2. Gastric Cancer Elshami Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS - USA 10/17/2015 2

3. INTRODUCTION  Gastric cancer is defined as any malignant tumor arising from the region extending between the gastroesophageal (GE) junction and the pylorus.  The incidence and mortality of gastric cancer have been declining in most developed countries.  The age-adjusted risk fell 5% from 1985-1990. 10/17/2015 3

4. Risk Factors  Low vegetable, fruit  Nitrates  Coal mining, nickel, rubber  Intestinal metaplasia  Blood group A  ?Gastrectomy  Pernicious anemia 10/17/2015 4

5. Pathology  Adenoca: 95%  Intestinal  Diffuse  Mixed  Lymphoma  Squmous  Leimyosarcoma  Carcinoid 10/17/2015 5

6. Clinical Classification  Superficial  Focal, fungating, polypoid  Infiltrative, linitis plastica 10/17/2015 6

7. Physical exam  Hepatomegaly  Ascites  Virchow’s node (Lt. SCV)  Irish node (Lt. Ant. Axilla.)  Sister Mary Joseph nodule/sign (palpable nodule bulging into the umblicus)  Krukenberg’s tumor  Blumer’s shelf 10/17/2015 7

8. Staging  IA:T1 (invade lamina propria/submucosa)  IB:T1, N1 (1-6 +ve) T2 (invade muscularis/subserosa  II:T1, N2 ( 7-15 +ve) T2, N1 T3 (penetrate visceral peritoneum only)  IIIA:T2, N2 T3, N1 T4 (invade structures)  IIIB:T3, N2  IV: T1-3, N3 (>15 +ve) T4, N1-3 OR M1 10/17/2015 8

9. Prognostic factors  Aneuploidy:  poor prognosis in patients with adenocarcinoma of the distal stomach.  High plasma levels of vascular endo-thelial growth factor (VEGF)  presence of CEA in peritoneal washings  predict poor survival in surgically resected patients.  intratumoral levels of dihydropyrimidine dehydrogenase (DPD)  low levels appear to predict better response to 5-FU based chemotherapy and longer survival.  The prognostic implications of tumor-suppressor genes and oncogenes are an area of active investigation.  Patients with cancers of the diffuse type worse than those with intestinal-type lesions. 10/17/2015 9

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11. H&PH&P CBC/CMPCBC/CMP C-x-rayC-x-ray CTCT EGDEGD H. pyloriH. pylori BariumBarium EUSEUS PET/CTPET/CT Locoregional I - III IV 10/17/2015 11 Multi- Disciplinary eval

12. Locoregional I-III Operable/Med fit Inoperable Unresectable/Med unfit 10/17/2015 12

13. TREATMENT  Resection provides the only chance for cure.  Radiotherapy and chemotherapy  potential roles as adjuncts to surgery  patients with unresectable tumors.  Preoperative chemo and chemoradiation therapy are active areas of current investigation. 10/17/2015 13

14. Confirmation of resectability  CT scan +/- EUS  Laparoscopy  assess the extent of disease and resectability.  adds to the accuracy of preoperative imaging  peritoneal spread or small liver metastases.  peritoneal washings  Laparoscopic ultrasonography  identify lesions with a high risk of recurrence (T2b or >, N+),  for which a preoperative chemotherapy protocol may be available. 10/17/2015 14

15. Extent of resection  Depends on:  The site and extent of the primary cancer.  Subtotal gastrectomy is preferred over total gastrectomy  comparable survival benefit but lower morbidity.  A 5-cm proximal and distal resections margins.  If total gastrectomy is necessary:  transection of the distal esophagus and proximal duodenum  omentectomy  In Japan, there is a growing experience with more limited resections of early-stage gastric cancer.  Endoscopic Mucosal Resection (EMR) of non-ulcerated T1 N0 lesions  pylorus-preserving gastrectomy.  Laparoscopic resections are also being performed more frequently. 10/17/2015 15

16. Extent of surgery  Routine or prophylactic splenectomy is not required  Splenectomy is acceptable if:  Spleen or hilum is involved 10/17/2015 16

17. Extent of lymphadenectomy  Regional lymphatics:  Perigastric (paracardial, paragastric, parapyloric) (D1)  Retroperitoneal “second echelon” and LN along the named vessels:  celiac trunk, left gastric artery, hepatic artery, splenic artery, and splenic hilus (D2)  The goal is > 15 LN 10/17/2015 17

18.  Improved long-term survival rates for Japanese patients had been attributed to the extended lymphadenectomies routinely performed in this country (D2 or more).  Retrospective data had shown that D2 lymphadenectomy is safe and does not increase morbidity.  Two European randomized trials showed no sig differences in OS between D1 and D2  higher postop morbidity and mortality in the D2 due to a higher rate of splenectomy and/or partial pancreatectomy.  When a subset of patients with N2 disease were studied in long- term follow-up in the Dutch randomized trial, a survival advantage was shown with D2 dissection.  Extended lymphadenectomy should primarily be performed in specialized centers by experienced surgeons:  splenectomy and pancreatectomy should be avoided 10/17/2015 18

19. Reconstruction  Billroth I  BillrothII  Roux-en-Y esophagojejunostomy 10/17/2015 19

20. Surgicaloutcomes Ro R1 R2 M1 Observe T2 palliative 10/17/2015 20 T3-4 or N+ Tis-T1 RT + chemoRT + 5FU/LV or ECF if given preop Observe or chemoRT (high risk) or ECF if given preop RT + chemoRT + 5FU/LV RT + chemoRT + 5FU/LV or Chemo or BSC

