case presentationcase presentation • 57 year old african-american female – presented to kings...

CASE PRESENTATION

ALIREZA SADEGHI MDGeneral Surgery Service

Kings County Medical CenterOctober 6th 2006

ACGME Core Competencies

• 1) Medical Knowledge• 2) Patient Care• 3) Interpersonal & Communication Skills• 4) Practice Based Learning• 5) Systems Based Practice• 6) Professionalism

Case Presentation

• 57 year old African-American Female – presented to Kings County ED on 8/17 with chief

complaint of abdominal pain for 10 weeks• Associated complaints

– 20 lbs weight loss over 3 months– Progressive abdominal distention– Early satiety & Postprandial vomiting– Denied fever/chills, diarrhea, constipation,

hematemesis or hematochezia

ACGME: 1,2

Case Presentation

• Medical History:– Denies any medical or surgical history

• No outpatient medications & NKDA• Afebrile, Stable vitals• Admission Labs:

– CBC: 7.6/12.2/39.2/482– Chem:137/4.7/102/24/9/0.9/82– LFTs: AlkPhos 208 T.Bili 0.5– Coags: 12.6/21/1.1

ACGME: 1,2

Case Presentation

• Physical Exam:– Awake & Alert, NAD– Chest:

• CTA B/L• RRR S1&S2 present, No murmurs

– Abdomen:• Soft, markedly distended, voluntary guarding, no rebound, distant

bowel sounds.• Palpable and firm abdominal mass in all quadrants

– Non-pulsatile and immobile• Rectal: Guiac Negative

ACGME: 1,2,4,6

Case Presentation

• Previously presented to Kings County ED on 6 weeks prior with similar complaints– Had imaging studies

• Was seen by GYN service & was followed up as outpatient by GYN– Dx: Ovarian Mass

• CA 125: Elevated• AFP, CEA: Normal

Case Presentation

• Diagnosis: – Large abdominal mass

• Gastrointestinal Stromal Tumor• Pancreatic Cystadenoma/Cystadenocarcinoma• Pancreatic Cyst/Pseudocyst

ACGME: 1,2,4,6

Case Presentation

• Operative Course: 08/20/06– Exploratory Laparotomy: R2 Resection– Unable to explore abdomen due to size of tumor– Controlled entry into the tumor

• Removal of >3 liters of necrotic fluid

– En-bloc resection of greater curvature of stomach along with the mass and the mid transverse colon

– Palpable lesion in segment 3 of liver• Wedge resection

– Omentectomy

ACGME: 1,2,3,4,5,6

ACGME: 1,2,3,4,5,6

Pathology

• Abdominal mass: Portion of stomach with malignant gastrointestinal stromal tumor, partially cystic with ulceration. Necrosis seen. High mitotic figures noted. Resection margins are negative for tumor. Transverse colon: Negative for tumor

• Omentum: Metastatic tumor present.• Liver: Metastatic GIST. Negative resection margins.

– Note: Immunohistochemistry for CD117 & CD34 is positive.

ACGME: 3,5,6

CD117 CD34

Case Presentation

• Postoperative Course:– Patient experienced delayed gastric emptying with

high NGT outputs for 7 days• Responded to Prokinetics

– NGT removed on POD 8– Patient tolerated regular diet by POD 13.– Patient seen by Oncology Service

• Started on Gleevec 400mg Once Daily– Patient discharged on POD 14.

• Follow up in 3 months with imaging.

