Chemotherapy of Colorectal Cancer Prof. Richard Herrmann Basel University, Switzerland.

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

*

**

*

*

*


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

(%)


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


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


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

**

*


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


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

**

*


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

Chemotherapy of Colorectal Cancer Prof. Richard Herrmann Basel University, Switzerland.

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