01082002133035Colorectal

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14 Δεκ 2013 (πριν από 3 χρόνια και 9 μήνες)

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Oral Xeloda
®
: improving patient
care in colorectal cancer

The role of fluoropyrimidines


5
-
FU remains the backbone of colorectal

cancer therapy


Infused 5
-
FU offers efficacy benefits, but its

use is inconvenient and cumbersome


Infused 5
-
FU is thought to have a superior
safety profile compared with i.v. bolus 5
-
FU

Oral therapy


Oral administration should


provide prolonged exposure to 5
-
FU


lack complications associated with
i.v. administration


provide convenient therapy


be preferred by patients

Enzymatic activation of Xeloda
®

5
'
-
DFCR = 5
'
-
deoxy
-
5
-
fluorocytidine; 5
'
-
DFUR = 5
'
-
deoxy
-
5
-
fluorouridine;

CE = carboxylesterase; CyD = cytidine deaminase

Intestine

Liver

Xeloda

5
'
-
DFCR

5
'
-
DFUR

CyD

5
'
-
DFCR

5
'
-
DFUR

5
-
FU

Tumour >> normal tissue

Xeloda

CyD

CE

Thymidine

phosphorylase (TP)

Thymidine phosphorylase (TP)


Also known as tumour
-
associated

angiogenic factor or platelet
-
derived

endothelial cell growth factor (PD
-
ECGF)


Possesses high neovascularisation

potential and has anti
-
apoptotic properties
1,2


Correlates with


fast malignant growth


aggressive invasion potential


poor patient prognosis

1
Matsuura T et al. Cancer Res 1999;59:5037

40

2
Kitazono M et al. Biochem Biophys Res Commun 1998;253:797

803

TP activity in human tissues

TP activity (µg 5
-
FU/mg protein/hour)


0

100

200

300

400

500

115

115

291

351

309

309

8

13

17

18

14

23

24

37

13

11

36

35

25

27

16

20

Colorectal

Gastric

Breast

Cervical

Uterine

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

*

*

*

*

*

*

*

*

*

*

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

Mean ratio of 5
-
FU


Xeloda
1

5
-
FU
2

1
Schüller J et al. Cancer Chemother Pharmacol 2000;45:291

7

2
Kovach JS, Beart RW Jr. Invest New Drugs 1989;7:13

25

Primary tumour:healthy colon/rectum

Healthy colon/rectum:plasma

Primary tumour:plasma

Xeloda
®

monotherapy

Xeloda
®

phase III studies


Two phase III trials versus Mayo Clinic regimen

(5
-
FU/LV)


identical protocols and conduct


pre
-
planned integrated analysis


Patients were randomised to first
-
line


Xeloda: 1,250mg/m
2

b.i.d. for 14 days followed

by a 7
-
day rest period


Mayo Clinic regimen: LV 20mg/m
2

+ 5
-
FU

425mg/m
2

days 1

5 every 28 days, i.v. bolus

Hoff PM et al. J Clin Oncol 2001;19:2282

92

Overall tumour response rate

Confirmed by Independent Review Committee (p=0.0001)

Response rate by subpopulation

*
p<0.05


Predominant site of metastases

Response rate (%)


Overall

Prior

No prior

Liver


Lung


Single

Multiple



adjuvant

adjuvant



metastatic

metastatic



(5FU)




site

sites

*

*

*

*

*

*

40

35

30

25

20

15

10

5

0

Xeloda (n=603)

5
-
FU/LV (n=604)

p=0.0002

Overall survival


Hazard ratio = 0.96

(0.85

1.08)

Log
-
rank

p=0.48


0

5

10

15

20

25

30

35

40

45

Estimated probability

Time (months)

12.8

12.9

1.0

0.8

0.6

0.4

0.2

0

Xeloda (n=603)

5
-
FU/LV (n=604)

