Transcript Gastric Cancer

Gastric Cancer
Chris Smith R5
Surgery grand Rounds
November 24, 2009
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
Case 1
•CT shows 5cm
lesion mid
body of
stomach
•No LN
involvement
•No evidence
of metastatic
disease
•?through
serosa
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?
Objectives
 Review Epidemiology of Gastric Cancer
 Discuss Management
 Surgical Management
 Degree of Lymphadenectomy
 Adjuvant vs. Neoadjuvant therapy
 Role of minimally invasive techniques
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
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
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
Presentation
 Present with variety of signs/symptoms
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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
Diagnosis
 Contrast studies
 CT
 Endoscopy with biopsy gold standard
 Intraoperative
 DDx: GIST, lymphoma, carcinoid, leiomyosarcoma
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
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
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
TNM Staging
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
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
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
Reconstructive options
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
Extent of Lymphadenectomy
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
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)
LN stations
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
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
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%
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
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
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
Summary of LND results
(retrospective)
Stage
1
2
3
4
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%
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
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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 (???)
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
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
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
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
Adjuvant therapy
 181/281 patients completed treatment
 Median overall survival 27 months in surgery only group vs.
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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
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
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
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
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)
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
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
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)
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
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
Questions?