Презентация на тему Treatment of Advanced and Metastatic Gastric Cancer

global health problem. Recent data indicate

that 1.4 million new cases of gastroesophageal and gastric cancer are diagnosed annually, and 1.1 million deaths are attributed to this disease

survival

Palliation/symptom control

Improve/preserve quality of life (QoL)

De Velde, Kelsen D…Gastric cancer.2008

showing improved survival of 4-8 months with combined chemotherapy

Scheithauer et al. 1995 ELF vs. BSC

Pyrhonen et al. 1995 FEMTX vs. BSC

Glimelius et al. 1997 ELF vs. BSC

Murad et al. 1999 FAMTX vs. BSC
QOL reported to be better

Systematic Review and Meta-Analysis Based on Aggregate Data

Anna D. Wagner, Wilfried Grothe, Johannes Haerting, Gerhard Kleber, Axel Grothey, Wolfgang E. Fleig

Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2903-2909

on overall survival

survival
DoxorubiciSA

combinations (without anthracyclines)

combinations (without cisplatin)

and FU bolus
ECF; 327 patients:
epirubicin, cisplatin, and

FU cont.
The rate of treatment-related deaths was 3.3% for PELF versus 0.6% for ECF (OR = 5.36; 95% CI, 1.1 to 27.4; Fisher's exact test,
P = .02834

Quality of life was analyzed in two studies evaluating ECF compared with FU, doxorubicin, and methotrexate and mitomycin, cisplatin, and FU and was superior in patients treated with ECF.

ECF (epirubicin plus CF) regimens have been investigated

widely in clinical studies and were until recently presented as the reference regimens.

JL, Bonnetain F, et al: Randomized multicenter phase II

trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: A Fédération Francophone de Cancérologie Digestive Group study-FFCD 9803. J Clin Oncol 22:4319-4328, 2004
Moehler M, Eimermacher A, Siebler J, et al: Randomized phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) versus 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer. Br J Cancer 92:2122-2128, 2005
Dank M, Zaluski J, Valvere V, et al: Randomized phase III trial of irinotecan (CPT 11) + 5- FU/folinic acid (FA) vs CDDP + 5-FU in first line advanced gastric cancer patients. J Clin Oncol 23:308s, 2005 (suppl 16, abstr 4003)
Irinotecan-containing regimens exhibit a benefit in survival of approximately 1 month and a lower rate of treatment-related deaths over the reference regimen, which was FU and cisplatin in two of three studies.

advanced, untreated gastric or gastroesophageal junction carcinoma Results of a

Phase II study
A. Ajani, M.D., Jackie Baker, R.N, …
65 mg/m2 CPT-11 plus 30 mg/m2 cisplatin, both administered intravenously 1 day per week for 4 consecutive weeks


Median TTP - 24 weeks

Median survival - 9 months (range, 1-23+ months).

al, Ann Oncol. 2008
Arm A
Irinotecan (80mg/m2) D1
LV (500mg/m2) D1
5FU

(2,000mg/m2) CIVI 22hrs
Cycle weekly for 6/7 weeks

Arm B
Cisplatin (100mg/m2) D1
5FU (1000mg/m2) CIVI
D1-5
cycle q28 days

97% metastatic
No palliative/prior treatment within 12 months
Baseline characteristics with slightly worse PS in IF arm

Dank et al, ASCO 2005

randomized controlled phase III trial (TAX 325) comparing docetaxel

(T) combined with cisplatin (C) and 5-fluorouracil (F) to CF in patients (pts) with metastatic gastric adenocarcinoma (MGC).
Moiseyenko VM, Ajani J, Tjulandin SA, et al.
J Clin Oncol 23:308s, 2005 (suppl 16, abstr 4002)

CIVI D1-5
cycles q21 days
Arm B

C 100mg/m2 D1
F 1000mg/m2

CIVI D105
cycles q28 days

International Phase III
457 chemotherapy-naive patients
Median age 55
97% had metastatic disease
Patient characteristics well balanced

month

The small survival advantage for DCF

compared with cisplatin and FU observed in this randomized phase III study, although statistically significant (median survival, 9.2 v 8.6 months, respectively P = .02), seems to be of questionable clinical relevance in the light of a considerably increased toxicity, especially in patients older than 65 years of age.

mg/m2 on days 1, 15 and 29
Leucovorin

500 mg/m2 and Fluorouracil 2000 mg/m2 on days 1, 8, 15, 22, 29 and 36, every 8 weeks (1 cycle)

The doses were amended to:
Docetaxel 40 mg/m2, Cisplatin 40 mg/m2, LCV 200 mg/m2, and Fluorouracil 2000 mg/m2 after treatment of the first 15 patients.

alternative regimens substituting Oxaliplatin for Cisplatin

Capecitabine for 5-fluorouracil.