ACGME: 1,2,3,4,5,6

Gastrointestinal Stromal TumorsFrom Biology & Pathology to the GIST of Targeted

Cancer Therapy

ALIREZA SADEGHI MDUniversity Hospital Brooklyn Downstate Medical CenterKings County Hospital Center October 6th 2006

Historical Overview

• 1930-1950s (GIST = Smooth Muscle Tumor)– On the basis of Light Microscopy

• Stromal Tumors of the GI tract thought to be neoplasms of smooth muscle cell origin

• Leiomyoma, Leiomyosarcoma or Leiomyoblastomas

• 1960-1970s– On the basis of Electron Microscopy &

Immunohistochemistry studies in early 1980s• Inconsistent evidence of smooth muscle differentiation

Corless CL et al. Biology of Gastrointestinal Stromal Tumors. J Clin Oncol (2004) 22;3813–3825

ACGME: 5

Historical Overview

• Inconsistent Evidence:– Expression of Actins & Desmin found to be variable

compared to those in smooth muscle neoplasms arising from the myometrium or blood vessel walls

– Subset of Stromal Tumors stained positively for neural crest markers not present in smooth muscle neoplasms

• S100, Neuron-specific Enolase, PGP9.5• Gastrointestinal Autonomic Nerve Tumors (GANT)


ACGME: 5

Historical Overview

• Origin of Stromal Tumor– Mazur & Clark (1983)

• Introduced the term Stromal Tumor in recognition of the distinct clinical & pathological presentation of these tumor

– Mikael et al (1994)• Demonstrated the expression of CD34 on GISTs

– Poor specificity (~70%)• The term and entity of Gastrointestinal Stromal Tumor

was widely accepted in the late 90s.– Any Mesenchymal tumor of the GI tract.


ACGME: 5

Origin of GIST

• Controversy to the line of differentiation:– Myogenic Phenotypes– Neural differentiation– Mixed differentiation– Null Phenotype

• Hirota et al. Science 1998– Gain-of-function mutations of c-kit in human

gastrointestinal stromal tumors. • Separation of GIST from other GI Mesenchymal Tumors• True GIST definition is Born

Hirota et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998; 279:577-80

ACGME: 5

Origin of GIST

• Definition of GIST– Mesenchymal tumors affecting the entire GI tract– Express the KIT Protein

• CD117: Stem cell factor receptor detected by immunohistochemistry

– Three types:• Cellular Spindle Cell• Epitheloid• Pleomorphic (combination of spindle & epitheliod)

– Exclusion of true smooth muscle tumors, schwannomas and neurofibromas

Sabah M et al. Gastrointestinal stromal tumors – an update. Current Diagnostic Pathology (2005) 11;400–410

ACGME: 5

Origin of GIST

• Definition of GIST– Up to now positive immunoreactivity for KIT has been

regarded as the definition for GISTs.– Recently, it has become apparent that some GISTs that

lacked c-kit mutations were found to have activating mutations of platelet derived growth factor receptor (PDGFRα).

– Revised Definition:• GISTs now encompass Mesenchymal Tumors that express KIT

protein or have activating mutations of receptor tyrosine kinase genes (c-kit or platelet derived growth factor receptor alpha (PDGFRα)).


ACGME: 5

Cell of Origin

• Histogenesis:– Suggests that GISTs originate from

• Interstitial Cell of Cajal (ICC) or • A primitive stem cell that differentiates towards both the ICC &

smooth muscle phenotype.

– The ICCs are intercalated between the autonomic nerves & smooth muscle cells.

– Their principal function is to generate autonomous rhythmic contractions, involved in digestion & peristalsis.

• GI ‘pacemaker’ cells


Cell of Origin

• Immunohistochemical studies – GISTs have similar features to ICC

• Both positive with CD34 & CD117 and negative for other neural and smooth muscle markers.

• GISTs arise from organs in which ICC are present including– Stomach, Small Bowel, Colon, Rectum, Oral Cavity,

Biliary Tree, Omentum & Liver


ACGME: 5

Interstitial Cells of Cajal

Who is Cajal?

• Spanish Histologist

– Pioneering work on the fine structure of the nervous system in the Spanish universities

– In 1889 he discovered the mechanisms governing the morphology & connective processes of nerve cells in the gray matter of the CNS.

– First to isolate the nerve cells, called Cajal's cells, that are located near the surface of the brain.

– For his work in this field Cajal shared the 1906 Nobel Prize in physiology & medicine with the Italian cytologist Camillo Golgi.

