Gastric Cancer Elshami Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS - USA
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.
Risk Factors • Low vegetable, fruit • Nitrates • Coal mining, nickel, rubber • Intestinal metaplasia • Blood group A • ?Gastrectomy • Pernicious anemia
Pathology • Adenoca: 95% • Intestinal • Diffuse • Mixed • Lymphoma • Squmous • Leimyosarcoma • Carcinoid
Clinical Classification • Superficial • Focal, fungating, polypoid • Infiltrative, linitis plastica
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
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
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.
H&P CBC/CMP C-x-ray CT EGD H. pylori Barium EUS PET/CT Locoregional I - III Multi- Disciplinary eval IV
Operable/Med fit Locoregional I-III Inoperable Unresectable/Med unfit
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.
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.
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.
Extent of surgery • Routine or prophylactic splenectomy is not required • Splenectomy is acceptable if: • Spleen or hilum is involved
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
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
Reconstruction • Billroth I • BillrothII • Roux-en-Y esophagojejunostomy
Observe Tis-T1 Ro Observe or chemoRT (high risk) or ECF if given preop T2 T3-4 or N+ RT + chemoRT + 5FU/LV or ECF if given preop R1 Surgical outcomes RT + chemoRT + 5FU/LV R2 RT + chemoRT + 5FU/LV or Chemo or BSC M1 palliative
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
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
INT-0116 (SWOG 9008) Adj Option • Macdonald et al; N Engl J Med. 2001 Sep 6;345(10):725-30. • Randomized lll Trial: • Resectableadeno 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]
? 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.
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
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
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
The MAGIC TrialThe Medical Research Council Adjuvant Gastric Infusional Chemotherapy Periop. option • D. Cunningham, et al ; N Engl J Med. 2006 Jul 6;355(1):11-20. • Operableadeno 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
Other options of ChemoRT • Docetaxel or Taxol + 5-FU/Xeloda • Cisplatin + 5-FU/Xeloda
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 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.
REAL-2: Phase III Capecitabinevs 5-FU and OxaliplatinvsCisplatin ECF (n = 249) ECX(n = 241) • Epirubicin 50 mg/m2 IV 3 weekly • Cisplatin 60 mg/m2 IV 3 weekly • 5-FU 200 mg/m2/day IV given continuously • Epirubicin 50 mg/m2 IV 3 weekly • Cisplatin 60 mg/m2 IV 3 weekly • Capecitabine 625 mg/m2 BID PO continuously EOF (n = 235) EOX(n = 239) • Epirubicin 50 mg/m2 IV 3 weekly • Oxaliplatin 130 mg/m2 IV 3 weekly • 5-FU 200 mg/m2/day IV given continuously • Epirubicin 50 mg/m2 IV 3 weekly • Oxaliplatin 130 mg/m2 IV 3 weekly • Capecitabine 625 mg/m2 BID PO continuously • Cunningham D, et al. N Engl J Med. 2008;358:36-46.
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 DCF Docetaxel 75 mg/m2 IV over 1 hr on Day 1 + Cisplatin 75 mg/m2 IV over 1-3 hrs on Day 1 + 5-FU 750 mg/m2/day by CIV over 5 days q3w (n = 227) • Patients with advanced gastric cancer and no previous palliative chemotherapy • (N = 457) • R CF Cisplatin 100 mg/m2 IV over 1-3 hrs on Day 1 + 5-FU 1000 mg/m2/day by CIV over 5 days q4w (n = 230) • Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.
ToGa results 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