◊ Pazopanib is new.

Useful in Certain Circumstances:

◊ Sulindac or other nonsteroidal anti-inammatory drugs (NSAIDs),

including celecoxib (for pain) moved from Other recommended

regimens.

(NCCN

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NCCN Guidelines Version 2.2021

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NCCN Guidelines Index

Table of Contents

Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

EXTSARC-1

WORKUP

ESSENTIAL:

• Prior to the initiation of therapy, it is highly recommended that all

patients be evaluated and managed by a multidisciplinary team with

expertise and experience in sarcoma

• H&P

• Adequate imaging of primary tumor

is indicated for all lesions with a

reasonable chance of being malignant

• Carefully planned core needle [preferred] or incisional biopsy after

adequate imaging (See SARC-D)

Place biopsy along future resection axis with minimal dissection and

careful attention to hemostasis

Biopsy should establish grade and histologic subtype

As appropriate, use ancillary diagnostic methodologies

• Chest imaging

USEFUL UNDER CERTAIN CIRCUMSTANCES:

• Additional imaging as indicated;

see Principles of Imaging (SARC-A)

• The following conditions are linked to increased incidence of sarcoma

and other cancers:

For patients with neurobromatosis

see NCCN Guidelines for

Central Nervous System Cancers (PSCT-3)

For Li-Fraumeni syndrome, see NCCN Guidelines for Genetic/Familial

High-Risk Assessment: Breast, Ovarian, and Pancreatic

For hereditary non-polyposis colorectal cancer (HNPCC or Lynch

syndrome), see NCCN Guidelines for Genetic/Familial High-Risk

Assessment: Breast, Ovarian, and Pancreatic

For patients with personal/family history suggestive of other cancer

predisposition syndromes, consider further genetics assessment

Special

considerations

for unique

histologies

Other soft tissue

sarcomas of the

extremity/body

wall, head/neck

Desmoid tumors

(Aggressive

bromatosis)

Ewing sarcoma

Rhabdomyosarcoma (RMS)

See DESM-1

See NCCN

Guidelines for

Bone Cancer

See RMS-1

Stage II, III, and select Stage

IV (any T, N1, M0) resectable

disease with adverse functional

outcomes or Unresectable

primary disease

Stage II, III, and select Stage

IV (any T, N1, M0) resectable

disease with acceptable

functional outcomes

Stage I

Stage IV

synchronous disease

Recurrent disease

See Primary

(EXTSARC-2)

See Primary

(EXTSARC-3)

See Primary

(EXTSARC-4)

See Primary

(EXTSARC-5)

See Primary

(EXTSARC-6)

See footnotes on EXTSARC-1A

Gastrointestinal

stromal tumors

(GISTs)

See NCCN

Guidelines for

Gastrointestional

Stromal Tumors

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Extremity/Body Wall, Head/Neck

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Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

FOOTNOTES

These guidelines are intended to treat the adult population. For adolescent and young adult patients, refer to the

See NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology.

Imaging studies should include cross-sectional imaging (MRI with and without contrast +/- CT with contrast) to provide details about the size of tumor and contiguity to nearby visceral

structures and neurovascular landmarks. Other imaging studies such as angiogram and plain radiograph may be warranted in selected circumstances. See Principles of Imaging

(SARC-A).

In selected institutions with clinical and pathologic expertise, a fine-needle aspiration biopsy (FNAB) may be acceptable.

See Principles of Pathologic Assessment of Sarcoma Specimens (SARC-B).

See Principles of Ancillary Techniques Useful in the Diagnosis of Sarcomas (SARC-C).

Different subtypes have different propensities to spread to various locations.

Patients with neurofibromatosis are at risk for multiple sarcomas at various locations and their assessment and follow-up should be different. (Reilly KM, et al. J Natl Cancer Inst

2017;109:djx124.

Diagnoses that will impact the overall treatment plan. See SARC-F for special considerations for unique histologies.

Patients with dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous changes and/or malignant transformations should be treated according to this algorithm. For DFSP without

fibrosarcomatous elements refer to treatment in the NCCN Guidelines for Dermatofibrosarcoma Protuberans.

EXTSARC-1A

(NCCN

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NCCN Guidelines Version 2.2021

Extremity/Body Wall, Head/Neck

NCCN Guidelines Index

Table of Contents

Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

EXTSARC-2

See Principles of Imaging (SARC-A).

See American Joint Committee on Cancer (AJCC) Staging, 8th Edition (ST-5 and ST-6).

See Principles of Surgery (SARC-D).

Resection should be tailored to minimize surgical morbidity for patients with atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLS). En bloc resection

with negative margins is generally sufficient to obtain long-term local control.

In the settiing where wide surgical margins may be difficult or morbid, neoadjuvant radiation may be an option.

It may be appropriate to consider RT prior to re-resection for R2 resections.

Treatment options including revision surgery versus observation should be presented at an experienced multidisciplinary sarcoma tumor board to determine

advantages and disadvantages of the decision.

Randomized clinical trial data support the use of radiation therapy as an adjunct to surgery in appropriately selected patients based on an improvement in disease-free

survival (although not overall survival). (Yang J, et al. J Clin Oncol 1998;16:197-203). See Principles of Radiation Therapy (SARC-E).

For patients with ALT/WDLS, observation is recommended for focally positive margins if re-resection, in the event of recurrence, would not be unduly morbid. RT is

reserved for selected patients with recurrent or deeply infiltrative primary lesions with a risk of local recurrence, depending on the tumor location and patient’s age.

In situations where the area is easily followed by physical examination, imaging may not be required.

After 10 years, the likelihood of developing a recurrence is small and follow-up should be individualized.

PRIMARY

TREATMENT

FOLLOW-UP

Stage IA

/Stage IB

(low grade)

Oncologically

appropriate

margins

Failure to obtain

oncologically

appropriate margins

For R2 resection,

re-image prior to

initiating additional

treatment options

• Re-resection

(See SARC-D)

• Observation (for

stage 1A tumors)

• Consider RT

p,q

(category 2B for

stage 1A tumors;

category 1 for

stage 1B tumors)

• Evaluation for rehabilitation

(See SARC-D 2 of 2)

• H&P every 3–6 mo for 2–3 y,

then annually

• Consider chest imaging

• Consider obtaining

postoperative baseline MRI

• Imaging of primary site

based on estimated risk of

locoregional recurrence

r,s

If recurrence,

See

Recurrent

Disease

(EXTSARC-6)

Surgical

wide

resection

k,l,m

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NCCN Guidelines Index

Table of Contents

Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

EXTSARC-3

PRIMARY TREATMENT (

MULTIMODALITY TREATMENT IS CRITICAL) FOLLOW-UP

Stage II, III

Resectable

with

acceptable

functional

outcomes

Stage II

Surgery

to obtain oncologically

appropriate margins

(category 1)

Observation

u,z

Surgery

k,y

to obtain oncologically

appropriate margins

Surgery

k,v

to obtain oncologically

appropriate margins

Preoperative RT

(category 1)

Preoperative

systemic therapy

w,x

+ RT

Preoperative

systemic therapy

w,x

Surgery

to obtain

oncologically

appropriate

margins

Surgery

to obtain

oncologically

appropriate

margins

(category 1)

+ adjuvant systemic therapy

Consider adjuvant systemic

therapy

+ adjuvant systemic therapy

• Evaluation for rehabilitation

(See SARC-D 2 of 2)

• H&P

every 3–6 mo for 2–3 y,

then every 6 mo for next

2 y, then annually

• Chest imaging

• Obtain postoperative

baseline and periodic

imaging of primary site

based on estimated risk of

locoregional recurrence

r,s

If recurrence,

See

Recurrent

Disease

(EXTSARC-6)

Preoperative RT

(category 1)

See Principles of Imaging (SARC-A).

See American Joint Committee on Cancer (AJCC) Staging, 8th Edition (ST-2 and ST-3).

See Principles of Surgery (SARC-D).

In situations where the area is easily followed by physical examination, imaging may not be

required.

After 10 years, the likelihood of developing a recurrence is small and follow-up should be

individualized.

Results of a randomized study showed a non-significant trend toward reduced late toxicities

(fibrosis, edema, and joint stiffness) with preoperative compared to postoperative radiation

and a significant association between these toxicities and increasing treatment field size.

Because postoperative radiation fields are typically larger than preoperative fields, the

panel has expressed a general preference for preoperative radiation, particularly when

treatment volumes are large. (Davis AM, et al. Radiother Oncol 2005;75:48-53 and Nielsen

OS, et al. Int J Radiat Oncol Biol Phys 1991;21:1595-1599.)

See Principles of Radiation

Therapy (SARC-E).

A prospective study demonstrated low rates of local recurrence with surgery alone in

carefully selected patients with high-grade tumors <5 cm (Pisters PW, et al. Ann Surg

2007;246(4):675-81). Consider omission of RT for tumors <5 cm resected with wide

margins; if a repeat resection would be feasible with low morbidity in the case of a

recurrence.

In selected cases when margin status is uncertain, consultation with a radiation oncologist is

recommended. Re-resection, if feasible, may be necessary to render margins >1.0 cm.

See Systemic Therapy Agents and Regimens with Activity in Soft Tissue Sarcoma

Subtypes (SARC-F).

PET/CT may be useful in determining response to systemic therapy (Schuetze SM, et al.

Cancer 2005;103:339-348).

Re-imaging using MRI with and without contrast (preferred for extremity imaging) or CT with

contrast to assess primary tumor and rule out metastatic disease. See Principles of Imaging

(SARC-A).

Resections with wide negative margins may be considered for observation alone if the risk

of radiation is unacceptable.

Stage III

or select

Stage IV

(any T, N1,

M0)

(NCCN

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

EXTSARC-4

Stage II, III or

select Stage IV

(any T, N1, M0)

Resectable

with adverse

functional

outcomes

Unresectable

primary

disease

PRIMARY

TREATMENT

Chemoradiation

t,w

Systemic therapy

w,x

Isolated limb

perfusion/infusion

Amputation

/radical

resection

Resectable

with

acceptable

functional

outcomes

Unresectable

primary disease

Options:

• If not previously irradiated,

Denitive RT

• Systemic therapy

• Palliative surgery

• Observation, if asymptomatic

• Best supportive care

FOLLOW-UP

• Evaluation for

rehabilitation (See

SARC-D 2 of 2)

• H&P

every 3–6 mo for 2–3 y,

then every 6 mo

for next 2 y,

then annually

• Chest imaging

• Obtain baseline and

periodic imaging of

primary site

b,r

If recurrence

or progression,

See Recurrent

Disease

(EXTSARC-6)

Resectable

with

adverse

functional

outcomes

Amputation

/radical resection

Denitive RT

See EXTSARC-3

See Principles of Imaging (SARC-A).

See Principles of Surgery (SARC-D).

Randomized clinical trial data support the use of radiation therapy as an adjunct to surgery in appropriately selected patients based on an improvement in disease-free

survival (although not overall survival). (Yang J,et al. J Clin Oncol 1998;16:197-203). See Principles of Radiation Therapy (SARC-E).

In situations where the area is easily followed by physical examination, imaging may not be required.

Results of a randomized study showed a non-significant trend toward reduced late toxicities (fibrosis, edema, and joint stiffness) with preoperative compared to

postoperative radiation and a significant association between these toxicities and increasing treatment field size. Because postoperative radiation fields are typically

larger than preoperative fields, the panel has expressed a general preference for preoperative radiation, particularly when treatment volumes are large. [Davis AM, et

al. Radiother Oncol 2005;75(1):48-53 and Nielsen OS, et al. Int J Radiat Oncol Biol Phys 1991;21(6):1595-1599.] See Principles of Radiation Therapy (SARC-E).

See Systemic Therapy Agents and Regimens with Activity in Soft Tissue Sarcoma Subtypes (SARC-F).

PET/CT may be useful in determining response to systemic therapy. (Schuetze SM, et al. Cancer 2005;103:339-348).

Should only be done at institutions with experience in isolated limb perfusion/infusion.

Radiation for patients who are not surgical candidates where definitive radiation is planned should receive radiation to an initial larger volume, akin to what is used for

preoperative radiation followed by a boost to the gross tumor with more limited margin. Doses to the initial volume should be 50 Gy with a boost to at least 63 Gy, but

higher doses in the range of 70–80 Gy can be considered, limited by tolerance of normal structures. (Kepka L, et al. Int J Radiat Oncol Biol Phys 2005;63:852-859).

