XELODA
(brand name: capecitabine)

Ann Oncol. 2005 May 12;
Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature.
Hennessy BT, Gauthier AM, Michaud LB, Hortobagyi G, Valero V.
Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.

Background: Capecitabine is active against anthracycline- and taxane-pretreated metastatic breast cancer. Post-marketing use of capecitabine at the FDA-approved dose (2500 mg/m(2)/day) leads to unacceptable toxicity in many patients. Dose reductions anecdotally improve tolerability without compromising efficacy. This retrospective analysis was designed to verify these anecdotal reports. Patients and methods: We retrospectively reviewed the records of 141 consecutive patients with metastatic breast cancer identified from pharmacy records as receiving capecitabine outside of a clinical trial between May 1998 and February 1999. Responses were defined as clinical improvement (ID), stabilization of disease (SD) for 6 weeks or longer, or progression (PD). Patients were grouped according to the starting dose level of capecitabine: A=2500+/-5% (dose range 2385-2560) mg/m(2)/day; B=2250+/-5% (range 2130-2350) mg/m(2)/day; C </= 2000+5% (range 1000-2100) mg/m(2)/day. We also reviewed the safety profile of capecitabine at these doses and performed a safety review of capecitabine in phase II and III metastatic breast and colorectal cancer trials. Results: Clinical data were available for 113 patients (105 for response, 106 for toxicity). The median age was 52.5 years and the mean number of prior metastatic chemotherapy regimens was 2 (range 0-7). The mean capecitabine starting dose was 2220 mg/m(2)/day and the median number of cycles administered was 4 (range 1-19). The mean tolerated dose was 2040 mg/m(2)/day (range 960-2670). Grade 3/4 toxic effects at dose levels A, B and C, respectively, included palmar-plantar erythrodysesthesia (33%, 63%, 20%), diarrhea (13%, 12%, 3%), stomatitis (8%, 0%, 3%), and nausea/vomiting (4%, 6%, 5%). Forty per cent of all patients required capecitabine dose reductions; fewer patients treated with 2000 mg/m(2)/day required dose modification (28%). Five per cent of the patients required discontinuation of capecitabine owing to toxicity. Patients started at the lowest doses of capecitabine did not have poorer response rates or shorter time to progression. Conclusions: This retrospective analysis supports a starting dose of 2000 mg/m(2)/day because of its superior therapeutic index; however, patients may still have toxic effects and individualization of dosing is necessary. A phase III, multicenter, randomized study to establish the safety and efficacy of different doses of capecitabine is urgently needed.

Cancer. 2005 May 12;
Capecitabine plus docetaxel combination therapy.
Verma S, Maraninchi D, O'shaughnessy J, Jamieson C, Jones S, Martin M, McKendrick J, Miles D, Twelves C, Hornberger J.
Department of Medical Oncology, Ottawa Regional Cancer Centre, Ottawa, Canada.

BACKGROUND: For patients with anthracycline-pretreated metastatic breast carcinoma, capecitabine plus docetaxel significantly increased overall survival compared with docetaxel alone. The current study evaluated the cost-effectiveness of the capecitabine/docetaxel combination versus docetaxel monotherapy, comparing the gain in quality-adjusted survival with associated health care costs. METHODS: Patients were randomized to receive 21-day cycles of oral capecitabine 1250 mg/m(2) twice daily, on Days 1-14, plus docetaxel 75 mg/m(2) Day 1 (n = 255), or docetaxel 100 mg/m(2) on Day 1 (n = 256). Health and cost outcomes in the two arms were compared, and cost-effectiveness was estimated. Data on survival time and medical care resource use were prospectively collected in the trial. Costs associated with medical care resource use and quality-of-life adjustments were obtained from the published literature. The incremental cost-effectiveness ratio was calculated as the cost per quality-adjusted life year (QALY) gained. RESULTS: Capecitabine/docetaxel increased the median overall survival by 3 months compared with docetaxel alone (14.5 vs. 11.5 months). The mean quality-adjusted survival was increased by 1.8 months in the capecitabine/docetaxel group. The total medical-resource utilization cost per patient was 8.9% higher with the combination: $24,475 for combination therapy versus $22,477 for single-agent docetaxel. The mean cost per QALY gained with combination therapy was $13,558 (standard deviation, $6742). Cost savings due to reduced docetaxel dose and hospital use were the major cost offsets with the combination. Sensitivity analyses showed that varying the mean hospital cost per day from the 5th to the 95th percentile resulted in cost-utility ratios ranging from $20,326 to as low as $6360. CONCLUSIONS: Capecitabine/docetaxel was a cost-effective treatment in patients with anthracycline-pretreated advanced breast carcinoma, and had an incremental cost-effectiveness ratio that compares very favorably with that of many other oncology therapies. Cancer 2005. (c) 2005 American Cancer Society.

Anticancer Drugs. 2005 Apr;16(4):441-5.
Preoperative chemotherapy with epidoxorubicin, docetaxel and capecitabine plus pegfilgrastim in patients with primary breast cancer.
Wenzel C, Bartsch R, Locker GJ, Hussian D, Pluschnig U, Sevelda U, Gnant MF, Jakesz R, Zielinski CC, Steger GG.
aDepartment of Internal Medicine I, Division of Oncology bDepartment of Surgery cChair of Medical Experimental Oncology dLudwig Boltzmann Institute for Clinical Oncology, University of Vienna, Vienna, Austria.

