i3 Health is pleased to make the Clinical Decision Aid from this activity available for use as a non-accredited self-study or teaching resource. Gain insights and perspectives from this multidisciplinary panel of experts as they discuss cases and explore strategies to optimize treatment outcomes for patients with advanced soft tissue sarcoma. This distinguished Virtual Tumor Board features Shreyaskumar R. Patel, MD, Medical Director of the Sarcoma Center at the University of Texas MD Anderson Cancer Center; Kathleen Polson, NP, Nurse Practitioner at Dana-Farber Cancer Institute; and Brian Rubin, MD, PhD, Professor of Pathology at Cleveland Clinic Cancer Center STATEMENT OF NEED Sarcomas, which represent 1% to 2% of adult cancers, are a rare, heterogeneous group of neoplasms originating in the connective tissue. Soft tissue sarcomas, which begin in the muscle, tendons, fat, lymph, blood vessels, and nerves, encompass more than 80 histological subtypes. Approximately 25% of patients develop metastatic disease after curative-intent surgery, and for these patients, treatment options are limited and prognosis is very poor. In recent decades, the identification of genetic alterations in soft tissue sarcoma has led to the rise of targeted therapy, significantly expanding the therapeutic landscape. Remaining up to date on pathological characteristics and emerging data on novel therapies is crucial (Riskjell et al, 2023; NCI, 2023). In this Virtual Tumor Board, Shreyaskumar R. Patel, MD, Medical Director of the Sarcoma Center at the University of Texas MD Anderson Cancer Center; Kathleen Polson, NP, Nurse Practitioner at Dana-Farber Cancer Institute; and Brian Rubin, MD, PhD, Professor of Pathology at Cleveland Clinic Cancer Center, will present cases and explore multidisciplinary strategies to optimize treatment outcomes for patients with advanced soft tissue sarcoma. TARGET AUDIENCE Medical/surgical/radiation oncologists, pathologists, nurse practitioners, physician assistants, oncology nurses, and other health care professionals involved in the treatment of patients with soft tissue sarcoma. LEARNING OBJECTIVES Upon completion of this activity, participants should be able to Distinguish patient and tumor characteristics that can inform personalized therapeutic approaches in soft tissue sarcoma Evaluate emerging data on novel therapies for soft tissue sarcoma Appraise multidisciplinary strategies to optimize treatment outcomes of patients with advanced soft tissue sarcoma FACULTY Shreyaskumar R. Patel, MD Robert R. Herring Distinguished Professor of Medicine Center Medical Director, Sarcoma Center The University of Texas MD Anderson Cancer Center Kathleen Polson, NP Nurse Practitioner Dana-Farber Cancer Institute Brian Rubin, MD, PhD Professor of Pathology Chairman, Robert J. Tomsich Pathology and Laboratory Medicine Institute Cleveland Clinic Cancer Center

1. © i3 Health. Last updated August 2023.
CLINICAL DECISION AID:
Soft Tissue Sarcoma
The clinical decision aids and resources contained herein are provided as educational
adjuncts to the CME/NCPD–approved online Virtual Tumor Board: Multidisciplinary
Management of Advanced Soft Tissue Sarcoma. This document has been reviewed by
Shreyaskumar R. Patel, MD; Brian P. Rubin, MD, PhD; and Kathleen Polson, NP. To
access the activity and earn CME/NCPD credit, visit:
i3health.com/advanced-soft-tissue-sarcoma
CONTENTS
I: Types of Intermediate/Malignant Soft Tissue Sarcoma: 2020 WHO ............................2
II. Diagnosis and Workup.................................................................................................5
III: Cancer Gradng and Staging for Soft Tissue Sarcomas ...............................................8
IV: Proposed Guidelines for Assessing Malignant Potential of GISTs............................11
V: Initial Treatment Options: Stage 2 and 3...................................................................12
VI: Systemic Therapies for Non-Specific Subtypes ........................................................14
VII: Systemic Therapies for Specific Histologies.............................................................16
VIII: Stage IV or Local Recurrence: Limbs, Outer Torso, Head, and Neck .....................21
IX: Supportive Care for Selected Tyrosine Kinase Inhibitors..........................................22
X. References .................................................................................................................27

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I: TYPES OF INTERMEDIATE/MALIGNANT SOFT TISSUE
SARCOMA: 2020 WHO
Adipocytic tumors
• Atypical lipomatous tumor
• Liposarcoma, well-differentiated, NOS
• Dedifferentiated liposarcoma
• Myxoid liposarcoma
• Pleomorphic liposarcoma
• Myxoid pleomorphic liposarcoma
Fibroblastic/
myofibroblastic
tumors
• Palmar/plantar–type fibromatosis
• Desmoid-type fibromatosis
• Dermatofibrosarcoma protuberans, NOS
• Solitary fibrous tumor
• Inflammatory myofibroblastic tumor
• Myofibroblastic sarcoma
• Superficial CD34-positive fibroblastic tumor
• Myxoinflammatory fibroblastic sarcoma
• Infantile sarcoma
• Fibrosarcoma, NOS
• Myxofibrosarcoma
• Low-grade fibromyxoid sarcoma
• Sclerosing epithelioid fibrosarcoma
So-called
fibrohistiocytic
tumors
• Plexiform fibrohistiocytic tumor
• Giant cell tumor of soft tissue
• Malignant tenosynovial giant cell tumor
Smooth muscle
tumors
• Leiomyosarcoma, NOS
Pericytic
(perivascular)
tumors
• Malignant glomus tumor
Skeletal muscle
tumors
• Embryonal rhabdomyosarcoma