Consider adjuvant

systemic therapy

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Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

EXTSARC-5

Synchronous-

Stage IV

j,cc

disease

Single organ (primarily

pulmonary) with

limited tumor bulk that

is amenable to local

therapy

Disseminated

metastases

PRIMARY

TREATMENT (

MULTIMODALITY TREATMENT IS CRITICAL)

FOLLOW-UP

• Evaluation for

rehabilitation (See

SARC-D 2 of 2)

• H&P every 2–6 mo for

2–3 y, then every 6 mo for

next 2 y, then annually,

if patient remains free of

disease recurrence

• Imaging of chest and other

known sites of metastatic

disease

• Consider obtaining

postoperative baseline

and periodic imaging

of primary site

based

on estimated risk of

locoregional recurrence

r,s

If recurrence,

See

Recurrent

Disease

(EXTSARC-6)

Primary tumor management as per EXTSARC-3 and

consider the following options for metastases:

• Consider systemic therapy

for all patients

• Metastasectomy

dd,ee

± RT

• For lung metastases, resection (preferred) or SBRT

• Stereotactic body radiation therapy (SBRT)



• Ablation procedures

• Embolization procedures (non-lung)

• Observation

Palliative treatment options:

• Systemic therapy

• RT

/SBRT



• Surgery

• Observation, if asymptomatic

• Supportive care

• Ablation procedures

• Embolization procedures (non-lung)

See Principles of Imaging (SARC-A).

See American Joint Committee on Cancer (AJCC) Staging, 8th Edition (ST-2 and ST-3).

In situations where the area is easily followed by physical examination, imaging may not be required.

After 10 years, the likelihood of developing a recurrence is small and follow-up should be individualized.

See Systemic Therapy Agents and Regimens with Activity in Soft Tissue Sarcoma Subtypes (SARC-F).

For

N1M0 patients, please refer to EXTSARC-3 or EXTSARC-4.

Patients with lymph node involvement (including isolated regional nodal metastastic disease) should undergo regional lymph node dissection ± RT.

Metastasectomy is the historical standard for patients with oligometastatic disease (primarily lung); the ultimate choice of local control modality may depend on

factors such as performance status, patient preference, lesion location/accessibility, ability to preserve normal tissue function, and anticipated morbidity of a treatment

modality.

In retrospective studies, various SBRT dosing regimens have been reported to be effective for treatment of sarcoma metastases. Dose and fractionation should be

determined by an experienced radiation oncologist based on normal tissue constraints (Dhakal S, et al. Int J Radiat Oncol Biol Phys 2012;82:940-945 and Navarria P,

et al. Eur J Cancer 2015;51:668-674).

Palliative RT requires balancing expedient treatment with sufficient dose expected to halt the growth of or cause tumor regression. Numerous clinical issues regarding

rapidity of growth, the status of systemic disease, and the use of systemic therapy must be considered. Recommended only for palliative therapy in patients with

synchronous stage IV or recurrent disease with disseminated metastases.

(NCCN

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Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

EXTSARC-6

RECURRENT DISEASE TREATMENT

Local

recurrence

Follow Workup, then appropriate Primary Treatment

pathway

(EXTSARC-2, EXTSARC-3, EXTSARC-4)

Metastatic

disease

Single organ and

limited tumor bulk

that are amenable

to local therapy

Options:

• Metastasectomy

dd,ee

± preoperative or postoperative systemic therapy

± RT

• SBRT



± systemic therapy

• Ablation procedures

• Embolization procedures (non-lung)

• Observation

Disseminated

metastases

Isolated regional

disease or nodes

Palliative options:

• Systemic therapy

• RT

/SBRT

• Surgery

• Observation, if asymptomatic

• Supportive care

• Ablation procedures

• Embolization procedures (non-lung)

Options:

• Regional node dissection for nodal involvement ± RT ± systemic therapy

• Metastasectomy

dd,ee

± preoperative or postoperative systemic therapy

± RT

• SBRT



• Isolated limb perfusion/infusion

± surgery

See footnotes on EXTSARC-6A

(NCCN

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NCCN Guidelines Index

Table of Contents

Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

See Systemic Therapy Agents and Regimens with Activity in Soft Tissue Sarcoma Subtypes (SARC-F).

Patients with lymph node involvement (including isolated regional nodal metastastic disease) should undergo regional lymph node dissection ± RT.

Metastasectomy is the historical standard for patients with oligometastatic disease (primarily lung); the ultimate choice of local control modality may depend on

factors such as performance status, patient preference, lesion location/accessibility, ability to preserve normal tissue function, and anticipated morbidity of a treatment

modality.

In retrospective studies, various SBRT dosing regimens have been reported to be effective for treatment of sarcoma metastases. Dose and fractionation should be

determined by an experienced radiation oncologist based on normal tissue constraints (Dhakal S, et al. Int J Radiat Oncol Biol Phys 2012;82:940-945 and Navarria P,

et al. Eur J Cancer 2015;51:668-674).

Palliative RT requires balancing expedient treatment with sufficient dose expected to halt the growth of or cause tumor regression. Numerous clinical issues regarding

rapidity of growth, the status of systemic disease, and the use of systemic therapy must be considered. Recommended only for palliative therapy in patients with

synchronous stage IV or recurrent disease with disseminated metastases.

If local recurrence can be excised, a decision will need to be made on a case-by-case basis whether re-irradiation is possible. Some case series suggest benefit

with re-irradiation (Catton C, et al. Radiother Oncol 1996;41:209-214) while others do not (Torres MA, et al. Int J Radiat Oncol Biol Phys 2007;67:1124-1129), likely

reflecting differences in selection of patients for treatment with surgery and radiotherapy or surgery alone. Brachytherapy, IMRT, and/or proton therapy may be utilized

to reduce the morbidity of re-irradiation.

Should only be done at institutions with experience in isolated limb perfusion/infusion.

FOOTNOTES

EXTSARC-6A

(NCCN

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NCCN Guidelines Index

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Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

RETSARC-1

WORKUP

These guidelines are intended to treat the adult population. For adolescent and young adult patients, refer to the

See NCCN Guidelines for Adolescent and Young Adult

(AYA) Oncology.

See Principles of Imaging (SARC-A).

Biopsy for retroperitoneal/intra-abdominal sarcomas should try to avoid the free intra-abdominal space. See Principles of Surgery (SARC-D).

Patients with neurofibromatosis are at risk for multiple sarcomas at various locations and their assessment and follow-up should be different.

• Prior to the initiation of therapy, all patients should be

evaluated and managed by a multidisciplinary team with

expertise and experience in sarcoma.

• H&P

• Imaging

• Image-guided core needle biopsy

should be performed

if preoperative therapy is being given or for suspicion of

malignancy other than sarcoma.

• Preresection biopsy is not necessarily required for well-

dierentiated liposarcoma.

• For patients with neurobromatosis,

see NCCN

Guidelines for Central Nervous System Cancers (PSCT-3)

• For Li-Fraumeni syndrome, see NCCN Guidelines for

Genetic/Familial High-Risk Assessment: Breast, Ovarian,

and Pancreatic.

• For HNPCC or Lynch syndrome, see NCCN Guidelines for

Genetic/Familial High-Risk Assessment: Breast, Ovarian,

and Pancreatic

• For patients with personal/family history suggestive of

other cancer predisposition syndromes, consider further

genetics assessment.

Resectable

Unresectable or

Stage IV disease

See Primary Treatment

(RETSARC-2)

See Primary Treatment

(RETSARC-4)

(NCCN

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Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

RETSARC-2

See Principles of Pathologic Assessment of Sarcoma Specimens (SARC-B).

If considering preoperative therapy, biopsy required, including endoscopic

ultrasound-guided biopsy for suspected GIST lesions.

Biopsy may not be required if diagnostic imaging is consistent with well-

differentiated liposarcoma (WD-LPS).

For other soft tissue sarcomas such as Ewing sarcoma, see NCCN Guidelines

for Bone Cancer; for RMS, see RMS-1.

See Principles of Surgery (SARC-D).

Consider postoperative systemic therapy for histologies with high risk for

metastatic disease and/or high risk for local recurrence. Systemic therapy is not

recommended for low-grade tumors.

If preoperative RT is anticipated, IMRT would be preferred to optimize sparing of

nearby critical structures.

See Principles of Radiation Therapy (SARC-E).

See Systemic Therapy Agents and Regimens with Activity in Soft Tissue

Sarcoma Subtypes (SARC-F).

PRIMARY

TREATMENT

Resectable

disease

Biopsy

e,f,g

Desmoid tumors

(Aggressive

bromatosis)

Sarcoma

See NCCN Guidelines for Gastrointestional

Stromal Tumors (GISTs)

See (DESM-1)

Surgery

i,j

to obtain oncologically

appropriate margins

Preoperative therapy

• RT

k,l

• Systemic therapy

Surgery

to obtain

oncologically

appropriate margins

± intraoperative

RT (IORT)

See Postoperative

Treatment

(RETSARC-3)

GISTs

(NCCN

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Discussion

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

RETSARC-3

SURGICAL

OUTCOMES/CLINICAL

PATHOLOGIC

FINDINGS

POSTOPERATIVE

TREATMENT

FOLLOW-UP TREATMENT

FOR

RECURRENT

DISEASE

R1/R2

Post-op RT should not be

administered routinely with the

exception of highly selected

patients and unless local

recurrence would cause undue

morbidity

l,n

Post-op RT should not be

administered routinely with the

exception of highly selected

patients and unless local

recurrence would cause undue

morbidity

l,n

In highly selected cases, consider

boost (10–16 Gy) if preoperative

RT was given

Consider re-resection if the

biology of the cancer (grade,

invasiveness), the technical

aspects of the operation (R0

resection anticipated as a

reasonable possibility), and

the comorbidities of the patient

allow for a safe intervention at

the judgment of the operating

surgeon

See Primary Treatment

(Unresectable) (RETSARC-4)

Physical exam

with imaging

every 3–6 mo

for 2–3 y,

then every 6 mo

for next 2 y, then

annually

Recurrent

disease

Unresectable

Stage IV

disease

(See

RETSARC-4)

Resectable

(See

RETSARC-5)

Consider

postoperative

systemic

therapy

for histologies

with high risk

for metastatic

disease

See Principles of Imaging (SARC-A).

See Principles of Surgery (SARC-D).

See Principles of Radiation Therapy (SARC-E).

See Systemic Therapy Agents and Regimens with Activity in Soft Tissue

Sarcoma Subtypes (SARC-F).

For example, critical anatomic surface where recurrence would cause morbidity.

Systemic therapy not recommended for low-grade tumors.

If not previously administered, consider preoperative RT and/or systemic therapy.

(NCCN

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Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

RETSARC-4

See Principles of Imaging (SARC-A).

See Principles of Pathologic Assessment of Sarcoma Specimens (SARC-B).

See Principles of Radiation Therapy (SARC-E).

See Systemic Therapy Agents and Regimens with Activity in Soft Tissue Sarcoma Subtypes (SARC-F).

The most active systemic therapy regimen in an unselected patient population is AIM (doxorubicin/ifosfamide/mesna) in terms of response rate. Judson I, et al. Lancet

Oncol 2014;15(4):415-23.

Resection of resectable metastatic disease should always be considered if primary tumor can be controlled.

INITIAL THERAPY

Unresectable

Stage IV

disease

Biopsy

• Observation, if asymptomatic

• Systemic therapy

m,q

and/or RT

Surgery for symptom control

Resectable

Unresectable

Progressive

disease

See Treatment as

per RETSARC-2

Palliative or

best supportive

care (See NCCN

Guidelines for

Palliative Care)

Imaging

to assess

treatment

response

(NCCN

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NCCN Guidelines Index

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Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Surgery

i,t

to obtain oncologically appropriate margins

Preoperative therapy

• RT

k,l,u

• Systemic therapy

Surgery

obtain

oncologically

appropriate

margins ± IORT

See Postoperative

Treatment

(RETSARC-3)

Resectable recurrent

disease

See Principles of Surgery (SARC-D).

See Systemic Therapy Agents and Regimens with Activity in Soft Tissue Sarcoma Subtypes (SARC-F).

Consider biopsy if recurrent disease diagnosis is not clinically definitive.

Consider postoperative systemic therapy for histologies with high risk for metastatic disease or history of several recurrences with a high risk for additional local

recurrences.

If no prior RT for the treatment of the primary sarcoma.

RETSARC-5

INITIAL THERAPY

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

WORKUP

• Prior to the initiation of therapy, all patients should be

evaluated and managed by a multidisciplinary team with

expertise and experience in sarcoma

• H&P

• Consider evaluation for Gardner's

syndrome

/familial adenomatous polyposis (FAP) if

biopsy is diagnostic of desmoid

(See NCCN Guidelines for Colorectal Cancer Screening)

• Appropriate imaging

of primary site as clinically

indicated

Biopsy

Anatomic location

where progression

would not be morbid

DESM-2

DESM-3

Gardner's syndrome is an autosomal dominant disorder characterized by a triad of colonic polyposis, osteoma, and soft tissue tumors. (Traill Z, et al. AJR Am J

Roentgenol 1995;165:1460-1461).

See Principles of Imaging (SARC-A).

See Principles of Pathologic Assessment of Sarcoma Specimens (SARC-B).

Anatomic location

where progression

would be morbid

DESM-1

(NCCN

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

See Principles of Imaging (SARC-A).

