Gastro Intestinal Stromal T m rlerde GIST Tedaviye Yanitin Degerlendirilmesinde

1. Gastro Intestinal Stromal T�m�rlerde (GIST) Tedaviye Yanitin Degerlendirilmesinde PET BT nin Degeri

2. AMA� GIST t�m�rleri tedavi y�netimi Imitanib ve Sunitib gibi yeni terap�tik ajanlar ile ciddi degisiklikler g�stermistir. BT tetkikinin t�m�r boyutlarindaki gerilemeyi g�stermesi ancak haftalar sonra m�mk�n olacagindan , t�m�r�n metabolik aktivitesini �l�ebilen PET-BT tedaviye cevabin degerlendirmesinde tercih edilen y�ntem olmaktadir. Bu �alismada GIST�li ve uzak metastazli olgularda Iminitab tedavisi �ncesinde ve takip d�nemlerinde yeni metastazlarin saptanmasinda ve �zellikle tedaviye erken d�nem cevabin degelendirlmesinde PET-BT tetkikinin katkisi arastirdik.

3. GIST Tarih�e

4. GIST Genel Bilgiler Tirozin kinaz inhibit�rleri ile devrimTirozin kinaz inhibit�rleri ile devrim

7. GERE� ve Y�NTEM 4 kadin ve 7 erkek Ortalama takip s�resi 11 ay Yerlesim: 5 hastada midede , 4 hastada jejunumda 1 hastada rektumda. 1 hastada hem jejunum hemde asendan kolonda t�m�r izlenmekteydi. Tani aninda ek bulgular: 5 hastada karaciger metastazi, 2 hastada kolon metastazi mevcut iken diger olgularda baslangi� d�neminde metastaz izlenmedi.

8. GERE� ve Y�NTEM T�m hastalara Imatinib tedavisi �ncesinde bazal PET-BT (Philips Gemini Dual sistem) tetkiki yapildi. T�m hastalara tedavi �ncesi �ekilen baz inceleme disinda bir PET-BT daha �ekildi. 3 hastaya ikinci PET-BT tedavinin 7. g�n�nde �ekilirken digerleri birinci ayin sonunda PET-BT �ektirdi.

9. GERE� ve Y�NTEM Tedaviye yanitin degerlendirilmesi ; Lezyonlarin degerlendirilmesinde BT i�in RECIST PET -BT i�in EORTC �nerileri kullanildi.

10. Recist kriterlerinde objektif cevap i�in y�zdelerde bir degisim s�zkonusu Hedef lezyonlarda ise kismi yanittan (PR) bahsedebilmek i�in lezyonlarin en uzun boyutlarinin toplami baslangi�ta �l��len deger ile karsilastirildiginda %30 veya daha fazla azalma g�stermis olmalidir. Hedef lezyonlara g�re ilerleyen hastalik (PD)cevabi belirlenebilmesi i�in ise lezyonlarin en uzun boyutlarinin toplami �l��len en k���k deger ile karsilastirildiginda %20 veya daha fazla artis g�stermis olmalidir. Lezyon boyutunu 100 birim kabul edersek�Recist kriterlerinde objektif cevap i�in y�zdelerde bir degisim s�zkonusu Hedef lezyonlarda ise kismi yanittan (PR) bahsedebilmek i�in lezyonlarin en uzun boyutlarinin toplami baslangi�ta �l��len deger ile karsilastirildiginda %30 veya daha fazla azalma g�stermis olmalidir. Hedef lezyonlara g�re ilerleyen hastalik (PD)cevabi belirlenebilmesi i�in ise lezyonlarin en uzun boyutlarinin toplami �l��len en k���k deger ile karsilastirildiginda %20 veya daha fazla artis g�stermis olmalidir. Lezyon boyutunu 100 birim kabul edersek�

11. were developed on the basis of multiple previous small studies of various tumors.12 GIST was not included. The definition of partial response as a 25% decrease in SUVmax is based on the reproducibility of the SUVmax measurement,12 similar to the 50% size decrease on physical examination,17 rather than any correlation with clinically relevant end points such as TTPwere developed on the basis of multiple previous small studies of various tumors.12 GIST was not included. The definition of partial response as a 25% decrease in SUVmax is based on the reproducibility of the SUVmax measurement,12 similar to the 50% size decrease on physical examination,17 rather than any correlation with clinically relevant end points such as TTP