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Vascular tumors
• Kaposiform hemangioendothelioma
• Papillary intralymphoatic angioendothelioma
• Composite hemangioendothelioma
• Kaposi sarcoma
• Retiform hemangioendothelioma
• Pseudomyogenic (epithelioid sarcoma-like)
hemangioendothelioma
• Epithelioid hemangioendothelioma
• Angiosarcoma of soft tissue
Chondro-osseous
tumors
• Extraskeletal osteosarcoma
Gastrointestinal
stromal tumors
• Gastrointestinal stromal tumor, malignant
Peripheral nerve
sheath tumors
• Malignant peripheral nerve sheath tumor
• Melanotic peripheral malignant triton tumor
• Malignant perineurioma
• Malignant triton tumor
• Malignant granular cell tumor
Tumors of
uncertain origin
• Hemosiderotic fibrolipomatous tumor
• Angiomyolipoma, epithelioid
• Atypical fibroxanthoma
• Angiomatoid fibrous histiocytoma
• Ossifying fibrous histiocytoma
• Ossifying fibromyxoid tumor
• Mixed tumor, malignant
• Myoepithelioma
• Ossifying fibromyxoid tumor, malignant
• NTRK-rearranged spindle cell neoplasm
• Stromal sarcoma, NOS
• Myoepithelial carcinoma
• Phosphaturic mesenchymal tumor, malignant
• Synovial sarcoma (NOS, spindle cell, biphasic)
• Epithelioid sarcoma

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• Alveolar soft part sarcoma
• Clear cell sarcoma of soft tissue
• Extraskeletal myxoid chondrosarcoma
• Extraskeletal Ewing sarcoma
• Desmoplastic small round cell tumor
• Rhabdoid tumor
• Perivascular epithelioid cell tumor (PEComa, NOS)
• Intimal sarcoma
Undifferentiated/
unclassified
sarcoma
• Undifferentiated (spindle cell sarcoma, pleomorphic
sarcoma, round cell sarcoma, epithelioid sarcoma, NOS)
WHO = World Health Organization; NOS = not otherwise specified; NTRK = neurotrophic tyrosine receptor kinase.
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf

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II. DIAGNOSIS AND WORKUP
Recommendations for Diagnosis of Soft Tissue Sarcoma
Needed
• Before starting therapy, all patients should be evaluated and
managed by a multidisciplinary team with expertise and experience
in sarcoma
• Medical history and physical exam
• Imaging of primary tumor and as needed for lesions that could be
cancer
• Carefully planned needle biopsy (preferred) or incisional biopsy
based on adequate imaging
Useful in some
cases (different
subtypes have a
tendency to
spread to various
locations)
• Other imaging as needed
• Consider more genetic testing in those with a personal or family
history of cancer predisposition syndromes
Tests for Sarcomas in the Limbs, Outer Torso, or Head and Neck
Needed
• Before starting therapy, all patients should be evaluated and
managed by a multidisciplinary team with expertise and experience
in sarcoma
• Medical history and physical exam
• Imaging of primary tumor using MRI with or without contrast and/or
CT with contrast.
• Carefully planned needle biopsy (preferred) or incisional biopsy
based on adequate imaging
o Place biopsy along future resection axis with minimal
dissection and attention to hemostasis
o Biopsy should establish grade and subtype
o Use other diagnostic techniques as necessary (IHC,
cytogenetics, electron microscopy, molecular genetic
testing, PCR, NGS)_
• Imaging of potential sites of metastasis

