neoadjuvant imatinib, surgery and then ?

Neoadjuvant Imatinib, Surgery and then ?Neoadjuvant Imatinib, Surgery and then ?

Seattle Seattle 20072007

Neoadjuvant Imatinib, Surgery and then ?

Department of SurgeryDepartment of Surgery11 and Medical Oncology and Medical Oncology22

Netherlands Cancer InstituteNetherlands Cancer Institute - - Antoni van Leeuwenhoek ziekenhuisAntoni van Leeuwenhoek ziekenhuis Amsterdam The NetherlandsAmsterdam The Netherlands

Frits van CoevordenFrits van Coevorden11, Koert Kuhlmann, Koert Kuhlmann11 , ,

J.Martijn KerstJ.Martijn Kerst22 and Annemieke Catsand Annemieke Cats22



•Imatinib has a well established role in metastatic GISTImatinib has a well established role in metastatic GIST

•Studies on Adjuvant Imatinib after surgery are ongoingStudies on Adjuvant Imatinib after surgery are ongoing

•ACOSOG Adjuvant Trial ACOSOG Adjuvant Trial primary endpoint: primary endpoint: RFSRFS

Early interim results presented in May 2007Early interim results presented in May 2007

•Scandinavian Sarcoma Group Adjuvant StudyScandinavian Sarcoma Group Adjuvant Study

primary endpoint: primary endpoint: RFSRFS

•EORTC Adjuvant Trial GIST(62024)EORTC Adjuvant Trial GIST(62024)primary endpoint : primary endpoint : Overall SurvivalOverall Survival



• Imatinib has a well established role in metastatic GISTImatinib has a well established role in metastatic GIST

• Studies on Adjuvant Imatinib after surgery are ongoingStudies on Adjuvant Imatinib after surgery are ongoing

• the role of surgery after initial treatment with Imatinib the role of surgery after initial treatment with Imatinib for locally advanced or metastatic GIST is evolvingfor locally advanced or metastatic GIST is evolving



Surgical strategy in metastatic GISTSurgical strategy in metastatic GIST

• Remove resectable metastasis(es) (for cure ?)Remove resectable metastasis(es) (for cure ?)



Surgical strategy in metastatic GISTSurgical strategy in metastatic GIST

• Remove resectable metastasis(es) (for cure ?)Remove resectable metastasis(es) (for cure ?)

• Perform surgical (long term) palliationPerform surgical (long term) palliation

• residual disease after Imatinibresidual disease after Imatinib

• focal active disease under Imatinibfocal active disease under Imatinib

• salvage in widely active residual disease ?salvage in widely active residual disease ?



When Neoadjuvant Imatinib ?When Neoadjuvant Imatinib ?

•Locally advanced tumor (Large Size)Locally advanced tumor (Large Size)

•(unclear) Involvement of surrounding organs(unclear) Involvement of surrounding organs

•Primary resection expected to be a R1 resectionPrimary resection expected to be a R1 resection

•Primary resectable but also very restricted metastatic disease ?Primary resectable but also very restricted metastatic disease ?



Several papers have dealt with Several papers have dealt with

the role of surgerythe role of surgery

after initial treatment with Imatinib after initial treatment with Imatinib

. . Raut et al 2006Raut et al 2006

. Rutkowski et al 2006. Rutkowski et al 2006

. Bonvalot et al 2006. Bonvalot et al 2006

. Gronchi et al 2007. Gronchi et al 2007

. DeMatteo et al 2007. DeMatteo et al 2007



Progression free and Overall survivalProgression free and Overall survival after surgery after surgery after initial treatment with Imatinib for locally advanced or metastatic GISTafter initial treatment with Imatinib for locally advanced or metastatic GIST

Raut et al. J Clin Oncol 2006

1,1,00

0,0,88

0,0,66

Stable diseaseStable disease

0,0,44

0,0,22

00

prob

abili

typr

obab

ility

Limited disease progressionLimited disease progression

P = 0.02P = 0.02

P < 0.0001P < 0.0001

Generalized disease progressionGeneralized disease progression

55 1100

1155

2200

2255

3300

3355

4400Time (months)Time (months)

OSOS

PFSPFS



PFS PFS andand OS OS after surgery after surgery after initial treatment with Imatinib for locally advanced or metastatic GISTafter initial treatment with Imatinib for locally advanced or metastatic GIST

Gronchi et al. Ann Surg 2007 DeMatteo Ann Surg 2007

Responding patients

Progressive patients

11,,0000,,8800,,6600,,4400,,22

00

pro

bab

ilit

yp

roba

bil

ity

Time Time (mo)(mo)

1100

4400

2200

5500

3300

6600

PFSPFS

OSOSPFSPFS



Locally advanced GIST stomach: start Imatinib feb 2006Result after 8 months

Case history Neoadjuvant Imatinib, 60 yr femaleCase history Neoadjuvant Imatinib, 60 yr female



Partial gastrectomyPartial gastrectomy

(greater curvature)(greater curvature)

Surgery 8 months after start Imatinib

R0 resection




What is the role of Imatinib after resection ?What is the role of Imatinib after resection ?

