GASTRIC CANCER  A MODEL FOR MULTIDISCIPLINARY TEAM APPROACH
Gastric cancer is a significant problem in some countries GLOBOCAN (2002) Incidence of gastric cancer (crude rate in males...
 
 
 
 
Years after surgery  Gastric Cancer Survival by stage CADO,1985  0 50 100% 5 10 years Stage III Stage II Stage I Stage 0 2...
Case 1  A 40-YEAR-OLD MAN WITH LOCALLY  ADVANCED GASTROESOPHAGEAL  ADENOCARCINOMA No relevant past history, excepting over...
Case 1  A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED  GASTROESOPHAGEAL ADENOCARCINOMA Physical exam: No pallor or icteric collo...
Case 1  A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED  GASTROESOPHAGEAL ADENOCARCINOMA A FIBEROPTIC ESOPHAGO-GASTROSCOPY   WAS  ...
Case 1  A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED  GASTROESOPHAGEAL ADENOCARCINOMA Systemic and local staging:  Thorax and a...
 
 
 
Years after surgery  Gastric Cancer Survival by stage CADO,1985  0 50 100% 5 10 years Stage III Stage II Stage I Stage 0 2...
META-ANALYSIS OT TRIALS INVOLVING ADJUVANT CHEMOTHERAPY VERSUS SURGERY ALONE FOR GASTRIC CANCER-1 0.44-076 0.58 Asian 0.83...
META-ANALYSIS OT TRIALS INVOLVING ADJUVANT CHEMOTHERAPY VERSUS SURGERY ALONE FOR GASTRIC CANCER-2 Marginal, though  signif...
RECENTLY PUBLISHED TRIALS OF ADJUVANT CHEMOTHERAPY FOR LOCALIZED GASTRIC CANCER 0.91 0.69-1.21 48% 43.5% 113 113 No CT ELF...
WHY HAS ADJUVANT CHEMOTHERAPY FAILED TO  SHOW ANY POSITIVE EFFECT AFTER SURGERY  IN GASTRIC CANCER? NON STANDARD SURGERY H...
STUDY DESIGN  SURGERY NO TREATMENT STRATIFICATION T 1-4 NODES  CT+ CT-RT + CT 0, 1-3, >3
 
 
LOCALIZED GASTRIC CANCER MOST PATIENTS ARE: T3 N+ METASTATIC PATTERN MAY BE PREDICTED  FROM CLINICAL FACTORS BIOLOGICAL PA...
LOCALIZED GASTRIC CANCER  AIMS OF NEOADJUVANT THERAPY TO INCREASE R0 RESECTION RATE EARLY TREATMENT OF MICROMETASTAES TO R...
<ul><li>Eligible patients: </li></ul><ul><li>Adenocarcinoma of the stomach or lower third of the oesophagus (from 1999), s...
Pre-operative chemotherapy and surgery trial profile Cunningham et al NEJM 2006 CSC N=250 Commenced pre-operative chemothe...
Postoperative morbidity/mortality Cunningham et al NEJM 2006 CSC S Postoperative deaths 6%  (14/219) 6%  (15/24 0) Postope...
Survival Logrank p-value = 0.0001 Hazard Ratio = 0.66   (95% CI 0.53 - 0.81) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 M...
<ul><li>In operable gastric and lower oesophageal cancer, perioperative chemotherapy: </li></ul><ul><li>leads to downsizin...
Can MAGIC be compared to INT0116? Direct comparison of results is difficult due to different inclusion criteria and differ...
Case 1  A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED  GASTROESOPHAGEAL ADENOCARCINOMA After a multidisciplinary team discussion...
Case 1  A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED  GASTROESOPHAGEAL ADENOCARCINOMA After 3 courses a  surgical procedure was...
Case 1  A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED  GASTROESOPHAGEAL ADENOCARCINOMA POSTOPERATIVE THERAPY WITH THREE MORE  CO...
LOCALIZED GASTRIC CANCER POST- OR PREOPERATIVE TREATMENT CONCLUSIONS-1 POSTOPERATIVE CT IS NOT STANDARD THERAPY  POSTOPERA...
CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV  GASTRIC CANCER She had no previous signs of disease Consulted due to weight loss...
CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV  GASTRIC CANCER LOCAL AND SYSTEMIC STAGING: Thorax and abdominopelvic CT: No lung...
CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV  GASTRIC CANCER THERAPEUTIC PLAN: This is a not curable disease The main aim of t...
 