The objective of this pilot trial was to evaluate the safety and activity profile of epidoxorubicin, docetaxel and oral capecitabine plus pegfilgrastim (TEX+P) as preoperative first-line treatment for patients with breast cancer. Eleven consecutive patients were enrolled in this prospective clinical pilot trial. Preoperative treatment consisted of epidoxorubicin [75 mg/m body surface area (BSA)] and docetaxel (75 mg/m BSA) administered sequentially on day 1 in combination with oral capecitabine 2000 mg/m daily divided into two doses on days 1-14 of each 3-week treatment cycle. Pegfilgrastim 6 mg fixed dose was administered s.c. on day 2 of every treatment cycle. Patients received a total of 58 cycles (median 6 cycles, range 1-6) of this therapeutic regimen. Outpatient TEX+P was well tolerated. No WHO grade IV toxicity was observed. A pathological major response to this preoperative therapy regimen could be demonstrated in eight of nine evaluable patients leading to breast-conserving surgery in seven of nine evaluable patients. We conclude that outpatient TEX+P is safe in the neoadjuvant treatment of patients with primary breast cancer. Thus, this regimen can be considered for further clinical trials.

Br J Cancer. 2005 Mar 14;92(5):820-6.
A phase I clinical and pharmacokinetic study of capecitabine (Xeloda((R))) and irinotecan combination therapy (XELIRI) in patients with metastatic gastrointestinal tumours.
Delord JP, Pierga JY, Dieras V, Bertheault-Cvitkovic F, Turpin FL, Lokiec F, Lochon I, Chatelut E, Canal P, Guimbaud R, Mery-Mignard D, Cornen X, Mouri Z, Bugat R.
1Institut Claudius Regaud, 20-24, rue du Pont Saint Pierre, Toulouse 31052, France.

Capecitabine is a highly active oral fluoropyrimidine that is an attractive alternative to 5-fluorouracil in colorectal cancer treatment. The current study, undertaken in 27 patients with gastrointestinal tumours, aimed to assess the toxicity and potential for significant pharmacokinetic interactions of a combination regimen incorporating capecitabine with 3-weekly irinotecan (XELIRI). Irinotecan (200 and 250 mg m(-2)) was administered as a 90-min infusion on day 1 in combination with escalating capecitabine doses (700-1250 mg m(-2) twice daily) administered on days 2-15 of a 3-week treatment cycle. Pharmacokinetics were characterised on days 1 and 2 of the first two cycles. A total of 103 treatment cycles were administered. The principal dose-limiting toxicities were diarrhoea and neutropenia. Capecitabine 1150 mg m(-2) twice daily with irinotecan 250 mg m(-2) was identified as the maximum-tolerated dose and capecitabine 1000 mg m(-2) with irinotecan 250 mg m(-2) was identified as the recommended dose for further study. Analyses confirmed that there were no significant pharmacokinetic interactions between the two agents. The combination was clinically active, with complete and partial responses achieved in heavily pretreated patients. This study indicates that XELIRI is a potentially feasible and clinically active regimen in patients with advanced gastrointestinal cancer.British Journal of Cancer (2005) 92, 820-826. doi:10.1038/sj.bjc.6602354 www.bjcancer.com Published online 1 March 2005.

Clin Cancer Res. 2005 Mar 1;11(5):1870-6.
Phase II Evaluation of Docetaxel-Modulated Capecitabine in Previously Treated Patients with Non-Small Cell Lung Cancer.
Kindwall-Keller T, Otterson GA, Young D, Neki A, Criswell T, Nuovo G, Soong R, Diasio R, Villalona-Calero MA.
Division of Hematology/Oncology, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

PURPOSE: Based on the preclinical observation of upregulation of thymidine phosphorylase, the last enzymatic step in the conversion of capecitabine to 5-fluorouracil, by docetaxel along with good clinical tolerability of the combination of docetaxel and capecitabine using an optimized schedule in a previous phase I trial, we conducted this phase II study of this combination in patients with refractory or relapsed non-small cell lung cancer (NSCLC).Patients and Methods: Patients with NSCLC previously treated with at least one platinum- or paclitaxel-based regimen received docetaxel 36 mg/m(2) on days 1, 8, and 15 and capecitabine 625 mg/m(2) twice daily on days 5 to 18, every 4 weeks. The primary objective of the study was evaluation of progression-free survival (PFS) 26 weeks from initiation of treatment.RESULTS: Thirty-six evaluable patients received 104 cycles of the combination. Severe toxicities were infrequent with only one patient requiring toxicity-related hospitalization. The 26-week PFS rate was 25% (95% confidence interval, 12-42) with an intent to treat median survival and 1-year survival rate of 9.1 months and 37%, respectively. Among 31 patients with measurable disease (Response Evaluation Criteria in Solid Tumors criteria), eight (26%; 95% confidence interval, 12-45) achieved partial responses.CONCLUSION: The combination of capecitabine and weekly docetaxel is well tolerated in previously treated patients with NSCLC. The relatively high 26-week PFS and 1-year survival, as well as the high response rate observed, encourages further evaluation of this regimen in NSCLC, either in randomized trials for refractory patients or as a potential treatment option for chemotherapy naive patients.

Semin Oncol. 2005 Feb;32(1):43-51.
Oral capecitabine: Bridging the Atlantic divide in colon cancer treatment.
Van Cutsem E, Verslype C, Tejpar S.

