Discussion Gastric Cancer LBA 4002, abstracts 4003, 4004 Florian Lordick, MD Germany

Gastric Cancer Lung (1.4 million deaths) Stomach (740 000 deaths) Liver (700 000 deaths) Colorectal (610 000 deaths) Breast (460 000 deaths) http://www.who.int factsheet N°297 February 2011

Yung-Jue Bang et al. LBA 4002 CLASSIC – Adjuvant Chemotherapy Asia: Korea, China, Taiwan Surgical technique: D2 resection R A N D O M I Z A T I O N 8 cycles of XELOX (6 months) n = 520 Surgically (D2) resected Stage II, IIIA, or IIIB* GC, 6 weeks prior to randomization No prior chemotherapy or radiotherapy Capecitabine: 1,000 mg/m2 bid, d1–14, q3w Oxaliplatin: 130 mg/m2, d1, q3w N = 1035 Observation: No adjuvant therapy n = 515 Primary endpoint: 3-year DFS‡ Secondary endpoints: overall survival and safety profile

CLASSIC – Primary Endpoint Met (3-year DFS at Interim Analysis) 1.0 74% 0.8 XELOX, n = 520 0.6 Observation, n = 515 60% 0.4 0.2 HR = 0.56 (95% CI 0.44–0.72) P < .0001 0.0 6 12 18 24 30 36 42 48 Time (months) No. left XELOX 520 443 410 333 246 166 74 30 10 Observation 515 414 352 286 209 147 58 22 6 ITT population Median follow-up 34.4 months (range 16–51)

CLASSIC – Overall Survival 1.0 0.8 XELOX, n = 520 0.6 Observation n = 515 0.4 0.2 HR = 0.74 (95% CI 0.53–1.03) P = .0775 0.0 6 12 18 24 30 36 42 48 Time (months) No. left XELOX 520 468 451 395 304 216 120 35 16 Observation 515 458 441 378 286 203 112 34 12 ITT population Median follow-up 34.4 months (range 16–51)

CLASSIC – Discussion Is the positive result of CLASSIC surprising? No, it’s not!

CLASSIC – Discussion ATCS-GC (Japan): S-1 vs. surgery alone Relapse-free survival Overall survival HR = 0.62 (95% CI, 0.50 to 0.77) P<0.001 HR = 0.68 (95% CI, 0.52 to 0.87) P = 0.003 Sakuramoto S et al. N Engl J Med 2007;357:1810-1820

CLASSIC – Discussion GASTRIC Group Meta-analysis 6% difference at 5 years HR = 0.82; p < 0.001 The Gastric Group. JAMA 2010; 303: 1729-1737

CLASSIC – Discussion Are the results of CLASSIC transferable to the Western World? There are some caveats!

CLASSIC – Discussion Median age (Classic): 56 years Age-specific incidence rate for gastric cancer in German males Robert-Koch-Institute 2010

CLASSIC – Discussion Tumor location (Classic): mid & distal 78% Change of gastric cancer epidemiology in the Western World Devesa et al. Cancer 1998; 83: 2049-2053

CLASSIC – Discussion D2 resection (Classic): median 42 lymph nodes examined (range 9-127) US INT 0116 (SWOG 9008) Macdonald et al. 2001 D2-Resection 10% D1-Resection 36% D0-Resection 54% UK MAGIC Cunningham et al. 2006 D2-Resection 41% D1-Resection 19% Other Resections 40%

Gastric Cancer – Discussion Does the surgical approach determine the optimal adjuvant treatment strategy? Asia: Radical resection (D2) Adjuvant chemotherapy Sub-radical resection (≤ D 1) Adjuvant chemoradiation

Charles S Fuchs et al. # 4003 CALGB 80101 – Adjuvant Chemoradiation North America: Intergroup study R A N D O M I Z E 5-FU/LV x 1 5-FU IVCI RT 5-FU/LV x 2 ECF x 1 5-FU IVCI RT ECF x 2 N = 540 Stratification by T stage, N stage, < or ≥ 7 examined lymph nodes Primary endpoint: improvement in overall survival

CALGB 80101 – Adverse Events ≥ 3 5FU/LV ECF Nausea 17% 15% Diarrhea 7% Mucositis Dehydration 9% 4% Anorexia 16% 13% Fatigue 11% Neutropenia 52% 48% Grade ≥ 4 Neutropenia 33% 19% Death 3% (8) 0% (1)

CALGB 80101 – Disease-free Survival P, log rank = 0.99

CALGB 80101 – Overall Survival P, log rank = 0.80

Is the result of CALGB 80101 surprising? No, it’s not surprising! CALGB 80101 – Discussion Is the result of CALGB 80101 surprising? No, it’s not surprising!

