Gastrointestinal stromal tumor medical therapy: Difference between revisions

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{{Gastrointestinal stromal tumor}}{{CMG}}{{AE}}{{PSD}}
{{Gastrointestinal stromal tumor}}
{{CMG}};{{AE}}{{Akshun}}{{PSD}}


==Overview==
==Overview==
The predominant therapy for gastrointestinal stromal tumor is surgical resection. Adjunctive [[chemotherapy]]/[[tyrosine Kinase Inhibitor]] therapy may be required.
The mainstay of treatment  for gastrointestinal stromal tumor (GIST) is surgical [[resection]]. [[Medicine|Medical]] [[therapy]] with [[Protein kinase inhibitor|tyrosine kinase inhibitors]] are indicated in [[Patient|patients]] with unresectable [[Lesion|lesions]], to decrease [[tumor]] size prior to [[surgery]] and for prevention of recurrent [[disease]]. [[Imatinib]] 400 mg to 800 mg PO q24h is the [[drug]] of choice for [[Patient|patients]] with aforementioned conditions. [[Patient|Patients]] resistant to [[imatinib]] are treated with [[sunitinib]] 50 mg PO q24h. [[Medicine|Medical]] [[therapy]] such as fluid [[resuscitation]], [[Antibiotic|antibiotics]] cover, [[deep venous thrombosis]] prophylaxis should also be given to decrease [[perioperative]] [[morbidity]] associated with [[resection]] of GIST.


==Medical Therapy==
==Medical Therapy==
*
*The treatment options for gastrointestinal stromal tumor (GIST) include surgical [[therapy]], [[chemotherapy]] and [[Tyrosine kinase inhibitors|tyrosine kinase inhibitor]] [[therapy]].<ref name="pmid29760538">{{cite journal |vauthors=Sanchez-Hidalgo JM, Duran-Martinez M, Molero-Payan R, Rufian-Peña S, Arjona-Sanchez A, Casado-Adam A, Cosano-Alvarez A, Briceño-Delgado J |title=Gastrointestinal stromal tumors: A multidisciplinary challenge |journal=World J. Gastroenterol. |volume=24 |issue=18 |pages=1925–1941 |date=May 2018 |pmid=29760538 |pmc=5949708 |doi=10.3748/wjg.v24.i18.1925 |url=}}</ref><ref name="pmid23847717">{{cite journal |vauthors=Rammohan A, Sathyanesan J, Rajendran K, Pitchaimuthu A, Perumal SK, Srinivasan U, Ramasamy R, Palaniappan R, Govindan M |title=A gist of gastrointestinal stromal tumors: A review |journal=World J Gastrointest Oncol |volume=5 |issue=6 |pages=102–12 |date=June 2013 |pmid=23847717 |pmc=3708046 |doi=10.4251/wjgo.v5.i6.102 |url=}}</ref><ref name="pmid30697609">{{cite journal |vauthors=Iwatsuki M, Harada K, Iwagami S, Eto K, Ishimoto T, Baba Y, Yoshida N, Ajani JA, Baba H |title=Neoadjuvant and adjuvant therapy for gastrointestinal stromal tumors |journal=Ann Gastroenterol Surg |volume=3 |issue=1 |pages=43–49 |date=January 2019 |pmid=30697609 |pmc=6345649 |doi=10.1002/ags3.12211 |url=}}</ref><ref name="pmid24293969">{{cite journal |vauthors=Sreevathsa MR |title=Caecal gastrointestinal stromal tumor with perforation and obstruction |journal=Indian J Surg Oncol |volume=3 |issue=4 |pages=311–3 |date=December 2012 |pmid=24293969 |pmc=3521553 |doi=10.1007/s13193-012-0185-8 |url=}}</ref><ref name="pmid26405414">{{cite journal |vauthors=Bava EP, Sharma A, Chumber S, Anand RK |title=Gastrointestinal Stromal Tumour in a Patient with Multiple Cutaneous and Uterine Leiomyomatosis- Implications and Anaesthetic Management |journal=Indian J Surg Oncol |volume=6 |issue=2 |pages=106–9 |date=June 2015 |pmid=26405414 |pmc=4577480 |doi=10.1007/s13193-014-0366-8 |url=}}</ref>
*[[Laparoscopic surgery|Laparoscopic]] or [[Endoscopic surgery|endoscopic]] surgical [[resection]] is the first-line treatment for primary and localized GIST. However, with advanced [[disease]] where [[surgery]] is not an option (unresectable lesions), [[Patient|patients]] are treated with [[tyrosine kinase inhibitor]] [[therapy]]. 
*[[Medical]] [[therapy]] is also given as part of [[Pre op work up|pre]] and post-operative care to reduce the risk of [[morbidity]] associated with surgical [[resection]] of GIST.
**Peri-operative [[fluid resuscitation]] and [[Blood transfusion|transfusion]] preferably with ringer lactate or [[normal saline]] may be given along with urinary foley's catheter to monitor fluid intake and output.
**[[Diet]] and [[nutrition]]:
***Specific peri-operative diet and nutrition ([[multivitamin]] and [[mineral supplements]]) may given either through a Ryle's tube or a peripheral/central line.
**[[Antibiotics]] cover:
***[[Patient|Patients]] with signs and [[Symptom|symptoms]] of [[bowel perforation]] or [[infarction]] should be treated with intravenous [[antibiotic]] prophylaxis to prevent surgical wound [[infection]] and [[sepsis]].
**[[Pain]] and [[deep venous thrombosis]] ([[Deep vein thrombosis|DVT]]) [[prophylaxis]]:
***Appropriate [[pain]] control ([[NSAID]] or [[morphine]]) and [[prophylaxis]] for [[Deep vein thrombosis|DVT]] ([[heparin]]) may be given as a precautionary [[therapy]] in [[Patient|patients]] complaining of [[pain]] or [[Dyspnea|breathlessness]].


