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Cancers of the Esophagus and Stomach A Decade in Review

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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% % % Ca Cancer J Clin 2012; 62: ePub We have moved the needle in improving survival…what has occurred over the past 10 years that has contributed to us altering the natural history of these two cancers.

3 Gastric Adenocarcinoma Relative 5 Year Survival Rates
Stomach Cancer 15% % % Ca Cancer J Clin 2012; 62: ePub We have moved the needle in improving survival…what has occurred over the past 10 years that has contributed to us altering the natural history of these two cancers.

4 Cancers of the Esophagus and Stomach A Decade in Review
Prevention/Screening Diagnosis/Imaging/Staging Treatment esophageal tumors gastric tumors Applied research I will try to highlight the seminal events in all of these areas in a very brief and not adequate amount of time…please do not be insulted if there are other worthy advances that I just did not have the time to mention.

5 H. pylori Esophageal vs. Gastric Cancer
Serologic test results† Case subjects, N (%) Control subjects, N (%) Unadjusted OR (95% CI) Adjusted OR (95% CI)‡ Noncardia gastric cancer H. pylori negative 12 (7) 43 (25) 1.00 (referent) H. pylori positive   CagA-negative strains 51 (29) 44 (25) 5.05 (2.11 to 12.07) 6.55 (2.31 to 18.53)   CagA-positive strains 110 (64) 86 (50) 5.64 (2.47 to 12.88) 8.93 (3.27 to 24.40) Gastric cardia cancer 25 (41) 15 (25) 11 (18) 24 (39) 0.34 (0.14 to 0.85) 0.21 (0.06 to 0.81)   CaA-positive strains 22 (36) 0.81 (0.35 to 1.85) 0.43 (0.12 to 1.52 Gastric cardia and esophagus are essentially synonymous…H. pylori is strongly associated with the risk of non-cardia gastric cancer… Kamangar F et al. J Natl Cancer Inst. 2006;

6 Innovative Endoscopic Techniques Diagnosis
High Resolution Endoscopy Chromoendoscopy Multiple improvements in endoscopic techniques and technology have enhanced our abilities to diagnose cancer and detect it at an earlier stage. Narrow Band Imaging

7 Innovative Endoscopic Techniques Diagnosis
Autofluorescence Imaging Confocal Laser Endomicroscopy

8 Esophageal Malignancy Depth of Invasion
In addition, our ability to translate findings on EUS regarding depth of invasion and improved staging accuracy has led to novel treatment options to manage premalignant and early invasive cancers. Ortiz-Fernando-Sorto J et al. World J Gastrointest Endosc. 2011

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

10 Endoscopic Mucosal Resection Barrett’s Esophagus
Look at these results with EMR for HGD and IMC…10years ago all these patients would have been subjected to the morbidity and mortality of esophagectomy. Ortiz-Fernando-Sorto J et al. World J Gastrointest Endosc. 2011

11 Endoscopic Submucosal Dissection Esophageal Cancer
ESD…our east Asian colleagues are leading the way Ortiz-Fernando-Sorto J et al. World J Gastrointest Endosc. 2011

12 “Early” Esophageal Cancer Treatment Algorithm
Based on these recent innovations this is our current algorithm at U of C…we use EMR as our diagnostic tool of choice. Konda VJ et al.Am J Gastroenterol. 2012

13 Value of PET Esophageal vs. Gastric Cancer
Primary (sensitivity) Metastases (undetected) Esophageal > 95% % …but more importantly we can use PET as a surrogate for determining clinical efficacy of treatment Gastric ~ 65% % Heeren PA et al. J Nucl Med. 2004 Smyth E et al. Cancer 2012

14 Study Design MUNICON-I (Lordick et al. Lancet Oncol 2007)
Non-Responder Resect CTx AEG type I-II PET d14 PET d0 CTx: 3 months Resect Responder Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35% Weber et al. J Clin Oncol 2001;19: Ott et al. J Clin Oncol 2006;24:4692-8 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 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 Lordick et al. Lancet Oncol 2007; 8:

16 Study Design MUNICON-II
Radio-Ctx Cispl Gy Non-Responder Resect CTx AEG type I-II PET d14 PET d0 CTx: 3 months Resect Responder Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35% Weber et al. J Clin Oncol 2001;19: Lordick et al. Lancet Oncol 2007;8:797-85 AEG: adenocarcinoma of the esophago-gastric junction; C: cisplatinum; d: day CTX: chemotherapy PET: positron emission tomography; SUV: standard uptake value

