https://doi.org/10.53964/jmmo.2022003

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Journal ofModern Medical Oncology
Open Access

ISSN 2708-0005 (Online)

Short Commentary
Overview of Advancement and Management of Gastrointestinal Stromal Tumors
Mahim Koshariya1*, Bhoomika Agarwal1, Rahul Rathod1
1

Department of Surgery, Gandhi Medical College and Hamidia Hospital Bhopal, Madhya Pradesh, India

Correspondence to: Mahim Koshariya, MS, Professor, Department of Surgery, Gandhi Medical College and
Hamidia Hospital Bhopal, Sultania Road, Madhya Pradesh 462001, India; Email: mahimk2000@yahoo.co.uk

Received: June 28, 2022 Revised: August 2, 2022 Accepted: August 29, 2022 Published: September 22, 2022

Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of gastrointestinal
tract with different expressions of CD117 (transmembrane KIT receptor tyrosine kinase) from otherrelated tumors, which provides insights into the disease management of GIST. Tyrosine kinase inhibitors
reduce the incidence of tumor recurrence and make the tumor resectable. Despite the malignant potentialof GISTs, gastric GIST shows a better prognosis versus GISTs at other locations. Contrast-enhanced
computed tomography (CECT) is considered the radiological diagnosis of choice because biopsy increases
the risk of bleeding and tumor spreading. In addition to surgical resection which remains the mainstay
of GIST treatment, active surveillance is also available for gastric tumor with a size <2cm. Currently,
given the clinical consensus of an increased response of the tumor to chemotherapy after resectionof the advanced lesion, patients with metastasis are also indicated for cytoreductive surgery. Various
minimally invasive techniques including endoscopic (endoscopic band ligation, endoscopic muscularis
dissection, endoscopic submucosal dissection, endoscopic submucosal tunnelling, endoscopic fullthickness resection), laparoscopic and combined techniques (laparoscopic endoscopic cooperative surgery,combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique) havebeen developed for surgical resection of tumors. Due to the high recurrence rate even during treatment,
patients receive a physical examination and CECT follow-up every 3-5 months for 5 years followed byannual visits.
Keywords: GIST, Imatinib, Tyrosine Kinase Inhibitors, resection
Citation: Koshariya M, Agarwal B, Rathod R.Overview of Advancement and Management of Gastrointestinal Stromal Tumors. J
Mod Med Oncol, 2022; 2: 3. DOI: 10.53964/jmmo.2022003.

1 INTRODUCTION
Gastrointestinal stromal tumor (GIST) is the mostcommon mesenchymal tumor of the gastrointestinal (GI)tract with a high risk of malignancy. Before the 1990s,
GISTs were commonly misinterpreted and classified
as leiomyomas, leiomyosarcomas, leiomyoblastomas,

schwannomas, and GI autonomic nerve tumors[1]. Recent research has found expressions of CD117 antigen(transmembrane KIT receptor tyrosine kinase) in GISTs,
which is undetectable in other GI tract spindle cell tumors[2].
The identification of oncogenic mutations in the genes
c-KIT and platelet derived growth factor alpha (PDGFRA)

Copyright © 2022 The Author(s). This open-access article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, sharing, adaptation, distribution, and reproduction in any medium,provided the original work is properly cited.

