Approach
All patients should be referred to an expert centre for management. Considerations in treatment depend on the histological diagnosis of the sarcoma and the staging.[10][11] Treatment planning requires multi-disciplinary input from surgeons, radiation oncologists, and medical oncologists.
For most types, surgery is the mainstay of treatment. Participation in a clinical trial is recommended, and specialist institutions should be consulted for availability of suitable trials.
Treatment is approached according to the site of the soft-tissue sarcoma (STS): extremity (on a limb), intra-abdominal/retroperitoneal, or gastrointestinal.
The use of chemotherapy and targeted agents varies between regions and institutions. Small trials and corresponding meta-analyses provide some data, but larger studies are required to reliably determine treatment effects.[53][54][55][56]
Extremity: stage I STS
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 tumour would render a limb non-functional. A surgeon with expertise in treating STS should be consulted before considering amputation.[11]
Extremity: stage II STS, resectable
Two potential routes of treatment are recommended for patients with stage II resectable STS: neoadjuvant radiotherapy, followed by wide local excision; or wide local excision, followed by adjuvant radiotherapy or observation.[11]
Neoajuvant radiotherapy followed by wide local excision
Neoadjuvant external beam radiotherapy (EBRT) is recommended.[11] For patients with positive margins following neoadjuvant radiotherapy and surgery, observation or radiotherapy boost may be considered. There is no clear benefit of an adjuvant radiotherapy boost for these patients, therefore the decision should be individualised and take into account potential toxicities.[11]
Potential benefits of neoadjuvant radiation:
Lower total radiation dose
Shorter treatment time
Smaller field sizes
Potential for reduced late toxicities (i.e., fibrosis, oedema, joint stiffness)
Potential for tumour downstaging
Potential disadvantages for neoadjuvant radiation:
Increased frequency of early wound healing complications, particularly for lower extremity tumours
Wide local excision followed by adjuvant radiotherapy or observation
For adjuvant radiotherapy, the total dose should be determined by normal tissue tolerance.[11]
Potential benefits of adjuvant radiation:
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:
Larger field sizes, higher radiation doses
Potential for increased risk of late toxicities (i.e., fibrosis, oedema, joint stiffness)
Patients with wide resection margins may be considered for observation alone if the risk of radiotherapy is unacceptable. Radiotherapy may be omitted for patients with tumours <5 cm, with a wide resection margin, if repeat resection would be possible with low morbidity in the event of a recurrence.[11]
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]
Extremity: stage III or select stage IV (any T, NI, M0) STS, resectable
Potential treatments for stage III or select stage IV (any T, NI, M0) STS include neoadjuvant radiotherapy and/or neoadjuvant systemic therapy, surgery to obtain oncologically appropriate margins, and/or adjuvant radiotherapy with or without adjuvant systemic therapy.[11]
This section includes recommended treatments for the primary tumour, for sarcoma with regional nodal metastatic disease please see the sections on metastatic disease below.
There are four recommended treatment pathways:[11]
Neoadjuvant RT, followed by surgery, consider adjuvant systemic therapy
Neoadjuvant systemic therapy plus neoadjuvant radiotherapy, followed by surgery, consider adjuvant systemic therapy
Neoadjuvant systemic therapy, followed by surgery, followed by radiotherapy OR radiotherapy plus adjuvant systemic therapy
Surgery, followed by adjuvant radiotherapy or adjuvant radiotherapy plus adjuvant systemic therapy
For information on neoadjuvant or adjuvant radiotherapy, please see the section on extremity stage II STS, resectable.
