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

2. Gastric Cancer Lung (1.4 million deaths) Stomach (740 000 deaths)
Liver ( deaths)
Colorectal ( deaths)
Breast ( deaths)
factsheet N°297 February 2011

3. 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

4. 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)

5. 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)

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

7. 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:

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

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

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

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

12. 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%

13. 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

14. 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

15. 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)

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

17. CALGB 80101 – Overall Survival
P, log rank = 0.80

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

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

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

21. 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

22. What could we make better?
CALGB Discussion
What could we make better?
Radiation quality assurance
CALGB (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

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

24. 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:
ESMO Practice Guidelines
Okines et al. Ann Oncol 2010, 21 (suppl5); v50-v54
NCCN Guidelines v

25. 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!

26. 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

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

28. 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, NCT

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

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

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

32. 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

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