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22. 10/17/2015 22 Any role for Chemo/RT  <30% of locally advanced Gastric/GEJ adeno could be cure with surgery alone  Previous adj chemo failed to show clinical benefit

23. ADJUVANT THERAPY  The 5Y survival rate after “curative resection”  30-40%  A North American Intergroup trial randomizing resected patients (stages IB– IV[M0]) to receive chemoRT or observation:  sig improvement in median DFS (median 19 vs 30 m) and OS (26 vs 35 m)  Adj chemoRT (usually C.I. 5-FU) is the standard of care in the United State 10/17/2015 23

24. 10/17/2015 24 INT-0116 (SWOG 9008)  Randomized lll Trial:  Resectable adeno of stomach  GEJ (lB-IVA)  5-FU/LVx5d--> RT+5-FU/LV during first 4d and last 3d of RT --> 2cycles of 5-FU/LVx5d  postop CT/RT improve DFS&OS in R0 (resected locally advanced)  [standard of care] Adj Option Macdonald et al; N Engl J Med. 2001 Sep 6;345(10):725-30.

25. ? Is D2 LND required ?  D2 LND was performed in only 10% of the patients in this trial.  Subgroup analysis revealed that outcome did not differ based upon the type of lymphadenectomy (P =.80).  Still, since only a small percentage of pts underwent the recommended D2 dissection, further research is necessary before firm conclusions can be made in this area. 10/17/2015 25

26. Radiotherapy  Radiotherapy can decrease the rate of locoregional failure but has not been shown to improve survival as a single postop modality  Postop RT may be appropriate in patients who are not candidates for chemo 10/17/2015 26

27. Chemotherapy  Randomized trials of surgery +/- chemo:  No definite survival advantage, with the possible exception of pts with widespread nodal involvement.  One meta-analysis included both Western and Asian studies:  showed a sig survival benefit with the use of chemo in the Asian trials, but there was no benefit in the Western studies, possibly due to differences in biology or drug metabolism.  No specific regimen could be recommended 10/17/2015 27

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29. Clinical > T2 or N + 10/17/2015 29

30.  European Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) by Cunningham and associates.  The 5Y survival rate for ECF + surgery was 36%, vs 23% for surgery  Chemo also enhanced resectability 10/17/2015 30

31. 10/17/2015 31 The MAGIC Trial The Medical Research Council Adjuvant Gastric Infusional Chemotherapy  Operable adeno of the stomach, the lower third of the esophagus, and the GEJ ( 74% of pts had tumors in the stomach)  ECFx3->surg->ECFx3 (250 pts) vs Surgery alone (253 pts):  5Y survival: 36% vs 23%  Chemo sig. improves resectability, PFS and OS Periop. option D. Cunningham, et al ; N Engl J Med. 2006 Jul 6;355(1):11-20.

32. Other options of ChemoRT  Docetaxel or Taxol + 5-FU/Xeloda  Cisplatin + 5-FU/Xeloda 10/17/2015 32

33. 10/17/2015 33 Preoperative Chemotherapy vs Surgery Alone  FNLCC ACCORD 07-FFCD 9703, multicenter, randomized trial indicated benefit of preoperative chemotherapy vs surgery alone for resectable adenocarcinoma of stomach and lower esophagus [1]  Higher rate of R0 resection (87% vs 74%; P =.04)  Higher 5-yr OS (38% vs 24%; P =.021)  No increase in postoperative morbidity or mortality Boige V, et al. ASCO 2007; Abstract 4510.

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35. ECF (n = 249)ECX (n = 241) EOF (n = 235)EOX (n = 239) Epirubicin50 mg/m 2 IV 3 weekly Cisplatin 60 mg/m 2 IV 3 weekly 5-FU 200 mg/m 2 /day IV given continuously Epirubicin 50 mg/m 2 IV 3 weekly Cisplatin 60 mg/m 2 IV 3 weekly Capecitabine625 mg/m 2 BID PO continuously Epirubicin 50 mg/m 2 IV 3 weekly Oxaliplatin130 mg/m 2 IV 3 weekly 5-FU 200 mg/m 2 /day IV given continuously Epirubicin 50 mg/m 2 IV 3 weekly Oxaliplatin130 mg/m 2 IV 3 weekly Capecitabine 625 mg/m 2 BID PO continuously REAL-2: Phase III Capecitabine vs 5-FU and Oxaliplatin vs Cisplatin Cunningham D, et al. N Engl J Med. 2008;358:36-46.

36. TAX325: Phase III Docetaxel/Cisplatin/5- FU (DCF) vs Cisplatin/5-FU (CF)  Primary endpoint: TTP from 4 → 6 mos  Secondary endpoints: OS, RR, safety, QoL, clinical benefit Patients with advanced gastric cancer and no previous palliative chemotherapy (N = 457) DCF Docetaxel 75 mg/m 2 IV over 1 hr on Day 1 + Cisplatin 75 mg/m 2 IV over 1-3 hrs on Day 1 + 5-FU 750 mg/m 2 /day by CIV over 5 days q3w (n = 227) CF Cisplatin 100 mg/m 2 IV over 1-3 hrs on Day 1 + 5-FU 1000 mg/m 2 /day by CIV over 5 days q4w (n = 230) R Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.

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38. Trastuzumab + chemo associated with increased OS: 11.1 months vs. 13.8 months (HR=0.74; 95% CI, 0.60-0.91) Trastuzumab + chemo associated with an improved overall response rate: 47.3% vs. 34.5% (P=.0017) The treatment was generally well tolerated with no unexpected adverse effects in the trastuzumab group ToGa results 10/17/2015 38

39. THANKS 10/17/2015 39