Capecitabine (Xeloda)/5FU

[Rich66]

Gan To Kagaku Ryoho. 2009 Jan;36(1):131-134.

[Pharmacokinetic Monitoring of 5-Fluorouracil May Improve the Clinical Benefit with an Individualized Regimen-A Case Report.]

[Article in Japanese]


Muneoka K, Shirai Y, Sasaki M, Kanda J, Wakai T, Asakura T, Wakabayashi H, Hatakeyama K.
Dept. of Surgery, Niitsu Medical Center Hospital.
Serum levels of 5-fluorouracil(5-FU)were measured in a patient receiving pharmacokinetic modulation chemotherapy( PMC), with 5-FU, as well as a combination of oxaliplatin and infusional 5-FU plus leucovorin(FOLFOX). A 77- year-old man presented with unresectable multiple hepatic metastases after abdominoperineal resection of rectal / carcinoma, and was successfully treated by PMC. The patient initially received infusional 5-FU at 750 mg/m(2) once a week, and showed a partial response. Serum 5-FU levels were higher at night, and the peak concentration of 5-FU was / 398 ng/mL. After 13 months of PMC, second-line chemotherapy with FOLFOX was initiated because new liver metastases had appeared. After 4 cycles of FOLFOX4, progression was observed, and the concentration profile of 5-FU / was measured. The area under the concentration vs. time curve(AUC ngxh/mL)was smaller with FOLFOX4 than with PMC, so the FOLFOX6 regimen was tried instead. The AUC increased and disease progression was suppressed. This case shows that individual adjustment of the dose and regimen based on pharmacokinetic monitoring can increase the clinical benefit of fluorouracil.
PMID: 19151579 [PubMed - as supplied by publisher]

Large Open-label Expanded Access Study Confirms Effectiveness of Tykerb® and Xeloda® in Metastatic HER2+ Breast Cancer

Researchers involved in the LEAP (Lapatinib Expanded Access Program) international trial have reported that Tykerb® (lapatinib) and Xeloda® (capecitabine) is effective and safe for the treatment of patients with HER2-positive (HER2+) over-expressing locally advanced or metastatic breast cancer who had previously failed treatment with an anthracycline, a taxane, and Herceptin® (trastuzumab). The details of this study appeared early online in the Annals of Oncology on October 8, 2009.[1]
Tykerb is an oral small molecule that targets both ErbB1 and ErbB2 tyrosine kinases. Tykerb has demonstrated activity in HER2-positive breast cancers and continues to be evaluated in different patient populations. Randomized trials have shown that Tykerb plus Xeloda is more effective than Xeloda alone in patients with HER2+ breast cancer who have failed treatment with an anthracycline, a taxane, and Herceptin. The current study was undertaken to determine if the results of Tykerb and Xeloda treatment hold up when evaluated in a broader population.
The current study was an open-label expanded access study involving 4,283 patients with HER2+ locally advanced or metastatic breast cancer treated in 45 countries. All had failed an anthracycline, a taxane, and Herceptin. The average treatment time was 25 weeks. The most common grade 3-4 side effects reported were diarrhea, vomiting, and nausea; all occurring with a frequency of <10%. Decreased left ventricle ejection fraction occurred in 0.5%, interstitial pneumonitis occurred in 0.2%, and serous hepatic problems in 0.4%. The median progression-free survival was 21 weeks, and the median overall survival was 39.6 weeks. Patients who had not been previously treated with Xeloda had longer survivals.
Comment: This large study validates the results of randomized trials showing improvement of progression-free and overall survival with acceptable toxicity following treatment with Tykerb and Xeloda compared with Xeloda alone.
Reference:
[1] Capri G, Chang J, Chen S-C, et al. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Annals of Oncology [early online publication] 2009; on October 8.