===Treatment Option Overview for GIST===
==Chemotherapy==
 
*The advent of [[molecular genetics]] has drastically changed the management and outlook of [[Patient|patients]] with GIST.<ref name="pmid20436835">{{cite journal |vauthors=Peralta EA |title=Rare anorectal neoplasms: gastrointestinal stromal tumor, carcinoid, and lymphoma |journal=Clin Colon Rectal Surg |volume=22 |issue=2 |pages=107–14 |date=May 2009 |pmid=20436835 |pmc=2780247 |doi=10.1055/s-0029-1223842 |url=}}</ref>
*Surgical Therapy
*The [[tyrosine kinase inhibitors]] are the [[drug]] of choice for [[medical]] management of [[Patient|patients]] with GIST.<ref name="pmid12181401">{{cite journal |vauthors=Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H |title=Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors |journal=N. Engl. J. Med. |volume=347 |issue=7 |pages=472–80 |year=2002 |pmid=12181401 |doi=10.1056/NEJMoa020461 |url=}}</ref>
*Chemotherapy
**Prior to the use of [[Protein kinase inhibitor|tyrosine kinase inhibitors]], conventional [[chemotherapy]] were not effective in treating [[Patient|patients]] with GIST.<ref name="pmid19303137">{{cite journal |vauthors=Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K |title=Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial |journal=Lancet |volume=373 |issue=9669 |pages=1097–104 |year=2009 |pmid=19303137 |pmc=2915459 |doi=10.1016/S0140-6736(09)60500-6 |url=}}</ref>
*Tyrosine Kinase Inhibitor Therapy
**[[Cell (biology)|Cells]] with MRP1 ([[multidrug resistance]] [[protein]]-1) and [[MDR]]-1 (multidrug resistance-1) gene produce [[P-glycoprotein]] that led to increased expression of cellular [[efflux pumps]] and prevented conventional [[chemotherapy]] agents to attain appropriate [[therapeutic]] levels.
===Chemotherapy===
 
Before the advent of molecularly targeted therapy with tyrosine Kinase Inhibitor, efforts to treat GIST with conventional cytotoxic chemotherapy were essentially futile. The extreme resistance of GIST to chemotherapy may be caused, in part, by the increased expression of P-glycoprotein, the product of the MDR-1 (multidrug resistance-1) gene, and MRP1 (multidrug resistance protein-1), which are cellular efflux pumps that may prevent chemotherapeutic agents from reaching therapeutic intracellular concentrations in GIST. There is universal agreement that standard chemotherapy has no role in the primary therapy of GIST.
 