 
 
CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV  GASTRIC CANCER THERAPEUTIC PLAN: PALLIATIVE CHEMOTHERAPY WAS RECOMENDED THREE CO...
CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV  GASTRIC CANCER THERAPEUTIC PLAN: ASSESSMENT OF RESPONSE PERFORMANCE STATUS 0, 6 ...
 
 
 
CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV  GASTRIC CANCER THERAPEUTIC PLAN: UP TO SIX COURSES OF DOCETAXEL, CISPLATIN AND 5...
CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV  GASTRIC CANCER THERAPEUTIC PLAN: ASSESS THE PATIENT CLINICALLY EVERY 6-8 WEEKS N...
 
CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV  GASTRIC CANCER WHAT ARE OUR PLANS IN CASE OF DISEASE PROGRESSION? SECOND LINE CH...
RANDOMIZED TRIALS COMPARING CT  VERSUS BEST SUPPORTIVE CARE IN ADVANCED GASTRIC CANCER CT RR-PD TTP OS   (%)   (months) PY...
RANDOMIZED TRIAL OF EARLY CT VS AT  SYMPTOMATIC PROGRESSION IN ADVANCED  GASTRIC CANCER PATIENTS WITHOUT SYMPTOMS EARLY EL...
Which are the active drugs? <ul><li>5-Fluorouracil </li></ul><ul><li>Oral Fluoropirymidines (capecitabine, S1, UFT) </li><...
What are the active drugs that have shown superiority in randomized trials? <ul><li>5-Fluorouracil </li></ul><ul><li>Oral ...
<ul><ul><li>International phase III trial </li></ul></ul><ul><ul><ul><li>Screened 3807 patients </li></ul></ul></ul><ul><u...
<ul><ul><li>HER2 gen amplification or over-expression may be predictive of poor prognosis </li></ul></ul><ul><ul><li>In To...
<ul><ul><li>Primary and secondary aims met </li></ul></ul><ul><ul><ul><li>mOS: 11.1 vs 13.8 months HR: 0.74 p: 0.0046 </li...
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...
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...
Best supportive care 1 5-FU monotherapy 1 Transtuzumab + Chemotherapy 6 EOX 5 5-FU + LV + Oxaliplatin (FLO) 4 Capecitabine...
5-FU monotherapy 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...
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 ...
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Medical Students 2011 - A. Cervantes - GASTROINTESTINAL CANCER - Treatment of Gastrointestinal Malignancies

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Medical Students 2011 - A. Cervantes - GASTROINTESTINAL CANCER - Treatment of Gastrointestinal Malignancies