Most common treatment
-
related

clinical adverse events


Diarrhoea

Stomatitis

Hand
-
foot

Nausea

Vomiting

Alopecia

Fatigue




syndrome

Patients (%)

*

*

*

*

*

*
p<0.0001

80

70

60

50

40

30

20

10

0

Xeloda (n=596)

5
-
FU/LV (n=593)

Grade 3/4 treatment
-
related

adverse events

Xeloda (n=596)

5
-
FU/LV (n=593)

Patients (%)


Hand
-
foot

Stomatitis

Diarrhoea

Vomiting

Neutro
-

Neutropenic


syndrome




penia

fever + sepsis

*

*

*

*
p<0.05

25

20

15

10

5

0

*

Patient education


Patient education is essential for the
management of Xeloda toxicities


Patients should be educated to


recognise the symptoms and severity of

side effects


interrupt treatment upon the development

of moderate or more severe toxicities


contact their oncology team (physician or
nurse) for further advice


Age >65 years


Performance status >0




Abnormal LDH


Prior adjuvant therapy


More than one metastatic site at baseline

Irinotecan plus 5
-
FU/LV combination therapy:

patient subgroups deriving little or no benefit

LDH, lactate dehydrogenase

Knight RD et al. Proc Am Soc Clin Oncol
2000;19:255a (Abstr 991/Poster)


Treatment selection strategy

Irinotecan plus 5
-
FU/LV combination
therapy: subgroup analysis (US trial)

PS, performance status;

LDH, lactate dehydrogenase;

ULN, upper limit of normal

Knight RD et al. Proc Am Soc Clin Oncol
2000;19:255a (Abstr 991/Poster)


Phase III trials of 1st line treatment in MCRC


Response

rate (%)















Relation to Mayo


Clinic regimen


Capecitabine

25.7


16.7


Superior


<0.0002


UFT/LV


11.7


14.5


Equivalent


NS


De Gramont regimen


32.6


14.5


Superior


0.0004


AIO regimen


20.5


11.5


Equivalent


NS


European Journal of Cancer 37 (2001) 826
-
834



Mayo Clinic

regimen

Study

drug


Xeloda
®

monotherapy in CRC: conclusions

Xeloda is a convenient oral agent for first
-
line
treatment of metastatic CRC


High efficacy compared with i.v. 5
-
FU/LV

(Mayo Clinic regimen)


Better tolerated than i.v. 5
-
FU/LV


Ideal for patients who derive little or no benefit


from combination therapy

Xeloda
®

in combination

Review of Xeloda
®

in combination with
oxaliplatin, irinotecan or radiotherapy

Xeloda
®

plus oxaliplatin (XELOX):
highly active, first
-
line combination
therapy for metastatic CRC

XELOX trial in first
-
line metastatic CRC


Large, international, phase II trial (n=96):

first
-
line therapy for metastatic CRC
1


Regimen recommended from phase I trial
2

1
Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)

2
Díaz
-
Rubio E et al. Ann Oncol 2002;13:558

65




1

8

15

21

Oxaliplatin

130mg/m
2

(2
-
hour infusion)

Oral Xeloda


1,000mg/m
2

twice daily

Days
1

14

Rest

Repeat cycle at day 22

Day

Impressive response rate with XELOX

Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)


Response rate was consistently >50% in all patient
subgroups: prior adjuvant chemotherapy, liver or lung
metastases, KPS

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Stable disease was prolonged (lasting >3 months) in
all patients achieving this outcome (n=31)

*
WHO criteria

XELOX achieves median overall

survival of >16 months (n=96)

Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)

20
months after study start

(12 months after last inclusion):



1
-
year survival = 72%



57 patients (59%) are still alive

Estimated probability

1.0

0.8

0.6

0.4

0.2

0.0


0

2

4

6

8

10

12

14

16

18

20

22

Time (months)

XELOX: favourable safety profile

compared with FOLFOX
4

1
de Gramont A et al. J Clin Oncol 2000;18:2938

47

2
Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)

