1. Rationale for the development of Xeloda®
To generate 5-FU at the tumour site to improve tolerability and/or maximise antitumour activity
Oral administration
is capable of mimicking the mechanism of action of continuous infusion 5-FU
lacks complications associated with i.v. administration
provides convenient therapy
1. Rationale for the development of Xeloda®
Xeloda (capecitabine), the first of a new class of oral fluoropyrimidines, was rationally designed to mimic continuous infusion 5-fluorouracil (5-FU) and to generate 5-FU preferentially in tumour tissue. The tumour-selective activation of Xeloda is achieved through exploitation of the high concentrations of thymidine phosphorylase (TP) present in tumour tissue compared with normal tissue.1 The oral administration of Xeloda enables chronic daily dosing, thus mimicking continuous infusion 5-FU without the complications and inconvenience associated with central venous access. In addition, Xeloda offers the potential for a convenient, oral, outpatient treatment, which most patients prefer to i.v. therapies.2–4
1. Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998;34:1274–81.
2. Liu G, Franssen E, Fitch M, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110–5.
3. Borner M, Schöffski P, de Wit R et al. A randomized crossover trial comparing oral UFT (uracil/tegafur) + leucovorin (LV) and intravenous fluorouracil (FU) + LV for patient preference and pharmacokinetics in advanced colorectal cancer. Proc Am Soc Clin Oncol 2000;19:191a (Abstract 741).
4. Payne SA. A study of quality of life in cancer patients receiving palliative chemotherapy. Soc Sci Med ;35:1505–9.

2. Patient preference
89% of patients in a questionnaire-based survey preferred oral therapy compared with i.v. infusions1
In a randomised trial
84% of patients preferred oral to i.v. therapy
this preference was due primarily to the ability to take medication at home2
Self-administered therapy is associated with improved quality of life for patients compared with hospital-based care3
There is an unmet need for an effective, oral, outpatient therapy
2. Patient preference
In a questionnaire-based study, the majority of patients (89%) indicated that they preferred oral to i.v. palliative chemotherapy provided that efficacy was maintained.1 This finding was confirmed in a randomised, crossover trial in which patients experienced both i.v. and oral therapy.2 Eighty-four per cent preferred oral therapy. The most important reasons for the preference for oral therapy were that the medication was a pill (73%), that medication was taken at home (69%) and that treatment interfered less with patients’ daily activities (46%) enabling patients to maintain a relatively normal lifestyle. Furthermore, a study comparing palliative chemotherapy administered at home or in hospital found that home-based therapy is associated with a better patient quality of life.3 This was attributed to reduced anxiety and depression in patients receiving home-based therapy. Patients treated in hospital tend to be less active and experience more gastrointestinal side effects, whereas patients receiving home-based chemotherapy tend to require fewer analgesics for pain and experience less psychosocial morbidity.3
1. Liu G, Franssen E, Fitch M, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110–5.
2. Borner M, Schöffski P, de Wit R et al. A randomized crossover trial comparing oral UFT (uracil/tegafur) + leucovorin (LV) and intravenous fluorouracil (FU) + LV for patient preference and pharmacokinetics in advanced colorectal cancer. Proc Am Soc Clin Oncol 2000;19:191a (Abstract 741).
3. Payne SA. A study of quality of life in cancer patients receiving palliative chemotherapy. Soc Sci Med ;35:1505–9.
1Liu G et al. J Clin Oncol 1997;15:110–5
2Borner M et al. Proc Am Soc Clin Oncol 2000;19:191a (Abst 741)
3Payne SA. Soc Sci Med 1992;35:1505–9

3. Enzymatic activation of Xeloda®
Intestine
Liver
Xeloda
Xeloda
Tumour CE
5'-DFCR
5'-DFCR
CyD
CyD
3. Enzymatic activation of Xeloda®
Xeloda and its intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR) are cytotoxic only after conversion to 5-FU and its cytotoxic anabolites via a three-step enzymatic cascade.1
Following rapid and almost complete absorption of the intact molecule, Xeloda is hydrolysed by carboxylesterase in the liver to 5'-DFCR. The next step occurs in the liver and/or tumour tissue, where cytidine deaminase converts 5'-DFCR to 5'-DFUR. The third and final stage of conversion to 5-FU involves TP, which is highly active in tumour tissue compared with healthy tissue. This results in the tumour-selective activation of Xeloda.2
1. Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998;34:1274–81.
2. Schüller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor following oral administration in colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291–7.
5'-DFUR
5'-DFUR
Thymidine
phosphorylase (TP)
5-FU
5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine;
CyD = cytidine deaminase; CE = carboxylesterase

