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Gastric cancer discussion slides final version.pptnew.ppt
 

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    Gastric cancer discussion slides final version.pptnew.ppt Gastric cancer discussion slides final version.pptnew.ppt Presentation Transcript

    • Gastric Cancer: Discussion Prof David Cunningham Royal Marsden Hospital United Kingdom
    • Issues highlighted by these cases Optimal management of early stage gastric cancer with regards to…… staging peri-operative treatment surgery Role of chemotherapy in advanced gastric cancer
    • Operable Disease: Staging Local assessment Assessment for distal disease Endoscopy (diagnostic) CT Thorax/abdomen/pelvis EUS Laparoscopy – Local staging and – identifies CT occult assessing proximal & metastatic disease distal extent of (OGJ) tumour Improve selection of – Staging accuracy ~75% patients for radical Rx in gastric cancer1 PET can provide additional information regarding local and distal disease less sensitive but more specific than CT2 for local LN metastases ● limitation ~30% of gastric cancer are non-FDG avid3 ● potential role for early response assessment to neo-adjuvant Rx ●1. Abdalla & Pisters, Seminars in Oncology 2004 2. Kim et al, Eur J Nucl Med Mol Imaging 2006 3. Ott et al., Clin Cancer Res 2008
    • Peri-operative Chemotherapy: The MRC MAGIC Trial Post- Pre-operative Surgical operative Resectable ECX x3 resection ECX x3adenocarcinoma of within 3-6/52 Randomised within 6-the stomach, OGJ 12/52 or lower Surgicaloesophagus n=503 resection within 6/52 Median OS: 24 v 20 months 5 yr OS: 36% v 23% 13% OS benefit for ECF HR for death 0.75, p=0.009 Pre-op chemo well tolerated (5% did not complete pre-op Rx due to toxicity) No increase in post-op complications Cunningham et al., NEJM 2006
    • Peri-operative Rx:Advantages Disadvantages Increase rate of curative (R0) Risk of disease progression during resection1 by tumour pre-operative treatment downstaging/downsizing Definitive surgery may be delayed if Eradication of micro-metastatic significant toxicity occurs disease Risk of increased peri-operative Demonstrates in vivo chemo- morbidity - NOT seen in the sensitivity MAGIC2 trial Better tolerated than post- operative therapy – MAGIC2 Peri-operative chemotherapy is -91% pts able to complete pre- now standard of care in Europe op Rx -66% of pts able to commence post-op Rx1. Boige et al., ASCO 2007 2. Cunningham et al., NEJM 2006
    • Post-operative Chemoradiation: SWOG 9008/Intergroup 0116 TrialResected stage Ib-IV (M0) Observation n=275 gastric or OGJ adenocarcinoma n=556 Randomised (<D1 resection 54% 5-FU/LV Chemoradiation D1 = 36%, D2 = 10%) (4500Gy) n=281 Median OS: 27 v 36m HR for death 1.35; p=0.006 Highly selected population (All had R0 resection + recovered from surgery) yet only 64% completed Rx Significant Rx related toxicity: 1% toxic death 73% grade 3/4 AEs Macdonald et al., NEJM 2001
    • Adjuvant Chemotherapy: ACTS-GT1 Observation n=530 Stage II-III gastric cancer treated with curative Randomisedgastrectomy; all with at least D2 Adjuvant S-1 80mg/m2/day dissection n=1059 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 3 yr OS: 81.1% v 70.1% Meta-analysis adjuvant Rx2: HR for death 0.68, p=0.003 Despite selected nature of the pt population, benefit of adjuvant chemo is modest (Relative risk of death 0.85, 95% CI 0.80-0.90) 1. Sakuramoto et al., NEJM 2007, 2. Liu et al., Eur J Surg Oncol 2008
    • Surgery: Extended D2 Lymph nodedissectionD2 v D1 resection no survival advantage namely due to excess morbidity and mortality related to distal pancreatectomy & splenectomy1,2,3 D2 dissection without distal pancreatectomy & splenectomy by an experienced surgeon at a high volume centre is recommended current clinical practice1.Cuschieri et al., BJC 1999, 2. Bonenkamp et al., NEJM 1999 Hartgrink et al., JCO 2004
