Introduction
Purpose of these guidelines
Revision methods
A (High quality) | Further research is very unlikely to change our confidence in the estimate of effect |
B (Moderate quality) | Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate |
C (Low quality) | Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate |
D (Very low quality) | Any estimate of effect is very uncertain |
Strength of recommendation | ||
---|---|---|
Strong | Weak | |
Direction of recommendations | ||
For | We recommend… | We suggest… |
Against | We recommend not… | We suggest not… |
Strength of recommendation | Quality of evidence |
---|---|
1 (Strong recommendation) | A (High quality) |
2 (Weak recommendation) | B (Moderate quality) |
C (Low quality) | |
D (Very low quality) |
External evaluation
Algorithms and supplement
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Algorithm 1 (Fig. 1), Outline of diagnosis and therapy for gastrointestinal submucosal tumors
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Algorithm 2 (Fig. 2), Differential diagnosis of spindle cell type GIST
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Algorithm 3 (Fig. 3), Differential diagnosis of epithelioid cell type GIST
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Algorithm 4 (Fig. 4), Treatment strategy for resectable and localized gastrointestinal submucosal tumors
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Algorithm 5 (Fig. 5), Surgical treatment for localized GIST
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Algorithm 6 (Fig. 6), Post-operative therapy for localized GIST
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Algorithm 7 (Fig. 7), First-line drug therapy for GIST
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Algorithm 8 (Fig. 8), Therapy for imatinib-resistant GIST
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Supplemental Algorithm 1 (Fig. S1), Genotype of GIST
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Supplemental Algorithm 2 (Fig. S2), Differential diagnosis for multiple GISTs
Radiological diagnosis part
Overview of the radiological diagnosis part
Diagnostic imaging useful for diagnosing submucosal tumors
Lesions less than 2 cm in diameter
Lesions larger than 2 cm in diameter
Diagnostic imaging useful for determining the effect of drug therapy
Gastrointestinal imaging, endoscopy, and ultrasonography
Contrast-enhanced CT and MRI
Response | Definition (The sum of longest diameters of target lesions as defined in RECIST 1.1) |
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CR | Disappearance of all lesions |
No new lesions | |
PR | A decrease in size of ≥ 10% or a decrease in tumor density (HU) ≥ 15% on CT |
No new lesions | |
No obvious progression of nonmeasurable disease | |
SD | Does not meet the criteria for CR, PR, or PD |
No symptomatic deterioration attributed to tumor progression | |
PD | An increase in tumor size of ≥ 10% and does not meet criteria of PR by tumor density (HU) on CT |
New lesions |
FDG-PET/CT
Questions
Radiology 1 (BQ): Is EUS-FNA useful for making a definitive diagnosis of GIST?
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Recommendation: We suggest that EUS-FNA is performed to make a definitive diagnosis of GIST.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: B (Moderate quality)
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Consensus rate: 100%
Radiology 2 (BQ): Are CT and MRI useful for determination of the clinical staging and recurrence of GIST?
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Recommendation: We recommend that CT and MR images are taken for determination of the clinical staging and recurrence of GIST.
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Strength of recommendation: 1 (Strong recommendation)
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Quality of evidence: B (Moderate quality)
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Consensus rate: 82.4%
Radiology 3 (BQ): Is FDG-PET useful for determination of the clinical staging and recurrence of GIST?
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Recommendation: We suggest that FDG-PET is performed for determination of the clinical staging and recurrence of GIST.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 94.1%
Radiology 4 (CQ): Is additional FDG-PET useful for evaluation of the drug effect on GIST?