For tumors that are symptomatic, or impairing or threatening in function, patients should be offered therapy with the decision based on the location of the tumor and

potential morbidity of the therapeutic option.

Optimal frequency for imaging depends on the anatomical location of tumor, risk of progression, and symptoms of disease progression. Imaging every 3 months is

recommended. More frequent imaging may be indicated in symptomatic patients.

Spontaneous regression has been reported in 20% of patients, supporting an initial period of observation in patients with newly diagnosed desmoid tumors (Gounder

MM, et al. N Engl J Med 2018;379:2417-2428).

A course of ongoing observation is an appropriate option even for patients with disease progression, if the patient is minimally symptomatic and the anatomical location

of the tumor is not critical.

Anatomic location

where progression

would not be morbid

Observation

with imaging

b,e

and symptom

management

Stable/regression

Progression

Continue

observation

with imaging

b,e

Consider

ongoing

observation

with imaging

b,e

See DESM-4 for ongoing

progression with potential

morbidity or signicant symptoms

DESM-2

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

DESM-3

Anatomic location

where progression

would be morbid

Documented

progression

No documented

progression

DESM-4

Stable/regression

Documented

progression

See DESM-4

if concerns for

morbidity or

signicant symptoms

DESM-4

Continue

observation

with imaging

See Principles of Imaging (SARC-A).

For tumors that are symptomatic, or impairing or threatening in function, patients should be offered therapy with the decision based on the location of the tumor and

potential morbidity of the therapeutic option.

Optimal frequency for imaging depends on the anatomical location of tumor, risk of progression, and symptoms of disease progression. Imaging every 3 months is

recommended. More frequent imaging may be indicated in symptomatic patients.

Spontaneous regression has been reported in 20% of patients, supporting an initial period of observation in patients with newly diagnosed desmoid tumors (Gounder

MM, et al. N Engl J Med 2018;379:2417-2428).

Consider short

course of observation

with imaging

b,e

and

symptom management

(NCCN

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Active therapy

for progressive,

morbid, or

symptomatic

disease

Abdominal wall

Observation

Consider re-resection

Adjuvant RT

(category 2B)

Observation

Denitive RT

Systemic therapy

Radical surgery to be

considered if other

modalities fail

Ablation procedures

Observation

DESM-4

Intra-abdominal/

Retroperitoneal/

Pelvic

Truncal/

Extremity

Head/Neck/

Intrathoracic

Surgery (if resectable)

Systemic therapy

Denitive RT

Surgery (if resectable)

Systemic therapy

Surgery (if resectable)

Denitive RT

Surgery + RT

h,i

ACTIVE THERAPY FOR

PROGRESSIVE, MORBID,

OR SYMPTOMATIC DISEASE

FOLLOW-UP

Based on the situation, any of these treatment options may potentially be first- or second-line.

Consider RT for lesions where recurrence would be technically challenging to resect and would lead to significant morbidity.

R1 margins are acceptable if achieving R0 margins would produce excessive morbidity (Cates JM, et al. Am J Surg Pathol 2014;38:1707-1714; Crago AM, et al. Ann

Surg 2013; 258:347-353; and Salas S, et al. J Clin Oncol 2011;29:3553-3558).

See (SARC-A)

for Principles of

Imaging

Ablation procedures

(NCCN

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Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

RMS-1

RMS that is identified within another histology should be treated as the original histology. This pathway refers to patients diagnosed with pure RMS after full slide

review.

PET or PET/CT scan may be useful for initial staging because of the possibility of nodal metastases and the appearance of unusual sites of initial metastatic disease in

adult patients.

Referral to centers with expertise in the management of pediatric cancers is recommended.

Not to be confused with anaplastic variant in children.

Up to 13% of RMS in younger patients may have anaplastic features and should not be confused with the high-grade tumors seen in adults designated as pleomorphic

RMS.

Pleomorphic RMS is usually excluded from RMS and soft tissue sarcoma randomized clinical trials. Consideration for treatment according to soft tissue sarcoma may

be reasonable, including choices for systemic therapy. See Systemic Therapy Agents and Regimens with Activity in Soft Tissue Sarcoma Subtypes (SARC-F)

Systemic therapy options for RMS may be different than those used with other soft tissue sarcoma histologies. See Systemic Therapy Agents and Regimens

with Activity in Soft Tissue Sarcoma Subtypes (SARC-F).

DIAGNOSIS HISTOLOGY TREATMENT

Rhabdomyosarcoma

(RMS)

a,b,c

Pleomorphic RMS

Non-pleomorphic RMS

(includes alveolar, embryonal,

and spindle cell/sclerosing

[VGGL2-related fusions or

MYOD1 mutation])

Recommend treating like soft tissue sarcoma

• Referral to institutions with expertise in treating patients

with RMS is strongly recommended

• Multidisciplinary evaluation involving pediatric, medical,

surgical, and radiation oncologists is strongly encouraged

• Multimodality treatment planning and risk stratication is

required

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PRINCIPLES OF IMAGING

GENERAL

• CT and MRI performed with contrast is recommended throughout the guideline unless contraindicated or otherwise noted.

• As appropriate, abdominal/pelvic MRI with contrast can be substituted for abdominal/pelvic CT if contraindicated (ie, due to dye allergy).

• If obtaining abdominal/pelvic CT, chest CT may be performed without contrast unless simultaneously attained with contrast-enhanced

abdominal/pelvic CT.

• Cross-sectional imaging should completely image the lesion from its cephalocaudal extent within the compartment(s) from which it

originates.

• Chest imaging without contrast preferred unless contrast is needed for mediastinal imaging.

• If recurrent disease, follow imaging recommendations for Workup, then use Follow-up recommendations per appropriate primary treatment

pathway.

• PET/CT scan may be useful in staging, prognostication, grading, and determining response to neoadjuvant therapy.

• In addition to recommendations above, these additional imaging studies should be included as part of the workup and follow-up, for specic

histologic subtypes, based upon unique patterns of recurrence/metastatic disease:

Abdominal/pelvic CT for myxoid/round cell liposarcoma, epithelioid sarcoma, angiosarcoma, and leiomyosarcoma

MRI of total spine for myxoid/round cell liposarcoma

CNS imaging with MRI (or CT if MRI is contraindicated) for alveolar soft part sarcoma and angiosarcoma, and left-sided cardiac sarcoma

For certain histologies with a propensity for nodal metastatic disease, imaging assessment of the regional lymph node basin may be

appropriate for staging and during follow-up.

Continued

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PRINCIPLES OF IMAGING

SARC-A

2 OF 3

Continued

EXTREMITY/BODY WALL, HEAD/NECK

Workup

• Primary tumor imaging using MRI with and without contrast ± CT with contrast is recommended.

Other imaging studies such as angiogram and plain radiograph may be warranted in certain circumstances.

• Chest imaging

X-ray or CT without contrast (preferred)

Follow-up

• General considerations for assessing primary tumor site in follow-up

Obtain imaging of the primary site after neoadjuvant therapy, postoperatively and periodically based on estimated risk of locoregional

recurrence.

MRI with and without contrast and/or CT with contrast is recommended.

In patients with no radiographic evidence of disease, imaging of primary site, chest, and other sites at risk of metastatic disease is

recommended every 3–6 months for 2–3 years, then every 6 months for the next 2 years, then annually.

For patients with known radiographic evidence of disease, imaging of known sites of metastatic disease is recommended every 2–3

months.

Consider ultrasound for small lesions that are supercial. Ultrasound should be performed by an ultrasonographer experienced in

musculoskeletal disease.

• Low risk for distant recurrence

Consider chest imaging every 6–12 months. X-ray or CT is preferred. Contrast may be used if also imaging abdomen/pelvis.

• Intermediate/high risk for distant recurrence

Chest imaging using x-ray or CT is recommended every 3–6 months for 2–3 years, then every 6 months for the next 2 years, then annually.

Choi H, Varma DGK, Fornage BD, et al. Soft-tissue sarcoma: MR imaging vs sonography for detection of local recurrence after surgery. AJR Am J Roentgenol

1991;157:353-358.

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PRINCIPLES OF IMAGING

RETROPERITONEAL/INTRA-ABDOMINAL

Workup

• Primary tumor imaging with chest/abdominal/pelvic CT ± abdominal/pelvic MRI is recommended.

• Consider PET/CT as a tool to help dierentiate between well-dierentiated and dedierentiated liposarcoma and to help determine site for

biopsy.

Follow-up

• Obtain chest imaging, x-ray, or CT (preferred).

• Obtain imaging of the primary site after neoadjuvant therapy, postoperatively and periodically based on estimated risk of locoregional

recurrence.

• In patients with no radiographic evidence of disease, imaging of primary site, chest, and other sites at risk of metastatic disease is

recommended every 3–6 months for 2–3 years, then every 6 months for the next 2 years, then annually.

• For patients with known radiographic evidence of disease, imaging of known sites of metastatic disease is recommended every 2–3 months.

• Imaging may include chest/abdominal/pelvic CT, or chest CT without contrast and abdominal/pelvic MRI with contrast.

DESMOID TUMORS (Aggressive Fibromatosis)

Workup

• Primary site imaging with CT or MRI as indicated

Follow-up

• Imaging with CT or MRI every 3–6 months for 2–3 years, then every 6–12 months thereafter

• Ultrasound may be considered for select locations (ie, abdominal wall) for long-term follow-up. Ultrasound should be done by an

ultrasonographer experienced in musculoskeletal disease.

Well-differentiated liposarcoma does not require chest imaging.

Choi H, Varma DGK, Fornage BD, et al. Soft-tissue sarcoma: MR imaging vs sonography for detection of local recurrence after surgery. AJR Am J Roentgenol

1991;157:353-358.

Parkes A, Urquiola E, Bhosale P, et al. PET/CT imaging as a diagnostic tool in distinguishing well-differentiated versus dedifferentiated liposarcoma. Sarcoma

2020;8363986.

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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SARC-B

See Principles of Ancillary Techniques Useful in the Diagnosis of Sarcomas (SARC-C).

Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and

Bone, Fourth Edition. IARC, Lyon, 2013.

PRINCIPLES OF PATHOLOGIC ASSESSMENT OF SARCOMA SPECIMENS

• Biopsy should establish malignancy, provide a specic diagnosis where possible, and provide a grade where appropriate or feasible,

recognizing that limited biopsy material may underestimate grade.

• In patients without a denitive diagnosis following initial biopsy due to limited sampling size, repeat image-guided core needle biopsy

should be considered to make a diagnosis.

• Pathologic assessment of biopsies and resection specimens should be carried out by an experienced sarcoma pathologist.

• Morphologic diagnosis based on microscopic examination of histologic sections remains the gold standard for sarcoma diagnosis. However,

since several ancillary techniques are useful in support of morphologic diagnosis (including immunohistochemistry [IHC], classical

cytogenetics, and molecular genetic testing), sarcoma diagnosis should be carried out by pathologists who have access to these ancillary

methods.

• The pathologic assessment should include evaluation of the following features, all of which should be specically addressed in the

pathology report:

Organ, site, and operative procedure

Primary diagnosis (using standardized nomenclature, such as the

WHO Classication of Tumors of Soft Tissue and Bone

)

Depth of tumor

◊ Supercial (tumor does not involve the supercial fascia)

◊ Deep

Size of tumor

Histologic grade (at the least, specify low or high grade if

applicable); ideally, grade using the French Federation of Cancer

Centers Sarcoma Group (FNCLCC), NCI system, or appropriate

diagnosis-specic grading system if applicable

Necrosis

◊ Present or absent

◊ Microscopic or macroscopic

◊ Approximate extent (percentage)

Status of margins of excision

◊ Uninvolved

◊ Involved (state which margins)

◊ Close (state which margins and measured distance)

Quality of margin (a more limited fascial margin may be equivalent

to a wider soft tissue margin)

Status of lymph nodes

◊ Site

◊ Number examined

◊ Number positive

Results of ancillary studies

◊ Type of testing (ie, electron microscopy, IHC, molecular genetic

analysis)

◊ Where performed

Additional tumor features of potential clinical value

◊ Mitotic rate per 10 HPF

◊ Presence or absence of vascular invasion

◊ Character of tumor margin (well circumscribed or inltrative)

◊ Inammatory inltrate (type and extent)

TNM Stage (See ST-5 through ST-9)

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Molecular genetic analysis involves highly complex test methods. None of the methods is absolutely sensitive or provides results that are absolutely specific; test results must always be

interpreted in the context of the clinical and pathologic features of the case. Testing should therefore be carried out by a pathologist with expertise in sarcoma diagnosis and molecular

diagnostic techniques.

This table is not exhaustive for either sarcomas with characteristic genetic changes or the genes involved. For example, additional genetic aberrations can be found in alveolar RMS,

including PAX3-NCOA1, PAX3-NCOA2, and PAX3-INO80D. NCOA2 gene rearrangements and MyoD mutation have been identified in spindle cell RMS. Receptor tyrosine kinase/RAS/

PIK3CA aberrations are found in 93% of RMS cases. MIR143-NOTCH fusion has recently been identified in glomus tumor. Loss of TSC1 (9q34) or TSC2 (16p13.3) (mTOR pathway) or

gene fusions of the TFE3 gene (microphthalmia-associated transcription factor family) have been identified in PEComa.

