Case PresentationCase Presentation

Daron Geldwert, MDDaron Geldwert, MDKings County Medical CenterKings County Medical Center

March 18, 2005March 18, 2005

Gastrointestinal Stromal Tumors: A Gastrointestinal Stromal Tumors: A Molecular and Surgical ApproachMolecular and Surgical Approach

What is GIST?What is GIST?

<1% all primary GI cancers.<1% all primary GI cancers.Most common form of mesenchymal Most common form of mesenchymal (connective) tumors of the GIT.(connective) tumors of the GIT.1515--20% small bowel malignancies.20% small bowel malignancies.~5000 cases per year in US.~5000 cases per year in US.Occurs in 5Occurs in 5thth –– 77thth decade.decade.Incidence probably underestimated Incidence probably underestimated previously.previously.

Historical EvolutionHistorical Evolution

19401940’’ss-- late 1960late 1960’’ss-- Defined as smooth muscle Defined as smooth muscle neoplasmneoplasm19701970’’ss-- EM showed that only a few of these EM showed that only a few of these tumors has smooth muscle differentiationtumors has smooth muscle differentiation19831983-- Mazur and Clark coined the neutral term Mazur and Clark coined the neutral term ‘‘Gastric Stromal TumorGastric Stromal Tumor’’ after revealing that after revealing that many SMT lacked the immunohistochemical or many SMT lacked the immunohistochemical or EM evidence of smooth muscle.EM evidence of smooth muscle.

(Mazur M, Clarke H (Mazur M, Clarke H Am J Am J SurgSurg Path, 1983)Path, 1983)

Where do these tumor cells Where do these tumor cells originate from?originate from?

Originate from stem cells that differentiate Originate from stem cells that differentiate towards the interstitial cells of Cajal (ICC).towards the interstitial cells of Cajal (ICC).ICC arise from precursor mesenchymal cells that ICC arise from precursor mesenchymal cells that intercalate between nerve fibers and muscle intercalate between nerve fibers and muscle cells in the adult intestine acting as pacemaker cells in the adult intestine acting as pacemaker cells of the GIT, with regulation of peristalsis.cells of the GIT, with regulation of peristalsis.Both ICC and GIST express KIT protein and Both ICC and GIST express KIT protein and have similar ultrastructural features.have similar ultrastructural features.

((KindblomKindblom, LG et al. , LG et al. Am J Path, 1998).Am J Path, 1998).

Not all Not all GISTsGISTs arise from ICC, as some come arise from ICC, as some come from the mesentery or omentum which lack from the mesentery or omentum which lack ICCsICCs, suggesting an origin in multipotential , suggesting an origin in multipotential mesenchymal stem cells.mesenchymal stem cells.

ICCICC

CC--KIT: A Defining MarkerKIT: A Defining MarkerKIT, a 145KIT, a 145--KD transmembrane glycoprotein, is the KD transmembrane glycoprotein, is the product of the cproduct of the c--kit (CD117) protokit (CD117) proto--oncogene.oncogene.A member of the tyrosine kinase receptor.A member of the tyrosine kinase receptor.The kit receptor can be detected by IHC staining for The kit receptor can be detected by IHC staining for CD117, a cell surface antigen on the extracellular CD117, a cell surface antigen on the extracellular domain of the KIT receptor.domain of the KIT receptor.StemStem--cell factor (SCF), also known as Steel factor (SLF), cell factor (SCF), also known as Steel factor (SLF), is the ligand for Kit. is the ligand for Kit. Binding of SLF to Kit results in receptor homoBinding of SLF to Kit results in receptor homo--dimerization, activation of KIT tyrosine kinase activity, dimerization, activation of KIT tyrosine kinase activity, and resultant phosphorylation of a variety of substrates and resultant phosphorylation of a variety of substrates that serve as effectors of intracellular signal that serve as effectors of intracellular signal transduction.transduction.This activation of signal transduction pathways leads to This activation of signal transduction pathways leads to cellular growth and proliferation.cellular growth and proliferation.

KIT and its relationship to GISTKIT and its relationship to GISTHirotaHirota et al investigated the mutational status of cet al investigated the mutational status of c--kit in kit in mesenchymal tumors of the GI tract. mesenchymal tumors of the GI tract. They examined 49 mesenchymal tumors that were They examined 49 mesenchymal tumors that were diagnosed as gastrointestinal stromal tumors. diagnosed as gastrointestinal stromal tumors.

