The Combination of Bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) is highly active in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal Study Group (AIO trial 0604) A. Reinacher-Schick 1 , S. Kubicka 2 , W. Freier 3 , D. Arnold 4 , G. Dietrich 5 , M. Geißler 6 , S. Hegewisch-Becker 7 , U. Graeven 8 , H.-J. Schmoll 4 and W. Schmiegel 1 , Ruhr University Bochum 1 , University Hannover 2 , Center of Oncology Hildesheim 3 , Martin-Luther-University Halle-Wittenberg 4 , Hospital Bietigheim, Bietigheim-Bissingen 5 , Community Hospital Esslingen 6 , Center of Oncology Eppendorf, Hamburg 7 , Maria Hilf Hospital Mönchengladbach 8 , Germany
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The Combination of Bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) is highly active in advanced colorectal.
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The Combination of Bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin
(CapOx/Bev) is highly active in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal
Study Group (AIO trial 0604)
A. Reinacher-Schick1, S. Kubicka2, W. Freier3, D. Arnold4, G. Dietrich5, M. Geißler6, S. Hegewisch-Becker7, U. Graeven8, H.-J. Schmoll4 and W. Schmiegel1,
Ruhr University Bochum1, University Hannover2, Center of Oncology Hildesheim3, Martin-Luther-University Halle-Wittenberg4, Hospital Bietigheim, Bietigheim-Bissingen5, Community Hospital Esslingen6, Center of Oncology Eppendorf, Hamburg7, Maria Hilf Hospital Mönchengladbach8,
Germany
• Addition of Bevacizumab to 5FU/FA/irinotecan1 and 5FU/FA/oxaliplatin2,3 improves progression free survival (PFS) in advanced CRC (aCRC)
• Efficacy of Capecitabine/Oxaliplatin (CapOx) is similar to 5-FU/FA/Oxaliplatin
• Data on Capecitabine/Irinotecan (CapIri) combinations remains controversial, due to toxicity 4-7
note dose reduction of CapIri compared to previous trials for safety reasons
Patient accrualRekrutierungsbersicht
0
50
100
150
200
250
300
Jul05
Aug05
Sep05
Oct05
Nov05
Dec05
Jan06
Feb06
Mar06
Apr06
May06
Jun06
Jul06
Aug06
Sep06
Oct06
Soll
Ist
observedexpected
Baseline characteristics (n=247) No. Patients
Arm A127
Arm B120
Median age (range), years 64 (27-83) 64.5 (30-82) Distribution of age, % < 40 years 4 2 40-49 years 8 7 50-59 years 23 23 60-69 years 35 42 70-79 years 29 22 > 80 years 2 2 Male, female % 66 / 34 67 / 33 ECOG Performance status, %
0 52 52 1 45 46 2 3 2
Prior adjuvant therapy, % No 77 79 Yes 23 21
Dirk Arnold
Mean? really?
Treatment characteristics (n=247)
Number of pats.
Arm A127
Arm B120
Total247
Number of cycles (evaluable pats.)
1158 1269 2427
Mean no. of cycles (+/- SD)
9.1 (+/- 6.7) 10.6 (+/-7.1) 9.9 (+/-6.9)
Range 1-37 1-38 1-38
Median 8 9 9
Reasons for end of treatment, EOT (n=222)
Reason for EOT
n
Arm A
116
Arm B
108
Total
222
Disease Progression
46 (40%) 35 (32%) 81 (36%)
Progression free 70 (60%) 73 (68%) 143 (64%)
- toxicity 27 (39%) 12 (16%) 39 (27%)
- SAE 5 (7%) 8 (11%) 13 (9%)
- death, not tumor related
4 (6%) - 4 (3%)
- protocol violation 2 (3%) 5 (7%) 7 (5%)
- consent withdrawn 11 (16%) 14 (19%) 25 (17%)
- lost to follow-up 1 (1%) 2 (3%) 3 (2%)
- Resection/Ablation 4 (6%) 6 (8%) 10 (7%)
- Other 16 (23%) 26 (36%) 42 (29%)*end of treatment information available for n=222 pts.