Sorafenib (Nexavar)

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October 22, 2009
ONCOLOGY. Vol. 23 No. 11 Research Reports
Sorafenib Plus Chemotherapy Significantly Prolongs Progression-Free Survival in Advanced Breast Cancer

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Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc, announced the full results from their first collaborative group-sponsored randomized, double-blind, placebo-controlled phase II trial showing that sorafenib (Nexavar) tablets in combination with the oral chemotherapeutic agent, capecitabine (Xeloda), significantly extended progression-free survival in patients with advanced breast cancer. The data were presented at the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress in Berlin.
74% Improvement
Jose Baselga, MD, chairman and professor of medicine at Vall d’Hebron Institute of Oncology in Barcelona, scientific chairman of the Spanish Breast Cancer Cooperative Group SOLTI and the principal investigator of this study, reported that patients receiving sorafenib plus capecitabine had a 74% improvement in the time they lived without their disease progressing compared to those who received the chemotherapy alone. The difference in median progression-free survival with sorafenib plus capecitabine vs capecitabine plus placebo was statistically significant, 6.4 vs 4.1 months (hazard ratio = 0.576, P = .0006).
“Onyx and Bayer have built a strong foundation with Nexavar in treating unresectable liver cancer and advanced kidney cancer—both disease areas with a previously unmet treatment need,� said Todd Yancey, md, vice president of clinical development at Onyx. “These new results signify another step in understanding the potential role of Nexavar in breast cancer.�
Breast Cancer Trial Design
The randomized, double-blind, placebo-controlled phase II study evaluated sorafenib in combination with capecitabine in 229 patients with locally advanced or metastatic HER2-negative breast cancer. These patients had received no more than one prior chemotherapy in this setting. The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, time to progression, and safety. Patients were randomized to receive 400 mg of oral sorafenib or matching placebo twice daily, in addition to 1,000 mg/m² of capecitabine twice daily for 14 days followed by a 7-day rest from capecitabine.
Overall, treatment with sorafenib plus capecitabine was tolerable and resulted in no new side effects. Common grade 3 or 4 treatment-related adverse events included hand-foot skin reaction, diarrhea, dyspnea, neutropenia and mucositis.

Anticancer Drugs. 2010 Jan 13. [Epub ahead of print]
Oral combination chemotherapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: A phase II study.

Tanaka M, Takamatsu Y, Anan K, Ohno S, Nishimura R, Yamamoto Y, Masuda N, Mitsuyama S, Tamura K; the Kyushu Breast Cancer Study Group (KBCSG).
aDepartment of Surgery, Social Insurance Kurume Daiichi Hospital bDivision of Medical Oncology, Hematology and Infectious Disease, Department of Medicine, Fukuoka University Hospital cDepartment of Surgery, Kitakyushu Municipal Medical Center dDepartment of Surgery, National Kyushu Cancer Center eDepartment of Breast and Endocrine Surgery, Kumamoto City Hospital fDepartment of Breast Surgery, Kumamoto University Hospital gDepartment of Surgery, Osaka National Hospital, Japan.
Capecitabine (Xeloda, X) and cyclophosphamide (C) can be given orally and they have synergistic effects with nonoverlapping toxicities in preclinical studies. A phase I study of the XC combination therapy was conducted in patients with metastatic breast cancer (MBC) and determined the recommended dose and schedule of 1657 mg/m/day capecitabine and 65 mg/m/day cyclophosphamide given orally for 2 weeks at a 3-week interval. A phase II study of the oral XC regimen was then conducted. This study enrolled patients with HER2-negative MBC who were earlier treated with anthracyclines. XC was given at the recommended doses on a 3-week schedule for at least six courses unless disease progression or unacceptable toxicities occurred. The primary endpoint was the response rate. Progression-free survival, overall survival, and adverse events were investigated as secondary endpoints. Forty-eight patients with the median age of 58 (range 32-72 years) years were registered. Three patients withdrew by choice before starting the treatment. A complete response was obtained in two of the 45 evaluable patients, and partial response in 14, resulting in an overall response rate of 35.6%. The median progression-free survival and overall survival were 199 (115-231) days and 677 (437 approximately ) days, respectively. Grade 3 neutropenia and leukopenia developed in 11%, and that of anemia and thrombocytopenia in 2% patients. Nonhematological toxicities were mild. Hand--foot syndrome was observed in 14 patients but no one had grade 3-4 toxicity. Oral XC combination is effective with acceptable toxicities in patients with MBC.

