werner scheithauer professor of internal medicine, cancer center at the vienna university hospital,...
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Werner ScheithauerProfessor of Internal Medicine,
Cancer Center at the Vienna University Hospital, Austria
Capecitabine: the new standard chemotherapy in advanced
gastric cancer?
Werner Scheithauer University Hospital
Vienna, Austria
Second most common cause of cancer mortalityWorldwide: 934, 000 new cases and 700, 000 deaths/year
Gastric cancer: a global disease
www.cancer.govKamangar F, et al. J Clin Oncol 2006;24:2137–50
20/100,000
<10/100,000
10 to 20/100,000
Gastric cancerincidence
17%
15% 68%
10–15%
25–30% 30–35%
25–30%
Japan1
Resectable
Locally advanced
Metastatic
Western countries2
Resectable
Locally advanced
Metastatic
Unstaged
1http://www.ncc.go.jp/en/ncch/annrep/20002sanofi-aventis Internal Epidemiology Data
Stage at diagnosis
Non-measurable lesions
Variable study inclusion criteria
Heterogeneous patient populations
Inadequate number of patients
Response rate rather than survival
Palliative chemotherapy for advanced gastric cancer (AGC)
Chemotherapy improves survival in metastatic gastric cancer (MGC)
Med
ian
OS
(m
on
ths)
FAMTX1
(n=30)BSC1
(n=10)FEMTX2
(n=21)BSC2
(n=20)ELF3
(n=31)BSC3
(n=30)CLF4
(n=51)BSC4
(n=52)
1Murad AM, et al. Cancer 1993;72:37–41; 2Pyrhonen S, et al. Br J Cancer 1995;71:587–91; 3Glimelius B, et al. Ann Oncol
1997;8:163–8; 4Scheithauer W, et al. Second International Conference on Biology, Prevention and Treatment of GI
Malignancy, Koln, Germany, 1995;68 (Abstract)
12
10
8
6
4
2
0
Chemotherapy
Best supportive care (BSC)
OS = overall survival; 5-FU = 5-fluorouracilFAMTX = 5-FU, doxorubicin, methotrexateFEMTX = 5-FU, epirubicin, methotrexateELF = etoposide, leucovorin, 5-FUCLF = cisplatin, leucovorin, 5-FU
FAM = 5-FU, doxorubicin, mitomycin CFP = 5-FU, cisplatin; ECF = epirubicin, cisplatin, 5-FU
BSC1
5-FU monotherapy2,3
FAM2,4
FAMTX5–7
FP2,3,6 and ECF5,8,9
4 months
7 months
6–7 months
6–7 months
7–9 months
Median OS
1Wagner AO, et al. Cochrane Database Syst Rev 2005;2:CD004064; 2Kim NK, et al. Cancer 1993;71:3813–183Ohtsu A, et al. J Clin Oncol 2003;21:54–9; 4Wils JA, et al. J Clin Oncol 1991;9:827–31
5Waters JS, et al. Br J Cancer 1999;80:269–72; 6Vanhoefer U, et al. J Clin Oncol 2000;18:2648–57 7Cocconi G, et al. Ann Oncol 2003;14:1258–63; 8Ross P, et al. J Clin Oncol 2002;20:1996–2004
9Webb A, et al. J Clin Oncol 1997;15:261–7
Survival has improvedwith conventional regimens
Chemotherapy in patients with MGC Conventional regimens prolong survival and achieve acceptable
response rates
BUT . . .
Median OS still <12 months
Complete response rate is low
Response duration is short
Inconvenient drug administration
Regimens may be toxic
No standard treatment
– all options have similar survival outcomes and safety profiles
– FP/ECF most common reference therapy in Europe
There is a clear need for new active treatments
New treatment options for AGC aim to improve survival
Epirubicin Cisplatin Fluorouracil
New treatment options for AGC aim to improve survival
Paclitaxel Irinotecan Docetaxel
Epirubicin? Oxaliplatin Capecitabine, S-1
Capecitabine: the new standard chemotherapy in AGC?