===Tyrosine Kinase Inhibitor Therapy===
===Tyrosine Kinase Inhibitor Therapy===
 
*[[Imatinib]] is a selective [[tyrosine kinase inhibitor]] (TKI) effective against KIT, PDGFRA, and [[chronic myelogenous leukemia]] specific [[BCR/ABL|BCR-ABL]] [[protein]].<ref name="pmid22453568">{{cite journal |vauthors=Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P |title=One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial |journal=JAMA |volume=307 |issue=12 |pages=1265–72 |year=2012 |pmid=22453568 |doi=10.1001/jama.2012.347 |url=}}</ref><ref name="pmid20457867">{{cite journal |vauthors=Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, Pisters PW, Raut CP, Riedel RF, Schuetze S, Sundar HM, Trent JC, Wayne JD |title=NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors |journal=J Natl Compr Canc Netw |volume=8 Suppl 2 |issue= |pages=S1–41; quiz S42–4 |year=2010 |pmid=20457867 |pmc=4103754 |doi= |url=}}</ref><ref name="pmid17046465">{{cite journal |vauthors=Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG |title=Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial |journal=Lancet |volume=368 |issue=9544 |pages=1329–38 |year=2006 |pmid=17046465 |doi=10.1016/S0140-6736(06)69446-4 |url=}}</ref><ref name="pmid21814597">{{cite journal |vauthors=Jung SH, Suh KS, Kang DY, Kang DW, Kim YB, Kim ES |title=Expression of DOG1, PDGFRA, and p16 in Gastrointestinal Stromal Tumors |journal=Gut Liver |volume=5 |issue=2 |pages=171–80 |date=June 2011 |pmid=21814597 |pmc=3140662 |doi=10.5009/gnl.2011.5.2.171 |url=}}</ref><ref name="pmid238477172">{{cite journal |vauthors=Rammohan A, Sathyanesan J, Rajendran K, Pitchaimuthu A, Perumal SK, Srinivasan U, Ramasamy R, Palaniappan R, Govindan M |title=A gist of gastrointestinal stromal tumors: A review |journal=World J Gastrointest Oncol |volume=5 |issue=6 |pages=102–12 |date=June 2013 |pmid=23847717 |pmc=3708046 |doi=10.4251/wjgo.v5.i6.102 |url=}}</ref><ref name="IshikawaKanda2018">{{cite journal|last1=Ishikawa|first1=Takashi|last2=Kanda|first2=Tatsuo|last3=Kameyama|first3=Hitoshi|last4=Wakai|first4=Toshifumi|title=Neoadjuvant therapy for gastrointestinal stromal tumor|journal=Translational Gastroenterology and Hepatology|volume=3|year=2018|pages=3–3|issn=24151289|doi=10.21037/tgh.2018.01.01}}</ref>
TKIs have revolutionized the management of GIST. The TKI [[imatinib mesylate]] is used as the first-line treatment for unresectable, metastatic, or recurrent GIST. Although complete responses are rare, a large majority of patients with metastatic or inoperable GIST have either a partial response or disease stabilization after starting [[imatinib]]. Median survival rates have gone from less than 2 years to more than 5 years since the advent of imatinib therapy.
*In addition, around 95 % [[Patient|patients]] with GIST [[stain]] positive for [[mutated]] [[CD117]] (KIT) and 5-10% for [[Mutation|mutated]] PDGFRA. These [[Patient|patients]] may be treated with agents acting against CD117 and PDGFRA ([[tyrosine kinase inhibitor]] [[therapy]]).
 
*The [[tyrosine kinase inhibitor]] (TKI) [[imatinib mesylate]] is used as the first-line treatment for unresectable [[Lesion|lesions]] (such as large primary GIST, [[Metastasis|metastatic]] or recurrent GIST).
Therapy with neoadjuvant imatinib to reduce the tumor volume may be used for patients with very large primary GIST that cannot be removed without the risk of unacceptable morbidity. Additional therapy with adjuvant imatinib is being studied to determine whether imatinib reduces recurrence, which is common after resection of primary GIST.
*[[Surgery]] is associated with greater [[morbidity]] and [[mortality]] in [[Patient|patients]] with unresectable [[Lesion|lesions]].
 