PMID: 20075712 [PubMed - as supplied by publisher]


Ann Oncol. 2009 Nov 25. [Epub ahead of print]
Gemcitabine and capecitabine in previously anthracycline-treated metastatic breast cancer: a multicenter phase II study (SOLTI 0301 trial).

Ciruelos EM, Cortés J, Cortés-Funes H, Mayordomo JI, Bermejo B, Ojeda B, GarcÃ*a E, RodrÃ*guez CA, Muñoz M, Gómez P, Manso L, Andrés R, Lluch A, Saura C, Mendiola C, Baselga J.
Medical Oncology Department, University Hospital 12 de Octubre, Madrid.
BACKGROUND: On the basis of clinical activity of capecitabine and gemcitabine for metastatic breast cancer, we carried out a multicenter phase II clinical trial on the combination of these two agents in advanced anthracycline-pretreated breast cancer patients. Main objectives were to assess its efficacy and safety profile. PATIENTS AND METHODS: Seventy-six anthracycline-pretreated breast cancer patients were evaluated and were stratified according to previous treatment of advanced disease (group-1: not previously treated and group-2: previously treated). Study treatment consisted of gemcitabine 1000 mg/m(2), i.v., as 30 min-infusion, days 1 and 8 every 21 days, plus oral capecitabine 830 mg/m(2) b.i.d., days 1-14 every 21 days. RESULTS: Overall response rate was 61% for group-1, 48.5% for group-2 and 55.2% for the whole population. Clinical benefit rate was 73% for group-1, 80% for patients in group-2 and 76% for all patients. Median time to progression was 13.0 months for group-1, 8.2 months for group-2 and 11.1 months for the whole population. Most frequent grade 3-4 observed toxic effects per patient were neutropenia (60%), asymptomatic liver toxicity (13.5%), asthenia (14%) and hand-foot syndrome (16%). Only one patient presented febrile neutropenia. No treatment-related deaths occurred. CONCLUSION: Combination of gemcitabine and capecitabine is an active and safe regimen in anthracycline-pretreated breast cancer patients.

PMID: 19940004 [PubMed - as supplied by publisher]

Acta Oncol. 2009 Oct 20. [Epub ahead of print]
Gemcitabine and capecitabine in combination for advanced anthracycline and taxane pre-treated breast cancer patients: A phase II study.

Malmström A, Hansen J, Malmberg L, Carlsson L, Svensson JH, Ahlgren J, Ahlin C, Jansson T, Westberg R.
Unit of Advanced Palliative Home Care, Linköping University Hospital, Sweden.
Aim. The aim of this study was to explore the clinical value of gemcitabine combined with capecitabine (GC) in heavily pre-treated patients with metastatic breast cancer. Material and methods. All patients had failed anthracyclines and taxanes. In 14 patients (41%), more than two metastatic sites were diagnosed with bone (68%) and liver (62%) being the most prominent. chemotherapy for metastatic disease. Laboratory tests were done on day 1+8 in cycles. Subjective toxicity was recorded according to the NCI-CTC v. 2.0 criteria. Tumour evaluations were done every 12th week according to the RECIST criteria. The primary objective was to investigate time to progression. Secondary objectives were response rate with special focus on the proportion of patients achieving PR or SD of at least three months, toxicity and survival. Results. Gemcitabine (1 250 mg/m(2), d1+8) and capecitabine (800 mg/m(2) twice daily, d1-14) were administered according to a 3-week schedule. The majority of patients received GC as 3rd or 4th lineA total of 34 patients were enrolled. All subjects are eligible for toxicity, response and time to event analyses. Treatment was given until progressive disease, severe toxicity or until the patient wanted to withdraw. The Kaplan-Meier median time to progression was estimated to 4.3 months and the overall survival time to 13.7 months. Partial response was noted in 12 of 29 evaluable patients (41%). The best outcome amongst remaining patients was stable disease in nine (31%) or tumour progression in eight (28%). A delay of disease progression of more than three months was noted in 53% of the study population. The main side effect was granulocytopenia with 44% and 15% of patients suffering from grade 3 or grade 4 events respectively however, no neutropenic infections were observed. Pre-dominant grade 3 subjective toxicities were: fatigue (21% of patients) and hand-foot syndrome (15% of patients). Discussions. We investigated the value of the GC combination as a treatment for late stage breast cancer patients. Tumour progression was delayed and the treatment was well tolerated. We believe that the GC therapy can achieve meaningful palliation.

