CASE PRESENTATION ALIREZA SADEGHI MD. General Surgery Service Kings County Medical Center October 6 th 2006

Transcription

1 CASE PRESENTATION ALIREZA SADEGHI MD General Surgery Service Kings County Medical Center October 6 th 2006

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

3 ACGME: 1,2 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

4 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

5 ACGME: 1,2,4,6 Case Presentation Physical Exam: Awake & Alert, NAD Chest: CTA B/L RRR S 1 &S 2 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

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

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19 ACGME: 1,2,4,6 Case Presentation Diagnosis: Large abdominal mass Gastrointestinal Stromal Tumor Pancreatic Cystadenoma/Cystadenocarcinoma Pancreatic Cyst/Pseudocyst

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

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

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25 ACGME: 3,5,6 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.

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30 CD117 CD34

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

32 Gastrointestinal Stromal Tumors From Biology & Pathology to the GIST of Targeted Cancer Therapy ALIREZA SADEGHI MD University Hospital Brooklyn Downstate Medical Center Kings County Hospital Center October 6 th 2006

33 ACGME: 5 Historical Overview s (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 s 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;

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

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

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

37 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

38 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;

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

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

41 ACGME: 5 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 Corless CL et al. Biology of Gastrointestinal Stromal Tumors. J Clin Oncol (2004) 22;

42 Interstitial Cells of Cajal

43 Spanish Histologist Who is Cajal? 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 ( ) Sabah M et al. Gastrointestinal stromal tumors an update. Current Diagnostic Pathology (2005) 11;

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

45 Tyrosine Kinase Membrane Receptor Families

46 Tyrosine Kinase Membrane Receptor Families Epidermal Growth Factor Receptor & Family

47 Tyrosine Kinase Membrane Receptor Families Insulin Receptor & Family

48 Tyrosine Kinase Membrane Receptor Families Platelet-Derived Growth Factor Receptor& Family including KIT

49 Tyrosine Kinase Membrane Receptor Families Vascular Endothelial Growth Factor Receptor & Family

50 Tyrosine Kinase Membrane Receptor Families Fibroblast Growth Factor Receptor & Family

51 Tyrosine Kinase Membrane Receptor Families Hepatocyte Growth Factor Receptor & Family

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

53 TK Receptor Activation and Signal Transduction Ligand Extracellular Intracellular Inactive Receptor

54 TK Receptor Activation and Signal Transduction Ligand Extracellular Intracellular Receptor Dimerization

55 TK Receptor Activation and Signal Transduction Extracellular Intracellular P P P P P P Receptor Auto-Phosphorylation & Activation

56 TK Receptor Activation and Signal Transduction Ligand Extracellular Intracellular P P P P P P

57 TK Receptor Activation and Signal Transduction Ligand Extracellular Intracellular Y Intracellular Signaling Molecule P P P P P P

58 TK Receptor Activation and Signal Transduction Ligand Extracellular Intracellular Y P P Y P P P P Recruitment & Phosphorylation of Signaling Molecule

59 TK Receptor Activation and Signal Transduction Ligand Extracellular Intracellular Y P P Y P P P P ATP ADP Recruitment & Phosphorylation of Signaling Molecule

60 TK Receptor Activation and Signal Transduction Ligand Extracellular Intracellular Y P P Y P P Y P ATP P P ADP Activation of Signaling Molecule & downstream Signaling Pathway

61 ACGME: 5 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 Sabah M et al. Gastrointestinal stromal tumors an update. Current Diagnostic Pathology (2005) 11;

62 ACGME: 5 KIT Gain-Of-Function Mutations 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 Corless CL et al. Biology of Gastrointestinal Stromal Tumors. J Clin Oncol (2004) 22;

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

64 ACGME: 5 Changing Incidence University of Miami Experience: Age & population-adjusted gastrointestinal mesenchymal tumor incidence. 13 center tumor registry: NCI (17% US population) Cancer cases in Florida since 1981 (2 million cases) Perez EA et al. Current Incidence and outcomes of Gastrointestinal Mesenchymal Tumors Including Gastrointestinal Tumors. J AM Coll Surg 2006;202:

65 ACGME: 5 Anatomic Locations & Age Perez EA et al. Current Incidence and outcomes of Gastrointestinal Mesenchymal Tumors Including Gastrointestinal Tumors. J AM Coll Surg 2006;202:

66 ACGME: 5 Anatomic Locations & Incidence of Localized Disease at Presentation Sabah M et al. Gastrointestinal stromal tumors an update. Current Diagnostic Pathology (2005) 11;

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

68 Pathology Microscopic Features Spindle cell type (70%)

69 Spindle-cell tumor with High mitotic rate

70 Pathology Microscopic Features Epithelioid type (20%) more commonly kit negative found in omentum & mesentery

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72 Pathology Microscopic Features Mixed type (5%) & Pleomorphic type (5%)

73 ACGME: 5 Immunohistochemistry: Essential for making the diagnosis

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

75 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;

76 ACGME: 5 Surgical Resection: Primary GIST DeMatteo: MSKCC 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;

77 ACGME: 5 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. Sabah M et al. Gastrointestinal stromal tumors an update. Current Diagnostic Pathology (2005) 11;

78 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

79 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

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

81 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;

82 Imaging

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

87 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

88 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?

