1. Chris Smith R5 Surgery grand Rounds November 24, 2009 Gastric Cancer

2. Case 1 63 male Referred by GI History of epigastric discomfort OGD – lesion mid body of stomach Bx shows invasive adenocarcinoma Otherwise healthy H & P unremarkable

3. Case 1 CT shows 5cm lesion mid body of stomach No LN involvement No evidence of metastatic disease ?through serosa

4. Case 1 Surgical management? Role for laparoscopy to assess for M1 disease? How many lymph nodes? Role for neoadjuvant therapy? Role for minimally invasive techniques?

5. Objectives Review Epidemiology of Gastric Cancer Discuss Management Surgical Management Degree of Lymphadenectomy Adjuvant vs. Neoadjuvant therapy Role of minimally invasive techniques

6. Background Described as early as 3000 BC One of the most common forms of cancer worldwide 650,000 deaths/year Incidence has declined steadily since 1930’s Proximal lesions increasing with decline of esophageal adenocarcinoma Affects slightly more men than women Prevalent in Asian and South American countries

7. Background Risk factors Smoking, salt, nitrites, obesity, prior gastrectomy, pernicious anemia, family history Lauren classification Intestinal – arises from gastric mucosa Associated with older patients and distal tumours Diffuse – lamina propria Grows in an infiltrative, submucosal pattern Younger patients and proximal tumours Incidence increasing

8. Background 1-3% associated with inherited gastric cancer predisposition syndromes HNPCC, FAP, Peutz Jegehers, Li Fraumeni E-cadherin mutation Autosomal dominant Diffuse type Genetic counselling Prophylactic gastrectomy Germ line truncating CDH1 mutations with high penetrance

9. Presentation Present with variety of signs/symptoms Anemia Dyspepsia Nausea/vomiting Early satiety Epigastric pain Weight loss Often present with advanced disease Palpable abdominal mass Sister Mary Joseph nodule Blumer’s shelf

10. Diagnosis Contrast studies CT Endoscopy with biopsy gold standard Intraoperative DDx: GIST, lymphoma, carcinoid, leiomyosarcoma

11. Staging CT 43-82% accuracy for T stage Sensitivity and specificity for N stage 78% and 62% PET 56% sensitivity and 92% specificity for N stage Not used routinely May be useful in conjunction with CT EUS Useful for determining T stage 65-92% accurate Not useful for assessing distant LN involvement

12. Staging Laparoscopy May detect occult metastases not seen on CT May spare unnecessary laparotomy in certain patients Subject of debate Peritoneal cytology Identify patients who are at risk following curative resection False positives Positive cytology very poor prognostic indicator

13. Role of laparoscopy for staging Avoid if symptomatic or obvious M1 disease Prospective studies show that of laparoscopic M1 patients only 50% will require subsequent intervention Laparotomy in 12% Remainder endoscopic/radiologic procedures Multivariate analyses identify tumor located at the GEJ, diffuse lesions, or presence of lymphadenopathy on spiral CT as independent risk factors for metastatic disease May be useful/avoided in certain patients

14. TNM Staging

15. Surgery – Extent of gastrectomy R0 resection No difference in survival between total and distal subtotal gastrectomy Favourable profile for distal subtotal Proximal subtotal oncologically equivalent to total gastrectomy Validated in RCT’s

16. Extent of gastrectomy Proximal subtotal gastrectomy controversial One third of patients will develop reflux esophagitis ? Ability to adequately remove LN’s from lesser curvature Further quality of life analyses required Reconstruction – distal gastrectomy BI vs. BII vs. Roux-en-Y No functional difference

17. Reconstruction Total gastrectomy Jejunal pouch/interposition described No benefit in QOL and other functional assessment measurement tools ? Higher weight gain, intake with pouch/ interposition Roux-en-Y generally considered equivalent

18. Reconstructive options

19. Surgery – Extent of gastrectomy 4-6cm gross resection margin Potential for submucosal spread Microscopically positive margins Controversial Repeat resection to negative margins may provide some survival benefit in patients with R1 resection Only in patients with N0 or N1 nodal status N2+ no prognostic significance attributable to margin status