12. BULGULAR 7. g�nde PET-BT �ekilen 3 olguda da karacger metastazi mevcuttur. Bu olgularda %31-37 SUV max degeri azalmasi izlenmis olup, parsiel cevap olarak kabul edildi. BT de ise RECIST kriterlerine g�re cevap izlenmedi. Diger olgulardan 7si nde cerrahi rezeksiyon sonrasinda 28.g�nde incelmelerinde metastaz izlenmedi. Diger bir hasta ise tani aninda jejunun t�m�r� karaciger metastazi olan olguda 28. g�nde FDG tutulumu saptanmadi. Ilgin� olan nokta ise bu olguda iki yillik takipte BT lezyon sebat ederken FDG-PET hep negatifdi.

14. YG nisan eyl�l aaralik 2008YG nisan eyl�l aaralik 2008

16. Konvansiyonel Yanit Degerlendirme Kriterlerinin (RECIST/SWOG) Sinirliliklari T�m�rde k���lme yavas gelisebilir Yanit veren nekrotik GIST�te sivi ekspansiyonu t�m�r boyutunda b�y�meye neden olabilir1 Kriterler t�m�r dansitesindeki degisiklikleri degerlendirmez1 T�m�r boyutunda k���lme olsa bile lokal progresif lezyonlar gelisebilir1 Kriterler stabil hastaligi degerlendirmedigi i�in genel klinik yanit oldugundan d�s�k hesaplanmaktadir1,2 Stabil hastalikli hastalardaki sagkalim objektif yanit alinan hastalardakiyle benzerdir (B2222 �alismasi)3 RECIST are limited in assessing response to imatinib in GIST and may underestimate overall clinical benefit of imatinib in such tumors1,2 In general, when GISTs respond to imatinib, there is a decrease in tumor size. However, changes in tumor size do not always correlate with response, and size may increase because of expansion of fluid in responding necrotic tumors1 Appearance of focal progressive lesions, regardless of change in tumor size, may occur in GISTs responding to imatinib1 Results from several studies suggest that size-based criteria underestimate overall clinical benefit from imatinib1,2 The phase 2, open-label, randomized B2222 study used the SWOG criteria to measure objective response. At 5 years, there was no significant difference in survival between patients with stable disease (SD) and those with PR, indicating a potential lack of sensitivity in response criteria3 Choi H. Critical issues in response evaluation on computed tomography: lessons from the gastrointestinal stromal tumor model. Curr Oncol Rep. 2005;7:307-311. LeCesne A, Van Glabbeke M, Verweij J, et al. Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate (IM) included in the intergroup EORTC/ISG/AGITG trial? [ASCO abstract 9510]. J Clin Oncol. 2006;24(suppl):522s. 3. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized Phase II trial of standard versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620-625. RECIST are limited in assessing response to imatinib in GIST and may underestimate overall clinical benefit of imatinib in such tumors1,2 In general, when GISTs respond to imatinib, there is a decrease in tumor size. However, changes in tumor size do not always correlate with response, and size may increase because of expansion of fluid in responding necrotic tumors1 Appearance of focal progressive lesions, regardless of change in tumor size, may occur in GISTs responding to imatinib1 Results from several studies suggest that size-based criteria underestimate overall clinical benefit from imatinib1,2 The phase 2, open-label, randomized B2222 study used the SWOG criteria to measure objective response. At 5 years, there was no significant difference in survival between patients with stable disease (SD) and those with PR, indicating a potential lack of sensitivity in response criteria3 Choi H. Critical issues in response evaluation on computed tomography: lessons from the gastrointestinal stromal tumor model. Curr Oncol Rep. 2005;7:307-311. LeCesne A, Van Glabbeke M, Verweij J, et al. Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate (IM) included in the intergroup EORTC/ISG/AGITG trial? [ASCO abstract 9510]. J Clin Oncol. 2006;24(suppl):522s. 3. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized Phase II trial of standard versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620-625.

