GASTRIC CANCER:  SYSTEMIC TREATMENT OF ADVANCED DISEASE   Andrés Cervantes BALKAN MASTERCLASS IN CLINICAL ONCOLOGY Dubrovn...
Current Questions in Advanced Gastric Cancer Management <ul><li>Which are the aims of therapy? </li></ul><ul><li>Should pa...
Which are the aims of therapy? <ul><li>Symptomatic control </li></ul><ul><li>Improve QoL or avoid its deterioration </li><...
Should patients with advanced gastric cancer receive chemotherapy? Wagner A, et al. JCO 2006.
When should patients with advanced gastric cancer receive chemotherapy? Glimelius B, et al.  Ann Oncol 1994. INITIAL ELF-F...
Is primary tumor location relevant for  treatment decisions? Chau I, et al. Ann Oncol 2009.
What are the main prognostic factors? PS 2 Liver mets Peritoneal mets Alkaline Phosphatase  Chau I, et al.  J Clin Oncol 2...
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 ...
Chau I,  et al.  J Clin Oncol 2009.
Which are the active drugs? <ul><li>5-Fluorouracil </li></ul><ul><li>Oral Fluoropirymidines (capecitabine, S1, UFT) </li><...
Monotherapy or combination of drugs? Wagner A, et al. JCO 2006.
What are the active drugs that have shown superiority in randomized trials? <ul><li>5-Fluorouracil </li></ul><ul><li>Oral ...
SPIRITS: Study Design AGC No prior Chemo. R S-1 alone S-1: 40-60 mg BID for 28 days q6wks S-1 + CDDP S-1: 40-60 mg BID for...
Koizumi W, et al.   Lancet Oncol 2008
Docetaxel-based chemotherapy in advanced gastric cancer: Phase III trial DCF Docetaxel 75 mg/m 2  over 1 h, Day 1 Cisplati...
Docetaxel-CF vs CF in advanced gastric cancer: Overall survival   Van Cutsem E, et al.   J Clin Oncol 2006
Docetaxel-CF vs CF in advanced gastric cancer: Time to definitive Karnofsky PS deterioration   Ajani JA, et al.   J Clin O...
Docetaxel-CF vs CF in advanced gastric cancer: Time to 5% definitive Global Health status  deterioration   Ajani JA, et al...
The HERs,  a dysfunctional family of receptors Adapted from Tzahar and Yarden.  Biochim Biophys Acta . 1998;1377:M25. The ...
ToGA trial design HER2-positive advanced GC  (n=584) 5-FU or capecitabine a   + cisplatin (n=290) R a Chosen at investigat...
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 2...
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...
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 resp...
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...
<ul><ul><li>No increase in hematological or GI toxicity </li></ul></ul><ul><ul><li>No increase in clinicaly detected cardi...
What are the active drugs that have shown non inferiority in randomized trials? <ul><li>5-Fluorouracil </li></ul><ul><li>O...
REAL-2: First line phase 3 trial in oesophagogastric cancer <ul><li>Primary end point of demonstrating non-inferiority in ...
REAL-2: Overall survival  fluoropyrimidin comparison HR for ITT population = 0.88 (0.77 – 1.00) p= 0.058 Cunningham et al,...
REAL-2: Overall survival  platinum comparison Cunningham et al, NEJM 2008 HR for ITT population = 0.91 (0.79-1.04)  p=0.159
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
Kang YK et al, Ann Oncol 2009 5-FU CDDP VERSUS CAPECITABINE-CDDP.  A RANDOMISED PHASE III NONINFERIORITY TRIAL (ML17032)
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,...
Irinotecan and Gastric Cancer <ul><li>Many phases II studies:  </li></ul><ul><ul><li>Anti-tumoral activity in gastric canc...
FFCD-GERCOR-FNCLCC 03-07 Phase III Study <ul><li>Stratification : </li></ul><ul><li>Mesurable or not </li></ul><ul><li>PS ...
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...
Progression Free Survival  and  Overall Survival Arm A (ECX 1 st  line) :  9.49 m.   [8.77; 11.14] Arm B (FOLFIRI 1 st  li...
