[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) October 22, 2009
ONCOLOGY. Vol. 23 No. 11 Research Reports Sorafenib Plus Chemotherapy Significantly Prolongs Progression-Free Survival in Advanced Breast Cancer
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, Garc*a E, Rodr*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.
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 antagonismbetween TAM and 5-FU. Thymidine phosphorylase (TP) activatesX to 5-FU in tumors. X activity correlates with tumor TP concentrationsin vivo. Methods: We studied antitumor efficacy of X + TAM invivo and in vitro in human BC models. Nude mice were inoculateds.c. with estradiol, then MCF-7 cells 1 day later. When tumorswere 300 mm3, mice received 6 weeks’ oral vehicle (control),X (d1–14 q21d) at MTD (539 mg/kg) or 2/3 MTD, and/or TAMat 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 monitoredby expression of green fluorescent protein (GFP) in MCF-7 BCcells transfected with the estrogen-responsive element (ERE)-GFPgene (MCF-7-E10). GFP expression was induced in MCF-7-E10 cellsin the presence of estradiol at 3 pM or BC tissue supernatant.Results:X at 2/3 MTD + TAM 30 mg/kg were significantly moreactive than the highest dose of X or TAM alone. Tumor TP concentrationswere significantly higher in TAM- than vehicle-treated mice.In the ER signal system, GFP expression of MCF-7-E10 was reducedby 4-hydroxytamoxifen (4-OHT, active form of TAM) at 0.01 and0.1 nM. When added to 4-OHT, 5-FU 0.3–30 µM or 5'-DFUR3–10 µM reduced GFP expression more than eitheragent alone. In vitro, 5-FU and 5'-DFUR inhibited proliferationof MCF-7-E10 cells regardless of 4-OHT. Additive effects couldnot be confirmed as 4-OHT alone showed only marginal anti- proliferativeactivity at 0.01–0.1 nM. Conclusion: X and TAM are notantagonistic in this model. TAM may augment X activity via TPupregulation in BC tissues. TAM and X intermediates showed noclear 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.
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]
J Clin Oncol. 2005 Feb 1;23(4):792-9. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.
Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS.
Indiana University, Indianapolis, IN, USA. kathmill@iupui.edu
PURPOSE: This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. PATIENTS AND METHODS: Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. The primary end point was progression-free survival (PFS), as determined by an independent review facility. RESULTS: From November 2000 to March 2002, 462 patients were enrolled. Treatment arms were balanced. No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment--Breast were comparable in both treatment groups. CONCLUSION: Bevacizumab was well tolerated in this heavily pretreated patient population. Although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.
PMID: 15681523 [PubMed - indexed for MEDLINE]
Gastrointest Cancer Res. 2009 Jul;3(4):134-40. Safety of chronic low-dose capecitabine as maintenance therapy in gastrointestinal cancers.
Sun JF, Wu RR, Norris C, Noone AM, Amankwa-Sakyi M, Slack R, Marshall JL.
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
BACKGROUND: Maintenance chemotherapy is not routinely used in gastrointestinal (GI) cancers. Capecitabine is an oral formulation that is enzymatically converted to 5-fluorouracil preferentially in tumor tissue. We hypothesize that capecitabine could be used as a long-term maintenance therapy to improve outcomes in patients with high-risk GI cancers following standard chemotherapy regimens. METHODS: We conducted a retrospective study to assess the toxicity of maintenance capecitabine in 28 patients with a variety of advanced GI malignancies. Capecitabine 1,000 mg twice daily without interruption was used for the first 11 patients. The dose was reduced to 1,000 mg twice daily 5 days per week in 8 patients who developed hand-foot syndrome. The remaining patients began treatment on the same abbreviated schedule. All documented clinical adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (v3.0, 2003). RESULTS: Main toxicities were grade 1/2 fatigue and hand-foot syndrome. Only one grade 3 toxicity was observed and no grade 4 toxicities were seen. We also observed a significant increase in red blood cell mean corpuscular volume in participants, which may have potential use as a biomarker to monitor therapeutic response. CONCLUSIONS: Fixed therapeutic doses of oral capecitabine 1,000 mg twice daily, 5 days on, 2 days off, can be administered chronically with a high level of safety and should be explored in larger prospective studies to demonstrate efficacy in GI malignancies, especially pancreatic and metastatic colorectal cancers.
PMID: 19742139 [PubMed - in process]
Capecitabine: Have We Got the Dose Right?
