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Highligths in management of gastrointestinal cancer

Highligths in management of gastrointestinal cancer. April 11, 2008. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER. Enrico Cortesi, Martina Puglisi. Sapienza Università di Roma. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER.

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Highligths in management of gastrointestinal cancer

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  1. Highligths in management of gastrointestinal cancer April 11, 2008 CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER Enrico Cortesi, Martina Puglisi Sapienza Università di Roma

  2. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main experimental adjuvant modalities Pre-operative CT Surgery Post-operative CT Post-operative CT-RT Follow-up

  3. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main exeperimental adjuvant modalities SCIENTIFIC EVIDENCES... ...CLINICAL PRACTICE ?

  4. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main experimental adjuvant modalities SCIENTIFIC EVIDENCES… Post-operative CT-RT

  5. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE CHEMO-RADIOTHERAPY SWOG 9008/INT 0116 Macdonald, NEJM 2001

  6. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE CHEMO-RADIOTHERAPY SWOG 9008/INT 0116 P<0.001 3-year OS: 50%(CT-RT) vs 41%(Surgery)‏ Macdonald, NEJM 2001

  7. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE CHEMO-RADIOTHERAPY SWOG 9008/INT 0116 Surgery Macdonald, NEJM 2001

  8. Surgery in Gastric cancer D1 DISSECTION D2 DISSECTION

  9. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE CHEMO-RADIOTHERAPY SWOG 9008/INT 0116 Up-date: Subset analyses - OS in D2 resection Macdonald, ASCO 2004

  10. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main studied adjuvant modalities SCIENTIFIC EVIDENCES… Post-operative CT

  11. Author N° of studies ODDs Ratio/Hazard Ratio for death Hermans, JCO 1993 11 OR0.88 (95%CI0.78-1.08)‏ Earle, EJC 1999 13 OR0.80 (95% CI0.66-0.97)‏ Mari, Ann Onc 2000 20 OR0.82 (95% CI0.75-0.89)‏ Gianni, Ann Onc 2001 17 OR0.72 (95% CI0.62-0.84)‏ Janunger, Eur J Surg 2002 21 OR0.84 (95% CI0.74-0.96)‏ Panzini, Tumori 2002 17 OR0.72 (95% CI0.62-0.84)‏ SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...Meta-analyses

  12. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...Meta-analyses...What’s the problem? METHODOLOGICAL LIMITS OF META-ANAYSES: 1.Literature-Based (selection bias)‏ 2.Heterogeneus criteria for selections of patientsand for selections of studies 3.Studies with low statistical power 4.Old chemotherapy regimens

  13. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses * Etoposide-Adriamycin-cisPlatin (x 2)  FU/LV (x 2)‏ 1992-97 [274pts] Surgery * FU icp x 5 d FU icp x 5 d - cisPlatin d 2 (x 4) 1989-97 [260pts] Surgery cisPlatin-Epirubicin-Leucovorin-FU (x 4) * 1995-00 [258pts] Surgery * CDDP-based chemotherapy Epirubicin-Lederfolin-FU-Etoposide (x 6) 1996-01 [228pts] Surgery cisPlatin-Epirubicin-Leucovorin-FU (x 4) 1998-03 [400pts] FU/LV (x 4)‏

  14. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses Etoposide-Adriamycin-cisPlatin (x 2)  FU/LV (x 2)‏ [274pts] Surgery P = 0.22 HR 0.93 [95% CI 0.65-1.34] 5-year OS: 52%(CT arm) vs 48%(f-up arm)‏ Bajetta, Ann Oncol 2002

  15. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses cisPlatin-Epirubicin-Leucovorin-FU (x 4) [258pts] Surgery P=0.542 HR 0.90 [95% CI 0.64-1.26] 5-year OS: 47.6%(CT arm) vs 48.7%(f-up arm) Di Costanzo, JNCI 2008

  16. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses FU icp x 5 d FU icp x 5 d - cisPlatin d 2 (x 4) Closed prematurely owing to poor accrual [260pts] Surgery P = 0.22 HR 0.74 [95% CI 0.54-1.02] 5-year OS: 46.6%(CT arm) vs 41.9%(f-up arm)‏ Bouchè, Ann Oncol 2005