5-Fluorouracil (5-FU) plus leucovorin (LV) has been the mainstay of treatment for colorectal cancer (CRC), with infused schedules more widely adopted in Europe and bolus schedules preferred in North America. However, the effective, oral fluoropyrimidine capecitabine is increasingly replacing intravenous (IV) 5-FU/LV on both sides of the Atlantic. Capecitabine generates 5-FU preferentially in tumor and is a well-established, first-line treatment for metastatic CRC. In this setting, capecitabine achieves a superior response rate, at least equivalent time to disease progression (TTP) and overall survival, and favorable safety compared with bolus 5-FU/LV. The benefits of capecitabine have been transfered into the adjuvant setting. Recent data from a large, international, randomized trial (Xeloda Adjuvant Chemotherapy Trial [X-ACT]) confirm that capecitabine (Xeloda, Roche Laboratories, Nutley, NJ) achieves favorable safety versus 5-FU/LV (Mayo Clinic regimen) and is at least as effective as IV 5-FU/LV in the adjuvant treatment of patients with resected stage III colon cancer. Capecitabine is also an effective and well-tolerated combination partner for oxaliplatin (XELOX) and irinotecan (XELIRI), achieving high efficacy with a good safety profile. An extensive phase III clinical trial program is further establishing the potential of the simplified capecitabine combinations to improve outcomes and unify treatment practices in the metastatic and adjuvant settings. New combinations with novel agents such as capecitabine/oxaliplatin plus erlotinib or bevacizumab are currently under investigation. Capecitabine has also shown promising activity and good tolerability in combination with radiotherapy in rectal cancer.

Zhonghua Zhong Liu Za Zhi. 2004 Dec;26(12):746-8.
[Oxaliplatin plus capecitabine as a second line chemotherapy for patients with advanced gastric cancer.]
[Article in Chinese]
Qian J, Qin SK, Mei JF, Chen YX, Shao ZJ, He ZM.
Department of Medical Oncology, PLA Oncology Center, 81st Hospital, Nanjing 210002, China.

OBJECTIVE: To evaluate the effect and toxicity of oxaliplatin combined with capecitabine (Xeloda) as a second-line chemotherapy regimen for patients with advanced gastric cancer. METHODS: Twenty-four patients with advanced gastric cancer who had been treated by multiple chemotherapy regimens presenting poor responses were allotted. LX regimen (oxaliplatin 85 mg/m(2) in 2-hour infusion on D1 and D15, capecitabine 1250 mg/m(2)/d divided in two daily doses given from D1 to D14) was adopted. The cycles were repeated every 28 days. All patients received two or more cycles. RESULTS: All 24 patients were evaluated after having received 2 to 6 cycles of chemotherapy, totally 92 cycles. The overall response rate was 29.2% (including 2 CR, 5 PR, 10 NC and 7 PD). The time to tumor progression (TTP) was 2 to 18 months (median 5 months), and duration of remission was 4 to 14 months (median 8 months). The major toxicities were bone marrow suppression and nausea/vomiting. CONCLUSION: Oxaliplatin combined with capitabine is effective as a secondary line regimen for patients with advanced gastric cancer. This protocol is active and well tolerated. Further clinical studies are warranted.

Zhonghua Zhong Liu Za Zhi. 2004 Sep;26(9):565-6.
[Capecitabine combined with TACE for advanced liver cancer.]
[Article in Chinese]
Li L, Sun F, Chen AJ, Li XY, Hu MD, Ran JH, Tang JH.
Department of Hepatoductopancreas, Second Hospital, Kunming Medical College, Kunming 650101, China. E-mail: ynkmlili@yahoo.com.cn.

OBJECTIVE: To evaluate the clinical efficacy of capecitabine combined with transcatheter arterial chemoembolization (TACE) for advanced liver cancer. METHODS: Forty-nine patients with liver cancer were retrospectively divided into two groups: Treatment group, on the basis of TACE, 23 patients received oral capecitabine at 2500 mg/m(2), twice-daily for 14 days followed by 7-day rest period and repeated in every three week intervals for more than two cycles. Control group, 26 patients received TACE only at 2-month intervals for at least two cycles. RESULTS: In capecitabine and TACE group: there were 1 CR, 14 PR, 5 SD and 3 PD; the overall response rate was 65.2%; the AFP and tumor reduction rates were 68.8% and 73.9%; the median survival time was 11.9 months. In the TACE only group: there were 0 CR, 7 PR, 12 SD and 7 PD; the overall response rate was 26.9%; the AFP and tumor reduction rates were 31.6 % and 30.8%; the median survival time was 8.3 months. The most common side-effects of capecitabine were hand-foot syndrome and diarrhea. CONCLUSION: Capecitabine combined with TACE is safe and effective for advanced liver cancer.

Breast Cancer Res Treat. 2004 Nov;88(2):117-29.
Efficacy and safety of single agent capecitabine in pretreated metastatic breast cancer patients from the French compassionate use program.
Pierga JY, Fumoleau P, Brewer Y, Zelek L, Martin D, Turpin FL, Goudier MJ, Gil-Delgado M, Baticle JL, Namer M, Chollet P, Sutherland W, Barats JC.
Institut Curie, Paris, 75005, France.

