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Cancers of the Esophagus and Stomach A Decade in Review Mitchell C. Posner M.D., FACS Thomas D. Jones Professor and Vice Chairman Chief, Section of General.

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Presentation on theme: "Cancers of the Esophagus and Stomach A Decade in Review Mitchell C. Posner M.D., FACS Thomas D. Jones Professor and Vice Chairman Chief, Section of General."— Presentation transcript:

1 Cancers of the Esophagus and Stomach A Decade in Review Mitchell C. Posner M.D., FACS Thomas D. Jones Professor and Vice Chairman Chief, Section of General Surgery and Surgical Oncology Medical Director, Clinical Cancer Programs University of Chicago

2 Esophageal Adenocarcinoma Relative 5 Year Survival Rates Esophageal Cancer 5% 10% 19% Ca Cancer J Clin 2012; 62: ePub

3 Gastric Adenocarcinoma Relative 5 Year Survival Rates Stomach Cancer 15% 20% 27% Ca Cancer J Clin 2012; 62: ePub

4 Prevention/Screening Diagnosis/Imaging/Staging Treatment esophageal tumors gastric tumors Applied research Cancers of the Esophagus and Stomach A Decade in Review

5 Serologic test results†Case subjects, N (%)Control subjects, N (%)Unadjusted OR (95% CI)Adjusted OR (95% CI)‡ Noncardia gastric cancer H. pylori negative12 (7)43 (25)1.00 (referent) H. pylori positive CagA-negative strains51 (29)44 (25)5.05 (2.11 to 12.07)6.55 (2.31 to 18.53) CagA-positive strains110 (64)86 (50)5.64 (2.47 to 12.88)8.93 (3.27 to 24.40) Gastric cardia cancer H. pylori negative25 (41)15 (25)1.00 (referent) H. pylori positive CagA-negative strains11 (18)24 (39)0.34 (0.14 to 0.85)0.21 (0.06 to 0.81) CaA-positive strains25 (41)22 (36)0.81 (0.35 to 1.85)0.43 (0.12 to 1.52 H. pylori Esophageal vs. Gastric Cancer Kamangar F et al. J Natl Cancer Inst. 2006;

6 Innovative Endoscopic Techniques Diagnosis High Resolution EndoscopyChromoendoscopy Narrow Band Imaging

7 Innovative Endoscopic Techniques Diagnosis Autofluorescence Imaging Confocal Laser Endomicroscopy

8 Ortiz-Fernando-Sorto J et al. World J Gastrointest Endosc Esophageal Malignancy Depth of Invasion

9 Esophageal Malignancy Histology Dictating Therapy Konda VJ et al.Am J Gastroenterol. 2012

10 Endoscopic Mucosal Resection Barrett’s Esophagus Ortiz-Fernando-Sorto J et al. World J Gastrointest Endosc. 2011

11 Endoscopic Submucosal Dissection Esophageal Cancer Ortiz-Fernando-Sorto J et al. World J Gastrointest Endosc. 2011

12 “Early” Esophageal Cancer Treatment Algorithm Konda VJ et al.Am J Gastroenterol. 2012

13 Value of PET Esophageal vs. Gastric Cancer Primary (sensitivity) Metastases (undetected) Esophageal > 95% 20% Gastric ~ 65% 10% Heeren PA et al. J Nucl Med Smyth E et al. Cancer 2012

14 Study Design MUNICON-I (Lordick et al. Lancet Oncol 2007) Resect Non-Responder Responder CTx: 3 months Resect Response definition: Decrease of the SUV mean PET d14 / PET baseline > 35% Weber et al. J Clin Oncol 2001;19: Ott et al. J Clin Oncol 2006;24: Response definition: Decrease of the SUV mean PET d14 / PET baseline > 35% Weber et al. J Clin Oncol 2001;19: Ott et al. J Clin Oncol 2006;24: AEG type I-II CTx PET d0 PET d14 AEG: adenocarcinoma of the esophago-gastric junction; C: cisplatinum; d: day CTX: chemotherapy PET: positron emission tomography; SUV: standard uptake value

15 Results MUNICON-I Lordick et al. Lancet Oncol 2007; 8: Median event-free survival [95% CI] in months: Metabolic Responder: 29.7 [23.6; 35.7] Metabolic Non-Responder: 14.1 [7.5; 20.6] Hazard ratio 2.18 [1.32; 3.62] Log-rank p-value: p<0.002 Median follow-up: 28.0 months

