BALKAN MCO 2011 - A. Cervantes - Systemic treatment of advanced disease
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BALKAN MCO 2011 - A. Cervantes - Systemic treatment of advanced disease
- 1. GASTRIC CANCER: SYSTEMIC TREATMENT OF ADVANCED DISEASE Andrés Cervantes BALKAN MASTERCLASS IN CLINICAL ONCOLOGY Dubrovnik, 13 May 2011
- 4. Should patients with advanced gastric cancer receive chemotherapy? Wagner A, et al. JCO 2006.
- 5. When should patients with advanced gastric cancer receive chemotherapy? Glimelius B, et al. Ann Oncol 1994. INITIAL ELF-FULV DELAYED CT AT PD CT 100% 50% TIME TO CT 8 DAYS 82 DAYS QOL IMPROVEMENT 70% 25% SURVIVAL 10 MONTHS 4 MONTHS
- 6. Is primary tumor location relevant for treatment decisions? Chau I, et al. Ann Oncol 2009.
- 7. What are the main prognostic factors? PS 2 Liver mets Peritoneal mets Alkaline Phosphatase Chau I, et al. J Clin Oncol 2004.
- 8. What are the main prognostic factors? Group Score median OS 1-year Surv Good 0 11.8 m 48.5% Moderate 1 o 2 7.4 m 25.7% Poor 3 o 4 4.1 m 11.0% Chau I, et al. J Clin Oncol 2004.
- 9. Chau I, et al. J Clin Oncol 2009.
- 11. Monotherapy or combination of drugs? Wagner A, et al. JCO 2006.
- 14. Koizumi W, et al. Lancet Oncol 2008
- 16. Docetaxel-CF vs CF in advanced gastric cancer: Overall survival Van Cutsem E, et al. J Clin Oncol 2006
- 17. Docetaxel-CF vs CF in advanced gastric cancer: Time to definitive Karnofsky PS deterioration Ajani JA, et al. J Clin Oncol 2007
- 18. Docetaxel-CF vs CF in advanced gastric cancer: Time to 5% definitive Global Health status deterioration Ajani JA, et al. J Clin Oncol 2007
- 19. The HERs, a dysfunctional family of receptors Adapted from Tzahar and Yarden. Biochim Biophys Acta . 1998;1377:M25. The epidermal growth factor family of receptors comprises 4 transmembrane proteins with distinct properties, which all regulate cell proliferation Extracellular Intracellular
- 21. Primary end point: OS Time (months) 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 No. at risk 11.1 13.8 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Event FC + T FC Events 167 182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 Median OS 13.8 11.1 T, trastuzumab Van Cutsem E, et al. ASCO 2009 abstract 4509
- 22. Secondary end point: PFS 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Event 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 5.5 6.7 No. at risk 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time (months) FC + T FC Events 226 235 HR 0.71 95% CI 0.59, 0.85 p value 0.0002 Median PFS 6.7 5.5
- 23. Secondary end point: tumor response rate 2.4% 5.4% 32.1% 41.8% 34.5% 47.3% Intent to treat ORR= CR + PR CR, complete response; PR, partial response p=0.0599 p=0.0145 F+C + trastuzumab F+C p=0.0017 Patients (%) CR PR ORR
- 24. OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) 11 3 1.0 0.8 0.6 0.4 0.2 0.0 36 34 32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0 Time (months) 11.8 16.0 FC + T FC Events 120 136 HR 0.65 95% CI 0.51, 0.83 Median OS 16.0 11.8 Event 0.1 0.3 0.5 0.7 0.9 218 198 4 0 5 3 12 4 20 11 228 218 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 1 0 0 0 No. at risk 39 20 28 13
- 28. REAL-2: Overall survival fluoropyrimidin comparison HR for ITT population = 0.88 (0.77 – 1.00) p= 0.058 Cunningham et al, NEJM 2008
- 29. REAL-2: Overall survival platinum comparison Cunningham et al, NEJM 2008 HR for ITT population = 0.91 (0.79-1.04) p=0.159
- 30. REAL-2: Overall survival: ECF vs EOX comparison HR: 0.80 (95% CI: 0.66-0.97) Log rank p=0.02 Cunningham et al, NEJM 2008
- 31. Kang YK et al, Ann Oncol 2009 5-FU CDDP VERSUS CAPECITABINE-CDDP. A RANDOMISED PHASE III NONINFERIORITY TRIAL (ML17032)
- 32. Okines AFC et al, Ann Oncol 2009 5-FU VERSUS CAPECITABINE A META-ANALYSIS OF REAL2 AND ML17032 HR:0.87 (95% CI: 0.77-098, p=0.006)
- 35. Primary end point : 1 st line Time To Treatment Failure p (Log-rank) = 0.008 HR (Arm B vs Arm A) = 0.77 [0.63;0.94] Arm A (ECX 1 st line) : 4.24 m [3.48; 4.65] Arm B (FOLFIRI 1 st line) : 5.09 m [4.53; 5.68] Bras A 209 108 33 8 4 2 1 1 1 Bras B 207 123 50 19 6 3 2 1 0 TTF 0.0 0.2 0.4 0.6 0.8 1.0 Time (months) 0 4 8 12 16 20 24 28 32 Events Arm A 203 Arm B 203