4. 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 properties1,2
Correlates with
fast malignant growth
aggressive invasion potential
poor patient prognosis
4. Thymidine phosphorylase (TP)
As described above, the tumour-selective conversion of Xeloda to 5-FU is mediated by the enzyme TP, which shows significantly higher activity in tumour tissue than in healthy tissue.1 TP is identical in structure and function to tumour-associated angiogenic factor and platelet-derived endothelial cell growth factor. It induces neovascularisation, prevents tumour cells from entering apoptosis and correlates with fast malignant growth and aggressive invasion potential.2,3 High levels of TP expression in a range of tumour types have been correlated with increased angiogenesis as well as poor prognosis. 4–7
1. Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998;34:1274–81.
2. Matsuura T, Kuratate I, Teramachi K, Osaki M, Fukuda Y, Ito H. Thymidine phosphorylase expression is associated with both increase of intratumoral microvessels and decrease of apoptosis in human colorectal carcinomas. Cancer Res 1999;59:5037–40.
3. Kitazono M, Takebayashi Y, Ishitsuka K et al. Prevention of hypoxia-induced apoptosis by the angiogenic factor thymidine phosphorylase. Biochem Biophys Res Commun 1998;253:797–803.
4. Danenberg K, Metzger R, Groshen S et al. Thymidylate synthase and thymidine phosphorylase are prognostic indicators of survival for colorectal cancer. Proc Am Soc Clin Oncol 1997;16:257a (Abstract 914).
5. Toi M, Ohashi T, Takatsuka Y et al. Selective effect of adjuvant 5’-deoxy-5-fluorouridine treatment for thymidine phosphorylase positive tumors in primary breast cancer. Proc Am Soc Clin Oncol 1997;16:136a (Abstract 481).
6. Takebayashi Y, Akiyama S, Akiba K et al. Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 1996;88:1110–7.
7. Imazono Y, Takebayashi Y, Nishiyama K et al. Correlation between thymidine phosphorylase expression and prognosis in human renal cell carcinoma. J Clin Oncol 1997;15:2570–8.
1Matsuura T et al. Cancer Res 1999;59:5037–40
2Kitazono M et al. Biochem Biophys Res Commun 1998;253:797–803

5. TP activity in human tissues TP activity (µg 5-FU/mg protein/hour)
Colorectal
Gastric
Breast
Cervical
Uterine
Ovarian
Renal
Bladder
Thyroid
Liver
Liver (metastasis)
115 *
291
351 *
309 * 8 13 * 17 18 * 14 23 * 24 37 *
5. TP activity in human tissues
In a study by Miwa and colleagues, the activity of the three enzymes (cytidine deaminase, carboxylesterase and TP) involved in the conversion of Xeloda to 5-FU was measured.1 Samples of healthy and tumour tissue were taken from each patient. TP activity was found to be significantly higher in tumour tissue than in healthy tissue from the same individual in breast, gastric, colorectal, cervical, uterine, renal, bladder, thyroid and ovarian cancers. The study also showed that carboxylesterase was found almost exclusively in the liver and showed little variation in activity between normal and tumour tissue. Analysis of cytidine deaminase revealed that this enzyme was more active in tumour tissue and the liver than in normal tissue adjacent to malignant cells.
1. Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998;34:1274–81. 13 11 * 36 35 * 25 27
Healthy tissue
Tumour tissue 16 20 *
TP activity (µg 5-FU/mg protein/hour)
*p<0.05
Miwa M et al. Eur J Cancer 1998;34:1274–81

6. TP upregulation in tumour xenografts TP activity (unit/mg protein)
(mg/kg)
Control
Paclitaxel 100
Docetaxel 15
Vincristine 1.5
Vinblastine 3
Vindesine 5
Mitomycin C 5
Doxorubicin 7.5
Cisplatin 10
Methotrexate 50
Cyclophosphamide 200
6. TP upregulation in tumour xenografts
In preclinical studies, a number of cytotoxic drugs have demonstrated the ability to upregulate TP activity in tumour tissue. This slide shows that the activity of TP in WiDr human colon cancer xenografts is significantly enhanced compared with control following administration of paclitaxel, docetaxel, vinblastine, vindesine, mitomycin C or cyclophosphamide.1 In addition, both gemcitabine and vinorelbine upregulate TP in tumour tissue. These agents, which may enhance the antitumour activity of Xeloda by upregulating TP, have shown promise in preclinical and clinical studies as combination partners for Xeloda.
1. Ishitsuka H. Capecitabine: preclinical pharmacology studies. Invest New Drugs 2000;18:343–54.
TP activity (unit/mg protein)
Gemcitabine and vinorelbine also upregulate TP
Ishitsuka H. Invest New Drugs 2000;18:343–54