16 Study Design MUNICON-II Resect Non-Responder Responder CTx: 3 months Resect Radio-Ctx Cispl Gy Response definition: Decrease of the SUV mean PET d14 / PET baseline > 35% Weber et al. J Clin Oncol 2001;19: Lordick et al. Lancet Oncol 2007;8: Response definition: Decrease of the SUV mean PET d14 / PET baseline > 35% Weber et al. J Clin Oncol 2001;19: Lordick et al. Lancet Oncol 2007;8: AEG type I-II CTx PET d0 PET d14 AEG: adenocarcinoma of the esophago-gastric junction; C: cisplatinum; d: day CTX: chemotherapy PET: positron emission tomography; SUV: standard uptake value

17

18 CALGB Schema T3/4 or N1 Esophageal Adenoca PET Scan pre-treatment Induction Chemo: modified FOLFOX6 days 1,15, 29 PET-responders: ≥ 35% SUV decrease: continue initial chemo + concurrent RT (5040cGy in 180cGy fx) PET Scan day Surgical resection 6 weeks post-RT PET- nonresponders: < 35% SUV decrease: cross-over to alternative chemo + concurrent RT (5040cGy in 180cGy fx) Induction Chemo: Carboplatin/ Paclitaxel days 1,8,22,29 Randomize

19 Esophageal Cancer Surgical Approach Transhiatal Esophagectomy Transthoracic Esophagectomy Minimally Invasive Esophagectomy Robotic-Assisted Esophagectomy

20 Outcome VariablesTransthoracic (n = 643)Transhiatal (n = 225)p Value Thirty-day mortality (%) Hospital length of stay (days) Need for anastomotic dilatation (%) Overall survival (%) 1 year years years Esophageal Cancer Transhiatal vs Transthoracic Resection Chang AC et al. Ann Thorac Surg 85(2): 424-9, 2008 Population-based study: SEER

21 GI Cancer Resections Birkmeyer J SSO 2011

22 Proportion of population-wide extirpative procedures performed at low volume centers Birkmeyer J SSO 2011

23 Finks JF et al. N Engl J Med Esophageal Cancer – Resection Trends in Operative Mortality

24 Bedenne, L. et al. J Clin Oncol; 25: Esophageal Cancer – Squamous Cell CA Role of Surgery CRT + Surgery CRT alone

25 Bedenne, L. et al. J Clin Oncol; 25: Esophageal Cancer – Squamous Cell CA Role of Surgery 6 month mortality 16% SGY vs. 6% CRT

26 Esophageal Cancer – Squamous Cell CA Role of Surgery Stahl, M. et al. J Clin Oncol; 23:

27 Esophageal Cancer – Squamous Cell CA Role of Surgery Stahl, M. et al. J Clin Oncol; 23: CRT + Surgery CRT postop mortality = 11%

28 multicenter phase III trial n= 363 pts. EUS T2-3,N0-1(74% adeno, 67% N+) carboplatin/paclitaxel/41.4 Gy Results: CRT+ surgery surgery alone median surv.49mo26mop=0.011 R0 resection90%65% pCR rate33% -- op mortality3.8%3.7% ESOPHAGEAL CANCER Preoperative Chemoradiotherapy Van Gaast A et al. ASCO 2010

29 Esophageal Cancer Neoadjuvant Chemotherapy vs. Surgery Alone Mortality p = 0.05 Gebski V et al. Lancet Oncol 8: , 2007

30 Comparison of MRC and Intergroup Study MRC Intergroup Chemotherapy 90% 71% (all cycles) Surgical resection 92% 80% Esophageal Cancer Preoperative Chemotherapy

31 Allum W H et al. JCO 2009;27: ©2009 by American Society of Clinical Oncology Esophageal Cancer Preoperative Chemotherapy - MRC OEO2

32 Allum W H et al. JCO 2009;27: ©2009 by American Society of Clinical Oncology Esophageal Cancer Preoperative Chemotherapy - MRC OEO2

33 Kelsen D P et al. JCO 2007;25: ©2007 by American Society of Clinical Oncology Esophageal Cancer Preoperative Chemotherapy – INT 0113

34 Kelsen D P et al. JCO 2007;25: ©2007 by American Society of Clinical Oncology Esophageal Cancer Preoperative Chemotherapy – INT 0113

35 Mortality P=0.002 Esophageal Cancer Neoadjuvant Chemoradiotherapy vs. Surgery Alone Gebski V et al. Lancet Oncol 8: , 2007