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genes encoding receptor tyrosine kinase, revolutionized theconcept in GIST diagnosis and its therapeutic management.
This has enabled the use of tyrosine kinase inhibitors(TKIs) such as imatinib, which has transformed a disease
with minimal therapeutic options other than surgery into a
disease with multimodal therapy, prolonged survival, andpossible cure. This review aims to give a broad overview
of the histogenesis, molecular pathogenicity, clinicalappearance, diagnostics, and surgical and non-surgicalmanagement of GIST.
2 EPIDEMIOLOGYGISTs account for 0.1% to 3% of all cancers in GI tract.
Its prevalence has shown a trend of increase in the last
decade due to better categorization of tumors or a genuine
increase in occurrence. Data on Indian GIST patients are
scarce, where the prevalence of small bowel GISTs haveshown an increase, resulting in small bowel as the mostprevalent site of GIST in India (40.7%) versus gastric
GISTs (25.4%) worldwide[3].
GIST is most diagnosed in elderly patients around theage of 60, with a male preponderance. The majority of GIST
cases are sporadic; however, familial GISTs with germline
KIT and PDGFRA mutations have also been reported[4].
Exons 9, 11, 13, and 17 of the KIT gene while exon 12
and 18 of the PDGFRA gene are frequently mutated[5].
GISTs are also responsible to form Von Recklinghausen
Neurofibromatosis type 1 partially and Carney’s triad, bothof which are characterised by the absence of KIT mutations.
3 PATHOGENESISInterstitial cells of Cajal (Intestinal pacemaker cells) areconsidered the source of GI stromal tumors with CD34
positive on immunohistochemistry. KIT (CD117) is
an immunohistochemical marker of GIST, which is
generally observed in 95% of cases[6]. The c-KIT protooncogene codes for the transmembrane receptor tyrosine
kinase KIT, which is involved in haematopoiesis,
gametogenesis, and intestinal pacemaker cell development
and maintenance. By binding its cytokine ligand, steel
factor or stem cell factor, the KIT receptor is activated,which leads to the activation of an intracellular signalling
pathway and further regulates essential cellular processes
such as proliferation, differentiation, and anti-apoptotic
signalling. Gain of functional mutations in the c-KIT genecauses the receptor to be activated even without ligand,resulting in overgrowth of cancer or other benign lumps.
In GIST pathogenesis, KIT and PDGFRA mutations
are mutually exclusive events; however, there arelittle difference in the activation of downward signalling.
There are no KIT or PDGFRA mutations in wild type
GISTs, but there are other mutations observed such as
B-type raf proto-oncogene (BRAF) V600E exon 15 andInnovation Forever Publishing Group

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insulin-like growth factor-1 receptor overexpression[7].
4 CLINICAL PRESENTATION
Extra GI GISTs account for around 5% of GISTs andmay develop in the retroperitoneum, omentum, mesentry,
gall bladder, appendix, and urinary bladder[8]. They are mostcommonly found in the stomach (50-70%), small intestine(25-35%), colon and rectum (5-10%), and oesophagus(5%)[9]. Most GIST patients are symptomatic (69%), few
are detected by chance (21%), and 10% are diagnosed
after autopsy[10]. Most patients complain of nonspecificabdominal aches, followed by bleeding in the form of
melena and hematemesis.
Bleeding is attributable to the erosion of tumors in the
GI tract. Due to its high vascularity, erosion of GI tract
tumors can also lead to life threatening haemorrhage
or even intraperitoneal bleeding in the event of tumor
rupture. Other symptoms include abdominal distension,
nausea, and vomiting. Depending on the location of themass, larger tumors may block the lumen of the GI tract
due to endogenous growth or compress the GI tract due
to exogenous growth, resulting in dysphagia, obstructive
jaundice, or constipation[11].
Around 15-47% of patients with GIST present withmetastatic disease[12]. Distant metastases are mostly
observed in the peritoneum, omentum, and liver but not inlymph node metastases.
5 DIAGNOSISThe diagnosis of GIST requires a thorough medical
history review and physical examination, followed byradiological and tissue diagnosis if feasible. The radiologicalapproach of choice for characterizing an abdominal tumor
suspected or confirmed for GIST is contrast-enhanced CT(oral+IV contrast) of the abdomen and pelvis[13]. Typicalappearance of GIST on contrast enhanced computerized
tomography (CECT) is a soft, well-circumscribed mass
within the wall of hollow viscera (subepithelial) and may
be heterogenous due to necrosis or haemorrhage within themass. Abdominal CECT is also used for treatment response
assessment (Choi Criteria) and surveillance. Magnetic
resonance imaging outperformed CT for peri-rectal GIST
and metastasis.
18

F-Fluoro-2-deoxy-D-glucose positron emission
tomography combined with CT provides high sensitivity
for the detection of tumors with high glucose metabolism.
Tyrosine kinase receptor increases glucose transport protein
signalling, which accounts for the detection of even small
ill-defined tumors/metastases on PET-CT. It may also
be utilized to distinguish between benign and malignant
lesions, as well as to evaluate TKI treatment response, sincemetabolic alterations occur prior to anatomical changes[11].
However, it has not yet supplanted abdominal CECT as the