PMID: 19839920 [PubMed - as supplied by publisher]

1: Anticancer Res. 2009 Feb;29(2):667-70.

A phase II trial of oral vinorelbine and capecitabine in anthracycline pretreated patients with metastatic breast cancer.

Finek J, Holubec L Jr, Svoboda T, Sefrhansova L, Pavlikova I, Votavova M, Sediva M, Filip S, Kozevnikova R, Kormunda S.
University Hospital Pilsen, Czech Republic. finek@fnplzen.cz
BACKGROUND: Optimal chemotherapy (CT) for advanced breast treatment should be effective, well tolerated and convenient. In this study the efficacy and safety of the fully oral combination of oral vinorelbine (Navelbine Oral) plus capecitabine (Xeloda) in metastatic breast cancer (MBC) patients pretreated with anthracycline, was evaluated. PATIENTS AND METHODS: In this phase II multicenter study, this combination CT was given as a first- or second-line therapy for MBC. The treatment schedule was: oral vinorelbine 60 mg/m2 day 1 and day 8 plus capecitabine 1,000 mg/m2 twice daily from day 1 to day 14, every 21 days. RESULTS: One hundred and fifteen patients were included in this trial. The median age was 58 years (range: 40-75). All the patients had received prior anthracycline-based chemotherapy. The combination was well tolerated, with, in particular, only 0.8% of patients presenting with febrile neutropenia. In the intention-to-treat (ITT) population, an objective response was achieved in 65 patients (56.5%). A complete response was achieved in 22 patients (19.1%); partial response in 43 patients (37.4%); stable disease in 36 patients (31.3%), and progressive disease was observed in 14 patients (12.2%). After a median follow-up of 10.0 months, the median progression-free survival (PFS) was 10.5 months and the median survival was 17.5 months. CONCLUSION: Oral vinorelbine-capecitabine shows very promising activity and low toxicity in MBC treatment, with high compliance of the patients.

PMID: 19331218 [PubMed - indexed for MEDLINE

Anticancer Drugs. 2009 Mar;20(3):204-7.
Low-dose capecitabine plus docetaxel as first-line therapy for metastatic breast cancer: phase II results.

Michalaki V, Gennatas S, Gennatas K.
Oncology Clinic Department of Surgery, Areteion Hospital, University of Athens, Athens, Greece.
The addition of capecitabine to docetaxel significantly improves overall survival in anthracycline-pretreated metastatic breast cancer. We evaluated a low-dose capecitabine-docetaxel regimen as first-line therapy. Patients who had received adjuvant anthracyclines received docetaxel 75 mg/m2 on day 1 and capecitabine 950 mg/m2 twice daily, days 1-14, every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was time to progression. Forty-five patients were evaluable (median age 56 years, range 35-75). The response rate was 42%, including two complete responses. Nine patients (20%) attained stable disease. Median time to progression was 8 months and median overall survival was 23 months. Five patients (11%) experienced grade 3 neutropenia but febrile neutropenia was absent. Three patients (7%) experienced grade 3 hand-foot syndrome; there was no significant gastrointestinal toxicity. This capecitabine-docetaxel regimen is an active first-line therapy and appears better tolerated than regimens using a higher capecitabine dose. Data from the randomized trial comparing the registered versus a lower capecitabine dose, both in combination with docetaxel, should definitively answer whether a lower dose provides a better safety profile while maintaining the considerable efficacy of this combination.