Santiago Ramón y Cajal(1852 - 1934)


The Phenotypic Marker

• KIT Tyrosine Kinase (CD117)– Phenotypic Marker of Most GISTs– The c-kit proto-oncogene is located on the long arm of

chromosome 4• Encodes a trans membrane TK Receptor• KIT protein consists of an extra cellular ligand-binding site and an

intracellular kinase domain• The ligand for KIT is a growth factor called

– the stem cell factor (SCF)

– KIT-SCF axis is essential to the development of ICC• ICC fails to develop if either factor is missing


Tyrosine Kinase Membrane Receptor Families


Epidermal Growth Factor Receptor & Family


Insulin Receptor & Family


Platelet-Derived Growth Factor Receptor& Familyincluding KIT


Vascular Endothelial Growth Factor Receptor & Family


Fibroblast Growth Factor Receptor & Family


Hepatocyte Growth Factor Receptor & Family

The Phenotypic Marker• Extra cellular binding of

stem cell factor results in dimerization of the receptor, triggering phosphorylation of the kinase domain. – Induces a signaling cascade

that propagates through the cytoplasm into the nucleus which affects many aspects of cellular behavior including proliferation, differentiation, adhesion & apoptosis


Extracellular

Intracellular

Ligand

Inactive Receptor

TK Receptor Activation and Signal Transduction

Ligand

Extracellular

Intracellular

Receptor Dimerization


P

P

P

P

P

P

Extracellular

Intracellular

Receptor Auto-Phosphorylation& Activation


P

P

P

P

P

P

Extracellular

Intracellular

Ligand


P

P

P

P

P

P

Extracellular

Intracellular

Ligand

Y

Intracellular SignalingMolecule


P

P

P

P

P

P

Extracellular

Intracellular

Ligand

YY

Recruitment & Phosphorylationof Signaling Molecule


P

P

P

P

P

P

Extracellular

Intracellular

Ligand

ATP ADP

YY

Recruitment & Phosphorylationof Signaling Molecule


P

P

P

P

P

P

Extracellular

Intracellular

P

Ligand

ATP ADP

Y YY

Activation of SignalingMolecule &downstream

Signaling Pathway


KIT ‘Gain-Of-Function’ Mutations• The most common mutations are in

the – Juxtamembrane region in exon 11,

resulting in ligand-independent activation of tyrosine kinase

– Exon 9 (extracellular domain)– Exon 13 (kinase domain)– Exon 17 (phosphotransferase

domain)• Around 10–15% of GISTs lack KIT

expression– Within this group a large subset

have gain of function mutations of PDGFRα

– Mutations in PDGFRα provide an alternative mechanism in GIST oncogenesis


ACGME: 5

• These mutations result in:• Auto-phosphorylation of c-kit• Ligand-independent tyrosine kinase activity• Stimulation of downstream signaling pathways

leading to uncontrolled cell proliferation• Other activating mutations in Kit exist

• Germ Cell Tumors• Myleofibrosis, CML & Mastocytosis

KIT ‘Gain-Of-Function’ Mutations


ACGME: 5

Epidemiology & Risk Factors• Incidence of GISTs

– 10-20/million persons/yr for symptomatic tumors • 20-30% Malignant

– 3% GI tract Neoplasms / 5 % of all sarcomas– 80 % of gastrointestinal mesenchymal tumors– Occur in older individuals over 50 years of age

• Median age 60; Rare before age of 40– No gender preference (M>F?)

• Carney’s (F): Gastric GIST, Pulmonary Chondroma & Paraganglioma– No known risk factors for the disease– Genetic influence has been described

• Von Recklinghausen’s disease

Perez EA et al. Current Incidence and outcomes of Gastrointestinal Mesenchymal Tumors Including Gastrointestinal Tumors. J AM Coll Surg 2006;202:623-629

Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;465-475

ACGME: 5

Changing IncidenceUniversity of Miami Experience: 1992-2002Age & population-adjusted gastrointestinal mesenchymal tumor incidence.

