Feb 22, Kovalam

GIST

Chandramohan K

RCC

TILL THE PAST DECADE

• Treated them as Leiomyomas or Leiomyosarcomas

• Treated them with RT

• Treated them with conventional chemo

FAILED MISERABLY

LAST DECADE

• Molecular genetics

• Epidemiology

• Management

EPIDEMIOLOGY

• 80 % of GI Sarcoma.

• GIST = 1% to 3% of all malignant GI tumors.

• Annual incidence rate across the world = 10 to 15 cases / million people.

Cassier PA et al Br J Cancer 2010;103(2):165–170

The Development of A Molecular Understanding of GIST

• CD117 antigen a marker for the presence of KIT protein.

• KIT protein is present in nearly 95% of GIST.

• KIT mutations lead to uncontrolled, ligand-independent phosphorylation by the KIT kinase.

Wang L et al. Arch Pathol Lab Med 2000;124:1471.

• KIT mutations - 85% of GIST lesions.– 70% of cases in exon 11 of KIT, others are exon 9, 13,

17.

• 10 % have mutation in PDGFR- A.Heinrich MC et al Science 2003;299:708

Principles of surgery

• Mainstay of therapy for patients with primary

non metastatic GIST

• Initial therapy if the tumor is technically

resectable with minimum morbidity or loss of function.

Goals

Complete gross resection

Intact pseudo capsule

Negative microscopic margins

Minimum morbidity

Stomach Wedge resection

Small intestine Segmental resection

Omentum, mesentery en bloc removal

Rectum, oesophagus W/E

prognosis favourable intermediate unfavourable

histology spindle epithelioid Mixed

Size in cm <5 5-10 >10

gender female male

mitosis <3 3 -15 >15

Kit mutation Exon 11

Mis sense

Exon 11

Del / ins

Exon 9, 13

Disease specific survival and tumor size

Ann Surg 231:51-57, 2000

IMMUNOHISTOCHEMICAL MARKERS IN DIAGNOSIS OF GIST

• KIT MUTATION

• PDGFRA MUTATION

• ADDITIONAL MARKERS

• CD-34

• H-Caldesmon

• SMA

• EMERGING MARKERS:-DOG1(Discovered On GIST).DOG 1 IN D/D of GIST

• PKC-THETA

Emerging Marker: PKCθ

PKCθ, protein kinase C theta.

Images reproduced with permission from Blay P et al. Clin Cancer Res. 2004;10:4089-4095.

1. Blay P et al. Clin Cancer Res. 2004;10:4089-4095.

2. Motegi A et al. Pathol Int. 2005;55:106-112.

3. Duensing A et al. Cancer Res. 2004;64:5127-5131.

GIST

×10

KIT PKCθ

5% of GIST lack detectable KIT expression 85% to 100% of GIST stain positive for PKCθ1,2

Other similar mesenchymal neoplasias do not stain positive for PKCθ3

Emerging Marker: DOG1

*DOG1.1 antibody was used to detect DOG1; DOG1, discovered on GIST-1; Images reproduced with permission from Espinosa I et al. Am J Surg Pathol. 2008;32:210-218.

Espinosa I et al. Am J Surg Pathol. 2008;32:210-218.

87% of GIST stain positive for DOG1 Other similar mesenchymal neoplasms do not stain positive for DOG1

DOG1 and KIT show similar staining patterns consistent with ICC staining in the small bowel

DOG1.1* KIT

PROGNOSTIC FACTORS OF GIST

• TUMOR SIZE

• MITOTIC RATE

• LOCATION OF PRIMARY TUMOR

• COMPLETENESS OF RESECTION

• TUMOR RUPTURE

• CELLULAR PROLLIFERATION INDEX

• DIFFUSE MUCOSAL INVASION

• ANEUPLOIDY

• TELOMERASE EXPRESSION

• EXTENT OF DISEASE

Modality of Rx

Operable = Operate

Non operable = TKI

SURGERY

• R0 resection

• No routine lymphadenectomy

• No tumour rupture or spillage

• Peritoneum & Liver carefully examined

• LAP safe in low risk and localised

Influence of Tumour Rupture on Recurrence Free Survival

No rupture

Rupture

Pro

ba

bil

ity

of

rela

ps

e-f

ree

su

rviv

al p=0.00001

Time [years]

Rutkowski et al. EJSO 2011 Jul 5 [Epub ahead of print].

Are Any GIST Benign?

• Surgery is the principal treatment and only curative therapy for localised, resectable primary disease

• All lesions ≥ 2 cm should be resected

• In the past, lesions < 2 cm have been followed (often by endoscopy) rather than resected

• Rationale for observation now called into question

– All GIST have malignant potential

– tumours < 2 cm and < 5 mitoses / 50 HPF may have low risk of

recurrence, but it is IMPOSSIBLE to assess mitotic rate on small

endoscopic biopsy samples

Casali et al. Ann Oncol 2008;19 (suppl 2):ii35–ii38.