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preferred imaging modality.
GIST presents endoscopically on endoscopic ultrasound(EUS) as a submucosal lesion, with or without ulceration,
present in the upper and lower GI tract. Irregular extraluminal
borders, heterogenous echogenicity and cystic spaces within
the lesion are suggestive of high grade tumor[14]. EUS can beused to determine the depth of GIST invasion and acquiretissue samples for biopsy. EUS-guided biopsy forceps are oflimited use due to the subepithelial location of the tumor, andtherefore EUS-guided fine-needle aspiration (FNA) if desired
is preferred over biopsy[15].
Colonoscopy is often used to detect masses suspected ofbeing GIST in the colon, rectum and anus.
Although a pre-operative biopsy is not always necessary, it
should be performed if required for the differential diagnosis
of a inoperable tumor.
6 HISTOPATHOLOGY
Histologically, GIST is divided into Spindle cell appearance (70%), epithelioid (20%), and mixed type cellmorphology (10%).
Immunohistochemistry is introduced to differentiate
GIST from other mesenchymal tumors. IHC staining todetect the CD117 (tyrosine kinase KIT receptor) level is themost important diagnostic test for GIST (tyrosine kinase
KIT receptor). It is estimated 88% of GISTs are positive forCD117 and DOG-1. DOG1 is a receptor-activated chloride
channel, which is calcium dependant. DOG1 is expressedin GIST and therefore can be used to diagnose KIT-negative
tumors. Previous research revealed that DOG-1 has better
sensitivity and specificity as compared to CD117[16].
For c-KIT negative GIST, few cases are found to havemutations in BRAF V600E gene, overexpression of insulinlike growth factor, neurotrophic tyrosine kinase receptor type3, or fibroblast growth factor receptor 1.
7 STAGING
The tumor node metastasis staging, which is routinely
utilised in cancer, has significant limitations in GIST staging
and is not advised in this condition.
8 PROGNOSTIC FACTORS AND RISK STRATIFICATIONAll GISTs have malignant potential. Gastric GISTs havea better prognosis than tumors at other locations. The threemost important prognostic factors are tumor size, mitotic
index (per 50 high power field) and tumor location, withmitotic index having the most weightage[17]. A prior study
found that tumors with a size of >10cm or >5cm with mitotic
count >5/50hpf was associated with a poor prognosis[5].
Another important risk factor is tumor rupture. Moreover,Innovation Forever Publishing Group

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mutations, such as deletion in exon 11 are associated withworse prognosis as compared to other point mutations.
Ki67 reflects the ability of the tumor to proliferate andmetastasize, and a high value indicates poor prognosis. For
GISTs, as seen in studies, Ki67>5% signifies an increased
risk of recurrence and metastasis (P<0.001)[5]. To the bestof our knowledge, several classification systems have beendeveloped to predict the risk of recurrence and metastasis. In
the earliest classification systems given by National Instituteof Health (NIH), patients were classified into very low, low,intermediate and high-risk groups depending on size of thetumor and mitotic index. Another system was proposed by
Armed Forces Institute of Pathology that also considers thelocation of the tumor. Joensuu and colleagues developed the
updated NIH classification in 2008, which found that tumour
rupture during surgery resulted in poor prognosis[16].
Completeness of surgical resection has also been
considered a prognostic factor; however ideal margin ofresection is still unknown. These risk assessment systems
facilitate the administration of neoadjuvant and adjuvant
therapies.
9 TREATMENT
GISTs require a multidisciplinary approach to treatment
which requires the cooperation of specialists from various
fields such as histopathologists, radiologists, surgeons, andoncologists, as well as nuclear medicine specialists. A wide
variety of treatment options are available for the treatment of
GISTs, and patient selection of various treatments is a criticaland challenging decision. The mainstay of treatment still is acomplete surgical excision.
9.1 Active Surveillance
Debates exist in the management of GISTs less than
2cm in diameter. Despite their malignant potentials, most ofthese tumors remains insidious and are found on autopsies.
Low-risk gastric submucosal tumours without evidence ofmalignancy on esophagodudenoscopy (EGD) (ulceration,
irregular margins, or fast growth) might be treated bycontinuous monitoring only[18]. However, common consensus
suggests that surgery should be performed for a confirmed
GIST, and active surveillance is considered if patient refuses
surgery.
For active surveillance, National Comprehensive Cancer
Network (NCCN) guidelines suggest endoscopy with EGD+/- EUS every 6-12 months. Malignant findings on EUS
warrant surgery or further workup including CECT, EUS, or
EUS-FNA.
9.2 Surgery
Surgery may be the only treatment option that offersa cure for patients with primary, resectable and localised
GISTs. The major objective of surgery is to remove the

