Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

extremity: stage I

1st line – excision

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ACUTE
|
extremity: stage I
1st line – 

excision

Stage I is: regional lymph nodes cannot be assessed or no regional lymph node metastasis; no distant metastasis; low grade.

Surgery is the mainstay of treatment; the general principle is disease control, usually involving wide local excision with clear margins, with preservation of limb function if possible.[10][11][40]​ 

Amputation is occasionally necessary, especially if total resection of the tumor would render a limb nonfunctional. A surgeon with expertise in treating soft-tissue sarcoma should be consulted before considering amputation.[11] 

extremity: stage II resectable

1st line – excision

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ACUTE
|
extremity: stage II resectable
1st line – 

excision

Stage II is defined as: regional lymph nodes cannot be assessed or no regional lymph node metastasis; no distant metastasis; high grade.

The general principle of surgery is disease control, usually involving wide local excision with clear margins, with preservation of limb function if possible.[10][11][40]

Amputation is occasionally necessary, especially if total resection of the tumor would render a limb nonfunctional. A surgeon with expertise in treating soft-tissue sarcoma should be consulted before considering amputation.[11]

Consider – adjuvant radiation therapy

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ACUTE
|
extremity: stage II resectable
Consider – 

adjuvant radiation therapy

Treatment recommended for SOME patients in selected patient group

For adjuvant radiation therapy, the total dose should be determined by normal tissue tolerance.[11]

The benefit of adjuvant radiation is the ability to review final surgical pathology including margin status and lower rate of wound healing complications (especially in the lower extremity). Potential disadvantages of adjuvant radiation include: larger field sizes, higher radiation doses, potential for increased risk of late toxicities (i.e., fibrosis, edema, joint stiffness).

Post radiation (neoadjuvant or adjuvant) and surgery, if margin status is uncertain, a consultation with a radiation oncologist is recommended. Further surgery may be necessary to render margins >1.0 cm.[11]

Patients with wide resection margins may be considered for observation alone if the risk of radiation therapy is unacceptable. Radiation therapy may be omitted for patients with tumors <5 cm, with a wide resection margin, if repeat resection would be possible with low morbidity in the event of a recurrence.[11]

1st line – neoadjuvant radiation therapy

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ACUTE
|
extremity: stage II resectable
1st line – 

neoadjuvant radiation therapy

Neoadjuvant dose external beam radiation therapy is recommended.[11] For patients with positive margins following neoadjuvant radiation therapy and surgery, observation or radiation therapy boost may be considered. There is no clear benefit of an adjuvant radiation therapy boost for these patients; therefore, the decision should be individualized and take into account potential toxicities.[11]

Potential benefits of neoadjuvant radiation include: lower total radiation dose, shorter treatment time, smaller field sizes, potential for reduced late toxicities (i.e., fibrosis, edema, joint stiffness), potential for tumor downstaging. One disadvantage is the increased frequency of early wound healing complications, particularly for lower extremity tumors.[11]

Plus – excision

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ACUTE
|
extremity: stage II resectable
Plus – 

excision

Treatment recommended for ALL patients in selected patient group

The general principle of surgery is disease control, usually involving wide local excision with clear margins, with preservation of limb function if possible.[10][11][40]

Amputation is occasionally necessary, especially if total resection of the tumor would render a limb nonfunctional. A surgeon with expertise in treating STS should be consulted before considering amputation.[11]

extremity: stage III or select stage IV (any T, N1, M0), resectable

1st line – neoadjuvant radiation therapy or chemoradiation

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ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), resectable
1st line – 

neoadjuvant radiation therapy or chemoradiation

Stage III is: deep primary tumor >5 cm in greatest dimension; regional lymph nodes cannot be assessed or no regional lymph node metastasis; no distant metastasis; high grade. Stage IV is: any primary tumor size and depth; regional lymph node metastasis and no distant metastasis, or any regional lymph node involvement and distant metastasis; any grade.

Neoadjuvant external beam radiation therapy is recommended.[11] For patients with positive margins following neoadjuvant radiation therapy and surgery, observation or radiation therapy boost may be considered. There is no clear benefit of an adjuvant radiation therapy boost for these patients; therefore, the decision should be individualised and take into account potential toxicities.[11] 

Potential benefits of neoadjuvant radiation include: lower total radiation dose, shorter treatment time, smaller field sizes, potential for reduced late toxicities (i.e., fibrosis, edema, joint stiffness), potential for tumor downstaging. One disadvantage is the increased frequency of early wound healing complications, particularly for lower extremity tumors.[11]

Preferred regimens for neoadjuvant systemic therapy are: doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

Plus – excision

Back
ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), resectable
Plus – 

excision

Treatment recommended for ALL patients in selected patient group

The general principle of surgery is disease control, usually involving wide local excision with clear margins, with preservation of limb function if possible.[10][11][40]

Amputation is occasionally necessary, especially if total resection of the tumor would render a limb nonfunctional. A surgeon with expertise in treating STS should be consulted before considering amputation.[11]

Consider – adjuvant systemic therapy

Back
ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), resectable
Consider – 

adjuvant systemic therapy

Treatment recommended for SOME patients in selected patient group

In adults, adjuvant chemotherapy remains controversial, but may be beneficial for the most advanced tumors.[62]​ One study of over 1500 patients found that adjuvant doxorubicin-based chemotherapy prolonged survival at 5 years in patients with grade 3 soft-tissue sarcoma, but there was no benefit in patients with grade 2 sarcoma.[63]

Preferred regimens for adjuvant systemic therapy are: doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

1st line – neoadjuvant systemic therapy

Back
ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), resectable
1st line – 

neoadjuvant systemic therapy

Preferred regimens for neoadjuvant systemic therapy are: doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

