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
Endoscopy (diagnostic) EUS Local staging and assessing proximal & distal extent of (OGJ) tumour Staging accuracy ~75% in gastric cancer1

Assessment for distal disease CT Thorax/abdomen/pelvis Laparoscopy identifies CT occult metastatic disease
Improve selection of patients for radical Rx

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

Resectable adenocarcinoma of the stomach, OGJ or lower oesophagus n=503 Pre-operative ECX x3
Randomised

Surgical resection within 3-6/52

Postoperative ECX x3 within 612/52

Surgical 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 significant toxicity occurs Eradication of micro-metastatic disease Risk of increased peri-operative morbidity - NOT seen in the Demonstrates in vivo chemosensitivity MAGIC2 trial Better tolerated than postoperative 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 Rx

1. Boige et al., ASCO 2007 2. Cunningham et al., NEJM 2006

Post-operative Chemoradiation: SWOG 9008/Intergroup 0116 Trial

Resected stage Ib-IV (M0) gastric or OGJ adenocarcinoma n=556 (<D1 resection 54% D1 = 36%, D2 = 10%)

Observation n=275 Randomised 5-FU/LV Chemoradiation (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 gastrectomy; all with at least D2 dissection n=1059 Randomised Adjuvant S-1 80mg/m2/day 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 nonAsian population 3 yr OS: 81.1% v 70.1% HR for death 0.68, p=0.003 Meta-analysis adjuvant Rx2: 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 node dissection

D2 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 practice
1.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 months3

1. 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 considered

Rougier 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)

HR 0.77 (0.62-0.95)

OS is superior with the addition of anthracyclines to platinum/ fluorouracil

1. Wagner et al., JCO 2006

REAL 2
Epirubicin Cisplatin + infused 5-FU (ECF) Randomised Untreated advanced oesophageal, OGJ or gastric cancer n=1002 Epirubicin + cisplatin + capecitabine (ECX) 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 neuropathy
Cunningham et al., NEJM 2008

Survival: ECF v EOX

Arm ECF EOX OS (m) 9.9 11.2 1 year survival (95% CI) 37.7 (31.8-43.6) 46.8 (40.4-52.9) 0.020 0.80 (0.66-0.97) p-value HR (95% CI)

Improved efficacy of EOX compared to ECF for survival

EOX now an accepted first-line therapy option

Cunningham et al., NEJM 2008

V-325 phase III trial: DCF

Untreated advanced gastric cancer (n=445)

Randomised

Docetaxel +cisplatin + infused 5-FU Cisplatin + infused 5-FU

Primary objective: Superior TTP with DCF relative to FP Results: TTP OS BUT Grade 3/4 AEs* All 69 v 59% 5.6m v 3.7m HR 1.47; p<0.001 9.2m v 8.6m HR 1.29; p=0.02

*Neutropenia 82 v 57%, complicated neutropenia 29 v 12%

Van Cutsem et al., JCO 2006

DCF.reducing toxicity ATTAX - randomised phase II trial

Untreated advanced gastric cancer

Randomised DX (n=56) 26% 4.6 10.5

DCF (n=50) Confirmed RR Median PFS Median OS 47% 5.8 11.4

Weekly docetaxel 30mg/m2 D1, D8 + cisplatin 60mg/m2 D1 + infused 5-FU 200mg/m2/day Weekly docetaxel 30mg/m2 D1, D8 + capecitabine 1600mg/m2 D1-14 q21d

Toxicity: 4% febrile neutropenia with DCF, 2% with DCX

DCF with weekly docetaxel may be an alternative, less toxic regimen
Tebbutt 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 Docetaxel1
(75mg/m2 q3 weeks)

n 49 38 37 49

RR 16% 29% 20% 20%

Median TTP or PFS /months 2.5 3.7 2.6 2.7

Median OS/ months 8.3 6.4 5.2 8.9

FOLFIRI2 Irinotecan3
(125m/m2 d1, 8,15 q4 weeks)

Irinotecan (160mg/m2) + docetaxel (65mg/m2)4

1. 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

ST03 (MAGIC-B)
Resectable adenocarcinoma of the stomach or Type III OGJ ECX x3 ECX + bevacizumab x3 Surgery ECX x3 Surgery ECX + bevacizumab x3

CRITICS:
Resectable adenocarcinoma of the stomach or Type III OGJ

ECX x3

Surgery

ECX x3

ECX x3

Surgery

CX +RT 45Gy

REAL3
Untreated advanced adenocarcinoma or undifferentiated carcinoma of the oesophagus, OGJ or stomach

EOX

EOX panitumumab