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tumor with negative margins both macroscopically andmicroscopically (R0). The procedure is frequently a wedge
resection or segmental resection of the affected area of thestomach or small intestine. In the event of locally advanced
tumors, involvement of adjacent organs requires total
resection of part or all of the involved organ. If the surgery
will lead to substantial functional complications, such as
total gastrectomy or abdomino-perineal rectum resection,neoadjuvant treatment is encouraged to shrink the tumour
before surgery. Lymph node excision is not necessary unlessenlarged as lymph node metastasis is very rare. However, thesurgery needs to be performed with extreme caution, becauseof the extreme fragility of the tumor and the risk of lifethreatening hemorrhage and tumor spreading after rupture.
Therefore, tumors should be managed with “no-touch”
technique.
Cytoreductive surgery for advanced metastatic disease has
become an accepted practice for disseminated solid tumors.
Despite the lack of prospective trials, it has beensuggested that laparoscopic surgery is indicated for tumorsof <5cm in size or located in favourable anatomic locations,
given a low recurrence rate, shorter hospital stay and low
mortality. To eliminate spilling or spreading of tumors, thespecimen is collected from the abdomen in a plastic bag[11].
For laparoscopic resection, modified lithotomy or split leg
position may be considered for benefit of better visualisationof the tumor.
For gastric tumors, exophytic tumors towards greater
curvature or anterior stomach, can easily be visualised andresected. An intraluminal tumor can be identified using
intraop endoscopy or laparoscopic ultrasound. Posterior
gastric tumors require mobilisation of stomach. A partial
gastrectomy is adequate for the management of most tumors,and open surgery is preferred for gastroesophageal junction
tumors. Tumors involving jejunum and ileum are easily
resected under laparoscopy; however, tumors located in 2ndpart of duodenum may require pancreatico-duodenectomy.
GISTs located in 3rd and 4th part of duodenum, can beresected followed by either direct anastomosis to jejunum or
Roux-en-Y anastomosis to jejunum.
Neo-adjuvant chemotherapy is encouraged for patientwith rectal GISTs to allow abdomino-perineal resection andpermanent colostomy in the patient.
9.3 Role of Endoscopy
During Endoscopy, GISTs can be divided into 4 types
according to the location of the tumor.
Type 1-protruding into the lumen, attached to muscularis
propria via a narrow connection;
Type 2-protruding into the lumen, wider connection to
muscularis propria;
Type 3-in the middle of the gastric wall;

