Mide Kanserinde Literatür Güncellemesi

Mide Kanserinde Literatür Güncellemesi Dr. Faysal DANE Medikal Onkoloji Bilim Dalı Marmara Üniversitesi Tıp fakültesi

INTERGRUP 0116 çalışması N:556 Medyan sağkalım:35 ay vs 26 ay; p:0.006 D2 diseksiyon :10 %

CALGB-80101 546 hasta rezeke edilmiş mide kanseri R A N D O M I Z E 1 kür FUFA, RT+infüzyonel FU 1 kür ECF, RT+infüzyonel FU 2 kür FUFA 2 kür ECF

CALGB-80101: SONUÇLAR (FUFA vs ECF) Medyan OS: 37 ay vs 38 ay (HR, 1.03; 95% CI, 0.80-1.34; p=0.80). 3yr-OS: 50% vs 52%. Medyan DFS: 30 ay vs 28 ay (HR, 1.00; 95% CI, 0.79-1.27; p=0.99). 3yr-DFS: 46% vs 47%.

D2 diseksiyon yapılan hastalarda: Cerrahi+1 yıl S1 vs Cerrahi 1059 hasta, 5 yıllık OS: 71% vs 61%, HR:0.67)

CLASSIC study design Surgically (D2) resected Stage II, IIIA, or IIIB GC, 6 weeks prior to randomization No prior chemotherapy or radiotherapy n=1035 R A N D O M I Z A T I O N 1:1 n=520 8 cycles of XELOX (6 months) Capecitabine: 1,000mg/m 2 bid, d1 14, q3w Oxaliplatin: 130mg/m 2, d1, q3w Observation: No adjuvant therapy n=515 Primary endpoint: 3-year DFS Secondary endpoints: overall survival and safety profile Stratified by stage and country with age, sex, and nodal status as covariates GASTRIC project: 3-year DFS and 5-year overall survival are strongly associated, Burzykowski et al. ASCO 2009

3-yr DFS: 74% vs 59% HR 0.56, 95% CI 0.44-0.72; p<0.0001 3-yr OS: 83% vs 78% HR 0.72, 95% CI 0.52-1.00; p=0.049

Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) trial: Comparison of a sequential treatment with FOLFIRI followed by docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment for radically resected gastric cancer Pts radically resected for gastric or GEJ adenocarcinoma, with D1- lymphadenectomy, node involvement (pn+) or pn0 with pt2b-3-4; within 3-8 weeks after surgery R A N D O M I Z E 4 cycles FOLFIRI followed by docetaxel 75 mg/m2 d1, cisplatin 75 mg/m2 d1, q 21; for 3 cycles (arm A) (n = 562) LV 100 mg/m2 d1-2, 5-FU 400-600 mg/m2 d1-2, q 14 for 9 cycles (arm B) (n = 538) J Clin Oncol 30, 2012 (suppl; abstr LBA4001) 2012 ASCO Annual Meeting

RESULTS: ITACA-S Trial Median follow-up : 49 months (quartile range: 36-62) 558 events for DFS (HR 0.98; 95%CI 0.83-1.16;p=0.83) accounting for 88% of the target number and 440 deaths (HR: 1.00; 95%CI 0.83-1.20;p=0.98). Toxicity was consistent with literature. Conclusions: Intensive chemotherapy did not result in a significant prolongation of DFS and OS when compared to bolus/infusion FU/LV regimen in adjuvant setting J Clin Oncol 30, 2012 (suppl; abstr LBA4001) 2012 ASCO Annual Meeting

Perioperative chemotherapy for locally advanced Gastric Cancer: The MAGIC and the French trials MAGIC trial: ECF x 3 => Surgery => ECF x 3 French trial: CF x 2-3 => Surgery => CF x 3-4

Perioperative chemotherapy (CTX) MAGIC Trial Randomized phase III study (N=503)

Perioperative chemotherapy (CTX) MAGIC Trial Randomized phase III study (N=503)

İleri Evre Mide Kanserinde Kemoterapi: ECF İngiliz Çalışması (274 hasta) (JCO 15, 261, 1997) RR TTP to progr. Sağkalım FAMTX: %21 3.4 ay 5.8 ay ECF : %45 7.4 ay 8.9 ay