Factors that influence metabolism and toxicity of Capecitabine/Xeloda
This Review summarizes why there may indeed not be a universally applicable starting dose for capecitabine because of interpatient differences in basic physiology, pharmacogenomics and diet. This article also explores which of these factors contribute to the observed inter-regional geographical variation in capecitabine toxicity, and explains why even within a region various factors should prompt a clinician to modify the starting dose.
Sidebar: Key Points
Capecitabine is an oral fluoropyrimidine prodrug that is selectively converted within cancer cells to the active drug 5-fluorouracil.
Clinical trials have indicated that capecitabine is a safe and useful alternative to 5-fluorouracil in the treatment of solid tumors, especially when there is a desire to avoid the use of indwelling venous catheters
The starting dose of capecitabine varies in different regions of the world
Individual patient exposure to capecitabine and its active metabolites will depend upon a number of factors including age, sex, body weight, hepatorenal function, concomitant drug exposure, pharmacogenetic imprinting, and dietary folate intake.
Individual clinicians should attempt to consider as many of these factors as possible before selecting an appropriate dose of capecitabine for their patients.
BMC Cancer. 2009 Dec 17;9:446. Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma.
Moen I, Tronstad KJ, Kolmannskog O, Salvesen GS, Reed RK, Stuhr LE.
Department of Biomedicine, University of Bergen, Bergen, Norway. ingrid.moen@biomed.uib.no
BACKGROUND: Hypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen) has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. The aim of this study was to elucidate whether hyperoxia also enhances any actual uptake of 5FU (5-fluorouracil) into the tumor tissue and if this can be explained by changes in the interstitium and extracellular matrix. METHODS: One group of tumor bearing rats was exposed to repeated hyperbaric oxygen (HBO) treatment (2 bar, pO(2)= 2 bar, 4 exposures * 90 min), whereas one group was exposed to one single identical HBO treatment. Animals housed under normal atmosphere (1 bar, pO(2) = 0.2 bar) served as controls. Three doses of 5FU were tested for dose response. Uptake of [3H]-5FU in the tumor was assessed, with special reference to factors that might have contributed, such as interstitial fluid pressure (Pif), collagen content, oxygen stress (measured as malondialdehyd levels), lymphatics and transcapillary transport in the tumors. RESULTS: The uptake of the cytostatic agent increases immediately after a single HBO treatment (more than 50%), but not 24 hours after the last repeated HBO treatment. Thus, the uptake is most likely related to the transient increase in oxygenation in the tumor tissue. Factors like tumor Pif and collagen content, which decreased significantly in the tumor interstitium after repeated HBO treatment, was without effect on the drug uptake. CONCLUSION: We showed that hyperoxia increases the uptake of [3H]-5FU in DMBA-induced mammary tumors per se, independently of changes in Pif, oxygen stress, collagen fibril density, or transendothelial transport alone. The mechanism by which such an uptake occur is still not elucidated, but it is clearly stimulated by elevated pO(2).
PMID: 20017908 [PubMed - in process]
Breast Cancer. 2009;16(1):88-92. Epub 2008 May 14. Successful treatment of leptomeningeal metastases from breast cancer using the combination of trastuzumab and capecitabine: a case report.
Shigekawa T, Takeuchi H, Misumi M, Matsuura K, Sano H, Fujiuchi N, Okubo K, Osaki A, Aogi K, Saeki T.
Department of Breast Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan. takshige@saitama-med.ac.jp
We report a case of metastatic breast cancer with leptomeninges and multiple bone metastases that showed an excellent response to the combination of trastuzumab and capecitabine; therapeutic effect was evaluated by MRI at follow-up. A 44-year-old woman underwent modified radical mastectomy in February 1997. In April 2003, a tumor at the right basis cerebri and multiple bone metastases were noted, and in October 2003, she underwent enucleation of the tumor. Histopathologically, the tumor was consistent with a basal skull metastasis from breast cancer. In March 2004, the patient began to experience pain, weakness, and paresthesia of both legs. She was diagnosed, with leptomeningeal metastasis (LM) from breast cancer using MRI. In December 2005, the combination of trastuzumab and capecitabine administered as sixth-line treatment was very effective for LM. Although it is generally very difficult to diagnose LM and assess the therapeutic effect with MRI, in this case, it was possible. To our knowledge, there has been no report in the literature describing the combination of trastuzumab and capecitabine for LM from breast cancer. Although the mechanism underlying the efficacy of this combination is still unknown, the treatment would be worth trying because of its few side effects in extensively treated patients with LM from breast cancer. To confirm the antitumor efficacy of trastuzumab and capecitabine, however, further investigations are required.