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Useful
• Other imaging, such as PET/CT for cancer stage, prognosis, and
grade
• Other imaging, such as angiogram and x-ray
• Consider CT of abdomen/pelvis for myxoid/round cell liposarcoma,
epithelial sarcoma, and angiosarcoma
• Consider MRI of total spine for myxoid/round cell liposarcoma
• Consider central nervous system imaging with MRT or CT for
alveolar part sarcoma, left-sided cardiac sarcoma, and
angiosarcoma
• Consider retroperitoneal/intraabdominal CT, MRI, or PET/CT for
well-differentiated liposarcoma/dedifferentiated liposarcoma
• Consider more genetic testing in those with personal or family
history of Li-Fraumeni syndrome, neurofibromatosis, hereditary
non-polyposis colorectal cancer (HNPCC), or Lynch syndrome, and
patients with personal/family history suggestive of other cancer
predisposition syndromes
Tests for Sarcomas in the Inner Abdomen
Needed
• Before starting therapy, all patients should be evaluated and
managed by a multidisciplinary team with expertise and experience
in sarcoma
• Medical history and physical exam
• CT, MRI, or possibly PET/CT of inner abdomen
• Image-guided core needle biopsy, unless imaging is sufficient for
subtype identification (such as for well-differentiated liposarcoma)
with no preoperative therapy planned
Useful
• Consider more genetic testing in those with personal or family
history of Li-Fraumeni syndrome, neurofibromatosis, HNPCC, or
Lynch syndrome, and patients with personal/family history
suggestive of other cancer predisposition syndromes
Tests for GIST
Very small GIST
of less than 2 cm
• CT with contrast and/or MRI with contrast
• Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) or
endoscopic ultrasound-guided core needle biopsy (EUS-CNB)

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All other GISTS
• CT of abdomen/pelvis and/or MRI of abdomen/pelvis
• Chest imaging using x-ray or CT
• Biopsy to confirm GIST
• Genotyping should be performed when medical therapy is planned
o Test for mutations in KIT and PDGFRA
o For GIST lacking mutations in KIT and PDGFRA, test for
SDH deficiency and alternative driver mutations using NGS
Tests for Desmoid Tumors
Needed
• Before starting therapy, all patients should be evaluated and
managed by a multidisciplinary team with expertise and experience
in sarcoma
• Medical history and physical exam
• Evaluation for Gardner syndrome or familial adenomatous
polyposis (FAP)
• Imaging of primary site with CT or MRI, as needed
• Biopsy
Tests for Rhabdomyosarcoma (RMS)
Pleomorphic
RMS
• PET or PET/CT scan may be useful for initial staging
• For pleomorphic RMS, recommend treating like soft tissue sarcoma
Non-
pleomorphic
RMS (includes
alveolar and
embryonal)
• PET or PET/CT scan may be useful for initial staging
• Referral to center that has expertise in treating RMS is strongly
recommended for non-pleomorphic RMS
• Multidisciplinary evaluation involving pediatric, medical, surgical,
and radiation oncologists is strongly encouraged
• Treatment planning should include risk levels and combination of
treatments
MRI = magnetic resonance imaging; CT = computed tomography; IHC = immunohistochemistry; PET = positron
emission tomography; GIST = gastrointestinal stromal tumor; SDH = succinate dehydrogenase; PDGFRA =
platelet-derived growth factor receptor A;.
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: gastrointestinal stromal
tumors. Version 1.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf

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III: CANCER GRADNG AND STAGING FOR SOFT TISSUE
SARCOMAS
Soft tissue sarcoma grade is based on differentiation, mitotic activity, and extent of
necrosis. Scores are added to determine the grade.
Grading criteria for soft tissue sarcomas
Tumor
differentiation
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 undifferentiated sarcomas, sarcomas of doubtful
type, synovial sarcomas, soft tissue osteosarcoma, Ewing
sarcoma/primitive neuroectodermal tumor (PNET) of soft tissue
Mitotic count
1 0-9 mitoses per 10 HPF
2 10-19 mitoses per 10 HPF
3 ≥20 mitoses per 10 HPF
Necrosis
0 No necrosis
1 < 50% tumor necrosis
2 ≥50% tumor necrosis
Grade determination for soft tissue sarcoma
GX Grade cannot be assessed
G1 Score of 2 or 3
G2 Score of 4 or 5
G3 Score of 6, 7, or 8
HPF = high-power field.
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
Soft tissue sarcoma stage is determined based on the characteristics of the primary
tumor, regional lymph nodes, and histologic grade
Limbs and Outer Torso
Stage 1
Stage 1A • T1, N0, M0, and G1 or GX
Stage 1B
• T2, N0, M0, and G1 or GX
• T3, N0, M0, and GI or GX

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• T4, N0, M0, and GI or GX
Stage 2 • T1, N0, M0, and G2 or G3
Stage 3
Stage 3A • T2, N0, M0, and G2 or G3
Stage 3B
• T3, N0, M0, and G2 or G3
• T4, N0, M0, and G2 or G3
Stage 4
• Any T, N1, M0, any G
• Any T, any N, M1, any G (metastatic)
Retroperitoneum
Stage 1
Stage 1A • T1, N0, M0, and G1 or GX
Stage 1B
• T2, N0, M0, and GI or GX
• T3, N0, M0, and GI or GX
• T4, N0, M0, and GI or GX
Stage 2 • T1, N0, M0, G2, or G3
Stage 3
Stage 3A • T2, N0, M0, and G2 or G3
Stage 3B
• T3, N0, M0, and G2 or G3
• T4, N0, M0, and G2 or G3
Stage 4
• Any T, N1, M0, any G
• Any T, any N, M1, any G (metastatic)
GIST in the Stomach
Stage 1
Stage 1A
• T1 or T2, N0, M0, low mitotic
rate
Stage 1B • T3, N0, M0, low mitotic rate
Stage 2
• T1, N0, M0, high mitotic rate
• T2, N0, M0, high mitotic rate
• T4, N0, M0, low mitotic rate
Stage 3
Stage 3A • T3, N0, M0, high mitotic rate
Stage 3B • T4, N0, M0, high mitotic rate