Neoadjuvant or adjuvant systemic therapy
Preferred regimens for neoadjuvant or adjuvant systemic therapy include:[11]
Doxorubicin plus ifosfamide plus mesna
Ifosfamide plus epirubicin plus mesna
In adults, adjuvant chemotherapy remains controversial, but may be beneficial for the most advanced tumours.[57] One study of over 1500 patients found that adjuvant doxorubicin-based chemotherapy prolonged survival at 5 years in patients with grade 3 STS, but there was no benefit in patients with grade 2 sarcoma.[58]
Previous unplanned excision or failure to obtain negative margins
If patients present with previous unplanned excision of an extremity, imaging to stage the primary tumour site will help determine the optimal treatment for local control.[11]
If margins are unexpectedly positive on final pathology (or following an unplanned excision) of soft tissue, then surgical re-resection to obtain negative margins should be considered if possible with minimal adverse impact on functionality.[11]
For close positive soft tissue margin which cannot be re-resected adjuvant radiotherapy should be considered, for close positive margins on critical structures (bone, nerve, or major blood vessels) adjuvant radiotherapy can only be considered if neoadjuvant radiotherapy has not been given.[11]
Extremity: stage II-III STS or select stage IV (any T, NI, M0) STS, unresectable
Recommended treatments for patients with primary stage II-III STS or select stage IV STS which is unresectable include definitive radiotherapy, chemoradiation, systemic therapy, or amputation/radical resection.[11] This includes patients for whom resection is possible but would lead to unacceptable functional outcomes.
Definitive radiotherapy
Definitive radiotherapy for unresectable disease is a reasonable option, although long term control with radiotherapy alone may not be as effective as with multimodal therapy. For these patients radiotherapy doses are based on individual patient factors, considering histology and anatomical location.[11]
Systemic therapy
Systemic therapy should be considered in selected patients where the risk-benefit ratio is favourable. The doses and types of chemotherapy will depend on the aims of treatment.
Preferred first-line regimens for advanced STS include the following.
Anthracycline-based regimens:
Doxorubicin
Epirubicin
Liposomal doxorubicin
Doxorubicin plus ifosfamide plus mesna
Ifosfamide plus epirubicin plus mesna
NTRK gene fusion-positive sarcomas only (regardless of soft-tissue sarcoma subtype):
Larotrectinib
Entrectinib
Repotrectinib
Amputation or palliative surgery
Amputation was once considered the standard treatment to achieve local control in patients with extremity sarcomas; however, radical excision/entire anatomic compartment resection is not routinely necessary.[11]
Amputation should be considered to treat an extremity sarcoma based on patient preference, or if total resection of the tumour is expected to result in the limb being non-functional.[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 radiotherapy).
Best supportive care
Best supportive care should be part of any good non-curative approach, regardless of the use of anti-cancer 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.
Extremity: stage IV STS, oligometastases with limited tumour bulk or regional nodes
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 tumour may include surgery, systemic therapy, radiotherapy, or chemoradiation. Definitive surgical treatment of metastatic adult-onset STS remains an option, particularly with small-volume metastases to the lungs. For further information on radiotherapy or first-line systemic therapy options for advanced or metastatic STS, see the section: stage II, III or select stage IV unresectable disease.