Background . A retrospective source review identifying predictive factors and assessing safety and efficacy in pretreated metastatic breast cancer (MBC) patients treated with capecitabine in a French compassionate-use program. Patients and methods . 197 patients received capecitabine at an initial total dose 0.25-3.0g/m(2)/day, twice daily for 14 consecutive days, every 3weeks. Results . Median patient age was 56years (range, 31-88), 19% had performance status (PS) 3-4. Prior palliative and adjuvant treatment was reported in 96 and 61% of patients respectively. Best overall response rate (ORR) was 15% (95% confidence interval [CI], 11-21%) and 49% had benefit (CR, PR or SD). Median time to progression (TTP) and overall survival were 4.8 and 14.7 months, respectively. Median TTP in responders was 8.9months (95%CI 6.1-11.7). Grade 3/4 neutropenia and grade 3 thrombocytopenia occurred in 8 and 3% of patients respectively. Hand-foot syndrome (grade 3/4 in 16% of patients), diarrhea, stomatitis and asthenia were prevalent. Multivariate analysis showed ORR was significantly influenced by PS>/=2 ( p =0.004), time from metastases diagnosis to capecitabine treatment ( p =0.015) and presence of liver metastases at inclusion ( p =0.047). Abnormal liver function tests at baseline were associated with severe thrombocytopenia and anemia. Four treatment-related deaths occurred. Conclusion . Capecitabine is active in heavily pretreated MBC patients and has a favorable toxicity profile with the added advantage of being an oral drug administered in an outpatient setting.

Breast Cancer. 2004;11(2):116-20.
Capecitabine plus docetaxel combination chemotherapy for metastatic breast cancer.
Saeki T, Takashima S.
Department of Clinical Research and Surgery, National Shikoku Cancer Center, 13 Horinouchi, Matsuyama 790-0007, Japan. tsaeki@shikoku-cc.go.jp

Doxifluridine(5'-DFUR)is converted to its metabolite 5-FU by the enzyme thymidine phosphorylase(TP). TP is expressed significantly higher in tumor tissue than in normal tissue. Capecitabine(N4-pentoxylcarbonyl -5'-deoxy-5-fluorocytidine)is a pro-drug of 5'-DFUR and a novel fluoropyrimidine carbamate that is converted to 5-FU preferentially in tumor tissue through a three-step enzymatic cascade. Expression of TP in tumor tissue may clinically predict efficacy of capecitabine. Induction of TP activity has brought about enhancement of capecitabine efficacy by taxanes in human cancer xenografts. In addition, a phase III study directly comparison docetaxel monotherapy and docetaxel plus capecitabine has been conducted for metastatic breast cancer patients who had received anthracyclines. The overall response rate of the combination group was 42%(n=255), and that of the monotherapy group was 30%(n=256)(p=0.006). The primary endpoints were time to disease progression, and time to treatment failure, and these parameters were superior in the combination arm than in the single arm, suggesting that capecitabine sensitization by docetaxel might be a new approach to breast cancer treatment.

Ann Oncol. 2004 Dec;15(12):1760-5.
Capecitabine and vinorelbine in elderly patients (>=65 years) with metastatic breast cancer: a phase I trial (SAKK 25/99).
Hess D, Thurlimann B, Pagani O, Aebi S, Rauch D, Ballabeni P, Rufener B, Castiglione-Gertsch M, Goldhirsch A.
SAKK Group, SAKK Coordination Center, Effingerstrasse 40, CH-3008 Bern, Switzerland.

BACKGROUND: Few chemotherapy regimens are suitable for the treatment of elderly patients with advanced breast cancer. With the aim of finding a regimen with a low burden of subjective non-overlapping toxic effects, vinorelbine and capecitabine were chosen to be investigated in a phase I dose-finding study. PATIENTS AND METHODS: Thirty-six patients with advanced breast cancer were stratified for the presence of bone and non-bone involvement and treated at four dose levels from capecitabine 800 mg/m(2) orally days 1-14 and vinorelbine 20 mg/m(2) intravenously days 1 and 8, to capecitabine 1250 mg/m(2) orally days 1-14 and vinorelbine 25 mg/m(2) intravenously days 1 and 8, for a maximum of six cycles. None of the patients had received prior chemotherapy for metastatic/advanced disease. Fifty-three per cent of patients with bone metastases and 67% of patients without bone metastases had visceral disease. The median age was 70 years for the 15 with bone involvement patients and 73 years for the 21 without bone involvement patients. RESULTS: Twenty-eight patients were fully evaluable for hematological dose-limiting toxicity (DLT), and all patients for other DLTs and for antitumor activity. One DLT with grade 3 venous thrombosis at dose level 2 and two dose-limiting neutropenia events at level 3 occurred in patients without bone involvement. Two dose-limiting neutropenia events were observed at dose level 2 for patients with bone involvement. Thus, the recommended dose was defined at level 1 (capecitabine 1000 mg/m(2) days 1-14 and vinorelbine 20 mg/m(2) days 1 and 8) for patients with bone involvement. For patients without bone involvement, the recommended dose was at level 2 (capecitabine 1250 mg/m(2) days 1-14 and vinorelbine 20 mg/m(2) days 1 and 8). For patients without bone involvement the overall response rate was 48% and the time to progression (TTP) was 4.5 months [95% confidence interval (CI) 3.3-6.9]. For patients with bone involvement the overall response rate was 53% and TTP was 5.3 months (95% CI 2.7-7.8). CONCLUSIONS: This regimen of capecitabine and vinorelbine is well tolerated and effective in elderly patients with metastatic breast cancer. Toxicity was mainly hematological and was observed at a lower dose in patients with bone involvement. A phase II study with the two different dose levels for elderly patients with and without bone involvement is currently being conducted.