  17. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses cisPlatin-Epirubicin-Leucovorin-FU (x 4) [400pts] FU/LV (x 4)‏ HR 0.95 [95% CI 0.70-1.29] 5-year OS: 52%(PELFw) vs 50%(5-FU) Cascinu, JNCI 2007

  18. Trial CT N°p ↑ 5-OS rate ↑5DFS rate EAP5-FU/LV 274 4% (p=0.7)‏ 5% (p=0.29)‏ PELF 200 1% (p=0.54)‏ 5-FUFUP 278 5% (p=0.22)‏ 8%(p=0.19)‏ PELFw VS FU/LV 400 2% (n.s.)‏ 1% (n.s.)‏ ELFE 228 4,5% (p=0.6)‏ 5% (p=0.3)‏ SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses GOIM

  19. Trial CT N°p ↑ 5-OS rate ↑5DFS rate EAP5-FU/LV 274 4% (p=0.7)‏ 5% (p=0.29)‏ PELF 200 1% (p=0.54)‏ 5-FUFUP 278 5% (p=0.22)‏ 8%(p=0.19)‏ PELFw VS FU/LV 400 2% (n.s.)‏ 1% (n.s.)‏ ELFE 228 4,5% (p=0.6)‏ 5% (p=0.3)‏ SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses...What’s the problem? GOIM

  20. Trial Control Arm (5-years OS)‏ Experimental Arm (5-years-OS)‏ ITMO 30 45 GOIM 20 32 FFCD 8801 40 55 GISCAD 20 35 GOIM 20 35 SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses...What’s the problem? STATISTICAL ENPOINTS Increase in 5-year OS: 15% ...BUT... Meta-analyses Survival benefit:4%

  21. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE CHEMOTHERAPY ...And now?... S U R G E R Y CPT-11 + 5-FU/LV  CDDP/TXT INAG: 5-FU/LV Using a two tailed long-rank test with α=0.05 and power of 0.80 (β=0.20), assuming that the DFS in the control group is 50% and that expected Hazard-Ratio is 0.80 in favour of sequential group, the number of events requested to show a significant difference is 482 ... 555 pts per arm should be included for a total of 1110 pt

  22. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY Sasako, ASCO 2007 Sasako, ASCO 2007

  23. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY Sasako, ASCO 2007

  24. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses...take home messages

  25. MAGIC INT0016 ITMO GOIRG FFDC GISCAD S CSC S C/RT S S+CT S S+CT S S+CT PELF FU/LV 48% 52% 48% 47% 41% 46% 52% 50% SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses...take home messages 5-years OS rates : 45-50% ...higher than expected!... 48% 52% 48% 47% 41% 46% 52% 50% 23% 36% 30% 50%

  26. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses...take home messages 2) LocoregionalvsDistant recurrence: GOIM FFCD GISCAD SWOG 9008 ITMO

  27. ITMO GOIRC FFDC GISCAD MedianN°LN 25 17 18 24 SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses...take home messages 3) Surgery: High number of lymph nodes examined

  28. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY Retrospective Analysis 2 groups Scartozzi, BJC 2005

  29. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY ...After Meta-analyses...take home messages 4) Compliance to chemotherapy

  30. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main experimental adjuvant modalities SCIENTIFIC EVIDENCES… Pre-operative CT

  31. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY Two positive randomized trials about peri-operative chemotherapy The first randomized trial of neo-adjuvant versus adjuvant chemotherapy

  32. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY Two positive randomized trials about peri-operative chemotherapy The first randomized trial of neo-adjuvant versus adjuvant chemotherapy

  33. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY ...Two positive randomized trials MAGIC TRIAL FNLCC-FFCD 9703 503 pt 224 pt • Adk of the stomach or lower third of the oesophagus • Stage II or grater • Suitable for curative resection R R ECF x 3 Surgery CF x 2-3 Surgery Surgery Surgery ECF x 3 CF x 3-4 Cunningham, NEJM 2006 Boige, Asco 2007

  34. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY ...Two positive randomized trials MAGIC TRIAL FNLCC-FFCD 9703 Primary endpoint: Overall Survival 5-y OS: 23% vs 36% 5-y OS: 24% vs 38%