Plus – excision

Back
ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), resectable
Plus – 

excision

Treatment recommended for ALL patients in selected patient group

The general principle of surgery is disease control, usually involving wide local excision with clear margins, with preservation of limb function if possible.[10][11][40]

Amputation is occasionally necessary, especially if total resection of the tumor would render a limb nonfunctional. A surgeon with expertise in treating STS should be consulted before considering amputation.[11]

Plus – adjuvant radiation therapy or chemoradiation

Back
ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), resectable
Plus – 

adjuvant radiation therapy or chemoradiation

Treatment recommended for ALL patients in selected patient group

For adjuvant radiation therapy, the total dose should be determined by normal tissue tolerance.[11]

The benefit of adjuvant radiation is the ability to review final surgical pathology including margin status and lower rate of wound healing complications (especially in the lower extremity). Potential disadvantages of adjuvant radiation include: larger field sizes, higher radiation doses, potential for increased risk of late toxicities (i.e., fibrosis, edema, joint stiffness).

Post radiation (neoadjuvant or adjuvant) and surgery, if margin status is uncertain, a consultation with a radiation oncologist is recommended. Further surgery may be necessary to render margins >1.0 cm.[11]

Preferred regimens for adjuvant systemic therapy are: doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

1st line – excision

Back
ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), resectable
1st line – 

excision

The general principle of surgery is disease control, usually involving wide local excision with clear margins, with preservation of limb function if possible.[10][11][40]

Amputation is occasionally necessary, especially if total resection of the tumor would render a limb nonfunctional. A surgeon with expertise in treating STS should be consulted before considering amputation.[11]

Plus – adjuvant radiation therapy or chemoradiation

Back
ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), resectable
Plus – 

adjuvant radiation therapy or chemoradiation

Treatment recommended for ALL patients in selected patient group

For adjuvant radiation therapy, the total dose should be determined by normal tissue tolerance.[11]

The benefit of adjuvant radiation is the ability to review final surgical pathology including margin status and lower rate of wound healing complications (especially in the lower extremity). Potential disadvantages of adjuvant radiation include: larger field sizes, higher radiation doses, potential for increased risk of late toxicities (i.e., fibrosis, edema, joint stiffness).

Post radiation (neoadjuvant or adjuvant) and surgery, if margin status is uncertain, a consultation with a radiation oncologist is recommended. Further surgery may be necessary to render margins >1.0 cm.[11]

Preferred regimens for adjuvant systemic therapy are: doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

extremity: stage III or select stage IV (any T, N1, M0), unresectable

1st line – radiation therapy or chemoradiation or systemic therapy

Back
ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), unresectable
1st line – 

radiation therapy or chemoradiation or systemic therapy

Stage III is: deep primary tumor >5 cm in greatest dimension; regional lymph nodes cannot be assessed or no regional lymph node metastasis; no distant metastasis; high grade. Stage IV is: any primary tumor size and depth; regional lymph node metastasis and no distant metastasis, or any regional lymph node involvement and distant metastasis; any grade. This includes patients for whom resection is possible but would lead to unacceptable functional outcomes.

Definitive radiation therapy for unresectable disease is a reasonable option, although long term control with radiation therapy alone may not be as effective as with multimodal therapy. For these patients radiation therapy doses are based on individual patient factors, considering histology and anatomic location.[11]​ The initial dose volume should be 50Gy with a boost of at least 64Gy; however higher doses of 70-80 Gy can be considered based on the tolerance of normal structures. Alternatively, hypofractionated regimens may be considered.[11]

Preferred first-line regimens for systemic therapy are anthracycline-based and include: doxorubicin; epirubicin; liposomal doxorubicin; doxorubicin plus dacarbazine; doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

Larotrectinib, entrectinib, or repotrectinib may be used for NTRK gene fusion-positive sarcomas, regardless of soft-tissue sarcoma subtype.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

doxorubicin liposomal

OR

doxorubicin

and

dacarbazine

OR

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

OR

larotrectinib

OR

entrectinib

OR

repotrectinib

Consider – surgery

Back
ACUTE
|
extremity: stage III or select stage IV (any T, N1, M0), unresectable
Consider – 

surgery

Treatment recommended for SOME patients in selected patient group

Amputation should be considered to treat an extremity sarcoma based on patient preference, or if total resection of the tumor is expected to result in the limb being nonfunctional.[11] Prior to considering amputation, patients should be evaluated by a surgeon with expertise in the treatment of soft-tissue sarcomas.[11]

Palliative surgery has a definite role, especially where local control is important (and not achievable through radiation therapy).

extremity: stage IV, oligometastases with limited tumor bulk or regional nodes

1st line – radiation therapy or chemoradiation or systemic therapy or excision

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ACUTE
|
extremity: stage IV, oligometastases with limited tumor bulk or regional nodes
1st line – 

radiation therapy or chemoradiation or systemic therapy or excision

Stage IV is: any primary tumor size and depth; regional lymph node metastasis and no distant metastasis, or any regional lymph node involvement and distant metastasis; any grade.

Data to guide optimal management of these patients is lacking. Referral to an oncologist with experience in the treatment STS is recommended and clinical trial enrolment is encouraged.[11] Patient preference, performance status, availability of treatments, and metastasis location and symptoms all influence treatment strategy. 

Treatment for the primary tumor may include surgery, systemic therapy, radiation therapy, or chemoradiation.

Definitive surgical treatment of metastatic adult-onset STS remains an option, particularly with small-volume metastases to the lungs.

