Axel Grothey Professor of Oncology Mayo Clinic, Rochester, Minnesota, USA Vice Chair and Director of Cancer Treatment of the North Central Cancer Treatment Group (NCCTG) Co-chair of the gastrointestinal program of NCCTG Former Senior Consultant and Head of the Oncological Research Laboratory at the Martin-Luther- University in Halle, Germany Prior posts at the MD Anderson Cancer Center, Houston, USA and the University of Essen and University of Bochum, Germany Author of many papers in English and German Mayo Clinic, Rochester
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Axel Grothey Professor of Oncology Mayo Clinic, Rochester, Minnesota, USA Vice Chair and Director of Cancer Treatment of the North Central Cancer Treatment.
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Axel GrotheyProfessor of Oncology
Mayo Clinic, Rochester, Minnesota, USA
Vice Chair and Director of Cancer Treatment of the North Central Cancer Treatment Group (NCCTG)
Co-chair of the gastrointestinal program of NCCTG
Former Senior Consultant and Head of the Oncological Research Laboratory at the Martin-Luther-University in Halle, Germany
Prior posts at the MD Anderson Cancer Center, Houston, USA and the University of Essen and University of Bochum, Germany
Author of many papers in English and German
Mayo Clinic, Rochester
Mounting evidence in early CRC
Axel GrotheyMayo Clinic, Rochester,
Minnesota, USA
Adjuvant chemotherapy of colon cancer: steps ahead
Time from surgery to randomisation (days) 1.004 0.997–1.012 0.2418
Treatment effect (capecitabine vs 5-FU/LV) 0.828 0.705–0.971 0.0203
Twelves C, et al. N Engl J Med 2005;352:2696–704
Treatment duration and intensity
Capecitabine(n=995)
Bolus 5-FU/LV(n=974)
Completed full course of treatment (%) 84 88
Needed dose reduction (%) 42 44
Needed dose reduction, interruption or delay (%) 57 52
Twelves C, et al. N Engl J Med 2005;352:2696–704
Neutropenia
Nausea/
vomiti
ng
Stom
atitis
Diarrhoea
Febrile
neutropenia HFS
Pat
ien
ts (
%)
Scheithauer W, et al. Ann Oncol 2003;14:1735–43
**
* *
*p<0.001HFS = hand foot syndrome
Capecitabine (n=993)
5-FU/LV (n=974)
Grade 3/4 adverse events
X-ACT: improved safety with capecitabine50
40
30
20
10
0
X-ACT and MOSAIC: projection of OS in stage III patients
ITT population
Est
ima
ted
pro
bab
ilit
y
0 2 4 6 8
1.0
0.8
0.6
0.4
Years
X-ACT1
Bolus 5-FU/LV (n=983)
Capecitabine (n=1,004)
MOSAIC2
LV5FU2 (n=675)
FOLFOX (n=672)
1Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)2De Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007)
Est
ima
ted
pro
bab
ilit
y
1.0
0.8
0.6
0.4
Years0 2 4 6 8
X-ACT: 5-year survival update –conclusions
Update shows that capecitabine is at least equivalent to bolus 5-FU/LV with a trend to superiority (p=0.06) in terms of 5-year OS
First indication in the adjuvant setting from a cross-trial comparison showing that capecitabine is equivalent to infusional 5-FU
Capecitabine is known to be an effective/better tolerated alternative to bolus 5-FU/LV (Mayo Clinic) in the adjuvant treatment of stage III colon cancer
Chemo/radiotherapy-naïve
stage III colon cancer
Bolus 5-FU/LVMayo Clinic or Roswell Park
CAPOXCapecitabine 1,000mg/m2 b.i.d. days 1–15
Oxaliplatin 130mg/m2 day 1 q3w
Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23
CAPOX: a new optionin the adjuvant setting
Primary endpoint: disease-free survival
n=944
n=942
RANDO MISATION
Grade 3/4 adverse events
Pat
ien
ts (
%)
CAPOX1 (n=938)
FOLFOX42 (n=1,108)
FLOX3 (n=1,200)
Cross-trial comparison*Not reported
Neutropenia
Nausea
Stom
atitis
Diarrhoea
Febrile
neutropenia HFS
Vomiti
ng
Neurosensory
1Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034)2André T, et al. N Engl J Med 2004;350:2343–51
3Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500)
*
Adjuvant CAPOX: favourable toxicity compared with FOLFOX and FLOX
* *
50
40
30
20
10
0
Before After Before After Before After
HFS Diarrhoea Stomatitis
Grade 2
Grade 3
Grade 4
Active patient management minimises adverse events: before and after dose modification
Rationale for anti-VEGF therapy in the adjuvant setting
The roles of angiogenesis and VEGF in colorectal tumour growth are well established1
Using anti-VEGF therapy such as bevacizumab when micrometastases are dormant and potentially reliant on VEGF may prevent the angiogenic switch,2 thereby improving outcomes
In preclinical studies, bevacizumab causes regression of human tumour xenografts,3–5 and a reduction in the number and size of liver metastases6
Bevacizumab may have a greater impact in earlier disease stages
1Bergers G, et al. Nat Rev Cancer 2003;3:401–10; 2Poon RT, et al. J Clin Oncol 2001;19:1207–25; 3Gerber HP, et al. Cancer Res 2000;60:6253–8; 4Wildiers H, et al.
Br J Cancer 2003;88:1979–86; 5Shen B-Q, et al. Proc Amer Assoc Cancer Res 2004;45 (Abstract 2203); 6Warren RS, et al. J Clin Invest 1995;95:1789–97
VEGF = vascularendothelial growth factor
Anti-VEGF therapy regresses some existing tumour microvasculature
Reduction in tumour vessel blood flow after 1 day of anti-VEGF therapy
Inai T, et al. Am J Pathol 2004;165:35–52 Rugo HS, et al. J Clin Oncol 2005;23:5474–83*AG013736 (VEGF tyrosine kinase inhibitor)
Control Anti-VEGF therapy*
Abnormal vasculature normalised following VEGF inhibition*
Inai T, et al. Am J Pathol 2004;165:35–52 Rugo HS, et al. J Clin Oncol 2005;23:5474–83*AG013736 (VEGF tyrosine kinase inhibitor)
Normalisation of tumour vasculature improves delivery of chemotherapy
46% increase in intratumoral availability of irinotecan after pretreatment with an anti-VEGF antibody*
Wildiers H, et al. Br J Cancer 2003;88:1979–86
20
15
10
5
0 Placebo A4.6.1
Tu
mo
ur
irin
ote
can
co
nce
ntr
atio
n (
mg
/g)
10.93
15.98
*In a preclinical model
Withdrawal of anti-VEGF therapyresults in vessel regrowth
Continue anti-angiogenic therapy to avoid vessel regrowth