36 Van Hagen P et al. N Engl J Med Preoperative Chemoradiotherapy CROSS Trial

37 Methods Data Source The National Cancer Data Base (NCDB) –1450 Commission on Cancer (CoC) hospitals –>70% of all new cancers –Standardized definitions Patients Esophageal Cancer –8,562 patients ( ) –Clinical Stage I-III –Middle & lower third tumors –Adenocarcinoma and squamous cell carcinoma

38 Merkow RP et al. Ann Surg Oncol Esophageal Cancer - Neoadjuvant Therapy Trends in Utilization Neoadjuvant + surgery

39 Results: Margins, Nodes, Mortality Unadjusted Rate (%) Adjusted Odds Ratio (95% CI) P-value Positive Margins Surgery alone (referent) Neoadjuvant ( )P<0.001 Positive Lymph Nodes Surgery alone (referent) Neoadjuvant ( ) P< day Mortality Surgery alone (referent) Neoadjuvant ( ) P=0.651

40 Molecular Targets: Esophagogastric Cancer KRAS mutation: < 5-10% BRAF mutation: < 5% EGFr over expression: 50-80% EGFr mutation: < 5% CMET: < 10% HER2 over expression: 10-25% Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006

41 HER2 and trastuzumab mechanism of action HER2 receptor trastuzumab Trastuzumab Inhibits HER2-mediated signalling in HER2-positive tumors Prevents HER2 activation by blocking extracellular domain cleavage Activates antibody-dependent cellular cytotoxicity

42 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) Stratification factors −advanced vs metastatic −GC vs GEJ −measurable vs non-measurable −ECOG PS 0-1 vs 2 −capecitabine vs 5-FU Phase III, randomized, open-label, international, multicenter study 1 Bang et al; Abstract 4556, ASCO patients screened HER2-positive (22.1%)

43 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= p= F+C + trastuzumab F+C p= Patients (%) CRPRORR

44 RTOG 1010: Phase II Study of Neoadjuvant Trastuzumab and Chemoradiation for Esophageal Adenocarcinoma (Siewert I, II) ‘ CHEMORADIATION HER-2 (+) (FISH) HER-2 (+) (FISH) TRASTUZUMAB + CHEMORADIATION TRASTUZUMAB + CHEMORADIATION SURGERY + TRASTUZUMAB (1 YR) SURGERY + TRASTUZUMAB (1 YR) HER-2 (-) (FISH) HER-2 (-) (FISH) ALTERNATIVE STUDIES  Chemoradiation: Carbo + Paclitaxel, RT 5040 cGy  Surgery Maintenance trastuzumab post op  Sample Size = 130 Her-2 (+) Pts, Increase 3-Yr Survival from 30% to 50% pts to be screened

45 Gastric Cancer Surgery Extent of LND

46 Songun I et al. Lancet Oncol 2010 Gastric Cancer Resection Tumor Control

47 Songun I et al. Lancet Oncol 2010 Gastric Cancer Resection Tumor Control D1=41%D2=25%

48 Songun I et al. Lancet Oncol 2010 Gastric Cancer Resection Tumor Control D1=41%D2=25% INT 0116 LR = 24% DGCT LR = 25%

49 INT 0116 DGCT Gastric Cancer Resection Value of Adequate Surgery

50 NCCN v guidelines: Gastric resection should include the regional lymphatics: perigastric lymph nodes (D1) and those along the named vessels of the celiac axis (D2) with a goal of examining at least 15 or greater lymph nodes. Surgical experience & hospital volume matter! NCCN v guidelines: Gastric resection should include the regional lymphatics: perigastric lymph nodes (D1) and those along the named vessels of the celiac axis (D2) with a goal of examining at least 15 or greater lymph nodes. Surgical experience & hospital volume matter! Appropriate Extent of Resection Gastric Cancer

51 Median OS: 27 v 36m Highly selected population (All had R0 resection + recovered from surgery) yet only 64% completed treatment. Significant treatment-related toxicity: 1% toxic death 73% grade 3/4 AEs Post-operative Chemoradiation: SWOG 9008/Intergroup 0116 Trial Resected stage Ib-IV (M0) gastric or OGJ adenocarcinoma n=556 (