20. Extent of Lymphadenectomy

21. Extent of lymphadenectomy Controversial Generally refers to lymph node stations surrounding the stomach divided into 16 stations 1-6 perigastric Remaining 10 located adjacent to major vessels, behind the pancreas and along the aorta D1 vs. D2 vs. D3 vs. D4

22. lymphadenectomy D0 – failure to remove N1 LN’s D1 – perigastric LN’s D2 – nodes along hepatic, left gastric, celiac and splenic arteries as well as splenic hilum (1-11) D3 – D2 + porta hepatis and periaortic stations (12-16) +/- splenectomy, distal pancreatectomy D4 – para-aortic nodal dissection (PAND)

24. LN stations

25. lymphadenectomy Retrospective studies have shown increased survival with extended lymphadenectomy Japanese data Up to 60-70% 5 year survival Much higher than seen with limited lymphadenectomy in western series

26. lymphadenectomy Japanese traditionally thinner making procedure technically easier Early screening programs All pts over age 40 eligible for screening endoscopy Different tumour biology Led to further RCT’s

27. Japan Clinical Oncology Group Sano et. al; J Clin Oncol 2004 JCOG study 9501 Randomly assigned 523 patients to D2 vs. D3 Defined D3 as D2 + PAND Significantly higher perioperative complications 28.1% vs. 20.9% No difference in major complications (pancreatic fistula, abdominal abscess, etc. ) No difference in progression free/ overall survival Overall 5 year survival 70 and 69%

28. Dutch Gastric Cancer Group Bonenkamp et. al; N Engl J Med 1999 Multicenter RCT 996 patients randomized between 1989-93 D2 vs. D1 LN dissection 711 treated with curative intent

29. Dutch Gastric Cancer Group D2: significantly more postoperative deaths and perioperative morbidity No difference in 5 year survival Much of the morbidity associated with splenectomy/ distal pancreatectomy Conclude there is no role for routine use of D2 lymphadenectomy

30. Medical Research Council Cuschieri et. al; Br J Cancer 1999 400 patients randomized to D1 vs. D2 5 year survival 35% and 33% Complication rate 46% in D2 vs. 28% for D1 Age, male sex, stage II and III, and removal of spleen and pancreas independently associated with poor survival Conclude no survival advantage of D2 over D1

31. Summary of LND results (retrospective) Stage 1 2 3 4

32. Extended lymphadenectomy Sierra et. al; Ann Surg Oncol 2003 Single center retrospective study from Spain D1 - 85 D2 - 71 No difference in LOS, perioperative morbidity/mortality 5 year survival significantly better for D2 group 50.6% vs. 41.4%

33. Extended lymphadenectomy Wu et. al; Lancet Oncol 2006 Single center RCT from Japan 221 patients randomized to D1 vs. D2 Performed by surgeons well trained in technique of extended LND All specimens examined by a single pathologist 5 year survival 59.5 vs. 53.6% (p=0.04) No difference in recurrence between groups among patients who underwent R0 resection Perioperative morbidity and mortality not reported (???)

34. Lymphadenectomy - conclusion Some evidence for D2 dissection Mostly retrospective, single center, with only one RCT in favour of D2 Morbidity seen in earlier studies offset by elimination of splenectomy, pancreatectomy Should only be performed to maintain R0 resection Most benefit seen in patients with N2 involvement Some evidence to support recovery of at least 15LN’s More accurate staging and predictive ability

35. Lymphadenectomy - conclusion D2 Recommended as part of national comprehensive cancer network guidelines although not required should be performed by experienced surgeons ?Maruyama index as alternative to standard D2 Computer generated likelihood of having nodal disease left behind based on patient characteristics Retrospective studies have consistently shown MI<5 to be independent predictor of survival Based on Dutch data and others