  1. 1. GASTRIC CANCER A MODEL FOR MULTIDISCIPLINARY TEAM APPROACH
  2. 2. Gastric cancer is a significant problem in some countries GLOBOCAN (2002) Incidence of gastric cancer (crude rate in males [all ages] per 100,000 population) <3.1 <7.0 <13.8 <22.2 <118.6
  3. 7. Years after surgery Gastric Cancer Survival by stage CADO,1985 0 50 100% 5 10 years Stage III Stage II Stage I Stage 0 21.9 47.6 79.2 91.6 82.0 66.9 36.4 14.7
  4. 8. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA No relevant past history, excepting overweight No peptic ulcer disease. Ocasional dyspepsia and gastroesophageal reflux Active smoker. No previous surgery CURRENT DISEASE: He consulted due to haematemesis. No weight loss or anorexia.
  5. 9. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA Physical exam: No pallor or icteric collour No hepatomegaly. No ascitis. No edema. No supraclavicullar lymph nodes Cardiopulmonar and neurological without findings of interest A DIAGNOSTIC TEST WAS PERFORMED A FIBEROPTIC ESOPHAGO-GASTROSCOPY
  6. 10. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA A FIBEROPTIC ESOPHAGO-GASTROSCOPY WAS DONE: Two cm. above the gastroesophageal junction, an ulcerated circumferential mass with elevated and hard borders with some rigidity and moving in block with surrounding tissues was observed. A biopsy showed a diffuse gastric adenocarcinoma poorly differentiated STAGING
  7. 11. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA Systemic and local staging: Thorax and abdominopelvic CT scan : No liver mets nor lung mets were detected. Thickness of the gastroesophageal union area. Some locoregional lymph nodes of more than 1 cm. size were detected at the perigastric area. Endoscopy with ultrasonography : Tumor fully involving the muscular layer of the stomach antrum with invasion of the serosa. At least four lymph nodes of significant size were observed (uT3uN1) Laparoscopy was not recommended
  8. 15. Years after surgery Gastric Cancer Survival by stage CADO,1985 0 50 100% 5 10 years Stage III Stage II Stage I Stage 0 21.9 47.6 79.2 91.6 82.0 66.9 36.4 14.7
  9. 16. META-ANALYSIS OT TRIALS INVOLVING ADJUVANT CHEMOTHERAPY VERSUS SURGERY ALONE FOR GASTRIC CANCER-1 0.44-076 0.58 Asian 0.83-1.12 0.96 Western Very heterogeneous group of trials 0.74-0.96 0.84 3962 21 2002 Januger Eur J Surg Small survival benefit 0.75-0.89 0.82 3658 20 2000 Mari Ann Oncol Small survival benefit In N+ patients 0.66-0.97 0.80 1990 13 1999 Earle Eur J Cancer No benefit 0.78-1.08 0.88 2096 11 1993 Hermanns J Clin Oncol Conclusions 95% CI Odds Ratio Nr. Pts Nr. Trials Year Meta-analysis
  10. 17. META-ANALYSIS OT TRIALS INVOLVING ADJUVANT CHEMOTHERAPY VERSUS SURGERY ALONE FOR GASTRIC CANCER-2 Marginal, though significant benefit P< 0.0001 0.80-0.90 0.85 2286 19 2008 Liu et al Eur J Surg Oncol Marginal, though significant benefit P: 0.001 0.84-0.96 0.90 3212 15 2008 Zhao et al Cancer Investigation Conclusions 95% CI Odds Ratio Nr. Pts Nr. Trials Year Meta-analysis
  11. 18. RECENTLY PUBLISHED TRIALS OF ADJUVANT CHEMOTHERAPY FOR LOCALIZED GASTRIC CANCER 0.91 0.69-1.21 48% 43.5% 113 113 No CT ELFE De Vita Ann Oncol 2007 0.95 0.70-1.29 52% 50% 201 196 FU-LV PELFw Cascinu JNCI 2007 0.93 0.65-1.34 52% 48% 137 137 No CT EAP 5FU-LV Bajetta Ann Oncol 2002 0.90 0.64-1.26 47.6 % 48.7% 130 128 No CT PELF Di Constanzo JNCI 2008 HR (CI at 95%) Median Survival CT 5-year Survival Control Nr. Pts CT Nr. Pts Control CT Trial