XELOX: impressive efficacy and
favorable safety (summary)


XELOX is a highly active first
-
line therapy for
metastatic CRC


55% RR, with consistently high RR (>50%)
in patient subgroups


31 patients (32%) experienced disease

stabilization lasting >3 months


median progression
-
free survival of 7.6
months


median overall survival of >16 months


Manageable safety profile, which is similar to

that of FOLFOX4

Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)

Xeloda
®

plus irinotecan: under intensive
investigation in metastatic CRC

Xeloda
®

plus
3
-
weekly irinotecan:

an active and convenient regimen


Day

1

8

15

21

Irinotecan

250mg/m
2

as a 30
-
minute
i.v. infusion

Oral Xeloda

1,000mg/m
2

twice daily

Days 1

14

Rest

Repeat cycle at day 22

Kerr DJ et al. Proc Am Soc Clin Oncol 2002;21:161a (Abst 643)

Xeloda
®

plus
3
-
weekly irinotecan: results
of phase I/II trial

Kerr DJ et al. Proc Am Soc Clin Oncol 2002;21:161a (Abst 643)




MTD


Irinotecan
300
mg/m
2
+ Xeloda
1000
mg/m
2




Recommended dose


Irinotecan
250
mg/m
2
+ Xeloda
1000
mg/m
2




Overall RR
-

48
%

Xeloda
®

plus radiotherapy

Rationale for Xeloda
®

in chemoradiation


TP activity is higher in tumour than normal
tissues
1
and is further upregulated by
radiotherapy
2


Combined Xeloda/radiotherapy showed highly
enhanced activity versus either agent alone in

human colon cancer xenograft models;
radiotherapy plus 5
-
FU showed no clear additive
effect
2

1
Schüller J et al. Cancer Chemother Pharmacol
2000
;
45
:
291

7

2
Sawada N et al. Clin Cancer Res
1999
;
5
:
2948

53

Xeloda
®

plus radiotherapy

phase I study: conclusions



The recommended dose is: Xeloda
825
mg/m
2

twice
daily in combination with radiotherapy


Xeloda simplified chemoradiotherapy and was

highly appealing to the patients


In combination with radiotherapy, Xeloda offers the
potential to replace bolus or continuous infusion
5
-
FU

as the standard treatment for rectal cancer

Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

Xeloda
®

as the backbone of combination
therapy for CRC


Oral Xeloda is an effective and convenient
combination partner for oxaliplatin, irinotecan
and radiotherapy


Ongoing and planned phase III trials should
further confirm the ability of Xeloda to replace
5
-
FU in combination therapy

Back
-
ups


Recommended Dose Modifications

Toxicity


During a Course of Therapy


Dose Adjustment for resumption
of

NCIC Grades





treatment





Grade 1


Maintain dose level



Maintain dose level


Grade 2


-
1st appearance

Interrupt until resolved to grade 0
-
1

100%


-
2nd appearance

Interrupt until resolved to grade 0
-
1

75%


-
3rd appearance

Interrupt until resolved to grade 0
-
1

50%


-
4th appearance

Discontinue treatment permanently

-


Grade 3


-
1st appearance

Interrupt until resolved to grade 0
-
1

75%


-
2nd appearance

Interrupt until resolved to grade 0
-
1

50%


-
3rd appearance

Discontinue treatment permanently

-


Grade 4


-
1st appearance

Discontinue treatment permanently

50%




or, at physician’s discretion interrupt




until resolved to grade 0
-
1








Xeloda
®

dose reduction:

impact on adverse events

No. of patients

100

80

60

40

20

0


Before

After

Before

After

Before

After


Hand
-
foot syndrome

Diarrhoea

Stomatitis

Grade 4

Grade 3

Hospitalisations for key

treatment
-
related adverse events

Xeloda (n=596)

5
-
FU/LV (n=593)

No. of patients hospitalised

*
p<
0.05

*

*

*

120

100

80

60

40

20

0