Demetri et al. J Natl Compr Canc Netw. 2007;5 (suppl 2):S1-29.34

GIST Recurrence After Surgery

• Recurrence of moderate to high-risk GIST following surgery is common

– Majority of high-risk patients experience recurrence

– Median time to recurrence for those who recur is 2 years

• Five-year survival rates of primary GIST patients before Imatinib era was approximately 30–60%

• Recurrent disease should be treated as metastatic disease

DeMatteo et al. Hum Pathol. 2002;33:466-477.

Pierie et al. Arch Surg. 2001;136:383-389.

Rossi et al. Int J Cancer. 2003;107:171-176.

DeMatteo et al. Ann Surg. 2000;231:51-58.

Ng et al. Cancer. 1992;69:1334-1341.35

Management of Metastatic, Unresectable, or Recurrent GIST: The Paradigm Changes for Advanced Disease

• Failure of Traditional Systemic and Locoregional CytotoxicChemotherapy.

• Rates of objective antitumor response to a variety of chemotherapy agents for patients with GIST in the range of 0% to, at best, less than 5%. Goss GA et al. Proc Am Soc Clin Oncol 2000;19 .

• RT rarely plays any role in the management of patients with metastatic GIST.

• Multifocal hepatic metastases or multiple sites of intra-abdominal metastatic disease- Role of Sx dismal.

• What to use ?

• Why to use ?

• When to use ?

• Till when to use ?

• What next to use ?

This TKI…. active in Lab

Addition of imatinib to GIST cells in culture rapidly and completely blocked the constitutive activation of KIT, arrested cell proliferation, and induced apoptosis in the tumor cells.

Tuveson DA et al Oncogene 2001;20:5054.

Case report to clinical practice

• single-patient pilot study in Helsinki, Finland, with close intellectual collaboration from U.S.-based investigators.

• Treatment with four 100-mg capsules of STI571 once daily was started in March 2000.

Summary of Clinical Studies of Imatinib Mesylate in Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors (GISTs)

Study (Ref.) N Imatinib Dosage (mg) Results

Joensuu et al., 2001 (74) 1 400 daily Major response, durable for more than 2 y

van Oosterom et al., 2001 (75) 40 (36 GIST) 400 to 1,000 daily Partial remissions in 19/36 (53%) GIST patients

with additional minor responses in 6/36 (17%)

Total clinical benefit rate = 70%

No responses in non-GIST patients

Demetri et al., 2002 (61) 147 400 or 600 daily Partial remissions in 97/147 (66%) with additional

minor responses and durable stable disease in

25/147 (17%)

Total clinical benefit rate 83%, no differences for

different doses

Verweij et al., 2003 (76) 51 (27 GIST) 800 daily Complete remissions in 4%, partial remissions in

67%, with additional minor responses and durable

stable disease in 18%

Total clinical benefit rate 89%

Verweij et al., 2003 (87) 946 400 or 800 daily Complete remissions in 5%, partial remissions in

45%, with additional minor responses and durable

stable disease in 32%

Total clinical benefit rate 82%, no differences for

different doses

Blanke et al., 2008 (86) 746 400 or 800 daily Complete remissions in 2%, partial remissions in

46%, with additional minor responses and durable

stable disease in 26%

Total clinical benefit rate 74%, no differences for

different doses

Feb 22, Kovalam

Optimal dose….

Median f/u- 4.5yrs.PFS -18MNTH—400mg/dy

20mnth---800mg/dy.OS

55 mnth—400mg/day51 mnth—800mg/dy

Both ESMO and NCCN guidelines recommend that patients with exon 9 mutations should be treated with 800mg/day imatinib

Feb 22, Kovalam

Duration of imatinib……..

® at 1 yr

Randomised at 3 years

Randomised at 1 year(Blay et al, JCO 2007)

Randomised at 3 years(Le Cesne et al, Lancet Oncol 2010)

Discontinue Imatinib?

Randomised at 1 year

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Months

Surv

ival

pro

bab

ility

CONT group

19 evts / 26 patients

1-year PFS: 85%

Median PFS : 29 months ; CI95 = [18 - 41]

STOP group

29 evts / 32 patients

1-year PFS: 28%

Median PFS : 7 months ; CI95 = [3 - 9]

Log-rank P value < 0.0001

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Months

Surv

ival

pro

bab

ility

CONT group

9 evts / 25 patients

1-year PFS: 92% ; CI95 = [72 - 98]

2-years PFS: 80% ; CI95 = [58 - 91]

STOP group

21 evts / 25 patients

1-year PFS: 32% ; CI95 = [15 - 50]

2-years PFS: 16% ; CI95 = [5 - 33]