PRINCIPLES OF ANCILLARY TECHNIQUES USEFUL IN THE DIAGNOSIS OF SARCOMAS

Morphologic diagnosis based on microscopic examination of histologic sections remains the gold standard for sarcoma diagnosis. However,

several ancillary techniques are useful in support of morphologic diagnosis, including IHC, classical cytogenetics, electron microscopy,

and molecular genetic testing. Molecular genetic testing has emerged as an ancillary testing approach since many sarcoma types harbor

characteristic genetic aberrations, including single base pair substitutions, deletions and amplications, and translocations. Most molecular

testing utilizes uorescence in situ hybridization (FISH) approaches or polymerase chain reaction (PCR)-based methods and next-generation

sequencing (NGS)-based methods.

Recurrent genetic aberrations in sarcoma

are listed below:

TUMOR ABERRATION GENE(S) INVOLVED

Malignant Round Cell Tumors

Alveolar RMS t(2;13)(q35;q14)

t(1;13)(p36;q14)

t(X;2)(q13;q35)

PAX3-FOXO1

PAX 7-FOXO1

PAX3-AFX

Desmoplastic small round cell tumor t(11;22)(p13;q12) EWSR1-WT1

Embryonal RMS Complex alterations Multiple,

MYOD1, KRAS, HRAS, TP53, NF1, NRAS,

PIK3CA, FBXW7, FGFR4, BCOR

Ewing sarcoma/peripheral

neuroectodermal tumor

t(11;22)(q24;q12)

t(21;22)(q22;q12)

t(2;22)(q33;q12)

t(7;22)(p22;q12)

t(17;22)(q12;q12)

inv(22)(q12q;12)

t(16;21)(p11;q22)

EWSR1-FLI1

EWSR1-ERG

EWSR1-FEV

EWSR1-ETV1

EWSR1-E1AF

EWSR1-ZSG

FUS-ERG

Continued

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PRINCIPLES OF ANCILLARY TECHNIQUES USEFUL IN THE DIAGNOSIS OF SARCOMAS

TUMOR ABERRATION GENE(S) INVOLVED

Undierentiated round cell sarcoma t(4;19)(q35;q13) or t(10;19)(q26;q13)

inv(X)(p11.4p11.22)

CIC-DUX4

BCOR-CCNB3

Lipomatous Tumors

Atypical lipomatous tumor/well-

dierentiated liposarcoma (ALT/WDLS)

Supernumerary ring chromosomes; giant marker

chromosomes

Amplication of region 12q14-15,

including MDM2, CDK4, HMGA2, SAS,

GLI

Dedierentiated liposarcoma Same as for ALT/WDLS Same as for ALT/WDLS

Myxoid/round cell liposarcoma t(12;16)(q13;p11)

t(12;22)(q13;q12)

FUS-DDIT3

EWSR1-DDIT3

Pleomorphic liposarcoma Complex alterations Unknown

Other Sarcomas

Alveolar soft part sarcoma der(17)t(X;17)(p11;q25) ASPL-TFE3

Angiomatoid brous histiocytoma t(12;22)(q13;q12)

t(2;22)(q33;q12)

t(12;16)(q13;p11)

EWSR1-ATF1

EWSR1-CREB1

FUS-ATF1

Clear cell sarcoma t(12;22)(q13;q12)

t(2;22)(q33;q12)

EWSR1-ATF1

EWSR1-CREB1

Congenital/infantile brosarcoma t(12;15)(p13;q25) ETV6-NTRK3

Dermatobrosarcoma protuberans t(17;22)(q21;q13) and derivative ring chromosomes COL1A1-PDGFB

Desmoid bromatosis Trisomy 8 or 20; loss of 5q21 CTNNB1 or APC mutations

High-grade endometrial stromal sarcoma t(10;17)(q22;p13)

t(x;22)(p11;q13)

YWHAE-NUTM2

ZC3H7B-BCOR

Continued

Yoshimoto T, Tanaka M, Homme M, et al. CIC-DUX4 induces small round cell sarcomas distinct from Ewing sarcoma. Cancer Res 2017;77(11):2927-2937.

Kao YC, Owosho AA, Sung YS, et al. BCOR-CCNB3-fusion positive sarcomas: A clinicopathologic and molecular analysis of 36 cases with comparison to morphologic spectrum and

clinical behavior of other round cell sarcomas. Am J Surg Path 2018;42(5):604-615.

Yamamoto H, Yoshida A, Taguchi K, et al. ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Histopathology 2016;69:72-83.

Lewis N, Soslow RA, Delair DF, et al. ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity. Mod Pathol 2018;31:674-684.

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TUMOR ABERRATION GENE(S) INVOLVED

Epithelioid hemangioendothelioma t(1;13)(p36;q25)

t(X;11)(q22;p11.23)

WWTR1-CAMTA1

YAP1 - TFE3

Other Sarcomas - continued

Epithelioid sarcoma Inactivation, deletion, or mutation of INI1

(SMARCB-1)

INI1 (SMARCB-1)

Extrarenal rhabdoid tumor Inactivation of INI1 (SMARCB-1) INI1 (SMARCB-1)

Extraskeletal myxoid chondrosarcoma t(9;22)(q22;q12)

t(9;17)(q22;q11)

t(9;15)(q22;q21)

t(3;9)(q11;q22)

EWSR1-NR4A3

TAF2N-NR4A3

TCF12-NR4A3

TFG-NR4A3

Sporadic and familial GIST

Carney-Stratakis syndrome

(gastric GIST and paraganglioma)

Activating kinase mutations

Krebs cycle mutation

KIT or PDGFRA

Germline SDH subunit mutations

Inammatory myobroblastic tumor (IMT) t(1;2)(q22;p23)

t(2;19)(p23;p13)

t(2;17)(p23;q23)

t(2;2)(p23;q13)

t(2;11)(p23;p15)

inv(2)(p23;q35)

TPM3-ALK

TPM4-ALK

CLTC-ALK

RANBP2-ALK

CARS-ALK

ATIC-ALK

Leiomyosarcoma Complex alterations Unknown

Low-grade bromyxoid sarcoma t(7;16)(q33;p11)

t(11;16)(p11;p11)

FUS-CREB3L2

FUS-CREB3L1

Malignant peripheral nerve sheath tumor NF1, CDKN2A and EED or SUZ12

Mesenchymal chondrosarcoma t(8;8)(q13;q21) HEY1 - NCOA2

Solitary brous tumor inv(12)(q13q13) NAB2 - STAT6

Synovial sarcoma t(X;18)(p11;q11)

t(X;18)(p11;q11)

SS18-SSX1

SS18-SSX2

SS18-SSX4

Tenosynovial giant cell tumor/pigmented

villonodular synovitis (TGCT/PVNS)

t(1;2)(p13;q35) CSF1

PRINCIPLES OF ANCILLARY TECHNIQUES USEFUL IN THE DIAGNOSIS OF SARCOMAS

Yamamoto H, Yoshida A, Taguchi K, et al. ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Histopathology 2016;69:72-83.

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1 OF 2

PRINCIPLES OF SURGERY

Multidisciplinary team management including plastic, reconstructive,

and vascular surgeons is recommended.

Biopsy

• A pretreatment biopsy to diagnose and grade a sarcoma is highly

preferred. Biopsy should be carried out by an experienced surgeon

(or radiologist) and may be accomplished by open incisional or

needle technique. Core needle biopsy is preferred; however, an

open incisional biopsy may be considered by an experienced

surgeon. Image-guided needle biopsy may be indicated for

extremity/truncal sarcomas.

• For certain histologies with a propensity for nodal metastatic

disease, sentinel node biopsy can be considered, especially if the

presence of occult nodal metastatic disease would change the

multimodality treatment plan.

Surgery

• The surgical procedure necessary to resect the tumor with

oncologically appropriate margins should be used. Close margins

may be necessary to preserve critical neurovascular structures,

bones, joints, etc.

• Evaluate preoperatively for rehabilitation (see SARC-D 2 of 2)

• Ideally, the biopsy site should be excised en bloc with the denitive

surgical specimen. Dissection should be through grossly normal

tissue planes uncontaminated by tumor. If the tumor is close to or

displaces major vessels or nerves, these do not need to be resected

if the adventitia or perineurium is removed and the underlying

neurovascular structures are not involved with gross tumor.

• Radical excision/entire anatomic compartment resection is not

routinely necessary.

• Surgical clips should be placed to mark the periphery of the surgical

eld and other relevant structures to help guide potential future RT.

If closed suction drainage is used, the drains should exit the skin

close to the edge of the surgical incision (in case re-resection or

radiation is indicated).

Resection Margins

• Surgical margins should be documented by both the surgeon and

the pathologist evaluating the resected specimen.

• If surgical resection margins are positive on nal pathology (other

than bone, nerve, or major blood vessels), surgical re-resection to

obtain negative margins should strongly be considered if it will not

have a signicant impact upon functionality.

• Consideration for adjuvant RT should be given for a close soft

tissue margin or a microscopically positive margin on bone, major

blood vessels, or a major nerve.

• ALT/WDLS: RT is not indicated in most cases.

• In selected cases when margin status is uncertain, consultation with

a radiation oncologist is recommended.

R0 resection - No residual microscopic disease

R1 resection - Microscopic residual disease

R2 resection - Gross residual disease

• Special consideration should be given to inltrative histologies such

as myxobrosarcoma, DFSP, and angiosarcoma.

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Multidisciplinary team management including plastic,

reconstructive, and vascular surgeons is recommended.

Limb-Sparing Surgery

• For extremity sarcomas, the goal of surgery should be functional

limb preservation, if possible, within the realm of an appropriate

oncologic resection.

Amputation

• Prior to considering amputation, patients should be evaluated by a

surgeon with expertise in the treatment of soft tissue sarcomas.

• Consideration for amputation to treat an extremity should be made

for patient preference or if gross total resection of the tumor is

expected to render the limb nonfunctional.

Rehabilitation

Rehabilitation evaluation is recommended preoperatively,

postoperatively, and in the outpatient setting in order to optimize

functional outcomes and quality of life.

Prior to amputation or limb-sparing surgery, rehabilitation Physical

Medicine and Rehabilitation (PM&R) physician consultation should

be oered to provide education about functional outcomes of the

planned surgery, set postoperative goals, and establish care for

longitudinal follow-up.

In the immediate postoperative period, patients should receive a

functional evaluation, typically by a physical therapist, to ensure

that they are able to safely discharge home. If further rehabilitation

is needed, a PM&R and occupational therapist should also evaluate

the patient.

The oncology rehabilitation (PM&R, physical/occupational therapy)

team and the orthopedic/surgical oncology team should be well-

coordinated to optimize patient care. This includes communicating

the rehabilitation/surgical restrictions, precautions, and

rehabilitation protocol prior to initiating therapy.

When possible, the rehabilitation plan of care should be overseen

by a PM&R physician, who can prescribe medications, order and

interpret diagnostic tests, and prescribe/oversee therapies. The

plan should consider oncology treatment-related side eects and

comorbidities such as lymphedema, systemic therapy-induced

neuropathy and fatigue, radiation brosis, and impaired bone

healing that may impact treatment.

Pain management should be integrated into the rehabilitation

program to optimize outcomes. Phantom limb pain should be

treated early. Interventions may include mirror therapy, motor

imagery, massage, oral and topical analgesics, coping strategies,

and patient education.

Special consideration should be given when progressing

rehabilitation interventions for limb-sparing surgeries (ie, oncologic

proximal humerus replacement, proximal tibia replacement, internal

hemipelvectomy) that require adequate scar tissue formation

essential for functional joint recovery.

The rehabilitation plan must address any psychological distress

associated with the surgery, and include referrals to appropriate

mental health providers when necessary. All patients should be

connected to peer support groups.

PRINCIPLES OF SURGERY

SARC-D

2 OF 2

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1 OF 4

PRINCIPLES OF RADIATION THERAPY FOR SOFT TISSUE SARCOMA

Radiation Therapy Guidelines for Soft Tissue Sarcoma of Extremity/Body Wall/Head and Neck

1,2,3

• Potential benets of preoperative radiation therapy:

Lower total radiation dose

Shorter course of treatment

Treatment eld size is frequently smaller

◊ Associated with less late radiation toxicity and improved extremity function

The primary sarcoma is a dened target for radiation treatment planning

Treatment delivery not impacted by postoperative wound healing issues

Potential downstaging of borderline resectable extremity sarcomas for possible limb salvage

Ability to restage patients after preoperative radiation but before wide resection

◊ Presence of distant metastases would prevent proceeding with a noncurative surgery

• Based on the pros and cons of preoperative versus postoperative radiation, the panel has expressed a general preference for preoperative

radiation.