17 No improvement in R0 rate or TTP and OS.

18 CALGB Schema PET-responders: ≥ 35% SUV decrease: continue initial chemo + concurrent RT (5040cGy in 180cGy fx) Induction Chemo: modified FOLFOX6 days 1,15, 29 T3/4 or N1 Esophageal Adenoca PET Scan pre-treatment Surgical resection 6 weeks post-RT PET Scan day 36-42 Randomize This serves as the basis for a current active ALLIANCE trial Induction Chemo: Carboplatin/ Paclitaxel days 1,8,22,29 PET- nonresponders: < 35% SUV decrease: cross-over to alternative chemo + concurrent RT (5040cGy in 180cGy fx) 18

19 Esophageal Cancer Surgical Approach
Transhiatal Esophagectomy Transthoracic Esophagectomy Minimally Invasive Esophagectomy Robotic-Assisted Esophagectomy To focus on surgery for a few moments

20 Transhiatal vs Transthoracic Resection
Esophageal Cancer Transhiatal vs Transthoracic Resection Population-based study: SEER Outcome Variables Transthoracic (n = 643) Transhiatal (n = 225) p Value Thirty-day mortality (%) 13.1 6.7 0.009 Hospital length of stay (days) 20.7 21.4 0.65 Need for anastomotic dilatation (%) 34.5 43.1 0.02 Overall survival (%)  1 year 55.5 57.3 0.64  3 years 29.4 40.0 0.003  5 years 22.7 30.5 In 2001 a phase III trial showed no difference in cancer outcomes when patients were randomized to THE vs. TTE. A population based study again confirmed these findings although it still remains controversial…what is not controversial is… Chang AC et al. Ann Thorac Surg 85(2): 424-9, 2008

21 GI Cancer Resections Birkmeyer J SSO 2011
…and in really experienced hands, mortality is less than 5% Birkmeyer J SSO 2011

22 Proportion of population-wide extirpative procedures performed at low volume centers
In contrast, a substantial proportion of esophageal and pancreatic cases had been shifted to higher volume centers, with only roughy17-18% remaining at low volume centers. Birkmeyer J SSO 2011 22

23 Esophageal Cancer – Resection Trends in Operative Mortality
Effects of market concentration and hospital volume has in part led to a substantial fall in operative mortality…more than for any other cancer Finks JF et al. N Engl J Med. 2011

24 Esophageal Cancer – Squamous Cell CA
Role of Surgery CRT + Surgery CRT alone We have begun to define the role of surgery in the context of multimodality treatment of esophageal cancer…one’s perspective can depend on how we interpret the results of scientifically designed trials. Bedenne, L. et al. J Clin Oncol; 25:

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

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 postop mortality = 11% CRT + Surgery CRT CRT + Surgery CRT Stahl, M. et al. J Clin Oncol; 23:

28 ESOPHAGEAL CANCER Preoperative Chemoradiotherapy
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. 49mo 26mo p=0.011 R0 resection 90% 65% pCR rate 33% op mortality 3.8% 3.7% Van Gaast A et al. ASCO 2010

29 Neoadjuvant Chemotherapy vs. Surgery Alone
Esophageal Cancer Neoadjuvant Chemotherapy vs. Surgery Alone Mortality Generally accepted that neoadjuvant therapy is the standard of care…what form it should take is still debatable…this meta-analysis is drive by the MRC trial, certainly the largest trial…opposite findings in the INT trial. p = 0.05 Gebski V et al. Lancet Oncol 8: , 2007

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

31 Esophageal Cancer Preoperative Chemotherapy - MRC OEO2
(A) Disease-free survival (DFS) by allocated treatment. DFS was calculated from a landmark time of 6 months from random assignment to allow for the difference in timing of surgery between the two groups. (B) Overall survival by allocated treatment. S, surgery alone; CS, two cycles of combination cisplatin and fluorouracil before surgery; HR, hazard ratio. Allum W H et al. JCO 2009;27: ©2009 by American Society of Clinical Oncology

32 Esophageal Cancer Preoperative Chemotherapy - MRC OEO2
Survival by type of resection for all patients. An R0 resection was defined as all margins histologically free of tumor, R1 resection as macroscopically complete with microscopically positive margins, and R2 resection as macroscopically incomplete. NR, not resected. Allum W H et al. JCO 2009;27: ©2009 by American Society of Clinical Oncology

