(NCCN

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

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Gastrointestinal Stromal

Tumors (GISTs)

Version 1.2021 — October 30, 2020

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NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

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Table of Contents

Discussion

ξ Bone marrow

transplantation

‡ Hematology/

Hematologic oncology

Þ Internal medicine

† Medical oncology

τ Orthopedics/Orthopedic

oncology

≠ Pathology

¥ Patient advocacy

€ Pediatric oncology

§ Radiotherapy/Radiation

oncology

¶ Surgery/Surgical

oncology

* Discussion writing

committee member

*Margaret von Mehren, MD/Chair †

Fox Chase Cancer Center

*John M. Kane, III, MD/Vice-Chair ¶

Roswell Park Comprehensive

Cancer Center



Mott Cancer Center

Edwin Choy, MD, PhD †

Massachusetts General Hospital

Cancer Center

Mary Connelly, LSW ¥

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

Sarah Dry, MD 

UCLA Jonsson Comprehensive Cancer Center

Kristen N. Ganjoo, MD †

Stanford Cancer Institute

Suzanne George, MD †

Dana-Farber/Brigham and

Women’s Cancer Center

Ricardo J. Gonzalez, MD ¶

Mott Cancer Center

Martin J. Heslin, MD ¶

O'Neal Comprehensive

Cancer Center at UAB

Jade Homsi, MD †

UT Southwestern Simmons

Comprehensive Cancer Center

Vicki Keedy, MD, MSCI †

Vanderbilt-Ingram Cancer Center

Ciara M. Kelly, MD †

Memorial Sloan Kettering Cancer Center

Edward Kim MD §

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

David Liebner, MD Þ †

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

Martin McCarter, MD ¶

University of Colorado Cancer Center



Fred & Pamela Buffett Cancer Center

Christian Meyer, MD, PhD †

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

Alberto S. Pappo, MD €

St. Jude Children’s Research Hospital/

University of Tennessee Health Science Center

Amanda M. Parkes, MD ‡ †

University of Wisconsin

Carbone Cancer Center

I. Benjamin Paz, MD ¶

City of Hope National Medical Center

Ivy A. Petersen, MD §

Mayo Clinic Cancer Center

Matthew Poppe, MD §

Huntsman Cancer Institute

at the University of Utah

Richard F. Riedel, MD †

Duke Cancer Institute



Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer Center

and Cleveland Clinic Taussig Cancer Institute

Scott Schuetze, MD, PhD †

University of Michigan

Rogel Cancer Center

Jacob Shabason, MD §

Abramson Cancer Center

at the University of Pennsylvania

Jason K. Sicklick, MD

UC San Diego Moores Cancer Center

Matthew B. Spraker, MD, PhD §

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine



UCSF Helen Diller Family

Comprehensive Cancer Center

NCCN

Mary Anne Bergman

Giby V. George, MD

NCCN Guidelines Panel Disclosures

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NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

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

NCCN Guidelines Index

Table of Contents

Discussion

The NCCN Guidelines

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

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

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

(NCCN

) makes no representations

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

Guidelines are copyrighted by National Comprehensive Cancer Network

NCCN Soft Tissue Sarcoma Panel Members

Summary of the Guidelines Updates

Gastrointestinal Stromal Tumors (GISTs)

• Workup at Primary Presentation (GIST-1)

• Resectable GIST with Signicant Morbidity (GIST-2)

• Postoperative Outcomes (GIST-3)

• Unresectable, Recurrent, or Metastatic GIST (GIST-4)

• Treatment for Progressive Disease (GIST-5)

• Principles of Biopsy and Risk Stratication for GISTs (GIST-A)

• Principles of Mutation Testing (GIST-B)

• General Principles of Surgery for GIST (GIST-C)

• Systemic Therapy Agents and Regimens for GISTs with Signicant Morbidity (GIST-D)

• Principles of Imaging (GIST-E)

Staging (ST-1)

Clinical Trials: NCCN believes that

the best management for any patient

with cancer is in a clinical trial.

Participation in clinical trials is

especially encouraged.

To nd clinical trials online at NCCN

Member Institutions, click here:

nccn.org/clinical_trials/member_

institutions.aspx.

NCCN Categories of Evidence and

Consensus: All recommendations

are category 2A unless otherwise

indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

(NCCN

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

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for GISTs from the Version 2.2020:

Global changes:

• The algorithm for GISTs was removed from the NCCN Guidelines for

Soft Tissue Sarcoma and published under the NCCN Guidelines for

Gastrointestinal Stromal Tumors (GISTs).

GIST-1

• 

Consider neoadjuvant imatinib or avapritinib (for PDGFRA exon 18

mutations that are insensitive to imatinib, including the D842V mutation) to

decrease surgical morbidity

Footnotes:

• See Principles of Biopsy and Risk Stratification for GISTs (GIST-A).