18. 3. ve 4. Basamak GIST Tedavisinde Yanit Degerlendirme: PET�in Rol� Sonu�lar PET ile, anlamli olmamakla birlikte yanit verenler ve vermeyenler arasinda PS a�isindan fark g�zlenmistir (P=0.15) PET�in bu hasta serisinde GS�yi �ng�rd�r�c� degeri saptanmamistir Bu verilerin daha genis hasta serilerinde ileri d�zeyde arastirilmasi gereklidir Hedefe y�nelik tedavilerle klinik yanitlarin daha �ng�r�lmesi konusunda ilerleme saglanmalidir

19. Choi et al: Modifiye BT Yanit Degerlendirme Kriterleri Choi et al conducted a study to determine whether changes in tumor size and density on CT correlate with FDG-PET responses, with the goal of developing reliable, quantitative CT response criteria RECIST have been shown to be insensitive in evaluating tumor responses in GISTs treated with imatinib1 Choi et al conducted a study to determine whether changes in tumor size and density on CT scans correlate with tumor responses to imatinib by 18FDG-PET and to develop reliable, quantitative CT response criteria1 The study evaluated a total of 172 lesions in 40 patients with metastatic GISTs who received treatment with imatinib1 CT and 18FDG-PET scans were carried out on patients before treatment and 2 months after treatment. Multivariate analysis was carried out with the following parameters: tumor size and density (HU) on CT and maximum standardized uptake value (SUVmax) on 18FDG-PET. Patients were followed for up to 28 months1 Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753- 1759. Choi et al conducted a study to determine whether changes in tumor size and density on CT correlate with FDG-PET responses, with the goal of developing reliable, quantitative CT response criteria RECIST have been shown to be insensitive in evaluating tumor responses in GISTs treated with imatinib1 Choi et al conducted a study to determine whether changes in tumor size and density on CT scans correlate with tumor responses to imatinib by 18FDG-PET and to develop reliable, quantitative CT response criteria1 The study evaluated a total of 172 lesions in 40 patients with metastatic GISTs who received treatment with imatinib1 CT and 18FDG-PET scans were carried out on patients before treatment and 2 months after treatment. Multivariate analysis was carried out with the following parameters: tumor size and density (HU) on CT and maximum standardized uptake value (SUVmax) on 18FDG-PET. Patients were followed for up to 28 months1 Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753- 1759.

20. Choi et al: Modifiye BT Yanit Degerlendirme Kriterleri The Choi criteria measure response on the basis of changes in both tumor size and tumor density, whereas RECIST measure response on the basis of changes in tumor size alone The modified CT response evaluation criteria proposed by Choi and colleagues represent a more sensitive alternative to RECIST for monitoring responses to therapy in GIST1 The Choi criteria define PR as a decrease in tumor size of =10%, measured as the sum of the longest diameters of target lesions as defined in RECIST, or a decrease in tumor density, measured in HU, of =15% on CT1 CR is defined as the disappearance of all lesions and the absence of new lesions1 PD is defined as an increase in tumor size of =10% and a failure to meet tumor-density (HU) criteria for PR by CT, the appearance of new lesions, the appearance of new intratumoral nodules, or an increase in size of existing intratumoral nodules1 SD is defined as a failure to meet criteria for CR, PR, or PD, with no symptomatic deterioration attributed to tumor progression1 Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753- 1759. The Choi criteria measure response on the basis of changes in both tumor size and tumor density, whereas RECIST measure response on the basis of changes in tumor size alone The modified CT response evaluation criteria proposed by Choi and colleagues represent a more sensitive alternative to RECIST for monitoring responses to therapy in GIST1 The Choi criteria define PR as a decrease in tumor size of =10%, measured as the sum of the longest diameters of target lesions as defined in RECIST, or a decrease in tumor density, measured in HU, of =15% on CT1 CR is defined as the disappearance of all lesions and the absence of new lesions1 PD is defined as an increase in tumor size of =10% and a failure to meet tumor-density (HU) criteria for PR by CT, the appearance of new lesions, the appearance of new intratumoral nodules, or an increase in size of existing intratumoral nodules1 SD is defined as a failure to meet criteria for CR, PR, or PD, with no symptomatic deterioration attributed to tumor progression1 Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753- 1759.