PMID: 19174694 [PubMed - indexed for MEDLINE]

Surg Today. 1999;29(2):149-56.
Effects of experimental chemoendocrine therapy with a combination of a pure antiestrogen and 5-fluorouracil on human breast cancer cells implanted in nude mice.

Ogasawara Y, Doihara H, Shiroma K, Kanaya Y, Shimizu N.
Department of Surgery II, Okayama University Medical School, Japan.
The antitumor effects of an experimental chemoendocrine therapy combining a new pure antiestrogen ICI 182780 and 5-fluorouracil (5-FU) were studied on MCF-7 human breast cancer cells implanted in nude mice. ICI 182780 had a dose-dependent antitumor activity, which was potentiated by the concomitant use of 5-FU. When compared with the control group, the estrogen receptor (ER) level in the ICI 182780 group was lower and that in the combination group was markedly lower. Cell cycle analysis by flow cytometry (FCM) resulted in a lower percentage of S-phase cells (%S) in the treated mice. No significant difference was observed in the 5-FU concentrations in tumor cells, while the 5-FU content in RNA was significantly higher in the combination group. The changes in free thymidylate synthetase (TS) concentration indicated TS synthesis after the administration of 5-FU to be more greatly suppressed in the combination group than in the 5-FU group. These results suggest that ICI 182780 and 5-FU exert their combination effect mainly on ER-positive cells, and that the suppression of TS synthesis in tumor cells and the potentiation of the 5-FU-induced metabolic dysfunction of RNA are thus involved in the mode of action of this combination therapy.

PMID: 10030740 [PubMed - indexed for MEDLINE]





http://www.springerlink.com/content/9n75721824648854/

Cancer Chemother Pharmacol. 2009 May 20. [Epub ahead of print]
Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer.

Kurebayashi J, Nukatsuka M, Sonoo H, Uchida J, Kiniwa M.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan, kure@med.kawasaki-m.ac.jp.
PURPOSE: Our previous study indicated that concurrent administration of 4-OH-tamoxifen (TAM) and 5-fluorouracil (5-FU), but not doxorubicin (Dox), resulted in additive antitumor effects on endocrine-responsive breast cancer cells. We further clarified the effects of combined administration of endocrine therapy with chemotherapeutic agents in this study. METHODS: Concurrent treatment with 4-OH-TAM and paclitaxel (Ptx) was investigated in estrogen receptor (ER)-positive breast cancer cells. Additionally, the combined effects of estrogen depletion from culture medium mimicking estrogen ablative therapy with 5-FU, Dox, and Ptx were investigated. RESULTS: Concurrent treatment with 4-OH-TAM and Ptx yielded less than additive antitumor effects in ER-positive breast cancer cells, as observed with Dox in our previous study. More interestingly, estrogen depletion with 5-FU, but with neither Dox nor Ptx, yielded additive antitumor effects on these cells. We also performed preliminary experiments to elucidate the mechanisms of action responsible for the combined antitumor effects observed. Ptx up-regulated the level of expression of one of the molecules related to TAM resistance, Eph-A2, as observed with Dox in our previous study. Estrogen depletion down-regulated the level of expression of one of the molecules related to 5-FU resistance, thymidylate synthase, as observed with 4-OH-TAM in our previous study. CONCLUSIONS: These findings, together with those of our previous study, suggest that concurrent treatment with endocrine therapy, administration of TAM, or estrogen ablative therapy and 5-FU but neither Dox nor Ptx may yield additive antitumor effects on endocrine-responsive breast cancer.