REAL-2 2x2 randomize çalışma; ECF vs Oxa-Sis-Kap/5 FU ECF (E 50mg/m2); (C 60mg/m2); (FU 200mg/m2) EOX (E 50mg/m2); (O 130mg/m2); (C 1000/1250mg/m2) ECX (E 50mg/m2); (C 60mg/m2); (X 1000/1250mg/m2) EOX (E 50mg/m2); (O 130mg/m2); (X 1000/1250mg/m2) 21günlük periyotlarla Kap 14/21 gün EOX rejimi ön plana çıktı

İleri Evre Mide Kanserinde Dosetaksel bazlı kemoterapi: Faz III çalışması (TAX 325) Ölçülebilir/değerlendirilebilir metastatik veya ölçülebilir lokal rekürrent mide adenokarsinomu Yaş >18 yaş KPS >70 Yeterli hematolojik/ biyokimyasal parametreler Önceden palyatif kemoterapi almamış R A N D O M İZ A S Y O N DCF Dosetaksel 75 mg/m 2 1 saatte, Gün 1 Sisplatin 75 mg/m 2 1 3 saatte, Gün 1 5-FU 750 mg/m 2 /gün 5 günde, 3 haftada 1 (n=227) PD ye, olurun geri çekilmesine veya kabul edilemez toksisiteye kadar tedavi; tümör değerlendirmeleri 8 haftada bir CF Sisplatin 100 mg/m 2 1 3 saate, Gün 1 5-FU 1000 mg/m 2 /gün 5 günde, 4 haftada bir (n=230) Primer sonlanım noktası: TTP Sekonder sonlanım noktaları: OS, yaşam kalitesi (QoL), Klinik Yarar, ORR, güvenlilik Hastaların prognostik faktörlere göre katmanlara ayrılmıştır Febril nötropeni/ nötropenik enfeksiyon durumunda G-CSF önerilir (primer profilaksi ø)

Olasılık (%) TAX 325: Etkinlik Progresyona kadar geçen süre 100 90 TTP DCF CF Medyan (ay) 5.6 3.7 95% CI 4.9 5.9 3.4 4.5 80 70 60 50 40 30 Log-rank p < 0.001 Hazard ratio: 1.47 (% 95 CI: 1.19 1.82) Risk azalması: % 32 20 10 0 0 DCF CF 3 6 9 12 15 18 21 24 Zaman (ay) Van Cutsem E, et al. J Clin Oncol vol 24 N 31 Nov 2006

Olasılık (%) TAX 325:Etkinlik Genel sağkalım OS DCF CF Medyan (ay) 9.2 8.6 100 90 80 % 95 CI 8.4 10.6 7.2 9.5 1-yıl (%) 40 32 2-yıl (%) 18 9 70 60 50 40 30 Log-rank p=0.02 Hazard ratio: 1.29 (% 95 CI: 1.0 1.6) Risk azalması: 23% 20 10 0 DCF CF 0 3 6 9 12 15 18 21 24 27 30 33 36 Zaman (ay) Van Cutsem E, et al. J Clin Oncol vol 24 N 31 Nov 2006

Bevacizumab: Faz III Çalışma Metastatik mide kanseri 1.basamak AVAGAST Lokal ileri veya metastatik ösefagogastrik adenokanser n=774 R Cisplatin + kapesitabin + Bevacizumab Cisplatin + kapesitabin

ToGA çalışmasının tasarımı Faz III, randomize, açık etiketli, uluslararası, çok merkezli çalışma 3807 hasta tarandı 1 810 HER2-pozitif (%22.1) Sınıflandırma faktörleri HER2-pozitif ileri evre GC (n=584) ileri evreye karşı metastatik evre GC ye karşı GEJ* ölçülebilire karşı ölçülebilir olmayan ECOG PS 0-1 e karşı 2 Kapesitabine karşı 5-FU R 5-FU veya kapesitabin a + sisplatin (n=290) 5-FU veya kapesitabin a + sisplatin + Trastuzumab (n=294) a Araştırmacının kararına göre seçilmiştir *GEJ: gastroözofageal bileşke 1 Bang ve ark; 4556, ASCO 2009

Primer sonlanım noktası : OS Olay 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 FC + T FC 11.1 13.8 Olay 167 182 Medyan OS 13.8 11.1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 HR 0.74 %95 CI 0.60, 0.91 Zaman (ay) p değeri 0.0046 Ölüm riskinde %26 azalma risk altındaki hasta sayısı 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 0 1 0 0 0 T: trastuzumab