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Recommendation: We suggest that FDG-PET is additionally performed for evaluation of the drug effect on GIST.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 100%
Pathological diagnosis part
Overview of the pathological diagnosis part
Pathological diagnosis of GIST
Histology and immunohistochemistry
Differential diagnosis
Recurrence risk classification of GIST
Classification systems
Recurrence risk | Tumor size (cm) | Mitotic count (/50 HPFs) |
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Very low | < 2 | < 5 |
Low | 2–5 | < 5 |
Intermediate | < 5 | 6–10 |
5–10 | < 5 | |
High | > 5 | > 5 |
> 10 | Any | |
Any | > 10 |
Tumor parameters | Recurrence risk classification (%)a | ||||
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Tumor size (cm) | Mitotic count (/50 HPFs) | Stomach | Small intestine | Duodenum | Rectum |
< 2 | < 5 | None (0) | None (0) | None (0) | None (0) |
> 2 to ≤ 5 | < 5 | Very low (1.9) | Low (4.3) | Low (8.3) | Low (8.5) |
> 5 to ≤ 10 | < 5 | Low (3.6) | Moderate (24) | High (34)c | High (57)c |
> 10 | < 5 | Moderate (12) | High (52) | ||
< 2 | > 5 | None (0)b | High (50)b | No datad | High (54) |
> 2 to ≤ 5 | > 5 | Moderate (16) | High (73) | High (50) | High (52) |
> 5 to ≤ 10 | > 5 | High (55) | High (85) | High (86)c | High (71)c |
> 10 | > 5 | High (86) | High (90) |
Tumor parameters | Recurrence risk classification | ||
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Tumor size (cm) | Mitotic counts (/50 HPFs)a | Stomach | Other sites |
< 2 | < 5 | Very low | Very low |
> 2 to ≤ 5 | < 5 | Low | Low |
> 5 to ≤ 10 | < 5 | Intermediate | High |
< 2 | > 5 to ≤ 10 | Intermediate | High |
> 2 to ≤ 5 | > 5 to ≤ 10 | Intermediate | High |
> 5 to ≤ 10 | > 5 to ≤ 10 | High | High |
Tumor size > 10 cm (any mitotic counts) | High | High | |
Mitotic counts > 10/50 HPFs (any tumor size) | High | High | |
Presence of tumor rupture (any mitotic counts and/or tumor size) | High | High |
How to count the mitotic figures
Field number | Diameter (mm) | Field area (mm2) | Upper: number of fields per 5 mm2 |
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Lower: field areas of a total of 50 HPFs, and how to convert to 5 mm2 | |||
14 | 0.35 | 0.096 | 52.1 |
50 HPFs = 4.8 mm2, × 1.04 | |||
16 | 0.40 | 0.126 | 39.7 |
50 HPFs = 6.3 mm2, × 0.79 | |||
18 | 0.45 | 0.159 | 31.4 |
50 HPFs = 7.95 mm2,, × 0.63 | |||
20 | 0.50 | 0.196 | 25.5 |
50 HPFs = 9.8 mm2,, × 0.51 | |||
22 | 0.55 | 0.238 | 21 |
50 HPFs = 11.9 mm2, × 0.42 | |||
24 | 0.60 | 0.283 | 17.7 |
50 HPFs = 14.15 mm2, × 0.35 | |||
26 | 0.65 | 0.332 | 15.1 |
50 HPFs = 16.6 mm2, × 0.30 |
Gene alterations in GIST
Questions
Pathology 1 (BQ): Are histological diagnosis by hematoxylin–eosin (HE) staining and immunohistochemistry for KIT useful for differential diagnosis of GIST?
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Recommendation: We recommend that histological diagnosis by HE staining and immunohistochemistry for KIT are carried out for differential diagnosis of GIST.
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Strength of Recommendation: 1 (Strong recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 100%
Pathology 2 (BQ): Is immunohistochemistry for markers other than KIT useful for differential diagnosis of GIST?
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Recommendation: We recommend that immunohistochemistry for markers other than KIT is carried out for differential diagnosis of GIST.
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Strength of Recommendation: 1 (Strong recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 88.2%
Pathology 3 (BQ): Is gene analysis useful for diagnosis of KIT-negative or KIT-weak GIST?
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Recommendation: We suggest that gene analysis is carried out for diagnosis of KIT-negative or KIT-weak GIST.
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Strength of Recommendation: 2 (Weak recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 100%
Pathology 4 (BQ): Are frequency and malignant potential different in GIST depending on the primary site?
