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D r Padmini Moffett Dr Aisha Zaidi (fellow hematology/oncology ). Gist an update . GIST is a rare neoplasm that has recently become an intense focus of scientific investigation as it serves as a model for molecular therapy for cancer
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DrPadmini Moffett Dr Aisha Zaidi (fellow hematology/oncology) Gist an update
  • GIST is a rare neoplasm that has recently become an intense focus of scientific investigation as it serves as a model for molecular therapy for cancer
  • Although surgery remains the principal treatment of primary localized GIST
  • Imatinibmesylate is a selective inhibitor of KIT protein that achieves dramatic responses in metastatic GIST as well as an adjuvant therapy
  • synopsis
  • GIST is the most common mesenchymal (i.e. Sarcoma) tumor of the GI tract
  • It is thought to originate from Interstitial cells of Cajal (ICC)
  • ICC are located in and around the myenteric plexus and are thought to function as intestinal pacemaker cells that regulate intestinal motility
  • Mazur and Clark first coined the term GIST to describe GI neoplasms that neither fit features of Schwann cells nor of smooth muscle cells*
  • In 1998 Hirota et al first reported that majority of GIST harbored gain-of-function mutations in KIT (also called CD117)proto-oncogene (85%), a hallmark of GIST*
  • 3% to 5% harbor mutations in PDGFR and 10% to 15% contain wild type forms
  • background *Mazur et al Am J Surg Path 1983;6:505-519 * Hirota et al Science 1998 276;577-580 Interstitial cells of the GI CAjal
  • It has been estimated that there are 3,300 to 6,000 new GIST cases per year in the United States*
  • A study based on Surveillance, Epidemiology and End Results (SEER) registry data found that yearly incidence of GIST in the United States was 6.8 per million from 1992 to 2000*
  • GIST about equal male to female ratio, reported in people of all ages, most patients are between 40-80 years
  • Median age is 60.
  • The majority of Gist are sporadic
  • epidemiology *Annual Rev Patho 3 2008:557-586 *Am J Gastro 100 2005:162-168. location cases per year in the United States*
  • GIST may occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum
  • Esophagus (2%) Colon/Rectum (5%) Other (mesentery, retroperitoneum) 8% Major sites of GIST metastases: liver peritoneum bone lung 25% Small intestine 60% Stomach Adapted from: Corless et al. J Clin Oncol 2004;22:3813-25. Location cases per year in the United States*
  • Rectal Gist
  • Gastric Gist
  • GIST range in size from less than 1 cm to more than 40 cm cases per year in the United States*
  • Average size of approximately 5 cm when diagnosed clinically*
  • SMALL GIST
  • < 2 cm
  • sub-serosal
  • intramural or
  • less frequently polypoid intraluminal masses.
  • LARGER GIST
  • >5cm
  • form external masses attached to the outer aspect of the gut involving the muscular layers
  • *Annu Rev Pathol 3:2008 557-86
  • size Symptoms depend on the site and size of the tumor Include: cases per year in the United States*
  • Abdominal pain
  • Dysphagia
  • Gastrointestinal bleeding
  • Symptoms of bowel obstruction
  • Small tumors may be asymptomatic
  • symptoms
  • Spindle cells (70%). cases per year in the United States*
  • Epithelioid cells (20%).
  • Mixed spindle and epithelioid cells (10%)
  • CD117 antigen, marker expressed by ICC, most commonly used marker for GIST
  • 95% of GISTs are +ve for CD117 Ag, an epitope of the KIT receptor tyrosine kinase*
  • Positivity alone without a typical morphological appearance may be a false positive
  • < 2% of tumors are negative for CD 117
  • Such tumors are labeled “Stromal cell neoplasm most consistent with GIST”
  • 60-70% of tumors are also positive for CD 34,smooth muscle actin (SMA)30% to 40% and S-100(5%)
  • Ann Oncol 17 (suppl 10)2006 :280-286
  • Histopathology MORPHOLOGY cases per year in the United States* Spindle cell 70% Epithelioid 20%
  • KIT, a trans-membrane glycoprotein, is the product of the c-kit (CD117) proto-oncogene.
  • It is found on chromosome 4q11-q12and controls KIT expression.
  • A member of the tyrosine kinase receptor.
  • The kit receptor can be detected by IHC staining for CD117, a cell surface antigen on the extracellular domain of the KIT receptor.
  • Stem-cell factor (SCF), also known as Steel factor (SLF),is the ligand for Kit.
  • Kit mutation occurs in 85% of GIST , the most common site being kit exon 11(70% of GIST),exon 9(10%) .
  • Mutations of exon 13 or 17 are rarely found.