  35. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY ...Two positive randomized trials MAGIC TRIAL FNLCC-FFCD 9703 Secondary endpoints: Progression Free Survival 5-y DFS: 19% vs 33% 5-y DFS: 21% vs 34%

  36. S S + CT S S + CT R0 166(79%*)‏ 169(70%*)‏ p=.03 R0 81 (74%)‏ 95 (87%)‏ p=0.04 R+ 70 44 R1 6 (5%)‏ 4 (4%)‏ RX 5 4 R2 12 (11%)‏ 2 (2%)‏ * Of resections with know outcome RX 1(1%)‏ 1(1%)‏ SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY ...Two positive randomized trials MAGIC TRIAL FNLCC-FFCD 9703 Secondary endpoints: Curative Resections Safety: No difference in postoperative mortality and morbidity

  37. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY ...Two positive randomized trials MAGIC TRIAL FNLCC-FFCD 9703 TRIAL PROFILES CT + S N=250 S N=253 CT + S N=113 S N=111 Preop CT N=215 (86%)‏ Preop CT N=98 (87%)‏ Surgery N=240 (95%)‏ Surgery N=110 (99%)‏ Surgery N=219 (88%)‏ Surgery N=109 (96%)‏ Postop CT N=104 (42%)‏ Postop CT N=54 (50%)‏

  38. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY Two positive randomized trials about peri-operative chemotherapy The first randomized trial of neo-adjuvant versus adjuvant chemotherapy

  39. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY ...Adj vs Neo-adj CT: The first randomized trial SAKK-EIO Trial Surgery TCF x 3 R TCF x 3 Surgery Closed for poor accrual Roth, WCGC-Barcellona 2007

  40. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY ...Adj vs Neo-adj CT: The first randomized trial SAKK-EIO Trial Closed for poor accrual TCFS N=34 STCF N=34 Preop CT (x4)‏ Completed N=25 (74%)‏ Surgery N=34 (100%)‏ Postop CT (x4)‏ StartN=23(66%)‏ Completed N=12 (34%)‏ Surgery N=32 (95%)‏ Roth, WCGC-Barcellona 2007

  41. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main studied adjuvant modalities SCIENTIFIC EVIDENCES... ...CLINICAL PRACTICE

  42. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main studied adjuvant modalities Kattan, JCO 2003

  43. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main studied adjuvant modalities T3-4 or N+ cT3-4 or cN+ pT3-4 or pN+ PRE-OPERATIVE CT Look at surgery! Clinical trial! < D1 > D1 POST-OPERATIVE CT-RT POST-OPERATIVE CT Clinical trial!

  44. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main studied adjuvant modalities T3-4 or N+ cT3-4 or cN+ pT3-4 or pN+ PRE-OPERATIVE CT Look at surgery! Clinical trial! < D1 > D1 POST-OPERATIVE CT-RT POST-OPERATIVE CT Clinical trial!

  45. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER POST-OPERATIVE CHEMOTHERAPY ...Maybe we need a new category of HIGH RISK resected gastric cancer patients...

  46. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER ...Maybe we need a new category of HIGH RISK resected gastric cancer patients... T1/2, N0 T1/2, N1 T3, N0 T3, N1 Smith, JCO 2005

  47. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER ...Maybe we need a new category of HIGH RISK resected gastric cancer patients... T1/2, N0 T1/2, N1 T3, N0 T3, N1 Smith, JCO 2005

  48. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER ...Maybe we need a new category of HIGH RISK resected gastric cancer patients... Bouchè, Ann Oncol 2005

  49. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER ...Maybe we need a new category ofHIGH RISKresected gastric cancer patients... LBVI/PNI + LBVI/PNI - [734 pts] 2 groups Median OS: 45.5 months(A) vs “not reached”(B) Median OS: 32.1 months(A) vs “not reached”(B) Scartozzi, BJM 2006

  50. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER ...Maybe we need a new category ofHIGH RISKresected gastric cancer patients... Stage I Early Gastric Cancer Median OS: 82.6 months(A) vs “not reached”(B) Median OS: “ not reached” (A) + (B) Scartozzi, BJM 2006

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