Best supportive care 1 5-FU monotherapy 1 Transtuzumab + Chemotherapy 6 EOX 5 5-FU + LV + Oxaliplatin (FLO) 4 Capecitabine...
Chemotherapy vs BSC 1 SPIRITS 2 ToGA 7 EOX 6 FLO 5 XP 4 DCF 3 6.0 months   2.0 months   0.6 months 1.2 months 1.9 months 1...
Chemotherapy vs BSC 1 ToGA 6 EOX 5 FLO 4 XP 3 DCF 2 HR:0.39 p<0.00001 HR:0.77 p=0.02 HR:0.85 p=0.008   HR: not shown p=0.5...
GASTRIC CANCER: SECOND LINE CHEMOTHERAPY Irinotecan versus best supportive care (BSC) as 2nd-line  therapy in gastric canc...
Overall   survival (ITT-Population) Thuss-Patience PC et al, ECCO/ESMO 2009 abstr 6504 Logrank test: p = 0.023 Irino: n = ...
Recommended  approach to advanced gastric cancer patients <ul><li>Select patients with PS0-1 to participate in clinical tr...
Recommended  approach to improve results on gastric cancer patients <ul><li>Design better clinical trials within academic ...
MULTIDISCIPLINARY TEAM FOR GASTRO- ESOPHAGEAL CANCER   UNIVERSITY HOSPITAL VALENCIA   <ul><li>Radiology : Marta Rausell </...
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  • 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: &gt; 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]
  • Transcript of "BALKAN MCO 2011 - A. Cervantes - Systemic treatment of advanced disease "

    1. 1. GASTRIC CANCER: SYSTEMIC TREATMENT OF ADVANCED DISEASE Andrés Cervantes BALKAN MASTERCLASS IN CLINICAL ONCOLOGY Dubrovnik, 13 May 2011
    2. 2. Current Questions in Advanced Gastric Cancer Management <ul><li>Which are the aims of therapy? </li></ul><ul><li>Should patients with advanced gastric cancer receive chemotherapy and when? </li></ul><ul><li>Which are the main prognostic factors? </li></ul><ul><li>Is primary tumor location relevant for treatment decisions? </li></ul><ul><li>Which are the active drugs? </li></ul><ul><li>Is there any standard combination of drugs? </li></ul><ul><li>Why haven’t we been successful in getting better treatment for this disease? </li></ul>
    3. 3. Which are the aims of therapy? <ul><li>Symptomatic control </li></ul><ul><li>Improve QoL or avoid its deterioration </li></ul><ul><li>Delay tumor progression </li></ul><ul><li>Prolong survival </li></ul>
    4. 4. Should patients with advanced gastric cancer receive chemotherapy? Wagner A, et al. JCO 2006.
    5. 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. 6. Is primary tumor location relevant for treatment decisions? Chau I, et al. Ann Oncol 2009.
    7. 7. What are the main prognostic factors? PS 2 Liver mets Peritoneal mets Alkaline Phosphatase Chau I, et al. J Clin Oncol 2004.
    8. 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. 9. Chau I, et al. J Clin Oncol 2009.
    10. 10. Which are the active drugs? <ul><li>5-Fluorouracil </li></ul><ul><li>Oral Fluoropirymidines (capecitabine, S1, UFT) </li></ul><ul><li>Anthracyclines? </li></ul><ul><li>Cisplatin </li></ul><ul><li>Oxaliplatin </li></ul><ul><li>Docetaxel </li></ul><ul><li>CPT-11 </li></ul><ul><li>Transtuzumab </li></ul>
    11. 11. Monotherapy or combination of drugs? Wagner A, et al. JCO 2006.
