Pediatric GIST The New or forgotten Kid on the Block

1
Pediatric GIST- The New (or forgotten) Kid on the
Block
Alberto S. Pappo, M.D. Texas Childrens Cancer
Center Houston, TX
2
GIST a Relatively new Entity

• 1940s
• Smooth muscle origin Leiomyosarcoma, Leiomyoma,
  Leiomyoblastoma
• 1960s
• EM no consistent smooth muscle differentiation
• 1980s
• Variable immunocytochemical expression
• Stromal tumor (1983)
• 1990s
• CD34

3
GIST Historical Classification as Other
Soft-Tissue Sarcomas

• A retrospective Swedish study determined that 72
  of GI tumors now identified as GIST had been
  originally classified as other tumors

4
Gastrointestinal pacemaker cell tumor (GIPACT)
gastrointestinal stromal tumors show phenotypic
characteristics of the interstitial cells of
Cajal LG Kindblom, HE Remotti, F Aldenborg and JM
Meis-Kindblom
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Incidence

• Most common GI sarcoma
• 5 of all sarcomas
• 0.1-3 of all gastric tumors
• Incidence 14.5/million annually
• Prevalence 129/million
• About 5,000 new cases in the US
• Highest incidence 40-60 year old
• Syndromes
• Familial
• Carney
• NF-1

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GIST Circumstances of Detection
Autopsy

• Symptomatic
• pain
• mass
• bleeding
• anemia

Incidental

• Approximately one third of GIST are asymptomatic

Kindblom. At http//www.asco.org. Miettinen et
al. Hum Pathol. 1999301213.
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GIST Overall Survival by Risk Group
Risk Groups
1.0
Normal pop.
0.9
Very low
0.8
Low
0.7
Intermediate
0.6
High
0.5
Estimated proportion surviving
Overtly malignant
0.4
0.3
0.2
0.1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Years since diagnosis
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GIST Methods of Detection

• Endoscopic visualization
• MRI
• CT
• 18FDG-PET

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GIST CT Imaging of Advanced Disease
Hepatic metastasis Hyperdense or rim enhancing
lesions
Hepatic metastasis and peritoneal
implants Hyperdense masses filled with enhancing
tumor nodules or nodules at the periphery. Notice
small tumor vessels ( )
Peritoneal implants and a subcutaneous
mass Multiple hyperdense enhancing masses
Courtesy of Dr. H. Choi.
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GIST 18FDG-PET Imaging
Advanced GIST with numerous peritoneal metastasis
Primary gastric GIST
Courtesy of Dr. H. Choi.
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GIST CT and 18FDG-PET Comparison

• CT and FDG-PET should not be approached with an
  either/or perspective each provides critical
  information for diagnosis

12
GIST Poor Historical Survival Rates Prior to the
Availability of Imatinib Mesylate
1.0
0.8
Plt0.05
0.6
Leiomyosarcoma
Proportion surviving
0.4
GIST
0.2
0
0
12
24
36
36
60
Months after diagnosis
Plaat et al. J Clin Oncol. 2000183211.
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KIT and PDGFRA Mutations in GIST
KIT
PDGFRA
Overall mutation frequency 87.2
Exon 9 (11)
Membrane
Exon 11 (67.5)
Exon 12 (0.9)
Exon 13 (0.9)
Exon 14 (0.3)
Cytoplasm
Exon 17 (0.5)
Exon 18 (6.3)
Heinrich et al. Hum Pathol. 200233484. Corless
et al. Proc Am Assoc Cancer Res. 200344.
Abstract R4447.
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Imatinib Mesylate Background

• A selective tyrosine kinase inhibitor of
• KIT
• c-Abl/Arg
• PDGFRA/B
• First used in Philadelphia chromosomepositive
  (Ph) CML

C29H31N7OCH4SO3 MW 589.7
Class Phenylaminopyrimidines
Druker et al. Nat Med. 19962561.
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Imatinib Mesylate Proposed Mechanism of Action

• Imatinib mesylate occupies the ATP binding pocket
  of the KIT kinase domain
• This prevents substrate phosphorylation and
  signaling
• A lack of signaling inhibits proliferation and
  survival

Adapted from Savage and Antman. N Engl J Med.
2002346683. Scheijen and Griffin. Oncogene.
2002213314.
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Imatinib to the Rescue!!
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Phase I/II Trials of Imatinib in Adult GIST
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Phase III Trials of Imatinib in Adult GIST
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Imatinib Mesylate in GIST B2222 Trial Response
Rates Improve Over Time
Confirmed PR
67
65
66
70
62
58
60
49
43
50
33
40
of patients
30
20
10
0
9 mo
15 mo
7 mo
34 mo
Median follow-up
Study was not powered to find a statistical
difference in efficacy between the 2
doses. Gleevec (imatinib mesylate) PI. Demetri
et al. N Engl J Med. 2002347472.von Mehren et
al. Proc Am Soc Clin Oncol. 200221403a.
Abstract 1608. Blanke et al. ASCO 2004
Gastrointestinal Cancers Symposium. Abstract 2.
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Genotype vs. Overall Survival(Interim Analysis)
Exon 9 N33
Log-rank p-value0.0383 (NS)
Heinrich et al. ASCO, 2005
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Imatinib Mesylate in GIST Phase II TrialOverall
Survival
100
Imatinib mesylate
80
60
Survival ()
40
20
SWOG GIST 8616/9627
0
0
1
2
3
4
5
Years after registration

• With a median follow-up of 34 months, median
  survival has not been reached
• Imatinib mesylate therapy is compared with
  cytotoxic chemotherapy.