CALGB 80101 – Discussion GISCAD adjuvant PELF vs FU Cascinu et al. JNCI 2007; 99: 601-607

Combination with anthracycline CALGB 80101 – Discussion GASTRIC Group Meta-analysis Hazard Ratio 95% CI Monotherapy 0.56 0.42 - 0.75 Combination with anthracycline 0.85 0.75 – 0.97 Other combinations 0.86 0.77 – 0.88 The Gastric Group. JAMA 2010; 303: 1729-1737

Therapy of Gastric Cancer in the U.S. CALGB 80101 Fuchs et al. 2011 INT 0116 Macdonald et al. 2001 5-FU/LV ECF 5-FU/RT Control Median OS (mos) 37 38 36 27

What could we make better? CALGB 80101- Discussion What could we make better? Radiation quality assurance CALGB 80101 (Fuchs et al. 2011) 15% of the treatment plans were found to contain major deviations INT 0116 (Macdonald et al. 2001) 6.5% major deviations

What could we make better? CALGB 80101- Discussion What could we make better? Surgical quality assurance CALGB 80101 (Fuchs et al. 2011) D2 LN dissection not mandated 33% pts had <15 lymph nodes examined!

CALGB 80101- Discussion Role of D2 lymph node dissection Long-term follow-up of the Dutch D1/D2 trial Songun et al. Lancet Oncol 2010; 11: 439-449 ESMO Practice Guidelines Okines et al. Ann Oncol 2010, 21 (suppl5); v50-v54 NCCN Guidelines v 2.2011 www.nccn.com

CALGB 80101- Discussion NCCN v2.2011 guidelines: Gastric resection should include the regional lymphatics: perigastric lymph nodes (D1) and those along the named vessels of the celiac axis (D2) with a goal of examining at least 15 or greater lymph nodes. Surgical experience & hospital volume matter!

Summary Adjuvant Gastric Cancer N America Adjuvant R-CTx 45 Gy + 5FU/LV Asia Adjuvant CTx S-1 or Capox Europe Perioperative CTx (Epirubicin)-Platin-5FU

Advanced Gastric Cancer 1st line chemotherapy prolongs survival 1st line chemotherapy improves symptom control Wagner et al. J Clin Oncol 2006; 24: 2903-9 Established standard 1st line: Platin-fluoropyrimidine-combinations Park et al. # 4004 Is there a role for second-line chemotherapy?

2nd line Chemotherapy (SLC) Park et al. #4004 Screening & consent for RCT Refused RCT, but prefer SLC Willing to participate RCT Refused RCT, but prefer BSC 2:1 randomization SLC SLC BSC BSC Docetaxel or irinotecan RCT N = 202 RCT + PPT RCT: randomized controlled trial PPT: patient-preference trial ClinicalTrials.gov, NCT00821990

Survival (Park et al. #4004) Median f/u (95% CI): 17 mo (16-18 mo) 1.0 Median 95% CI 0.8 SLC + BSC 5.1 mo 4.0-6.2 BSC alone 3.8 mo 3.0-4.6 0.6 Survival Probability Log-rank P=0.009 0.4 0.2 0.0 6 12 18 Months

Critizism (Park et al. #4004) I missed… Data on quality of life Data on symptom improvement / control

Post progression chemotherapy German AIO Study Irinotecan (n = 21) BSC (n = 19) Symptom improvement 44 % 5 % Survival (median) 4 mon 2.4 mon P = 0.0027 HR = 0.48 95%CI [0,25-0,92] Thuss-Patience P. Eur J Cancer; 2011; accepted for publication

Park et al. #4004 Conclusion 2nd line chemotherapy has a proven benefit in advanced gastric cancer and should be offered to patients with an acceptable Karnofksy PS and motivation to receive further chemotherapy

Thank you for your kind attention… … and have a safe trip home!