Definitive radiation therapy for unresectable disease is a reasonable option, although long term control with radiation therapy alone may not be as effective as with multimodal therapy. For these patients radiation therapy doses are based on individual patient factors, considering histology and anatomic location.[11] The initial dose volume should be 50Gy with a boost of at least 64Gy; however higher doses of 70-80 Gy can be considered based on the tolerance of normal structures. Alternatively, hypofractionated regimens may be considered.[11]

Preferred first-line regimens for systemic therapy are anthracycline-based and include: doxorubicin; epirubicin; liposomal doxorubicin; doxorubicin plus dacarbazine; doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

Larotrectinib, entrectinib, or repotrectinib may be used for NTRK gene fusion-positive sarcomas, regardless of soft-tissue sarcoma subtype.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

doxorubicin liposomal

OR

doxorubicin

and

dacarbazine

OR

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

OR

larotrectinib

OR

entrectinib

OR

repotrectinib

Plus – metastases management

Back
ACUTE
|
extremity: stage IV, oligometastases with limited tumor bulk or regional nodes
Plus – 

metastases management

Treatment recommended for ALL patients in selected patient group

Options are: metastasectomy with or without radiation therapy or systemic therapy; ablation procedures; embolization procedures (nonlung metastases); stereotactic body radiation therapy (SBRT); or observation.[11]

Metastasectomy is the standard for patients with primarily lung oligometastatic disease; however, the mode of local control 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.[11]

SBRT delivers ablative doses of radiation to tumors using specialized patient immobilization, treatment planning, and image guidance to ensure a high degree of precision and facilitate protection of adjacent normal tissue. It is commonly used to treat tumors involving the lungs, liver, bone, lymph nodes, and other anatomic sites.[11] SBRT can be considered for patients with: oligometastatic disease; with oligoprogressive disease with other sites of disease stable or controlled by systemic therapy; who require treatment to a tumor within a previously irradiated field.[11] Dose and fractionation should be determined by an experienced radiation oncologist based on normal tissue constraints.[11]

Tumor ablation involves the application of thermal or nonthermal therapies to a tumor to achieve cell death.[11] Thermal ablation achieves tissue destruction by the induction of extreme hypothermia (cryoablation) or hyperthermia (radiofrequency ablation, microwave ablation, laser ablation, and high-intensity focused ultrasound). Non-thermal ablation such as irreversible electroporation results in permanent cellular membrane injury. The type of ablation used should be based on tumor size, location, and adjacent critical structures to optimize treatment effect while limiting potential adverse events. Ablation can include the target lesion in addition to a margin of radiologically normal tissue to ensure complete local treatment. Ablative therapies may benefit patients: with unresectable metastases; with medical comorbidities prohibiting surgical resection; whose disease progresses despite conventional therapies; as maintenance therapy for patients who have achieved disease stability after chemotherapy; with painful musculoskeletal metastases, for pain palliation.[11] Local ablative treatment of liver metastases has been shown to improve overall survival in patients with oligometastatic disease. High rates of local control can be obtained with percutaneous thermal ablation for patients with lung metastases, percutaneous ablation is an effective option for local tumor control in the setting of oligometastatic disease and pain palliation of metastatic sarcomas within the musculoskeletal system.[11] Patients with uncorrectable coagulopathy, active infection in the planned treatment area, or if it is not possible to displace or protect adjacent critical structures, should not undergo image guided ablation.[11]

Patients with liver dominant metastatic disease, or with medical comorbidities prohibiting surgical resection can be considered for catheter-directed therapies, which include transarterial (bland) embolization, transarterial chemoembolization, and transarterial radioembolization. Patients whose disease progresses despite conventional therapies could also be considered for transarterial treatments.[11] These therapies have been shown to be safe treatments for progressive disease with high rates of local disease control and overall survival. Patients with uncorrectable coagulopathy, active infection in the planned treatment area or decompensated liver failure should not undergo embolization procedures.[11]

extremity: stage IV, disseminated metastases

1st line – individualized palliative therapy plus best supportive care

Back
ACUTE
|
extremity: stage IV, disseminated metastases
1st line – 

individualized palliative therapy plus best supportive care

Stage IV is defined as: any primary tumor size and depth; regional lymph node metastasis and no distant metastasis, or any regional lymph node involvement and distant metastasis; any grade.

Treatment options for patients with disseminated metastases include palliative systemic therapy, radiation therapy, surgery, observation (if asymptomatic), and best supportive care.[11]

Best supportive care should be part of any good noncurative approach, regardless of the use of anticancer treatments in this setting.

Best supportive care is a treatment plan for people with cancer when a cure is not possible, with the goal of improving quality of life by managing symptoms such as pain, sickness or problems with eating, and helping people come to terms with their diagnosis.

Preferred first-line regimens for systemic therapy are anthracycline-based and include: doxorubicin; epirubicin; liposomal doxorubicin; doxorubicin plus dacarbazine; doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

Larotrectinib, entrectinib, or repotrectinib may be used for NTRK gene fusion-positive sarcomas, regardless of soft-tissue sarcoma subtype.[11]

For patients who have failed or cannot tolerate anthracycline-based chemotherapy, pazopanib, trabectedin, or eribulin can be considered for selected subtypes of STS.[11]

Pazopanib targets multiple tyrosine kinases, most notably vascular endothelial growth factor 2 (VEGF2), and is Food and Drug Administration (FDA)-approved for metastatic nonadipocytic, nongastrointestinal stromal tumor (non-GIST) STS. In the phase 3 PALETTE (pazopanib explored in soft-tissue sarcoma) trial, patients previously treated with chemotherapy who received pazopanib experienced longer median progression-free survival (4.6 months) compared with those receiving placebo (1.6 months).[64] There was a trend toward improved overall survival with pazopanib, though this was not statistically significant. Common and severe toxicities were fatigue, elevated aminotransferases, diarrhea, and hypertension.

