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

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

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

4. SCIENTIFIC EVIDENCES… CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main experimental adjuvant modalities 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 Macdonald, NEJM 2001 P<0.001 3-year OS: 50% (CT-RT) vs 41% (Surgery)‏

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

8. Surgery in Gastric cancer D1 DISSECTION D2 DISSECTION

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

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

11. ...Meta-analyses SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY OR 0.72 (95% CI 0.62-0.84)‏ 17 Panzini, Tumori 2002 OR 0.84 (95% CI 0.74-0.96)‏ 21 Janunger, Eur J Surg 2002 OR 0.72 (95% CI 0.62-0.84)‏ 17 Gianni, Ann Onc 2001 OR 0.82 (95% CI 0.75-0.89)‏ 20 Mari, Ann Onc 2000 OR 0.80 (95% CI 0.66-0.97)‏ 13 Earle, EJC 1999 OR 0.88 (95% CI 0.78-1.08)‏ 11 Hermans, JCO 1993 ODDs Ratio/Hazard Ratio for death N° of studies Author

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

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

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

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

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

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

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

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

20. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY 3520GISCAD 3520GOIM 5540 FFCD 8801 3220GOIM 4530ITMO Experimental Arm (5-years-OS)‏ Control Arm (5-years OS)‏ Trial STATISTICAL ENPOINTS Increase in 5-year OS: 15%...BUT... Meta-analyses Survival benefit: 4%...After Meta-analyses...What’s the problem?

21. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE CHEMOTHERAPY...And now?... INAG: SURGERY 5-FU/LV CPT-11 + 5-FU/LV  CDDP/TXT 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

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. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY 1) 5-years OS rates : 45-50%...higher than expected!......higher than expected!... 46 % S+ CT 41 % SFFDC 47 % S+ CT 48 % SGOIRG SITMO 52 % S+ CT 52 % PE LF GISCAD 50 % FU/ LV C/ RT SINT0016SMAGIC CSCCSCCSCCSC 52 52 % 48 48 % 47 47 % 48 48 % 41 41 % 46 46 % 52 52 % 50 50 % 36 36 % 23 23 % 50 50 % 30 30 %

26. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY 2) Locoregional vs Distant recurrence: 2) Locoregional vs Distant recurrence: ITMO GOIMFFCDGISCAD SWOG 9008...After Meta-analyses...take home messages

27. SCIENTIFIC EVIDENCES ABOUT POST-OPERATIVE ADJUVANT CHEMOTHERAPY 3) Surgery: 3) Surgery: High number of lymph nodes examined High number of lymph nodes examined 24181725 Median N°LN GISCADFFDCGOIRCITMO...After Meta-analyses...take home messages

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

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

30. SCIENTIFIC EVIDENCES… CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main experimental adjuvant modalities 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 FNLCC-FFCD 9703 MAGIC TRIAL RR SurgerySurgery CF x 2-3 Surgery CF x 3-4 224 pt 503 pt ECF x 3 Surgery Boige, Asco 2007 Cunningham, NEJM 2006 Adk of the Adk of the stomach or stomach or lower third of the lower third of the oesophagus oesophagus Stage II or grater Stage II or grater Suitable for Suitable for curative resection curative resection

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

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

36. SCIENTIFIC EVIDENCES ABOUT PRE-OPERATIVE ADJUVANT CHEMOTHERAPY...Two positive randomized trials MAGIC TRIAL FNLCC-FFCD 9703 Secondary endpoints: Curative Resections Safety: Safety: No difference in postoperative mortality and morbidity 4 44 169(70%*)‏ S + CT * Of resections with know outcome 5 RX 70 R+ p=.03166(79%*)‏ R0 S 1(1%)‏ 2 (2%)‏ 4 (4%)‏ 95 (87%)‏ S + CT 1(1%)‏ RX 12 (11%)‏ R2 6 (5%)‏ R1 p=0.04 81 (74%)‏ R0 S

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

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 The first randomized trial SAKK-EIO Trial R Surgery 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 The first randomized trial SAKK-EIO Trial Roth, WCGC-Barcellona 2007 TCF  S N=34 S  TCF N=34 Preop CT (x4)‏ Completed (74%)‏ N=25 (74%)‏ Surgery N=32 (95%)‏ Surgery N=34 (100%)‏ Postop CT (x4)‏ StartN=23(66%)‏ Completed (34%)‏ N=12 (34%)‏ Closed for poor accrual

41. SCIENTIFIC EVIDENCES... EVIDENCES... CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main studied adjuvant modalities...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! < D1 > D1 POST-OPERATIVE CT POST-OPERATIVE CT-RT 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! < D1 > D1 POST-OPERATIVE CT POST-OPERATIVE CT-RT 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... 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... Smith, JCO 2005 T1/2, N1T1/2, N0 T3, N1T3, N0

47. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER Smith, JCO 2005 T1/2, N1T1/2, N0 T3, N1T3, N0......Maybe we need a new category of HIGH RISK resected gastric cancer patients...