  • 3 % to 5 % of GIST harbor mutation in exons 12,14 and 18 of PDGFR alpha proto-oncogene
  • kit Binding of SLF to Kit results in receptor c-kit (CD117) proto-oncogene.homodimerization, activation of KIT tyrosine kinase activity Resultant phosphorylation of a variety of substrates That serve as effectors of intracellular signal transduction. This activation of signal transduction pathways leads to cellular growth and proliferation. Kit c-kit (CD117) proto-oncogene. Human pathology, Vol 33, May 2002 Hirota c-kit (CD117) proto-oncogene. et al investigated the mutational status of c-kit in mesenchymal tumors of the GI tract.
  • Examined 49 mesenchymal tumors diagnosed as GIST.
  • 94% (46/49) expressed KIT.
  • 82% (40/49) CD34-positive
  • 78% (38/49) positive for both KIT and CD34
  • Mutations of c-kit resulted in gain of function of the enzymatic activity of the KIT tyrosine kinase.
  • ICC were positive for kit and CD 34.
  • KIT and its relationship to GIST
  • Contrast-enhanced CT is a preferred initial Imaging study for screening and staging.
  • MRI : for specific sites where better anatomic definition is required prior to surgery. ( liver, rectum )
  • Preoperative biopsy is not generally recommended for a resectable lesion in which there is a high suspicion for GIST and the patient is otherwise operable.
  • Biospy only warranted when it will change clinical management.
  • Immunohistochemistry required for diagnosis.
  • 95% c-Kit (CD 117)
  • 60-70% CD 34
  • 20-30% SMA
  • 5% S-100
  • 1-2% Desmin
  • workup .
  • PET scanning using for screening and staging.fluorodeoxyglucose (FDG-PET) is highly sensitive for detecting tumors with a high glucose metabolism including GIST It is not specific for making a diagnosis
  • While a baseline PET may be indicated for patients in whom PET will be used to monitor the response to therapy with a tyrosine kinase inhibitor
  • All the data obtained by PET scan imaging can be found in a good quality traditional IV contrasted CT scan
  • Superior anatomic definition.
  • Diagnosis TNM staging for screening and staging. STAGING for screening and staging. After complete resection of primary disease without metastasis 5 year survival is 40-65%. The rate of recurrence is 50%* 5 year survival for patients with incomplete resection is 8-9% Median time to recurrence is 1½-2 years* Median survival after recurrence is 15 months Due to significant risk of late relapse patients should be followed for life. Survival at one year with imatinib in patients with unresectable recurrent or metastatic disease is almost 90% The interval between surgery for primary disease and development of hepatic metastases good predictor of survival patients with hepatic metastasis alone survived longer than those with distant spread esophageal GISTs have the longest survival and small intestinal GISTs have the worst* Other prognostic indicators include tumor size mitotic rate cellular proliferation Ki67 *. DeMatteo RP, Lewis JL, Leung D et al. Ann Surg 2000:231;51-57 Prognosis Fletcher et al.Hum Pathol 2002May;33(5):459–465 metastasis 5 year survival is 40-65%. The rate of recurrence is 50%* Risk of recurrence PRIMARY GIST RISK FACTORS FOR RECURRENCE AFTER SURGERY metastasis 5 year survival is 40-65%. The rate of recurrence is 50%* Tumour size 1.0 Rates of RFS were predicted by mitotic index and tumour size <5 cm 0.75 5-10 cm Mitotic index 0.50 Recurrence-free survival >10 cm 1.0 3 mitoses/30 HPF 0.25 0.75 P=0.03 >3 to 15 mitoses/30 HPF 0 Recurrence-free survival 0.50 0 20 40 60 80 Months 0.25 >15 mitoses/30 HPF P=0.0001 0 0 20 40 60 80 Months Singer et al. J ClinOncol 2002;20:3898-905. Adapted with permission from ASCO.
  • Localized: metastasis 5 year survival is 40-65%. The rate of recurrence is 50%*
  • Surgery remains the main treatment of localized primary GIST
  • Metastatic GIST
  • Imatinib is the primary treatment
  • Localized advanced or previously unresectable tumors after a favorable response to preoperative imatinib
  • Previously misclassified as leiomyosarcoma/other spindle cell cancers *Standard sarcoma adjuvant therapy is ineffective Chemo: RR ~ 5%, no impact on survival * RT: of limited value owing to location of tumor and the limit this poses on the doses that can be employed * Limited data regarding potential to control metastatic GIST by locoregional techniques such as hepatic artery embolization or chemoembolization*
  • Treatment Demetteo et al Ann of Surg 2001;234 ;540-547 *Joensuu et al Ann Oncol 2006 ;17:280-286 *D’ Amato et al Cancer control 2005;12:44-56 Treatment metastasis 5 year survival is 40-65%. The rate of recurrence is 50%*
  • Localized Disease
  • Role of adjuvant therapy
  • Duration of therapy
  • Will neoadjuvant therapy improve outcome?