Trabectedin is approved for patients with unresectable (or metastatic) liposarcoma or leiomyosarcoma refractory to an anthracycline-containing chemotherapy regimen. In one randomized phase 3 study assessing the efficacy of trabectedin versus dacarbazine in intermediate- and high-grade leiomyosarcoma and liposarcoma, a statistically significant improvement in progression-free survival was noted among patients receiving trabectedin (4.2 vs. 1.5 months), with no overall survival improvement.[66] Severe adverse events were mostly limited to neutropenia and reversible elevation of liver function tests.

Eribulin is an option for patients with high-grade liposarcoma who have previously received an anthracycline-containing regimen. In one open-label randomized phase 3 trial, eribulin prolonged overall survival by approximately 2 months compared with dacarbazine in patients with leiomyosarcoma or liposarcoma (13.5 months vs. 11.5 months, P=0.017).[65]​ In subset analysis, the overall survival was significant only in the patients with liposarcoma.

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

doxorubicin liposomal

OR

doxorubicin

and

dacarbazine

OR

doxorubicin

and

ifosfamide

and

mesna

OR

ifosfamide

and

epirubicin

and

mesna

OR

larotrectinib

OR

entrectinib

OR

repotrectinib

Secondary options

pazopanib

OR

trabectedin

OR

eribulin

Plus – metastases management

Back
ACUTE
|
extremity: stage IV, disseminated metastases
Plus – 

metastases management

Treatment recommended for ALL patients in selected patient group

Options include ablation procedures and embolization procedures (nonlung metastases).[11]

Tumor ablation involves the application of thermal or nonthermal therapies to a tumor to achieve cell death.[11] Thermal ablation achieves tissue destruction by the induction of extreme hypothermia (cryoablation) or hyperthermia (radiofrequency ablation, microwave ablation, laser ablation, and high-intensity focused ultrasound). Non-thermal ablation such as irreversible electroporation results in permanent cellular membrane injury. The type of ablation used should be based on tumor size, location, and adjacent critical structures to optimize treatment effect while limiting potential adverse events. Ablation can include the target lesion in addition to a margin of radiologically normal tissue to ensure complete local treatment. Ablative therapies may benefit patients: with unresectable metastases; with medical comorbidities prohibiting surgical resection; whose disease progresses despite conventional therapies; as maintenance therapy for patients who have achieved disease stability after chemotherapy; with painful musculoskeletal metastases, for pain palliation.[11] Local ablative treatment of liver metastases has been shown to improve overall survival in patients with oligometastatic disease. High rates of local control can be obtained with percutaneous thermal ablation for patients with lung metastases, percutaneous ablation is an effective option for local tumor control in the setting of oligometastatic disease and pain palliation of metastatic sarcomas within the musculoskeletal system.[11] Patients with uncorrectable coagulopathy, active infection in the planned treatment area, or if it is not possible to displace or protect adjacent critical structures, should not undergo image guided ablation.[11]

Patients with liver dominant metastatic disease, or with medical comorbidities prohibiting surgical resection can be considered for catheter-directed therapies, which include transarterial (bland) embolization, transarterial chemoembolization, and transarterial radioembolization. Patients whose disease progresses despite conventional therapies could also be considered for transarterial treatments.[11] These therapies have been shown to be safe treatments for progressive disease with high rates of local disease control and overall survival. Patients with uncorrectable coagulopathy, active infection in the planned treatment area or decompensated liver failure should not undergo embolization procedures.[11]

extremity: recurrent

1st line – individualized therapy

Back
ACUTE
|
extremity: recurrent
1st line – 

individualized therapy

Local recurrence of extremity STS is treated according to stage and site, as in patients with primary tumor.[11]

Recurrence of metastatic isolated regional disease or nodes, should be treated with regional node dissection for nodal involvement with or without radiation therapy, with or without systemic treatment.[11]

Recurrence of metastatic single organ and limited tumor bulk that are amendable to local therapy, recommended treatment options include: metastasectomy with or without neoadjuvant or adjuvant systemic therapy; stereotactic body radiation therapy with or without systemic therapy; ablation procedures; embolization procedures; observation, if asymptomatic.[11]

Palliative options for the treatment of recurrent disseminated metastases include: systemic therapy; radiation therapy; surgery; observation, if asymptomatic; ablation procedures; embolization procedures (non-lung metastases); and best supportive care.[11]

retroperitoneal/intra-abdominal: resectable (primary or recurrent)

1st line – excision

Back
ACUTE
|
retroperitoneal/intra-abdominal: resectable (primary or recurrent)
1st line – 

excision

Surgery to obtain oncologically appropriate margins is critical to successful outcomes. The major determinant of long-term survival with adult-type soft-tissue sarcoma within the abdomen is achieving clear margins. It is important to note that the eventual lethality of intra-abdominal liposarcoma is extremely high, although this is not the case for extremity disease of the same histologic subtype. This is thought to be entirely due to the ability to achieve clear margins.

