Pre-operative Imatinib for Pre-operative Imatinib for metastatic, recurrent and metastatic, recurrent and

locally advanced GISTslocally advanced GISTs

E. Efthimiou, S MudanE. Efthimiou, S Mudan

On behalf of the Sarcoma GroupOn behalf of the Sarcoma Group

The Royal Marsden HospitalThe Royal Marsden Hospital

IncidenceIncidence

• Gastrointestinal Stromal Tumours GIST Gastrointestinal Stromal Tumours GIST are the most common mesenchymal are the most common mesenchymal tumours of the gastrointestinal tract. tumours of the gastrointestinal tract.

• The incidence is 15 to 20 cases per The incidence is 15 to 20 cases per million population per year for million population per year for symptomatic and clinically detected symptomatic and clinically detected GIST.GIST.

Kindblom, LG et al : Ann Oncol 2002: 13 (Suppl 5):157, 2002.Kindblom, LG et al : Ann Oncol 2002: 13 (Suppl 5):157, 2002.

Organ distributionOrgan distribution

Stomach - 70% Stomach - 70%

Small bowel - 20% Small bowel - 20%

Colorectum, oesophagus, EGIST - Colorectum, oesophagus, EGIST - 10%.10%.

Omental GISTOmental GIST Gastric GISTGastric GIST

Gastric GISTGastric GIST Gastric GISTGastric GIST

BackgroundBackground• Surgical resection is feasible in Surgical resection is feasible in

approximately two thirds of patients approximately two thirds of patients with primary non-metastatic disease. with primary non-metastatic disease.

• Approximately half of these patients Approximately half of these patients eventually develop intra-peritoneal eventually develop intra-peritoneal recurrence or liver metastases. recurrence or liver metastases.

• The 5- and 10-year survival after The 5- and 10-year survival after curative resection is 32% to 78% and curative resection is 32% to 78% and 19% to 63%, respectively.19% to 63%, respectively.

Roberts PJ,et al Eur J Cancer 2002Roberts PJ,et al Eur J Cancer 2002

Lehnet T, et al Ann Chir Gynaecol 2003Lehnet T, et al Ann Chir Gynaecol 2003

BackgroundBackground

• Imatinib is the effective therapy for Imatinib is the effective therapy for metastatic and inoperable GIST.metastatic and inoperable GIST.

• A sufficient down staging may allow A sufficient down staging may allow surgical resection either with a surgical resection either with a curative intent before or at the time curative intent before or at the time of resistance. of resistance.

BackgroundBackground

• Stable disease rate 30%Stable disease rate 30%

• Partial response rate 50%Partial response rate 50%

• Complete response rate 2%. Complete response rate 2%.

PatientsPatients

• Twenty five cases of locally Twenty five cases of locally advanced primary, recurrent or advanced primary, recurrent or metastatic GIST treated metastatic GIST treated preoperatively with Imatinib were preoperatively with Imatinib were identified from the sarcoma database identified from the sarcoma database in our Unit.in our Unit.

DesignDesign• Sex, race, age at presentation.Sex, race, age at presentation.

• Site of primary tumour and extent of Site of primary tumour and extent of disease at presentation.disease at presentation.

• Dose of Imatinib prior to the operation, Dose of Imatinib prior to the operation, side effects and duration of treatment. side effects and duration of treatment.

• Maximal tumour diameter and Maximal tumour diameter and radiological response.radiological response.

• Surgical procedure and completeness Surgical procedure and completeness of resection.of resection.

• Disease status at last follow-up.Disease status at last follow-up.