Options for metastasis management include metastasectomy with or without radiotherapy or systemic therapy, radiotherapy/stereotactic body radiotherapy (SBRT), ablation procedures, embolisation procedures, or observation.[11]
Patients with lymph node involvement (including isolated regional nodal metastatic disease) should undergo regional lymph node dissection with or without radiotherapy.[11]
Metastasectomy
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]
Stereotactic body radiotherapy (SBRT)
SBRT delivers ablative doses of radiation to tumours using specialised patient immobilisation, 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 tumours involving the lungs, liver, bone, lymph nodes, and other anatomical sites.[11]
SBRT can be considered for patients with:[11]
Oligometastatic disease
Oligoprogressive disease with other sites of disease stable or controlled by systemic therapy
Who require treatment to a tumour within a previously irradiated field
Dose and fractionation should be determined by an experienced radiation oncologist based on normal tissue constraints.[11]
Ablation procedures
Tumour ablation involves the application of thermal or non-thermal therapies to a tumour 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 tumour size, location, and adjacent critical structures to optimise 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:[11]
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
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 tumour 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]
Embolisation procedures (non-lung metastases)
Patients with liver dominant metastatic disease, or with medical comorbidities prohibiting surgical resection can be considered for catheter-directed therapies, which include transarterial (bland) embolisation, transarterial chemoembolisation, and transarterial radioembolisation. 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 embolisation procedures.[11]
Extremity: stage IV STS, disseminated metastases
Treatment options for patients with disseminated metastases include palliative systemic therapy, radiotherapy, surgery, observation if asymptomatic, ablation procedures, or embolisation procedures for non-lung metastases.[11] For more information on ablation or embolisation procedures, please see section Extremity: stage IV STS, oligometastases with limited tumour bulk or regional nodes
Systemic treatment
Preferred first-line regimens include the following.[11]
Anthracycline-based regimens:
Doxorubicin
Epirubicin
Liposomal doxorubicin
Doxorubicin plus ifosfamide plus mesna
Ifosfamide plus epirubicin plus mesna
NTRK gene fusion-positive sarcomas only (regardless of soft-tissue sarcoma subtype):
Larotrectinib
Entrectinib
Repotrectinib
Subsequent lines of palliative therapy for metastatic disease include:
Pazopanib
Eribulin
Trabectedin
NTRK gene fusion-positive sarcomas only (regardless of soft-tissue sarcoma subtype)
Repotrectinib (if not previously given)
Pazopanib:
Targets multiple tyrosine kinases and is recommended for metastatic non-adipocytic, non-gastrointestinal stromal tumours (non-GIST) STS. In the phase 3 PALETTE (pazopanib explored in STS) 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).[59] There was a trend towards improved overall survival with pazopanib, though this was not statistically significant. Common and severe toxicities were fatigue, elevated aminotransferases, diarrhoea, and hypertension.
Eribulin:
An option for patients with high-grade liposarcoma who have previously received an anthracycline-containing regimen. In one open-label randomised 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).[60] In subset analysis, the overall survival was significant only in the patients with liposarcoma.
Trabectedin:
Recommended for patients with unresectable (or metastatic) liposarcoma or leiomyosarcoma refractory to an anthracycline-containing chemotherapy regimen. In one randomised 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.[61] Severe adverse events were mostly limited to neutropenia and reversible elevation of liver function tests.
Extremity: recurrent disease
Local recurrence of extremity STS is treated according to stage and site, as in patients with primary tumour.[11]
Recurrence of metastatic isolated regional disease or nodes, should be treated with regional node dissection for nodal involvement with or without radiotherapy, with or without systemic treatment.[11]
Recurrence of metastatic single organ and limited tumour bulk that are amendable to local therapy, recommended treatment options include:[11]
Metastasectomy with or without neoadjuvant or adjuvant systemic therapy
SBRT with or without systemic therapy
Ablation procedures
Embolisation procedures
Observation, if asymptomatic
Palliative options for the treatment of recurrent disseminated metastases include:[11]
Systemic therapy
Radiotherapy/SBRT
Surgery
Observation, if asymptomatic
Best supportive care
Ablation procedures
Embolisation procedures (non-lung metastases)
Retroperitoneal/abdominal STS: resectable (primary or recurrent)
Surgery to obtain oncologically appropriate margins is critical to successful outcomes, and is recommended as first-line treatment for patients with retroperitoneal/intra abdominal STS.[11] The major determinant of long-term survival with adult-type STS within the abdomen (typically liposarcoma and gastrointestinal stromal tumours) is achieving clear margins.[10] 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 histological subtype. This is thought to be entirely due to the ability to achieve clear margins.