Consider – neoadjuvant radiation therapy

Back
ACUTE
|
retroperitoneal/intra-abdominal: resectable (primary or recurrent)
Consider – 

neoadjuvant radiation therapy

Treatment recommended for SOME patients in selected patient group

Neoadjuvant radiation therapy should be considered for patients with tumors which are considered to be high risk for local recurrence.[11]

If neoadjuvant radiation therapy is anticipated, intensity-modulated radiation therapy (IMRT) and other advanced image-guided radiation techniques are recommended.[11]

If neoadjuvant radiation therapy is deemed appropriate, the following dose guidelines are recommended: 50 to 50.4 Gy external beam radiation therapy (1.8 to 2.0 Gy per fraction). Consider an intraoperative radiation therapy boost for known or suspected positive margins at the time of surgery of 10 to 12.5 Gy for microscopically positive disease and 15 Gy for gross disease Experienced centers may use alternative regimens.[11]

Maximum tolerated dose of radiation therapy is generally lower for retroperitoneal tumors than extremity sarcoma due to dose limitations of adjacent organs (liver, kidney, gut).

Consider – neoadjuvant systemic therapy

Back
ACUTE
|
retroperitoneal/intra-abdominal: resectable (primary or recurrent)
Consider – 

neoadjuvant systemic therapy

Treatment recommended for SOME patients in selected patient group

Consider neoadjuvant systemic therapy for patients who are at high risk for metastatic disease or if downstaging is needed to facilitate resection.[11]

Preferred regimens for neoadjuvant systemic therapy include: doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

Consider – adjuvant chemotherapy

Back
ACUTE
|
retroperitoneal/intra-abdominal: resectable (primary or recurrent)
Consider – 

adjuvant chemotherapy

Treatment recommended for SOME patients in selected patient group

Postoperative treatment options depend on surgical outcomes and clinical or pathologic findings following surgery.[11]

The use of chemotherapy varies between regions and institutions, with scarce data supporting its use.[76][77]​​ The National Comprehensive Cancer Network suggests options by site and subtype of malignancy.[11]​ Adjuvant systemic therapy should only be considered if patients are high risk of metastatic disease.[11]

Preferred regimens for adjuvant systemic therapy include: doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

retroperitoneal/intra-abdominal: unresectable

1st line – systemic therapy or radiation therapy or chemoradiation

Back
ACUTE
|
retroperitoneal/intra-abdominal: unresectable
1st line – 

systemic therapy or radiation therapy or chemoradiation

Stage IV is defined as: any primary tumor size and depth; regional lymph node metastasis and no distant metastasis, or any regional lymph node involvement and distant metastasis; any grade.

Radiation therapy can be administered as a primary treatment for patients with unresectable disease, or administered with systemic therapy.[11] Total radiation therapy doses are always determined based on tissue tolerance.[11]

Preferred first-line regimens for systemic therapy are anthracycline-based and include: doxorubicin; epirubicin; liposomal doxorubicin; doxorubicin plus dacarbazine; doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

Larotrectinib, entrectinib, or repotrectinib may be used for NTRK gene fusion-positive sarcomas, regardless of soft-tissue sarcoma subtype.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

doxorubicin liposomal

OR

doxorubicin

and

dacarbazine

OR

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

OR

larotrectinib

OR

entrectinib

OR

repotrectinib

Consider – surgery

Back
ACUTE
|
retroperitoneal/intra-abdominal: unresectable
Consider – 

surgery

Treatment recommended for SOME patients in selected patient group

Systemic therapy or chemoradiation may render the tumor resectable. Surgery, including multivisceral resection, can be considered for palliation. As with all sarcoma surgery, management in a center with experienced surgeons is critical for optimal outcomes. Palliative surgery for advanced intra-abdominal STS is most useful with slow-growing tumors limited to one area of the abdomen.

If the tumor remains unresectable post treatment, options include alternative systemic therapy, palliative radiation therapy, palliative surgery, or best supportive care.[11]

retroperitoneal/intra-abdominal: metastatic disease, single organ and limited tumor bulk amenable to local therapy

1st line – individualized local therapy

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ACUTE
|
retroperitoneal/intra-abdominal: metastatic disease, single organ and limited tumor bulk amenable to local therapy
1st line – 

individualized local therapy

Choice of local control modality is individualized and should take into account performance status, lesion location and accessibility, patient preference, ability to preserve normal tissue function, and anticipated side effects of treatment.[11]

Treatment options for patients with stage IV retroperitoneal/abdominal single organ and limited tumor bulk amendable to local therapy include: metastasectomy with or without neoadjuvant or adjuvant systemic therapy with or without radiation therapy; stereotactic radiation therapy with or without systemic therapy; ablation procedures; embolization procedures (nonlung metastases), and observation.[11]

Patients with lymph node involvement (including isolated regional nodal metastatic disease) should undergo regional lymph node dissection with or without RT.[11]

Tumor ablation involves the application of thermal or nonthermal therapies to a tumor to achieve cell death.[11] Thermal ablation achieves tissue destruction by the induction of extreme hypothermia (cryoablation) or hyperthermia (radiofrequency ablation, microwave ablation, laser ablation, and high-intensity focused ultrasound). Non-thermal ablation such as irreversible electroporation results in permanent cellular membrane injury. The type of ablation used should be based on tumor size, location, and adjacent critical structures to optimize treatment effect while limiting potential adverse events. Ablation can include the target lesion in addition to a margin of radiologically normal tissue to ensure complete local treatment. Ablative therapies may benefit patients: with unresectable metastases; with medical comorbidities prohibiting surgical resection; whose disease progresses despite conventional therapies; as maintenance therapy for patients who have achieved disease stability after chemotherapy; with painful musculoskeletal metastases, for pain palliation.[11] Local ablative treatment of liver metastases has been shown to improve overall survival in patients with oligometastatic disease. High rates of local control can be obtained with percutaneous thermal ablation for patients with lung metastases, percutaneous ablation is an effective option for local tumor control in the setting of oligometastatic disease and pain palliation of metastatic sarcomas within the musculoskeletal system.[13]Patients with uncorrectable coagulopathy, active infection in the planned treatment area, or if it is not possible to displace or protect adjacent critical structures, should not undergo image guided ablation.[11]