*The benefit of TKI is largely evident from the fact that median [[Survival rate|survival rates]] have gone from less than 2 years to more than 5 years with the use of [[imatinib]] [[therapy]].  
Because disease progression has been reported to follow the cessation of imatinib therapy, patients with unresectable or metastatic disease are often treated with a TKI indefinitely, as long as the disease does not progress and patient tolerance permits.
*Recent studies also recommend the use of [[imatinib]] to decrease the recurrence rate in [[Patient|patients]] undergoing [[resection]] for primary GIST.
*[[Imatinib]] is also used to shrink [[tumor]] prior to [[surgery]].
** 1.1 '''Tyrosine kinase inhibitor (TKI) '''
** 1.1.1 '''Unresectable lesions''' such as large primary GIST, [[Metastasis|metastatic]] or recurrent GIST.
*** Preferred regimen (1): [[Imatinib]] 400 mg to 800 mg PO q24h
**:'''Note (1):'''For unresectable [[Lesion|lesions]] the treatment is usually life long.
**:'''Note (2):'''Use of 800 mg daily dose has been observed with significant improvement in [[Patient|patients]] with KIT [[exon]] 9 [[mutation]].
**:'''Note (3):'''[[Patient|Patients]] resistant to 400 mg [[imatinib]] should have their dose increased to 800 mg PO q24h.
*** Alternative regimen (1): [[Sunitinib]]  50 mg PO q24h
**:'''Note (1):'''[[Sunitinib]] is given in 6 weeks cycle (with intake for 4 weeks and abstinence for 2 weeks).
**:'''Note (2):'''[[Sunitinib]] has both [[antiangiogenic]] and [[anti-tumor]] effects.
** 1.1.2 '''Adjuvant therapy after resection'''
*** Preferred regimen (1): [[Imatinib]] 400 mg PO q24h
**:'''Note (1):'''For [[Adjuvant therapy]] after [[resection]] the recommended duration of treatment is 3 years.


===Drug side effects===
===Drug side effects===
 
Common side effects of [[imatinib]] [[therapy]] include:<ref name="pmid10910906">{{cite journal |vauthors=Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ |title=Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor |journal=Blood |volume=96 |issue=3 |pages=925–32 |year=2000 |pmid=10910906 |doi= |url=}}</ref>
The most common toxicities associated with imatinib therapy, all of which may improve with prolonged treatment, include the following:
*[[Fluid]] [[retention]]
*Fluid retention (especially periorbital edema or peripheral edema; occasionally pleural effusion or ascites)
*[[Diarrhea]]
*[[Diarrhea]]
*[[Nausea]] (may be diminished if taken with food)
*[[Nausea]]
*[[Fatigue]]
*[[Fatigue]]
*[[Muscle cramps]]
*[[Muscle cramps]]
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*Mild (macrocytic) [[anemia]]
*Mild (macrocytic) [[anemia]]


Treatment with sunitinib may be considered for patients with life-threatening side effects from imatinib that cannot be managed by maximum supportive care.[4] Common side effects associated with sunitinib therapy include the following:[22,36]
Common side effects associated with [[sunitinib]] [[therapy]] include the following:
 
*[[Fatigue (physical)|Fatigue]]
*Fatigue
*[[Nausea and vomiting]]
*Nausea and vomiting
*[[Anemia]]
*Anemia
*[[Neutropenia]]
*[[Neutropenia]]
*Diarrhea
*[[Diarrhea]]
*Abdominal pain
*[[Abdominal pain]]
*[[Mucositis]]
*[[Mucositis]]
*[[Anorexia]]
*[[Anorexia]]
*Skin or hair discoloration
*[[Skin]] or [[hair]] discoloration
*[[Hypothyroidism]] (thyroid function monitoring with TSH is generally recommended to detect subclinical hypothyroidism)
*[[Hypothyroidism]]
 


==References==
==References==
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Latest revision as of 03:15, 4 March 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]Parminder Dhingra, M.D. [3]

Overview

The mainstay of treatment for gastrointestinal stromal tumor (GIST) is surgical resection. Medical therapy with tyrosine kinase inhibitors are indicated in patients with unresectable lesions, to decrease tumor size prior to surgery and for prevention of recurrent disease. Imatinib 400 mg to 800 mg PO q24h is the drug of choice for patients with aforementioned conditions. Patients resistant to imatinib are treated with sunitinib 50 mg PO q24h. Medical therapy such as fluid resuscitation, antibiotics cover, deep venous thrombosis prophylaxis should also be given to decrease perioperative morbidity associated with resection of GIST.

