chemotherapy of colorectal cancer prof. richard herrmann basel university, switzerland
TRANSCRIPT
Chemotherapy of Colorectal Cancer
Prof. Richard Herrmann
Basel University, Switzerland
Chemotherapy of Colorectal CancerSubjects to be Discussed
• potential uses and goals of chemotherapy• the role 5-FU and its modulators• new drugs in colorectal cancer• Xeloda in advanced colorectal cancer, results of
phase III• Xeloda in combination with other new drugs, phase I-
II• potential for Xeloda in other GI tumors
Colorectal Cancerwhen to use chemotherapy?
• preoperatively in rectal cancer (with RT)neoadjuvant situation
• postoperatively in stage Dukes Cadjuvant situation
• in metastatic diseasepalliative situation
• in unresectable liver metastasescurative aim (with surgery)
Role of 5-FU +/- Modulators in Colorectal Cancer
• most active drug for decades
• objective response rates of 5-15%
• probably superior to no treatment in terms of survival
• modulation with folinic acid or methotrexate improves response rate
• continuous infusion superior to bolus injection
Goals of Chemotherapy in Advanced Colorectal Cancer
to
• improve symptoms
• delay progression
• prolong survival
• achieve cures?
NEW DRUGS IN COLORECTAL CANCER
• irinotecan /CPT-11(Campto®)
• oxaliplatin (Eloxatin®)
• fluoropyrimidines – capecitabine (Xeloda®)– UFT +LCV (Orzel®)
Advantages of Oral Chemotherapy
• continuous application without the need to install a permanent venous access (port-a-cath)– no operation – no clotting– no infection– no external pump
• less doctor visits
• higher patient acceptance
• lower cost
IRINOTECAN
• other indications: NSCLC, SCLC,
• toxicities: bone marrow, diarrhea, alopecia
• single agent dose: 350 mg/m2 iv q3w or
125 mg/m2 iv qw x4 every 6 weeks
• mechanism of action:
inhibition of topoisomerase-I
Oxaliplatin
• 0ther indications: ovarian cancer, NSCLC, other GI?
• toxicities: neurotoxicity, bone marrow, GI• single agent dose: 130 mg/m2 q3w or
85 mg/m2 q2w• mechanism of action:
DNA inhibition by adduct formation
Progression-Free Survival Median follow-up : 27.7 months
LV5FU2 Oxaliplatin + LV5FU2
n = 210 n = 210 median 6.2 months 9 months
p = 0.0001
01020304050
60708090
100
0 5 10 15 20 25months
Oxaliplatin + Oxaliplatin + LV5FU2LV5FU2
LV5FU2LV5FU2
% of patients
Rationale for the development of Xeloda®
• Oral administration
– provides convenient patient-orientated therapy
– is capable of mimicking the mechanism of action of continuous infusion 5-FU
– lacks complications associated with i.v. administration
• Generate 5-FU at the tumour site to maximise antitumour activity and/or improve tolerability
TP activity in human tissues
TP activity (µg 5-FU/mg protein/hour)
0 100 200 300 400 500
115115291351309309
8131718142324371311363525271620
Colorectal
Gastric
Breast
Cervix
Uterus
Ovarian
Renal
Bladder
Thyroid
Liver
Liver (metastasis)
(n=)
Healthy tissue
Tumour tissue
*
*
*
*
*
*
*
*
*
*p<0.05 Miwa M et al. Eur J Cancer 1998;34:1274–81