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Recommendation: Frequency and malignant potential are different in GIST depending on the primary site.
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Strength of Recommendation: –
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Quality of evidence: –
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Consensus rate: 100%
Pathology 5 (BQ): Are risk classifications for recurrence useful for evaluation of the biological behavior of GIST?
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Recommendation: We recommend that risk classifications for recurrence in GIST are carried out for evaluation of the biological behavior of GIST.
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Strength of Recommendation: 1 (Strong recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 88.2%
Pathology 6 (BQ): Is taking a biopsy specimen useful in the evaluation of malignant potential (recurrence risk) in GIST?
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Recommendation: We suggest that taking a biopsy specimen is not useful in the evaluation of malignant potential (recurrence risk) in GIST.
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Strength of Recommendation: 2 (Weak recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 87.5%
Pathology 7 (BQ): Are there any correlations between KIT immunohistochemisry results and c-kit mutational status?
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Recommendation: There are no apparent correlations between KIT immunohistochemisry results and c-kit mutational status.
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Strength of Recommendation: –
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Quality of evidence: –
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Consensus rate: 100%
Pathology 8 (BQ): Is mutational analysis useful for evaluation of primary imatinib-resistant GIST?
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Recommendation: We suggest that mutational analysis is carried out for evaluation of primary imatinib-resistant GIST.
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Strength of Recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 94.1%
Pathology 9 (BQ): Are there any GISTs caused by gene abnormalities other than c-kit and PDGFRA mutations?
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Recommendation: There are GISTs caused by gene abnormalities other than c-kit and PDGFRA mutations.
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Strength of Recommendation: –
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Quality of evidence: –
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Consensus rate: 100%
Pathology 10 (BQ): Are there any pathological conditions with multiple GISTs?
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Recommendation: There are pathological conditions with multiple GISTs.
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Strength of Recommendation: –
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Quality of evidence: –
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Consensus rate: 100%
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Familial GISTs with inherited germline mutations of the c-kit or PDGFRA geneTo date, more than 30 families of inherited GISTs have been reported. Inherited GISTs have c-kit or PDGFRA mutations just as sporadic GISTs do. In families with germline c-kit mutations, multiple GISTs develop in the stomach and small intestine associated with hyperplasia of ICC. On the other hand, in families with germline PDGFRA mutations, multiple GISTs develop only in the stomach, and inflammatory fibroid polyps or lipomas also develop in some cases. Separate from families with c-kit mutations, hyperplasia of ICC has not been reported in families with PDGFRA mutations.
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NF1-associated GISTsThere have been reports of GISTs developing in some neurofibromatosis type 1 patients. In most cases, multiple GISTs develop in the small intestine and rarely in the stomach. Although dozens or hundreds of GISTs develop in some cases, they must not be mistakenly identified as tumor dissemination. Hyperplasia of ICC is also seen in the myenteric plexus.
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Carney–Stratakis syndrome and Carney triadIn patients with Carney–Stratakis syndrome, in which the development of GISTs and paragangliomas is an inherited condition, and in Carney triad patients, in which the development of GISTs, paragangliomas, and pulmonary chondromas is not an inherited condition, GISTs lacking expression of SDHB protein develop in the stomach, most of which are multifocal. One of the germline mutations of SDHB, SDHC, or SDHD genes, which encode subunits of the SDH enzyme complex, has been reported in families with Carney–Stratakis syndrome, and hypermethylation of the SDHC promoter region and subsequent decrease of gene expression have been reported in Carney triad tumors. Hyperplasia of ICC has not been reported in these cases.
Surgical management part
Overview of the surgical management part
Surgery for primary GIST
Treatment strategies for resectable localized submucosal tumor (SMT)
Surgery, neoadjuvant therapy and adjuvant therapy for localized GIST
Surgery for metastatic or recurrent GIST
Surgery as initial treatment
Surgery for GIST treated with TKIs
Questions
Surgery 1 (CQ): Is surgery recommended for GISTs less than 2 cm?