Medical Therapy

Chemotherapy

Tyrosine Kinase Inhibitor Therapy

Drug side effects

Common side effects of imatinib therapy include:[15]

Common side effects associated with sunitinib therapy include the following:

References

  1. ↑ Sanchez-Hidalgo JM, Duran-Martinez M, Molero-Payan R, Rufian-Peña S, Arjona-Sanchez A, Casado-Adam A, Cosano-Alvarez A, Briceño-Delgado J (May 2018). "Gastrointestinal stromal tumors: A multidisciplinary challenge". World J. Gastroenterol. 24 (18): 1925–1941. doi:10.3748/wjg.v24.i18.1925. PMC 5949708. PMID 29760538.
  2. ↑ Rammohan A, Sathyanesan J, Rajendran K, Pitchaimuthu A, Perumal SK, Srinivasan U, Ramasamy R, Palaniappan R, Govindan M (June 2013). "A gist of gastrointestinal stromal tumors: A review". World J Gastrointest Oncol. 5 (6): 102–12. doi:10.4251/wjgo.v5.i6.102. PMC 3708046. PMID 23847717.
  3. ↑ Iwatsuki M, Harada K, Iwagami S, Eto K, Ishimoto T, Baba Y, Yoshida N, Ajani JA, Baba H (January 2019). "Neoadjuvant and adjuvant therapy for gastrointestinal stromal tumors". Ann Gastroenterol Surg. 3 (1): 43–49. doi:10.1002/ags3.12211. PMC 6345649. PMID 30697609.
  4. ↑ Sreevathsa MR (December 2012). "Caecal gastrointestinal stromal tumor with perforation and obstruction". Indian J Surg Oncol. 3 (4): 311–3. doi:10.1007/s13193-012-0185-8. PMC 3521553. PMID 24293969.
  5. ↑ Bava EP, Sharma A, Chumber S, Anand RK (June 2015). "Gastrointestinal Stromal Tumour in a Patient with Multiple Cutaneous and Uterine Leiomyomatosis- Implications and Anaesthetic Management". Indian J Surg Oncol. 6 (2): 106–9. doi:10.1007/s13193-014-0366-8. PMC 4577480. PMID 26405414.
  6. ↑ Peralta EA (May 2009). "Rare anorectal neoplasms: gastrointestinal stromal tumor, carcinoid, and lymphoma". Clin Colon Rectal Surg. 22 (2): 107–14. doi:10.1055/s-0029-1223842. PMC 2780247. PMID 20436835.
  7. ↑ Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H (2002). "Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors". N. Engl. J. Med. 347 (7): 472–80. doi:10.1056/NEJMoa020461. PMID 12181401.
  8. ↑ Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K (2009). "Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial". Lancet. 373 (9669): 1097–104. doi:10.1016/S0140-6736(09)60500-6. PMC 2915459. PMID 19303137.
  9. ↑ Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P (2012). "One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial". JAMA. 307 (12): 1265–72. doi:10.1001/jama.2012.347. PMID 22453568.
  10. ↑ Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, Pisters PW, Raut CP, Riedel RF, Schuetze S, Sundar HM, Trent JC, Wayne JD (2010). "NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors". J Natl Compr Canc Netw. 8 Suppl 2: S1–41, quiz S42–4. PMC 4103754. PMID 20457867.
  11. ↑ Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG (2006). "Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial". Lancet. 368 (9544): 1329–38. doi:10.1016/S0140-6736(06)69446-4. PMID 17046465.
  12. ↑ Jung SH, Suh KS, Kang DY, Kang DW, Kim YB, Kim ES (June 2011). "Expression of DOG1, PDGFRA, and p16 in Gastrointestinal Stromal Tumors". Gut Liver. 5 (2): 171–80. doi:10.5009/gnl.2011.5.2.171. PMC 3140662. PMID 21814597.
  13. ↑ Rammohan A, Sathyanesan J, Rajendran K, Pitchaimuthu A, Perumal SK, Srinivasan U, Ramasamy R, Palaniappan R, Govindan M (June 2013). "A gist of gastrointestinal stromal tumors: A review". World J Gastrointest Oncol. 5 (6): 102–12. doi:10.4251/wjgo.v5.i6.102. PMC 3708046. PMID 23847717.
  14. ↑ Ishikawa, Takashi; Kanda, Tatsuo; Kameyama, Hitoshi; Wakai, Toshifumi (2018). "Neoadjuvant therapy for gastrointestinal stromal tumor". Translational Gastroenterology and Hepatology. 3: 3–3. doi:10.21037/tgh.2018.01.01. ISSN 2415-1289.
  15. ↑ Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ (2000). "Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor". Blood. 96 (3): 925–32. PMID 10910906.


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