Oncology. 2004;67(2):117-22.
Capecitabine with weekly paclitaxel for advanced breast cancer: a phase I dose-finding trial.
Uhlmann C, Ballabeni P, Rijken N, Brauchli P, Mingrone W, Rauch D, Pestalozzi BC, Rochlitz C, Aebi S; Swiss Group for Clinical Cancer Research; Swiss Institute for Applied Cancer Research.
Institute of Medical Oncology, Inselspital, University of Bern, Bern, Switzerland.

OBJECTIVE: To determine the maximum tolerated dose (MTD), toxicity and activity of combined weekly paclitaxel and capecitabine in patients with metastatic breast cancer. METHODS: Sixteen patients with metastatic breast cancer, of whom 15 were evaluable for toxicity and response, were enrolled in 7 Swiss centers. Paclitaxel 80 mg/m2 was given intravenously on days 1, 8 and 15. Capecitabine was administered orally on days 1 through 14 using five different dose levels. Both drugs were given in a 21-day schedule. RESULTS: Capecitabine could be administered at doses commonly used for the drug as a single agent, i.e. 1,250 mg/m2 twice daily in combination with weekly paclitaxel. Hematological and other toxicities did not appear to be dose-limiting; however, significant skin and nail toxicities were observed. A response or stable disease was observed in 87% of patients [13/15; exact 95% confidence interval (CI) 60-98%], with 2 complete responses, 4 partial responses (overall response rate 40%, exact 95% CI 16-68%) and 7 patients with stable disease for at least 9 weeks. CONCLUSION: The phase I evaluation of capecitabine in combination with fixed-dose weekly paclitaxel did not allow the definition of an MTD of capecitabine based on the predefined criteria. Instead, the dose for the phase II evaluation was determined based on the occurrence of toxicity in later courses and on experience with other regimens containing capecitabine. Capecitabine (1,000 mg/m2 twice daily, days 1-14, every 3 weeks) with paclitaxel (80 mg/m2 weekly) is a promising combination for advanced breast cancer now being investigated in a phase II trial. 2004 S. Karger AG, Basel.

Clin Breast Cancer. 2004 Oct;5(4):287-92.
Final results of a phase II clinical trial of weekly docetaxel in combination with capecitabine in anthracycline-pretreated metastatic breast cancer.
Mackey JR, Tonkin KS, Koski SL, Scarfe AG, Smylie MG, Joy AA, Au HJ, Bodnar DM, Soulieres D, Smith SW.
Cross Cancer Institute, Universite de Montreal Canada. johnmack@cancerboard.ab.ca

The addition of capecitabine to docetaxel on a 3-week schedule resulted in superior response rate, increased time to progression (TTP), and improved overall survival in patients with anthracycline-pretreated metastatic breast cancer (MBC). Because the toxicity profile of weekly docetaxel differs from the standard 21-day docetaxel schedule, we performed a phase I/II trial to test the efficacy and safety of weekly docetaxel in combination with capecitabine given for 14 days every 21 days. The phase I study identified the doses of docetaxel (30 mg/m2 weekly) and capecitabine (900 mg/m2 twice daily on days 1-14 every 21 days) used in phase II. Twenty female patients with measurable or assessable MBC were enrolled. Eighteen patients had previously received anthracyclines; 2 had contraindications to anthracyclines. Patients remained on study for a maximum of eight 3-week cycles or until tumor progression or unacceptable toxicity occurred; response assessments were scheduled after cycle 2, 5, and 8. Seventeen patients were assessed after cycle 2; 3 subjects (18%) had a partial response (PR), 9 had stable disease (53%; SD), and 5 patients (29%) had progressive disease (PD). Ten patients were assessable after cycle 5. Two patients (20%) had a PR, 5 patients (50%) had SD, and 3 patients (30%) had PD. The most common grade 3 toxicities were nail loss (45%), asthenia (30%), and hand-foot syndrome (30%), and toxicities led to study discontinuation in 10 patients. The median time to treatment failure was 10 weeks and median TTP was 26 weeks. The median duration of response was 9 weeks and the median duration of SD was 16 weeks. The median overall survival was 82 weeks. This schedule of weekly docetaxel in combination with day 1-14 capecitabine has activity; however, toxicity discourages the use of this schedule in lieu of the standard docetaxel/capecitabine regimen.

Clin Breast Cancer. 2004 Oct;5(4):273-8.
Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial.
Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Liu WY, Ayoub JP, O'Shaughnessy JA.
Guy's and St Thomas' Hospital, London, UK. david.miles@cancer.org.uk