Pathology report should include anatomic location, size, and an accurate

assessment of the mitotic rate measured in the most proliferative area of

the tumor

• for genotype-sensitive disease should be

considered for locally advanced GISTs in certain anatomical locations (eg,

rectum, esophageal and esophagogastric junction, and duodenum) or if a

multivisceral resection would be required to resect all gross tumor.

• for genotype-sensitive disease may prohibit

accurate assessment of recurrence risk following resection. Testing

tumor for mutation is recommended prior to starting preoperative imatinib

to ensure tumor has a genotype that is likely to respond to treatment.

Consider neoadjuvant imatinib only if surgical morbidity could be reduced

by downsizing the tumor preoperatively. Maximal response may require

treatment for 6 months or more to achieve.

GIST-2

• Mutational Testing is new to the pathway.

• 4th column modified: Imatinib

(category 1) or avapritinib for PDGFRA exon

18 mutation insensitive to imatinib (Also for 7th column under Follow-up

Therapy).

Footnotes:

• 

managed by maximum supportive treatment, then consider sunitinib. (Also

for GIST-3 and GIST-4)

GIST-3

• New pathway as follows: Completely resected after preoperative

avapritinib with an arrow to Observe.

GIST-3 (continued)

•  and imaging

GIST-4

Footnotes:

• Resection of metastatic disease, especially if complete

resection can be achieved, has been associated with improved outcomes

and may be benecial in patients on imatinib or sunitinib who have evidence

of radiographic response, or limited disease progression.

GIST-5

•  category 2B designation.

• 3rd sub-bullet modified: Palliative RT (category 2B) for rare patients with

bone metastases symptomatic lesions

• 



•  (widespread, systemic), the following sub-bullets are new:

If progression on regorafenib, change to ripretinib (category 1)

For PDGFRA exon 18 mutations, consider dasatinib (for PDGFRA D842V

mutation) or imatinib (for imatinib-sensitive PDGFRA exon 18 mutations).



progressing despite prior imatinib/sunitinib/regorafenib/ripretinib

therapies

Footnotes:

• 

• 

MRI with contrast with clinical interpretation; increase in tumor size in the

presence of decrease in tumor density is consistent with drug efficacy or

benefit. PET/CT scan may be used to clarify if CT or MRI are ambiguous.

• Treatment with avapritinib can be continued for limited

progression. There are no other appropriate treatment options for GIST

progressing on avapritinib. Clinical trial is recommended.

GIST-A (1 of 3)

• 3rd bullet: See SARC-B deleted; link added to NCCN Guidelines for Soft

Tissue Sarcoma

• : Some stratication schemes

have included tumor rupture, which has been associated with a much

poorer prognosis higher risk of recurrence.

Continued

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

(NCCN

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

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for GISTs from the Version 2.2020:

GIST-B

• Testing for KIT and PDGFRA mutations

is strongly recommended should be performed if TKIs are...

•  GISTs tumors 

• ripretinib

• for potential

identication of a targeted therapy. for non-gastric tumors or SDHB-

positive tumors.

GIST-C

Primary (Resectable) GIST

• 

low incidence of nodal metastases; however, resection of pathologically

enlarged nodes should be considered in patients with known SDH-

or known translocation-associated GISTs.

• A laparoscopic approach may be considered for select GISTs in

favorable anatomic locations (greater curvature or anterior wall of the

stomach, jejunum, and ileum) by surgeons with appropriate laparoscopic

experience.

Unresectable or Metastatic GIST

• Imatinib is the primary therapy for imatinib-sensitive metastatic GIST.

Considerations Prior to Surgery

•  sunitinib,

regorafenib, ripretinib, or avapritinib...

• 2nd bullet: Patients with SDH deciency or known SDH mutations

GIST-D (1 of 2)

Systemic Therapy Agents and Regimens for Resectable GISTs with

Signicant Morbidity

• Neoadjuvant Therapy/Preferred Regimens:

Imatinib (for imatinib-sensitive mutations)

Avapritinib (for PDGFRA exon 18 mutations that are insensitive to

imatinib, including the D842V mutation)

• Adjuvant Therapy/Preferred Regimens:

Imatinib

Footnotes:

• Data do not support routine use in wild-type GISTs, corresponding to

Imatinib for Adjuvant Therapy.

Systemic Therapy Agents and Regimens for Unresectable GISTs with

Signicant Morbidity

• Additional options after failure on approved therapies is new, with the

following footnotes:

Therapies based on identication of molecular drivers.

Regimens are ordered alphabetically and not according to order of

preference.

• Useful in Certain Circumstances:

Cabozantinib with the following reference: Schöffski P, Mir O, Kasper B,

et al. Eur J Cancer 2020;134:62-74. doi: 10.1016/j.ejca.2020.04.021. Online

ahead of print.

Larotrectinib or entrectinib (for NTRK gene-fusion GISTs) with the

following references:

– A, Laetsch TW, Kummar S, et al. Ecacy of larotrectinib in TRK

fusion-positive cancers in adult and children. N Engl J Med 2018

378(8):731-739.