21. Tedavi �ncesi Tedavinin 2 ayi damarlar kaldiTedavinin 4. ayi damarlarda yokTechnical Issues The liver is the most common organ for GISTmetastasis. As with primary GISTs, hepatic metastasis is hypervascular and as such can be unrecognized on enhanced CT scans obtained during the portal venous phase. A �new� homogeneous and hypoattenuating lesion without definite enhancing Tedavi �ncesi Tedavinin 2 ayi damarlar kaldiTedavinin 4. ayi damarlarda yokTechnical Issues The liver is the most common organ for GISTmetastasis. As with primary GISTs, hepatic metastasis is hypervascular and as such can be unrecognized on enhanced CT scans obtained during the portal venous phase. A �new� homogeneous and hypoattenuating lesion without definite enhancing

22. Benjamin et al: �zet ve Yorumlar The Choi criteria are reproducible and more reliable than RECIST in evaluating tumor response in GIST, and should be incorporated routinely into clinical practice and used for future clinical studies Benjamin et al demonstrated that the Choi response (modified CT) criteria were reproducible in an independent data set1 Moreover, the Choi response criteria were more sensitive and reliable than RECIST and correlated significantly with both TTP and DSS1 By contrast, RECIST significantly underestimated responses in GIST to imatinib treatment, lacking prognostic value in terms of both TTP and DSS1 Based on the findings of this validation study, Benjamin et al concluded that the Choi criteria should be incorporated routinely into clinical practice and used in evaluating future GIST trials1 Benjamin RS, Choi H, Macapinlac HA, et al. We should desist using RECIST, at least in GIST. J Clin Oncol. 2007;25:1760-1764.The Choi criteria are reproducible and more reliable than RECIST in evaluating tumor response in GIST, and should be incorporated routinely into clinical practice and used for future clinical studies Benjamin et al demonstrated that the Choi response (modified CT) criteria were reproducible in an independent data set1 Moreover, the Choi response criteria were more sensitive and reliable than RECIST and correlated significantly with both TTP and DSS1 By contrast, RECIST significantly underestimated responses in GIST to imatinib treatment, lacking prognostic value in terms of both TTP and DSS1 Based on the findings of this validation study, Benjamin et al concluded that the Choi criteria should be incorporated routinely into clinical practice and used in evaluating future GIST trials1 Benjamin RS, Choi H, Macapinlac HA, et al. We should desist using RECIST, at least in GIST. J Clin Oncol. 2007;25:1760-1764.

23. GIST: Cerrahiden Sonra GIST Monitorizasyonu i�in �neriler NCCN guidelines and ESMO consensus recommendations provide guidance on the use of CT and 18FDG-PET in monitoring metastatic or recurrent disease after surgery.1,2 NCCN recently issued new guidelines for following GIST patients after surgery.1 CT scans should be performed every 3-6 months for the first 5 years following surgery, then annually.1 Physicians treating patients with very low risk (<2 cm with low mitotic rate) may elect to perform CT scans .1 CT scans can predict response, based on tumor size, density and structure, 1 month following treatment start.1 18FDG-PET is similarly a good predictor of response; however, metabolic changes in GIST can be detected as soon as 1 to 2 weeks following therapy start.1 Recommendations from ESMO also provide guidance on monitoring metastatic or recurrent disease after surgery. In patients with high- or intermediate-risk tumors (greater than 5 cm or mitotic index >5/50 HPF), CT may be performed every 3-4 months for 3 years, then every 6 months until 5 years, then annually.2 In patients with low-risk tumors (<5 cm or mitotic index <5/50 HPF), CT should be performed every 6 months for 5 years.2 1. Demetri GD, Benjamin R, Blanke CD, et al. NCCN task force report: optimal management of patients with gastrointestinal stromal tumor (GIST)�expansion and update of NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2004;21(suppl 1):S1-S26. 2. Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol. 2005;16:566-578. NCCN guidelines and ESMO consensus recommendations provide guidance on the use of CT and 18FDG-PET in monitoring metastatic or recurrent disease after surgery.1,2 NCCN recently issued new guidelines for following GIST patients after surgery.1 CT scans should be performed every 3-6 months for the first 5 years following surgery, then annually.1 Physicians treating patients with very low risk (<2 cm with low mitotic rate) may elect to perform CT scans .1 CT scans can predict response, based on tumor size, density and structure, 1 month following treatment start.1 18FDG-PET is similarly a good predictor of response; however, metabolic changes in GIST can be detected as soon as 1 to 2 weeks following therapy start.1 Recommendations from ESMO also provide guidance on monitoring metastatic or recurrent disease after surgery. In patients with high- or intermediate-risk tumors (greater than 5 cm or mitotic index >5/50 HPF), CT may be performed every 3-4 months for 3 years, then every 6 months until 5 years, then annually.2 In patients with low-risk tumors (<5 cm or mitotic index <5/50 HPF), CT should be performed every 6 months for 5 years.2 1. Demetri GD, Benjamin R, Blanke CD, et al. NCCN task force report: optimal management of patients with gastrointestinal stromal tumor (GIST)�expansion and update of NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2004;21(suppl 1):S1-S26. 2. Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol. 2005;16:566-578.