33 Esophageal Cancer Preoperative Chemotherapy – INT 0113
Overall survival by study arm for chemotherapy followed by surgery versus surgery only. MST, median survival time. Kelsen D P et al. JCO 2007;25: ©2007 by American Society of Clinical Oncology

34 Esophageal Cancer Preoperative Chemotherapy – INT 0113
Overall survival by type of resection. R0, complete resection with negative microscopical margins; R1, all gross disease resected but microscopical examination reveals positive margins; R2, gross residual visible tumor; MST, median survival time. Kelsen D P et al. JCO 2007;25: ©2007 by American Society of Clinical Oncology

35 Esophageal Cancer Neoadjuvant Chemoradiotherapy vs. Surgery Alone
Mortality In the U.S. CRT is the adopted standard but up until recently the evidence was shaky at best. P=0.002 Gebski V et al. Lancet Oncol 8: , 2007

36 Preoperative Chemoradiotherapy CROSS Trial
Modern day CRT---Carboplatin and taxol Van Hagen P et al. N Engl J Med. 2012

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

38 Esophageal Cancer - Neoadjuvant Therapy Trends in Utilization
+ surgery Merkow RP et al. Ann Surg Oncol. 2012

39 Results: Margins, Nodes, Mortality
Unadjusted Rate (%) Adjusted Odds Ratio (95% CI) P-value Positive Margins Surgery alone 13.3 1.0 (referent) Neoadjuvant 5.7 0.60 ( ) P<0.001 Positive Lymph Nodes 52.3 37.4 0.24 ( ) 30-day Mortality 5.4 3.1 0.93 ( ) P=0.651 39

40 Molecular Targets: Esophagogastric Cancer
KRAS mutation: < 5-10% BRAF mutation: < 5% EGFr over expression: % EGFr mutation: < 5% CMET: < 10% HER2 over expression: % Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; 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 Phase III, randomized, open-label, international, multicenter study 5-FU or capecitabinea + cisplatin (n=290) 3807 patients screened1 810 HER2-positive (22.1%) HER2-positive advanced GC (n=584) R 5-FU or capecitabinea + 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 Eligibility criteria for the ToGA trial include: >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. aChosen at investigator’s discretion GEJ, gastroesophageal junction 1Bang et al; Abstract 4556, ASCO 2009 42

43 Secondary end point: tumor response rate
Intent to treat Patients (%) p=0.0017 F+C + trastuzumab p=0.0145 F+C 47.3% 41.8% 34.5% 32.1% p=0.0599 5.4% 2.4% CR PR ORR ORR= CR + PR CR, complete response; PR, partial response

44 RTOG 1010: Phase II Study of Neoadjuvant Trastuzumab and Chemoradiation for Esophageal Adenocarcinoma (Siewert I, II) CHEMORADIATION SURGERY HER-2 (+) (FISH) TRASTUZUMAB + CHEMORADIATION SURGERY + TRASTUZUMAB (1 YR) 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 Gastric Cancer Resection
Tumor Control Songun I et al. Lancet Oncol 2010

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

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

49 Gastric Cancer Resection Value of Adequate Surgery
DGCT INT 0116

50 Appropriate Extent of Resection Gastric Cancer
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!

51 Post-operative Chemoradiation: SWOG 9008/Intergroup 0116 Trial
Observation n=275 Resected stage Ib-IV (M0) gastric or OGJ adenocarcinoma n=556 (<D1 resection 54% D1 = 36%, D2 = 10%) Randomised 5-FU/LV Chemoradiation (4500Gy) n=281 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 HR for death 1.32; p=0.0046 INT 0116, the Macdonald Trial recently updated established adjuvant therapy in the U.S. in the form of postoperative chemoradiotherapy Smalley SR et al., J Clin Oncol. 2012

52 Peri-operative Chemotherapy: The MRC MAGIC Trial
Post-operative ECF x3 within 6-12/52 Pre-operative ECFx3 Surgical resection within 3-6/52 Resectable adenocarcinoma of the stomach, OGJ or lower oesophagus n=503 Randomised 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 This landmark trial by David Cunningham and colleagues established perioperative chemotherapy as the standard of care in Europe and has been adopted as a viable alternative to CRT in the U.S. HR for death 0.75, p=0.009 Cunningham et al., NEJM 2006

53 Adjuvant Chemotherapy for Resectable Gastric Cancer
CLASSIC Trial Further evidence for the value of chemotherapy alone post-resection as effective adjuvant therapy…in the Western part of the world Bang y et al. Lancet 2012