FP5-FU c.i. 800mg/m2 day 15
cisplatin 80mg/m2 day 1 every 3 weeks
XPCapecitabine 1, 000mg/m2 b.i.d. day 114cisplatin 80mg/m2 day 1 every 3 weeks
AGC and/orMGC
(n=316)
n=156
n=160
RANDO MISATION
Primary endpoint: non-inferiority in PFS
Can XP improve PFS versus FP?International phase III study in MGC (ML17032)
Kang Y-K, et al. Ann Oncol2006;17(Suppl. 6):vi19 (Abstract O-003)
PFS = progression-free survival; b.i.d. = twice dailyc.i. = continuous infusion
Why should XP be moreeffective than FP?
FP is a reference regimen for AGC
Capecitabine monotherapy is effective and well tolerated in AGC1–4
– ORR: 19–34%; SD: 30–56%
– median TTP: 2.8–4.8 months
– median OS: 8.1–10.0 months
XP was effective and well tolerated in phase II study5
– ORR: 55%; SD: 16.7%
– median TTP: 5.8 months
– median OS: 10.1 months 1Hong YS, et al. Ann Oncol 2004;15:1344–72Leon-Rodriguez E, et al. Ann Oncol2002;13(Suppl. 5):191 (Abstract 708)
3Sakamoto J, et al. Anticancer Drugs 2006;17:231–64Koizumi W, et al. Oncology 2003;64:232–6
5Kim TW, et al. Ann Oncol 2002;13:1893–8
ORR = overall response rateSD = stable diseaseTTP = time to progression
Primary endpoint met:XP improves PFS versus FP (HR=0.81)
Per protocol HR = hazard ratio; CI = confidence interval
Est
imat
ed p
rob
abil
ity
HR=0.81 (95% CI: 0.63–1.04)Compared to HR upper limit 1.25, p=0.0008
0 2 4 6 8 10 12 14 16 18 20 22 24 26Months
1.0
0.8
0.6
0.4
0.2
0
XP (n=139)
FP (n=137)
5.65.0
Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)
PFS: robust results in subgroups
Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)
PP population
Prior chemotherapy
No prior chemotherapy
Male
Female
65 years
>65 years
KPS <80%
KPS 80%
1 metastatic site
2 metastatic sites
276
28
248
185
91
238
38
30
246
98
178
HR (95% CI)
Favours XP Favours FP
0.2 0.6 1.0 1.4 1.8 2.2 2.6
KPS = Karnofsky performance status
Est
imat
ed p
rob
abil
ity
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Months
1.0
0.8
0.6
0.4
0.2
0
HR=0.85 (95% CI: 0.64–1.13)Compared to HR upper limit 1.25, p=0.0076
10.59.3
XP (n=139)
FP (n=137)
XP versus FP also showsnon-inferiority in OS (HR=0.85)
Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)Per protocol
Superior response ratewith XP versus FP
RECIST confirmed response (%)
XP(n=160)
FP(n=156) p value
ORR95% CI
41(33–49)
29(22–37)
0.033
CR 2 3 0.720
PR 39 26 0.022
SD 37 42 0.421
PD 10 18 0.051Intent-to-treat (ITT), investigators’ assessment
Kang Y-K, et al. Ann Oncol2006;17(Suppl. 6):vi19 (Abstract O-003)
RECIST = Response Evaluation Criteria in Solid TumoursCR = complete responsePR = partial responsePD = progressive disease
Similar incidence of grade 3/4 adverse events: XP versus FP
Grade 3/4 adverse events (AEs)
Neutropenia
Nausea/
vomiti
ng
Stom
atitis
Diarrhoea
Febrile
neutropenia
LeucopeniaHFS
Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)
Pat
ien
ts (
%)
XP (n=156)
FP (n=155)
60
50
40
30
20
10
0
HFS = hand-foot syndrome
XP: a potential new standardchemotherapy in AGC
As effective as FP
Improved tolerability
Avoids inconvenience and complicationsassociated with infused 5-FU
Multicentre phase III REAL-2 trial:can capecitabine improve OS versus 5-FU?