– Demetri GD, Paz-Ares L, Farago AF, et al. Ecacy and safety of

entrectinib in patients with NTRK fusion-positive tumours: pooled

analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Presented

at the European Society for Medical Oncology Meeting in Munich,

Germany; October12-23, 2018. Oral Presentation.

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-1

MANAGEMENT BASED ON THE RESULTS OF INITIAL DIAGNOSTIC EVALUATION

• Mass known to be or clinically

suspicious for GIST

Imaging

Consider chest imaging

Genotyping should be performed

when medical therapy is being

considered

Biopsy

b,m

and risk

assessment

See (GIST-3)

for

Postoperative

Outcomes and

Treatment

See (GIST-4)

Resectable with minimal morbidity

Resectable



morbidity

h,i

Consider neoadjuvant imatinib

or avapritinib (for PDGFRA exon

18 mutations that are insensitive

to imatinib, including the D842V

mutation) to decrease surgical

morbidity

g,l

See (GIST-2)

Unresectable or metastatic disease

• All patients should be evaluated

and managed by a multidisciplinary team with

expertise and experience in GIST/sarcoma

High-risk

EUS features

No high-risk

EUS features

Complete

surgical

resection

Consider periodic endoscopic or radiographic

surveillance

c,j

WORKUP AT PRIMARY

PRESENTATION

• For very small gastric GISTs <2 cm

Endoscopic ultrasound-guided



(EUS-FNAB)

Imaging

Sepe PS, et al. Nat Rev Gastroenterol Hepatol 2009;6:363-371.

See Principles of Biopsy and Risk Stratification for GISTs (GIST-A).

See Principles of Imaging (GIST-E).

See American Joint Committee on Cancer (AJCC) Staging, 8th Edition (ST-1).

Mutational analysis may predict response to therapy with tyrosine kinase inhibitors (TKIs)

(See GIST-B).

Possible high-risk EUS features include irregular border, cystic spaces, ulceration,

echogenic foci, and heterogeneity.

Some patients may rapidly become unresectable; close monitoring is essential.

Extensive surgery associated with significant morbidity (ie, total gastrectomy to reduce

risk of recurrence in stomach) is generally not recommended for SDH-deficient GIST with

multifocal disease.

Neoadjuvant therapy for genotype-sensitive disease should be considered for locally

advanced GISTs in certain anatomical locations (eg, rectum, esophageal and

esophagogastric junction, duodenum) or if a multivisceral resection would be required to

resect all gross tumor.

Endoscopic ultrasonography surveillance should only be considered after a thorough

discussion with the patient regarding the risks and benefits. Evans J, et al. Gastrointest

Endosc 2015;82:1-8.

See Principles of Surgery for GIST (GIST-C).

Neoadjuvant imatinib for genotype-sensitive disease may prohibit accurate assessment

of recurrence risk following resection. Testing tumor for mutation is recommended prior

to starting preoperative imatinib to ensure tumor has a genotype that is likely to respond

to treatment. Consider neoadjuvant imatinib only if surgical morbidity could be reduced

by downsizing the tumor preoperatively. Maximal response may require treatment for 6

months or more to achieve.

See NCCN Guidelines for Soft Tissue Sarcoma if the pathology results indicate sarcomas

of GI origin other than GIST.

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-2

See Principles of Imaging (GIST-E).

Mutational analysis may predict response to therapy with TKIs (See GIST-B).

Some patients may rapidly become unresectable; close monitoring is essential.

See Principles of Surgery for GIST (GIST-C).

Consider baseline PET/CT, if using PET/CT during follow-up. PET/CT is not a substitute for CT.

Medical therapy is the usual course of treatment. However, patient may proceed to surgery if bleeding or symptomatic tumor or poor treatment tolerance.

PET/CT may give indication of imatinib efficacy after 2–4 weeks of therapy when rapid readout of activity is necessary. Diagnostic abdominal/pelvic CT or MRI with

contrast is indicated every 8–12 weeks; routine long-term PET/CT follow-up is rarely indicated. Frequency of response assessment imaging may be decreased if

patient is responding to treatment.

Progression may be determined by abdominal/pelvic CT or MRI with contrast with clinical interpretation; increase in tumor size in the presence of decrease in tumor

density is consistent with drug efficacy or benefit. PET/CT scan may be used to clarify if CT or MRI are ambiguous.

Collaboration between medical oncologist and surgeon is necessary to determine the appropriateness and timing of surgery, following major response or sustained

stable disease. Maximal response may require treatment for 6 months or more to achieve.

Imatinib can be stopped right before surgery and restarted as soon as the patient is able to tolerate oral medications. If other TKIs such as sunitinib or avapritinib are

being used, therapy should be stopped at least one week prior to surgery and can be restarted based on clinical judgment or recovery from surgery.