    • Metastatic Gastric Cancer:The Role of Chemotherapy Survival with best supportive care (BSC) alone ~3 months1,2 Combination chemotherapy improves OS compared to BSC (HR 0.39, 95% CI 0.28-0.52, p<0.00001)3 Benefit in weighted mean average survival ~ 6 months31. Murad et al., Cancer 1993, Pyrhonen et al., BJC 995 3. Wagner et al., JCO 2006
    • Selection of patients for chemotherapy Patients of good performance status (ECOG 0-1) more likely to respond to chemotherapy1 and have improved median survival1,2 Linitus plastica is a feature of poor prognosis1 Response rate is lower in patients with peritoneal carcinomatosis3 Co-morbidities must be consideredRougier et al., EJC 1994 2. Lavin et al, Cancer 1982 3. Preusser et al., JCO 1989
    • Selection of chemotherapy for patients1 Combination chemotherapy superior to monotherapy for OS HR 0.83 (0.74-0.93) OS is superior with the addition of anthracyclines to platinum/ HR 0.77 (0.62-0.95) fluorouracil1. Wagner et al., JCO 2006
    • REAL 2 Epirubicin Cisplatin + infused 5-FU (ECF) Randomised Untreated advanced Epirubicin + cisplatin + capecitabine (ECX) oesophageal,OGJ or gastriccancer n=1002 Epirubicin + oxaliplatin + 5-FU (EOF) Epirubicin + oxaliplatin + capecitabine (EOX) Primary Endpoints: Non-inferiority for survival Capecitabine compared to Fluorouracil Oxaliplatin compared to Cisplatin Overall survival amongst the four regimens Cunningham et al., NEJM 2008
    • REAL-2 - Results HR 0.86 (0.8 – 0.99) Capecitabine is non-inferior to infused 5FU Toxicity: More G3/4 neutropenia (uncomplicated) hand foot syndrome Oxaliplatin is non-inferior to cisplatin HR 0.92 (0.8 – 1.10) Toxicity: Less G3/4 neutropenia (uncomplicated) thromboembolism, alopecia More G3/4 diarrhoea G3/4 peripheral neuropathyCunningham et al., NEJM 2008
    • Survival: ECF v EOX Arm OS (m) 1 year survival p-value HR (95% CI) (95% CI) ECF 9.9 37.7 (31.8-43.6) EOX 11.2 46.8 (40.4-52.9) 0.020 0.80 (0.66-0.97)Improved efficacy of EOX compared to ECF for survival EOX now an accepted first-line therapy optionCunningham et al., NEJM 2008
    • V-325 phase III trial: DCF Docetaxel +cisplatin + Untreated advanced infused 5-FU gastric cancer Randomised (n=445) Cisplatin + infused 5-FU Primary objective: Superior TTP with DCF relative to FP Results: TTP 5.6m v 3.7m HR 1.47; p<0.001 OS 9.2m v 8.6m HR 1.29; p=0.02 BUT Grade 3/4 AEs* All 69 v 59% *Neutropenia 82 v 57%, complicated neutropenia 29 v 12%Van Cutsem et al., JCO 2006
    • DCF….…reducing toxicity ATTAX - randomised phase II trial Weekly docetaxel Untreated advanced 30mg/m2 D1, D8 + gastric cancer Randomised cisplatin 60mg/m2 D1 + infused 5-FU 200mg/m2/day DCF DX (n=50) (n=56) Weekly docetaxel 30mg/m2 D1, D8 + Confirmed RR 47% 26% capecitabine 1600mg/m2 D1-14 q21d Median PFS 5.8 4.6 Median OS 11.4 10.5 Toxicity: 4% febrile neutropenia with DCF, 2% with DCX DCF with weekly docetaxel may be an alternative, less toxic regimenTebbutt et al., ASCO 2007
    • Second Line Chemotherapy No current phase III data to support 2nd line chemotherapy Patients sustaining prolonged benefit from first-line chemotherapy may be re-challenged with the same regimen on progression Phase II data: Response rates are low, but selected patients may benefit from second-line chemotherapy Treatment n RR Median TTP or Median OS/ PFS /months months Docetaxel1 49 16% 2.5 8.3 (75mg/m2 q3 weeks) FOLFIRI2 38 29% 3.7 6.4 Irinotecan3 37 20% 2.6 5.2 (125m/m2 d1, 8,15 q4 weeks) Irinotecan (160mg/m2) + 49 20% 2.7 8.9 docetaxel (65mg/m2)41. Lee et al., Cancer Chemother Pharmacol 2008, 2. Assersogn et al., Ann Oncol 2004, 3. Chun et al.,Jpn J Clin Oncol 2004, 4. Sym et al., Cancer Chemother Pharmacol 2008
    • Current randomised phase III trials ECX x3 Surgery ECX x3 ST03 (MAGIC-B) Resectable adenocarcinoma of the ECX + ECX + Surgerystomach or Type III OGJ bevacizumab x3 bevacizumab x3 CRITICS: ECX x3 Surgery ECX x3 Resectable adenocarcinoma of thestomach or Type III OGJ ECX x3 Surgery CX +RT 45Gy EOX REAL3Untreated advanced adenocarcinoma or undifferentiated carcinoma of the EOX oesophagus, OGJ or stomach panitumumab