PMID: 19455332 [PubMed - as supplied by publisher]




Cancer Chemother Pharmacol. 2007 Mar;59(4):515-25. Epub 2006 Aug 10.
Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells.

Kurebayashi J, Nukatsuka M, Nagase H, Nomura T, Hirono M, Yamamoto Y, Sugimoto Y, Oka T, Sonoo H.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. kure@med.kawasaki-m.ac.jp
PURPOSE: The sequential addition of tamoxifen (TAM) to chemotherapy seems superior to its concurrent addition in patients with breast cancer. This study was conducted to clarify the hypothesis that there are differential interactions among TAM and chemotherapeutic agents. METHODS: Estrogen receptor (ER)-alpha-positive or -negative breast cancer cells were treated with 4-hydroxy TAM (4OHT), 5-fluorouracil (FU) and/or doxorubicin (Dox). Changes in the expression levels of genes related to sensitivity and resistance to TAM, 5-FU or Dox were tested. RESULTS: Concurrent treatment of 4OHT with 5-FU but not with Dox additively inhibited the growth of ER-alpha-positive cells. 5-FU did not change the expression levels of any tested genes related to either sensitivity or resistance to TAM. Although Dox did not change the expression levels of any genes related to the sensitivity to TAM, Dox significantly increased the expression levels of some genes related to TAM resistance, Eph A-2, ER-beta, Fos and vascular endothelial growth factor. 4OHT significantly decreased thymidilate synthase (TS) activity. CONCLUSIONS: Although the antitumor effect of concurrent 4OHT and 5-FU was additive, that of concurrent 4OHT and Dox was less than additive in ER-alpha-positive cells. The increased expression of genes related to TAM resistance by Dox might be responsible for the interaction. Decreased TS activity by 4OHT might increase the antitumor activity of 5-FU. These findings may provide a preclinical rationale for concurrent use with 5-FU and TAM.

PMID: 16900372 [PubMed - indexed for MEDLINE]



In vivo and in vitro efficacy of capecitabine (X) + tamoxifen (TAM) in breast cancer (BC)

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 21092

K. Mori, Y. Yamaguchi, N. Sawada, K. Kondoh and S. Hayashi Chugai Pharmaceutical Co, Kamakura, Japan; Saitama Cancer Center, Ina-machi, Japan; School of Medicine, Tohoku University, Sendai, Japan
21092
Background: In vitro studies in BC cell lines suggested antagonism between TAM and 5-FU. Thymidine phosphorylase (TP) activates X to 5-FU in tumors. X activity correlates with tumor TP concentrations in vivo. Methods: We studied antitumor efficacy of X + TAM in vivo and in vitro in human BC models. Nude mice were inoculated s.c. with estradiol, then MCF-7 cells 1 day later. When tumors were 300 mm³, mice received 6 weeks’ oral vehicle (control), X (d1–14 q21d) at MTD (539 mg/kg) or 2/3 MTD, and/or TAM at 100 or 30 mg/kg/d. We also analyzed impact of 5-FU and doxifluridine (5'-DFUR, an intermediate of X) + TAM on estrogen receptor (ER) signals in an in-vitro culture system. ER signals were monitored by expression of green fluorescent protein (GFP) in MCF-7 BC cells transfected with the estrogen-responsive element (ERE)-GFP gene (MCF-7-E10). GFP expression was induced in MCF-7-E10 cells in the presence of estradiol at 3 pM or BC tissue supernatant. Results: X at 2/3 MTD + TAM 30 mg/kg were significantly more active than the highest dose of X or TAM alone. Tumor TP concentrations were significantly higher in TAM- than vehicle-treated mice. In the ER signal system, GFP expression of MCF-7-E10 was reduced by 4-hydroxytamoxifen (4-OHT, active form of TAM) at 0.01 and 0.1 nM. When added to 4-OHT, 5-FU 0.3–30 µM or 5'-DFUR 3–10 µM reduced GFP expression more than either agent alone. In vitro, 5-FU and 5'-DFUR inhibited proliferation of MCF-7-E10 cells regardless of 4-OHT. Additive effects could not be confirmed as 4-OHT alone showed only marginal anti- proliferative activity at 0.01–0.1 nM. Conclusion: X and TAM are not antagonistic in this model. TAM may augment X activity via TP upregulation in BC tissues. TAM and X intermediates showed no clear antagonism in vitro in an ER signal system. All-oral X + TAM merits evaluation as combination therapy in breast cancer.