Patients with liver dominant metastatic disease, or with medical comorbidities prohibiting surgical resection can be considered for catheter-directed therapies, which include transarterial (bland) embolization, transarterial chemoembolization, and transarterial radioembolization. Patients whose disease progresses despite conventional therapies could also be considered for transarterial treatments.[11] These therapies have been shown to be safe treatments for progressive disease with high rates of local disease control and overall survival.Patients with uncorrectable coagulopathy, active infection in the planned treatment area or decompensated liver failure should not undergo embolization procedures.[11]

Preferred first-line regimens for neoadjuvant or adjuvant systemic therapy are anthracycline-based and include: doxorubicin; epirubicin; liposomal doxorubicin; doxorubicin plus dacarbazine; doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

Larotrectinib, entrectinib, or repotrectinib may be used for NTRK gene fusion-positive sarcomas, regardless of soft-tissue sarcoma subtype.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

doxorubicin liposomal

OR

doxorubicin

and

dacarbazine

OR

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

OR

larotrectinib

OR

entrectinib

OR

repotrectinib

retroperitoneal/intra-abdominal: disseminated metastases

1st line – individualized palliative therapy plus best supportive care

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retroperitoneal/intra-abdominal: disseminated metastases
1st line – 

individualized palliative therapy plus best supportive care

Palliative options include: systemic therapy; radiation therapy/stereotactic radiation therapy; surgery, ablation procedures, embolization procedures (non-lung metastases), observation (if asymptomatic), and best supportive care.[11]

Tumor ablation involves the application of thermal or nonthermal therapies to a tumor to achieve cell death.[11] Thermal ablation achieves tissue destruction by the induction of extreme hypothermia (cryoablation) or hyperthermia (radiofrequency ablation, microwave ablation, laser ablation, and high-intensity focused ultrasound). Non-thermal ablation such as irreversible electroporation results in permanent cellular membrane injury. The type of ablation used should be based on tumor size, location, and adjacent critical structures to optimize treatment effect while limiting potential adverse events. Ablation can include the target lesion in addition to a margin of radiologically normal tissue to ensure complete local treatment.

Ablative therapies may benefit patients: with unresectable metastases; with medical comorbidities prohibiting surgical resection; whose disease progresses despite conventional therapies; as maintenance therapy for patients who have achieved disease stability after chemotherapy; with painful musculoskeletal metastases, for pain palliation.[11] Local ablative treatment of liver metastases has been shown to improve overall survival in patients with oligometastatic disease. High rates of local control can be obtained with percutaneous thermal ablation for patients with lung metastases, percutaneous ablation is an effective option for local tumor control in the setting of oligometastatic disease and pain palliation of metastatic sarcomas within the musculoskeletal system.[11] Patients with uncorrectable coagulopathy, active infection in the planned treatment area, or if it is not possible to displace or protect adjacent critical structures, should not undergo image-guided ablation.[11]

Patients with liver dominant metastatic disease, or with medical comorbidities prohibiting surgical resection can be considered for catheter-directed therapies, which include transarterial (bland) embolization, transarterial chemoembolization, and transarterial radioembolization. Patients whose disease progresses despite conventional therapies could also be considered for transarterial treatments.[11] These therapies have been shown to be safe treatments for progressive disease with high rates of local disease control and overall survival.Patients with uncorrectable coagulopathy, active infection in the planned treatment area or decompensated liver failure should not undergo embolization procedures.[11]

Best supportive care should be part of any good noncurative approach, regardless of the use of anticancer treatments in this setting.

Best supportive care is a treatment plan for people with cancer when a cure is not possible, with the goal of improving quality of life by managing symptoms such as pain, sickness or problems with eating, and helping people come to terms with their diagnosis.

Preferred first-line regimens for systemic therapy are anthracycline-based and include: doxorubicin; epirubicin; liposomal doxorubicin; doxorubicin plus dacarbazine; doxorubicin plus ifosfamide plus mesna; or ifosfamide plus epirubicin plus mesna.[11]

Larotrectinib, entrectinib, or repotrectinib may be used for NTRK gene fusion-positive sarcomas, regardless of soft-tissue sarcoma subtype.[11]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

doxorubicin liposomal

OR

doxorubicin

and

dacarbazine

OR

doxorubicin

and

ifosfamide

and

mesna

OR

epirubicin

and

ifosfamide

and

mesna

OR

larotrectinib

OR

entrectinib

OR

repotrectinib

gastrointestinal stromal tumors: resectable with minimal morbidity

1st line – excision

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gastrointestinal stromal tumors: resectable with minimal morbidity
1st line – 

excision

Surgery is the mainstay of treatment.[41][44][54]​​ Management begins with surgical resection if there is a minimal risk of morbidity.​​ Gastrointestinal stromal tumors are fragile and require handling with care. A minimally invasive approach may be considered for certain GIST if the anatomic location allows, performed by surgeons experienced in minimally invasive techniques.