54 Adjuvant Chemotherapy: ACTS-GT1
Observation n=530 Stage II-III gastric cancer treated with curative gastrectomy; all with at least D2 dissection n=1059 Randomised Adjuvant S-1 80mg/m2/day x28 days q 6 weeks x 12 months n=529 Screening programme in Japan allows detection of disease at an earlier stage S1 efficacy not proven in non-Asian population …and in the East our colleagues have convincingly shown Sakuramoto et al., NEJM 2007

55 Adjuvant Chemotherapy for Resectable Gastric Cancer
Meta- analysis and of course this idividual patient-level meta-analysis of all RCTs of chemotherapy post-resection… The GASTRIC Group JAMA 2010

56 Adjuvant Radiation Therapy Resectable Gastric Cancer
Large population based study…A group of investigators from Vanderbilt queried the SEER database and concluded based on their analysis that adjuvant XRT was independently associated (Cox multivariate regression analysis) with improved survival and that benefit persisted even in those patients who underwent extended i.e. D2 LND Snyder RA et al. Int J Surg Oncol. 2012

57 Adjuvant Chemotherapy vs. CRT ARTIST Trial
capecitabine + cisplatin (XP) 6 cycles (n = 228) 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) The ARTIST Trial was designed to test the worth of adjuvant XRT in GC patients who underwent a proper D2 LND

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

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

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

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

62 GIST >90% tumors  KIT or PDGFRα mutation
>80% metastatic GIST patients benefit from imatinib mesylate Resected primary GIST: 5-yr survival = 54% CP High risk is defined as tumors greater than 10cm, multifocal or ruptured at presentation. CP Nelson, Heidi kmy/mls 6/02/07

63 Complete gross resection tumor KIT +
GIST – Adjuvant Z9001 A phase III randomized double-blind study of adjuvant imatinib vs placebo in patients following resection of primary GIST Placebo x 1 year F O L W U P R a n d o m i z e Complete gross resection tumor KIT + Primary GIST 3 cm lmatinib x 1 year PI: Ron DeMatteo Z9001 remains the only double blind, placebo controlled trial in the world and the first to provide prospective validation of the efficacy of imatinib in the adjuvant setting. CP Nelson, Heidi kmy/mls 6/02/07

64 Recurrence free survival
GIST – Adjuvant Z9001 Recurrence free survival Recurrence-free and alive (%) Total Events Imatinib Placebo HR 0.35 (95% CI ); P<0.0001 Months Placebo Imatinib Imatinib 400 mg per day for 1 year significantly prolonged recurrence-free survival compared to those patients receiving placebo…the inflection point in the curve at the 1.5 year mark begs the question—How long patients should remain on the drug? Lancet Mar 28;373(9669): CP Nelson, Heidi kmy/mls 6/02/07

65 Multivariate Analyses For Recurrence: Placebo Group
GIST – Adjuvant Z9001 Multivariate Analyses For Recurrence: Placebo Group Tumor location Stomach Small bowel Rectum 2 4 6 8 10 12 14 16 18 20 Tumor size <5 cm 5-10 cm 10 cm Mitotic rate <5 5 Genotype Exon 9 Exon 11 Exon 13 PDGFRA WT As presented at ASCO 2010, an analysis of tumor pathologic and molecular factors demonstrated that mitotic rate was associated with markedly reduced RFS. The second factor that was most predictive of recurrence was genotype; specifically a KIT Exon 11 mutation. Hazard ratio ASCO 2010 CP Nelson, Heidi kmy/mls 6/02/07

66 RFS For Exon 11- Mutant Cases by Arm
GIST – Adjuvant Z9001 RFS For Exon 11- Mutant Cases by Arm RFS For Wildtype Cases by Arm Recurrence-free and alive (%) Imatinib (n=173) Placebo (n=173) Imatinib (n=32) Placebo (n=32) Treatment Treatment P< at 24 months HR 3.42 (95% CI ) P= at 24 months Finally, patients with KIT Exon 11 mutations clearly benefit from adjuvant imatinib while those with wild-type KIT had no improvement in RFS. Please note that the slope of the curve for Exon 11 mutation patients changes between 12 and 18 months again suggesting that 1 year duration of therapy is not adequate (being addressed by Scandinavian (1yr vs. 3yr) and EORTC (0 vs. 2yr) trials. Months ASCO 2010 CP Nelson, Heidi kmy/mls 6/02/07

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

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

69 Advanced GIST Sunitinib in Imatinib Resistant GIST

70 Advanced GIST Sunitinib in Imatinib Resistant GIST

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


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