Discussion Gastric CancerLBA 4002, abstracts 4003, 4004

Florian Lordick, MDGermany

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 4002CLASSIC – Adjuvant Chemotherapy

• Asia: Korea, China, Taiwan• Surgical technique: D2 resection

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, q3wOxaliplatin: 130 mg/m2, d1, q3w

RANDO MIZATION

8 cycles of XELOX (6 months)

Observation: No adjuvant therapy

N = 1035

n = 520

n = 515

• Primary endpoint: 3-year DFS‡

• Secondary endpoints: overall survival and safety profile

CLASSIC – Primary Endpoint Met(3-year DFS at Interim Analysis)

ITT populationMedian follow-up 34.4 months (range 16–51)

1.0

0.0

0.2

0.4

0.6

0.8

3-year DFS

74%

60%

HR = 0.56 (95% CI 0.44–0.72)P < .0001

Time (months)

Observation, n = 515

XELOX, n = 520

520 410 333 246 166 74 30 10443515 352 286 209 147 58 22 6414

XELOXObservation

No. left

0 6 12 18 24 30 36 42 48

CLASSIC – Overall Survival

ITT populationMedian follow-up 34.4 months (range 16–51)

1.0

0.0

0.2

0.4

0.6

0.8

Overall survival

0 6 12 18 24 30 36 42 48

HR = 0.74 (95% CI 0.53–1.03)P = .0775

Observation n = 515

XELOX, n = 520

Time (months)

520 451 395 304 216 120 35 16468515 441 378 286 203 112 34 12458

XELOXObservation

No. left

CLASSIC – Discussion

Is the positive result of CLASSIC surprising?

No, it’s not!

CLASSIC – Discussion

ATCS-GC (Japan): S-1 vs. surgery alone

Sakuramoto S et al. N Engl J Med 2007;357:1810-1820

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

CLASSIC – Discussion

GASTRIC Group Meta-analysis

The Gastric Group. JAMA 2010; 303: 1729-1737

6% difference at 5 yearsHR = 0.82; p < 0.001

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%

Devesa et al. Cancer 1998; 83: 2049-2053

Change of gastric cancerepidemiology in theWestern World

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 MAGICCunningham et al. 2006

D2-Resection 41%

D1-Resection 19%

Other Resections 40%

Gastric Cancer – Discussion

Does the surgical approach determinethe 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/LVx 1

5-FU/LVx 2

5-FU IVCI

RT

ECFx 1

ECFx 2

5-FU IVCI

RT

N = 540Stratification by T stage, N stage, < or ≥ 7 examined lymph nodesPrimary endpoint: improvement in overall survival

CALGB 80101 – Adverse Events ≥ 3

5FU/LV ECF

Nausea 17% 15%

Diarrhea 15% 7%

Mucositis 15% 7%

Dehydration 9% 4%

Anorexia 16% 13%

Fatigue 11% 13%

Neutropenia 52% 48%

Grade ≥ 4 Neutropenia 33% 19%

Death 3% (8) 0% (1)

CALGB 80101 – Disease-free Survival

0 1 2 3 4 5 6 7

Years from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n S

urv

ivin

g D

ise

as

e-F

ree

ECF5-FU

Disease_Free Survival by Arm

P, log rank = 0.99

CALGB 80101 – Overall Survival

0 1 2 3 4 5 6 7

Years from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n S

urv

ivin

g

ECF5-FU

Overall Survival by Arm

P, log rank = 0.80

CALGB 80101 – Discussion

Is the result of CALGB 80101 surprising?

No, it’s not surprising!

CALGB 80101 – Discussion

Cascinu et al. JNCI 2007; 99: 601-607

GISCAD adjuvant PELF vs FU

CALGB 80101 – Discussion

GASTRIC Group Meta-analysis

The Gastric Group. JAMA 2010; 303: 1729-1737

Hazard Ratio 95% CI

Monotherapy 0.56 0.42 - 0.75

Combination withanthracycline 0.85 0.75 – 0.97

Other combinations 0.86 0.77 – 0.88

Therapy of Gastric Cancer in the U.S.

CALGB 80101Fuchs et al. 2011

INT 0116Macdonald et al. 2001

5-FU/LV ECF 5-FU/RT Control

Median OS

(mos)37 38 36 27

CALGB 80101- Discussion

What could we make better?

Radiation quality assurance

CALGB 80101 (Fuchs et al. 2011)15% of the treatment plans were foundto contain major deviations

INT 0116 (Macdonald et al. 2001)6.5% major deviations

CALGB 80101- Discussion

Surgical quality assurance

CALGB 80101 (Fuchs et al. 2011)D2 LN dissection not mandated33% pts had <15 lymph nodes examined!

What could we make better?

• Role of D2 lymph node dissection

Long-term follow-upof the Dutch D1/D2 trial

Songun et al. Lancet Oncol 2010; 11: 439-449

ESMO Practice GuidelinesOkines et al. Ann Oncol 2010, 21 (suppl5); v50-v54

NCCN Guidelines v 2.2011www.nccn.com

CALGB 80101- Discussion

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

EuropePerioperative CTx(Epirubicin)-Platin-5FU

AsiaAdjuvant CTxS-1 or Capox

N America

Adjuvant R-CTx45 Gy + 5FU/LV

Advanced Gastric Cancer

Wagner et al. J Clin Oncol 2006; 24: 2903-9

• 1st line chemotherapy prolongs survival• 1st line chemotherapy improves symptom control

Established standard 1st line:Platin-fluoropyrimidine-combinations

Park et al. # 4004Is there a role for second-line chemotherapy?

2nd line Chemotherapy (SLC)Park et al. #4004

Refused RCT, but prefer SLC

Willing to participate RCT

Screening & consent for RCT

Refused RCT, but prefer BSC

SLC SLC BSC BSC

2:1 randomization

RCT

RCT + PPT

Docetaxelor irinotecan

ClinicalTrials.gov,NCT00821990

RCT: randomized controlled trialPPT: patient-preference trial

N = 202

Survival (Park et al. #4004)

0 6 12 180.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

alP

rob

abil

ity

Months

SLC + BSC 5.1 mo 4.0-6.2

BSC alone 3.8 mo 3.0-4.6

Median 95% CI

Log-rankP=0.009

Median f/u (95% CI): 17 mo (16-18 mo)

Critizism (Park et al. #4004)

• Data on quality of life

• Data on symptom improvement / control

I missed…

Post progression chemotherapy

Thuss-Patience P. Eur J Cancer; 2011; accepted for publication

Irinotecan(n = 21)

BSC(n = 19)

Symptomimprovement

44 % 5 %

Survival(median)

4 mon 2.4 mon P = 0.0027HR = 0.48

95%CI [0,25-0,92]

German AIO Study

Park et al. #4004 Conclusion

2nd line chemotherapy has aproven benefit in advanced gastric cancer

and should be offered to patients

with an acceptable Karnofksy PSand

motivation to receive further chemotherapy

Thank you for your kind attention…

… and have a safe trip home!