36. Adjuvant vs. Neoadjuvant therapy R0 resection provides best chance for long term survival >50% of patients will have regional node involvement at time of resection Survival with surgery alone 50% for T3N0 10-15% for N1/N2 10% for N3 Led to rationale for adjuvant and neoadjuvant chemo and radiation

37. Adjuvant therapy Macdonald et. al; N Engl J Med 2001 (Intergroup 0116) 556 patients with R0 resected adenoCa of stomach or GE junction randomized to surgery alone or in conjunction with adjuvant chemo/rads Post op 5FU and leucovorin 45 Gy in 25 fractions delivered to tumour bed, regional nodes and 2cm beyond the proximal and distal margins

38. Adjuvant therapy 181/281 patients completed treatment Median overall survival 27 months in surgery only group vs. 36 months with adjuvant Tx HR 1.52 for relapse (p=0.001) HR 1.35 for death (p=0.005) 32% with grade 4 toxic effects Conclusion: chemoradiotherapy should be considered for all patients at high risk of recurrence of adenocarcinoma of stomach or GE junction who have undergone curative resection

39. Neoadjuvant therapy MAGIC trial Cunningham et. al; New Engl J Med 2006 Randomly assigned 503 patients with resectable AdenoCa of stomach, GEJ, esophagus to perioperative chemo + surgery or surgery alone 3 cycles pre/postop of cisplatin, epirubicin and 5FU

40. Neoadjuvant therapy Rate of perioperative complications similar in each group 215 of 250 pts. Completed preoperative chemo 209 underwent surgery 137 started postoperative chemo 104 pts completed postoperative chemo (41.6%) Median follow up was 4 years

41. Neoadjuvant therapy Perioperative tx group had a higher likelihood of overall survival with HR for death of 0.75 (p=0.09) Better progression free survival with HR for progression of 0.66 (p<0.001) 5 year survival 36% vs. 23% favouring perioperative tx Perioperative tx decreased tumour size and stage and improved progression free and overall survival

42. Endoscopic mucosal resection Greatest experience in Japan 90% 5 year survival with T1N0 Limited resection sufficient Probability of LN metastasis influenced by tumour factors Size, submucosal invasion, poorly differentiated tumours, lymphatic and vascular invasion Guidelines developed by Japanese society for gastroenterological endoscopy (JSGE)

43. Endoscopic mucosal resection Pedunculated lesions <2cm Sessile lesions <1cm Intestinal type limited to mucosa No RCT’s comparing EMR to other techniques Long term follow up lacking Not recommended outside clinical trial and should be limited to centers with extensive experience

44. Laparoscopic resection Huscher et. al; Ann Surg 2005 59 patients randomized to laparoscopic vs. Open subtotal gastrectomy No difference in perioperative morbidity and mortality No difference in mean number of LN’s recovered 33.4 vs. 30.0 in the open group 5 year progression free and overall survival not significantly different Disease free 57.3 lap vs. 54.8 open Overall 58.9 lap vs. 55.7 open

45. Summary of guidelines CT +/- PET, EUS preop Laparoscopy in select patients Primary surgery for T1 lesions EMR for medically unfit patients Locoregional (stage IB-III) potentially resectable Neoadjuvant treatment as per MAGIC protocol Alternatively preop chemo/rads Unresectable/ medically unfit D2 lymphadenectomy recommended (not required)

46. Summary of guidelines Post op T3,T4 and/or nodal involvement Chemo/rads (Macdonald protocol) T2 with unfavourable tumor characteristics Poorly differentiated, high grade, LVI, age<50 Follow up endoscopy when clinically indicated (?) Palliative treatment Chemo – CEF, FOLFIRI Consider clinical trial Surgical bypass/venting gastrostomy

47. Conclusion Management of Gastric Cancer is complex Should involve multidisciplinary approach Primary surgery with role for extended lymphadenectomy in certain patients – controversial Consider laparoscopy to R/O M1 disease in certain patients Consider minimally invasive approach in appropriate patients Consider neoadjuvant/adjuvant therapy

48. Questions?