In a large phase III trial of 511 patients with anthracycline-pretreated advanced/metastatic breast cancer, capecitabine/docetaxel combination therapy was shown to have significantly superior efficacy compared with single-agent docetaxel, including superior progression-free and overall survival and objective response rate. An updated survival analysis with >/= 27 months follow-up shows that patients receiving combination therapy maintained significantly superior survival (hazard ratio [HR], 0.777 [95% CI, 0.645-0.942]; P < 0.01; median survival, 14.5 months vs. 11.5 months) compared with those receiving single-agent docetaxel. Following the failure of docetaxel monotherapy, 35% of patients did not receive additional cytotoxic chemotherapy. Among patients randomized to single-agent docetaxel, only those given poststudy single-agent capecitabine had significantly prolonged survival compared with those given any other poststudy chemotherapy (HR, 0.500; P = 0.0046; median survival, 21.0 months vs. 12.3 months, respectively). By contrast, poststudy vinorelbine-containing chemotherapy did not affect survival following progression on single-agent docetaxel compared with other poststudy chemotherapy regimens (HR, 1.014; P = 0.94; median survival, 13.5 months vs. 12.6 months, respectively). Among patients randomized to combination therapy, discontinuing docetaxel of capecitabine has a similar effect on survival (HR, 0.720; P = 0.20; median survival, 15.8 months vs. 18.3 months, respectively). Median survival was 18.3 months in patients who discontinued docetaxel and continued to receive capecitabine versus 15.8 months in patients who discontinued capecitabine and continued to receive docetaxel, with a trend toward improved survival in patients continuing to receive capecitabine. Although this is a retrospective analysis, these data suggest that the sequential administration of docetaxel followed by capecitabine is associated with prolonged survival in patients who are candidates for sequential single-agent therapy.

J Natl Cancer Inst. 2004 Oct 20;96(20):1500-9.
Accelerated approval of oncology products: a decade of experience.
Dagher R, Johnson J, Williams G, Keegan P, Pazdur R.
Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 1451 Rockville Pike, Rockville, MD 20852, USA. dagherr@cder.fda.gov

We review the regulatory history of the accelerated approval process and summarize the U.S. Food and Drug Administration experience with accelerated approvals in oncology. The accelerated approval regulations, promulgated in 1992, allow approval of drugs for serious or life-threatening diseases on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit, such as survival or symptom benefit, pending completion of studies designed to confirm clinical benefit, referred to as phase 4 commitments, which are required to be conducted with due diligence. From 1992 to 2004, 22 applications involving anticancer drugs or biologics were approved. Of these 22 applications, accelerated approval was granted to 15 on the basis of findings from studies without an active comparator (i.e., single-arm studies or studies comparing two dose levels) and to the remaining seven on the basis of one or more randomized studies. Of the 22 approved applications, six (i.e., applications for dexrazoxane, irinotecan, capecitabine, docetaxel, imatinib mesylate, and oxaliplatin) have had one or more indications converted to regular approval. This review reports information that was presented at an Oncologic Drugs Advisory Committee meeting held in March 2003; it also presents a discussion of accelerated approval study designs, the study populations evaluated in the accelerated approval and confirmatory settings, and the integration of accelerated approval into a comprehensive drug development plan.

Br J Cancer. 2004 Nov 15;91(10):1763-8.
Phase II clinical trial of capecitabine and gemcitabine chemotherapy in patients with metastatic renal carcinoma.
Waters JS, Moss C, Pyle L, James M, Hackett S, A'hern R, Gore M, Eisen T.
1Royal Marsden Hospital, London and Sutton, UK.

We report a single institution phase II study of gemcitabine 1200 mg m(-2) i.v. on days 1 and 8 and capecitabine 1300 mg m(-2) twice daily on days 1-14 of each 3-week cycle in patients with metastatic renal carcinoma. Patients had a WHO performance status of 0, 1 or 2. Of the 21 enrolled patients, 19 had received prior immunotherapy or chemoimmunotherapy. All had progressive disease at study entry. In all,19 patients had multiple sites of disease. The median duration of metastatic disease was 12.3 months (range 1.2-78.1 months). Three of the 19 evaluable patients achieved a partial response to treatment, with no complete responses, producing an objective overall response rate of 15.8% (95% CI, 3.4-39.6%). The median time to disease progression was 7.6 months, and median overall survival was 14.2 months. Treatment was reasonably well-tolerated, neutropenia being the most frequently observed grade 3 or 4 toxicity, occurring in 57% of patients. Other side effects were consistent with the established toxicity profile of the two drugs, including diarrhoea, palmar-plantar erythema, fatigue, nausea, vomiting and infection. This combination of gemcitabine and capecitabine has modest activity in immunotherapy-refractory metastatic renal carcinoma with manageable toxicity.British Journal of Cancer (2004) 91, 1763-1768. doi:10.1038/sj.bjc.6602209 www.bjcancer.com Published online 26 October 2004.

Semin Oncol. 2004 Oct;31(5 Suppl 10):45-50.
Future options with capecitabine (Xeloda) in (neo)adjuvant treatment of breast cancer.
Fumoleau P, Cameron D.
Centre Georges-Francois Leclerc, Dijon, France.

As an active and well-tolerated agent in the treatment of metastatic breast cancer, capecitabine (Xeloda, F. Hoffmann-La Roche, Basel, Switzerland) has the potential to confer significant clinical benefits in the primary treatment of breast cancer. The minimal myelosuppression and alopecia associated with capecitabine, together with its potential for synergistic activity with a range of other anticancer therapies, lend support to its use in combination regimens with other commonly used cytotoxic agents. Trials to date show that capecitabine combinations incorporating taxanes, vinorelbine, anthracyclines, and cisplatin are active and well tolerated in the metastatic setting. To more fully explore the clinical utility of capecitabine in early breast cancer, an extensive, worldwide phase II/III program is evaluating capecitabine as a component of adjuvant and neoadjuvant therapy. Results presented to date of the large adjuvant and neoadjuvant trials incorporating capecitabine are encouraging and suggest that women with breast cancer might benefit from the activity of capecitabine early in the disease course.