Sekonder sonlanım noktası: PFS Olay 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 5.5 6.7 FC + T FC Medyan Olaylar PFS 226 235 6.7 5.5 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 HR 0.71 %95 CI 0.59, 0.85 p değeri 0.0002 Zaman (ay) risk altındaki hasta sayısı 294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9 3 8 2 6 2 6 1 6 1 4 0 2 0 0 0

Sekonder sonlanım noktası: tümör yanıt oranı Hastalar (%) İTT (intent to treat) analiz p=0.0145 p=0.0017 F+C + trastuzumab F+C % 41.8 % 47.3 p=0.0599 % 32.1 % 34.5 2.4% 5.4% CR PR ORR ORR= CR + PR CR: tam yanıt; PR: kısmi yanıt

OS: IHC2+/FISH+ veya IHC3+ Olay 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 FC + T FC 11.8 16.0 Olaylar 120 136 Medyan OS 16.0 11.8 HR 0.65 %95 CI 0.51, 0.83 Ölüm riskinde %35 azalma 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Zaman (ay) risk altındaki hasta sayısı 228 218 218 198 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 39 20 28 13 20 11 12 4 11 3 5 3 4 0 1 0 0 0

Advanced gastric cancer: Phase III trial of everolimus (EVE) in previously treated patients with advanced gastric cancer (AGC): GRANITE-1 Pts (656) confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy R A N D O M I Z E EVE 10 mg/d + best supportive care (BSC) (n = 439) placebo (PBO) + BSC (n = 217) The primary endpoint : Overall survival(os) Secondary endpoints: Progression-free survival (PFS), overall response rate (ORR), and safety. J Clin Oncol 30, 2012 (suppl 4; abstr LBA3) 2012 Gastrointestinal Cancers Symposium

RESULTS: Phase III trial of everolimus (EVE) in previously treated patients with advanced gastric cancer (AGC): GRANITE-1 EVE 10 mg/d + BSC placebo (PBO) + BSC P-value & HR Resp. rate (%) 4.5 (2.6-7.1) 2.1 (0.6-5.3) N.S. PFS (mos) 1.68 1.41 HR, 0.66; 95% CI, 0.56-0.78; p<0.0001 OS (mos) 5.39 4.34 HR, 0.90; 95% CI, 0.75-1.08; P=0.1244 Conclusions: EVE monotherapy did not significantly improve OS in patients with AGC previously treated with 1 or 2 lines of systemic chemotherapy. EVE did improve PFS. J Clin Oncol 30, 2012 (suppl 4; abstr LBA3) 2012 Gastrointestinal Cancers Symposium

Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel (wptx) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial Patients with AGC refractory to the first-line FP regimen R A N D O M I Z E (1:1) N=223 CPT-11 (150 mg/m 2, q2w) (n = 112) wptx (80 mg/m 2, days 1, 8, 15, q4w) (n = 111) The primary endpoint : OS Secondary endpoints: PFS, ORR, adverse events and receiving rates of third-line CT J Clin Oncol 30, 2012 (suppl; abstr 4002) 2012 ASCO Annual Meeting

RESULTS: WJOG4007 trial CPT-11 (150 mg/m2, q2w) wptx (80 mg/m2, days 1, 8, 15, q4w) P-value HR Resp. rate (%) 13.6 (12/88) 20.9 (19/91) p=0.20 PFS (mos) 2.3 3.6 (HR 1.14; 95% CI, 0.88-1.49) p=0.33 OS (mos) 8.4 9.5 (HR 1.132; 95% CI, 0.86-1.49) p=0.38 Conclusions: The WJOG4007 trial, the first phase III study comparing second-line CT regimens for AGC, did not demonstrate the superiority of CPT-11 over wptx. Thus, wptx can be used as a control arm in the future phase III trials of second-line CT for AGC J Clin Oncol 30, 2012 (suppl 4; abstr LBA3) 2012 Gastrointestinal Cancers Symposium

REAL3 Trial Design (A randomised multi-centre trial) Untreated advanced adenocarcinoma or undifferentiated carcinoma of the oesophagus, OGJ or stomach R Arm A: EOC Arm B: meoc-p EOC (Arm A): Epirubicin 50mg/m 2 IV D1 Oxaliplatin 130mg/m 2 IV D1 Capecitabine 1250mg/m 2 /day PO in two divided doses D1-21 meoc-p (Arm B) 1: Epirubicin 50mg/m 2 IV D1 Oxaliplatin 100mg/m 2 IV D1 Capecitabine 1000mg/m 2 /day PO in two divided doses D1-21 Panitumumab 9mg/kg IV D1 Ref: Okines et al, JCO 2010