Blanke et al. ASCO 2004 Gastrointestinal Cancers
Symposium. Abstract 2.
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Hazard Ratio 0.887, Log-Rank test p0.6274
Median OVERALL SURVIVAL 248 wks (58 months)
24
STABLE DISEASE Median not reached
PROGRESSION On Imatinib Median 36 wks
PARTIAL RESPONSE Median 248 wks
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GIST NCCN Guideline Unresectable or Metastatic
Disease
Continue imatinib mesylate, obtain
surgical consultation,consider resection
Response
ConsiderBaseline PET, ifdiseasepotentiallyrese
ctable uponresponse toneoadjuvanttherapy
Considerincreasing doseof imatinib
mesylate(treat to maximumresponse by CT,may
take 3-6 mo)

• Assesstherapeuticresponse
• CT PET (within 3 mo of therapy)

Definitivelyunresectableor widespreadmetastatic
disease
Progression,See TherapyforProgressiveDisease(
GIST-5)
DocumentedGIST
Imatinibmesylate
No response
See TherapyforProgressiveDisease(GIST-5)
Progression
NCCN Sarcoma Guidelines (2004).
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GIST NCCN Guideline Therapy for Progressive
Disease

• Consider referral to a specialtycenter for
  clinical trial
• If resection is feasible, considerresection of
  progressing lesion(s)
• Consider referral to a specialist
• Consider radiofrequency ablation(RFA) or
  chemoembolization(category 2B)
• Consider increasing imatinib mesylate dose as
  tolerated reassess therapeutic response with
  PET or CT
• SUTENT??

Limited
IF PS 3-4 or rapidlyprogressive
disease, consider discontinuationof imatinib
mesylate
Best supportivecare
Progression

• Consider clinical trialfor performance status
  (PS) 0-2,
• Consider increasing imatinib mesylate doseas
  tolerated reassess therapeuticresponse with PET
  or CT

Generalized(widespread, systemic)
NCCN Sarcoma Guidelines (2004).
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What do we know about Pediatric GIST

• Short answer
• NOT MUCH

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Pediatric GISTIncidence

• SEER 2001-2002
• 3 cases
• Most population-based cancer registries (also
  COC's hospital registries) collect malignant
  tumors.
• The cancer registrar would not report the case.
• The medical record would have specify GIST
  malignant or gastrointestinal stromal sarcoma.
• 2 of NRSTS
• lt 2 of all GISTS

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GI Tumors in Childhood 1972-2005
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Large series of Pediatric GIST( 18 yrs of age)
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Pediatric GISTClinical Presentation

• Palpable mass
• Gastrointestinal bleeding (most common)
• Carneys (pulmonary chondroma, paraganglioma)

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Pediatric GISTCharacteristics n 67

• gt 10 yrs of age
• Female predominance
• Stomach location
• Epithelioid or mixed
• Carneys

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Pediatric GISTPatterns of spread and outcome

• Liver
• Nodal disease
• Local (multifocal)
• Median time to progression about 4 yrs

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Mutational Status in Pediatric GIST
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Imatinib Mesylate Proposed Mechanism of Action

• Imatinib mesylate occupies the ATP binding pocket
  of the KIT kinase domain
• This prevents substrate phosphorylation and
  signaling
• A lack of signaling inhibits proliferation and
  survival

Adapted from Savage and Antman. N Engl J Med.
2002346683. Scheijen and Griffin. Oncogene.
2002213314.
38
Imatinib PK in Pediatric Patients
Blood. 2004 Nov 1104(9)2655-60
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Do Pediatric GISTs Respond to Imatinib?
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Gene expression analysis of adult vs pediatric
GIST
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Sutinib in Pediatric GIST Abstr 9519 Janeway et
al ASCO 2006

• 3 patients (8, 13, 17)
• All Imatinib resistant recurrent (2) metastatic
  (1)
• All SD or PR. CR in lung in one patient
• No mutational status

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Adult vs Pediatric GIST
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S 0146ICAS Phase II for GIST Under 30 yrs

• Prospective collaborative study for patients with
  GIST younger than 30 years
• 3 strata
• Arm 1
• Banking-data collection
• Arm 2
• Observation Relapse Imatinib 400mg PD
  Imatinib 800mg
• Arm 3
• Unresected/metastatic- Imatinib 400mg PD
  Imatinib 800 mg

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Many unanswered questions

• Distinct clincopathologic entity
• Small numbers
• Poorly studied
• NF-1-like
• Carneys
• Minority of adult GISTS
• Joint effort
• Tissue repository
• Clinical Trials
• Define best therapies for children and
  adolescents
• IF NOT US WHOIF NOT NOW WHEN?

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Acknowledgements

• Norman Scherzer
• George Demetri
• Jonathan Fletcher
• Christopher Corless
• Lynn Ries