Perez EA et al. Current Incidence and outcomes of Gastrointestinal Mesenchymal Tumors Including Gastrointestinal Tumors. J AM Coll Surg 2006;202:623-629.

ACGME: 5

13 center tumor registry: NCI (17% US population) Cancer cases in Florida since 1981 (2 million cases)

Anatomic Locations & Age


ACGME: 5

Anatomic Locations & Incidence of Localized Disease at Presentation


ACGME: 5

Pathology

• Gross Features– GISTs range in size from several millimeters to over 30 cm– Most lesions are well circumscribed & unencapsulated

• Some are multi-nodular or may have a fleshy appearance• Areas of hemorrhage, cystic degeneration & central necrosis may be

seen

– GISTs tend to be primarily intramural tumors• Usually involving the submucosa & muscularis propria

– Large tumors may have a dumbbell appearance with the tumor protruding both into the lumen & from the serosa


Pathology

• Microscopic Features– Spindle cell type (70%)

Spindle-cell tumor withHigh mitotic rate

Pathology

• Microscopic Features– Epithelioid type (20%)

• more commonly kit negative – found in omentum & mesentery

• Microscopic Features– Mixed type (5%) & Pleomorphic type (5%)

Pathology

Immunohistochemistry:Essential for making the diagnosis

ACGME: 5

Clinical Presentation

• Spectrum– Clinically low risk tumor → high risk tumor– GISTs can occur at any level of the GI tract

• Symptoms vary according to the size and location• Small asymptomatic tumors found incidentally (< 1cm)

– Laparotomy, Endoscopy or radiological studies for other conditions

• Symptomatic tumors: Abdominal discomfort– Ulcerate and present as GI bleeding– Hemorrhage into peritoneal cavity from tumor rupture– Lesions may derive blood supply from contiguous organs & detach from stomach– Lesions in the esophagus may present with dysphagia– Intestinal neoplasms may present with abdominal mass, obstruction or perforation– Some patients present with metastases, particularly to the liver


ACGME: 5

Risk of Malignant Behavior

• Consensus guidelines– NIH/NCI Workshop

April 2001• Tumor Size

– 5 yr survival» >10 cm → 20%» <5 cm → 60%

• Mitotic Index• Location

– Gastric primary fare better than SB/Rectal Sabah M et al. Gastrointestinal stromal tumors – an update. Current Diagnostic Pathology (2005) 11;400–410

ACGME: 5

Surgical Resection: Primary GIST

DeMatteo RP. The GIST of Targeted Cancer Therapy: A Tumor (Gastrointestinal Stromal Tumor), a Mutated Gene (c-kit), and a Molecular Inhibitor (STI571). Ann Surg Oncol, 9(9) 2002;831-839

ACGME: 5

DeMatteo: MSKCC

Metastasis

• Up to 30% of newly diagnosed GISTs– Overtly Malignant– Progression

• Recurrence at site of resection• Intra-abdominal spread• Liver metastasis• LN mets & extra-abdominal disease

are uncommon

– Recurrence occurs as well with Low Malignant Potential GISTs: up to 10 yrs.


ACGME: 5

Classification System• In recent years, it has become clear that GISTs require site

evaluation because of differing behavior • It has been suggested that the site of the tumor is a prognostic

factor independent of the tumor size & mitotic count with small bowel tumors having the worst prognosis

Miettinen M et al. Gastrointestinal stromal tumors – definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch (2001) 438:1-12

ACGME: 5

Prognostic Factors• Tumor stage at presentation

• Presence of Liver or Peritoneal Metastasis → Bad outcome• Tumor size, site & mitotic activity• Incomplete resection margins• Tumor Rupture (Pre or Intra-operatively)• Epitheloid Variant

• Aggressive behavior in Small Bowel• Mucosal Invasion

• Poor outcome• Cellularity• Proliferation Markers (ki-67)