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Stage 4
• Any T, N1, M0, any rate
• Any T, any N, M1, any rate (metastatic)
GIST in the Small Intestine
Stage 1 • T1 or T2, N0, M0, low mitotic rate
Stage 2 • T3, N0, M0, low mitotic rate
Stage 3
Stage 3A
• T2, N0, M0, high mitotic rate
• T4, N0, M0, low mitotic rate
Stage 3B
• T2, N0, M0, high mitotic rate
• T3, N0, M0, high mitotic rate
• T4, N0, M0, high mitotic rate
Stage 4
• Any T, N1, M0, any rate
• Any T, any N, M1, any rate (metastatic)
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: gastrointestinal stromal
tumors. Version 1.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf

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IV: PROPOSED GUIDELINES FOR ASSESSING MALIGNANT
POTENTIAL OF GISTS
Gastric GISTS
Tumor Size Mitotic Rate Predicted Biologic Behavior
≤2 cm
≤5 mitoses/50 HPFs Metastasis rate: 0%
>5 mitoses/50 HPFs Metastasis rate: 0%
>2 cm to ≤5 cm
≤5 mitoses/50 HPFs Metastasis rate: 1.9%
>5 mitoses/50 HPFs Metastasis rate: 16%
>5 cm to ≤10 cm
≤5 mitoses/50 HPFs Metastasis rate: 3.6%
>5 mitoses/50 HPFs Metastasis rate: 55%
>10 cm
≤5 mitoses/50 HPFs Metastasis rate: 12%
>5 mitoses/50 HPFs Metastasis rate: 86%
GIST = gastrointestinal stromal tumor; HPF = high-power field.
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: gastrointestinal stromal
tumors. Version 1.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf
Non-Gastric GISTS
Tumor Size Mitotic Rate Predicted Biologic Behavior
≤2 cm
≤5 mitoses/50 HPFs Metastasis rate: 0%
>5 mitoses/50 HPFs Metastasis rate: 50%-54%
>2 cm to ≤5 cm
≤5 mitoses/50 HPFs Metastasis rate: 1.9%-8.5%
>5 mitoses/50 HPFs Metastasis rate: 50%-73%
>5 cm to ≤10 cm
≤5 mitoses/50 HPFs Metastasis rate: 24%
>5 mitoses/50 HPFs Metastasis rate: 85%
>10 cm
≤5 mitoses/50 HPFs Metastasis rate: 34%-57%
>5 mitoses/50 HPFs Metastasis rate: 71%-90%
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: gastrointestinal stromal
tumors. Version 1.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf

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V: INITIAL TREATMENT OPTIONS: STAGE 2 AND 3
Sarcomas in the Limbs, Outer Torso, Head, or Neck:
Resectable With Good Functional Outcomes
Stage 2
Surgery
Surgery followed by radiation therapy
Radiation therapy before surgery
Stage 3
Surgery followed by:
• Radiation therapy or
• Radiation therapy with systemic therapy
Radiation therapy before surgery. Consider systemic therapy after surgery
Chemoradiation before surgery. Surgery followed by:
• Radiation therapy or
• Radiation therapy with systemic therapy
Systemic therapy before surgery. Surgery followed by:
• Radiation therapy or
• Radiation therapy with systemic therapy
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
Sarcomas in the Limbs, Outer Torso, Head, or Neck:
Resectable With Poor Functional Outcomes, or Unresectable
• Radiation therapy
• Chemoradiation
• Systemic therapy
• Regional limb
therapy
• If amputation,
consider adjuvant
therapy
If resectable with good function, see primary treatment options
for stage II and III resectable with good functional outcomes
If resectable with poor function, then amputation or radiation
therapy
If unresectable, then:
• Radiation therapy, if not used before
• Systemic therapy
• Palliative surgery
• Observation, if no symptoms

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• Best supportive care
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
Resectable Sarcomas in the Inner Abdomen
GIST
Resectable with minimal morbidity
• Complete resection
• Adjuvant imatinib for patients with risk of recurrence
and imatinib-sensitive disease, or observation
Resectable with significant morbidity
• Mutational testing followed by neoadjuvant therapy
with an appropriate systemic therapy, followed by
surgery if feasible
• Continue imatinib if neoadjuvant imatinib was used and
risk of recurrence
• Observe if other neoadjuvant therapy was used
Desmoid tumors
Systemic therapy
Surgery
Sarcoma
Surgery, consider subsequent systemic therapy if high-risk for
metastasis
Radiotherapy followed by surgery, consider subsequent
systemic therapy if high risk for metastasis
Systemic therapy followed by surgery, consider subsequent
systemic therapy if high risk for metastasis
GIST = gastrointestinal stromal tumor.
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: gastrointestinal stromal
tumors. Version 1.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf

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VI: SYSTEMIC THERAPIES FOR NON-SPECIFIC SUBTYPES
Preferred regimens Other Recommended
Useful in Certain
Circumstances
Neoadjuvant/adjuvant
therapy
AIM (doxorubicin/
ifosfamide/mesna)
Ifosfamide/
epirubicin/mesna
AD (doxorubicin/
dacarbazine) for
leiomyosarcoma (LMS)
or if ifosfamide is not
appropriate
Doxorubicin
Gemcitabine/docetaxel
Ifosfamide
Trabectedin (for
myxoid liposarcoma)
First-line therapy
advanced/metastatic
Anthracycline-based:
• Doxorubicin
• Epirubicin
• Liposomal
doxorubicin
• AD
(doxorubicin/
dacarbazine)
• AIM
(doxorubicin/
ifosfamide/
mesna)
• Ifosfamide/
eipirubicin/
mesna
NTRK gene fusion-
positive:
• Larotrectinib
• Entrectinib
Gemcitabine-based:
• Gemcitabine
• Gemcitabine/
docetaxel
• Gemcitabine/
vinorelbine
• Gemcitabine/
dacarbazine
Pazopanib (patients
ineligible for IV
therapy or patients
who are not
candidates for
anthracycline-based
regimens)
MAID (mesna/
doxorubicin/
ifosfamide/
dacarbazine)
Trabadectin/
doxorubicin (for
leiomyosarcoma)
Selpercatinib (for RET
gene fusion-positive)
Subsequent therapy
advanced/metastatic
Pazopanib
Eribulin (category 1)
for liposarcoma,
category 2A for
others
Trabectedin (category
1 for liposarcoma and
leiomyosarcoma,
Dacarbazine
Ifosfamide
Temozolomide
Vinorelbine
Regorafenib
Gemcitabine-based:
Pembrolizumab or
nivolumab ±
ipilimumab
• For
myxofibrosarc
oma, UPS,
dedifferentiat
ed

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category 2A for
others)
• Gemcitabine
• gemcitabine/
docetaxel
• Gemcitabine/
vinorelbine
• Gemcitabine/
dacarbazine
• Gemcitabine/
pazopanib
(category 2B)
liposarcoma,
cutaneous
angiosarcoma
, and
undifferentiat
ed sarcomas
OR
• For TMB-H
regardless of
subtype
Pembrolizumab
• For MSI-H or
dMMR tumors
regardless of
subtype
IV = intravenous infusion; RET = rearranged during transfection; NTRK = neurotrophic tyrosine receptor kinase;
UPS = undifferentiated pleomorphic sarcoma; TMB-H = tumor mutational burden high; MSI-H = microsatellite
instability-high; dMMR = deficient mismatch repair.
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf

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VII: SYSTEMIC THERAPIES FOR SPECIFIC HISTOLOGIES
Tumor Therapy
Alveolar soft part sarcoma
(ASPS)
Preferred
• Sunitinib
• Pazopanib
• Pembrolizumab
• Pembrolizumab and axitinib
• Atezolizumab
Angiosarcoma
Preferred
• Paclitaxel
• Anthracycline- or gemcitabine-based regimens
for non-specific histologies
Other
• Docetaxel
• Vinorelbine (for palliative therapy)
• Pazopanib
Useful in certain circumstances
• Pembrolizumab (for cutaneous angiosarcoma)
• Regorafenib
• Sorafenib
• Sunitinib
• Bevacizumab
• Ipilimumab/nivolumab
Dedifferentiated Chordoma
• Anthracycline- and gemcitabine-based
regimens for general soft tissue sarcoma
Dermatofibrosarcoma
Protuberans (DFSP) with
Fibrosarcomatous
Transformation
Preferred
• Imatinib
Other
• Anthracycline-based regimens:
o Doxorubicin
o Epirubicin
o Liposomal doxorubicin
o AIM (doxorubicin/ifosfamide/mesna)
o Ifosfamide/epirubicin/mesna
o MAID (mesna/ doxorubicin/ ifosfamide/
dacarbazine)