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

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

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

51. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER Scartozzi, 2004......Maybe we need a new category of HIGH RISK resected gastric cancer patients... Molecular factors with a possible prognostic value in gastric cancer patients

52. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER Kattan, JCO 2003......Maybe we need a new category of HIGH RISK resected gastric cancer patients...

53. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER Kattan, JCO 2003......Maybe we need a new category of HIGH RISK resected gastric cancer patients... Distribution of nomogram prediction within each AJCCgage gropin Note the heterogeneity in several AJCC groups!

54. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main experimental adjuvant modalities Conclusion-1 The best choise is to treat patients into clinical trials The best choise is to treat patients into clinical trials We need to test new agents from metastatic setting We need to test new agents from metastatic setting (waiting for the data of on-going clinical trials...and waiting (waiting for the data of on-going clinical trials...and waiting for new clinical trial!)‏ for new clinical trial!)‏ Maybe we need a new category of high risk patients in both Maybe we need a new category of high risk patients in both adjuvant and neo-adjuvant setting adjuvant and neo-adjuvant setting

55. CONTROVERSIES IN THE ADJUVANT THERAPY OF GASTRIC CANCER The role of chemotherapy: Main experimental adjuvant modalities Conclusion-2 Neoadjuvant Chemotherapy.... Neoadjuvant Chemotherapy.......talk with your surgeons!!...talk with your surgeons!!

56. Open-label, multicenter, phase II study of docetaxel plus oxaliplatin, and infusional 5-FU/LV as neoadjuvant chemotherapy for potentially resectable gastric cancer Gruppo Oncologico Laziale

57. Open label, single arm phase II study Potentiallyresectable -T3-T4 -T3-T4 - N + FOLFOX-TXT X 2 CYCLES* FOLFOX-TXT SURGERY SD o PD SD o PD TC TXT 50 mg/mq TXT 50 mg/mq L-OHP 85 mg/mq L-OHP 85 mg/mq I-LV 200 mg/mq I-LV 200 mg/mq 5-FU 2600 mg/mq i.c.p. X 24 h 5-FU 2600 mg/mq i.c.p. X 24 h Q 14 * TC/ US- endos copy Gruppo Oncologico Laziale

58. Potentiallyresectable -T3-T4 -T3-T4 - N + FOLFOX-TXT X 2 CYCLES* FOLFOX-TXT SURGERY SD o PD SD o PD TC TXT 50 mg/mq TXT 50 mg/mq L-OHP 85 mg/mq L-OHP 85 mg/mq I-LV 200 mg/mq I-LV 200 mg/mq 5-FU 2600 mg/mq i.c.p. X 24 h 5-FU 2600 mg/mq i.c.p. X 24 h Q 14 * TC/ US- endos copy Gruppo Oncologico Laziale Open label, single arm phase II study

59. Docetaxel-Oxaliplatin Phase II study Advanced gastric tumor TXT 50 mg/mq TXT 50 mg/mq L-OHP 85 mg/mq L-OHP 85 mg/mq AF 200 mg/mq AF 200 mg/mq 5-FU 2600 mg/mq i.c.p. X 24 h 5-FU 2600 mg/mq i.c.p. X 24 h Q 14 59 pts 59 pts ORR 53% (2 RC + 25 RP)‏ ORR 53% (2 RC + 25 RP)‏ Neutropenia G 3-4 = 43% Neutropenia G 3-4 = 43% (Only one Febvrile Neutropenia) (Only one Febvrile Neutropenia) Al-batran, ASCO2007 Gruppo Oncologico Laziale

60. Objective Response Rate (ORR)‏ Objective Response Rate (ORR)‏ Safety Profile Safety Profile SECONDARY ENDPOINTS Patological complete response (pCR)‏ Patological complete response (pCR)‏ Patological Down-staging and R0 surgery rates Patological Down-staging and R0 surgery rates Disease Free Survival (DFS)‏ Disease Free Survival (DFS)‏ Treatment related morbidity and mortality Treatment related morbidity and mortality Gruppo Oncologico Laziale PRIMARY ENDPOINT