  • Metastatic
  • What is the right dosage in metastatic GIST ?
  • Duration of therapy
  • Treatment options for patients who progressed on Imatinib?
  • Mechanisms of Imatinib resistance
  • Since activation of Kit played a crucial role in the pathogenesis of GIST
  • inhibition of Kit would be therapeutic.
  • Imatinib was found to be an inhibitor not specific for ABL or the kinase domain of the BCR-ABL fusion protein.
  • Gist and kit with imatinib 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamidemonomethanesulfonate Mechanism of action
  • These agents block signaling via KIT or PDGFRA by binding to the ATP binding pocket required for the phosphorylation and activation of the receptor.
  • Imatinib structure
  • The development of 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-Imatinibmesylate has revolutionized the treatment of GIST
  • In 2001 Joensuu et al published their experience with the treatment of metastatic
  • GIST in a single patient with imatinib
  • 50 year old female with metastatic GIST diagnosed in 1996
  • Liver metastases and multiple small intraabdominal metastases were excised in 1998
  • Seven cycles of chemotherapy with doxorubicin ifosfamide and dacarbazine with no response
  • In March 1999 had bowel obstruction found at laparotomy to have diffuse intra-abdominal mets
  • Received thalidomide and α-interferon with no response
  • Treatment with 400 mg Imatinib once daily was started in March 2000
  • Joensuu h et al .N Eng J Med 2001 344:1052-1056
  • . History N. Engl. J. Med., 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-344: 1052-1056, 2001 MRI: – 2wks: 41% reduction tumor size – 8Mo: 75% reduction tumor size – 14Mo: >80% reduction tumor size Biological Response: Needle biopsy liver showed dramatic reduction in Kit positivity. FDG-PET scan: 4 weeks
  • Primary localized Gist surgical resection remains the primary modality
  • Resection can be accomplished with wedge resection of stomach or segmental resection of the small bowel
  • Effort should be made for gross negative margins but wide margins not associated with better prognosis as GIST does not exhibit an intramural spreading behavior
  • Since GIST rarely metastasize to lymph nodes formal lymphadenectomy is not required
  • Localized gist Phase ii trial ( primary modalityacosog) z9000:study
  • High-risk = any of the following: Tumor at least 10 cm in greatest dimension Presence of tumor rupture before or during surgery Intraperitoneal hemorrhage Multifocal intraperitoneal tumors
  • Complete resection of high-risk primary GIST Follow for OS DeMatteo RP, et al. ASCO 2008 GI Cancers Symposium, Abstract A-8
  • Objectives: primary modalityPrimary: OS on imatinibmesylatein adjuvant setting Secondary: 2- and 5-year recurrence Toxicity in adjuvant setting
  • Treatment: Imatinibmesylate 400 mg/d
  • Inclusion: High-risk GIST
  • Imatinibmesylate–naïve
  • tumor
  • c-KIT positive
  • No prior adjuvant therapy
  • No residual disease on post-op imaging
  • Phase ii trial (acosog z9000 N= 107 primary modality
  • Imatinib started at a median of 59 (range 25-84) days after operation
  • Median age = 58 years (range 19-79)
  • Median tumor size 13 cm (range 3-42)
  • 50% of tumors gastric, 42% small intestine
  • Imatinib therapy well tolerated (ASCO 2005 Annual Meeting)
  • Median follow-up of 4 years: 1 2 and 3 yr OS= 99, 97, and 97%, respectively 1 2 and 3 yr RFS= 94, 73, and 61%, respectively Imatinib 400 mg for 1 year after resection of high-risk primary GIST prolongs RFS and OS compared with historical controls
  • Z9000 4 year results ACOSOG Z9001 primary modality Patient assigned primary modality To placebo were Eligible to cross Over to imatinib Treatment in the Event of tumor Recurrence. Acosog z9001 Acosog primary modality z9001 With a median follow-up for surviving patients of 19.7 months (min-max: 0–56.4 months), the estimated one-year RFS was 98% on the imatinib arm versus 83% on the placebo arm with a p value <0.0001.
  • Reasons for OS being comparable
  • Relatively short follow up
  • Cross over design
  • Ongoing trials: EORTC: GIST >3cm,2yrs imatinib Vs placebo. Scand sarcoma group : 12 vs 36 month Treatment in high risk pt. Randomized trials in adjuvant setting primary modality
  • PHASE II TRIAL OF NEOADJUVANT/ADJUVANT IMATINIB FOR ADVANCED GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL
  • WILL NEOADJUVANT IMATINIB IMPROVE OUTCOME Burton et al J surg Oncol 2009 :99 42-47
  • 2 year PFS in group A was 83%and GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL
  • Group B was 77%
  • The estimated OS Group A 93 % and
  • Group B was 91%
  • Relatively small group of patients.