7. Tumour growth inhibition (%)
Tumour growth inhibition of human breast cancer xenografts in nude mice
120
100 80 60 40 20
–20
Xeloda
5-FU
UFT (uracil + tegafur)
Tumour growth inhibition (%)
7. Tumour growth inhibition of human breast cancer xenografts in nude mice
The tumour selectivity of Xeloda results in improved efficacy compared with non-selective fluoropyrimidines in human cancer xenograft models. This was demonstrated in a study that compared the antitumour activity of Xeloda, 5-FU and uracil/tegafur (UFT), administered for 10–28 days at their maximum tolerated dose (MTD).1 Xeloda was effective (i.e. inhibited tumour growth by more than 50%) in four of five human breast cancer xenograft models tested. In comparison, UFT was effective in only the ZR-75-1 breast cancer xenograft and 5-FU failed to achieve >50% tumour growth inhibition in any of the models tested.
Xenograft models of human colon, cervix, bladder, ovary and prostate cancers were also investigated and Xeloda demonstrated antitumour activity (>50% tumour growth inhibition) in 75% of the 24 tumour models tested. In contrast, 5-FU and UFT were effective in only 4% and 21% of models, respectively.
1. Ishikawa T, Sekiguchi F, Fukase Y et al. Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 1998;58:685–90.
Ishikawa T et al. Cancer Res 1998;58:685–90

8. Mean ratios of 5-FU concentrations following administration of Xeloda® or 5-FU in humans22 20 18 16 14 12 10 8 6 4 2
Primary tumour:healthy colon/rectum
Healthy colon/rectum:plasma
Primary tumour:plasma
Mean ratio of 5-FU
8. Mean ratios of 5-FU concentrations following administration of Xeloda® or 5-FU in humans
The tumour selectivity and preferential conversion of Xeloda in tumour tissue have been confirmed in a ‘proof of principle’ pharmacodynamic study.1 The study included 19 colorectal cancer (CRC) patients who received Xeloda 1,250mg/m2 twice daily for 5–7 days before tumour resection. The tumour selectivity of Xeloda was compared retrospectively with that of i.v. 5-FU (500mg/m2 bolus or 1,000mg/m2 24-hour infusion).2 Following administration of Xeloda, the mean concentration of 5-FU was more than three times higher in primary tumour tissue than in adjacent healthy tissue (p=0.002). Similarly, the 5-FU concentration was more than 21 times higher in tumour tissue than in plasma. These results confirm the tumour-selective activation of Xeloda. In contrast, following 5-FU administration the ratios of tumour:healthy tissue, healthy tissue:plasma and tumour:plasma were all close to 1, indicating no tumour selectivity.
1. Schüller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor following oral administration in colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291–7.
2. Kovach JS, Beart RW Jr. Cellular pharmacology of fluorinated pyrimidines in vivo in man. Invest New Drugs 1989;7:13–25.
Xeloda1 5-FU2
1Schüller J et al. Cancer Chemother Pharmacol 2000;45:291–7 2Kovach JS, Beart RW Jr. Invest New Drugs 1989;7:13–25

9. Xeloda® pharmacokinetic data Mean plasma concentration
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Xeloda
5'-DFCR
5'-DFUR
5-FU
Mean plasma concentration
(µg/mL)
9. Xeloda® pharmacokinetic data
Pharmacokinetic data show that following oral intake, Xeloda is absorbed rapidly (Tmax ranging from 0.3–3 hours) and almost completely through the intestinal wall.1,2
Subsequent conversion to 5-FU is also rapid with peak plasma concentrations of 5'-DFCR, 5'-DFUR and 5-FU reached within approximately 2 hours of administration.1 Plasma concentrations decline exponentially with half-lives of 0.6–0.8 hours.2
The plasma concentrations of 5-FU after Xeloda administration are low. After 2 weeks of treatment with Xeloda 1,250mg/m2 twice daily, systemic exposure to 5-FU is approximately 12 times lower than systemic exposure to 5'-DFUR.3
1. Reigner B, Blesch K, Weidekamm E. Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 2001;40:85–104.
2. Judson IR, Beale PJ, Trigo JM et al. A human capecitabine excretion balance and pharmaco-kinetic study after administration of a single oral dose of 14C-labelled drug. Invest New Drugs 1999;17:49–56.
3. Mackean M, Planting A, Twelves C et al. Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol ;16:2977–85.
Time (hours)
Reigner B et al. Clin Pharmacokinet 2001;40:85–104