Log-rank P value < 0.0001

Randomised at 5 years(Le Cesne et al. ASCO 2011, abstract 10015)

Treatment should be continued indefinitely, since treatment interruption is generally

followed by relatively rapid tumour progression in virtually all cases (Casali et al, ESMO

guidelines, Annals of Oncology 2010)

Randomization at 10 yrs? (ongoing BFR14 amendment)

BFR14: Imatinib Discontinuation Randomization at 5 yrs

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36

Months

Surv

ival

pro

bab

ility

CONT group

0 evts / 13 patients

1-year PFS: 100%

STOP group

7 evts / 14 patients

1-year PFS: 65% ; CI95 = [31 - 85]

Log-rank P value = 0.0056

BFR14

(i) Interruption of imatinib after 1, 3, or 5 years of treatment in patients with nonprogressive GIST was associated with a high risk of progression even in patients with a complete response.

(ii) Rechallenge with imatinib restored tumor control in most patients, but the tumor response seldom reached that before treatment interruption.

(iii) Patients receiving continuous imatinib had a high rate of prolonged tumor control, which increased with longer imatinib treatment.

Post OP Imatinib

• Complete resection possible in 85% of pts with primary GIST but approx 50% will develop mets or recurrence.

• Even in R0 resection look for Risk scoring.

Very low risk Low risk Intermediate risk High risk

NIH consensus

criteria1

<2 cm and <5 mitotic

index

2−5 cm and <5 mitotic

index

5−10 cm and <5 mitotic

index or

<5 cm and 6−10 mitotic

index

>5 cm and >5 mitotic

index or

>10 cm and any

mitotic index or

any size and >10

mitotic index

Modified NIH

consensus

classification2

Any location: <2 cm

and 5 mitotic index

Any location: 2.1−5 cm

and 5 mitotic index

Gastric: 2.1−5 cm and

>5 mitotic index or

5.1−10 cm and 5

mitotic index

Any location: <5 cm

and 6−10 mitotic index

Any location: Tumor

rupture, or >10 cm, or

>10 mitotic index, or

>5 cm and >5 mitotic

index

Non-gastric: 2.1−5

cm and >5 mitotic

index, or 5.1−10 cm

and 5 mitotic index

Mitotic index, number of mitoses per 50 high-power fields. RFS, recurrence-free survival1. Fletcher CD et al. Hum Pathol 2002;33:459-465. 2. Miettinen M et al. Arch Pathol Lab Med 2006;130:1466-1478. 3. Joensuu H. Hum Pathol 2008;39:1411-1419.

Risk Classification Systems

Mitotic index, number of mitoses per 50 high-power fields. RFS, recurrence-free survival1. Fletcher CD et al. Hum Pathol 2002;33:459-465. 2. Joensuu H. Hum Pathol 2008;39:1411-1419.

3-6 cm

6-10 cm

> 10cm

Duration of post OP imatinib

36 months of imatinib

12 months of imatinib

Number at risk

36 months of imatinib 198 184 173 133 82 39 8 0

12 months of imatinib 199 177 137 88 49 27 10 0

Re

curr

en

ce-f

ree

an

d a

live

(%

)100

60·1%

47·9%

86·6%

65·6%

Hazard ratio 0·46 (95% CI 0·32-0·65)

p<0·0001

Years since randomisation

0 1 2 3 4 5 6 70

20

40

60

80

36 months of imatinib

12 months of imatinibAliv

e (

%)

96·3%

Number at risk

36 months of imatinib 198 192 184 152 100 56 13 0

12 Months of imatinib 199 188 176 140 87 46 20 0

Years since randomisation

Hazard ratio 0·45 (95% CI 0·22-0·89)

p=0·019

92·0%

94·0%

81·7%

0 1 2 3 4 5 6 7

0

20

40

60

80

100

Risk Assessment

Algorithm: Management of Unresectableor Metastatic GIST1–3

CR, complete response; PR, partial response; RFA, radiofrequency ablation; SD, stable disease; TKI, tyrosine kinase inhibitor.

1. Reichardt P. EJC Suppl. 2006;4(suppl 1):19-26.

2. National Comprehensive Cancer Network. Clinical Practice Guidelines. Soft tissue Sarcoma. V.2.2011.

http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

3. Casali P et al. Ann Oncol 2010: 21:v98-v102.

Progression

Progression

Metastatic

KIT exon 9+

Imatinib 800 mg/d

Dose-escalate

Imatinib 800 mg/d

Metastatic

Imatinib 400 mg/d

Unresectable

Imatinib 400 mg/d

CR, PR, or SD

Secondary surgery

Continue imatinib

CR or SD

Continue imatinib

CR, PR, or SD

Continue imatinib

• Continue imatinib at same dose or

• Increase imatinib dose as tolerated or

• Switch to sunitinib

• Consider surgery, RFA

• Increase imatinib dose as tolerated or

• Change to sunitinib

• Consider clinical trial

Limited/Local Generalized/Systemic

73

Suggested Treatment Algorithm for GIST Patients Who Experience Progression on Imatinib

*May not be available in all countries

Patel S. Cancer Treat Rev 2011.