Consider – targeted systemic therapy

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gastrointestinal stromal tumors: resectable with minimal morbidity
Consider – 

targeted systemic therapy

Treatment recommended for SOME patients in selected patient group

For patients with complete resected tumors (R0/R1), observation is recommended for those with low-risk disease or non-imatinib sensitive tumors.[41]

Adjuvant imatinib is recommended for patients with significant risk of recurrence. Patients are considered to be intermediate or high risk if they have imatinib-sensitive tumors; however, the optimal duration of adjuvant imatinib is unknown.[41]

Data support the use of adjuvant imatinib in patients with a KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutation (except PDGFRA exon 18 mutations insensitive to imatinib) and thought to be at intermediate or high risk of recurrence. Assessment of risk is based on factors such as tumor size and mitotic rate/high power field (HPF). For gastric GIST, high risk is defined as tumor size >5 cm with >5 mitoses per 50 high-power fields.[41][68]​​​

Imatinib should be given for at least 3 years postoperatively, as this has been shown to prolong survival compared with 1 year of adjuvant imatinib. Caution is needed in patients with heart failure or short life expectancy, as imatinib has adverse effects of diarrhea, fatigue, anemia, and edema.[68][69][70]

See local specialist protocol for dosing guidelines.

Primary options

imatinib

gastrointestinal stromal tumors: resectable with significant morbidity

1st line – neoadjuvant targeted systemic therapy

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gastrointestinal stromal tumors: resectable with significant morbidity
1st line – 

neoadjuvant targeted systemic therapy

Testing tumors for mutation is recommended prior to starting neoadjuvant therapy to ensure the tumor has a genotype that is likely to benefit from treatment.[41]

Patients with gastrointestinal stromal tumors (GIST) that are operable but resection is likely to cause significant morbidity (e.g., locally advanced GIST that would require multivisceral resection or patients with comorbidities who are not fit for surgery) should be managed with neoadjuvant tyrosine kinase inhibitor (TKI) therapy, with the intention of decreasing tumor size before surgery.[41][71][72]​ Resection offers the greatest chances of successful treatment.

Neoadjuvant therapy should be considered only if surgical morbidity could be reduced by downsizing the tumor preoperatively. Six months of neoadjuvant treatment may be needed to achieve maximal response. Decisions about the appropriateness and timing of resection should be made by the oncologist and surgeon after optimal response or sustained stable disease.[41]

Imatinib is recommended as first-line neoadjuvant therapy for GIST with KIT or PDGFRA mutations (except PDGFRA exon 18 mutations insensitive to imatinib), or with unknown mutational status pending mutational analysis.[41] 

Avapritinib is recommended as neoadjuvant therapy for GIST with PDGFRA exon 18 mutations that are insensitive to imatinib (including PDGFRA D842V).[41]

For succinate dehydrogenase (SDH)-deficient GIST, options include sunitinib neoadjuvant therapy, observation or a clinical trial. Larotrectinib, entrectinib, or repotrectinib are recommended for NTRK gene fusion-positive GIST. Dabrafenib plus trametinib are recommended for BRAF V600E mutated GIST.[41][78][79]

Imatinib therapy may be continued after complete resection for patients with imatinib-sensitive GIST and intermediate or high risk of recurrence. Data support the use of adjuvant imatinib for at least 3 years.[69]​ For patients treated with neoadjuvant avapritinib, larotrectinib, entrectinib, sunitinib, or dabrafenib plus trametinib, observation is recommended after complete resection.[41]

If resection is not possible, targeted systemic therapy should be continued until the tumor progresses or there are intolerable adverse effects.[41]

Primary options

imatinib

OR

avapritinib

OR

sunitinib

OR

larotrectinib

OR

entrectinib

OR

repotrectinib

OR

dabrafenib

and

trametinib

Consider – excision

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gastrointestinal stromal tumors: resectable with significant morbidity
Consider – 

excision

Treatment recommended for SOME patients in selected patient group

Surgery is the mainstay of treatment.[41][44][54]​​​ The aim of neoadjuvant targeted systemic therapy is to render the tumor operable. Gastrointestinal stromal tumors are fragile and require handling with care.

gastrointestinal stromal tumors: unresectable

1st line – targeted systemic therapy

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gastrointestinal stromal tumors: unresectable
1st line – 

targeted systemic therapy

Imatinib is the preferred first-line treatment for unresectable gastrointestinal stromal tumors (GIST) with KIT or PDGFRA mutations (except PDGFRA exon 18 mutations insensitive to imatinib). Tumors with a KIT exon 9 mutation treated with imatinib have a lower response rate and progression-free survival than tumors with KIT exon 11 mutations.[73] However, high-dose imatinib was found to improve outcomes and should be considered in patients with a KIT exon 9 mutation.[41]

Avapritinib is recommended for GIST with PDGFRA exon 18 mutations that are insensitive to imatinib (including PDGFRA D842V). Larotrectinib, entrectinib, and repotrectinib are preferred for NTRK gene-fusion positive GIST. Options for SDH-deficient GIST are sunitinib, regorafenib, pazopanib, or imatinib plus binimetinib. GIST with BRAF V600E mutation is treated with dabrafenib plus trametinib.[41]

If GIST responds to systemic treatment, resection may be reconsidered. If resection is not possible and disease remains stable, treatment should be continued until the tumor progresses or intolerable adverse effects occur. Lifelong systemic therapy is recommended for metastatic disease.[41]

See local specialist protocol for dosing guidelines.

Primary options

imatinib

OR

avapritinib

OR

larotrectinib

OR

entrectinib

OR

repotrectinib

OR

sunitinib

OR

regorafenib

OR

pazopanib

OR

imatinib

and

binimetinib

OR

dabrafenib

and

trametinib

Consider – excision

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gastrointestinal stromal tumors: unresectable
Consider – 

excision

Treatment recommended for SOME patients in selected patient group

If GIST responds to systemic treatment, resection may be reconsidered. Surgery is the mainstay of treatment.[41][44][54]​ Gastrointestinal stromal tumors are fragile and require handling with care.