Miettinen M et al. Gastrointestinal stromal tumors – definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch (2001) 438:1-12

ACGME: 5

GIST Rupture

• Perforation or tumor rupture & incomplete tumor resection

• Associated with a significantly reduced disease-free & overall survival

– 5-yr survival rate: 54% Complete Resection– 5-yr survival rate: 9% Incomplete Resection

• Tumor rupture eliminates the survival advantage conferred by complete resection of a primary GIST

– It reduces the median survival from 46 to 17 months which is comparable to the median survival after incomplete resection

» ~20 Months


ACGME: 5

Imaging

• X-ray /CT Scan / Gastrograffin Studies / MRI / US & EUS / Endoscopy

Lau et al. Imaging of gastrointestinal stromal tumor (GIST). Clinical Radiology (2004) 59;487–498

ACGME: 5

Imaging

Treatment Options

• Surgical Resection• Adjuvant Chemotherapy• Radiotherapy• Molecular Target Therapy

– Imatinib Mesylate / STI571 (Gleevec®)• Tyrosine Kinase Inhibitor• Neoadjuvant vs. Adjuvant role in Primary &

Recurrent/Metastatic GISTs

Clinical Trials

• Gleevec®– What is the right dose?– Duration of therapy?– Adjuvant therapy?– Neo-adjuvant therapy?– Influence of mutations on response to therapy?– Role of surgery in recurrence?

What is Gleevec?

• Formally known as STI-571• Molecular Formula C29H31N7O·CH4SO3

• Manufactured Novartis Pharmaceutical• FDA approval just after 32 months after

the first dose– Fastest approval by FDA of all cancer drugs

in history• Contains Imatinib Mesylate

Jean-Pierre et al. The effect of Surgery and Grade on Outcome of Gastrointestinal Stromal Tumors. Arch Surg. 2001; 136:383-389

ACGME: 5

PROMOTESAPOPTOSIS

Introduction of Gleevec:

• February 2000: Finland– First patient with metastatic GIST was treated with

Gleevec– Previously failed a variety of therapies– Therapy produced a rapid partial response

• Dramatic reduction in tumor size on CT scan & tumor uptake on PET scan

• Subsequent complete surgical resection• Histology: Myxoid degeneration of GIST

Bauer et al. Locally advanced and metastatic sarcoma (adult type) including gastrointestinal stromal tumors, Critical Reviews in Oncology/Hematology (2006), doi:10.1016/j.critrevonc.2006.06.010

ACGME: 5

Outcome


ACGME: 5

Timeline of Gleevec Development


ACGME: 5

Treatment Options

• Treatment of Primary GIST• Surgical Resection • Adjuvant Therapy: Gleevec?

VS.

Principal Treatment of Primary GIST: Surgical Resection

• Resection:– Complete tumor resection can be accomplished in

• 40% - 60% of all patients who have GIST • >70% of those who have primary nonmetastatic disease

– Fragile, especially if large with extensive hemorrhage or necrosis

• Avoid uncontrolled rupture of tumor– Preoperative biopsy not recommended

• Avoid risk of rupture, bleeding or tumor extravasation– Associated with poor prognosis


ACGME: 5

Surgical Resection: Primary GIST• Only wedge/segmental resection of underlying organ

• Protrude from tissue of origin & displace surrounding structure• Non-Invasive (unlike intra-abdominal malignancies)• Negative resection margins only for small tumors• No Lymphadenectomy required• Resect all organs en bloc to avoid spillage


ACGME: 5


• Memorial Sloan-Kettering Cancer Center– DeMatteo et al prospective study of 200 patients– 93/200 presented with Primary Tumor & No Mets

• 80 underwent complete surgical resection– 5 year survival 54%– Similar to survival at MD Anderson CC Trial

• Median survival ↓– 5 months with incomplete resection of recurrent & metastatic– 10 months with incomplete resection of metastatic lesion– 16 months with complete resection of metastatic lesion– 54 months with complete resection of locally recurrent disease

Bauer et al. Locally advanced and metastatic sarcoma (adult type) including gastrointestinal stromal tumors, Critical Reviews in Oncology/Hematology (2006), doi:10.1016/j.critrevonc.2006.06.010

DeMatteo RP et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg2000; 231:51-8.