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Recommendation: We suggest that surgery is carried out for GISTs less than 2 cm.
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Strength of Recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 91.7%
Surgery 2 (CQ): Is surgery recommended for submucosal tumors (SMTs) between 2 and 5 cm?
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Recommendation: We recommend that surgery is carried out for SMTs sized 2–5 cm which are diagnosed as GISTs or strongly suspected of being malignant tumors including GISTs.
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Strength of Recommendation: 1 (Strong recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 100%
Surgery 3 (CQ): Is laparoscopic surgery recommended for submucosal tumors (SMTs) 5 cm or larger?
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Recommendation: We suggest that laparoscopic surgery is carried out for SMTs 5 cm or larger.
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Strength of Recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 100%
Surgery 4 (BQ): Is organ function-preserving surgery recommended for GISTs requiring surgical resection?
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Recommendation: We recommend that organ function-preserving surgery is carried out for GISTs requiring surgical resection.
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Strength of Recommendation: 1 (Strong recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 100%
Surgery 5 (CQ): Is neoadjuvant imatinib therapy useful for large GIST and where incomplete resection is suspected?
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Recommendation: We suggest that neoadjuvant imatinib therapy is carried out for large GIST 10 cm or larger and for GIST where incomplete resection is suspected.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 100%
Surgery 6 (CQ): Is adjuvant imatinib therapy useful for GIST with preoperative or intraoperative rupture?
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Recommendation: We recommend that adjuvant imatinib therapy is carried out for GIST with preoperative or intraoperative rupture.
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Strength of recommendation: 1 (Strong recommendation)
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Quality of evidence: B (Moderate quality)
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Consensus rate: 100%
Surgery 7 (BQ): Is routine follow-up useful for GIST after complete resection?
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Recommendation: We suggest that routine follow-up is carried out for GIST after complete resection.
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Strength of Recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 94.1%
Surgery 8 (CQ): Is upfront surgery useful for metastatic GIST?
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Recommendation: We suggest that upfront surgery is not carried out for metastatic GIST.
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Strength of Recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 94.1%
Surgery 9 (CQ): Is surgery useful for metastatic or recurrent GIST responding to imatinib?
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Recommendation: We suggest that surgery is not carried out for metastatic or recurrent GIST responding to imatinib.
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Strength of Recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 94.1%
Surgery 10 (CQ): Is surgery useful for metastatic or recurrent GIST resistant to tyrosine kinase inhibitors?
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Recommendation: We suggest that surgery is not carried out for metastatic or recurrent GIST resistant to tyrosine kinase inhibitors.
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Strength of Recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 100%
Medical management part
Overview of the medical management part
Treatment for metastatic, recurrent, or unresectable GIST
Medical treatment of GIST (first-line treatment)
Medication for imatinib-resistant GIST (Secondary treatment or later)
Other treatments
Adjuvant therapy
Questions
Medicine 1 (CQ): Is initiating therapy with low-dose imatinib compared to standard-dose useful for metastatic, recurrent, or unresectable GIST for which standard-dose imatinib is indicated?
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Recommendation: We recommend not initiating therapy with low-dose imatinib for metastatic, recurrent, or unresectable GIST for which standard-dose imatinib is indicated.
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Strength of recommendation: 1 (Strong recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 92.9%
Medicine 2 (BQ): Is discontinuation of therapy useful for metastatic, recurrent, or unresectable GIST when tyrosine kinase inhibitors demonstrate efficacy?
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Recommendation: We suggest that therapy not be discontinued for metastatic, recurrent, or unresectable GIST when tyrosine kinase inhibitors demonstrate efficacy.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: C (Low quality)
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Consensus rate: 88.2%
Medicine 3 (CQ): Is blood concentration measurement of imatinib useful for metastatic, recurrent, or unresectable GIST?
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Recommendation: We suggest that blood concentration measurement of imatinib is carried out for metastatic, recurrent, or unresectable GIST.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 87.5%
Medicine 4 (CQ): Is dose escalation useful for metastatic, recurrent, or unresectable GIST which exacerbate at a dose of imatinib 400 mg/day?