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Type 4-exophytic (protruding through serosa).
Types 1 and 2 are mostly indicated for endoscopic
enucleation, while types 3 and 4 require more sophisticatedendoscopic and laparoscopic combined procedures[19].
Endoscopic excision of GIST, which is usually linked to
muscularis propria, has a risk of a positive deep margin that
may lead to perforation.
Among endoscopic techniques, endoscopic band ligation
can be considered for tumors of <=12mm or locatedsuperficial to muscularis propria. This involves aspiration of
the tumor using a transparent cap followed by band ligation.
For tumors <2cm, and 2-5cm, located in the superficial
layer, endoscopic submucosal dissection can be considered.
Following the labelling of tumour borders, a solution (acombination of normal saline, epinephrine, and indigo
carmine dye) is injected into the submucosal layer, whichisolates the tumour from the rest of the layers and allows forbetter enbloc excision. Endoscopic muscularis dissection
is a new technique that is available for tumors attached to
muscularis propria. Endoscopic submucosal tunnelling isbased on the principle of peroral endoscopic submucosal
tumor resection (POET). A solution is injected into thesubmucosal layer and a tunnel is formed 5cm above thetumor followed by dissection of the tumor from muscularis
layer. Nevertheless, the operation is not suitable for tumors
located at fundus, greater curvature or tumors >4cm in size.
In endoscopic full-thickness resection, complete thicknessof the esophageal wall from where tumor is located isremoved via circumferential incision, creating a perforation
which is then sealed with an endoscopic clip and endo loop
ligature. Creation of this pseudo perforation exponentially
increases the risk of spreading of the tumor. To avoid thisspreading, non-endoscopic wall-inversion surgery that uses
both endoscopy and laparoscopy to push the tumor into theesophageal lumen, and suturing is done laparoscopically.
Nonetheless, it is only suitable for tumors with a sizeof <3cm. Combination of laparoscopic and endoscopic
approaches to neoplasia without exposure techniques is being
developed for larger tumours. Another combined surgicalprocedure for GISTs is laparoscopic endoscopic cooperative
surgery.
10 FOLLOW-UPS AFTER SURGERY
Follow-up after surgical resection of GISTs typically
includes a medical history and physical examination every
3 to 6 months for 5 years and by yearly intervals, as well as
serial CT scans every 3 to 6 months for 3 to 5 years and thenyearly intervals. Disease recurrence is closely monitored.
11 SYSTEMIC THERAPY
Until about 2003, GIST was considered to have a poor
prognosis due to a high incidence of recurrence evenafter complete resection of tumors, and conventional
chemotherapy is ineffective. In early 2000s, after the

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discovery of the pathologic role of KIT mutations in GIST,
targeted chemotherapy agents significantly improved thetreatment outcome of the disease. One such agent is imatinib
mesylate (tyrosine kinase inhibitor), which was used in thetreatment of chronic myelogenous leukaemia with bcr-abl
mutation and was trialed upon for GIST. It is an effective,
well tolerated, orally available compound that has completely
revolutionized the treatment of GIST.
11.1 Neoadjuvant Chemotherapy
Initially, chemotherapy was given only in patients withmetastatic disease that were not suitable for surgery. In
contrast, imatinib has proven its efficacy as a neoadjuvant
and adjuvant chemotherapy agent. It downsizes the locallyadvanced GISTs, thereby significantly improving adjacentorgan preservation and decreasing morbidity[20]. It also
decreases the risk of tumor rupture and spillage in theabdominal cavity and demonstrates great potential as aneoadjuvant agent in primary tumors located at difficult
locations such as gastro-esophageal junction, duodenum, andrectum. This may convert the need for open laparotomy fortumor resection to laparoscopical resection[21].
Mutation studies are recommended before start ofneoadjuvant therapy to predict the treatment response, anda CT scan should be performed after 1st month of therapy
to determine the treatment response[22]. The usual followup schedule is to perform abdominal CECT every 3months. The response evaluation criteria in solid tumors isused to estimate the response from abdominal CECT but
fails to deliver satisfactory outcomes. In contrast, the Choi
Criteria contributes to the determination of early treatment
response by incorporating assessment of tumor density
and size[23]. Neoadjuvant trials of GIST have demonstrated
that maximum radiographic response to imatinib generally
requires 3-6 months of treatment[24], and current NCCN
guidelines recommend a starting dose of 400mg for imatinib
daily. There is no defined timing for surgery, which should
be recommended after the tumor has shrunk to the point
suitable for complete resection, or when a plateau responseis achieved. If surgical resection is scheduled, imatinib can
be discontinued shortly before surgery and resumed once GI
function is restored.
11.2 Adjuvant Chemotherapy
Incidence of recurrence even after complete resection of
the tumor is as high as 90% in the first 2 years after surgery,out of which 50% of the patients die of the recurrent disease.
Role of adjuvant therapy with imatinib following surgery
has been explored in several clinical trials. In localised
disease, adjuvant therapy is recommended for intermediateand high-risk groups. In a randomised study of high-riskpatients, 3 years of adjuvant imatinib treatment was linked
with increased relapse-free and overall survival comparedto 1 year after therapy[25]. Overall survival benefit is seen inpatients receiving therapy for at least 3 years, and shorter