  • The progression and survival rates are quite favorable in comparison to historical single institutional surgical series for high risk GIST patients where median DFS ranged from 7 to 20 months*. *Dematteo et al.Ann Surg.2000;231:51-58
  • Rtog trial A multicenter phase II trial of GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIALSTI571(imatinib) was initiated in July 2000
  • 147 Patients with un-resectable or metastatic GIST were randomized to receive 400 or 600 mg of STI571 per day
  • Side effects: mild-to-moderate edema diarrhea and fatigue were common
  • Gastrointestinal or intraabdominal hemorrhage occurred in approximately 5% of patients
  • There were no significant differences in toxic effects or response between the two doses.
  • 88 %were alive one year after the initiation of treatment with Imatinib
  • B222 trial * Demetri et al NEJM Volume 2002 347:472-480 B222 trial GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIALcont
  • No patient with complete response
  • 53.7% had partial response . 27.9 % had stable disease
  • Disease progression in 13.6%
  • Reduction in bulk of tumor was 50 to 96%
  • Median time to objective response was 13 weeks
  • No significant differences in rate of response between the two doses
  • 86% of tumor specimens analyzed GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL
  • (72 patients) had activating mutations
  • of KIT
  • 71% exon 11
  • 14% exon 9
  • Patients whose tumor had no detectable KIT mutation were more likely to have primary progression in response to STI571 compared with patients whose tumor expressed an exon 11 activating KIT mutation
  • B222 trial
  • EORTC Study design GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL:
  • 946 patients were randomly allocated to imatinib 400mg either once a day or twice a day
  • Those assigned the once a day regimen who had progression were offered the option of crossover
  • Primary End Point
  • Progression free survival
  • Secondary End Point
  • Overall survival
  • Response to treatment and toxic effects
  • Inclusion
  • Histologically proven advanced or metastatic gist characterized by C-kit expression
  • Other criteria
  • WHO performance status less than 4
  • ANC >1.5x109
  • platelet ct 100x109
  • serum creatinineupto 1.5 times the upper limit of normal and total
  • Bilirubin less than 1.5 times the upper limit of normal
  • At median follow up of 760 days GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL
  • 263(56%) of 473 patients allocated in Imatinib once a day had progressed compared to 235 (50%) of 473 that were assigned treatment twice a day
  • Side effects were frequent but mostly mild and arose in 468/472 (99%) in the twice daily arm and 465/470(98%) in the once daily arm
  • Similar response induction b/w the 2 groups.
  • Eortctrial Eortc GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL cont.. Eortc GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL Clinical Studies: R GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIALelationship Between Kinase Genotypeand Responseon ImatinibMesylate Therapy
  • The presence of GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIALKIT exon 9 mutations was the strongest prognostic factor of risk for progression and death
  • The risk for progression and death were also increased in patients with no detectable KIT or PDGFRA mutations
  • PFS (but not OS) for the exon 9 genotypes in this trial was significantly better in the high-dose imatinib arm (400 mg twice daily) compared with the standard-dose arm (400 mg daily)
  • In addition the response rate after crossover from 400 mg of imatinib daily to 400 mg twice daily was much higher among patients with KIT exon 9 mutations (57%) than among those with KIT exon 11 mutations (7%).
  • conclusion Blanke GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL et al .J clinOncol 2008 26; 626:632
  • 746 patients with metastatic and GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIALunresectable GIST were enrolled in this multicenter open label phase III trial to receive standard dose 400mg vs high dose 400mg twice a day
  • If progression occurred patients on standard dose arm could cross over to the higher dose arm
  • Primary end point : Progression Free Survival
  • Median follow up: 4.5 years
  • 2 year PFS rate of 41% in standard arm vs 46% in high dose arm
  • Median progression free survival : 18 months in standard arm vs 20 months in high dose arm
  • No difference on OR.
  • s0033 The SWOG S0033 GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL Confirmed the findings of B222 and EORTC that kit exon 11 is associated With favorable outcome in advanced GIST Compared to Kit exon 9 and WT GIST. The PFS advantage seen in Patients treated with high dose imatinib With exon 9 mutations was not seen In S0033. However patients with exon 9 mutations treated with 800mg imatinib Had improved response rates(67%vs17%) Compared with 400mg imatinib respectively Swog s0033 Impact of Genotype on Response GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIALin KIT+ GIST (S0033) Heinrich et al. J Clin Oncol. 2005;23(Suppl 16):3s. metagist GIST PRIMARYAND METASTATIC RECURRENT OPERABLE , RESULTS OF RTOG TRIAL
  • End Points : PFS and OS
  • Investigated cofactors : age
  • sex
  • PS
  • primary tumor
  • Size
  • t
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