PRIMARY

PRESENTATION

PRIMARY TREATMENT

FOLLOW-UP THERAPY

Resectable

GIST with



morbidity

Baseline

Imaging

c,n

Imatinib

e,o

(category 1)

or avapritinib

for PDGFRA

exon 18

mutation

insensitive to

imatinib

Imaging

to assess

treatment

response

c,p,q

and evaluate

patient

adherence

Response

or stable

disease

Progression

Continue the

same dose

of imatinib

avapritinib

for PDGFRA

exon 18

mutation

insensitive

to imatinib

Surgery, if

feasible

k,r,s

Surgery, if

feasible

k,r,s

If surgery not

feasible,

see GIST-5

See (GIST-3)

for

Postoperative

Outcomes

and Treatment

Mutational

testing

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-3

See Principles of Imaging (GIST-E).

Mutational analysis may predict response to therapy with TKIs (See GIST-B).

The PERSIST study has shown the feasibility of 5-year adjuvant imatinib with no evidence of recurrence in patients with imatinib-sensitive GIST [Raut CP, et al. JAMA

Oncol 2018;4(12):e184060].

Less frequent surveillance may be acceptable for very small tumors (<2 cm), unless they are associated with high mitotic rate.

POSTOPERATIVE

OUTCOMES

ADJUVANT TREATMENT FOLLOW-UP

If Recurrence,

See (GIST-4)

Persistent microscopic residual

disease (R1 resection) or gross

residual disease (R2 resection)

Completely resected

after preoperative

imatinib

Completely resected

(no preoperative imatinib)

Consider continuation of adjuvant

imatinib if taken prior to resection

Observe (low-risk disease)

Adjuvant imatinib

for patients with



or high risk) (category 1)

(See GIST-A)

• 

every 3 mo for

high risk, every

3–6 mo for 5 y

(every 3 mo if high

if high risk), then

annually

See (GIST-4)

Completely resected

after preoperative

avapritinib

Observe

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-4

See Principles of Imaging (GIST-E).

Mutational analysis may predict response to therapy with TKIs (See GIST-B).

See Principles of Surgery for GIST (GIST-C).

Consider baseline PET/CT, if using PET/CT during follow-up. PET/CT is not a

substitute for CT.

PET/CT may give indication of imatinib efficacy after 2–4 weeks of therapy when

rapid readout of activity is necessary. Diagnostic abdominal/pelvic CT or MRI with

contrast is indicated every 8–12 weeks; routine long-term PET/CT follow-up is

rarely indicated. Frequency of response assessment imaging may be decreased if

patient is responding to treatment.

Progression may be determined by abdominal/pelvic CT or MRI with contrast with

clinical interpretation; increase in tumor size in the presence of decrease in tumor

density is consistent with drug efficacy or benefit. PET/CT scan may be used to

clarify if CT or MRI are ambiguous.

Collaboration between medical oncologist and surgeon is necessary to determine

the appropriateness and timing of surgery, following major response or sustained

stable disease. Maximal response may require treatment for 6 months or more to

achieve.

Imatinib can be stopped right before surgery and restarted as soon as the patient

is able to tolerate oral medications. If other TKIs such as sunitinib or avapritinib

are being used, therapy should be stopped at least one week prior to surgery and

can be restarted based on clinical judgment or recovery from surgery.

Consider resection or ablation/liver-directed therapy for hepatic metastatic

disease.

Resection of metastatic disease, especially if complete resection can be achieved,

and may be beneficial in patients on imatinib or sunitinib who have evidence of

radiographic response, or limited disease progression.

PRIMARY

PRESENTATION

PRIMARY TREATMENT FOLLOW-UP THERAPY

Unresectable,

recurrent,

or metastatic

GIST

Response

or stable

disease

Continue TKI,

obtain surgical

consultation,

consider

resection

k,r,v,w

Resection

Continue TKI if

resection not

feasible

See (GIST-3)

for

Postoperative

Outcomes and

Treatment

See (GIST-5)

Imaging

to assess

treatment

response

c,p,q

and evaluate

patient

adherence

Baseline

Imaging

c,n

Progression



imaging

c,q

every

3–6 mo

TKI

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-5

See Principles of Surgery for GIST (GIST-C).

Imatinib can be stopped right before surgery and restarted as soon as the patient is able to tolerate oral medications. If other TKIs, such as sunitinib or avapritinib, are

being used, therapy should be stopped at least one week prior to surgery and can be restarted based on clinical judgment or recovery from surgery.

Clinical experience suggests that discontinuing TKI therapy, even in the setting of progressive disease, may accelerate the pace of disease progression and worsen

symptoms.

Reintroduction of a previously tolerated and effective TKI can be considered for palliation of symptoms. Consider continuation of TKI therapy life-long for palliation of

symptoms as part of best supportive care.