Nobody knows or at least unclearNobody knows or at least unclear

NKI AvL protocolNKI AvL protocol

Complete resection (R0): Complete resection (R0): Stop ImatinibStop Imatinib

Resection dubious Resection dubious

Resection incomplete (R1)Resection incomplete (R1) Continue ImatinibContinue Imatinib

or metastases or metastases }



Gist database in theGist database in the NKINKI--AVLAVL

• all GIST patients seen in the period 2000-2007all GIST patients seen in the period 2000-2007

• 119 patients119 patients• 15 second opinion only15 second opinion only

• 6 incidentalomas and/or missing data6 incidentalomas and/or missing data

• 98 evaluable patients98 evaluable patients56 males,56 males, 42 females 42 females



Overall survival all evaluable patientsOverall survival all evaluable patients

from date of diagnosisfrom date of diagnosis



• 98 evaluable patients98 evaluable patients

• 2323 Surgery, no Imatinib in follow upSurgery, no Imatinib in follow up

• 7 of them in 62024, 6 refused 620247 of them in 62024, 6 refused 62024

• 5 Surgery with adjuvant Imatinib in 620245 Surgery with adjuvant Imatinib in 62024




• 2323 Surgery, no Imatinib in follow up Surgery, no Imatinib in follow up


• 5 5 Surgery with adjuvant Imatinib in 62024Surgery with adjuvant Imatinib in 62024

• 33 Imatinib for LocAdv/Meta-GIST, 33 Imatinib for LocAdv/Meta-GIST, no secondary surgeryno secondary surgery




• 2323 Surgery, no Imatinib in follow up Surgery, no Imatinib in follow up


• 55 Surgery with adjuvant Imatinib in 62024 Surgery with adjuvant Imatinib in 62024

• 3333 Imatinib for LA/Met GIST, no secondary surgery Imatinib for LA/Met GIST, no secondary surgery

• 21 Neoadjuvant Imatinib, 21 Neoadjuvant Imatinib, followed by surgeryfollowed by surgery

• 16 Surgery after Imatinib, on other indications16 Surgery after Imatinib, on other indications

• Debulking at max response, salvage (focal) progressive disease, bleedingDebulking at max response, salvage (focal) progressive disease, bleeding



Survival all groupsSurvival all groups




21 Neoadjuvant Imatinib 400 mg, 21 Neoadjuvant Imatinib 400 mg, followed by surgeryfollowed by surgery

• StomachStomach: 15: 15 Small bowel:Small bowel: 5 5 Rectum:Rectum: 1 1

• Median size: Median size: 1414 cm cm



21 Neoadjuvant Imatinib 400 mg, 21 Neoadjuvant Imatinib 400 mg, followed by surgeryfollowed by surgery

• StomachStomach: 16: 16 Small bowel:Small bowel: 4 4 Rectum:Rectum: 1 1

• Median size: Median size: 1414 cm cm

• 1313 locally advanced but non metastatic disease locally advanced but non metastatic disease

• 88 locally advanced with locally advanced with (suspicion of)(suspicion of) limited metastases limited metastases

• 2 hepatic mets2 hepatic mets 6 peritoneal mets6 peritoneal mets



21 Neoadjuvant Imatinib 400 mg21 Neoadjuvant Imatinib 400 mg

• RECIST based response:RECIST based response: 15 PR 6 SD 15 PR 6 SD

• CHOI based response:CHOI based response: 16 PR 5 SD 16 PR 5 SD






• Interval start Imatinib – Surgery:Interval start Imatinib – Surgery: 8 months (4-18) 8 months (4-18)

Primary: Primary: 7 mo ( 4 – 11 ) 7 mo ( 4 – 11 ) Metast: Metast: 13 mo ( 5 – 18 )13 mo ( 5 – 18 )






• Interval start Imatinib – Surgery:Interval start Imatinib – Surgery: 8 months (4-18) 8 months (4-18)

Primary: Primary: 7 mo ( 4 – 11 ) 7 mo ( 4 – 11 ) Metast: Metast: 13 mo ( 5 – 18 )13 mo ( 5 – 18 )