89 ACGME: 5 What is Gleevec? Formally known as STI-571 Molecular Formula C 29 H 31 N 7 O CH 4 SO 3 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:

90 PROMOTES APOPTOSIS

91 ACGME: 5 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: /j.critrevonc

92 ACGME: 5 Outcome 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;

93 ACGME: 5 Timeline of Gleevec Development 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;

94 Treatment Options Treatment of Primary GIST Surgical Resection Adjuvant Therapy: Gleevec? VS.

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

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

97 ACGME: 5 Surgical Resection: Primary GIST 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: /j.critrevonc DeMatteo RP et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231:51-8.

98 ACGME: 5 Surgical Resection: Primary GIST 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: ~ months 5 yr survival: % 10 yr survival: % Median Survival: 5 yrs Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;

99 ACGME: 5 Treatment Options 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 Margaret von Mehren et al. Gastrointestinal Stromal Tumors. Hematol Oncol Clin N Am.19 (2005)

100 ACGME: 5 Outcomes Introduction of Gleevec Perez EA et al. Current Incidence and outcomes of Gastrointestinal Mesenchymal Tumors Including Gastrointestinal Tumors. J Am Coll Surg 2006;202:

101 ACGME: 5 Rational For Resection Short term: Elimination of pain & risk of rupture and hemorrhage Long term: Gleevec: Lesser risk of tumor recurrence through emergence of resistant clones 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;

102 Pre & Post Gleevec Lau et al. Imaging of gastrointestinal stromal tumor (GIST). Clinical Radiology (2004) 59;

103 ACGME: 5 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 Margaret von Mehren et al. Gastrointestinal Stromal Tumors. Hematol Oncol Clin N Am.19 (2005)

104 ACGME: 5 Surgical Options: Metastatic/Recurrent GIST 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 Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;

105 ACGME: 5 Surgical Options: Metastatic/Recurrent GIST 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 Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004; Mudan SS et al. Results of hepatic resection for sarcoma metastatic to liver. Ann Surg 2001;234:540-7.

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

107 ACGME: 5 Chemotherapy: Metastatic/Recurrent Disease 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 Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;

108 ACGME: 5 Chemotherapy: Metastatic/Recurrent Disease 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

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

110 ACGME: 5 Gleevec: Metastatic/Recurrent Disease Phase I Trial Gleevec (400mg BID) Well tolerated Phase II Trials US-Finland Study Group 400 mg vs. 600 mg in GIST EORTC 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 imagingstandard for the future Margaret von Mehren et al. Gastrointestinal Stromal Tumors. Hematol Oncol Clin N Am.19 (2005) Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;

111 ACGME: 5 Gleevec: Metastatic/Recurrent Disease 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 Margaret von Mehren et al. Gastrointestinal Stromal Tumors. Hematol Oncol Clin N Am.19 (2005) Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;

112 ACGME: 5 Gleevec: Metastatic/Recurrent Disease Response rate with Daily dose of mg 48-54% Disease stabilization & Minor remission 20-35% Median Time to Progression 19 Months Median duration of remission 27 Months Margaret von Mehren et al. Gastrointestinal Stromal Tumors. Hematol Oncol Clin N Am.19 (2005) Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;

113 ACGME: 5 Gleevec: Metastatic/Recurrent Disease 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% (Exon11) 40 % (Other Kit Mutations) Margaret von Mehren et al. Gastrointestinal Stromal Tumors. Hematol Oncol Clin N Am.19 (2005)

114 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 SU (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:

115 ACGME: 5 Newer Agents in Horizon Margaret von Mehren et al. Gastrointestinal Stromal Tumors. Hematol Oncol Clin N Am.19 (2005)

116 ACGME: 5 Role of Neoadjuvant Therapy Mainly for induction of resectability in metastatic disease Three separate studies looked at this concept Resection performed after 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 Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;

117 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 imatinib mesylate? Am J Surg 2003;186: Bauer S et al. Imatinib may enable complete resection in previously unresectable or metastatic GIST. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition). vol. 22, No. 14S (July 15 Supplement).

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

119 ACGME: 5 Adjuvant Therapy for Primary Tumors 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) tumors Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;

120 ACGME: 5 Adjuvant Therapy for Primary Tumors ACOSOG Z9001 (Phase III trial) in sponsorship by Cancer Therapy Evaluation Program & Novartis STI 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 arms Eisenberg et al. Surgery and Imatinib in the Management of GIST: Emerging Approaches to Adjuvant and Neoadjuvant Therapy. Ann Surg Oncol, 11(5) 2004;

121 ACGME: 5 Adjuvant Therapy for Primary Tumors ACOSOG-Z9000 ACOSOG-Z9001

122 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:

123 ACGME: 5

124 ACGME: 5