Feb 22, Kovalam

Imatinib in Neo-adjuvant setting

• After maximal response (usually occurring within 4 to 6 months), definitive surgery could be performed.

• Marginally resectable or resectable with high risk of morbidity.

• Imatinib to be started soon after surgery irrespective of surgical margins.

Adverse effect of Imatinab

Adverse effects of Imatinib are generally mild (grade 1 or 2).

– Edema - approx 74% ; especially notable in the loose subcutaneous tissues of

the facial periorbital region),

– Diarrhea - 45%,

– Myalgia or musculoskeletal pain - 40%,

– Skin rashes -30%,

– Headache -25%.– Myelotoxicity is markedly less common in GIST patients than in

patients with CML.

Feb 22, Kovalam

What next when Imatinabfails……

• In stratum 1-

– stable disease -36%

– progressive disease -54%

• In stratum 2-

– partial response- 2%,

– stable disease - 43% SD,

– progressive disease - 32%.

Phase III GRID Trial

(GIST – Regorafenib In Progressive Disease)

Phase III Data on Bayer’s Regorafenib Met Primary Endpoint Showing Significant Improvement in Progression-Free Survival in Patients with GIST.

• INCLUSION criteria: Pt whose disease progressed despite prior treatment with imatinib and sunitinib.

• Patients were randomized in a 2:1 ratio to receive either regorafenib (160 mg once daily, three weeks on/ one week off) plus best supportive care (BSC) or placebo plus BSC to evaluate efficacy and safety

• The GRID study met its primary endpoint of improvement in progression-free survival (PFS) (HR=0.27, p<0.0001).

• The median PFS was 4.8 months in the regorafenib arm versus 0.9 months in the placebo arm.

Mutation Type Likely Influences Efficacy of Adjuvant Therapy

• PDGFRA mutation D842V is considered imatinib resistant– Frequency, 8.7% of the tumours in SSGXVIII

• KIT exon 9 mutation may require 800 mg/d dose1

– Frequency, 7.1% of the tumours in SSGXVIII

• Wt GIST (9.0% in SSGXVII) – Many may not be imatinib sensitive (NF1 or Carney/Carney-Stratakis

syndrome-associated GIST); succinate dehydrogenase (SDHA, SDHB, SDHC) mutations2,3 ?

1.GIST Meta-Analysis Group (MetaGIST). J Clin Oncol. 2010;28(7):1247-1253.

2.Janeway KA et al. PNAS 2011;108:314-8.

3.Pantaleo MA et al. JNCI 2011;103:1-5.84

FUTURE

• TAILORED THERAPY ( PDGFRA D842 mutation)

• Blood level testing of imatinib

• Intermediate risk group

• Adjuvant ? 3 yrs

• Other drives and other inhibitors

History , physical examination

Abdominal/pelvic CT

with contrast, and/or MRI

Chest imaging

Endoscopic ultrasound

Endoscopy as indicated

FDG PET in indicated cases

Localized or potentially resectable disease

Resect

Pathologyandriskassessment

Negative microscopic

margins

Positive Microscopic

margins

Gross residual d/s

DocumentedGIST

Negative microscopic margins

Adjuvant Imatinib

At least 12 monthsDeMatteo et al. Adjuvant imatinib mesylate increases recurrence free survival in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup Phase III trial ACOSOG Z9001. 2007 ASCO

optimal duration has not yet been determined.

Observe

ACOSOG Z9001 (american college of surgeons oncology group)

Follow-up of 1.2 yearsEnd point Recurrence

At 1.2 yrs 21% of the expected events had occurredRFS

Imatinib - 91% Placebo - 83%

OS - Same

Subset analysis ( high risk group )RFS

Imatinib - 96%Placebo - 67-86%

Management not well defined

No evidence for re-excision.

OptionsRe-excision,

Watchful waiting, ? Adjuvant imatinib.

Positive Microscopic Margin

Gross residual d/s

ImatinibConsiderReresection

NED

Persistentgross disease

imatinib

Function sparing

Marginally resectable

Technically resectable, but considerable morbidity

Neo adjuvant Imatinib

BaselineCT ± MRIConsiderPET

neo adjuvant Imatinib

Imatinib

Assess therapeutic effect

No Progression

Continue imatinib

Consider resection

Unresectable or Metastatic disease

Unresectable or Metastatic disease

On Rx with TKI Response, stable d/s

Limited – 1 or more (limited) foci of progression

Generalised – diffuse, multiple foci of progressionsystemic d/s

progression