  12. 19. WHY HAS ADJUVANT CHEMOTHERAPY FAILED TO SHOW ANY POSITIVE EFFECT AFTER SURGERY IN GASTRIC CANCER? NON STANDARD SURGERY HIGH RISK OF LOCAL RELAPSE CHEMOTHERAPY NOR VERY ACTIVE IN ADVANCED DISEASE: COMPLETE RESPOSE RATE LESS THAN 10% HETEREOGENEOUS SAMPLES, LOW SIZE SAMPLES, MOST PATIENTS N- INADEQUATE ESTATISTICAL DESIGN PROLONGUED AND SLOW ACCRUAL
  13. 20. STUDY DESIGN SURGERY NO TREATMENT STRATIFICATION T 1-4 NODES CT+ CT-RT + CT 0, 1-3, >3
  14. 23. LOCALIZED GASTRIC CANCER MOST PATIENTS ARE: T3 N+ METASTATIC PATTERN MAY BE PREDICTED FROM CLINICAL FACTORS BIOLOGICAL PARAMETERS MAY BETTER PREDICT OUTCOME
  15. 24. LOCALIZED GASTRIC CANCER AIMS OF NEOADJUVANT THERAPY TO INCREASE R0 RESECTION RATE EARLY TREATMENT OF MICROMETASTAES TO REDUCE LOCOREGIONAL RELAPSES BIOLOGICAL STUDIES
  16. 25. <ul><li>Eligible patients: </li></ul><ul><li>Adenocarcinoma of the stomach or lower third of the oesophagus (from 1999), suitable for curative resection </li></ul><ul><li>Non-metastatic disease </li></ul><ul><li>Stage II or greater </li></ul>Chemotherapy (ECF): Epirubicin 50mg/m2, IV day 1 Cisplatin 60mg/m2, IV day 1 5-FU 200mg/m2/day, continuous infusion, days 1-21 (cycles repeated every 3 weeks) Primary Overall survival Secondary Progression-free survival Surgical resectability Quality of Life Recruitment: July 1994-April 2002 Study Design Study entry and randomization Pre-operative chemotherapy : ECFx3 Post-operative chemotherapy: ECFx3 Surgery Surgery S arm N=253 CSC arm N=250 3-6 weeks 6-12 weeks Cunningham et al NEJM 2006
  17. 26. Pre-operative chemotherapy and surgery trial profile Cunningham et al NEJM 2006 CSC N=250 Commenced pre-operative chemotherapy N=237 (95%) Completed pre-operative chemotherapy N=215 (86%) Proceeded to surgery N=219 (88%) Proceeded to surgery N=240(95%) S N=253
  18. 27. Postoperative morbidity/mortality Cunningham et al NEJM 2006 CSC S Postoperative deaths 6% (14/219) 6% (15/24 0) Postoperative complications 46% 46% Median duration of post - operative hospital stay 13 days 13 days
  19. 28. Survival Logrank p-value = 0.0001 Hazard Ratio = 0.66 (95% CI 0.53 - 0.81) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months from randomisation 0 12 24 36 48 60 72 163 250 190 253 Events Total Progression-free Survival rate Logrank p-value = 0.009 Hazard Ratio = 0.75 (95% CI 0.60 - 0.93) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months from randomisation 0 12 24 36 48 60 72 Survival rate *Included relapse, PD and death from any cause. PFS* Overall <ul><li>On multivariate analysis, treatment effect unchanged after adjustment for age, performance status, site of primary and gender </li></ul><ul><li>Hazard ratio for death </li></ul><ul><ul><li>Adjusted: 0.74 (95%CI: 0.59-0.93) </li></ul></ul><ul><ul><li>Unadjusted: 0.75 </li></ul></ul>Cunningham et al NEJM 2006 CSC S 149 250 170 253 Events Total CSC S 4 mo 13% 9% Benefit to CSC arm 20 mo 23% 41% S 24 mo 36% 50% CSC Median survival 5 year survival 2 year survival
  20. 29. <ul><li>In operable gastric and lower oesophageal cancer, perioperative chemotherapy: </li></ul><ul><li>leads to downsizing of primary tumour </li></ul><ul><li>significantly improves progression-free survival </li></ul><ul><li>significantly improves overall survival </li></ul>MAGIC: Conclusions Cunningham et al NEJM 2006
  21. 30. Can MAGIC be compared to INT0116? Direct comparison of results is difficult due to different inclusion criteria and different time of randomization. * Estimated from curve 1 Cunningham NEJM 2006 2 MacDonald NEJM 2001; 2004 GI Cancers Symposium 0.76 (0.62-0.93) P=0.006 0.75 (0.60-0.93) P=0.009 Hazard ratio (95% CI) 27 months 35 months 20 months 24 months Median survival 26%* 40%* 23% 36% 5 year survival 50%* 58%* 41% 50% 2 year survival Surgery only N=277 Post-op chemoRT + surgery N=282 Surgery only N=253 Peri-op chemo + surgery N=250 INT116 2 (N=556) MAGIC 1 (N=503)