    12. 12. What are the active drugs that have shown superiority in randomized trials? <ul><li>5-Fluorouracil </li></ul><ul><li>Oral Fluoropirymidines (capecitabine, S1, UFT) </li></ul><ul><li>Anthracyclines? </li></ul><ul><li>Cisplatin </li></ul><ul><li>Oxaliplatin </li></ul><ul><li>Docetaxel </li></ul><ul><li>CPT-11 </li></ul><ul><li>Transtuzumab </li></ul>
    13. 13. SPIRITS: Study Design AGC No prior Chemo. R S-1 alone S-1: 40-60 mg BID for 28 days q6wks S-1 + CDDP S-1: 40-60 mg BID for 21 days q5wks CDDP: 60 mg/m 2 iv on day 8 <ul><li>Central Randomization </li></ul><ul><li>(dynamic balancing) </li></ul><ul><li>Adjustment Factors: </li></ul><ul><li>Institute </li></ul><ul><li>PS </li></ul><ul><li>Unresectable vs Recurrent </li></ul>Koizumi W, et al. Lancet Oncol 2008
    14. 14. Koizumi W, et al. Lancet Oncol 2008
    15. 15. Docetaxel-based chemotherapy in advanced gastric cancer: Phase III trial DCF Docetaxel 75 mg/m 2 over 1 h, Day 1 Cisplatin 75 mg/m 2 over 1–3 h, Day 1 5-FU 750 mg/m 2 /day over 5 days, q3w (n=227) CF Cisplatin 100 mg/m 2 over 1–3 h, Day 1 5-FU 1000 mg/m 2 /day over 5 days, q4w (n=230) <ul><li>Measurable/evaluable metastatic or measurable locally recurrent gastric adenocarcinoma </li></ul><ul><li>Age  18 years </li></ul><ul><li>KPS >70 </li></ul><ul><li>Adequate haematological/ biochemical parameters </li></ul><ul><li>No prior palliative chemotherapy </li></ul>RANDOM I S A T I ON Treatment until PD, consent withdrawn or unacceptable toxicity; tumour assessments q8w Van Cutsem E, et al. J Clin Oncol 2006
    16. 16. Docetaxel-CF vs CF in advanced gastric cancer: Overall survival Van Cutsem E, et al. J Clin Oncol 2006
    17. 17. Docetaxel-CF vs CF in advanced gastric cancer: Time to definitive Karnofsky PS deterioration Ajani JA, et al. J Clin Oncol 2007
    18. 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. 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
    20. 20. ToGA trial design HER2-positive advanced GC (n=584) 5-FU or capecitabine a + cisplatin (n=290) R a Chosen at investigator’s discretion GEJ, gastroesophageal junction 5-FU or capecitabine a + cisplatin + trastuzumab (n=294) <ul><li>Stratification factors </li></ul><ul><ul><li>advanced vs metastatic </li></ul></ul><ul><ul><li>GC vs GEJ </li></ul></ul><ul><ul><li>measurable vs non-measurable </li></ul></ul><ul><ul><li>ECOG PS 0-1 vs 2 </li></ul></ul><ul><ul><li>capecitabine vs 5-FU </li></ul></ul><ul><ul><li>Phase III, randomized, open-label, international, multicenter study </li></ul></ul>1 Bang et al; Abstract 4556, ASCO 2009 3807 patients screened 1 810 HER2-positive (22.1%)
    21. 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. 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. 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. 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
    25. 25. <ul><ul><li>No increase in hematological or GI toxicity </li></ul></ul><ul><ul><li>No increase in clinicaly detected cardiac events, but a higher rate of asymptomatic decrease of LVEF (4.6% vs 1,1 %) </li></ul></ul><ul><ul><li>The median duration of transtuzumab treatment is shorter than in breast cancer trials ( 4.9 months) </li></ul></ul><ul><ul><li>Cardiotoxicity might be more prevalent when used in other settings (perioperative, with anthracyclines or after second line therapy) </li></ul></ul>ToGA TRIAL: TOXICITY DERIVED FROM THE ADDITION OF TRANSTUZUMAB