*
Mean ratios of 5-FU concentrations following administration of Xeloda® or 5-FU in humans
22
20
18
16
14
12
10
8
6
4
2
0
Mea
n r
atio
of
5-F
U
Primary tumor:healthy colon/rectum
Healthy colon/rectum:plasma
Primary tumor:plasma
Xeloda®1 5-FU2
1Schüller J et al. Cancer Chemother Pharmacol 2000;45:291–72Kovach JS, Beart RW Jr. Invest New Drugs 1989;7:13–25
Clinical development programme in CRC
Phase I: Europe(two trials)
Phase I: USA
Randomisedphase II
(SO14797)
Phase III: Americas (SO14695)
Phase III: EU, Australasia,Taiwan (SO14796)
Phase IIIb: adjuvantX-ACT trial
Phase III studies of Xeloda® in CRC• Two randomised, open-label, multicentre, phase III trials
• Oral Xeloda® versus i.v. 5-FU/leucovorin (LV) (Mayo Clinic regimen) as first-line treatment for advanced and/or metastatic CRC
• One study in the Americas, one study in Europe, Israel and Australasia using identical protocols
• Treatments– Xeloda®: 1,250mg/m2 twice daily for 14 days followed
by a 7-day rest period– Mayo Clinic regimen: LV 20mg/m2 + 5-FU 425mg/m2
days 1–5 every 28 days, i.v. bolus
Rationale for integrated analysis
• Identical protocols
• Identical conduct and monitoring
• Protocol pre-defined to pool data
• To obtain information on a largerpatient population
DemographicsXeloda®
(n=603)5-FU/LV(n=604)
Male/female (%) 59/41 61/39
Age (years): median, range 64 (23–86) 63 (24–87)
KPS (%): median, range 90 (70–100) 90 (70–100)
Colon/rectal cancer (%) 70/30 71/29
Predominant metastatic siteLiver (%)Lung (%)
7733
7732
Prior adjuvant treatment (%) 23 25
Hoff PM. Proc ESMO 2000 (Abst 263)KPS = Karnofsky Performance Score
Overall tumour response rateXeloda®
(n=603)5-FU/LV(n=604)
InvestigatorPR + CR (%) 25.7 16.7 p<0.0002
Stable disease (%) 47.8 52.2
IRCPR + CR (%) 22.4 13.2 p<0.0001
Stable disease (%) 52.9 57.6
PR = partial response; CR = complete response; IRC = Independent Review Committee
Hoff PM. Proc ESMO 2000 (Abst 263)
Response rates by subpopulation
*p<0.05†Predominant site of metastases
0
5
10
15
20
25
30
35
Res
po
nse
rat
e (%
)
Xeloda® (n=603)
5-FU/LV (n=604)
Prior No prior Liver† Lung† 60 years >60 yearsadjuvant adjuvant
*
**
*
*
*
Hoff PM. Proc ESMO 2000 (Abst 263)
Time to first response
0
2
4
6
8
10
12
14
0–63 64–105 106–147 >147
Xeloda® (n=603)
5-FU/LV (n=604)
Study day
Res
po
nd
ers
(%)
Hoff PM. Proc ESMO 2000 (Abst 263)
Time to disease progression
Xeloda® (n=603)
5-FU/LV (n=604)
Time (months)
Est
imat
ed p
rob
abil
ity
1.0
0.8
0.6
0.4
0.2
04.6 4.7
0 5 10 15 20 25
Median (CI)Xeloda®: 4.6 (4.3–5.3)5-FU/LV: 4.7 (4.3–5.4)
Hazard ratio = 0.997(0.885–1.123)
Log rankp=0.9535
Hoff PM. Proc ESMO 2000 (Abst 263)
Overall survival
Xeloda® (n=603)
5-FU/LV (n=604)
12.9 12.9
0 5 10 15 20 25 30 35
Time (months)
Est
imat
ed p
rob
abil
ity
1.0
0.8
0.6
0.4
0.2
0
Median (CI)Xeloda®: 12.9 (12.0–14.0)5-FU/LV: 12.9 (11.8–14.0)
Hazard ratio = 1.01(0.89–1.14)
Log rankp=0.91
Hoff PM. Proc ESMO 2000 (Abst 263)