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duration of imatinib therapy delays recurrence but disease
trajectory remains unchanged. Extended adjuvant therapy
in high risk patients appears appropriate in the absenceof disease progression or adverse effects[26]. The usual
dose of imatinib is 400-600mg daily, and a higher dose isrecommended for GISTs with exon 9 mutation given the lowtreatment response of GISTs.
Adjuvant therapy is discouraged for NF-1-related GISTs
that are unresponsive to imatinib in the advanced setting.
Experts are divided as to whether KIT/PDGFRA wildtype SDH-negative GISTs should be treated with adjuvant
treatment.
12 METASTATIC DISEASESGIST metastasis is commonly seen in the liver, mesentery,and omentum, and less frequently in the lungs, subcutaneous
tissue, and lymph nodes.
Imatinib is the primary treatment modality for metastatic/recurrent disease, approved by Food and Drug Administrationin 2002. This was approved after the results of a multicentric
trial that tested 2 doses of imatinib (400 and 600mg) for
treatment of advanced GIST in which patients achieved
partial response in a median duration of 3 months[27]. Serious
side effects are rarely observed in majority cases. Commonside effects included periorbital edema, nausea, diarrhea,
fatigue, rash, myalgia, headache.
Therefore, the starting recommended dose of imatinib is400mg once daily with the highest safe dose being 800mg
once daily, usually recommended for patients with exon
9 mutation on KIT. In patients who progress on imatinib
400mg daily, dose escalation is considered; however, toxicity
also increases with the increasing dose. Research has provedthat a high dose of imatinib is of no clinical advantages
except for few particular mutations, which demonstrates theadvantage of gene sequencing before therapy[28].
As in resectable tumors, duration of imatinib therapy
is debatable, but the accepted standard is indefinite. Somestudies have shown that disease recurs within a short periodof time after cessation of treatment, with a high risk of diseaseprogression, as in a randomized trial in France[29].
If the disease starts progressing after the use of imatinib,
sunitinib, 2nd line drug approved for the treatment, is adopted.
Sunitinib targets KIT, PDGFRA, vascular endothelial growth
factor, and RET proto-oncogene and is effective in resistantcases. Sunitinib was initially given on a four-week-on, twoweek-off schedule, with a beginning dosage of 50mg daily.
Continuous regimen is now considered more effective with adose of 37.5mg daily[30].
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with metastatic/recurrent disease, cytoreductive surgery has
gained popularity in patients with resectable tumors. Few
reasons behind cytoreductive surgery gaining inertia arepartial response to imatinib, including progression of thedisease on imatinib. Once the disease becomes resistant toimatinib, disease progression may be localised or systemic.
Cytoreductive surgery considered beneficial for patientswith non-progressive or locally progressive disease, andpatients who remain responsive to TKI have the greatest
advantages in terms of resectability of the tumor. The
primary goal of surgery in such patients is macroscopic
resection of the disease R0 or R1 which improves the
response to TKI in some cases. If complete resection isunavailable, progressing lesions can be removed.
If a patient is not indicated for surgery, radiofrequency
ablation can be considered. Treatment with imatinib
should also be continued indefinitely after surgery to avoid
recurrence/progression.
13 RECENT ADVANCESAs research into GIST management continues, novel
drugs are emerging, particularly for treatment of GISTs
resistant to imatinib. Alternate pathways of treatment arealso being explored.
In addition to imatinib, sunitinib, and regorafenib,
sorafenib targets multiple kinases including KIT andPDGFRA[31]. It is currently used in hepatocellular carcinoma
and renal cell carcinoma. Nilotinib is another 2nd generation
TKI that targets KIT, PDGFRA and BCR-ABL. KIT withexon 9 mutation should be avoided. It has shown variable
results in terms of efficacy and action in various clinical
trials for GIST. Pazopanib functioned in the PLAETTE
trial in non-GIST soft tissue sarcoma and is a multi-targetedangiogenesis inhibitor that has achieved excellent quality oflife results in metastatic renal cell carcinoma. Low response
to Pazopanib in conjunction with limited evidence warrants
selective use. Another highly selective TKI with inhibitory
effect of KIT and WT-GIST, Mastinib, has been found tohave a similar profile as imatinib and also has fewer side
effects as compared to Sunitinib.
BLU-285, crenolanib and dabrafenib in patients withresistant mutations to PDGFRA D842V and BRAFmutated GIST also provided therapeutic benefits. ETV1
and mitogen activated protein kinase inhibitor also showedsignificant gains. Imatinib and binimetinib disrupted ETV1
protein, resulting in the suppression of GIST cell growth.
Repretinib[32], also a KIT and PDGFRA kinases inhibitor,
is a potent agent for advanced GIST. Common side effects
were alopecia, myalgia, nausea, fatigue, palmar-plantar
erythrodysesthesia and diarrhoea. Avapritinib, a potent,
highly selective oral inhibitor of PDGFRα mutant kinases
was well tolerated in patients with advanced GIST[32].