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• Gemcitabine-based regimens
o Gemcitabine
o Gemcitabine/docetaxel
o Gemcitabine/vinorelbine
o Gemcitabine/dacarbazine
• Pazopanib (patients ineligible for IV systemic
therapy or patients who are not candidates for
anthracycline-based regimens)
Desmoid tumors
Preferred
• Sorafenib (category 1)
• Methotrexate and vinorelbine
• Methotrexate and vinblastine
• Imatinib
• Liposomal doxorubicin
• Doxorubicin ± dacarbazine
• Pazopanib
Useful in certain circumstances
• Sulindac or other NSAIDS, including celecoxib
(for pain)
Epithelioid sarcoma • Tazemetostat
Extraskeletal osteosarcoma
• Treated as soft tissue sarcoma with ifosfamide
or platinum-based therapy (cisplatin/
doxorubicin)
Gastrointestinal stromal tumors
(GIST)
First-line preferred
• Imatinib (for KIT or PDGFRA mutations
excluding PDGFRA exon 18 mutations
insensitive to imatinib, including D842V)
• Avapritinib (for PDGFRA exon 18 mutations
insensitive to imatinib including PDGFRA
D842V)
First-line Useful in certain circumstances
• NTRK gene fusion-positive GIST
o Larotrectinib
o Entrectinib
• SDH-deficient GIST
o Sunitinib
o Regorafenib

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o Pazopanib
o Imatinib/binimetinib (category 2B)
• BRAF V600E mutations
o Dabrafenib + trametinib
Second-line preferred
• Sunitinib (category 1)
• For patients intolerant of second-line sunitinib,
consider ripretinib 150 mg daily
• Dasatinib
Third-line preferred
• Regorafenib (category 1)
Fourth line preferred
• Ripretinib 150 mg daily (category 1)
Additional Options after progression on approved
therapies
• Avapritinib
• Cabozantinib
• Everolimus + TKI
• Nilotinib
• Pazopanib
• Ripretinib dose escalation to 150 mg BID (if
previously treated with ripretinib 150 mg daily)
• Sorafenib
• Ponatinib
Inflammatory myofibroblastic
tumor (IMT) with anaplastic
lymphoma kinase (ALK)
translocation
• Alectinib
• Brigatinib
• Ceritinib
• Crizotinib
Lorlatinib
Malignant perivascular
epithelioid cell tumor (PEComa)
for locally advanced
unresectable or metastatic
disease
Preferred
• Albumin-bound sirolimus
Other
• Sirolimus
• Everolimus
• Temsirolimus

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Non-pleomorphic
rhabdomyosarcoma
Preferred regimens
• Vincristine/ dactinomycin/ cyclophosphamide
(VAC)
• Vincristine/ dactinomycin/ ifosfamide (VAI-
Europe)
Other
• Vincristine/ doxorubicin/ cyclophosphamide
alternating with ifosfamide/ etoposide
• Vincristine/ doxorubicin/ cyclophosphamide
• Vincristine/ doxorubicin/ ifosfamide
• Cyclophosphamide/ topotecan
• Ifosfamide/ doxorubicin
• Ifosfamide/ etoposide
• Irinotecan/ vincristine
• Carboplatin/ etoposide
• Vinorelbine/ low-dose cyclophosphamide
• Vincristine/ irinotecan/ temozolomide
• Irinotecan
• Topotecan
• Vinorelbine
• Vinorelbine/ cyclophosphamide/ temsirolimus
Useful in certain circumstances
• Maintenance chemotherapy
(cyclophosphamide/ vinorelbine) for patients
with intermediate-risk RMS with CR following
treatment with VAC or VAI
Recurrent angiomyolipoma and
lymphangioleiomyomatosis
• Sirolimus
• Everolimus
• Temsirolimus
Retroperitoneal well-
differentiated or
dedifferentiated liposarcoma
Useful in certain circumstances
• Palbociclib
Solitary fibrous
tumor/hemangiopericytoma
Preferred
• Bevacizumab/temozolomide
• Sunitinib
• Sorafenib
• Pazopanib

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Other
• Anthracycline-based regimens
o Doxorubicin
o Epirubicin
o Liposomal doxorubicin
o AD (doxorubicin/dacarbazine)
o AIM (doxorubicin/ifosfamide/mesna)
o Ifosfamide/epirubicin/mesna
o MAID (mesna/doxorubicin/ifosfamide/
dacarbazine)
• Gemcitabine-based regimens
o Gemcitabine
o Gemcitabine/docetaxel
o Gemcitabine/vinorelbine
o Gemcitabine/dacarbazine
• Trabectedin (palliative)
Tenosynovial giant cell
tumor/pigmented villonodular
synovitis
Preferred
• Pexidartinib (category 1)
Useful in certain circumstances
• Imatinib
• Nilotinib
NSAIDS = nonsteroidal anti-inflammatory drug; PDGFRA = platelet derived growth factor receptor alpha; NTRK =
neurotrophic tyrosine receptor kinase; SDH = succinate dehydrogenase; TKI = tyrosine kinase inhibitors;
BID = two times a day; RMS = rhabdomyosarcoma; CR = complete response.
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: gastrointestinal stromal
tumors. Version 1.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf

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VIII: STAGE IV OR LOCAL RECURRENCE: LIMBS, OUTER
TORSO, HEAD, AND NECK
Treatment for Confined Cancer
Treat primary tumor and consider the following:
• Metastatectomy
• Metastatectomy with radiation therapy
• Metastatectomy with pre- or post-surgery systemic therapy (radiation therapy might
be added)
• SBRT alone or with systemic therapy
• Ablation
• Embolization
• Observation
Palliative Care Treatment Options for Metastases
• Systemic therapy
• Radiation therapy or SBRT
• Surgery
• Observation, if no symptoms
• Supportive care
• Ablation
• Embolization
Recurrence Treatment Options: Isolated Disease or Found in Lymph Nodes
• Regional lymph node dissection (surgery to remove lymph node)
• Regional lymph node dissection with radiation therapy or systemic therapy or both
SBRT = stereotactic body radiation therapy.
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue sarcoma.
Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf

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IX: SUPPORTIVE CARE FOR SELECTED TYROSINE KINASE
INHIBITORS
Selected tyrosine kinase
inhibitors
Warnings, most common adverse events,
and laboratory abnormalities
Entrectinib
Most common adverse events (in ≥20%)
• Fatiguea
• Constipation
• Dysgeusia
• Edemaa
• Dizziness
• Diarrhea
• Nauseaa
• Dysesthesia
• Dyspnea
• Myalgia
• Cognitive impairment
• Increased weight
• Cough
• Vomitinga
• Pyrexia
• Arthralgia
• Vision disorders
Imatinib
Most common adverse events (in ≥30%)
• Edemaa
• Nauseaa
• Vomitinga
• Muscle cramps
• Musculoskeletal pain
• Diarrheaa
• Rash
• Fatiguea
• Abdominal pain
Larotrectinib
Most common adverse events (in ≥20%)
• Increased aspartate aminotransferase (AST)
• Increased alanine transaminase (ALT)

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• Anemia
• Musculoskeletal pain
• Fatiguea
• Hypoalbuminemia
• Neutropenia
• Increased alkaline phosphatase
• Cough
• Leukopenia
• Constipation
• Diarrhea
• Dizziness
• Hypocalcemia
• Nauseaa
• Vomitinga
• Pyrexia
• Lymphopenia
• Abdominal pain
Pexidartinib
Boxed warning
• Serious and potentially fatal liver injury
• Monitor liver tests prior to initiating and permanently
discontinue based on severity of hepatotoxicity
• Available only under a Risk Evaluation and Mitigation
Strategy (REMS) program
Most common adverse events (in ≥20%)
• increased lactate dehydrogenase
• Increased aspartate aminotransferase
• Hair color changes
• Fatigue
• Increased alanine aminotransferase
• Decreased neutrophils
• Increased cholesterol
• Increased alkaline phosphatase
• Decreased lymphocytes
• Eye edema
• Decreased hemoglobin
• Rash
• Dysgeusia

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• Decreased phosphate
Regorafenib
Boxed warning
• Severe and sometimes fatal liver toxicity
• Monitor hepatic function prior to and during treatment
• Interrupt, and then reduce or discontinue for
hepatotoxicity
Most common adverse events (in ≥20%)
• Pain (including gastrointestinal and abdominal)
• Hand-foot syndromea
• Asthenia/fatigue
• Diarrheaa
• Decreased appetite/food intake
• Hypertension
• Infection
• Dysphonia
• Hyperbilirubinemia
• Fever
• Mucositis
• Weight loss
• Rash
• Nauseaa
Ripretinib
Most common adverse events (in ≥20%)
• Alopecia
• Fatiguea
• Nauseaa
• Abdominal pain
• Constipation
• Myalgia
• Diarrheaa
• Decreased appetite
• Hand foot syndrome
• Vomitinga
Sunitinib
Boxed warning
• Severe and potentially fatal liver injury
• Monitor hepatic function and interrupt, dose reduce, or
discontinue as recommended
Most common adverse events (in ≥25%)
• Fatigue/astheniaa

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• Diarrheaa
• Mucositis/stomatitis
• Nauseaa
• Decreased appetite/anorexia
• Vomitinga
• Abdominal pain
• Hand-foot syndromea
• Hypertension
• Bleeding events,
• Dysgeusia/altered taste
• Dyspepsia
• Thrombocytopenia
a
For management information, see below
Rozlytrek® (Entrectinib) prescribing information (2023). Genentech, Inc. Available at: https://www.rozlytrek-hcp.com/
Gleevec® (imatinib) prescribing information (2022). Novartis. Available at: https://www.us.gleevec.com/
Vitrakvi® (Larotrectinib) prescribing information (2022). Bayer. Available at: https://www.vitrakvi-us.com/
Turalio® (pexidartinib) prescribing information (2022). Daiichi Sankyo, Inc. Available at: https://www.turaliohcp.com
Stivarga® (regorafenib) prescribing information (2020). Bayer. Available at: https://www.stivargahcp.com/
Qinlock® (ripretinib) prescribing information (2022). Deciphera Pharmaceuticals, LLC. Available at:
https://www.qinlockhcp.com/
Sutent® (sunitinib malate) prescribing information (2021). Pfizer Inc. Available at: https://labeling.pfizer.com/
Diarrhea
Dietary changes: bland diet
Loperamide
Diphenoxylate/atropine
GI consult for bacterial overgrowth, bile acid sequestrant
GI = gastrointestinal.
Bossi P, Antunuzzo A, Cherny NI, et al (2018). Diarrhoea in adult cancer patients: ESMO clinical practice guidelines.
Ann Oncol, 29(suppl_4):iv126-iv142. DOI:10.1093/annonc/mdy145
Edema/fluid retention
Low sodium diet
Elevate head on pillows at night for eye edema
Diuretic may be useful
Monitor blood pressure and daily weights
American Cancer Society (2021). Swelling, edema, and ascites. Available at:
https://www.cancer.org/cancer/managing-cancer/side-effects/swelling/edema-ascites.html
Fatigue
Labs to rule out anemia, hypothyroidism
Consider nighttime dosing if taking in the morning
Regulated sleep/wake cycle, sleep hygiene
Possibly methylphenidate
Dose modification