TREATMENT FOR PROGRESSIVE DISEASE

Progression

Limited

Generalized

(widespread,

systemic)

• Continue with the same dose of TKI and consider

the following options for lesions progressing on

imatinib:

Resection,

if feasible

Ablation procedures or embolization

or chemoembolization

Palliative RT (category 2B) for symptomatic

lesions or

• Dose escalation of imatinib as tolerated or

• Change to sunitinib (category 1)

For performance status (PS) 0–2 and progression on

imatinib:

• Dose escalation of imatinib

as tolerated

Change to sunitinib (category 1)

• If progression on sunitinib,

then regorafenib

(category 1)

• If progression on regorafenib, change to ripretinib

(category 1)

• For PDGFRA exon 18 mutations, consider dasatinib

(for PDGFRA D842V mutation) or imatinib (for

imatinib-sensitive PDGFRA exon 18 mutations)

If disease is progressing despite

prior therapies, consider the following

options:

Clinical trial

Consider other options listed in GIST-D

(based on limited data)

Consider repeat tumor biopsy to

potentially identify uncommon mutations

that may have a corresponding targeted

therapy

Best supportive care

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-A

1 OF 3

PRINCIPLES OF BIOPSY AND RISK STRATIFICATION FOR GIST

• An endoscopic transmural biopsy would be favored over a percutaneous transperitoneal biopsy, if the risk for peritoneal seeding by the





diagnosis of primary GIST prior to the initiation of preoperative therapy.

• Morphologic diagnosis based on microscopic examination of histologic sections is the standard for GIST diagnosis. Several ancillary

techniques are recommended in support of GIST diagnosis, including immunohistochemistry (IHC) for CD117, DOG1, and CD34 and

molecular genetic testing for KIT and PDGFRA mutations.

• Diagnosis is based on the Principles of Pathologic Assessment (See NCCN Guidelines for Soft Tissue Sarcoma); referral to centers

with expertise and experience in the diagnosis and management of GIST/sarcoma is recommended for cases with complex or unusual

histopathologic features.

• 





Most gastric GISTs behave in an indolent manner, especially when less than 2 cm. See Table 1: Gastric GISTs: Proposed Guidelines for

Assessing the Malignant Potential (GIST-A 2 of 3).

GIST of the small intestine tends to be more aggressive than its gastric counterpart. See Table 2: Non-Gastric GISTs: Proposed Guidelines

for Assessing the Malignant Potential (GIST-A 3 of 3).

GIST of the colon is most commonly seen in the rectum; colorectal GIST tends to have an aggressive biological behavior, and tumors with

mitotic activity can recur and metastasize despite a small size of <2 cm.

.

Continued

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-A

2 OF 3

PREDICTORS OF GIST BIOLOGIC BEHAVIOR

Data from Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Sem Diag Path 2006;23:70-83.

The mitotic rate should be measured in the most proliferative area of the tumor, and reported as the number of mitoses per 50 HPF of tissue. Per 50 HPF is a total of

5mm

. For most modern microscopes, 20 to 25 HPF 40 x lenses/fields encompasses 5 mm

. Laurini JA, Blanke CD, Cooper K, et al. Protocol for the Examination of

Specimens From Patients With Gastrointestinal Stromal Tumor (GIST). Version 4.0.1.0, June 2017.

Available at: https://cap.objects.frb.io/protocols/cp-gisofttissue-gist-17protocol-4010.pdf.

Table 1: Gastric GISTs: Proposed Guidelines for Assessing the Malignant Potential

Tumor Size Mitotic Rate

Predicted Biologic Behavior



 Metastasis rate: 0%

>5 mitoses/50 HPFs Metastasis rate: 0%*

>2 cm to 

 Metastasis rate: 1.9%

>5 mitoses/50 HPFs Metastasis rate: 16%

>5 cm to 

 Metastasis rate: 3.6%

>5 mitoses/50 HPFs Metastasis rate: 55%

>10 cm

 Metastasis rate: 12%

>5 mitoses/50 HPFs

Metastasis rate: 86%

 tumor category with very small numbers

Continued

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-A

3 OF 3

Data from Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Sem Diag Path 2006;23:70-83.

The mitotic rate should be measured in the most proliferative area of the tumor, and reported as the number of mitoses per 50 HPF of tissue. Per 50 HPF is a total of

5mm

. For most modern microscopes, 20 to 25 HPF 40 x lenses/fields encompasses 5 mm

. Laurini JA, Blanke CD, Cooper K, et al. Protocol for the Examination of

Specimens From Patients With Gastrointestinal Stromal Tumor (GIST). Version 4.0.1.0, June 2017.

Available at: https://cap.objects.frb.io/protocols/cp-gisofttissue-gist-17protocol-4010.pdf.

Table 2: Non-Gastric GISTs: Proposed Guidelines for Assessing the Malignant Potential

Tumor Size Mitotic Rate

Predicted Biologic Behavior



 Metastasis rate: 0%

>5 mitoses/50 HPFs Metastasis rate: 50%–54%



 Metastasis rate: 1.9%–8.5%

>5 mitoses/50 HPFs Metastasis rate: 50%–73%



 Metastasis rate: 24%

>5 mitoses/50 HPFs Metastasis rate: 85%

>10 cm

 Metastasis rate: 34%–52%

>5 mitoses/50 HPFs Metastasis rate: 71%–90%



PREDICTORS OF GIST BIOLOGIC BEHAVIOR

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-B

PRINCIPLES OF MUTATION TESTING

• Approximately 80% of GISTs have a mutation in the gene encoding the KIT receptor tyrosine kinase; another 5%–10% of GISTs have a mutation in the gene

encoding the related PDGFRA receptor tyrosine kinase. The presence and type of KIT and PDGFRA mutations are not strongly correlated with prognosis.