52 Peri-operative Chemotherapy: The MRC MAGIC Trial Cunningham et al., NEJM 2006 Resectable adenocarcinoma of the stomach, OGJ or lower oesophagus n=503 Randomised Pre-operative ECFx3 Surgical resection within 3-6/52 Post- operative ECF x3 within 6- 12/52 Surgical resection within 6/52 Median OS: 24 v 20 months 5 yr OS: 36% v 23% 13% OS benefit for ECF Pre-op chemo well tolerated (5% did not complete pre-op treatment due to toxicity) No increase in post-op complications HR for death 0.75, p=0.009

53 Bang y et al. Lancet 2012 Adjuvant Chemotherapy for Resectable Gastric Cancer CLASSIC Trial

54 Adjuvant Chemotherapy: ACTS- GT 1 Stage II-III gastric cancer treated with curative gastrectomy; all with at least D2 dissection n=1059 Randomised Adjuvant S-1 80mg/m 2 /day x28 days q 6 weeks x 12 months n=529 Observation n=530 Sakuramoto et al., NEJM 2007 Screening programme in Japan allows detection of disease at an earlier stage S1 efficacy not proven in non-Asian population

55 The GASTRIC Group JAMA 2010 Adjuvant Chemotherapy for Resectable Gastric Cancer Meta- analysis

56 Snyder RA et al. Int J Surg Oncol Adjuvant Radiation Therapy Resectable Gastric Cancer

57 Adjuvant Chemotherapy vs. CRT ARTIST Trial Stage II-III gastric cancer treated with curative gastrectomy; all D2 dissection n=458 Randomised XP 2 cycles capecitabine + 45GY XRT XP 2 cycles (n = 230) capecitabine + cisplatin (XP) 6 cycles (n = 228)

58 Chemotherapy vs. Chemoradiotherapy for Resectable Gastric Cancer ARTIST Trial: all patients Lee J et al. JCO 2012

59 3 yr DFS 77.5% vs. 72.3% Treat 20 patients to prevent recurrence in 1 patient Chemotherapy vs. Chemoradiotherapy for Resectable Gastric Cancer ARTIST Trial: node + patients Lee J et al. JCO 2012

60 Chemotherapy vs. Chemoradiotherapy for Resectable Gastric Cancer Lee J et al. JCO 2012 ARTIST Trial

61 Gastric Cancer Targeted Agents – ToGA Trial Bang YJ et al. Lancet. 2010

62 CP >90% tumors  KIT or PDGFRα mutation >80% metastatic GIST patients benefit from imatinib mesylate Resected primary GIST: 5-yr survival = 54% GIST

63 A phase III randomized double-blind study of adjuvant imatinib vs placebo in patients following resection of primary GIST Primary GIST  3 cm Complete gross resection tumor KIT + RandomizeRandomize Placebo x 1 year FOLLOWUPFOLLOWUP lmatinib x 1 year PI: Ron DeMatteo Z9001 GIST – Adjuvant

64 Recurrence free survival Placebo Imatinib HR 0.35 (95% CI ); P< Recurrence-free and alive (%) GIST – Adjuvant Z9001 Months Lancet Mar 28;373(9669): TotalEvents Imatinib35930 Placebo35470

65 Multivariate Analyses For Recurrence: Placebo Group GIST – Adjuvant Z9001 Hazard ratio ASCO 2010 Tumor location Stomach Small bowel Rectum Tumor size <5 cm  5-10 cm  10 cm Mitotic rate <5  5 Genotype Exon 9 Exon 11 Exon 13 PDGFRA WT

66 RFS For Exon 11- Mutant Cases by Arm Recurrence-free and alive (%) GIST – Adjuvant Z9001 Months ASCO 2010 P< at 24 months HR 3.42 (95% CI ) Imatinib (n=173) Placebo (n=173) RFS For Wildtype Cases by Arm Treatment P= at 24 months Imatinib (n=32) Placebo (n=32)

67 Imatinib for 12 months An open-label Phase III study Imatinib for 36 months Follow-up SSGXVIII: Study design Random assignment 1:1 Stratification: 1) R0 resection, no tumor rupture 2) R1 resection or tumor rupture

68 GIST – Adjuvant Imatinib One vs. Three Years Joensuu H et al. JAMA 2012

69 Advanced GIST Sunitinib in Imatinib Resistant GIST

70

71 Esophageal/Gastric Cancer Incidence / Mortality 2012 Ca Cancer J Clin 2012; 62: epub 17,460 15,070 Esophageal Cancer 10,540 21,320 Stomach Cancer


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