GenderGender

13 female12 male

Site of primary tumour originSite of primary tumour origin

0GJ

Small bowel

Gastric greater curveGastric lesser curve

rectum

10

8

12

4

State of response at the time State of response at the time of of surgery surgery

Stable disease

20

Progressive disease

5

progression

stable

Histological GradeHistological Grade

High

20

Intermediate

4

Low1

Pathologic response to Pathologic response to ImatinibImatinib

No resection 3No response 2Partial response 20

ResectionResection

R1OCR0R2

13 pts (52%)

6 pts (24%)3pts (12%)

3pts (12%)

Recurent/metastatic Recurent/metastatic Locally advancedLocally advanced

• Number ofpatients Number ofpatients 7 7 1818

• Male/Female Male/Female 1/6 1/6 11/711/7

• Median age at diagnosisMedian age at diagnosis 48 63 48 63

• Side effects of Imatinib 7 Side effects of Imatinib 7 11 11

Diarrhea 1 3Diarrhea 1 3

Rash 1 5Rash 1 5

Neutropenia 1 -Neutropenia 1 -

Peri-orbital oedema 4 4Peri-orbital oedema 4 4

Indigestion 2 2 Indigestion 2 2

Pleural effusion 1 -Pleural effusion 1 -

Ankle edema - 3Ankle edema - 3

• Pre Imatinib diameterPre Imatinib diameter 6.7cm 6.7cm 14.1cm14.1cm

• Post imatinib diameterPost imatinib diameter 6.6cm 6.6cm 9.8cm 9.8cm

Recurent/metastatic Recurent/metastatic Locally advancedLocally advanced

• Pathological responsePathological response

• Partial response 5 15Partial response 5 15

• No response 2 -No response 2 -

• Tumour not resected - 3Tumour not resected - 3

  

• Median Glivec DurationMedian Glivec Duration 27 months (range 6-62) 9 months 27 months (range 6-62) 9 months (range 5-32)(range 5-32)

•   Median Overall survivalMedian Overall survival  46 months (range 20-77) 9.5 months   46 months (range 20-77) 9.5 months (range 5-52) (range 5-52)

• Disease status at follow upDisease status at follow up

• Disease free 2 11Disease free 2 11

• Liver and peritoneal metastases 3 4 Liver and peritoneal metastases 3 4

• Primary disease - 2Primary disease - 2

• Dead 2 1 Dead 2 1

Postoperative survival in Postoperative survival in metastatic and recurrent metastatic and recurrent versus locally advanced GISTSversus locally advanced GISTS

Locally advanced GISTs 94%

Reccurent/metastaticGISTS 71%

Survival and site of origin of Survival and site of origin of primary GISTprimary GIST

77%

Gastric GISTsGastric GISTs

33%

90%

Survival and extent of Survival and extent of resectionresection

50%

Survival in R2 resectionsSurvival in R2 resections

Survival and pathologic Survival and pathologic responseresponse

50%

90%

90%

50%

Post operative survival and Post operative survival and status of response at status of response at operationoperation

90%

80%

Overall survivalOverall survival

Median 32monts (range 8-77 months)

Summary 1Summary 1

• 2/7 of the metastatic and recurrent 2/7 of the metastatic and recurrent GIST patients achieved macroscopic GIST patients achieved macroscopic clearance .clearance .

• 5/7 alive after a median period of 46 5/7 alive after a median period of 46 months (range 20-77)months (range 20-77)

Summary 2Summary 2

• 94% of the locally advanced group 94% of the locally advanced group are alive at median FU 9.5 monthsare alive at median FU 9.5 months

(range 5-52).(range 5-52).

• Median duration on Imatinib was 27 Median duration on Imatinib was 27 months for recurrent and metastatic months for recurrent and metastatic GIST versus 9 months for locally GIST versus 9 months for locally advanced.advanced.

Summary 3Summary 3

• R2 resection was associated with R2 resection was associated with worse survival.worse survival.

• Absence of pathological response Absence of pathological response was associated with 50% survival was associated with 50% survival versus 90% for partial response.versus 90% for partial response.

Conclusions

• Recurrent /metastatic patients Recurrent /metastatic patients required longer duration of treatment required longer duration of treatment before surgery and were less likely to before surgery and were less likely to achieve the goal of complete achieve the goal of complete macroscopic clearance.macroscopic clearance.

• Hence the survival was inferior to the Hence the survival was inferior to the locally advanced group.locally advanced group.