ECF (E 50mg/m2); (C 60mg/m2); (FU 200mg/m2)
EOF (E 50mg/m2); (O 130mg/m2); (FU 200mg/m2)
ECX (E 50mg/m2); (C 60mg/m2); (X 1000/1250mg/m2)
EOX (E 50mg/m2); (O 130mg/m2); (X 1000/1250mg/m2)

Cycles q21 days

(ECF + EOF versus ECX + EOX) and platinum-containing

arms (ECF + ECX versus EOF + EOX).

of
5-FU versus capecitabine:
1 y OS -

39.4% (median OS 9.6 months) versus 44.6% (median OS 10.9 months) (HR:0.86 (95% CI:0.75-0.99))

of cisplatin versus oxaliplatin:
1 y OS -

40.1% (median OS 10.0 months) versus 43.9% (median OS 10.4 months)
(HR:0.92 (95% CI: 0.80-1.05

is not inferior to cisplatin in the first-line treatment

of oesophago-gastric cancers.

In a comparison of survival by regimen, the median overall survival for ECF, EOF, ECX and EOX was 9.9, 9.3, 9.9 and 11.2 months respectively.
EOX was associated with a significantly better median OS compared to ECF (p=0.02).

3, 2008
Capecitabine and oxaliplatin are as effective as fluorouracil

and cisplatin,respectively, in patients with previously untreated esophagogastric cancer.

table

cisplatin/S-1 vs. cisplatin/5FU
28 day cycles
S-1

given daily 21/28 days

Japanese: Trials with S-1,RAD001
German: Irinotecan vs. BSC

an ongoing Phase III, randomised, open-label, multicentre study evaluating

the efficacy and safety of Herceptin in combination with a fluoropyrimidine (Xeloda or 5-fluorouracil at the investigator’s discretion) and cisplatin versus chemotherapy alone as first-line therapy in patients with HER2-positive advanced gastric cancer.

cisplatin
(n=290)



R
5-FU or capecitabinea + cisplatin
+ trastuzumab
(n=294)
Stratification factors
advanced vs metastatic

GC vs GEJ
measurable vs non-measurable
ECOG PS 0-1 vs 2
capecitabine vs 5-FU

Phase III, randomized, open-label, international, multicenter study
HER2 over expression – 6-35% (20%)

1Bang et al; Abstract 4556, ASCO 2009

3807 patients screened1
810 HER2-positive (22.1%)

800 mg/m2/day continuous iv infusion d1-5 q3w x 6

Cisplatin

80 mg/m2 q3w x 6

Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg q3w until PD

PFS

overall response rate ORR
clinical benefit rate
duration of response
safety profile
quality of life
pharmacokinetics of Herceptin

improved with H+CT compared to CT alone

13.8 vs. 11.1 mo
p=0.0048; HR 0.74; 95% CI 0.60, 0.91
ORR - 47.3% in the H+CT arm
34.5% in the CT arm p=0.0017
There was no difference in symptomatic congestive heart failure between arms. Asymptomatic left ventricular ejection fraction decreases were reported in 4.6% of pts in the H+CT arm and 1.1% in the CT arm.