    26. 26. What are the active drugs that have shown non inferiority in randomized trials? <ul><li>5-Fluorouracil </li></ul><ul><li>Oral Fluoropirymidines ( Capecitabine , S1, UFT) </li></ul><ul><li>Anthracyclines? </li></ul><ul><li>Cisplatin </li></ul><ul><li>Oxaliplatin </li></ul><ul><li>Docetaxel </li></ul><ul><li>CPT-11 </li></ul><ul><li>Trastuzumab </li></ul>
    27. 27. REAL-2: First line phase 3 trial in oesophagogastric cancer <ul><li>Primary end point of demonstrating non-inferiority in both PPP comparisons for survival was met (upper limit of CI of HR<1.23) </li></ul>Cunningham et al, NEJM 2008 ITT=1002 PPP=961 ECX EOF EOX ECF Arm No. (ITT) OS ORR, % Med, mo 1yr ECF 263 9.9 37.7% 40.7% EOF 250 9.3 40.4% 42.4% ECX 245 9.9 40.8% 46.4% EOX 244 11.2 46.8% 47.9%
    28. 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. 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. 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. 31. Kang YK et al, Ann Oncol 2009 5-FU CDDP VERSUS CAPECITABINE-CDDP. A RANDOMISED PHASE III NONINFERIORITY TRIAL (ML17032)
    32. 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)
    33. 33. Irinotecan and Gastric Cancer <ul><li>Many phases II studies: </li></ul><ul><ul><li>Anti-tumoral activity in gastric cancer </li></ul></ul><ul><ul><li>Usually combined with 5FU </li></ul></ul><ul><ul><li>Good safety profile </li></ul></ul><ul><li>One large randomized phase II study (LV5FU2 vs LV5FU2 – Platine vs FOLFIRI): </li></ul><ul><ul><li>In favour of FOLFIRI regimen (RR, PFS, OS, tolerance) </li></ul></ul><ul><li>One large phase III study (IF vs Platine-5FU): </li></ul><ul><ul><li>Non inferiority of IF vs PF </li></ul></ul>Bouché O et al. J Clin Oncol. 2004;22:4319-4328 Dank M et al. Ann Oncol. 2008;19(8):1450-7. Curran D et al. Qual. Life Res. 2009;18:853-61. CPT11 usually done in CRC (FOLFIRI): Well known and managed drug
    34. 34. FFCD-GERCOR-FNCLCC 03-07 Phase III Study <ul><li>Stratification : </li></ul><ul><li>Mesurable or not </li></ul><ul><li>PS WHO 0-1 or 2 </li></ul><ul><li>Adj (R)CT or not </li></ul><ul><li>Linitis or not </li></ul><ul><li>Cardial or gastric </li></ul><ul><li>Center </li></ul>A: B: ECX until progression ; then FOLFIRI 2d line FOLFIRI until progression ; then ECX 2d line Time between Randomisation and: 1/ Progression Or 2/ tt discontinuation Or 3/ Death <ul><li>Objective I : 1 st line Time to Treatment Failure ( TTF) </li></ul><ul><li>Objectives II : </li></ul><ul><li>PFS, OS, (TTF 2 d line) </li></ul><ul><li>Toxicity, </li></ul><ul><li>Response rate, QoL* </li></ul><ul><li>QLQC30 et STO-22 </li></ul><ul><li>Data not shown </li></ul>ECX : D1 = Epirubicin 50 mg/m² (15 min.), Cisplatin 60 mg/m² (1 h) ; D2 to 15 : Capecitabine 1 g/m² x 2/d. D1 = D21 Cumulated dose of Epirubicin < 900 mg/m² (max 18 cures) FOLFIRI : D1 = Irinotecan 180 mg/m² (90 min) + LV 400 mg/m² (2h), 5FU b 400 mg/m², 5FU c.i. 2400 mg/m² (46h). D 1 = D14 R Guimbaud et al, ESMO 2010
    35. 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. 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
