role of capecitabine in metastatic ca breast

2. • Capecitabine is an oral chemotherapeutic agent used in the
treatment of metastatic breast and colorectal cancers.
• Capecitabine is a fluoropyrimidine carbamate derivative that was
designed as an orally administered, tumor-activated and tumor-
selective cytotoxic agent
• Capecitabine is a prodrug, that is enzymatically converted to 5-
fluorouracil in the tumor.
Capecitabine

3. Mechanism of Action
• Capecitabine is enzymatically converted to 5-fluorouracil in the
tumor, where it inhibits DNA synthesis and slows growth of tumor
tissue.
• The activation of capecitabine follows a pathway with three
enzymatic steps and two intermediary metabolites, 5'-deoxy-5-
fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to
form 5-fluorouracil.
• Formation of 5-FU is catalysed preferentially at the tumor site by
the tumor-associated angiogenic factor thymidine phosphorylase
(dThdPase), thereby minimising the exposure of healthy tissues to
systemic 5-FU.

4. Mechanism of Action

5. *
Schüller J, et al. Cancer Chemother Pharmacol 2000;45:291–7
x3.2*
Tumour tissue
*Ratio of median values
Normal tissue Plasma
5-FU
x21.4*
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU 5-FU
5-FU

6. Indications in MBC
• Monotherapy - For the treatment of patients with MBC
resistant to both paclitaxel and an anthracycline
containing chemotherapy regimen or resistant to
paclitaxel and for whom further anthracycline therapy
is not indicated
• In combination with Docetaxel is indicated for the
treatment of patients with metastatic breast cancer
after failure of prior anthracycline containing
chemotherapy.

7. Dosages
• The recommended monotherapy starting dose of Capecitabine is
1250 mg/m2 administered twice daily (morning and evening;
equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by
a 7-day rest period.
• In combination with docetaxel, the recommended starting dose of
Capecitabine is 1250 mg/m2 twice daily for 2 weeks followed by a
7-day rest period, combined with docetaxel at 75 mg/m2 as a 1-
hour intravenous infusion every 3 weeks.
• Capecitabine tablets should be swallowed with water within 30
minutes after a meal.

8. *Dosage may need to be indivisualized to
optimize patient management
*Do not treat patients if ANC< 1.5 X 10^9/L OR
Platelets < 100 x 10^9/L
*RENAL IMPAIRMENT:
CrCI 30-50 ML/min:reduce dose by 25 %
CrCI < 30 Ml/min : contraindicated
PREGNANCY Category:D

9. Trials in MBC
(Combination Therapy)
Superior survival with capecitabine plus docetaxel combination therapy in
anthracycline-pretreated patients with advanced breast cancer: phase III trial
results.
JCO 2002 Jun 15;20(12):2812-23.
PURPOSE:
This international phase III trial compared efficacy and tolerability of
capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-
pretreated patients with MBC.
PATIENTS AND METHODS:
Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2)
twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to
docetaxel 100 mg/m(2) on day 1 (n = 256).

10. • Approximately three-quarters of patients had predominantly visceral
metastases
• 74.1% in the Capecitabine + docetaxel arm and 71.5% in the docetaxel alone
arm had predominantly visceral metastases.
Capecitabine + Docetaxel
(n=255)
Docetaxel alone
(n=256)
Trials in MBC
(Combination Therapy)

11. • Capecitabine + docetaxel reduced the risk of progression and death over
docetaxel alone.
• The overall response rate with Capecitabine plus docetaxel was 32% vs 22% with docetaxel
alone (P=0.009)
35.7 % reduced risk of progression with
Capecitabine plus Docetaxel over
docetaxel alone.
22.5 % reduced risk of death with
Capecitabine plus Docetaxel over docetaxel
alone.
Capecitabine + Docetaxel (n=255) Capecitabine + Docetaxel (n=255)
Trials in MBC
(Combination Therapy)

12. The Capecitabine pivotal monotherapy trial enrolled a challenging
patient population.
Trials in MBC
(Monotherapy)

13. *
Primary objective:
• To determine the time to progression
Secondary objective:
• To determine the overall response rate,
the duration of response, the clinical benefit
rate
• To evaluate the safety + toxicity
• To assess the quality of life
• To determine the overall survival
Statistics:
The following assumptions
were made:
There will be a median TTP of
30 weeks for patients treated
with capecitabine.
The objective was to exclude a
TTP of less than or equal to 25
weeks with an alpha of 0.05.
Schedule:
Capecitabine 2000 mg/m², days 1 - 14 q 22
A prospective, open label, non randomised phase II trial