• The mutations in KIT and PDGFRA in GISTs result in expression of mutant proteins with constitutive tyrosine kinase activity. Testing for KIT and PDGFRA

mutations should be performed if TKIs 

regions of the KIT and PDGFRA

• KIT or PDGFRA show some correlation with tumor phenotype, but mutations are not strongly correlated wih the biologic potential

of individual tumors. The accumulated data show that KIT mutations are not preferentially present in high-grade tumors, and can also be found in small

incidental tumors as well as tumors that have an indolent course. Similary, mutational analysis of PDGFRA cannot be used to predict the behavior of

individual tumors.

• KIT exon 11 mutation, and 50% for

tumors that have a KIT exon 9 mutation; the likelihood of response improves with the use of imatinib 400 mg BID. Most PDGFRA mutations are associated

with a response to imatinib, with the exception of D842V, which is unlikely to respond to imatinib and most other approved TKIs for GIST except

avapritinib.

• Metastatic disease with acquired drug resistance is usually the result of secondary, imatinib-resistant mutations in KIT or PDGFRA. Sunitinib treatment

is indicated for patients with imatinib-resistant tumors or imatinib intolerance. Regorafenib is indicated for patients with disease progression on imatinib

and sunitinib. Referral to clinical trial is strongly recommended for patients with mutations resistant to imatinib, sunitinib, regorafenib, ripretinib, and

avapritinib.

• About 10%–15% of GISTs lack mutations in KIT or PDGFRA. The vast majority of these GISTs have functional inactivation of the succinate dehydrogenase

(SDH) complex, which can be detected by lack of expression of SDHB on IHC. Inactivation of the SDH complex may result from a mutation or from

epigenetic silencing. A small minority of GISTs that retain SDH expression have alternative driver mutations.

• Testing for alternative driver mutations is indicated for tumors that are negative for KIT or PDGFRA mutations. Testing includes assessment for SDHB

 SDH  sequencing (NGS) testing for

alternative driver mutations (eg, BRAF, NF1, NTRK, and FGFR 

• GISTs with SDH mutations typically arise in the stomach in younger individuals, frequently metastasize, may involve lymph nodes, and usually grow

slowly. They are usually resistant to imatinib. In the absence of KIT and PDGFRA

NF1, BRAF

 a genetic counselor for germline testing assessment is recommended for all

NF1 or SDH mutations. Patients with SDH mutations are at risk of paraganglioma;

24-hour urine testing is recommended prior to surgery (See GIST-C).

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NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-C

GENERAL PRINCIPLES OF SURGERY FOR GIST

Primary (Resectable) GIST

The surgical procedure performed should aim to resect the tumor with histologically negative margins.

• Given the limited intramural extension, extended anatomic resections (such as total gastrectomy) are rarely indicated. Segmental or wedge

resection to obtain negative margins is often appropriate.

• Lymphadenectomy is usually not required given the low incidence of nodal metastases; however, resection of pathologically enlarged nodes



• 

tumor spillage or fracture, laceration of the tumor capsule with or without macroscopic spillage, piecemeal resection, and incisional biopsy

occurring either before or at the time of the operation).

• 

Resection should be accomplished with minimal morbidity and, in general, complex multivisceral resection should be avoided. If the surgeon

feels that a multivisceral resection may be required, then multidisciplinary consultation is indicated regarding a course of preoperative

imatinib. Similarly, rectal GIST should be approached via a sphincter-sparing approach. If abdominoperineal resection (APR) would be

necessary to achieve a negative margin resection, then preoperative imatinib should be considered.

A laparoscopic approach may be considered for select GISTs in favorable anatomic locations by surgeons with appropriate laparoscopic

experience.

• All oncologic principles of GIST resection must still be followed, including preservation of the pseudocapsule and avoidance of tumor

spillage.

• Resection specimens should be removed from the abdomen in a plastic bag to prevent spillage or seeding of port sites.

Unresectable or Metastatic GIST

Imatinib is the primary therapy for imatinib-sensitive metastatic GIST. Surgery may be indicated for:

• Limited disease progression refractory to imatinib.

• Locally advanced or previously unresectable tumors or low-volume stage IV disease after a favorable response to systemic imatinib therapy.

• Management of symptomatic bleeding or obstruction.

Considerations Prior to Surgery

• Imatinib can be stopped right before surgery and restarted as soon as the patient is able to tolerate oral medications. If other TKIs, such as

sunitinib, regorafenib, ripretinib, or avapritinib, are being used, therapy should be stopped at least one week prior to surgery and can be

restarted based on clinical judgment or recovery from surgery.

•  SDH mutations are at risk of paraganglioma and therefore serum/urine catecholamine/metanephrine

testing should be considered before an operation.