• Preoperative RT

4,5,6,7

50 Gy external beam RT (EBRT)

Following preoperative 50 Gy EBRT and surgery, for positive margins, consider observation or RT boost in select situations

Use of a boost after positive margins is controversial, if elected doses of additional 14–20 Gy can be considered with fractionated EBRT or

brachytherapy.

See references on SARC-E 4 of 4

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PRINCIPLES OF RADIATION THERAPY FOR SOFT TISSUE SARCOMA

Radiation Therapy Guidelines for Soft Tissue Sarcoma of Extremity/Body Wall/Head and Neck

1,2,3

• Potential benets of postoperative radiation therapy:

Allow for denitive pathologic assessment, including margin status, where there was not a denitive indication for preoperative radiation.

Lower rate of postoperative wound healing complications, especially in the lower extremity.

• Based on the pros and cons of preoperative versus postoperative radiation, the panel has expressed a general preference for preoperative

radiation.

• Postoperative RT following surgery

with clips

EBRT (50 Gy) to larger volume followed by a boost to the tumor bed of 10–20 Gy depending on surgical margins.

8,12

Brachytherapy ± EBRT

◊ Positive margins:

– Low dose-rate (16–20 Gy) or high dose-rate equivalent (14–16 Gy) brachytherapy + 50 Gy EBRT

◊ Negative margins:

– 45 Gy low dose-rate or high dose-rate equivalent (ie, 36 Gy in 3.6 Gy BID over 10 fractions in 5 days)

brachytherapy

• Denitive RT for unresectable disease

See references on SARC-E 4 of 4

Radiation for patients who are not surgical candidates where definitive radiation is planned should receive radiation to an initial larger volume, akin to what is used for

preoperative radiation followed by a boost to the gross tumor with more limited margin. Doses to the initial volume should be 50 Gy with a boost of at least 63 Gy; however,

higher doses in the range of 70–80 Gy can be considered, limited by tolerance of normal structures. (Kepka L, et al. Int J Radiat Oncol Biol Phys 2005;63:852-859).

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

Radiation Therapy Guidelines for Retroperitoneal/Intra-Abdominal Sarcoma

14,15

• Preoperative RT

50 Gy EBRT

8,16

◊ Consider IORT boost for known or suspected positive margins at the time of surgery

– 10–12.5 Gy for microscopically positive disease

– 15 Gy for gross disease

◊ A postoperative EBRT boost is discouraged. If deemed necessary in highly selected cases, consider the following doses:

– 16–18 Gy for microscopic disease

11,17

– 20–26 Gy for gross residual disease,

if normal tissue spared (likely requiring tissue displacement with omentum or other biologic or

synthetic tissue spacer)

◊ In experienced centers only – 45–50 Gy in 25–28 fractions to entire CTV with dose-painted simultaneous integrated boost (SIB) to total

dose of 57.5 Gy in 25 fractions to the high-risk retroperitoneal margin jointly dened by the surgeon and radiation oncologist (no boost

after surgery)

See references on SARC-E 4 of 4

SARC-E

3 OF 4

PRINCIPLES OF RADIATION THERAPY FOR SOFT TISSUE SARCOMA

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Soft Tissue Sarcoma

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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SARC-E

4 OF 4

PRINCIPLES OF RADIATION THERAPY FOR SOFT TISSUE SARCOMA

If an R1 or R2 resection is anticipated, clips to high-risk areas for recurrence are

encouraged. When EBRT is used, sophisticated treatment planning with IMRT

and/or protons can be used to improve the therapeutic ratio:

Alektiar KM, Brennan MF, Healey JH, Singer S. Impact of intensity-modulated

radiation therapy on local control in primary soft-tissue sarcoma of the

extremity. J Clin Oncol 2008;26:3440-3444;

Kraybill WG, Harris J, Spiro IJ, et al. Phase II study of neoadjuvant

chemotherapy and radiation therapy in the management of high-risk, high-

grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy

Oncology Group Trial 9514. J Clin Oncol 2006;24:619-625.

Haas RL, DeLaney TF, O'Sullivan B, et al. Radiotherapy for management of

extremity soft tissue sarcomas: why, when, and where? Int J Radiat Oncol Biol

Phys, 2012; 84:572-580.

These guidelines are intended to treat the adult population. For adolescent and

young adult patients, refer to the NCCN Guidelines for Adolescent and Young

Adult (AYA) Oncology.

Li XA, Chen X, Zhang Q, et al. Margin reduction from image guided radiation

therapy for soft tissue sarcoma: Secondary analysis of Radiation Therapy

Oncology Group 0630 results. Pract Radiat Oncol 2016 Jul-Aug;6(4):e135-40.

5Wang D, Zhang Q, Eisenberg BL, et al. Significant reduction of late toxicities in

patients with extremity sarcoma treated with image-guided radiation therapy to

a reduced target volume: Results of Radiation Therapy Oncology Group RTOG-

0630 Trial. J Clin Oncol 2015 Jul 10;33(20):2231-2238.

6Bahig H, Roberge D, Bosch W, et al. Agreement among RTOG sarcoma radiation

oncologists in contouring suspicious peritumoral edema for preoperative radiation

therapy of soft tissue sarcoma of the extremity. Int J Radiat Oncol Biol Phys 2013

Jun 1;86(2):298-303.

7Wang D, Bosch W, Roberge D, et al. RTOG sarcoma radiation oncologists reach

consensus on gross tumor volume and clinical target volume on computed

tomographic images for preoperative radiotherapy of primary soft tissue sarcoma

of extremity in Radiation Therapy Oncology Group studies. Int J Radiat Oncol

Biol Phys 2011 Nov 15;81(4):e525-e528.

EBRT in 1.8 to 2.0 Gy per fraction.

There are data to suggest that some patients with positive margins following

preoperative RT such as those with low-grade, well-differentiated liposarcoma

and a focally,“planned” positive margin on an anatomically fixed critical

structure may do well without a boost. (Gerrand CH, et al. J Bone Joint Surg

Br 2001;83:1149-1155). There are also data to suggest that delivery of a boost

for positive margins does not improve local control. Since delivery of a post-op

boost does not clearly add benefit, the decision should be individualized and the

potential toxicities should be carefully considered. (Al Yami, et al. Int J Radiat

Oncol Biol Phys 2010;77:1191-1107; Pan, et al. J Surg Oncol 2014;110:817-822).

Delaney TF, Kepka L, Goldberg SI, et al. RT therapy for control of soft

tissue sarcomas resected with positive margins. Int J Radiat Oncol biol Phys

2007;67:1460-1469.

See Resection Margins on Principles of Surgery (SARC-D).

Total doses should always be determined by normal tissue tolerance.

Kepka L, Delaney TF, Suit HD, et al. Results of radiation therapy for unresected

soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2005;63:852-859.

Postoperative RT following surgery is discouraged for retroperitoneal/intra-

abdominal sarcoma. If RT is not given prior to surgical resection, consider

follow-up with possible preoperative EBRT at time of localized recurrence.

See (SARC-D). In highly select cases where a postoperative EBRT boost is

considered, intraoperative placement of clips at areas of high risk for recurrence

or anticipated R1/R2 resection is encouraged. When EBRT is used in these rare

situations, sophisticated treatment planning with IMRT, IGRT, and/or protons can

be used to improve the therapeutic ratio.

Trans-Atlantic RPS Working Group. Management of primary retroperitoneal

sarcoma (RPS) in the adult: a consensus approach from the Trans-Atlantic

RPS Working Group. Ann Surg Oncol 2015;22:256-263.

Musat E, Kantor G, Caron J, et al. Comparison of intensity-modulated

postoperative radiotherapy with conventional postoperative radiotherapy for

retroperitoneal sarcoma. Cancer Radiother 2004;8:255-261.

Swanson EL, Indelicato DJ, Louis D, et al. Comparison of three-dimensional

(3D) conformal proton radiotherapy (RT), 3D conformal photon RT, and

intensity-modulated RT for retroperitoneal and intra-abdominal sarcomas. Int J

Radiat Oncol Biol Phys 2012 Aug 1;83(5):1549-57.

Baldini EH, Wang D, Haas RL, et al. Treatment guidelines for preoperative

radiation therapy for retroperitoneal sarcoma: Preliminary consensus of an

international expert panel. Int J Radiat Oncol Biol Phys 2015;92:602-612.

Baldini EH, Bosch W, Kane JM, et al. Retroperitoneal sarcoma (RPS) high

risk gross tumor volume boost (HR GTV boost) contour delineation agreement

among NRG sarcoma radiation and surgical oncologists. Ann Surg Oncol 2015

Sep;22(9):2846-2852..

Tzeng CW, Fiveash JB, Popple RA, et al. Preoperative radiation therapy with

selective dose escalation to the margin at risk for retroperitoneal sarcoma.

Cancer 2006;107:371-379.

RT does not substitute for definitive surgery with negative margins; re-resection

may be necessary.

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Soft Tissue Sarcoma

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Preferred Regimens Other Recommended Regimens Useful in Certain Circumstances

Neoadjuvant/Adjuvant

Therapy

• AIM (doxorubicin, ifosfamide,

mesna)

1-4,

• Ifosfamide, epirubicin, mesna

• AD (doxorubicin,

dacarbazine)

1,2,6,7

- if ifosfamide

is not considered appropriate

• Doxorubicin

1,2,9

• Gemcitabine and docetaxel

10,11

• Ifosfamide

5,9,10-14

• Trabectedin (for myxoid

liposarcoma)

First-Line Therapy Advanced/

Metastatic

• Anthracycline-based regimens:

Doxorubicin

1,2,8,9

Epirubicin

Liposomal doxorubicin

AD (doxorubicin, dacarbazine)

1,2,6,7

AIM (doxorubicin, ifosfamide,

mesna)

1-4,8

Ifosfamide, epirubicin, mesna

• Gemcitabine-based regimens:

Gemcitabine

Gemcitabine and docetaxel

10,11

Gemcitabine and vinorelbine

Gemcitabine and dacarbazine

• Pazopanib

(patients

ineligible for IV systemic

therapy)

• Larotrectinib

h,22

(for NTRK

gene-fusion sarcomas)

• Entrectinib

i,23

(for NTRK

gene-fusion sarcomas

• MAID (mesna, doxorubicin,

ifosfamide,dacarbazine)

1,2,19,20

Subsequent Lines of Therapy

for Advanced/Metastatic

Disease

• Pazopanib

f,g,21

• Trabectedin

f,25-27

(category 1

recommendation for liposarcoma

and leiomyosarcoma, category 2A for

other subtypes)

• Eribulin

f,24

(category 1

recommendation for liposarcoma,

category 2A for other subtypes)

• Dacarbazine

• Ifosfamide

5,9,10-13,15

• Temozolomide

f,28

• Vinorelbine

f,29

• Regorafenib

g,30

• Pembrolizumab

31,87

(for myxobrosarcoma,

undierentiated pleomorphic

sarcoma [UPS], cutaneous

angiosarcoma, and

undierentiated sarcomas)

Soft Tissue Sarcoma Subtypes with Non-Specic Histologies

SYSTEMIC THERAPY AGENTS AND REGIMENS WITH ACTIVITY IN SOFT TISSUE SARCOMA SUBTYPES

a,b,c

SARC-F

1 OF 9

(Regimens Appropriate for General Soft Tissue Sarcoma;

d,e

see other sections for histology-specic recommendations)

Footnotes see SARC-F, 5 of 9

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Soft Tissue Sarcoma

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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SYSTEMIC THERAPY AGENTS AND REGIMENS WITH ACTIVITY IN SOFT TISSUE SARCOMA SUBTYPES

SARC-F

2 OF 9

Footnotes see SARC-F, 5 of 9

Extraskeletal Osteosarcoma

Preferred Regimens

• Usually treated as soft tissue sarcoma with the following:

Ifosfamide or

platinum-based therapy (cisplatin/doxorubicin)

Preferred Regimens Useful in Certain Circumstances

• Time to

response

less critical

Time to

response

more critical

• Methotrexate and vinorelbine

• Methotrexate and vinblastine

• Sorafenib (category 1)

• Imatinib

36-37

• Pazopanib

• Liposomal doxorubicin

• Doxorubicin ± dacarbazine

40-42

• Sulindac

or other nonsteroidal

anti-inammatory drugs (NSAIDs),

including celecoxib (for pain)

Desmoid Tumors (Aggressive Fibromatosis)

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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SYSTEMIC THERAPY AGENTS AND REGIMENS WITH ACTIVITY IN SOFT TISSUE SARCOMA SUBTYPES

Angiosarcoma

Preferred Regimens Other Recommended Regimens

• Paclitaxel

59,60

• Anthracycline- or gemcitabine-based regimens

recommended for Soft Tissue Sarcoma

Subtypes with Non-Specic Histologies

(See SARC-F, 1 of 9)