Grade 3/4 treatment-relatedadverse events
0
2
4
6
8
10
12
14
16
18Xeloda® (n=596)5-FU/LV (n=593)
Pat
ien
ts (
%)
Diarrhoea Stomatitis Hand-foot Nausea Vomiting Neutropenicsyndrome fever + sepsis
*p<0.0001
**
*
Hoff PM. Proc ESMO 2000 (Abst 263)
Most common grade 3/4 laboratory abnormalities
Xeloda® (%)(n=596)
5-FU/LV (%)(n=593)
HaematologyHaemoglobin (<80g/L)White blood cells (<2.0x109/L)Neutrophils (<1.0x109/L)Platelets (<50x109/L)
2.01.32.21.0
1.711.621.1
0.3
ChemistryASAT (SGOT) (>5.0 x ULN)Alkaline phosphatase (>5.0 x ULN)Total bilirubin (>1.5–3 x ULN)Total bilirubin (>3 x ULN)
0.73.4
18.34.5
1.24.13.42.5
NCIC common toxicity criteria; ULN = upper limit of normal
Hoff PM. Proc ESMO 2000 (Abst 263)
Hospitalisations for key adverse events
0
20
40
60
80
100
120Xeloda® (n=596)5-FU/LV (n=593)
Diarrh
oea
Vomiti
ng
Stom
atiti
s
Neutro
penic
feve
r + s
epsi
sOve
rall
No
. o
f p
atie
nts
ho
spit
alis
ed
Hand-fo
ot
syndro
me
Infe
ctio
ns
*p<0.005
**
*
Hoff PM. Proc ESMO 2000 (Abst 263)
New Combinations
• Irinotecan+ Xeloda®
• Oxaliplatin+ Xeloda®
• Irinotecan+Oxaliplatin
• Irinotecan+Oxaliplatin+ Xeloda®
Xeloda® + Oxaliplatinin metastatic colorectal cancer
preliminary results of a Swiss study
• Xeloda® 2500 mg/m2/d x 14Oxaliplatin 130 mg/m2 iv day 1every 3 weeks
• patients without prior chemotherapy:response rate ~45%
• patients pretreated with 5-FUresponse rate ~22%
• main toxicity: diarrhea
Nov, 99
Xact-Study
patients: Dukes C colon canceradjuvant treatment for 6 months
• Xeloda® 2500mg/m2/d x 14 every 3 weeks x8
versus
• Mayo-regimen x65-FU 425mg/m2/d iv+ FA 20mg/m2/d iv, days 1-5, every 4 weeks
Xeloda® + Gemcitabine in pancreatic cancer
Treatment regimen
Xeloda® 1300 mg/m2/d orally days 1 - 14 in 2 equally
divided doses
Gemcitabine 1000mg/m2 iv over 30‘ days 1 and 8
every 3weeks
Result
response rate (PR) ~25%
excellent tolerance
Evolution of Ca 19-9 (in %)
0
50
100
150
200
250
Baseline Cycle 2 Cycle 4 Cycle6
Pe
rce
nta
ge
1001
3001
3002
5003
3005
3006
3007
5006
5007
1002
3009
4003
5005
Ca 19-9 of patients with initially elevated levels, who received at least 2 complete treatment cycles and had a minimum of 2 measurements.dose level 1, level 2, level 3
Liver Metastases of Pancreatic Cancer.Effect of Chemotherapy with Gemcitabine and
Xeloda®
June 07, 2000 September 20, 2000
76 years old patient
CA19-9: 451’800 U/ml 12’600 U/ml
0
50000
100000
150000
200000
250000
300000
350000
400000
450000
500000
2000-5-4
2000-6-23
2000-8-12
2000-10-1
2000-11-20
2001-1-9
2001-2-28
2001-4-19
CA
19-
9Course of CA 19-9 in a patient with pancreatic cancer
Chemotherapy with Gemcitabine and Xeloda
Conclusion• Xeloda® is a valuable new drug for the treatment
of advanced colorectal cancer• its major advantages compared to 5-FU+FA are
– oral application– faster response– higher response rate– lower toxicity
• further advances are to be expected with the– combination of Xeloda® with other new agents– introduction into the adjuvant situation