If resection is not possible and disease remains stable, treatment should be continued until the tumor progresses or intolerable adverse effects occur.[41]

gastrointestinal stromal tumors: progressive

1st line – continue targeted systemic therapy

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gastrointestinal stromal tumors: progressive
1st line – 

continue targeted systemic therapy

If progression occurs but is limited in patients on imatinib or avrapritinib, tyrosine kinase inhibitor (TKI) treatment may be continued and resection reconsidered (if feasible). If resection is not possible, switching to sunitinib or use of high-dose imatinib may be considered if previously treated with standard-dose imatinib. Other options if resection is not feasible may include ablation procedures, embolization or chemoembolization, and palliative radiation therapy.

If progression is widespread and systemic, an alternative TKI or a higher dose of imatinib (if previously treated with standard-dose imatinib) may be considered alongside best supportive care. The National Comprehensive Cancer Network suggests further TKI options for progressive disease, although data is limited.[41][80]

Further treatment options for patients with local or generalized disease progression include a clinical trial, a repeat biopsy to potentially identify uncommon mutations that may have corresponding targeted therapy, or best supportive care.[41] Reintroduction of imatinib can be considered for palliation of symptoms, and should be considered as part of best supportive care.[41]

Primary options

imatinib

OR

sunitinib

Consider – excision or ablation or chemoembolization or palliative radiation therapy

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gastrointestinal stromal tumors: progressive
Consider – 

excision or ablation or chemoembolization or palliative radiation therapy

Treatment recommended for SOME patients in selected patient group

Feasibility of resection should be reconsidered for patients with limited progression on imatinib or avrapritinib.[41]

Other options if resection is not feasible may include ablation procedures, embolization or chemoembolization, and palliative radiation therapy, for patients with progression on imatinib or avrapritinib.[41]

For patients on other treatments, consult a specialist for guidance on treatment of progressive disease.

Ablation modality is based on tumor size, location, and adjacent critical structures to optimize treatment effect while limiting potential adverse events. Ablation can include the target lesion in addition to a margin of radiologically normal tissue to ensure complete local treatment. Adjunct passive and active thermoprotective techniques, such as hydrodissection, may be used to protect adjacent critical structures during percutaneous ablation.

For patients with limited progressive GIST who have been previously treated with a TKI thermal ablation is feasible and safe.[41] Intraoperative ablation may be complementary to surgical resection to obtain complete response in patients with metastatic disease that may have otherwise been inoperable.[41] Absolute contraindications to image-guided ablation include: uncorrectable coagulopathy; active infection in the planned treatment area; inability to displace or protect adjacent critical structures (relative based on risk-benefit discussion).[41]

Specific intra-arterial therapies include transarterial (bland) embolization (TAE) and transarterial chemoembolization (TACE).[41]

TAE involves the delivery of embolic agents within hepatic arteries supplying liver tumors with the goal of stasis, and may considered for treatment of liver metastases refractory to imatinib or imatinib with sunitinib.[41]

TACE consists of conventional TACE which involves targeted infusion of chemotherapeutic agents in addition to embolic agents and lipiodol into tumoral blood supply, and can be an effective and well tolerated treatment in patients with GIST with liver metastases not responsive to TKIs.[41]

Absolute contraindications to embolization or chemoembolization include: uncorrectable coagulopathy; active infection in the planned treatment area; and decompensated liver failure.[41]

gastrointestinal stromal tumors: recurrent or metastatic

1st line – targeted systemic therapy

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gastrointestinal stromal tumors: recurrent or metastatic
1st line – 

targeted systemic therapy

Lifelong targeted systemic therapy is recommended for patients with recurrent or metastatic tyrosine kinase inhibitor (TKI)-sensitive GIST until progression occurs at which point patients should be treated depending on whether the progression in limited on generalized.[41] Observation may be considered for tumors with SDH deficiency or NF1 mutations that lack mutations in KIT/PDGFRA as most, but not all, have more indolent behavior.[41] Gross residual disease (R2 resection) and tumor rupture should be treated as metastatic disease.[41]

Imatinib is the preferred first-line treatment for metastatic gastrointestinal stromal tumors (GIST) with KIT or PDGFRA mutations (except PDGFRA exon 18 mutations insensitive to imatinib). Tumors with a KIT exon 9 mutation treated with imatinib have a lower response rate and progression-free survival than tumors with KIT exon 11 mutations.[73]​ However, high-dose imatinib was found to improve outcomes and should be considered in patients with a KIT exon 9 mutation.[41]

Avapritinib is recommended for GIST with PDGFRA exon 18 mutations that are insensitive to imatinib (including PDGFRA D842V). Larotrectinib, entrectinib, and repotrectinib are preferred for NTRK gene-fusion positive GIST. Options for SDH-deficient GIST are sunitinib, regorafenib, pazopanib, or imatinib plus binimetinib. GIST with BRAF V600E mutation is treated with dabrafenib plus trametinib.[41]

Primary options

imatinib

OR

avapritinib

OR

larotrectinib

OR

entrectinib

OR

repotrectinib

OR

sunitinib

OR

regorafenib

OR

pazopanib

OR

imatinib

and

binimetinib

OR

dabrafenib

and

trametinib

Consider – surgery

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gastrointestinal stromal tumors: recurrent or metastatic
Consider – 

surgery

Treatment recommended for SOME patients in selected patient group

Surgery (peritoneal cytoreduction and/or liver metastasectomy) may be indicated in the following order: stage IV disease after a favorable response to systemic therapy when complete cytoreduction of peritoneal and/or hepatic disease can be accomplished by an experienced surgeon; unifocal progression of disease that is refractory to TKI therapy when other sites of disease are having a favorable response to therapy; low-volume multifocal progressive disease that is safely resectable; management of symptomatic bleeding, obstruction, or perforation.[41]

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