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Selective TKIs PLX3397, PLX9486 and AZD3229 are
next generation TKIs that target specific secondary KIT
mutations.
Dasatinib, multi TKI and Ipilimumab, anti-cytotoxic
T lymphocyte-associated protein 4 (CTLA4) antibody,in combination was found to be safe but not synergistic.
Nivolumab was also administered with or without
ipilimumab for advanced GIST where higher clinicalbenefits were observed in the single arm as compared to the
combination arm.
Mammalian/mechanistic target of Rapamycin (mTOR)
inhibitors such as sirolimus to TKI can be used for patientswith advanced cancer when imatinib refractory disease ispresent without available standard options[32]. Crenolanib,a selective inhibitor of PDGFRα and FMS such as tyrosine
kinase 3 with nanomolar activity against PDGFRα D842V
mutant GIST is also being investigated.
For chemotherapy, imatinib remains the drug ofchoice which forms the part of neo-adjuvant and adjuvant
regimens. As resistance to imatinib is inevitable, other
TKI drugs such as sunitinb and regorafinib have been
introduced for the management of GISTs resistant toimatinib. In addition to TKI, PDGFRA inhibitors, antiCTLA4 antibodies, and mTOR inhibitors are on trial for
management the advanced GISTs resistant to imatinib.
14 CONCLUSION
GISTs are rare but the most common mesenchymal
tumors with a high potential for malignant transformation.
With a better understanding of the pathogenesis, GISTs
almost universally express the CD117 antigen, which
contributes to distinguishing them from other GI
mesenchymal tumors. The identification of the oncogenic
mutations of c-KIT and PDGFRA as well as other rare
mutations facilitate further development of targeted
therapies. Though surgery remains the primary treatment
for patients with GISTs, imatinib plays an important role as
the primary drug for adjuvant and neoadjuvant treatment
for both resectable and metastatic GISTs. Since imatinib
resistance is almost inevitable due to development of
secondary mutations, along with other previously approved
drugs such as Sunitinib, Nilotinib, other drugs such aspazopanib and dasatinib that target multiple KIT andPDGFRA kinases have been developed. Other alternate
routes of targeting GISTs, such as anti-CTLA4 antibodies,mTOR inhibitors are also in trials. Cytoreductive surgery is
considered safe and beneficial for advanced and metastatic
GISTs. Due to high risk of surgery, minimally invasive
techniques for resection of GIST are being developedwith laparoscopy and endoscopy as well as combined
procedures. With all these new drugs and surgical
techniques, the clinical management of GISTs is developing
towards or personalised treatment of GISTs patients.

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However, more research and a multidisciplinary approach
are needed to further improve prognosis while identifying
more rare mutations, secondary mutations, and responses todeveloped drugs.
Acknowledgements
Not applicable.

[8]

[9]

Conflicts of Interest
There was no conflict of interest.

[10]

Author Contribution
All authors contributed to the manuscript and approved thefinal version.
Abbreviation List
BRAF, B-type raf proto-oncogene
CTLA4, Cytotoxic T lymphocyte associated protein 4
CECT, Contrast enhanced computed tomography
EGD, Esophagodudenoscopy
EUS, Endoscopic ultrasound
FNA, Fine needle aspiration
GIST, Gastrointestinal stromal tumor
GI, Gastrointestinal
mTOR, Mammalian/mechanistic target of Rapamycin
NIH, National Institute of Health
NCCN, National Comprehensive Cancer Network
PDGFRA, Platelet derived growth factor alphaTKI, Tyrosine kinase inhibitors

[11]

[12]

[13]
[14]

[15]

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