94% (46/49) of these expressed KIT. 94% (46/49) of these expressed KIT. 82% (40/49) CD3482% (40/49) CD34--positivepositive78% (38/49) positive for both KIT and CD34 78% (38/49) positive for both KIT and CD34

Demonstrated that ICC were positive for kit and CD 34.Demonstrated that ICC were positive for kit and CD 34.They also demonstrated that mutations of cThey also demonstrated that mutations of c--kit resulted kit resulted in gain of function of the enzymatic activity of the KIT in gain of function of the enzymatic activity of the KIT tyrosine kinase.tyrosine kinase.These mutations result in:These mutations result in:–– AutoAuto--phosphorylation of cphosphorylation of c--kit kit –– LigandLigand--independent tyrosine kinase activityindependent tyrosine kinase activity–– Stimulation of downstream signaling pathways Stimulation of downstream signaling pathways

leading to uncontrolled cell proliferation.leading to uncontrolled cell proliferation.

Clinical PresentationClinical Presentation

Occur in middle ages and older persons.Occur in middle ages and older persons.Range in size from millimeters to 40 cm. Range in size from millimeters to 40 cm. Average tumor size at diagnosis 8cm.Average tumor size at diagnosis 8cm.Often asymptomatic and discovered incidentally.Often asymptomatic and discovered incidentally.Commonest presentation is palpable abdominal Commonest presentation is palpable abdominal mass (50mass (50--70%), GI bleeding (30%), and 70%), GI bleeding (30%), and abdominal pain (20%). abdominal pain (20%). Abdominal fullness, obstruction or perforation.Abdominal fullness, obstruction or perforation.30% metastatic or locally infiltrating.30% metastatic or locally infiltrating.

DiagnosisDiagnosis

AXRAXREndoscopyEndoscopyCT scanCT scanPercutaneous BiopsyPercutaneous Biopsy

Gastric GISTGastric GIST

Gastric GISTGastric GIST

Rectal GISTRectal GIST

Histological CharacterizationHistological Characterization

EpitheloidEpitheloid (30%)(30%)Spindle (70%)Spindle (70%)

Low Risk versus High RiskLow Risk versus High Risk

ImmunohistochemistryImmunohistochemistry

Essential for the diagnosis.Essential for the diagnosis.The distinction between The distinction between GISTsGISTs and other and other tumors can be difficult by light microscopy tumors can be difficult by light microscopy alone.alone.

GIST GIST SchwannomaSchwannoma

GISTGIST LMSLMS

ImmunohistochemistryImmunohistochemistry

95% c95% c--Kit (CD 117)Kit (CD 117)6060--70% CD 3470% CD 342020--30% SMA30% SMA5% S5% S--10010011--2% Desmin2% Desmin

Predictors of BehaviorPredictors of Behavior

SizeSizeMitotic rateMitotic rateLocationLocationIncomplete Surgical ResectionIncomplete Surgical ResectionTumor RuptureTumor Rupture

Prognostic FactorsPrognostic Factors

Bucher, P et al. Swiss Med Wkly, 2004.Bucher, P et al. Swiss Med Wkly, 2004.

Disease Specific Survival After Disease Specific Survival After Complete ResectionComplete Resection

DeMateoDeMateo, R et al. , R et al. Ann Ann SurgSurg, 2000, 2000

Treatment OptionsTreatment Options

SurgerySurgeryRadiation/ChemotherapyRadiation/ChemotherapyTyrosine Kinase InhibitorsTyrosine Kinase Inhibitors

SurgerySurgery

Only treatment option that can definitively cure Only treatment option that can definitively cure the disease.the disease.Standard initial treatment for nonStandard initial treatment for non--metastatic metastatic disease.disease.Excise enExcise en--bloc, avoid tumor spillage.bloc, avoid tumor spillage.Lymphadenectomy not indicated.Lymphadenectomy not indicated.5 year survival in multiple studies noted to be 5 year survival in multiple studies noted to be 48%48%--65% after complete resection.65% after complete resection.Median time to recurrence in retrospective study Median time to recurrence in retrospective study about 19 months about 19 months ((PieriePierie, JP et al. , JP et al. Arch Arch SurgSurg 2001).2001).