ACGME: 5


• Outcomes– Long-term follow up for high-risk GISTs

• Surgery alone is not curative• Local recurrences / Metastasis develop in 50-90% of

patients with initial curative resection• Median Time to Recurrence: ~ 20- 25 months• 5 yr survival: 32-78 %• 10 yr survival: 19-63 %• Median Survival: 5 yrs

ACGME: 5


• Treatment of Metastatic/Recurrent GIST– Surgery– Conventional Chemotherapy/Intraperitoneal Chemotherapy– Radiotherapy: Palliation– STI571 (Gleevec)

• Outcomes before Gleevec– Median survival ranged from 6-18 month– Recurrence was the rule after resection of primary tumor

• Up to 90% had an adverse outcome (recurrence, metastasis or death)• Outcomes after Gleevec

– Median survival improved to > 24 months• Survival to 68 months after Gleevec & Aggressive surgical resection

Treatment Options

Margaret von Mehren et al. Gastrointestinal Stromal Tumors. Hematol Oncol Clin N Am.19 (2005) 547– 564

ACGME: 5

OutcomesIntroduction of Gleevec

Perez EA et al. Current Incidence and outcomes of Gastrointestinal Mesenchymal Tumors Including Gastrointestinal Tumors. J Am Coll Surg 2006;202:623-629.

ACGME: 5

Rational For Resection

• Short term:• Elimination of pain & risk of rupture and hemorrhage

• Long term:• Lesser risk of tumor recurrence through emergence of

resistant clones

• Gleevec:• Cytoreduction by decreasing volume & vascularity

– Less radical resections with less morbidity

• Tumor may under go myxoid/hyaline changes

Barnes G et al. A review of the surgical management of metastatic gastrointestinal stromal tumours(GISTs) on imatinib mesylate(Glivec). International Journal of Surgery (2005) 3; 206-212

ACGME: 5

Pre & Post Gleevec


Surgical Options:Metastatic/Recurrent GIST

• Incidence of recurrence after complete curative resection– M.D. Anderson Cancer Center Series

• 13/132 (10%) remained disease free after 68 months of follow up

• Median time to recurrence – ~ 2 years

• Site of recurrence: Abdomen– MSKCC Series

• First site of recurrence is typically Peritoneum (50%)

– 66% also had Liver involvement


ACGME: 5


• Results of surgical management of recurrence or spread– In patients whose primary tumor is a very-low-risk or

rectal/anal GISTs• Locally recurrent disease has been treated successfully with total

excision without further recurrence for 4 - 10 years.

– Clary et al studied 239 GISTs• Analysis outcomes after resection of primary, recurrent, or metastatic• Complete resection → improved disease-specific survival in all cases:

– 96 versus 26 months for primary disease– 49 versus 8 months for locally recurrent disease– 39 versus 11 months for metastatic disease


ACGME: 5


• Mudan et al reported a median survival of 15 months after surgery for recurrent GIST– The longest survival was observed in patients whose

recurrence consisted of hepatic metastasis alone– Hepatic Metastasectomy

– The only significant determinant of survival• the duration of the DFP between initial surgery & recurrence

– An indicator of the biologic aggressiveness of the tumor

• Unfortunately, resection of recurrent peritoneal GIST is seldom curative, even when all gross tumor is removed


Mudan SS et al. Results of hepatic resection for sarcoma metastatic to liver. Ann Surg 2001;234:540-7.