Drugs. 2003;63(2):217-36.
Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer.

Wagstaff AJ, Ibbotson T, Goa KL.
Adis International Limited, Mairanga Bay, Auckland, New Zealand. demail@adis.co.nz
Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1,250 mg/m(2) twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m(2) on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m(2) on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia).

PMID: 12515569 [PubMed - indexed for MEDLINE]


Cancer Chemother Pharmacol. 2010 Mar;65(4):755-63. Epub 2009 Aug 9.
Phase II study of oral vinorelbine in combination with capecitabine as second line chemotherapy in metastatic breast cancer patients previously treated with anthracyclines and taxanes.

Jones A, O'Brien M, Sommer H, Nowara E, Welt A, Pienkowski T, Rolski J, Pham ML, Perraud K, Trillet-Lenoir V.
Royal Free Hospital, Londres NW3 2QG, UK. alison.jones@royalfree.nhs.uk
PURPOSE: Effective treatment options for patients with metastatic breast cancer (MBC) resistant/refractory to anthracyclines and/or taxanes are limited. Intravenous and oral combination of vinorelbine (VRL) and capecitabine were shown to be feasible and effective in first-line MBC. In order to evaluate the activity of the combination of an all oral regimen in a more advanced setting, we investigated a regimen combining oral VRL and capecitabine in a phase II study as second-line chemotherapy of MBC patients previously treated with anthracyclines and taxanes. PATIENTS AND METHODS: Forty patients (median age 52 years) with MBC received the combination of oral VRL 60 mg/m(2) on days 1, 8 and 15 plus capecitabine 1,000 mg/m(2) bid given from day 1 to day 14 in an open-label, international, multicentre, phase II study. Cycles were repeated every 3 weeks. The primary endpoint was response rate (RR) evaluated by an independent panel review. Secondary objectives included safety, duration of response, progression-free survival, overall survival and quality of life. RESULTS: All the patients had received prior chemotherapy with anthracyclines and taxanes, 75% were refractory/resistant to anthracycline and/or taxane, 72.5% presented with visceral involvement and the last prior chemotherapy for 87.5% of the patients was for advanced disease setting. The median number of administered cycles per patient was 4 (range 1-31). Eight responses were documented and validated by an independent panel review, yielding RRs of 20% [95% CI: 9-35.6] in the intent-to-treat (treated) population and 23.5% [95% CI: 10.7-41.2] in the 34 evaluable patients. Median progression-free survival and median overall survival were 3.4 months [95% CI: 2.3-5.5] and 11.3 months [95% CI: 8.1-16.4], respectively. The principal toxicities were anaemia, neutropenia (rarely complicated; only one patient experienced febrile neutropenia), fatigue and gastrointestinal toxicities with very few grade 3-4 non-haematological toxicities. CONCLUSIONS: In second-line treatment of MBC patients previously treated with anthracyclines and taxanes, oral VRL plus capecitabine is a safe regimen with an efficacy comparable to the other available combination regimens used in this heavily and resistant/refractory (75% of patients) pre-treated patients' population. Moreover, this well-tolerated combination offers the advantages of an all oral regimen.

PMID: 19669644 [PubMed - in process]





Cancer Biol Ther. 2008 Aug;7(8):1305-12. Epub 2008 Aug 16.
Resveratrol displays converse dose-related effects on 5-fluorouracil-evoked colon cancer cell apoptosis: the roles of caspase-6 and p53.