Dirk Arnold
thematisch anordnen: SAE = toxicity...sind die doppelt gezaehlt, oder ist ds wirklich eine eigene kategorie, die dann (logischerweie) direkt unter toxicity stehen sollte.
Dirk Arnold
nach welcher medianen zeit / eval. zeitpunkt?
CTC V. 3.0 Grade 3 and 4 Toxicities (n=247)
Related toxicities
Arm A (127)3°/4° [%]
Arm B (120)3°/4° [%]
Diarrhoea 21/0 16/0
Sensory neuropathy 24/1 0
Hand-Foot-Syndrome 11/0 8/0
Neutropenia 2/0 8/2
Thrombocytopenia 6/0 0
Fatigue 2/1 3/0
Ileus 2/1 2/0
Nausea 3/0 3/0
Vomiting 4/0 5/0
Dirk Arnold
was machen die 2?" da?
Dirk Arnold
vielleicht isses uebersichtlicher und in der legende einfacher, wenn du nur 3 und 4 auffuehrst und den geneigten beobachter die paar zahlen selbst addieren laesst....
AEs of special interest (n=247)
AEs of special interest (Bev)
Arm A (127)3°/4° [%]
Arm B (120)3°/4° [%]
Thrombosis/Embolism - venous access thrombosis - other (incl. pulmonary emb.)
3/21/02/2
4/11/03/1
Hypertension 4/0 3/0
Cardiac ischemia/infarction 0 0/1
Hemorrhage/bleeding (GI) 1/0 0
Best overall response* (n=247)
Arm A
% of patients(n =127)
Arm B% of patients
(n =120)
CR 5 6 PR 48 49 SD 29 28 PD 5 6 NE/NA** 13 11
*ITT, RECIST criteria, investigator‘s assessment; **not evaluated/not available
Dirk Arnold
which analysis? ITT population?
Dirk Arnold
mach doch noch ne Zeile mehr
PFS rate after 6 months: Primary endpoint
Arm A% of patients
(n =127)
Arm B% of patients
(n =120)
PFS rate/6 mo.
76 84
Dirk Arnold
(egaenzen: "primary endpoint")
months
rate
with
out p
rogr
essi
on
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
Progression-free Survival by Treatment
Logrank test: p = 0.27
A : n = 127, 98 events, median = 10.4 monthsB : n = 120, 91 events, median = 12.1 months
Fig. 4.2_______
Progression free survival (PFS) - ITT analysis
months
rate
with
ou
t pro
gre
ssio
n
arnold
ausfüerlich: progression free survival, ITT analysis
0 6 12 18 24 30 36
months
0.0
0.2
0.4
0.6
0.8
1.0
surv
ival
rat
e
Overall Survival by Treatment
Fig. 4.5_______
Logrank test: p = 0.55
A : n = 127, 46 events, median = 26.7 monthsB : n = 120, 40 events, median = NA
months
Su
rviv
al r
ate
Overall survival (OS) - ITT analysis
arnold
ausfüerlich: progression free survival, ITT analysis
Conclusion• Both regimens, CapOx/Bev and CapIri/Bev,
are highly active in aCRC.
• The dose reduction of CapIri/Bev may lead to a favourable toxicity profile compared to previous capecitabine/irinotecan trials seemingly without compromising efficacy
• The CapIri/Bev arm - compared to the CapOx/Bev arm - seems to be associated with higher cycle numbers and a tendency towards longer PFS
Dirk Arnold
widerspricht sich ja innerhalb von 2 saetzen: erst sind es keine differences, und dann ist das safety profile "favourable"...und der einzige vorzug der fehlenden neurotox hat nix mit der lowered dosage zu tun. also: klar formulieren, dass die lowered dosage im vergleich mit historischen gaben zu einem guten toxprofil fuehrt.und: irgendwo sollte man den längeren behandlungsablauf mit irino (7.4 mos) mit dem konsekutiv längeren PFS (trend) einfliessen lassen, aber dazu braeuchte man halt die angabe von hinke, was da abesetzt wurde...
Acknowledgements
We would like to thank
- the patients and their families- the co-investigators- the study nurses and data monitors- Roche Pharma AG and Sanofi-Aventis for financial support