    37. 37. Best supportive care 1 5-FU monotherapy 1 Transtuzumab + Chemotherapy 6 EOX 5 5-FU + LV + Oxaliplatin (FLO) 4 Capecitabine + Cisplatin (XP) 3 Docetaxel +Cisplatin + 5FU 2 4 months 7 months 9.2 months 10.5 months 10.7 months 11.2 months 13.8 months HAVE WE MADE ANY PROGRESS IN THE TREATMENT OF ADVANCED GASTRIC CANCER? MEDIAN OVERALL SURVIVAL IN ADVANCED GASTRIC CANCER <ul><li>Wagner A, et al. JCO 2003, 2. van Cutsen E, et al. JCO 2006. 3.Kang YK et al, </li></ul><ul><li>Ann Oncol 2009. 4. Al Batran SE, et al. JCO 2009. 5. Cunningham D, et al. NEJM 2007. </li></ul><ul><li>6.van Cutsen E, et al. ASCO 2009. </li></ul>
    38. 38. Chemotherapy vs BSC 1 SPIRITS 2 ToGA 7 EOX 6 FLO 5 XP 4 DCF 3 6.0 months 2.0 months 0.6 months 1.2 months 1.9 months 1.2 months 2.7 months HAVE WE MADE ANY PROGRESS IN THE TREATMENT OF ADVANCED GASTRIC CANCER? ABSOLUTE INCREASE IN MEDIAN SURVIVAL IN ADVANCED GASTRIC CANCER <ul><li>Wagner A, et al. JCO 2003. 2. Kaizumi W,et al, Lancet Oncol 2008. 3 van Cutsen E, et </li></ul><ul><li>al. JCO 2006. 4.Kang YK et al, Ann Oncol 2009. 5. Al Batran SE, et al. JCO 2009. </li></ul><ul><li>6. Cunningham D, et al. NEJM 2007. 7.van Cutsen E, et al. ASCO 2009. </li></ul>CCT 1 1.0 months
    39. 39. Chemotherapy vs BSC 1 ToGA 6 EOX 5 FLO 4 XP 3 DCF 2 HR:0.39 p<0.00001 HR:0.77 p=0.02 HR:0.85 p=0.008 HR: not shown p=0.56 HR: 0.80 p=0.02 HR: 0.74 p=0.0046 HAVE WE MADE ANY PROGRESS IN THE TREATMENT OF ADVANCED GASTRIC CANCER? RISK OF DEATH REDUCTION IN ADVANCED GASTRIC CANCER <ul><li>Wagner A, et al. JCO 2003, 2. van Cutsen E, et al. JCO 2006. 3.Kang YK et al, </li></ul><ul><li>Ann Oncol 2009. 4. Al Batran SE, et al. JCO 2009. 5. Cunningham D, et al. NEJM 2007. </li></ul><ul><li>6.van Cutsen E, et al. ASCO 2009. </li></ul>Combination vs monotherapy 1 HR:0.83 p=0.001
    40. 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. 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
    42. 42. Recommended approach to advanced gastric cancer patients <ul><li>Select patients with PS0-1 to participate in clinical trials </li></ul><ul><li>CT should have a palliative role </li></ul><ul><li>Patient reported otcomes of value </li></ul><ul><li>Assess the risk of toxicity vs benefit </li></ul><ul><li>TCF, ECF, EOX, XP or similar schedules of value </li></ul><ul><li>Consider second line therapy for selected patients. More trials on this point are needed </li></ul>
    43. 43. Recommended approach to improve results on gastric cancer patients <ul><li>Design better clinical trials within academic and community centers </li></ul><ul><li>International Cooperation </li></ul><ul><li>Biological agents should be studied in randomized trials </li></ul><ul><li>Further studies on better predictive and prognostic biomarkers </li></ul>
    44. 44. MULTIDISCIPLINARY TEAM FOR GASTRO- ESOPHAGEAL CANCER UNIVERSITY HOSPITAL VALENCIA <ul><li>Radiology : Marta Rausell </li></ul><ul><li>Pathology : Samuel Navarro </li></ul><ul><li>Surgery : Fernando López, Roberto Martí, Radiation Oncology : Ana Hernández, Pepe López Torrecilla </li></ul><ul><li>Medical Oncology : Desamparados Roda, Alejandro Pérez-Fidalgo, Susana Roselló, Andrés Cervantes </li></ul>

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