Neoadjuvant radiotherapy should be considered for patients with tumours which are considered to be high risk for local recurrence.[11]
Consider neoadjuvant systemic therapy for patients who are at high risk for metastatic disease or if downstaging is needed to facilitate resection.[11]
Patients treated with neoadjuvant therapy should then undergo surgery to obtain oncologically appropriate margins, with or without intraoperative radiotherapy.[11]
Neoadjuvant radiotherapy for retroperitoneal/abdominal STS - resectable
If neoadjuvant radiotherapy is anticipated, intensity-modulated radiotherapy (IMRT) and other advanced image-guided radiation techniques are recommended.[11]
Data suggest that preoperative radiation improves local control, though overall survival is unchanged.[62] Maximum tolerated dose of radiotherapy is generally lower for retroperitoneal tumours than extremity sarcomas due to dose limitations of adjacent organs (liver, kidney, gut).
Neoadjuvant systemic therapy for retroperitoneal/abdominal STS - resectable
Preferred regimens for neoadjuvant systemic therapy include:[11]
Doxorubicin plus ifosfamide plus mesna
Ifosfamide plus epirubicin plus mesna
Adjuvant treatment for retroperitoneal/abdominal STS - resectable
Adjuvant treatment options depend on surgical outcomes and clinical or pathological findings following surgery. Adjuvant radiotherapy should not be administered routinely, and adjuvant systemic therapy should only be considered if patients are high risk of metastatic disease.[11] Preferred regimens for adjuvant systemic therapy include:[11]
Doxorubicin plus ifosfamide plus mesna
Ifosfamide plus epirubicin plus mesna
Retroperitoneal/abdominal STS: unresectable (primary or recurrent)
Patients with primary or recurrent unresectable disease can consider systemic therapy with or without radiotherapy, followed by imaging to assess potential treatment response.[11] If the tumour has become resectable post treatment, see section: retroperitoneal/abdominal STS: resectable.
If the tumour remains unresectable post treatment, options include alternative systemic therapy, palliative radiotherapy, palliative surgery, or best supportive care.[11]
Retroperitoneal/abdominal STS: metastatic disease, single organ and limited tumour bulk amendable to local therapy
Choice of local control modality is individualised 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 tumour bulk amendable to local therapy include:[11]
Metastasectomy with or without neoadjuvant or adjuvant systemic therapy with or without radiotherapy
SBRT with or without systemic therapy
Ablation procedures
Embolisation procedures (non-lung metastases)
Observation
For further information see section Extremity: stage IV STS, oligometastases with limited tumour bulk or regional nodes.
Patients with lymph node involvement (including isolated regional nodal metastatic disease) should undergo regional lymph node dissection with or without radiotherapy.[11]
Retroperitoneal/abdominal STS: disseminated metastases
Palliative options include:[11]
Systemic therapy
Radiotherapy/SBRT
Surgery
Observation, if asymptomatic
Best supportive care
Ablation procedures
Embolisation procedures (non-lung metastases)
Gastrointestinal stromal tumours (GIST): resectable with minimal morbidity
Recommended treatment for patients with GIST with minimal morbidity include complete surgical resection with adjuvant systemic treatment.[41][44][63] GISTs are fragile and require handling with care. A minimally invasive approach may be considered for certain GIST if the anatomical location allows, performed by surgeons experienced in minimally invasive techniques.[41]
Adjuvant systemic therapy
For patients with complete resected tumours (R0/R1), observation is recommended for those with low-risk disease or non-imatinib sensitive tumours.[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 tumours; 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 tumour size and mitotic rate/high power fields (HPFs).[41]
Risk levels for gastric GIST:[41]
High risk:
Tumour size: >5 cm to ≤10 cm; mitotic rate: >5 mitoses/50 HPFs
Tumour size: >10 cm; Miotic rate: >5 mitoses/50 HPFs
Moderate risk:
Tumour size: >2 cm to ≤5 cm; mitotic rate: >5 mitoses/50 HPFs
Tumour size: >10 cm; mitotic rate: ≤5 mitoses/50 HPFs
Low risk
Tumour size: >5 cm to ≤10 cm; mitotic rate: ≤5 mitoses/50 HPFs
Very low risk
Tumour size: >2 cm to ≤5 cm;mitotic rate: ≤5 mitoses/50 HPFs
Risk levels for non-gastric GIST (includes small bowel and colorectal GIST):
High risk
Tumour size: ≤2 cm; mitotic rate: >5 mitoses/50 HPFs - Insufficient data - High
Tumour size: >2 cm to ≤5 cm; mitotic rate: >5 mitoses/50 HPFs
Tumour size: >5 cm to ≤10 cm;mitotic rate:>5 mitoses/50 HPFs -Insufficient data - High
Tumour size: >10 cm; mitotic rate:≤5 mitoses/50 HPFs
Tumour size: >10 cm; mitotic rate:>5 mitoses/50 HPFs
Moderate
Tumour size:>5 cm to ≤10 cm; mitotic rate: ≤5 mitoses/50 HPFs - Insufficient data - Moderate
Low risk
Tumour size: >2 cm to ≤5 cm; mitotic rate: m ≤5 mitoses/50 HPFs
In the case of 'insufficient data', risk criteria for jejunum/ileum is recommended.