H
FC
CI, confidence interval; H, trastuzumab
Events
167 182
HR
0.74
95% CI
0.60, 0.91
p value
0.0046
Median OS
13.8 11.1

analysis

IHC0/FISH+
IHC1+/FISH+
IHC2+/FISH+
IHC3+/FISH+
IHC3+/FISH-
7.2
10.2
10.8
12.3
17.7
10.6
8.7
12.3
17.9
17.5
Exploratory analysis

IHC0 or 1+/FISH+
IHC2+/FISH+ or IHC3+
8.7
11.8
10.0
16.0
vs
vs



vs
vs
vs
vs
vs





0.92
1.24
0.75
0.58
0.83
0.48, 1.76
0.70,

2.20
0.51, 1.11
0.41, 0.81
0.20, 3.38

Hazard ratio

95% CI

0.74

0.60, 0.91

1.07
0.65

0.70, 1.62
0.51, 0.83

Risk ratio

Favors H

Favors no H

584

61
70
159
256
15

131
446

N

show a survival benefit in gastric cancer
Trastuzumab in combination

with chemotherapy is a new treatment option for patients with HER2-positive gastric adenocarcinoma

Cisplatin, and Bevacizumab in Patients With Metastatic Gastric or

Gastroesophageal Junction Adenocarcinoma

Manish A. Shah, Ramesh K. Ramanathan, David H. Ilson, Alissa Levnor, David D'Adamo, Eileen O'Reilly, Archie Tse, Robin Trocola, Lawrence Schwartz, Marinela Capanu, Gary K. Schwartz, David P. Kelsen


Journal of Clinical Oncology, Vol 24, No 33 (November 20), 2006: pp. 5201-5206

unresectable gastric/GEJ adenocarcinoma were treated with bevacizumab 15 mg/kg

on day 1,
irinotecan 65 mg/m2, and cisplatin 30 mg/m2 on days 1 and 8, every 21 days.

The primary end point was to demonstrate a 50% improvement in time to progression over historical values. Secondary end points included safety, response, and survival.

Median TTP was 8.3 months (95% CI, 5.5 to 9.9 months
Median overall survival was 12.3 months (95%CI, 11.3 to 17.2 months

with FOLFIRI in patients with untreated advanced gastric or

gastroesophageal junction adenocarcinoma (FOLCETUX study). Pinto C… Annals of Oncology Advance Access December 12, 2006
ORR - 44.1%
mTTP - 8 months (95% CI 7–9).
OS - 16 months (95% CI 9–23).

The combination of cetuximab and FOLFIRI is active in gastric and GEJ adenocarcinoma. The higher toxicity appears to be limited to neutropenia(41%)

with cisplatin and docetaxel in patients with untreated advanced

gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study) Pinto C…British Journal of Cancer (October 2009)
cetuximab – 400mg/m2 - initial dose i.v., followed by weekly doses of 250m2,
cisplatin 75mg/m2 i.v. on day 1,
docetaxel 75mg/m2 i.v. on day 1, every 3 weeks, for a maximum of 6 cycles, and then cetuximab maintenance treatment was allowed in patients with a complete response, partial response, or stable disease.
mTTP – 5mo
mOS – 9mo
ORR – 41.2%
Not improve the TTP and OS.
The toxicity of cisplatin/docetaxel chemotherapy was not affected by the addition of cetuximab.

(Xeloda, X) and cisplatin (P) versus XP alone

patients with metastatic gastric cancer (MGC) not previously treated

with fluoropyrimidines.
L. Di Lauro, S. I. Fattoruso, L. Giacinti …J Clin Oncol 27:15s, 2009

First-line therapy : epirubicin, docetaxel and cisplatin or oxaliplatin
Second line: irinotecan 180 mg/mq (150 mg/mq in pts >70 ys old)
day 1; leucovorin 100 mg/mq/day , bolus fluorouracil (FU) 400 mg/mq and a 22-h infusion of FU 600 mg/mq day 1-2, every 2 weeks for a maximum of 12 cycles or until disease progression, unacceptable toxicity or patients refusal.
Endpoints : response rate (RR), time to progression (TTP), overall survival (OS) and safety.

Median OS - 6.2 months (95% CI, 4.7-7.7).

FOLFIRI is an active and well tolerated second-line regimen for MGC pts not previously treated with fluoropyrimidines.

who may benefit? V Catalano, F Graziano …British Journal of Cancer (2008)

Median survival for the whole group was 6.1 months  
1-year OS - 20.5% (95% CI, 14.4–26.6
Overall response rate of 16.0% (95% CI, 10.6–21.4  
No statistically significative difference was found between each regimen used as second-line chemotherapy.

improvement, but increased toxicity
IF possible alternative for those unable

to tolerate a platinum agent
REAL-trial results with provide role for oxaliplatin and capecitabine