  22. 31. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA After a multidisciplinary team discussion: Preoperative chemotherapy was recomended Three courses of Oxaliplatin and capecitabine (XELOX) were given. Only grade 1 Nausea and grade 1 cold related dysestehesia were reported
  23. 32. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA After 3 courses a surgical procedure was performed: Esophagogastric resection with partial gastrectomy with lymphadenectomy The histopathological report showed: Absence of neoplastic cells or remaining tumors areas in the surgical specimen. None of 15 nodes proximal to the stomach and none of the 12 nodes resected at extraperigastric sites were involved with tumor. ypT0pN0 M0
  24. 33. Case 1 A 40-YEAR-OLD MAN WITH LOCALLY ADVANCED GASTROESOPHAGEAL ADENOCARCINOMA POSTOPERATIVE THERAPY WITH THREE MORE COUSES OF THE SAME CHEMOTHERAPY WAS RECOMMENDED No evidence of disease relapse 40 months after surgery.
  25. 34. LOCALIZED GASTRIC CANCER POST- OR PREOPERATIVE TREATMENT CONCLUSIONS-1 POSTOPERATIVE CT IS NOT STANDARD THERAPY POSTOPERATIVE CT+ RT MAY BENEFIT PATIENTS WITH STAGE II-III AND R0 RESECTION (PROLONGATION OF SURVIVAL) PREOPERATIVE CT HAS SHOWN BENEFIT IN SURVIVAL IN SEVERAL RANDOMIZED TRIAL (MAGIC-1, FFCD)
  26. 35. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER She had no previous signs of disease Consulted due to weight loss of 10% (8 Kg), anorexia, vomiting, dispepsia and constant dull pain in her right upper abdomen. Performance status was 1 Blood tests revealed: Mild anemia, increased LDH and Alkaline Phospatase A gastroscopy was done: Polipoid, ulcerated and infiltrating tumor in gastric fundus of 4 cm. Biopsy: Diffuse gastric adenocarcinoma poorly differentiated STAGING
  27. 36. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER LOCAL AND SYSTEMIC STAGING: Thorax and abdominopelvic CT: No lung mets. Multiple nodes in both liver lobes showing hypodensity indicating liver mets. Multiple perigastric and paraortic lymph nodes of 15 to 27 mm. Thickened wall of stomach at fundic area with suspected invasion of splenic hilum and tail of pancreas
  28. 37. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: This is a not curable disease The main aim of therapy is palliation SURGERY IS NOT RECOMENDED IN PATIENTS WITH METASTATIC DISEASE EXCEPTING FOR SYMPTOM CONTROL DO CONSIDER PROGNOSTIC FACTORS PALLIATIVE CHEMOTHERAPY WAS RECOMENDED
  29. 41. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: PALLIATIVE CHEMOTHERAPY WAS RECOMENDED THREE COURSES OF DOCETAXEL, CISPLATIN AND 5-FU WERE GIVEN GCSF SUPPORT ORAL CIPROFLOXACINE RECOMMENDED ASSESSMENT OF RESPONSE
  30. 42. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: ASSESSMENT OF RESPONSE PERFORMANCE STATUS 0, 6 KG WEIGHT GAIN MILD TOXICITY: GRADE 2 ALOPECIA GRADE 1 DIARRHEA NO FEVER, NO MUCOSITIS NO DOSE REDUCTION REQUIRED CT-SCAN: PARTIAL RESPONSE
  31. 46. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: UP TO SIX COURSES OF DOCETAXEL, CISPLATIN AND 5-FU WERE COMPLETED ASSESSMENT OF RESPONSE PERFORMANCE STATUS 0, WEIGHT STABLE MILD TOXICITY: NO DOSE REDUCTION REQUIRED CT-SCAN: PERSISTENT PARTIAL RESPONSE STOP CHEMOTHERAPY