10. Effect of hepatic dysfunction on kinetics of key Xeloda® metabolites
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Normal hepatic function (n=14)
Abnormal hepatic function (n=13)
Mean plasma concentration
(µg/mL)
10. Effect of hepatic dysfunction on kinetics of key Xeloda® metabolites
The pharmacokinetics of Xeloda (1,250mg/m2 as a single dose) have been evaluated in patients with mild to moderate hepatic dysfunction caused by liver metastases.1 Liver dysfunction was defined according to standard liver biochemistry tests (serum bilirubin, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase), with a dysfunction score of 5–9 graded as mild to moderate hepatic dysfunction. The study included 14 patients with normal liver function and 13 patients with abnormal liver function due to liver metastases. No significant differences in the pharmacokinetic parameters of the main metabolites (5'-DFUR, 5-FU and a-fluoro-b-alanine [FBAL]) were seen in patients with liver dysfunction compared with patients with normal hepatic function. These results indicate that there is no need for a-priori adjustment of the dose in this patient population.
1. Twelves C, Glynne-Jones R, Cassidy J et al. Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res 1999;5:1696–702.
Time (hours)
Twelves C et al. Clin Cancer Res 1999;5:1696–702

11. Xeloda®: phase I summary
A series of three phase I studies was performed in Europe and the USA to identify dose-limiting toxicities (DLT) and to determine the MTD and recommended dose level for Xeloda.1–3 The studies included patients with locally advanced or metastatic disease (predominantly CRC and breast cancer) that relapsed or was resistant to conventional cytotoxic therapy including 5-FU-based regimens. The MTD was defined as the oral twice-daily dose that caused drug-related toxicity of grade 3 or 4 in at least one-third of the patients treated for 6 weeks at that dose level.
A summary of the study designs and results is given in the slide. The intermittent schedule consisted of 14 days’ treatment followed by a 7-day rest period. For the continuous regimen, Xeloda was administered without interruption. In the combination therapy study, leucovorin (LV) was administered orally at a dose of 30mg twice daily.
1. Mackean M, Planting A, Twelves C et al. Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol ;16:2977–85.
2. Budman DR, Meropol NJ, Reigner B et al. Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine. J Clin Oncol 1998;16:1795–802.
3. Cassidy J, Dirix L, Bisset D et al. A phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors. Clin Cancer Res 1998;4:2755–61.
LV = leucovorin MTD = maximum tolerated dose DLT = dose-limiting toxicity HFS = hand-foot syndrome
1Mackean M et al. J Clin Oncol 1998;16:2977–85
2Budman DR et al. J Clin Oncol 1998;16:1795–802
3Cassidy J et al. Clin Cancer Res 1998;4:2755–61

12. Randomised, phase II study in colorectal cancer
Study objective: to identify the most appropriate regimen for phase III development
Efficacy
good response rates of 21–24% achieved with all three regimens as first-line treatment
median time to progression: 7.5 months for the intermittent monotherapy regimen
Well tolerated with all three regimens
Intermittent regimen (14 days’ treatment, 7-day rest) selected based on favourable time to progression, higher dose intensity and better therapeutic index
12. Randomised, phase II study in CRC
The recommended Xeloda doses established for the three different schedules investigated in phase I studies1–3 were subsequently evaluated in a multicentre, randomised, phase II study.4 The aim of the phase II study was to identify the most promising schedule for further clinical development. A total of 109 patients with untreated metastatic CRC were randomised to treatment with continuous Xeloda monotherapy (n=39), intermittent Xeloda monotherapy (n=35) or intermittent combination therapy (Xeloda plus LV) (n=35).
Confirmed tumour responses (complete or partial response) were seen in 21–24% of patients in each treatment group. The median time to disease progression was more favourable in patients receiving intermittent Xeloda monotherapy (7.5 months) than in patients receiving either the intermittent LV combination regimen (5.4 months) or the continuous monotherapy regimen (4.2 months).
All three treatment arms were generally well tolerated: the adverse events observed were characteristic of infused fluoropyrimidines and the majority were of mild to moderate intensity. The most frequent treatment-related grade 3/4 adverse events were diarrhoea and hand-foot syndrome, a cutaneous symptom affecting the palms and soles (grade 4 not applicable). The intermittent monotherapy regimen showed an acceptable safety profile over a wider dose range than the continuous regimen. The addition of LV did not enhance the efficacy of Xeloda and was associated with more pronounced toxicity.
The investigators involved recommended using the intermittent monotherapy regimen for further clinical development because of its more favourable time to disease progression, higher dose intensity and superior therapeutic index. In addition, the inclusion of a drug-free period in the intermittent schedule was considered more appealing to patients.
1. Mackean M, Planting A, Twelves C et al. Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol ;16:2977–85.
2. Budman DR, Meropol NJ, Reigner B et al. Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine. J Clin Oncol 1998;16:1795–802.
3. Cassidy J, Dirix L, Bisset D et al. A phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors. Clin Cancer Res 1998;4:2755–61.
4. Van Cutsem E, Findlay M, Osterwalder B et al. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol ;18:1337–45.
Van Cutsem E et al. J Clin Oncol 2000;18:1337–45