24. �zet: GIST�te G�r�nt�leme BT ile olasi cerrahi rezeksiyon i�in t�m�r(ler)in anatomik ayrintilari belirlenir ve �n tani konabilir1 Among available imaging techniques, CT and 18FDG-PET are the most useful in evaluating patients with suspected GIST and assessing response to treatment and disease progression.1-3 In assessing GIST, CT and 18FDG-PET are useful in initial evaluation of suspected tumors and in assessing response to treatment.1-3 CT provides insight into tumor anatomy, viability, and size and should be used for diagnosis and staging.1 18FDG-PET gives insight into the metabolic status of a tumor and, coupled with its sensitivity for GIST, is very helpful for disease staging. 18FDG-PET, however, is not specific for GIST and is therefore inappropriate (at least alone) for diagnosis.2,3 CT and 18FDG-PET are best used together to provide a coherent picture for diagnosis and patient management. 1. Demetri GD, Benjamin R, Blanke CD, et al. NCCN task force report: optimal management of patients with gastrointestinal stromal tumor (GIST)�expansion and update of NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2004;21(suppl 1):S1-S26. 2. Van den Abbeele AD, Badawi RD. Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer. 2002;38(suppl 5):S60-S65. 3. Stroobants S, Goeminne J, Seegers M, et al. 18FDG-positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer. 2003;39:2012-2020. Among available imaging techniques, CT and 18FDG-PET are the most useful in evaluating patients with suspected GIST and assessing response to treatment and disease progression.1-3 In assessing GIST, CT and 18FDG-PET are useful in initial evaluation of suspected tumors and in assessing response to treatment.1-3 CT provides insight into tumor anatomy, viability, and size and should be used for diagnosis and staging.1 18FDG-PET gives insight into the metabolic status of a tumor and, coupled with its sensitivity for GIST, is very helpful for disease staging. 18FDG-PET, however, is not specific for GIST and is therefore inappropriate (at least alone) for diagnosis.2,3 CT and 18FDG-PET are best used together to provide a coherent picture for diagnosis and patient management. 1. Demetri GD, Benjamin R, Blanke CD, et al. NCCN task force report: optimal management of patients with gastrointestinal stromal tumor (GIST)�expansion and update of NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2004;21(suppl 1):S1-S26. 2. Van den Abbeele AD, Badawi RD. Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer. 2002;38(suppl 5):S60-S65. 3. Stroobants S, Goeminne J, Seegers M, et al. 18FDG-positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer. 2003;39:2012-2020.

25. SONU� GIST�lerde; erken d�nemde tedaviye cevabin degerlendirmesinde, yeni metastatik odaklarin saptanmasinda, takiplerde tedaviye direncin ve cevabin saptanmasinda PET-BT tercih edilecek y�ntemdir.