Urol Oncol. 2004 Sep-Oct;22(5):387-92.
Combination therapy with capecitabine and interferon alfa-2A in patients with advanced renal cell carcinoma: a phase II study.
Padrik P, Leppik K, Arak A.
Clinic of Hematology & Oncology, Tartu University Clinics, Vallikraavi 7, Tartu, Estonia. peeter.padrik@kliinikum.ee

Capecitabine is a fluoropyrimidine carbamate capable of exploiting the high concentrations of thymidine phosphorylase in tumor tissue to achieve activation preferentially at the tumor site. Thymidine phosphorylase activity is high in renal cell carcinoma tissue. Interferon alfa has been proved to be the agent for standard therapy in metastatic renal cell carcinoma. The purpose of the study was to assess the efficacy and toxicity of combining capecitabine and interferon alfa-2A in patients with advanced renal cell carcinoma. Twenty-five patients with advanced renal cell carcinoma and no prior systemic therapy were treated with the combination of capecitabine at a dose of 1,250 mg/m2 twice daily for 2 weeks after every 21 days and interferon alfa-2A 6 million U three times a week. The overall response rate was 24.0% (95% CI, 9.4-45.1%), from 6 responded patients 5 had partial responses and 1 complete response. Stable disease status was achieved in 9 patients (36.0% with 95% CI 18.0-57.5%). The median survival time was 248 days (95% CI, 173-265 days). The median time to progression was 126 days (95% CI, 49-165 days). Grade 3-4 toxicities occurred in 12 patients and included fatigue (33.3%), nausea, hand-foot syndrome (both 12.5%), anorexia (8.3%), vomiting, anemia and neutropenia (all 4.2%). The capecitabine and interferon alfa-2A combination has clinical activity and an acceptable toxicity profile in patients with metastatic renal cell carcinoma. The importance of adding capecitabine to interferon alfa needs to be confirmed in a randomized trial.

Anticancer Drugs. 2004 Oct;15(9):877-81.
Studies of synergistic and antagonistic combinations of conventional cytotoxic agents with the multiple eicosanoid pathway modulator LY 293111.
Budman DR, Calabro A.
Don Monti Division of Oncology, North Shore University Hospital, New York University, Manhasset, NY 11030, USA. budman@nshs.edu

The arachidonic acid metabolic pathway is currently under active investigation as a promoter of malignancy and several molecules have been synthesized to block either the cyclooxygenase or lipoxygenase branches. LY 293111 is an oral agent known to be a leukotriene B4 antagonist, a 5-lipoxygenase inhibitor and a peroxisome proliferator-activated receptor (PPAR)-gamma agonist with cytotoxic properties in cell lines. We have studied this agent with classical chemotherapeutic agents in a 72-h culture with cell lines using median-effect analysis as a measure of antagonism or synergy. LY 293111 displays global synergy with the active metabolite of irinotecan, SN-38, in the majority of cell lines, synergistic to additive effects with gemcitabine in bladder cancer cell lines, and synergism with 5'-DFUR (the active metabolite of capecitabine) in two breast cancer and one sarcoma cell line. These effects occur at clinically attainable concentrations. The addition of a proteosome inhibitor to the LY 293111 and SN-38 combination markedly enhanced the cytotoxic effects in the sarcoma cell line. As the toxicity of LY 293111 in man is not hematological, this agent may have a role in combination therapy of selected malignancies.

Med Oncol. 2004;21(3):223-31.
Capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer.
Lee SH, Lee J, Park J, Park SH, Lee KE, Lee SI, Nam E, Park JO, Kim K, Jung CW, Park YS, Yoon SS, Kang WK, Lee MH, Park K, Im YH.
Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul, 135-710, Korea.

The selection of chemotherapeutic regimens is challenging for metastatic breast cancer (MBC) patients whose diseases have failed to respond to anthracyline and taxane. Capecitabine has advantages of oral administration and favorable toxicity profiles. This study was conducted to evaluate the efficacy of capecitabine and to identify the subgroup of patients who would potentially have benefit from capecitabine monotherapy in patients with anthracycline- and taxane-pretreated MBC. Female patients with MBC who had been previously treated with anthracycline and taxane received oral capecitabine 2500 mg/m(2) divided in two doses daily for 2 wk with 1-wk rest period. Between September, 1999, and December, 2002, a total of 38 patients were enrolled. Among the 36 evaluable patients, one patient achieved a complete response (CR), 9 patients had partial responses (PRs), and 13 patients had stable diseases (SDs). Response rate was 26% [95% confidence interval (CI), 12-40%] and the tumor control rate (TCR, CR+PR+SD) was 61% (95% CI, 45-77%). The median follow-up duration was 27.8 mo. The median duration of response was 8.9 mo, the median time to progression was 4.6 mo, and the median overall survival was 18.1 mo. The major toxicities were hand-foot syndrome, diarrhea, and emesis. There was no treatment-related death. The predictors of better overall survival were positivity of hormone receptor, disease-free survival longer than 1 yr, non-refractoriness to anthracycline, and fewer number (<or= 3) of involved organs. Capecitabine monotherapy is effective and well tolerated for MBC patients who had previously been treated with anthracycline and taxane. The TCR could predict overall survival as well as the objective response in this study, suggesting a possible role of TCR as a surrogate marker for survival in MBC patients on salvage chemotherapy. The patients who have relatively slow growing tumor and less tumor burden could have benefit from capecitabine monotherapy following anthracycline- and taxane-based chemotherapy.