ACGME: 5

Chemotherapy:Metastatic/Recurrent Disease

• Before the introduction of STI571 – GISTs notoriously refractory to conventional chemotherapy– Edmonson et al

• Trial of dacarbazine, mitomycin, doxorubicin & cisplatin• Enrolled two cohorts of patients: Leiomyosarcomas vs. GISTs

– Response rates: » 54% in leiomyosarcomas vs. 4.9% in GISTs

– Doxorubicin and ifosfamide (0-27%)– Paclitaxel (7%)– Gemcitabine (0%) – Response rates: poor survival of patients with metastatic disease


ACGME: 5


• Before the introduction of STI571– Eilber et al at UCLA studied adjuvant intraperitoneal

chemotherapy using mitoxantrone for treating peritoneal recurrence

– The median time to subsequent recurrence after therapy in patients who had disease isolated to the peritoneum

• ↑ from 8 months in 8 pts who had surgery alone → 21 months in 19 pts who had surgery & intraperitoneal mitoxantrone

• This treatment concept has been largely supplanted because of the clinical efficacy of imatinib.

• Along with hepatic arterial chemoembolization:– Reserved for tumor resistant STI571


ACGME: 5


Crosby JA et al. Malignant Gastrointestinal Stromal Tumors of the Small Intestine: A Review of 50 Cases From a Prospective Database. Annals of Surgical Oncology, 8(1) 2001:50–59

ACGME: 5

Gleevec: Metastatic/Recurrent Disease

• STI571 (Gleevec®)– Oral Tyrosine Kinase Inhibitor

• Activity against Abl, Bcr-Abl, KIT, PDGFR• Phase I testing demonstrated efficacy of the agent in

GIST at a dose of 400 mg twice daily.• Toxicities: Dose dependent

– Nausea 18%– Vomiting 18%– Edema 25%– Rash 13%– Intramural Bleeding 8%


ACGME: 5


• Phase I Trial– Gleevec (400mg BID)

• Well tolerated

• Phase II Trials– US-Finland Study Group

• 400 mg vs. 600 mg in GIST

– EORTC• 400 – 1000 mg daily in GIST

vs. non-GIST – Max dose tolerated was

400 mg BID

Response Evaluation Criteria in Solid Tumors (RECIST)- Multi-slice CT is considered to be the imaging modality of choice to assess response. (3 month intervals)- PET imaging standard for the future

Margaret von Mehren et al. Gastrointestinal Stromal Tumors. Hematol Oncol Clin N Am.19 (2005) 547– 564.Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy.

Ann Surg Oncol, 11(5) 2004;465-475

ACGME: 5


• Phase III Trials– Two International Trials assessed 400 mg QD to 400 mg BID

• North American Sarcoma Intergroup (S0033)• European Organization for Research & Treatment Cancer (EORTC)

– No statistical difference in the overall survival & progression free survival– Side effects are higher in second group but less when started at 400 mg

daily & then advanced to twice daily

– Recommended dose• Initial therapy: 400mg daily• Lack of response/Progression: 400mg twice daily

– French Sarcoma Group Trial looked at duration of therapy• Continuous treatment better than interrupted temporarily


Ann Surg Oncol, 11(5) 2004;465-475

ACGME: 5


• Response rate with Daily dose of 400-800 mg – 48-54%

• Disease stabilization & Minor remission– 20-35%

• Median Time to Progression– 19 Months

• Median duration of remission– 27 Months


Ann Surg Oncol, 11(5) 2004;465-475

ACGME: 5


• Type of Mutation: KIT/PDGFR response to Gleevec• The median event-free survival

– Wild type PDGFRα mutation 82 days– Exon 9 mutation 29 weeks– Exon 11 mutation 98 weeks

• 5 year recurrence free survival – 89% (Exon 11)– 40 % (Other Kit Mutations)


ACGME: 5

Gleevec: Problems??