• Docetaxel

• Vinorelbine

• Sorafenib

• Sunitinib

• Bevacizumab

k,64

• Pazopanib

• All other systemic therapy options

recommended for Soft Tissue Sarcoma

Subtypes with Non-Specic Histologies

(See SARC-F, 1 of 9)

SARC-F

3 OF 9

Footnotes see SARC-F, 5 of 9

Preferred Regimens Other Recommended Regimens

• Vincristine, dactinomycin, cyclophosphamide

(VAC)

• Vincristine, dactinomycin, ifosfamide (VAI-

Europe)

• Vincristine, doxorubicin, and cyclophosphamide

alternating with ifosfamide and etoposide

• Vincristine, doxorubicin, cyclophosphamide

• Vincristine, doxorubicin, ifosfamide

• Cyclophosphamide and topotecan

• Ifosfamide and doxorubicin

• Ifosfamide and etoposide

• Irinotecan and vincristine

51,52

• Carboplatin and etoposide

• Vinorelbine and low-dose cyclophosphamide

f,54

• Vincristine, irinotecan, temozolomide

• Irinotecan

51,52,56

• Topotecan

• Vinorelbine

f,58

Non-Pleomorphic Rhabdomyosarcoma

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Soft Tissue Sarcoma

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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SYSTEMIC THERAPY AGENTS AND REGIMENS WITH ACTIVITY IN SOFT TISSUE SARCOMA SUBTYPES

Tenosynovial Giant Cell Tumor/

Pigmented Villonodular Synovitis

Preferred Regimens

• Pexidartinib (category 1)

• Imatinib

Alveolar Soft Part Sarcoma (ASPS)

Preferred Regimens

• Sunitinib

71,72

• Pazopanib

• Pembrolizumab

SARC-F

4 OF 9

PEComa, Recurrent Angiomyolipoma,

Lymphangioleiomyomatosis

Preferred Regimens

• Sirolimus

75-78

• Everolimus

• Temsirolimus

80,81

Footnotes see SARC-F, 5 of 9

Solitary Fibrous Tumor

Preferred Regimens Other Recommended Regimens

• Bevacizumab

and temozolomide

• Sunitinib

63,66

• Sorafenib

• Pazopanib

All other systemic therapy options

recommended for Soft Tissue Sarcoma

Subtypes with Non-Specic Histologies

(See SARC-F, 1 of 9)

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Epithelioid Sarcoma

Preferred Regimens

Tazemetostat

m,88

Well-Dierentiated/Dedierentiated Liposarcoma

(WD-DDLS) for Retroperitoneal Sarcomas

Useful in Certain Circumstances

• Palbociclib

l,86

SARC-F

5 OF 9

FOOTNOTES

SYSTEMIC THERAPY AGENTS AND REGIMENS WITH ACTIVITY IN SOFT TISSUE SARCOMA SUBTYPES

Prior to the initiation of therapy, all patients should be evaluated and managed by a multidisciplinary team with expertise and experience in sarcoma.

For uterine sarcomas, see the NCCN Guidelines for Uterine Neoplasms.

Alveolar soft part sarcoma (ASPS), ALT/WDLS, and clear cell sarcomas are generally not sensitive to cytotoxic systemic therapy.

Anthracycline-based regimens are preferred in the neoadjuvant and adjuvant settings.

Regimens appropriate for pleomorphic rhabdomyosarcoma.

Recommended only for palliative therapy.

For non-adipocytic sarcoma.

Not intended for preoperative or adjuvant therapy of nonmetastatic disease. Not recommended for angiosarcoma or pleomorphic rhabdomyosarcoma.

Not intended for adjuvant therapy of nonmetastatic disease.

For patients with intermediate risk disease, consider maintenance therapy with vinorelbine and cyclosphamide for 6 months.

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

Single-agent therapy for the treatment of unresectable well-differentiated/dedifferentiated liposarcoma (WD-DDLS).

Single-agent therapy for the treatment of metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.

Inammatory Myobroblastic Tumor (IMT) with

Anaplastic Lymphoma Kinase (ALK) Translocation

Preferred Regimens

• ALK inhibitors

Crizotinib

Ceritinib

Brigatinib

84,85

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults:

Meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet

1997;350:1647-1654.

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 2008;113:573-581.

Grobmyer SR, Maki RG, Demetri GD, et al. Neo-adjuvant chemotherapy for

primary high-grade extremity soft tissue sarcoma. Ann Oncol 2004;15:1667-1672.

Edmonson J, Ryan L, Blum R, et al. Randomized comparison of doxorubicin

alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin

against advanced soft tissue sarcomas. J Clin Oncol 1993;11:1269-1275.

Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for soft

tissue sarcomas of the extremities and girdles: results of the Italian randomized

cooperative trial. J Clin Oncol 2001;19:1238-1247.

Zalupski M, Metch B, Balcerzak S, et al. Phase III comparison of doxorubicin and

dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas:

A Southwest Oncology Group Study. J Natl Cancer Inst 1991;83:926-932.

Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase Ill randomized

study of doxorubicin and dacarbazine with or without ifosfamide and mesna in

advanced soft tissue and bone sarcomas. J Clin Oncol 1993;11:1276-1285.

Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified

doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic

soft-tissue sarcoma: a randomised contolled phase 3 trial. Lancet Oncol 2014;15:

415-423.

Mack LA, Crowe PJ, Yang JL, et al. Preoperative chemoradiotherapy (modified

Eilber protocol) provides maximum local control and minimal morbidity in patients

with soft tissue sarcoma. Ann Surg Oncol 2005;12:646-653.

Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in

patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin

Oncol 2002;20:2824-2831.

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

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study 002. J Clin Oncol 2007;25:2755-2763.

Hensley ML, Wathen JK, Maki RG, et al. Adjuvant therapy for high-grade,

uterus-limited leiomyosarcoma: results of a phase 2 trial (SARC 005). Cancer

2013;119:1555-1561.

Dileo P, Morgan JA, Zahrieh D, et al. Gemcitabine and vinorelbine combination

chemotherapy for patients with advanced soft tissue sarcomas: results of a phase

II trial. Cancer 2007;109:1863-1869.

Garcia-Del-Muro X, Lopez-Pousa A, Maurel J, et al. Randomized phase II study

comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients

with previously treated soft tissue sarcoma: a Spanish Group for Research on

Sarcomas study. J Clin Oncol 2011;29:2528-2533.

Antman KH, Elias A. Dana-Farber Cancer Institute studies in advanced sarcoma.

Semin Oncol 1990;1(Suppl 2):7-15.

Gronchi A, Ferrari S, Quagliuolo V, et al. Histotype-tailored neoadjuvant

chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue

sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled,

phase 3 mutlicentre trial. Lancet Oncol 2017;18:812-822.

Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without

Ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol 2002;25:468-473.

Judson I, Radford J, Harris M, et al. Randomized phase II trial of pegylated

liposomal doxorubicin versus doxorubicin in the treatment of advanced or

metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone

Sarcoma Group. Eur J Cancer 2001; 37:870-877.

Elias A, Ryan L, Sulkes A, et al. Response to mesna, doxorubicin, ifosfamide,

and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no

prior chemotherapy. J Clin Oncol 1989;7:1208-1216.

Kraybill WG, Harris J, Spiro IJ, et al. Long-term results of a phase 2 study of

neoadjuvant chemotherapy and radiotherapy in the management of high-risk,

high-grade, soft tissue sarcomas of the extremities and body wall: Radiation

Therapy Oncology Group Trial 9514. Cancer 2010;116:4613-4621.

van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-

tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled

phase 3 trial. Lancet 2012;379:1879-1886.

Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-

positive cancers in adult and children. N Engl J Med 2018 378(8):731-739.

SARC-F

6 OF 9

SYSTEMIC THERAPY AGENTS AND REGIMENS WITH ACTIVITY IN SOFT TISSUE SARCOMA SUBTYPES

a,c

REFERENCES

Continued

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Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

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SYSTEMIC THERAPY AGENTS AND REGIMENS WITH ACTIVITY IN SOFT TISSUE SARCOMA SUBTYPES

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SARC-F

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Continued

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Little DJ, Ballo MT, Zagars GK, et al. Adult rhabdomyosarcoma: outcome

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Sandler E, Lyden E, Ruymann F, et al. Efficacy of ifosfamide and doxorubicin

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rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study

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Breitfeld PP, Lyden E, Raney RB, et al. Ifosfamide and etoposide are superior

to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when

administered with irradiation and combination chemotherapy: a report from

the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol

2001;23:225-233.

Pappo AS, Lyden E, Breitfeld P, et al. Two consecutive phase II window trials of

irinotecan alone or in combination with vincristine for the treatment of metastatic

rhabdomyosarcoma: the Children’s Oncology Group. J Clin Oncol 2007;25:362-

369.

Mascarenhas L, Lyden ER, Breitfeld PP, et al. Randomized phase II window

trial of two schedules of irinotecan with vincristine in patients with first relapse or

progression of rhabdomyosarcoma: a report from the Children’s Oncology Group.

J Clin Oncol 2010;28:4658-4663. Erratum in J Clin Oncol 2011;4629(4610):1394.

Klingebiel T, Pertl U, Hess CF, et al. Treatment of children with relapsed soft

tissue sarcoma: report of the German CESS/CWS REZ 91 trial. Med Pediatr

Oncol 1998;30:269-275.

Casanova M, Ferrari A, Bisogno G, et al. Vinorelbine and low-dose

cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the

upcoming European Rhabdomyosarcoma Protocol. Cancer 2004;101:1664-1671.

McNall-Knapp RY, Williams CN, Reeves EN, et al. Extended phase I evaluation

of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory

solid tumors. Pediatr Blood Cancer 2010;54:909-915.

Vassal G, Couanet D, Stockdale E, et al. Phase II trial of irinotecan in children

with relapsed or refractory rhabdomyosarcoma: a joint study of the French

Society of Pediatric Oncology and the United Kingdom Children’s Cancer Study

Group. J Clin Oncol 2007;25:356-361.

Pappo AS, Lyden E, Breneman J, et al. Up-front window trial of topotecan

in previously untreated children and adolescents with metastatic

rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol

2001;19:213-219.

Casanova M, Ferrari A, Spreafico F, et al. Vinorelbine in previously treated

advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma.

Cancer 2002;94:3263-3268.

Penel N, Bui BN, Bay J-O, et al. Phase II trial of weekly paclitaxel for

unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol 2008;26:5269-

5274.

Schlemmer M, Reichardt P, Verweij J, et al. Paclitaxel in patients with advanced

angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and

bone sarcoma group. Eur J Cancer 2008;44:2433-2436.

Van Hoesel QG, Verweij J, Catimel G, et al. Phase II study with docetaxel

(Taxotere) in advanced soft tissue sarcomas of the adult. EORTC Soft Tissue and

Bone Sarcoma Group. Ann Oncol 1994;5(6):539-542.

Maki RG, D’Adamo DR, Keohan ML, et al. Phase II study of sorafenib in patients

with metastatic or recurrent sarcomas. J Clin Oncol 2009;27:3133-3140.

George S, Merriam P, Maki RG, et al. Multicenter phase II trial of sunitinib

in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol

2009;27:3154-3160.

Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase

II study of bevacizumab for the treatment of angiosarcoma and epithelioid

hemangioendotheliomas. Ann Oncol 2013;24:257-263.

Park MS, Patel SR, Ludwig JA, et al. Activity of temozolomide and

bevacizumab in the treatment of locally advanced, recurrent, and metastatic

hemangiopericytoma and malignant solitary fibrous tumor. Cancer

2011;117:4939-4947.

Stacchiotti S, Negri T, Libertini M, et al. Sunitinib malate in solitary fibrous tumor

(SFT). Ann Oncol 2012;23:3171-3179.

Valentin T, Fournier C, Penel N, et al. Sorafenib in patients with progressive

malignant solitary fibrous tumors: a subgroup analysis from a phase II study of

the French Sarcoma Group (GSF/GETO). Invest New Drugs 2013;31(6):1626-

1627.

Ebata T, Shimoi T, Bun S, et al. Efficacy and safety of pazopanib for recurrent or

metastatic solitary fibrous tumor. Oncology 2018;94:340-344.

Tap WD, Gelderblom H, Palmerini E, et al. Pexidartinib versus placebo for

advanced tenosynovial giant cell tumor (ENLIVEN): a randomized phase 3 trial

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Continued

SYSTEMIC THERAPY AGENTS AND REGIMENS WITH ACTIVITY IN SOFT TISSUE SARCOMA SUBTYPES

REFERENCES

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib mesylate for

the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/

pigmented villonodular synovitis. Cancer 2012;118:1649-1655.

Stacchiotti S, Negri T, Zaffaroni N, et al. Sunitinib in advanced alveolar soft part

sarcoma: evidence of a direct antitumor effect. Ann Oncol 2011;22:1682-1690.