Locally advanced or metastatic oesophagogastric cancer (n=1,002)
R A N D O M I S A T I O N
EpirubicinCisplatin Fluorouracil
EpirubicinOxaliplatinFluorouracil
EpirubicinCisplatinCapecitabine
EpirubicinOxaliplatin Capecitabine
Epirubicin 50mg/m2 day 1
Cisplatin 60mg/m2 vs oxaliplatin 130mg/m2 day 1
5-FU 200mg/m2 c.i. daily vs capecitabine 500–625mg/m2 b.i.d. p.o. daily
For 24 weeks: eight cycles every 3 weeks
Cunningham D, et al. N Engl J Med 2008;358:36–46p.o. = orally
Regimen nORR(%)
TTP(months)
OS(months) Reference
FOLFOX 49 45 6.2 8.6 Louvet et al. 2002
FU(inf)/Ox 55 56 5.2 10.0 Chao et al. 2004
FUFOX 48 54 6.5 11.4 Dyster et al. 2005
FOLFOX4 61 38 7.1 11.2 DeVita et al. 2005
FLO 41 43 5.6 9.6 Al-Batran et al. 2005
Why should EOC be moreeffective than ECF?
Capecitabine is effective and well tolerated in AGC XP has become a new reference regimen for AGC Oxaliplatin has shown promising activity in phase II trials
EOC = epirubicin, oxaliplatin, capecitabineFOLFOX = 5-FU, leucovorin, oxaliplatin; FU(inf)/Ox = 5-FU infusion, oxaliplatinFUFOX = 5-FU, oxaliplatin; FLO = 5-FU, leucovorin, oxaliplatin
REAL-2: can capecitabine replace 5-FU, can oxaliplatin replace cisplatin?
In combination treatments of oesophagogastric cancer
– can capecitabine replace 5-FU?
– can oxaliplatin replace cisplatin?
Primary endpoint of non-inferiority in OS for capecitabine versus 5-FU, oxaliplatin versus cisplatin (PP population)
– based on ECF 1-year survival of 35%, 1,000 patients(250 per arm) needed to show non-inferiority (80% power, one-sided =0.05)
– upper limit of HR for experimental arms compared with standard arms should be <1.23
– secondary endpoint: superiority in OS among the four regimens (intent-to-treat)
Cunningham D, et al. N Engl J Med 2008;358:36–46
HR=0.86 (95% CI: 0.80–0.99)
REAL-2: primary endpoint met – non-inferior OS with capecitabine versus 5-FU
Per protocol
Est
imat
ed p
rob
abil
ity
Capecitabine combinations (n=480)
5-FU combinations (n=484)
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72
10.99.6
Months
Cunningham D, et al. N Engl J Med 2008;358:36–46
Similar OS with oxaliplatinversus cisplatin
HR=0.92 (95% CI: 0.8–1.1)
Oxaliplatin combinations (n=474)
Cisplatin combinations (n=490)
10.410.0
0 12 24 36 48 60 72Months
Est
imat
ed p
rob
abil
ity
1.0
0.8
0.6
0.4
0.2
0
Cunningham D, et al. N Engl J Med 2008;358:36–46Per protocol
Superior OS with EOC versus ECF
Intent-to-treat
HR=0.80 (95% CI: 0.66–0.97)Log-rank p=0.02
Median OS
(months)
ECF (n=249) 9.9
EOC (n=239) 11.2
0 12 24 36 48 60 72Months
Est
imat
ed p
rob
abil
ity
1.0
0.8
0.6
0.4
0.2
0
Cunningham D, et al. N Engl J Med 2008;358:36–46
Grade 3 / 4 AEs
Neutropenia
Nausea/
vomiti
ng
Stom
atitis
Diarrhoea
Febrile
neutropenia
Throm
boembolic
events
Cunningham D, et al. N Engl J Med 2008;358:36–46Starling N, et al. Proc ASCO GI 2007 (Abstract 74)
Pat
ien
ts (
%)
*p<0.05compared with ECF
Capecitabine-based regimensare well tolerated
ECF (n=236)
ECC (n=241)
EOF (n=235)
EOC (n=239)
60
50
40
30
20
10
0
*
* *
* ** *
HFS
ORR(%)
PFS*(months)
OS* (months)
ECC1 46 6.7 9.9ECF1 41 6.2 9.9EOC1 48 7.0 11.2EOF1 42 6.5 9.3
XP2 41 5.6 10.4FP2 29 5.0 8.9
REAL-2 versus ML17032: consistent efficacy with capecitabine regimens
Response evaluated every 3 months in REAL-2,1 every 1.5 months in ML170322