• Resistance to STI571– Treatment Options:

• Dose Escalation– Cross over to 400mg BID: Improved disease stabilization

• Local treatments– Radiofrequency or Laser ablation– Surgical Resection

• General Progression Despite of STI571– New Tyrosine Kinase Inhibitor under evaluation

• SU011248 (Sunitinib, Sutent®)– Multi-tyrosine kinase inhibitor with anti-angiogenetic properties– Targets KIT, PDGFR & VEGFR– Approved by FDA after phase III trials

» Reserved for Gleevec Resistance

Gupta M et al. Outcome Following Surgical Therapy for Gastrointestinal Stromal Tumors. J Gastrointest Surg 2006;10:1099-1105.

ACGME: 5

Newer Agents in Horizon


ACGME: 5

Role of Neoadjuvant Therapy

• Mainly for induction of resectability in metastatic disease– Three separate studies looked at this concept

• Resection performed after 10-12 months of Gleevec• Maximum therapeutic response assessed by CT or PET scan

– Decreased # of viable tumor cells at time of resection» Surgical therapy in responders is valuable

• Pain, rupture & hemorrhage → Resection– Impact on survival is currently unknown– Currently the RTOG-0132 is an ongoing study

• Gleevec 600 mg daily for 4-10 weeks preoperatively & then for 2 years postoperatively


ACGME: 5

Role of Neoadjuvant Therapy

• MD Anderson CC Trial• 16/17 patients treated with Gleevec → complete resection

– 2/17 patients had pathological complete response at surgery– 11/17 had partial pathological response to gleevec

» Variable tumor still present after therapy» Surgery remains an important part of therapy

• German Group• 11 patients treated with Gleevec → complete resection

– 10 patients R0 resection– 6 hepatic & 5 peritoneal metastasectomy– All patients alive at median follow up of 46 months

Scaife CL et al. Is there a role for surgery in patients with ‘‘unresectable’’ cKIT gastrointestinal stromal tumors treated with imatinibmesylate? Am J Surg 2003;186:665-9.

Bauer S et al. Imatinib may enable complete resection in previously unresectable or metastatic GIST. J Clin Oncol 2004. ASCO Annual Meeting Proceedings (Post-Meeting Edition). vol. 22, No. 14S (July 15 Supplement).

ACGME: 5

Adjuvant Therapy for Primary Tumors

• Logic for Gleevec after primary resection– Risk of recurrence after surgical resection is high– Chemotherapy is ineffective– Gleevec works in metastatic & recurrent GIST– Gleevec will have its greatest effect on survival when there is

minimal disease

• Currently under investigational studies in North America and Europe– Two studies (ACOSOG-Z9000 & ACOSOG-Z9001) – Results will be available in 2007!


ACGME: 5


• ACOSOG-Z9000 (Phase II trial) in sponsorship by Cancer Therapy Evaluation Program & Novartis– Testing 400 mg/day for 1 yr after complete resection in

patients with high risk primary GIST

• High Risk– Tumor size > 10cm– Tumor Rupture– Tumor Hemorrhage– Multifocal (>5) tumorsEisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy.

Ann Surg Oncol, 11(5) 2004;465-475

ACGME: 5


• ACOSOG – Z9001 (Phase III trial) in sponsorship by Cancer Therapy Evaluation Program & Novartis– STI571 400 mg/day vs. Placebo for 1 yr after

complete resection in patients with GIST ≥ 3 cm– Double-Blinded Randomized Trial– Placebo arm will cross over in case of recurrent

GIST– Primary end point is survival between the two armsEisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy.

Ann Surg Oncol, 11(5) 2004;465-475

ACGME: 5


ACOSOG-Z9000 ACOSOG-Z9001

ACGME: 5

Current Recommendations

• Operable GIST– Surgery: Complete Resection– Gleevec

• Incomplete resection• Tumor spillage• High-risk factors

• For marginally resectable GISTs or in cases of operable recurrent or metastatic GIST– Clinical trial of Gleevec– Surgical Resection

Gupta M et al. Outcome Following Surgical Therapy for Gastrointestinal Stromal Tumors. J Gastrointest Surg 2006;10:1099-1105.

ACGME: 5

ACGME: 5

case presentationcase presentation • 57 year old african-american female – presented to kings...

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