REAL 3; Endpoints Primary endpoint: OS Secondary endpoints: RR, PFS, toxicity, QoL, effect of KRAS mutation status Exploratory biomarker analyses

Probability of Survival (%) Primary Endpoint OS 100 80 Median OS (95% CI) % alive at 1 year (95% CI) 60 40 11.3m (9.6 13.0) 46% (38% - 54%) 8.8m (7.7 9.8) 33% (26% - 41%) HR 1.37, p = 0.013 20 EOC EOC-P HR 1.37 (95% CI: 1.07 1.76) 0 Number at risk 0 6 12 18 24 30 36 Months from Randomisation EOC 275 49 3 EOC-P 278 38 2 Based on 251 OS events

Probability of Survival (%) Trial Results - PFS 100 80 Median PFS (95% CI) % alive and progression-free at 1 year (95% CI) 60 7.4m (6.3 8.5) 21% (14% - 27%) 6.0m (5.5 6.5) 20% (14% - 26%) 40 HR 1.22, p = 0.068 20 EOC EOC-P HR 1.22 (95% CI: 0.98 1.52) 0 0 6 12 18 24 30 Number at risk Months from Randomisation EOC 275 25 2 EOC-P 278 24 0 Based on 333 PFS events

REAL 3; Conclusions Addition of panitumumab to EOC was not beneficial in an unselected gastric cancer population Poorer OS outcome is probably due to reduced chemotherapy delivery in meoc-p arm lower doses of oxaliplatin and capecitabine lower median number of cycles

EXPAND Trial Randomized, Controlled, Phase III trial Evaluated the addition of Erbitux to cisplatin and capecitabine as 1st-line therapy for patients with advanced gastric cancer. The primary endpoint: PFS Secondary endpoints included OS, ORR, safety, QoL, and biomarkers.

EXPAND: Erbitux plus chemo in 1st-line Lordick, Abstract LBA3, ESMO 2012

Lordick, Abstract LBA3, ESMO 2012 EXPAND: Efficacy data The addition of Erbitux to cisplatin/capecitabine did not improve efficacy. The median PFS was similar between treatment arms (Erbitux + chemo: 4.4 months, chemo: 5.6 months, HR: 1.091, p=0.3158). The median OS was similar between treatment arms (Erbitux + chemo: 9.4 months, chemo: 10.7 months, HR: 1.004, p=0.9547) The ORR was similar between treatment arms (Erbitux + chemo: 30%, chemo: 29%).

EXPAND: CONCLUSIONS Erbitux did not add clinical benefit when combined with chemotherapy as 1 st line treatment for advanced/metastatic gastric cancer. However, the patient population for this study was unselected for biomarkers. Retrospective biomarker analyses are ongoing. Lordick, Abstract LBA3, ESMO 2012; LBA3, ESMO 2012

Sonuçlar-1 Yoğun kemoterapiler adjuvan mide kanserinde FUFA dan ÜSTÜN DEĞİL. D2 nin altında diseksiyon yapılan hastalarda KRT standart tedavidir. (Bu hastalar aynı zamanda NEO-ADJUVAN ADAYIDIR). D2 diseksiyon yapılmış hastalarda, S-1 ve XELOX tedavileri etkin görünmektedir. D2 diseksiyon yapılan hastalarda KRT vs KT ( ARTIST çalışması: nod pozitif alt-grup hastalarda KRT daha iyi), yapılabilir.

Sonuçlar -2 Metastatik mide kanserinde HER-2 neu: NEGATİF ise ; DCF, CF, CX, ECF, EOX, ECX rejimlerinden biri tercih edilebilir. Metastatik mide kanserinde HER-2: Pozitif ise STANDART tedavi TRASTUZUMAB BAZLI TEDAVİ OLMALIDIR. EVE monoterapisi daha önce tedavi edilmiş mide kanserinde GENEL SAĞKALIMI ARTTIRMAZ. Daha önce tedavi edilmiş mide kanserinde HAFTALIK paklitaksel İRİNOTEKAN kadar etkilidir.

Sonuçlar -3 İleri evre mide kanserinde BEVA nın KT ye eklenmesinin OS ye etkisi yoktur. CETUXIMAB ve PANITUMUMAB ın daha önce tedavi almamış metastatik mide kanserinde kemoterapiye ek sağkalım katkısı yoktur.