- 36. Progression Free Survival and Overall Survival Arm A (ECX 1 st line) : 9.49 m. [8.77; 11.14] Arm B (FOLFIRI 1 st line) : 9.72 m. [8.54; 11.27] p (Log-rank)= 0.95 HR (B vs A)= 1.01 [0.82; 1.24] Arm A (ECX 1 st line) : 5.29 m. [4.53;6.31] Arm B (FOLFIRI 1 st line) : 5.75 m. [5.19; 6.74] p (Log-rank)= 0.96 HR (B vs A)= 0.99 [0.81; 1.21] 209 135 69 35 18 9 5 3 2 207 142 79 38 14 7 2 0 0 0.0 0.2 0.4 0.6 0.8 1.0 Time (months) 0 6 12 18 24 30 36 42 48 209 129 57 26 17 9 7 3 3 3 2 207 135 65 28 11 8 4 2 0 0 0 0.0 0.2 0.4 0.6 0.8 1.0 Time (months) 0 4 8 12 16 20 24 28 32 36 40 OS Events Arm A 175 Arm B 180 PFS Events Arm A 191 Arm B 197
- 40. GASTRIC CANCER: SECOND LINE CHEMOTHERAPY Irinotecan versus best supportive care (BSC) as 2nd-line therapy in gastric cancer 120 patients planned to be included Trial closed due to poor accrual (40 patients in 50 months) R Arm A Irinotecan 250 mg/m² q3w (1st cycle) to be increased to 350 mg/m², depending on toxicity * Arm B BSC Thuss-Patience PC et al, ECCO/ESMO 2009 abstr 6504
- 41. Overall survival (ITT-Population) Thuss-Patience PC et al, ECCO/ESMO 2009 abstr 6504 Logrank test: p = 0.023 Irino: n = 21, 21 events, median = 4.0 mths BSC: n = 19, 19 events, median = 2.4 mths HR: 0.48 (95% CI: 0.25 - 0.92) 0 40 80 120 160 200 240 280 320 360 400 440 480 520 560 600 days 0.0 0.2 0.4 0.6 0.8 1.0 survival rate
Editor's Notes
- Patients were stratified according to prognostic factors (liver involvement, prior gastrectomy, measurable/evaluable disease, weight loss in previous 3 months and centre). No patients had locally advanced disease or a PS of 2. Planned dose intensity of C and F was the same in both arms. Patients were treated until PD, intolerable toxicity or consent withdrawn. Major exclusion criteria were concurrent cancer, neuropathy, brain or leptomeningeal involvement, uncontrolled significant co-morbid conditions, or if patient could not comprehend the purpose of the study and could not comply with its requirements. Tumour assessments were planned every 8 weeks in both arms.
- The prototype HER family receptor HER1 has an extracellular domain that binds a variety of growth factors, including transforming growth factor-alpha (TGF- ), amphiregulin (AR), EGF, heparin-binding EGF (HB-EGF), beta-cellulin ( -CEL), and epiregulin (EPI).[Hung and Lau, 1999] Ligand binding to HER1 can activate tyrosine kinase activity within the cytoplasmic domain and through various signal transduction intermediates that trigger cell proliferation.[Hung and Lau, 1999] HER2 has no known ligand, but tyrosine kinase is transactivated through HER2 interaction with other types of HER receptors (heterodimerization), usually following ligand binding to those receptors.[Hung and Lau, 1999; Tzahar and Yarden, 1998] By stabilizing heterodimers, HER2 prolongs and enhances signal transduction initiated by a variety of growth factors; this effect may promote the growth of tumor cells. HER3 and HER4 bind neuregulins (eg, NRG1 or 2), but HER3 lacks inherent tyrosine kinase activity.[Hung and Lau, 1999] The HER signaling network, mediated by homotypic and heterotypic receptor interactions, is complex and can stimulate or regulate cell proliferation, motility, adhesion, and survival through various signaling pathways.[Pinkas-Kramarski et al, 1996]
- Eligibility criteria for the ToGA trial include: > 18 years of age, HER2-positive histologically confirmed gastric cancer or gastro-oesophageal adenocarcinoma, with inoperable, locally advanced or recurrent and/or metastatic disease. The ToGA trial planned to recruit 584 patients. An additional 10 patients, who had already signed the informed consent form when the screening cut-off was reached, were allowed to enter the trial, resulting in a total of 594 patients recruited. The primary end point is overall survival in the two treatment arms. Secondary end points include progression-free survival, overall response rate, clinical benefit rate, duration of response and safety profile.
- Ph II coréenne en 1 ère ligne : « safe et feasible » : Boku N et al .Lancet Oncol. 2009 Nov;10(11):1063-9 Am J Clin Oncol. 2010 Jun;33(3):246-50.A phase II study of irinotecan with biweekly, low dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFIRI) as first line therapy for patients with recurrent or metastatic gastric cancer.Kim BG, Oh SY, Kwon HC, Lee S, Lee DM, Kim SG, Kim DK, Jang JS, Kim MC, Kim SH, Kim HJ.
- Median Follow-up : Bras A: 20.99 [20.99;39.33] Bras B: Non atteinte [NA; NA]