Radiation/ChemotherapyRadiation/Chemotherapy

Rarely used.Rarely used.Highly radioHighly radio--resistant combined with the resistant combined with the radioradio--sensitivity of adjacent organs.sensitivity of adjacent organs.Chemotherapy response rates only 10Chemotherapy response rates only 10--15% with multiple drug regimens.15% with multiple drug regimens.

HUMAN PATHOLOGY, 2002.

Molecularly Targeted TherapyMolecularly Targeted Therapy

Since activation of Kit plays a crucial role in the Since activation of Kit plays a crucial role in the pathogenesis of GIST, inhibition of Kit would be pathogenesis of GIST, inhibition of Kit would be therapeutic.therapeutic.ImatinibImatinib ((GleevecGleevec) is a competitive and relatively ) is a competitive and relatively selective antagonist of ATP binding that blocks selective antagonist of ATP binding that blocks the ability of cthe ability of c--Kit to transfer phosphate groups Kit to transfer phosphate groups from ATP to tyrosine residues on substrate from ATP to tyrosine residues on substrate proteins, which in turn interrupts cproteins, which in turn interrupts c--kit mediated kit mediated signal transduction.signal transduction.

GleevecGleevec

DuffaudDuffaud et al. Oncology 2003et al. Oncology 2003

http://http://www.glivec.com/content/gist_video.www.glivec.com/content/gist_video.htmlhtml

Proof of Concept StudyProof of Concept Study50 year old female with metastatic GIST 50 year old female with metastatic GIST diagnosed in 1996.diagnosed in 1996.Liver metastases and multiple small intraLiver metastases and multiple small intra--abdominal metastases were excised in 1998. abdominal metastases were excised in 1998. Seven cycles of chemotherapy with doxorubicin, Seven cycles of chemotherapy with doxorubicin, ifosfamide, and dacarbazine with no response.ifosfamide, and dacarbazine with no response.In March 1999 had bowel obstruction found at In March 1999 had bowel obstruction found at laparotomy to have diffuse intralaparotomy to have diffuse intra--abdominal abdominal metsmets..Received thalidomide and Received thalidomide and αα--interferon with no interferon with no response.response.Treatment with 400 mg Treatment with 400 mg ImatinibImatinib once daily was once daily was started in March 2000. started in March 2000.

JoensuuJoensuu, H et al. N. Engl. J. Med., , H et al. N. Engl. J. Med., 344:344: 10521052--1056, 2001 1056, 2001

ResultsResults

MRI:MRI:–– 2wks: 41% reduction tumor size2wks: 41% reduction tumor size–– 8Mo: 75% reduction tumor size8Mo: 75% reduction tumor size–– 14Mo: >80% reduction tumor size14Mo: >80% reduction tumor size

Biological Response: Needle biopsy liver Biological Response: Needle biopsy liver showed dramatic reduction in Kit showed dramatic reduction in Kit positivity.positivity.FDGFDG--PET scan: 4 weeksPET scan: 4 weeks

Phase II Trial: Study DesignPhase II Trial: Study Design

Assess the clinical activity of Assess the clinical activity of GleevecGleevec as as reflected by objective response rates.reflected by objective response rates.Initiated July 2000Initiated July 2000Patients with unPatients with un--resectable or metastatic resectable or metastatic GIST were randomized to receive 400 or GIST were randomized to receive 400 or 600 mg of 600 mg of GleevecGleevec per day.per day.147 patients enrolled.147 patients enrolled.CR, PR, stable disease, progressive CR, PR, stable disease, progressive disease.disease.

DemetriDemetri, G. et al. NEJM, 2002., G. et al. NEJM, 2002.

Phase II: Phase II: ConCon’’dd

86% of tumor specimens analyzed (72 patients) 86% of tumor specimens analyzed (72 patients) had activating mutations of KIT had activating mutations of KIT –– 71% exon 1171% exon 11–– 14% exon 914% exon 9–– 1% exon 17 1% exon 17

Patients whose tumor had no detectable KIT Patients whose tumor had no detectable KIT mutation were eight times more likely to have mutation were eight times more likely to have primary progression in response to primary progression in response to GleevecGleevec(44%) compared with patients whose tumor (44%) compared with patients whose tumor expressed an exon 11 activating KIT mutation.expressed an exon 11 activating KIT mutation.Early registration approval from FDA in February Early registration approval from FDA in February 2002.2002.