Evidence suggests that adjuvant imatinib should be given for at least 3 years, as this has been demonstrated to prolong survival compared with 1 year of adjuvant imatinib. However, caution is needed in patients with heart failure or short life expectancy, as imatinib has adverse effects of diarrhoea, fatigue, anaemia, and oedema.[64][65][66]
Gastrointestinal stromal tumours (GIST): resectable with significant morbidity
Testing tumours for mutation is recommended prior to starting neoadjuvant therapy to ensure the tumour has a genotype that is likely to benefit from treatment.[41]
Neoadjuvant therapy
Patients with GIST that are operable but resection is likely to cause significant morbidity (e.g., locally advanced GIST that would require multi-visceral 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 tumour size before surgery.[41][67][68] Resection offers the greatest chance of successful treatment.
Neoadjuvant therapy should be considered only if surgical morbidity could be reduced by downsising the tumour preoperatively. Six months of neoadjuvant treatment may be needed to achieve maximal response. Once maximal response is achieved, consider surgical resection.[41]
Preferred regimens for neoadjuvant therapy:[41]
KIT or PDGFRA mutations (excluding PDGFRA exon 18 mutations that are insensitive to imatinib, including D842V)
Imatinib
GIST with PDGFRA exon 18 mutations that are insensitive to imatinib (including PDGFRA D842V)
Avapritinib
NTRK gene fusion-positive GIST
Larotrectinib
Entrectinib
Repotrectinib
SDH-deficient GIST
Sunitinib
BRAF V600E mutated GIST
Dabrafenib plus trametinib
Neoadjuvant therapy should be monitored to assess response and adherence. Decisions about the appropriateness and timing of resection should be made by the oncologist and surgeon after optimal response or sustained stable disease.[41]
Patients who achieve response or stable disease with neoadjuvant treatment
Imatinib therapy may be continued after complete resection (R0/R1) for patients with imatinib-sensitive GIST and intermediate or high risk of recurrence.[41] Data support the use of adjuvant imatinib for at least 3 years.[65]
For patients treated with neoadjuvant avapritinib, larotrectinib, entrectinib, sunitinib, or dabrafenib plus trametinib, observation is recommended after complete resection.[41]
Patients with tumours not amenable to surgery after neoadjuvant treatment
If resection is not possible, targeted systemic therapy should be continued until the tumour progresses or there are intolerable adverse effects.[41]
Gastrointestinal stromal tumours (GIST): unresectable
Preferred systemic therapy regimens for unresectable GIST include:[41]
Imatinib sensitive mutations (excluding PDGFRA exon 18 mutations that are insensitive to imatinib including D842V)
Imatinib
GIST with PDGFRA exon 18 mutations that are insensitive to imatinib (including PDGFRA D842V)
Avapritinib
NTRK gene fusion-positive GIST only
Larotrectinib
Entrectinib
Repotrectinib
SDH-deficient GIST
Sunitinib
Regorafenib
Pazopanib
Imatinib plus binimetinib
BRAF V600E mutated GIST
Dabrafenib plus trametinib
Tumours with a KIT exon 9 mutation treated with imatinib have a lower response rate and progression-free survival than tumours with KIT exon 11 mutations.[69] However, high-dose imatinib was found to improve outcomes and should be considered in patients with a KIT exon 9 mutation.[41] One long-term open-label randomised phase 3 trial of patients with advanced GIST demonstrated that interruption of imatinib treatment in non-progressing patients with GIST is associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up, compared with imatinib continuation in patients after 3 years and 5 years of imatinib.[70]
In a phase 1 trial of patients with PDGFRA exon 18 D842V mutation-positive GIST, avapritinib resulted in response rates of 88% overall.[71]