In REAL-2,1 maximum treatment duration: 6 months
1Cunningham D, et al. N Engl J Med 2008;358:36–462Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)* * Intent-to-treat
Capecitabine plus platinum-based chemotherapy approved in Europe
1Murad AM, et al. Cancer 1993;72:37–41 2Vanhoefer U, et al. J Clin Oncol 2000;18:2648–57; 3Van Cutsem E, et al. J Clin Oncol 2006;24:4991–7 4Dank M, et al. J Clin Oncol 2005;23(Suppl. 16S):403s (Abstract 4003);
5Cunningham D, et al. N Engl J Med 2008;358:36–46; 6Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)
Months
BSC1
FAMTX2
FP3
IF4
EOF5
DCF3
ECF5
XP6
ECx5
EOx5
0 2 4 6 8 10 12
IF = irinotecan + 5-FU
Putting the evidenceinto practice: case study
45-year-old male; ECOG PS: 0
Chief complaint: epigastric pain
No dysphagia or weight loss
Gastroscopy: largeulceroinfiltrative lesionencircling the antral lumen
Biopsy: tubularadenocarcinoma, M/D
ECOG = Eastern Cooperative Oncology Group; PS = performance status
Abdomen and pelvis computed tomography (CT)
Patient received EOC chemotherapy
Before treatment
After cycle 2: PR 01 October 2004
22 August 2004
After cycle 4: ++PR
After cycle 8: CR?
07 February 2005
10 November 2004
Upper limit of normal
August 04
Septem
ber 04
October 0
4
November 0
4
December 0
4
January 05
February
05
CE
A (
ng
/mL
)
Carcinoembryonic antigen (CEA) levels
18
16
14
12
10
8
6
4
2
0
Patient received EOC chemotherapy
Before treatment After cycle 7
Biopsy: no cancer
Patient was in remission for9 months without chemotherapy
Chemotherapy stopped in February 2005
Patient followed-up every 3 months
– abdomen and pelvis CT
– gastrofiberscopy (GFS)
– CEA
CT scans 22 September 2006revealed disease progression
Patient receivedsecond-line chemotherapy
Re-induction of EOC
– four cycles: SD (for 4 months)
Irinotecan 150mg/m2 day 1, 14 plus mitomycin C 8mg/m2 day 1 every 4 weeks1,2
– four cycles: SD (for 2 months)
Docetaxel 75mg/m2 every 3 weeks3
– three cycles: PD
1Giuliani F, et al. Am J Clin Oncol 2005;28:581–52Bamias A, et al. J Chemother 2003;15:275–81
3Lee JL, et al. Cancer Chemother Pharmacol 2008;61:631–7
CEA: 20.9ng/mL
4 December 2007: patient with PD,alive no longer receiving treatment
What other capecitabine-basedoptions are available?
EfficacyDCX1
(n=40)DCF2
(n=227)
ORR (%)95% CI
6852–83
3730–43
TTP/PFS (months) 7.8 5.6
OS (months) 16.9 9.2
1Kang Y-K, et al. J Clin Oncol 2004;22(Suppl. 14S):329s (Abstract 4066)2Van Cutsem E, et al. J Clin Oncol 2006;24:4991–7
Integrating docetaxel in the treatmentof AGC: high efficacy with capecitabine
Trial Setting n
Advanced disease
XP or FP ± trastuzumab (TOGA) HER2+ AGC 374
Capecitabine + cisplatin ± bevacizumab MGC 760
ECX FOLFIRI vs FOLFIRI ECX AGC/MGC 416
ECX ± panitumumab (REAL-3) AOGC 660
Operable disease
Perioperative ECX ± bevacizumab (STO-3) Adjuvant 1,100
XELOX vs observation (CLASSIC) Adjuvant 1,024
Capecitabine: the backbone of future standards in gastric cancer
HER2 = human epidermal growth factor receptor 2; AOGC = advanced oesophagogastric cancerXELOX = capecitabine + oxaliplatin
Capecitabine is effective and well tolerated
– can replace 5-FU in current treatment regimensfor AGC
Further data will support the use of capecitabine in this indication
Capecitabine is an effective, safe and convenient oral therapy for gastric cancer
Conclusions