Stacchiotti S, Tamborini E, Marrari A, et al. Response to sunitinib malate in

advanced alveolar soft part sarcoma. Clin Cancer Res 2009;15:1096-1104.

Stacchiotti S, Mir O, Le Cesne A, et al. Activity of pazopanib and trabectedin in

advanced alveolar soft part sarcoma. Oncologist 2018;23:62-70.

Groisberg R, Hong DS, Behrang A, et al. Characteristics and outcomes of

patients with advanced sarcoma enrolled in early phase immunotherapy trials. J

Immunother Cancer 2017;5:100.

Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma

in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med

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Davies DM, de Vries PJ, Johnson SR, et al. Sirolimus therapy for

angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a

phase 2 trial. Clin Cancer Res 2011;17:4071-4081.

Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR

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McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in

lymphangioleiomyomatosis. N Engl J Med 2011;364:1595-1606.

Gennatas C, Michalaki V, Kairi PV, et al. Successful treatment with the mTOR

inhibitor everolimus in a patient with perivascular epithelioid cell tumor. World J

Surg Oncol 2012;10:181.

Benson C, Vitfell-Rasmussen J, Maruzzo M, et al. A retrospective study

of patients with malignant PEComa receiving treatment with sirolimus or

temsirolimus: the Royal Marsden Hospital experience. Anticancer Res 2014

Jul;34(7):3663-3668.

Italiano A, Delcambre C, Hostein I, et al. Treatment with the mTOR inhibitor

temsirolimus in patients with malignant PEComa. Ann Oncol 2010;21(5):1135-

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Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged

inflammatory myofibroblastic tumor. N Engl J Med 2010;363:1727-1733.

Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell

lung cancer. N Engl J Med 2014;370(13):1189-97.

Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive

non-small-cell lung cancer. N Engl J Med 2018;379:2027-2039.

85Gettinger SN, Bazhenova LA, Langer CJ, et al. Activity and safety of brigatinib

in ALK-rearranged non-small –cell lung cancer and other malignancies: a single-

arm, open-label, phase 1/2 trial. Lancet Oncol 2016;17(12):1683-1696.

Dickson MA, Tap WD, Keohan ML, et al. Phase II trial of the CDK4 inhibitor

PD0332991 in patients with advanced CDK4-amplified well differentiated or

dedifferentiated liposarcoma. J Clin Oncol 2013;31(16):2024-2028.

Burgess MA, Bolejack V, Van Tine BA, et al. Multicenter phase II study of

pembrolizumab (P) in advanced soft tissue sarcoma (STS) and bone sarcomas

(BS): Final results of SARC028 and biomarker analyses. J Clin Oncol 2017;35

(Supplement; Abstract 11008).

Stacchiotti S, Schoffski P, Jones R, et al. Safety and efficacy of tazemetostat, a

first-in-class EZH2 inhibitor, in patients with epithelioid sarcoma (NCT0261950). J

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SYSTEMIC THERAPY AGENTS AND REGIMENS WITH ACTIVITY IN SOFT TISSUE SARCOMA SUBTYPES

REFERENCES

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Table 1

Histopathologic Type

Tumors included in the soft tissue category are listed below as per the 2020 World Health Organization classication of tumors:

Adipocytic Tumors

Benign

• Lipoma NOS

Intramuscular lipoma

Chondrolipoma

• Lipomatosis

Diuse lipomatosis

Multiple symmetrical lipomatosis

Pelvic lipomatosis

Steroid lipomatosis

HIV lipodystrophy

• Lipomatosis of nerve

Lipoblastomatosis

Localized (lipoblastoma)

Diuse (lipoblastomatosis)

• Angiolipoma NOS

Cellular angiolipoma

• Myolipoma

• Chondroid lipoma

• Spindle cell lipoma

• Atypical spindle cell/pleomorphic lipomatous tumor

• Hibernoma

Intermediate (locally aggressive)

• Atypical lipomatous tumor

Malignant

• Liposarcoma, well-dierentiated, NOS

Lipoma-like liposarcoma

Inammatory liposarcoma

Sclerosing liposarcoma

• Dedierentiated liposarcoma

• Myxoid liposarcoma

• Pleomorphic liposarcoma

Epithelioid liposarcoma

• Myxoid pleomorphic liposarcoma

Fibroblastic/Myobroblastic Tumors

Benign

• Nodular fasciitis

Intravascular fasciitis

Cranial fasciitis

• Proliferative fasciitis

• Proliferative myositis

• Myositis ossicans and bro-osseous pseudotumor to digits

• Ischemic fasciitis

• Elastobroma

• Fibrous hamartoma of infancy

• Fibromatosis colli

• Juvenile hyaline bromatosis

• Inclusion body bromatosis

• Fibroma of tendon sheath

• Desmoplastic broblastoma

• Myobroblastoma

• Calcifying aponeurotic broma

• EWSR1-SMAD3-positive broblastic tumor (emerging)

• Angiomyobroblastoma

• Cellular angiobroma

• Angiobroma NOS

• Nuchal broma

• Acral bromyxoma

• Gardner broma

Intermediate (locally aggressive)

• Solitary brous tumor, benign

• Palmar/plantar-type bromatosis

• Desmoid-type bromatosis

Extra-abdominal desmoid

Abdominal bromatosis

Lipobromatosis

Giant cell broblastoma

Used with permission, Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F, eds. World Health Organization Classification of Tumours of Soft Tissue and Bone.

Fifth Edition. Lyon: IARC;2020.

ST-1

Continued

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Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

Fibroblastic/Myobroblastic Tumors (continued)

Intermediate (rarely metastasizing)

• Dermatobrosarcoma protuberans NOS

Pigmented dermatobrosarcoma protuberans

Dermatobrosarcoma protuberans, brosarcomatous

Myxoid dermatobrosarcoma protuberans

◊ Dermatobrosarcoma protuberans with myoid dierentiation

Plaque-like dermatobrosarcoma protuberans

• Solitary brous tumor, NOS

Fat-forming (lipomatous) solitary brous tumor

Giant cell-rich solitary brous tumor

• Inammatory myobroblastic tumor

Epithelioid inammatory myobroblastic sarcoma

• Myobroblastic sarcoma

• Supercial CD34-positive broblastic tumor

• Myxoinammatory broblastic sarcoma

• Infantile brosarcoma

Malignant

• Solitary brous tumor, malignant

• Fibrosarcoma NOS

• Myxobrosarcoma

Epithelioid myxobrosarcoma

• Low-grade bromyxoid sarcoma

• Sclerosing epithelioid brosarcoma

So-called Fibrohistiocytic Tumors

Benign

• Tenosynovial giant cell tumor NOS

Tenosynovial giant cell tumor, diuse

• Deep benign brous histiocytoma

Intermediate (rarely metastasizing)

• Plexiform brohistiocytic tumor

• Giant cell tumor of soft parts NOS

Malignant

• Malignant tenosynovial giant cell tumor

Vascular Tumors

Benign

• Haemangioma NOS

• Intramuscular haemangioma

• Arteriovenous haemangioma

• Venous haemangioma

• Epithelioid haemangioma

Cellular epithelioid haemangioma

Atypical epithelioid haemangioma

• Lymphangioma NOS

Lymphangiomatosis

• Cystic lymphangioma

• Acquired tufted haemangioma

Intermediate (locally aggressive)

• Kaposiform haemangioendothelioma

Intermediate (rarely metastasizing)

• Retiform haemangioendothelioma

• Papillary intralymphatic angioendothelioma

• Composite haemangioendothelioma

Neuroendocrine composite haemangioendothelioma

• Kaposi sarcoma

Classic indolent Kaposi sarcoma

Endemic African Kaposi sarcoma

AIDS-associated Kaposi sarcoma

Latrogenic Kaposi sarcoma

• Pseudomyogenic (epithelioid sarcoma-like)

Haemangioendothelioma

Malignant

• Epithelioid haemangioendothelioma NOS

Epithelioid haemangioendothelioma with WWTR1-CAMTA1 fusion

• Epithelioid haemangioendothelioma with YAP1-TFE3 fusion

• Angiosarcoma

Table 1

Histopathologic Type

Tumors included in the soft tissue category are listed below as per the 2020 World Health Organization classication of tumors:

ST-2

Used with permission, Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F, eds. World Health Organization Classification of Tumours of Soft Tissue and Bone.

Fifth Edition. Lyon: IARC;2020.

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

Pericytic (perivascular) tumors

Benign and intermediate

• Glomus tumor NOS

Glomangioma

Glomangiomyoma

Glomangiomatosis

Glomus tumor of uncertain malignant potential

• Myopericytoma

Myobromatosis

Myobroma

Benign and intermediate

Infantile myobromatosis

• Angioleiomyoma

Malignant

• Glomus tumor, malignant

Smooth muscle tumors

Benign and intermediate

• Leiomyoma NOS

• Smooth muscle tumor of uncertain malignant potential

Malignant

• Leiomyosarcoma NOS

Skeletal muscle tumors

Benign

• Rhabdomyoma NOS

Fetal rhabdomyoma

Adult rhabdomyoma

Genital rhabdomyoma

Malignant

• Embryonal rhabdomyosarcoma NOS

Embryonal rhabdomyosarcoma, pleomorphic

Alveolar rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma NOS

Spindle cell rhabdomyosarcoma

Table 1

Histopathologic Type

Tumors included in the soft tissue category are listed below as per the 2020 World Health Organization classication of tumors:

Congenital spindle cell rhabdomyosarcoma with VGLL2/NCOA2/CITED2

rearrangements

MYOD1-mutant spindle cell/sclerosing rhabdomyosarcoma

Intraosseous spindle cell rhabdomyosarcoma with TFCP2/NCOA2 Intraosseous

spindle cell rhabdomyosarcoma with TFCP2/NCOA2 rearrangements

• Ectomesenchymoma

Chondro-osseous tumors

Benign

• Chondroma NOS

Chondroblastoma-like soft tissue chondroma

Malignant

• Osteosarcoma, extraskeletal

Peripheral nerve sheath tumors

Benign

• Schwannoma NOS

Ancient schwannoma

Cellular schwannoma

Plexiform schwannoma

Epithelioid schwannoma

Microcystic/reticular schwannoma

• Neurobroma NOS

Ancient neurobroma

Cellular neurobroma

Atypical neurobroma

Plexiform neurobroma

• Perineurioma NOS

Reticular perineurioma

Sclerosing perineurioma

• Granular cell tumor NOS

• Nerve sheath myxoma

• Solitary circumscribed neuroma

Plexiform solitary circumscribed neuroma

Reticular perineurioma

Sclerosing perineurioma

Used with permission, Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F, eds. World Health Organization Classification of Tumours of Soft Tissue and Bone.

Fifth Edition. Lyon: IARC;2020.

ST-3

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Discussion

Peripheral nerve sheath tumors (continued)

• Granular cell tumor NOS

• Nerve sheath myxoma

• Solitary circumscribed neuroma

Plexiform solitary circumscribed neuroma

• Meningioma NOS

• Benign triton tumor/neuromuscular choristoma

• Hybrid nerve sheath tumor

Perineurioma/schwannoma

Schwannoma/neurobroma

Perineuroma/neurobroma

Malignant

• Malignant peripheral nerve sheath tumor NOS

Malignant peripheral nerve sheath tumor, epithelioid

• Melanotic malignant peripheral malignant triton tumor

• Malignant granular cell tumor

• Perineurioma, malignant

Tumors of Uncertain Dierentiation

Benign

• Myxoma NOS

Cellular myxoma

• Aggressive angiomyxoma

Tumors of Uncertain Dierentiation

• Aggressive angiomyxoma

• Pleomorphic hyalinizing angiectatic tumor

• Phosphaturic mesenchymal tumor NOS

• Perivascular epithelioid tumor, benign

• Angiomyolipoma

Table 1

Histopathologic Type

Tumors included in the soft tissue category are listed below as per the 2020 World Health Organization classication of tumors:

Tumors of Uncertain Dierentiation (continued)

Intermediate (locally aggressive)

• Haemosiderotic brolipomatous tumor

• Angiomyolipoma, epithelioidntermediate (rarely metastasizing)

• Atypical broxanthoma

• Angiomatoid brous histiocytoma

• Ossifying bromyxoid tumor, NOS

• Mixed tumor NOS

• Mixed tumor, malignant, NOS

• Myoepithelioma NOS

Malignant

• Phosphaturic mesenchymal tumor, malignant

• NTRK-rearranged spindle cell neoplasm (emerging)

• Synovial sarcoma NOS

Synovial sarcoma, spindle cell

Synovial sarcoma, biphasic

Synovial sarcoma, poorly dierentiated

• Epithelioid sarcoma

Proximal or large cell epithelioid sarcoma

• Classic epithelioid sarcoma Alveolar soft part sarcoma

• Clear cell sarcoma NOS

• Extraskeletal myxoid chondrosarcoma

• Desmoplastic small round cell tumor

• Rhabdoid tumor NOS

• Perivascular epithelioid tumor, malignant

• Intimal sarcoma

• Ossifying bromyxoid tumor, malignant

• Myoepithelial carcinoma

• Undierentiated sarcoma

• Spindle cell sarcoma, undierentiated

• Pleomorphic sarcoma, undierentiated

• Round cell sarcoma, undierentiated

Used with permission, Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F, eds. World Health Organization Classification of Tumours of Soft Tissue and Bone.