• R0 resection:R0 resection: 14 14

• R1 resection:R1 resection: 7 7



Pathological response after neoadjuvant Imatinib:Pathological response after neoadjuvant Imatinib:

4 CR 4 CR (no vital tumor)(no vital tumor)

13 PR 13 PR (vital and non vital residual disease)(vital and non vital residual disease)

4 NC 4 NC (no effects of Imatinib)(no effects of Imatinib)



SurvivalSurvival neoadjuvant vs neoadjuvant vs othersothers (minus surgery alone)(minus surgery alone)





•Continued Imatinib after surgery in Continued Imatinib after surgery in 1414 patients patients

• 11 / 14 had recurrent GIST activity ½ yr after surgery / 14 had recurrent GIST activity ½ yr after surgery

> > Radiol and path mixed response with CD117 negative active GistRadiol and path mixed response with CD117 negative active Gist

> Increase to 800 mg, nor Sunitinib proved beneficial> Increase to 800 mg, nor Sunitinib proved beneficial

>> Died of disease 21 mo after start Imatinib and 14 mo after surgeryDied of disease 21 mo after start Imatinib and 14 mo after surgery

13 / 14 No relapse so far13 / 14 No relapse so far



•Discontinued Imatinib in Discontinued Imatinib in 77 patients patients

• all R0 resectionall R0 resection

• recurrent GIST in 2 patientsrecurrent GIST in 2 patients




•had a needle tract metastasis ½ yr after surgery had a needle tract metastasis ½ yr after surgery

> Radiol SD and Path > 50% vital tumor> Radiol SD and Path > 50% vital tumor

>> After resection abdominal wall, restart adjuvant ImatinibAfter resection abdominal wall, restart adjuvant Imatinib

> ½ yr later recurrent Gist, 800 mg, nor Sunitinib proved beneficial> ½ yr later recurrent Gist, 800 mg, nor Sunitinib proved beneficial

> > Died of disease 22 mo after start Imatinib and 17 mo after surgeryDied of disease 22 mo after start Imatinib and 17 mo after surgery

Pat 1, female 69 yrPat 1, female 69 yr




• abd recurrence 2 years after surgery primary tumor abd recurrence 2 years after surgery primary tumor

> Radiol SD and at Pathology vital tumor only> Radiol SD and at Pathology vital tumor only

>> Only short response (3 months) on restart ImatinibOnly short response (3 months) on restart Imatinib

> 18 months favorable response on Sunitinib, after which relapse> 18 months favorable response on Sunitinib, after which relapse

> Again favorable response on Nilotinib> Again favorable response on Nilotinib

Alive 63 mo after start Imatinib and 56 mo after surgeryAlive 63 mo after start Imatinib and 56 mo after surgery

Pat 2, male 77 yrPat 2, male 77 yr




• So, So, recurrent GIST in 2 patientsrecurrent GIST in 2 patients

would continued Imatinib have prevented this ??would continued Imatinib have prevented this ??

• 5 patients still NED5 patients still NED 6, 8, 12,14 and 22 months after 6, 8, 12,14 and 22 months after

surgerysurgery



•Continued Imatinib Continued Imatinib in 14 patients 1 failure (7 in 14 patients 1 failure (7 %)%)

•Discontinued ImatinibDiscontinued Imatinib in 7 patientsin 7 patients 2 failures (28%) 2 failures (28%)

•So is the NKI-AvL policy safe ?So is the NKI-AvL policy safe ?




Resection dubious Resection dubious

Resection incomplete (R1)Resection incomplete (R1) Continue Imatinib !Continue Imatinib !

or limited metastases or limited metastases }• Duration of continued Imatinib unclear Duration of continued Imatinib unclear

1 yr, 2 yrs, life long ?1 yr, 2 yrs, life long ?

• Results of adjuvant studies will hopefully guide us hereResults of adjuvant studies will hopefully guide us here



Complete resection (R0)Complete resection (R0)

Continue Imatinib ?Continue Imatinib ?

ProposalProposal: :

if imaging and pathology show clear response if imaging and pathology show clear response Imatinib may be Imatinib may be

discontinueddiscontinued(restart Imatinib will probably reinduce response) Blay et al.(restart Imatinib will probably reinduce response) Blay et al.

If imaging and pathology have mixed or no response If imaging and pathology have mixed or no response

Continue ImatinibContinue Imatinib

or consider adjuvant Sutentor consider adjuvant Sutent

( preferably in study )( preferably in study )



Thank youThank you

neoadjuvant imatinib, surgery and then ?

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