  32. 47. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER THERAPEUTIC PLAN: ASSESS THE PATIENT CLINICALLY EVERY 6-8 WEEKS NO SYMPTOMATIC PROGRESSION DURING SIX FURTHER MONTHS PS 0, NO WEIGT LOSS, SOCIAL LIFE OK. WHAT ARE OUR PLANS IN CASE OF DISEASE PROGRESSION?
  33. 49. CASE 2 A 69 YEAR-OLD WOMAN WITH STAGE IV GASTRIC CANCER WHAT ARE OUR PLANS IN CASE OF DISEASE PROGRESSION? SECOND LINE CHEMOTHERAPY: - RETREAT WITH DCF - FOLFIRI - FOLFOX vs XELOX - CLINICAL TRIAL CONSIDER EXPERIMENTAL APPROACHES IN CLINICAL TRIALS OPTIMAL APPROACH: SEQUENTIAL DOUBLETS?
  34. 50. RANDOMIZED TRIALS COMPARING CT VERSUS BEST SUPPORTIVE CARE IN ADVANCED GASTRIC CANCER CT RR-PD TTP OS (%) (months) PYRÖNEN FAMTX 29-24 5.4 12.3 (1995) BSC 0-80 1.7 3.1 MURAD FAMTX 50- -- 10.0 (1993) BSC 0- -- 3.0 SCHEITAUER FU-LV-EPI 38- 4 >5 >7.5 (1995) BSC 0-53 2 4.0 GLIMELIUS ELF-FULV 23-30 5 8.0 (1997) VS BSC 0- 2 5.0
  35. 51. RANDOMIZED TRIAL OF EARLY CT VS AT SYMPTOMATIC PROGRESSION IN ADVANCED GASTRIC CANCER PATIENTS WITHOUT SYMPTOMS EARLY ELF-FULV CT AT PROGR. CT 100% 50% TIME TO CT 8 DAYS 82 DAYS SYMPTOMATIC IMPROVEMENT 70% 25% QoL IMPROVEMENT 70% 25% SURVIVAL 10 MONTHS 4 MONTHS GLIMELIUS, ANN ONCOL 1994
  36. 52. 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>
  37. 53. 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>Trastuzumab </li></ul>
  38. 54. <ul><ul><li>International phase III trial </li></ul></ul><ul><ul><ul><li>Screened 3807 patients </li></ul></ul></ul><ul><ul><ul><li>Randomised 594 (15.6%) </li></ul></ul></ul><ul><ul><ul><li>The largest HER2 status data set on advanced gastric cancer </li></ul></ul></ul><ul><ul><li>First phase III trial in gastric cancer to: </li></ul></ul><ul><ul><ul><li>Select patients by a given molecular profile </li></ul></ul></ul><ul><ul><ul><li>Study the addition of a biological agent to a chemotherapy doublet </li></ul></ul></ul>TRANSTUZUMAB IN THE TREATMENT OF ADVANCED GASTRIC CANCER
  39. 55. <ul><ul><li>HER2 gen amplification or over-expression may be predictive of poor prognosis </li></ul></ul><ul><ul><li>In ToGA, HER2 status was positive in 22.1 % of patients determined by ICH or FISH, with a high concordance between techniques (87.1%) </li></ul></ul><ul><ul><li>Higher rates of HER2 over-expression are reported in EGJ (35%) than in gastric tumors (20%), as well in intestinal (32%)versus diffuse type histology (6%). </li></ul></ul>HER2: GASTROESOPHAGEAL CANCER
  40. 56. <ul><ul><li>Primary and secondary aims met </li></ul></ul><ul><ul><ul><li>mOS: 11.1 vs 13.8 months HR: 0.74 p: 0.0046 </li></ul></ul></ul><ul><ul><ul><li>PFS: 5.5 vs 6.7 months HR: 0.71 p:0.0002 </li></ul></ul></ul><ul><ul><ul><li>TTP: 5.6 vs 7,1 months HR: 0.70 p:0.0003 </li></ul></ul></ul><ul><ul><ul><li>ORR: 34.5% vs 47.3% p:0.0017 </li></ul></ul></ul><ul><ul><li>Excellent survival in both arms: </li></ul></ul><ul><ul><ul><li>cross-over (1%) </li></ul></ul></ul><ul><ul><ul><li>second line therapies (45%) </li></ul></ul></ul><ul><ul><ul><li>Asian origin (54%) </li></ul></ul></ul>TOGA TRIAL: RESULTS
  41. 57. 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
  42. 58. 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
  43. 59. 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>
  44. 60. 5-FU monotherapy 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
  45. 61. 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 or similar schedules of value </li></ul><ul><li>Consider second line therapy for selected patients </li></ul>
  46. 62. 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>

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