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National Cancer Institute (2023a). Fatigue (PDQ®)—health professional version. Available at:
https://www.cancer.gov/about-cancer/treatment/side-effects/fatigue/fatigue-hp-pdq#_7
Hand-foot syndrome (palmar plantar erythrodysesthesia [PPE])
Baseline skin assessment
Buff down calluses
Urea based creams
Epsom salt soaks
Steroid creams
Dermatology consult (retinoid-based creams)
Dose modify
Encourage to reach out with symptoms
Cancer.net (2019). Hand-foot syndrome or palmar-plantar erythrodysesthesia. Available at:
https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/managing-
physical-side-effects/hand-foot-syndrome-or-palmar-plantar-erythrodysesthesia
Said JT, Singer S, Iannattone L, et al (2022). Outcomes of acitretin treatment for refractory multikanse inhibitor-
induced hand-foot skin reaction. JAMA Dermatol, 158(7):824-826. DOI:10.1001/jamadermatol.2022.1425
Nausea/Vomiting
Antiemetics as needed or as premedication
Change time of day of daily dosing
With or without food criteria for dosing
Dose modify
National Cancer Institute (2023b). Nausea and vomiting related to cancer treatment (PDQ®)—health professional
version. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/nausea/nausea-hp-
pdq#_347

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X. REFERENCES
American Cancer Society (2021). Swelling, edema, and ascites. Available at:
https://www.cancer.org/cancer/managing-cancer/side-effects/swelling/edema-ascites.html
Bossi P, Antunuzzo A, Cherny NI, et al (2018). Diarrhoea in adult cancer patients: ESMO clinical practice
guidelines. Ann Oncol, 29(suppl_4)iv126-iv142. DOI:10.1093/annonc/mdy145
Cancer.net (2019). Hand-foot syndrome or palmar-plantar erythrodysesthesia. Available at:
https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-
cancer/managing-physical-side-effects/hand-foot-syndrome-or-palmar-plantar-
erythrodysesthesia
Gleevec® (imatinib) prescribing information (2022). Novartis. Available at: https://www.us.gleevec.com/
National Cancer Institute (2023a). Fatigue (PDQ®)—health professional version. Available at:
https://www.cancer.gov/about-cancer/treatment/side-effects/fatigue/fatigue-hp-pdq#_7
National Cancer Institute (2023b). Nausea and vomiting related to cancer treatment (PDQ®)—health
professional version. Available at: https://www.cancer.gov/about-cancer/treatment/side-
effects/nausea/nausea-hp-pdq#_347
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology: soft tissue
sarcoma. Version 2.2023. Available at:
https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
National Comprehensive Cancer Network (2023). Clinical Practice Guidelines in Oncology:
gastrointestinal stromal tumors. Version 1.2023. Available at:
https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf
Qinlock® (ripretinib) prescribing information (2022). Deciphera Pharmaceuticals, LLC. Available at:
https://www.qinlockhcp.com/
Rozlytrek® (Entrectinib) prescribing information (2023). Genentech, Inc. Available at:
https://www.rozlytrek-hcp.com/
Said JT, Singer S, Iannattone L, et al (2022). Outcomes of acitretin treatment for refractory multikanse
inhibitor-induced hand-foot skin reaction. JAMA Dermatol, 158(7):824-826.
DOI:10.1001/jamadermatol.2022.1425
Stivarga® (regorafenib) prescribing information (2020). Bayer. Available at:
https://www.stivargahcp.com/
Sutent® (sunitinib malate) prescribing information (2021). Pfizer Inc. Available at:
https://labeling.pfizer.com/
Turalio® (pexidartinib) prescribing information (2022). Daiichi Sankyo, Inc. Available at:
https://www.turaliohcp.com
Vitrakvi® (Larotrectinib) prescribing information (2022). Bayer. Available at: https://www.vitrakvi-us.com/