Unanswered Questions?Unanswered Questions?

What is the right dose?What is the right dose?Duration of therapy?Duration of therapy?Will neoadjuvant therapy improve Will neoadjuvant therapy improve outcome?outcome?Will adjuvant therapy improve outcome?Will adjuvant therapy improve outcome?Influence of mutations on response to Influence of mutations on response to therapy?therapy?Role of surgery in recurrence?Role of surgery in recurrence?

Southwest Oncology Group Southwest Oncology Group (S0033)(S0033)-- DosageDosage

US Study (US Study (Rankin, C et al. Rankin, C et al. Proc Am Proc Am Soc Soc ClinClin OncolOncol, 2004), 2004). .

–– 746 patients746 patients–– Response rates 43% for bothResponse rates 43% for both–– Two year progression free 50% Two year progression free 50%

LD vs. 53% HDLD vs. 53% HD–– Two year survival estimates Two year survival estimates

78% LD vs. 73% HD78% LD vs. 73% HD–– Higher dose not significantly Higher dose not significantly

better.better.European Study (European Study (VerweijVerweij J. et al. J. et al. Lancet, Lancet, 2004).2004).–– 946 patients946 patients–– RR: 50% LD vs. 54% HDRR: 50% LD vs. 54% HD–– Two year survival: 69% LD vs. Two year survival: 69% LD vs.

74% HD74% HD–– Two year progression free Two year progression free

survival: 44% LD vs. 50% HDsurvival: 44% LD vs. 50% HD

Duration of TherapyDuration of Therapy

French Trial in progress that is randomly French Trial in progress that is randomly assigning patients with advanced GIST and no assigning patients with advanced GIST and no evidence of progressive disease after one year evidence of progressive disease after one year of of GleevecGleevec to continuous therapy, or interruption to continuous therapy, or interruption of therapy until disease progression. of therapy until disease progression. Until results return continuous therapy advised Until results return continuous therapy advised until disease progression.until disease progression.

BlayBlay JY et al. JY et al. Proc Am Soc Proc Am Soc ClinClin OncolOncol, 2004., 2004.

Adjuvant: Phase II ACSOG Z9000Adjuvant: Phase II ACSOG Z9000

High RiskHigh Risk–– Tumor >10cmTumor >10cm–– Tumor RuptureTumor Rupture–– Tumor HemorrhageTumor Hemorrhage–– Multifocal TumorsMultifocal Tumors

Must start within 84 days Must start within 84 days of resection.of resection.Continue for 1 year in the Continue for 1 year in the absence of recurrence or absence of recurrence or unacceptable toxicity.unacceptable toxicity.

Adjuvant: Phase III ACSOG Adjuvant: Phase III ACSOG (Z9001)(Z9001)

Neoadjuvant TherapyNeoadjuvant Therapy

Currently in the Currently in the formulativeformulative stages.stages.Single center study of 126 pts. at MD Anderson Single center study of 126 pts. at MD Anderson deemed 16/17 unresectable tumors resectable deemed 16/17 unresectable tumors resectable after on average 10 months of after on average 10 months of GleevecGleevec ((ScaifeScaife, C. et , C. et al. al. Am J Am J SurgSurg, 2003)., 2003).

Radiographic EvidenceRadiographic Evidence–– 4% CR4% CR–– 35% PR35% PR–– 37% Stable37% Stable–– 18% Progression18% Progression–– 2% Died2% Died

Time to RecurrenceTime to Recurrence

Median time to recurrence is 1.5 to 2 years.Median time to recurrence is 1.5 to 2 years.Only 10% who undergo complete surgical Only 10% who undergo complete surgical resection are disease free after an average resection are disease free after an average followfollow--up of 68 months (MD Anderson data).up of 68 months (MD Anderson data).55--Year Survival is about 50Year Survival is about 50--65% after complete 65% after complete resection of localized GIST versus 35% with resection of localized GIST versus 35% with advanced disease.advanced disease.A total of 40%A total of 40%--90% surgically resected patients 90% surgically resected patients have posthave post--op recurrence or metastasis. op recurrence or metastasis. Most recur in the peritoneum and liver.Most recur in the peritoneum and liver.