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NCCN Guidelines Index

Table of Contents

Discussion

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

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

First-line therapy

Second-line therapy

(progressive disease

after imatinib)

Third-line therapy

(progressive disease

after imatinib and

sunitinib

Fourth-line therapy

(progressive disease

after imatinib, sunitinib,

and regorafenib)

Additional options after

failure on approved therapies

d,e

Preferred Regimens

• Imatinib

b,1,2

(category 1)

• Avapritinib

b,3

(for

GIST with PDGFRA

exon 18 mutations,

including the

PDGFRA D842V

mutation)

Preferred Regimen

• Sunitinib

b,4

(category 1)

Preferred Regimen

• Regorafenib

b,5

(category 1)

Preferred Regimen

• Ripretinib

b,6

(category 1)

Useful in Certain Circumstances

• Avapritinib

b,c,3

• Cabozantinib

• Dasatinib

(for patients with

PDGFRA D842V mutation)

• Everolimus + TKI

c,9

• Larotrectinib

or entrectinib

(for NTRK gene-fusion GISTs)

• Nilotinib

12-13

• Pazopanib

• Sorafenib

15-17

SYSTEMIC THERAPY AGENTS AND REGIMENS FOR RESECTABLE GISTWITH SIGNIFICANT MORBIDITY

Data do not support routine use in wild-type GISTs.

FDA-approved TKIs for the treatment of GIST.

TKIs to be considered for use in combination with everolimus include imatinib, sunitinib, or regorafenib.

Therapies based on identification of molecular drivers.

Regimens are ordered alphabetically and not according to order of preference.

GIST-D

1 OF 2

See references, on GIST-D (2 of 2)

Neoadjuvant Therapy Adjuvant Therapy

Preferred Regimens

• Imatinib (for imatinib-sensitive mutations)

• Avapritinib

(for PDGFRA exon 18

mutations that are insensitive to imatinib,

including the D842V mutation)

Preferred Regimen

• Imatinib

SYSTEMIC THERAPY AGENTS AND REGIMENS FOR UNRESECTABLE GISTWITH SIGNIFICANT MORBIDITY

(NCCN

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NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

Table of Contents

Discussion

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

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

GIST-D

2 OF 2

Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N EngI J Med 2002;347:472-480.

Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomized trial. Lancet

2004;364(9440):1127-1134.

Heinrich M, Jones RL, von Mehren M, et al. Clinical response to avapritinib by RECIST and Choi Criteria in ≥4th line and PDGFRA exon 18 gastrointestinal stromal

tumors (GIST). Connective Tissue Oncology Society Annual Meeting, Tokyo, Japan, November 15, 2019.

Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a

randomised controlled trial. Lancet 2006;368:1329-1338.

Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID):

an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:295-302.

von Mehren M, Serrano C, Bauer S, et al: INVICTUS: A phase III, interventional, double-blind, placebo-controlled study to assess the safety and ecacy of ripretinib as

fourth-line therapy in advanced GIST. 2019 ESMO Congress. Abstract LBA87.

Schöffski P, Mir O, Kasper B, et al. Eur J Cancer 2020;134:62-74. doi: 10.1016/j.ejca.2020.04.021. Epub 2020 May 26.

Trent JC, Wathen K, von Mehren M, et al. A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol

2011;29:Abstract 10006.

Choffski P, Reichardt P, Blay JY, et al. A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal

tumors. Ann Oncol 2010;21(10):1990-1998.

A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adult and children. N Engl J Med 2018 378(8):731-739.

Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumours: pooled analysis of STARTRK-2,

STARTRK-1 and ALKA-372-001. Presented at the European Society for Medical Oncology Meeting in Munich, Germany; October12-23, 2018. Oral Presentation.

Montemurro M, Schoffski P, Reichardt P, et al. Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib. Eur J

Cancer 2009;45:2293-2297.

Sawaki A, Nishida T, Doi T, et al. Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor. Cancer 2011;117:4633-4641.

Ganjoo KN, Villalobos VM, Kamaya A., et al. A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following

failure of at least imatinib and sunitinib. Ann Oncol 2014;25(1):236-40.

Montemurro M, Gelderblom H, Bitz U, et al. Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both

imatinib and sunitinib, and nilotinib: A retrospective analysis. Eur J Cancer 2013;49:1027-1031.

Kindler HL, Campbell NP, Wroblewski K, et al. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors

(GIST): Final results of a University of Chicago Phase II Consortium trial. J Clin Oncol 2011;29:Abstract 10009.

Park SH, Ryu MH, Ryoo BY, et al. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase

II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs 2012;30:2377-2383.

REFERENCES

SYSTEMIC THERAPY AGENTS AND REGIMENS FOR RESECTABLE/UNRESECTABLE GISTWITH SIGNIFICANT MORBIDITY

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NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

NCCN Guidelines Index

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Discussion

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

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

GIST

Workup

• For very small GIST <2 cm: Perform abdominal/pelvic CT with

contrast and/or abdominal/pelvic MRI with contrast.