Fifth Edition. Lyon: IARC;2020.

ST-4

Continued

NCCN Guidelines Version 2.2021

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

ST-5

American Joint Committee on Cancer (AJCC) Staging System for Soft Tissue Sarcoma of the Head and Neck (8th ed, 2017)

Table 2. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T1 Tumor ≤2 cm

T2 Tumor >2 cm to ≤4 cm

T3 Tumor >4 cm

T4 Tumor with invasion of adjoining structures

T4a Tumor with orbital invasion, skull base/dural invasion, invasion of

central compartment viscera, involvement of facial skeleton, or

invasion of pterygoid muscles

T4b Tumor with brain parenchymal invasion, carotid artery encasement,

prevertebral muscle invasion, or central nervous system

involvement via perineural spread

N Regional Lymph Nodes

N0 No regional lymph node metastasis or unknown lymph node status

N1 Regional lymph node metastasis

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

G Denition of Grade

FNCLCC Histologic Grade - see Histologic Grade (G)

GX Grade cannot be assessed

G1 Total dierentiation, mitotic count and necrosis score of 2 or 3

G2 Total dierentiation, mitotic count and necrosis score of 4 or 5

G3 Total dierentiation, mitotic count and necrosis score of 6, 7, or 8

Anatomic Stage/Prognostic Groups

This is a new classication that needs data collection before dening a stage

grouping for head and neck sarcomas.

Histologic Grade (G)

The FNCLCC grade is determined by three parameters: dierentiation, mitotic

activity, and extent of necrosis. Each parameter is scored as follows: dierentiation

(1-3), mitotic activity (1-3), and necrosis (0-2). The scores are added to determine

the grade.

Tumor Dierentiation

1 Sarcomas closely resembling normal adult mesenchymal tissue (e.g., low-

grade leiomyosarcoma)

2 Sarcomas for which histologic typing is certain (e.g., myxoid/round cell

liposarcoma)

3 Embryonal and undierentiated sarcomas, sarcomas of doubtful type,

synovial sarcomas, soft tissue osteosarcoma, Ewing sarcoma/primitive

neuroectodermal tumor (PNET) of soft tissue

Mitotic Count

In the most mitotically active area of the sarcoma, 10 successive high-power elds

(HPF; one HPF at 400× magnication= 0.1734 mm

) are assessed using a 40×

objective.

1 0-9 mitoses per 10 HPF

2 10-19 mitoses per 10 HPF

3 ≥20 mitoses per 10 HPF

Tumor Necrosis

Evaluated on gross examination and validated with histologic sections.

0 No necrosis

1 <50% tumor necrosis

2 ≥50% tumor necrosis

Histopathologic Type

Please see the WHO Classication of Tumors (ST-1)

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Continued

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

ST-6

American Joint Committee on Cancer (AJCC) Staging System for Soft Tissue Sarcoma of the Trunk and Extremities (8th ed, 2017)

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Table 3. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence for primary tumor

T1 Tumor 5 cm or less in greatest dimension

T2 Tumor more than 5 cm and less than or equal to 10 cm in

greatest dimension

T3 Tumor more than 10 cm and less than or equal to 15 cm in

greatest dimension

T4 Tumor more than 15 cm in greatest dimension

N Regional Lymph Nodes

N0 No regional lymph node metastasis or unknown lymph node status

N1 Regional lymph node metastasis

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

G Denition of Grade

FNCLCC Histologic Grade - See Histologic Grade (G)

GX Grade cannot be assessed

G1 Total dierentiation, mitotic count and necrosis score of 2 or 3

G2 Total dierentiation, mitotic count and necrosis score of 4 or 5

G3 Total dierentiation, mitotic count and necrosis score of 6, 7, or 8

Table 4. AJCC Anatomic Stage/Prognostic Groups

T N M G

Stage IA T1 N0 M0 G1, GX

Stage IB T2 N0 M0 G1, GX

T3 N0 M0 G1, GX

T4 N0 M0 G1, GX

T N M G

Stage II T1 N0 M0 G2, G3

Stage IIIA T2 N0 M0 G2, G3

Stage IIIB T3 N0 M0 G2, G3

T4 N0 M0 G2, G3

Stage IV Any T N1 M0 Any G

Any T Any N M1 Any G

Histologic Grade (G)

The FNCLCC grade is determined by three parameters: dierentiation, mitotic activity, and

extent of necrosis. Each parameter is scored as follows: dierentiation (1-3), mitotic activity

(1-3), and necrosis (0-2). The scores are added to determine the grade.

Tumor Dierentiation

1 Sarcomas closely resembling normal adult mesenchymal tissue (e.g., low-grade

leiomyosarcoma)

2 Sarcomas for which histologic typing is certain (e.g., myxoid/round cell liposarcoma)

3 Embryonal and undierentiated sarcomas, sarcomas of doubtful type, synovial

sarcomas, soft tissue osteosarcoma, Ewing sarcoma/primitive neuroectodermal tumor

(PNET) of soft tissue

Mitotic Count

In the most mitotically active area of the sarcoma, 10 successive high-power elds (HPF;

one HPF at 400× magnication= 0.1734 mm

) are assessed using a 40× objective.

1 0-9 mitoses per 10 HPF

2 10-19 mitoses per 10 HPF

3 ≥20 mitoses per 10 HPF

Tumor Necrosis

Evaluated on gross examination and validated with histologic sections.

0 No necrosis

1 <50% tumor necrosis

2 ≥50% tumor necrosis

Continued

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

ST-7

Table 5. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T1 Organ conned

T2 Tumor extension into tissue beyond organ

T2a Invades serosa or visceral peritoneum

T2b Extension beyond serosa (mesentery)

T3 Invades another organ

T4 Multifocal involvement

T4a Multifocal (2 sites)

T4b Multifocal (3-5 sites)

T4c Multifocal (>5 sites)

N Regional Lymph Nodes

N0 No regional lymph node involvement or unknown lymph

node status

N1 Lymph node involvement present

M Distant Metastasis

M0 No metastasis

M1 Metastases present

G Denition of Grade

FNCLCC Histologic Grade - See Histologic Grade (G)

GX Grade cannot be assessed

G1 Total dierentiation, mitotic count and necrosis score of 2 or 3

G2 Total dierentiation, mitotic count and necrosis score of 4 or 5

G3 Total dierentiation, mitotic count and necrosis score of 6, 7, or 8

American Joint Committee on Cancer (AJCC) Staging System for Soft Tissue Sarcoma of the Abdomen and Thoracic Visceral Organs (8th ed, 2017)

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Anatomic Stage/Prognostic Groups

There is no recommended prognostic stage grouping at this time.

Histologic Grade (G)

The FNCLCC grade is determined by three parameters: dierentiation,

mitotic activity, and extent of necrosis. Each parameter is scored as follows:

dierentiation (1-3), mitotic activity (1-3), and necrosis (0-2). The scores are

added to determine the grade.

Tumor Dierentiation

1 Sarcomas closely resembling normal adult mesenchymal tissue (e.g., low-

grade leiomyosarcoma)

2 Sarcomas for which histologic typing is certain (e.g., myxoid/round cell

liposarcoma)

3 Embryonal and undierentiated sarcomas, sarcomas of doubtful type,

synovial sarcomas, soft tissue osteosarcoma, Ewing sarcoma/primitive

neuroectodermal tumor (PNET) of soft tissue

Mitotic Count

In the most mitotically active area of the sarcoma, 10 successive high-power

elds (HPF; one HPF at 400× magnication= 0.1734 mm

) are assessed using

a 40× objective.

1 0-9 mitoses per 10 HPF

2 10-19 mitoses per 10 HPF

3 ≥20 mitoses per 10 HPF

Tumor Necrosis

Evaluated on gross examination and validated with histologic sections.

0 No necrosis

1 <50% tumor necrosis

2 ≥50% tumor necrosis

Continued

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

ST-8

Table 6. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor 2 cm or less

T2 Tumor more than 2 cm but not more than 5 cm

T3 Tumor more than 5 cm but not more than 10 cm

T4 Tumor more than 10 cm in greatest dimension

N Regional Lymph Nodes

N0 No regional lymph node metastasis or unknown lymph

node status

N1 Regional lymph node metastasis

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

Grading for GIST is dependent on mitotic rate

Low 5 or fewer mitoses per 5 mm

, or per 50 HPF

High Over 5 mitoses per 5 mm

, or per 50 HPF

Table 7. AJCC Anatomic Stage/Prognostic Groups

Gastric GIST*

T N M

Mitotic

Rate

Stage IA T1 or T2 N0 M0 Low

Stage IB T3 N0 M0 Low

Stage II T1 N0 M0 High

T2 N0 M0 High

T4 N0 M0 Low

Stage IIIA T3 N0 M0 High

Stage IIIB T4 N0 M0 High

Stage IV Any T N1 M0 Any rate

Any T Any N M1 Any rate

Small Intestinal GIST**

T N M

Mitotic

Rate

Stage I T1 or T2 N0 M0 Low

Stage II T3 N0 M0 Low

Stage IIIA T1 N0 M0 High

T4 N0 M0 Low

Stage IIIB T2 N0 M0 High

T3 N0 M0 High

T4 N0 M0 High

Stage IV Any T N1 M0 Any rate

Any T Any N M1 Any rate

*Note: Also to be used for omentum.

**Note: Also to be used for esophagus, colorectal, mesenteric, and peritoneal.

American Joint Committee on Cancer (AJCC) Staging System for Gastrointestinal Stromal Tumors (8th ed, 2017)

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Continued

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

ST-9

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC) Staging System for Soft Tissue Sarcoma of the Retroperitoneum (8th ed, 2017)

Table 8. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor 5 cm or less in greatest dimension

T2 Tumor more than 5 cm and less than or equal to

10 cm in greatest dimension

T3 Tumor more than 10 cm and less than or equal to

15 cm in greatest dimension

T4 Tumor more than 15 cm in greatest dimension

N Regional Lymph Nodes

N0 No regional lymph node metastasis or unknown lymph node status

N1 Regional lymph node metastases

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastases

G Denition of Grade

FNCLCC Histologic Grade - See Histologic Grade (G)

GX Grade cannot be assessed

G1 Total dierentiation, mitotic count and necrosis score of 2 or 3

G2 Total dierentiation, mitotic count and necrosis score of 4 or 5

G3 Total dierentiation, mitotic count and necrosis score of 6, 7, or 8

Table 9. AJCC Anatomic Stage/Prognostic Groups

T N M G

Stage IA T1 N0 M0 G1, GX

Stage IB T2 N0 M0 G1, GX

T3 N0 M0 G1, GX

T4 N0 M0 G1, GX

T N M G

Stage II T1 N0 M0 G2, G3

Stage IIIA T2 N0 M0 G2, G3

Stage IIIB T3 N0 M0 G2, G3

T4 N0 M0 G2, G3

Any T N1 M0 Any G

Stage IV Any T Any N M1 Any G

Histologic Grade (G)

The FNCLCC grade is determined by three parameters: dierentiation, mitotic activity, and

extent of necrosis. Each parameter is scored as follows: dierentiation (1-3), mitotic activity

(1-3), and necrosis (0-2). The scores are added to determine the grade.

Tumor Dierentiation

1 Sarcomas closely resembling normal adult mesenchymal tissue (e.g., low-grade

leiomyosarcoma)

2 Sarcomas for which histologic typing is certain (e.g., myxoid/round cell liposarcoma)

3 Embryonal and undierentiated sarcomas, sarcomas of doubtful type, synovial

sarcomas, soft tissue osteosarcoma, Ewing sarcoma/primitive neuroectodermal

tumor (PNET) of soft tissue

Mitotic Count

In the most mitotically active area of the sarcoma, 10 successive high-power elds (HPF;

one HPF at 400× magnication= 0.1734 mm

) are assessed using a 40× objective.

1 0-9 mitoses per 10 HPF

2 10-19 mitoses per 10 HPF

3 ≥20 mitoses per 10 HPF

Tumor Necrosis

Evaluated on gross examination and validated with histologic sections.

0 No necrosis

1 <50% tumor necrosis

2 ≥50% tumor necrosis

NCCN Guidelines Version 2.2021

Soft Tissue Sarcoma

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior ecacy, safety, and evidence; and, when appropriate,

aordability.

Other recommended

intervention

Other interventions that may be somewhat less ecacious, more toxic, or based on less mature data;

or signicantly less aordable for similar outcomes.

Useful in certain

circumstances

Other interventions that may be used for selected patient populations (dened with recommendation).

All recommendations are considered appropriate.

CAT-1