Influence on Mutations on Influence on Mutations on RecurrenceRecurrence

Approximately 90% of all Approximately 90% of all GISTsGISTs have a chave a c--Kit mutation.Kit mutation.All Kit mutant isoforms were All Kit mutant isoforms were associated with a clinical associated with a clinical response:response:–– Exon 11: 84% PRExon 11: 84% PR–– Exon 9: 48% PRExon 9: 48% PR

Time to treatment failureTime to treatment failure–– Exon 11: 687 daysExon 11: 687 days–– Exon 9: 200 daysExon 9: 200 days

Heinrich, MC et al. Heinrich, MC et al. J J ClinClin OncolOncol, 2003., 2003.

Peritoneal MetastasisPeritoneal Metastasis

Cytoreductive surgery followed by Cytoreductive surgery followed by intraperitonialintraperitonialchemotherapy with cisplatin and doxorubicin or chemotherapy with cisplatin and doxorubicin or mitoxantrone for peritoneal recurrence.mitoxantrone for peritoneal recurrence.In 27 patients with disease isolated to the In 27 patients with disease isolated to the peritoneum, the median time to recurrence was peritoneum, the median time to recurrence was increased from 8 months with surgery alone to increased from 8 months with surgery alone to 21 months with the addition of intraperitoneal 21 months with the addition of intraperitoneal mitoxantrone.mitoxantrone.Presently, only indicated for patients whose Presently, only indicated for patients whose tumors are resistant to tumors are resistant to GleevecGleevec..

EilberEilber, FC et al. , FC et al. SurgSurg OncolOncol, 2000., 2000.

Liver MetastasisLiver Metastasis

131 patients at MSKCC with liver 131 patients at MSKCC with liver metsmets–– 34 (26%) underwent complete resection of all 34 (26%) underwent complete resection of all

gross disease.gross disease.–– No periNo peri--operative deathsoperative deaths–– 1 and 31 and 3--yr survival were 90% and 58%.yr survival were 90% and 58%.–– Survival was predicted by the time interval Survival was predicted by the time interval

between the resection of the primary tumor between the resection of the primary tumor and the development of liver and the development of liver metsmets..

Liver MetsLiver Mets

Eisenberg, B. et al. Eisenberg, B. et al. Ann Ann SurgSurg OncolOncol, 2004., 2004.

Treatment AlgorithmTreatment Algorithm

Wu, P et al. Wu, P et al. SurgerySurgery, 2003, 2003

SummarySummary

GIST tumors are more common than previously GIST tumors are more common than previously observed.observed.IHC is essential for the diagnosis. IHC is essential for the diagnosis. The application of The application of ImatinibImatinib represents a major represents a major paradigm shift in cancer therapy, targeting the paradigm shift in cancer therapy, targeting the specific molecular abnormalities crucial in the specific molecular abnormalities crucial in the etiology of cancer.etiology of cancer.Clinical trials are in the process of elucidating Clinical trials are in the process of elucidating the role of the role of ImatinibImatinib for adjuvant and neofor adjuvant and neo--adjuvant purposes.adjuvant purposes.

QuestionsQuestionsWhat are the FDA approved indications for What are the FDA approved indications for ImatinibImatinib??

A. Completely resected GIST with negative marginsA. Completely resected GIST with negative marginsB. Metastatic GISTB. Metastatic GISTC. Locally C. Locally unresectableunresectable GISTGISTD. Incompletely excised GISTD. Incompletely excised GISTE. B and CE. B and C

Which IHC marker is most specific for GIST?Which IHC marker is most specific for GIST?A. CDA. CD--3434B. CDB. CD--117117C. cC. c--KITKITD. SD. S--100100E. B and CE. B and C

QuestionsQuestionsWhich test is most sensitive for early Which test is most sensitive for early monitoring of monitoring of GleveecGleveec efficacy?efficacy?

A.A. CT ScanCT ScanB.B. AXRAXRC.C. UltrasoundUltrasoundD.D. PET ScanPET Scan

What is the most common location of What is the most common location of GIST?GIST?

A.A. RectumRectumB.B. Small BowelSmall BowelC.C. StomachStomachD.D. EsophagusEsophagusE.E. None of the aboveNone of the above