• For all other GIST:

Abdominal/pelvic CT with contrast and/or abdominal/pelvic MRI

with contrast

Chest imaging using x-ray or CT

Response Assessment



• Obtain baseline abdominal/pelvic CT and/or MRI.

• Consider PET/CT

Obtain baseline PET/CT if using PET/CT during follow-up; PET is

not a substitute for CT.

• Imaging to assess response to preoperative TKI

Abdominal/pelvic CT or MRI is indicated every 8–12 weeks

PET may give indication of TKI activity after 2–4 weeks of therapy

when rapid readout of activity is necessary

• Progression may be determined by abdominal/pelvic CT or MRI with

clinical interpretation; PET/CT may be used to clarify if CT or MRI is

ambiguous.

• For R2 resection or discovery of metastatic disease, assess

response to postoperative TKI using abdominal/pelvic CT or MRI

every 8–12 weeks .



• Obtain baseline abdominal/pelvic CT and/or MRI

• Consider imaging of chest intermittently

• Consider PET/CT

Obtain baseline PET/CT if using PET/CT during follow-up; PET is

not a substitute for CT.

• Imaging to assess response to TKI

• Abdominal/pelvic CT or MRI every 8–12 weeks of initiating therapy;

in some patients, it may be appropriate to image before 3 months.

• Progression may be determined by abdominal/pelvic CT or MRI with

clinical interpretation; PET/CT may be used to clarify if CT or MRI is

ambiguous.

Follow-up

• For completely resected primary disease, perform abdominal/pelvic

CT every 3–6 months for 3–5 years, then annually.

Less frequent imaging surveillance may be acceptable for low-risk

or very small tumors (<2 cm).

More frequent imaging surveillance may be required for patients

with high-risk disease who discontinue TKI therapy.

• For incompletely resected disease or discovery of metastatic

disease during surgery, perform abdominal/pelvic CT every 3–6

months.

• Progression may be determined by CT or MRI with clinical

interpretation; PET/CT may be used to clarify if CT or MRI is

ambiguous.

• After treatment for progressive disease, reassess therapeutic

response with abdominal/pelvic CT or MRI.

Consider PET/CT only if CT results are ambiguous.

GIST-E

PRINCIPLES OF IMAGING

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

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Discussion

ST-1

Table 6. 

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor 2 cm or less

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

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

T4 Tumor more than 10 cm in greatest dimension

N Regional Lymph Nodes

N0 No regional lymph node metastasis or unknown lymph

node status

N1 Regional lymph node metastasis

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

Grading for GIST is dependent on mitotic rate

Low 5 or fewer mitoses per 5 mm

, or per 50 HPF

High Over 5 mitoses per 5 mm

, or per 50 HPF

Table 7. AJCC Anatomic Stage/Prognostic Groups

Gastric GIST*

T N M

Mitotic

Rate

Stage IA T1 or T2 N0 M0 Low

Stage IB T3 N0 M0 Low

Stage II T1 N0 M0 High

T2 N0 M0 High

T4 N0 M0 Low

Stage IIIA T3 N0 M0 High

Stage IIIB T4 N0 M0 High

Stage IV Any T N1 M0 Any rate

Any T Any N M1 Any rate

Small Intestinal GIST**

T N M

Mitotic

Rate

Stage I T1 or T2 N0 M0 Low

Stage II T3 N0 M0 Low

Stage IIIA T1 N0 M0 High

T4 N0 M0 Low

Stage IIIB T2 N0 M0 High

T3 N0 M0 High

T4 N0 M0 High

Stage IV Any T N1 M0 Any rate

Any T Any N M1 Any rate

*Note: Also to be used for omentum.

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

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

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

(2017) published by Springer International Publishing.

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Discussion

NCCN Categories of Evidence and Consensus

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

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

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

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

All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

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

aordability.

Other recommended

intervention

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

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

Useful in certain

circumstances

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

All recommendations are considered appropriate.

CAT-1

(NCCN

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

NCCN Guidelines Version 1.2021

Gastrointestinal Stromal Tumors (GISTs)

MS-1

Discussion

Table of Contents

Overview ........................................................................................ MS-2

Gastrointestinal Stromal Tumors ................................................. MS-2

General Principles ..................................................................... MS-2

Biopsy and Pathologic Assessment ...................................... MS-2

Prognostic Factors ................................................................. MS-3

Imaging ................................................................................... MS-4

Surgery ................................................................................... MS-4

Targeted Therapy ................................................................... MS-5

Initial Evaluation and Workup ................................................. MS-12

Treatment Guidelines............................................................... MS-12

Resectable Disease .............................................................. MS-12

Unresectable, Metastatic, or Recurrent Disease ................. MS-14

Progressive Disease ............................................................. MS-14

Continuation of TKI Therapy ................................................ MS-15

Surveillance .......................................................................... MS-15

References ................................................................................... MS-16

This discussion corresponds to the NCCN Guidelines for Gastrointestinal

Stromal Tumors (GISTs). Last updated on March 27, 2018.