Chan JY, Phoo MS, Clement MV, Pervaiz S, Lee SC.
National University Medical Institute, National University of Singapore, Singapore.
Comment in:

• Cancer Biol Ther. 2008 Aug;7(8):1313-4.

We have reported that resveratrol (RSV) evoked apoptosis through caspase-6 activation in HCT116 human colon cancer cells wild-type (p53+/+) or knockout (p53-/-) for p53. In this study, the role of caspase-6 activation in 5-fluorouracil (5-FU)-elicited apoptosis as well as the combination effects between RSV and 5-FU on their apoptosis induction was further investigated in the same colon cancer cell model. The combination effects were determined by calculation of combination indices (CI). We found that 5-FU triggered apoptosis and caspase-6 activation in the cancer cells, which were entirely abrogated by caspase-6 inhibitors. RSV (200 microM) increased 5-FU-triggered apoptosis and caspase-6 activation. Lower doses (25 or 50 microM) inhibited 5-FU-mediated apoptosis and caspase-6 activation only in p53+/+ cells. Moreover, G(1)-arrest of the p53+/+ cells was elicited by lower doses of RSV and 5-FU in combination, but not with either agent alone. RSV (200 microM) interacted with 5-FU in a synergistic manner (mean CI < 0.9). At lower doses (25 or 50 microM), it interacted with 5-FU in antagonistic (mean CI > 1.1) and additive manners (0.9 < mean CI < 1.1) in p53+/+ and p53-/- cells respectively. In conclusion, our results suggest that, like RSV, 5-FU triggers the cancer cell apoptosis by activating caspase-6. Their combination effect in apoptosis induction is dependent on the concentration of RSV and is mediated by caspase-6 activation. RSV synergistically promotes 5-FU-mediated apoptosis at its higher concentration irrespective of p53. Conversely, it inhibits 5-FU-triggered apoptosis at lower concentrations in p53+/+ cells.

PMID: 18497562 [PubMed - indexed for MEDLINE]




Breast Cancer. 2009 Sep 30. [Epub ahead of print]
Impact of prophylactic pyridoxine on occurrence of hand-foot syndrome in patients receiving capecitabine for advanced or metastatic breast cancer.

Yoshimoto N, Yamashita T, Fujita T, Hayashi H, Tsunoda N, Kimura M, Tsuzuki N, Yamashita H, Toyama T, Kondo N, Iwata H.
Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan, paris@s4.dion.ne.jp.
BACKGROUND: Capecitabine, an oral fluoropyrimidine, has shown consistently high efficacy in anthracycline- and/or taxane-pretreated advanced and metastatic breast cancer. The safety profile of capecitabine is characterized by hand-foot syndrome (HFS), which, although not life threatening, can impair patients' quality of life if it is not managed promptly and effectively. We conducted a study to assess the impact of prophylactic pyridoxine on HFS. METHODS: Prophylactic pyridoxine was given to 38 patients receiving capecitabine (alone or in combination with cyclophosphamide) for metastatic breast cancer and compared with historical data from 40 patients receiving capecitabine without pyridoxine in our clinic. The impact of urea ointment on HFS was also assessed. RESULTS: HFS developed in 20 patients (52.6%) receiving pyridoxine compared with historical data showing an 82.5% rate in patients receiving no pyridoxine prophylaxis (p < 0.01). A nonsignificant trend towards less severe HFS was seen among patients who received urea ointment at first appearance of symptoms. In addition, nonsignificant trends towards higher rates of HFS were seen among those who were >/=61 years and those who derived clinical benefit (clinical response or stable disease). CONCLUSIONS: Prophylactic pyridoxine and urea ointment at first appearance of symptoms appears to reduce the risk of severe capecitabine-induced HFS. However, randomized data are required to determine the true effect of these measures.

PMID: 19789949 [PubMed - as supplied by publisher]