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Recommendation: We suggest that dose escalation is not carried out for metastatic, recurrent, or unresectable GIST which exacerbate at a dose of imatinib 400 mg/day.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 94.1%
Medicine 5-1 (BQ): Is adjuvant imatinib therapy for 3 years after complete resection useful for GIST at high risk for recurrence and tumor rupture?
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Recommendation: We recommend adjuvant imatinib therapy for 3 years after complete resection is carried out for GIST at high risk for recurrence and tumor rupture.
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Strength of recommendation: 1 (Strong recommendation)
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Quality of evidence: B (Moderate quality)
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Consensus rate: 100%
Medicine 5-2 (CQ): Is adjuvant imatinib therapy for more than 3 years after complete resection useful for GIST at high risk for recurrence and tumor rupture?
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Recommendation: *Recommendation was not determined even after a second round of voting.
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Strength of recommendation: Not Graded
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Quality of evidence: D (Very low quality)
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Consensus rate: –%
Medicine 6 (BQ): Is sunitinib useful for metastatic, recurrent, or unresectable GIST in patients that are imatinib resistant or intolerant?
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Recommendation: We recommend that sunitinib is used for metastatic, recurrent, or unresectable GIST in patients that are imatinib resistant or intolerant.
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Strength of recommendation: 1 (Strong recommendation)
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Quality of evidence: B (Moderate quality)
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Consensus rate: 100%
Medicine 7 (BQ): Is regorafenib useful for metastatic, recurrent, or unresectable GIST in patients who are sunitinib resistant or intolerant?
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Recommendation: We recommend that regorafenib is used for metastatic, recurrent, or unresectable GIST in patients who are sunitinib resistant or intolerant.
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Strength of recommendation: 1 (Strong recommendation)
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Quality of evidence: B (Moderate quality)
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Consensus rate: 100%
Medicine 8 (CQ): Is rechallenge of imatinib or sunitinib useful for metastatic, recurrent, or unresectable GIST in patients who are regorafenib resistant or intolerant?
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Recommendation: We suggest that rechallenge of imatinib or sunitinib is carried out for metastatic, recurrent, or unresectable GIST in patients who are regorafenib resistant or intolerant.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 94.1%
Medicine 9 (CQ): Is radiation therapy useful for metastatic, recurrent, or unresectable GIST?
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Recommendation: We suggest that radiation therapy is not used for metastatic, recurrent, or unresectable GIST.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 94.1%
Medicine 10 (CQ): Is local therapy other than surgical resection useful for metastatic GIST of the liver?
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Recommendation: We suggest that local therapy other than surgical resection is carried out for metastatic GIST of the liver.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 100%
Medicine 11 (CQ): Is alteration of dosage and administration schedule of sunitinib and regorafenib recommended for GIST in patients who are sunitinib- and regorafenib-intolerant at the standard dosage and administration?
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Recommendation: We suggest that alteration of the dosage and administration schedule of sunitinib and regorafenib is carried out for GIST in patients who are sunitinib- and regorafenib-intolerant at the standard dosage and administration.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 94.1%
Medicine 12 (CQ): Is gene analysis useful for choice of tyrosine kinase inhibitors in GIST?
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Recommendation: We suggest that gene analysis is not carried out when choosing tyrosine kinase inhibitors in GIST.
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Strength of recommendation: 2 (Weak recommendation)
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Quality of evidence: D (Very low quality)
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Consensus rate: 88.2%
Medicine 13 (CQ): Is pimitespib useful for metastatic, recurrent, or unresectable GIST in patients who are regorafenib resistant or intolerant?
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Recommendation: We recommend that pimitespib is used for metastatic, recurrent, or unresectable GIST in patients who are regorafenib resistant or intolerant.
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Strength of recommendation: 1 (Strong recommendation)
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Quality of evidence: B (Moderate quality)
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Consensus rate: 86.7%