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 tumour progresses or intolerable adverse effects occur.[41]
Gastrointestinal stromal tumours (GIST): progressive
Treatment for patients who experience progression despite prior therapy will depend on whether disease progression is limited or widespread.[41]
Limited progressive GIST
Patients with limited progressive GIST should continue with the same dose of TKI and consider the following options for lesions progressing on imatinib or avapritinib:
Resection (if feasible)
Ablation procedures or embolisation or chemoembolisation
Palliative radiotherapy for symptomatic lesions
Or if previously treated with standard-dose imatinib:
Switch to sunitinib
Dose escalation of imatinib as tolerated (if previously treated with standard-dose imatinib; may be most effective for patients with KIT exon 9 mutation)
Ablation procedures
Ablation modality is based on tumour size, location, and adjacent critical structures to optimise 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:[41]
Uncorrectable coagulopathy
Active infection in the planned treatment area
Inability to displace or protect adjacent critical structures (relative based on risk-benefit discussion)
Embolisation/chemoembolisation procedures
Specific intra-arterial therapies include transarterial (bland) embolisation (TAE) and transarterial chemoembolisation (TACE).[41]
TAE involves the delivery of embolic agents within hepatic arteries supplying liver tumours 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 tumoural 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 embolisation or chemoembolisation include:[41]
Uncorrectable coagulopathy
Active infection in the planned treatment area
Decompensated liver failure
Generalised progressive GIST (widespread systemic)
Patients with a performance status of 0-2 who experience progression with imatinib or avapritinib should consider switching to an alternate TKI. Clinical experience suggests that discontinuing TKI therapy, even in the setting of progressive disease, may accelerate the pace of disease progression and worsen symptoms.[41] Dose escalation of imatinib as tolerated (if previously treated with standard-dose imatinib; may be most effective for patients with KIT exon 9 mutation).[41]
Local or generalised progression of GIST
Further treatment options for patients with local or generalised 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] Re-introduction of imatinib can be considered for palliation of symptoms, and should be considered as part of best supportive care.[41]
Gastrointestinal stromal tumours (GIST): recurrent or metastatic
Lifelong targeted systemic therapy is recommended for patients with recurrent or metastatic TKI-sensitive GIST until progression occurs at which point patients should be treated depending on whether the progression in limited on generalised (see sections: limited or generalised progression of GIST).[41] Observation may be considered for tumours with SDH deficiency or NF1 mutations that lack mutations in KIT/PDGFRA as most, but not all, have more indolent behaviour.[41]
Gross residual disease (R2 resection) and tumour rupture should be treated as metastatic disease.[41]
Molecularly guided systemic therapy is the primary therapy for metastatic GIST.[41] (For preferred systemic therapy options see section: resectable with significant morbidity or unresectable disease.)
Surgery (peritoneal cytoreduction and/or liver metastasectomy) may be indicated in the following order:[41]
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 favourable response to therapy.
Low-volume multifocal progressive disease that is safely resectable.
Management of symptomatic bleeding, obstruction, or perforation.
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