Int J Cancer. 2004 Oct 20;112(1):135-42.
Anti-metastatic effect of capecitabine on human colon cancer xenografts in nude mouse rectum.
Ninomiya I, Terada I, Yoshizumi T, Takino T, Nagai N, Morita A, Fushida S, Nishimura G, Fujimura T, Ohta T, Miwa K.
Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa Japan. nino@surg2m.kanazawa-u.ac.jp

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FU) by 3 sequential steps of enzyme reactions. We investigated the possibility of using capecitabine to prevent metastasis with a metastasis model of gastrointestinal cancer developed by the intrarectal injection of green fluorescent protein (GFP)-expressing colon cancer HT-29 cells (HT-29-GFP) into nude mice. Lung and lymph node metastasis in the HT-29-GFP rectal xenograft was assessed through both observation of GFP fluorescence and quantification of metastasis by amplification of a cancer-related human DNA by TaqMan PCR. Furthermore, for each organ, we examined mRNA levels of cancer-specific thymidine phosphorylase (dThdPase), which is an essential enzyme for capecitabine activation, by the quantitative RT-PCR method. Capecitabine inhibited the HT-29-GFP xenograft growth by 60.8% and 43.8% in the subcutaneous and rectal xenograft models, respectively. Furthermore, it inhibited both lung and lymph node metastasis by 99.9%. dThdPase expression in the tumor cells of both the rectal xenograft and metastatic lung tumor cells was upregulated by 10.0- and 24.3-fold that in the HT-29-GFP cells in vitro, respectively. These results indicated that capecitabine might effectively inhibit or suppress metastasis via upregulation of dThdPase expression. Capecitabine administration might be highly expected to reduce metastasis and improve survival of patients with gastrointestinal cancers.

Anticancer Res. 2004 May-Jun;24(3b):2085-91.
Combination chemotherapy with docetaxel and doxifluridine showed a beneficial outcome in advanced or recurrent breast cancer patients with longer disease-free interval.
Nishimura R, Tominaga T, Mitsuyama S, Aoyama H, Asaga T, Ohno S, Okuyama N, Kimura M, Iwase H, Kanda K, Koga T, Shiba E, Ikeda T.
Department of Surgery, Kumamoto City Hospital, 1-1-60 Kotoh, Kumamoto 862-8505, Japan. j_nishimura2002@yahoo.co.jp

Fundamental studies have confirmed that combination chemotherapy with docetaxel and doxifluridine (a capecitabine metabolite) is very useful in the treatment of breast cancer. This study investigated the usefulness and tolerability of a combination chemotherapy consisting of docetaxel administration on day 8 of doxifluridine therapy in 40 advanced/recurrent breast cancer patients. The overall response rate was 41.0% in 39 eligible patients. The median time to progression (TTP) for all patients was 295 days. Many responders had lung metastasis, soft tissue metastasis or a good performance status, whereas the clinical response showed no correlations with the estrogen receptor status or prior treatment with an anthracycline. The most common hematological toxicities were leukopenia and neutropenia, but dose reduction or delay of administration of either drug was unnecessary. CONCLUSION: The good response rate and long TTP of this doxifluridine plus docetaxel regimen indicate its potential as a first- or second-line treatment for advanced/recurrent breast cancer patients.

Cancer. 2004 Aug 1;101(3):578-86.
Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma.
Patt YZ, Hassan MM, Aguayo A, Nooka AK, Lozano RD, Curley SA, Vauthey JN, Ellis LM, Schnirer II, Wolff RA, Charnsangavej C, Brown TD.
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. yzpatt@umm.edu

BACKGROUND: The goal of the current study was to evaluate the efficacy and toxicity of capecitabine in patients with nonresectable hepatobiliary carcinoma. METHODS: The authors performed a retrospective analysis of all patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), or gallbladder carcinoma (GBC) who were ever treated with oral capecitabine. The medical records of 116 patients with hepatobiliary carcinoma who were treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between July 1998 and March 1999 were reviewed. RESULTS: A total of 63 patients were treated with capecitabine (37 with HCC, 18 with CCA, 8 with GBC). Capecitabine 1000 mg/m(2) was administered twice daily for 14 days. Treatment was repeated every 21 days. Each patient received 1-15 treatment cycles. Nine patients (14%)-11% of patients with HCC, 6% of patients with CCA, and 50% of patients with GBC-had either a complete response (CR) or a partial response. A CR was radiologically confirmed in one patient with HCC and in two patients with GBC. The median survival times were 10.1 months (95% confidence interval [CI], 4.5-15.7 months) for patients with HCC, 8.1 months (95% CI, 7.4-8.9 months) for patients with CCA, and 9.9 months (95% CI, 4.4-15.4 months) for patients with GBC. The most common toxicity was hand-foot syndrome (37%). Grade 3 thrombocytopenia occurred in 8% of patients with HCC. No other significant toxicities were observed. For all patients, response to treatment was positively correlated with survival and decline in tumor markers. CONCLUSIONS: Capecitabine was found to be safe for patients with hepatobiliary carcinoma, including those with cirrhosis. The antitumor activity of single-agent capecitabine was most pronounced in patients with GBC, was modest in patients with HCC, and was poor in patients with CCA.