14. *
* HER2-negative MBC
* No previous chemotherapy for MBC
* Good performance status (KI  60% )
* Measurable disease according to WHO criteria
* Life expectancy > 3 months
* Concurrent immunotherapy or hormonal therapy.
Bisphosphonates may be continued
* Female and male patients

15. *
N = 161
Age, years:
Median 65
Min, Max 37 years, 90 years
Pre-treatment:
Adjuvant chemotherapy 87 (54.0%)
Anthracycline 57 (35.8%)
Taxane 39 (24.5%)
Adjuvant endocrine therapy 96 (59.6%)
no adjuvant therapy 21(13%)
# patients can have more than one metastatic site
Metastatic site #
High Risk
Liver 70
Lung and Other 2
Low Risk
Lung Only 52
Skin 9
Bone 92
Lymph Nodes 43
Receptor Positive 96 (59.6%)
Receptor Negative 65 (40.4)

16. Median OS, weeks 74.22
95% CIfor median OS (60.59, 87.85)
Median TTP, weeks 31.63
95% CIfor median TTP (26.93, 36.32)
The actual result was a TTP of
31.63 weeks which (p<0.05)
excludes a TTP lower than 25
weeks.
Time To Progression, Overall Survival and
Overall Response
Clinical Response N %
CR 13 8.1
PR 29 18
CR+PR 42 26.1

17. *
With HFS Without
HFS
Median OS, weeks 99.7 61.7
95% CI for median OS 53.0, 146.5 46.5, 76.9
Hazard Ratio (CI) 0.545 (0.326,
0.912)
Log Rank 0.0189
With HFS Without HFS
Median TTP, weeks 40.75 20.4
95% CI for median TTP (28.5, 53.0) (10.3, 30.5)
Hazard Ratio (CI) 0.705 (0.494, 1.006)
Log Rank 0.0525
Age
>/= 65 yrs/
65 yrs
Hand-foot
syndrome
yes/ no
Age <= 65
(grp1)
Age > 65
(grp2)
Median OS, weeks 60.7 76.7
95% CI for median OS 52.9, 68.5 61.1, 92.2
HR (CI) 0.876 (0.548,
1.401)
Log Rank 0.5801
Age <= 65 (grp1) Age > 65
(grp2)
Median TTP, weeks 26.78 38.0
95% CI for median
TTP
(15.5, 38.1) (22.4, 53.6)
Events/censored 75/11 55/20
HR (CI) 0.578 (0.406, 0.822)
Log Rank Test 0.0020
TTP
TTP
OS
OS

18. *
• 87.0% of the cycles (n= 1220) were not interrupted;
86.9% of the cycles (n= 1219) were not delayed
• 121 patients treated until disease progression or death
(69x progression, 1x myocardial infection, 1x heart
circulation failure, 1x cerebral bleeding, 1x kidney failure)
• 35 patients discontinued therapy early
Reasons: 24x adverse events, 3x investigators decision,
3x patients wish, 5x withdrawal of consent
• 4 patients are still under therapy

19. *
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20. *
*Capecitabine demonstrates an excellent safety and high efficacy
with the dose of 2000 mg/m² even in elderly patients
*The occurrence of the hand-foot syndrome seems to be correlated
with a better outcome (TTP p= 0.0378;
OS p= 0.0256; MVA)
*Especially the older patients seem to benefit from the therapy
regarding the TTP (TTP p= 0.0142; OS p= 0.8150; MVA)
*Literature proposed that the occurrence of excessive toxicities
from capecitabine (HFS) seems to be associated with a DPD poor
metabolism. This leads to reduced excretion of capecitabine with
a potential overdosing or rather adequate dosing*
*Saif MW, Pak J Med Sci, 2007

21. Trials in MBC
(Monotherapy)
Capecitabine monotherapy delivered a clinical benefit (CR + PR
+ SD) for 60% of mBC patients in clinical trial (n=135)
Capecitabine monotherapy has shown a consistent clinical benefit
(CR+PR+SD) across trials.

22. *
*GRADING:
*1) Minimal skin changes or dermatitis
*2)peeling,blisters,bleeding,edema or pain,not
interfering with function
*3)Skin changes with pain,interfering with
function
Treatment:
1)Topical pain relievers
2)Topical moisturizing exfoliant
creams
3)Pain relievers
4)Ice packs under hands and feet

23. *
*GRADES:
*1)Increase of < 4 stools/day over baseline
*2)increase of 4-6 stools/day over baseline
*3)> 7 stools/day over baseline
*4)life threatening consequences including low
BP as a result of severe dehydration
*5)Death
MANAGEMENT:
Diet modifications
Fluid intake
Drugs:Loperamide

24. THANK YOU