PMID: 18478315 [PubMed - indexed for MEDLINE]
Cancer News Article Journal of Clinical Oncology on December 28, 2009.[1]
Xeloda® Adds to Effectiveness of Herceptin® and Taxotere® Regimen for Metastatic Breast CancerResearchers involved in an international multicenter study (CHAT) have reported that the addition of Xeloda® (capecitabine) to Herceptin® (trastuzumab) and Taxotere® (docetaxel) improves response rate and progression-free survival in women with advanced or metastatic HER2-positive breast cancer. However, Xeloda increased toxicities significantly. The details of this study were published early online in the Journal of Clinical Oncology on December 28, 2009.[1]
Xeloda is an active agent for the treatment of breast cancer and has the advantage of being administered orally. Herceptin is FDA approved as single-agent therapy in the treatment of HER2-positive patients with metastatic breast cancer. However, combining Herceptin with a taxane or other non-anthracycline drugs has been found to be more effective than single-agent therapy.
The CHAT trial enrolled 222 patients with advanced or metastatic HER2-positive breast cancer who had not received prior treatment except for adjuvant therapy. Preliminary results of this Phase II randomized trial were presented as a late-breaking abstract at the 2006 annual meeting of the European Society of Medical Oncology (ESMO) in Istanbul, Turkey. Table 1 shows the main findings of this trial.
Table 1:Regimen of Xeloda/Herceptin/Taxotere Versus Herceptin/Taxotere
Herceptin, Taxotere, Xeloda
Herceptin, Taxotere
Number of patients
112
110
Overall response
73%
71%
Complete response
23%
16%
Median progression-free survival
18 months
13 months
2-year overall survival
75%
66%
Febrile neutropenia
27%
15%
Grade ¾ neutropenia
77%
54%
Hand-foot syndrome
17%
<1%
Grade ¾ diarrhea
11%
4%
Congestive heart failure
1
1
.
It was concluded that the Xeloda-Herceptin-Taxotere regimen was effective first-line therapy for women with metastatic breast cancer. Comments: These authors cautioned that this therapy should be “reserved for patients with good performance status who are not receiving long-term steroids.”
Reference: J Clin Oncol. 2009 Dec 28. [Epub ahead of print] Randomized Phase II Trial of First-Line Trastuzumab Plus Docetaxel and Capecitabine Compared With Trastuzumab Plus Docetaxel in HER2-Positive Metastatic Breast Cancer.
Wardley AM, Pivot X, Morales-Vasquez F, Zetina LM, de Fátima Dias Gaui M, Reyes DO, Jassem J, Barton C, Button P, Hersberger V, Torres AA.
The Christie, Manchester, United Kingdom; University Hospital of Besançon, Besançon, France; Instituto Nacional de Cancerolog*a, Mexico City, Mexico; Hospital Roosevelt, Guatemala City, Guatemala; Instituto Nacional do Câncer, Rio de Janeiro, Brazil; Hospital Center for International Medicine Advanced, San José, Costa Rica; Medical University of Gdansk, Gdansk, Poland; F. Hoffmann-La Roche Ltd, Basel, Switzerland; Roche Products Pty Ltd, Dee Why, New South Wales, Australia; and Hospital Universitario Miguel Servet, Zaragoza, Spain.
PURPOSE: To evaluate trastuzumab (H) and docetaxel (T) with or without capecitabine (X) as first-line combination therapy for human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. PATIENTS AND METHODS: Patients with HER2-positive locally advanced or metastatic breast cancer were randomly assigned to H (8 mg/kg loading; 6 mg/kg every 3 weeks) plus T (75 mg/m(2) in HTX arm, 100 mg/m(2) in HT arm, every 3 weeks) with or without X (950 mg/m(2) twice per day on days 1 to 14 every 3 weeks). The primary end point was overall response rate (ORR). RESULTS: In 222 patients, median follow-up was approximately 24 months. ORR was high with both regimens (70.5% with HTX; 72.7% with HT; P = .717); complete response rate was 23.2% with HTX compared with 16.4% with HT. HTX demonstrated significantly longer progression-free survival: median 17.9 months compared with 12.8 months with HT (hazard ratio, 0.72; P = .045), which translates to a gain of around 5 months. Two-year survival probability was 75% with HTX compared with 66% with HT. Febrile neutropenia (27% v 15%) and grade 3/4 neutropenia (77% v 54%) incidences were higher with HT than HTX. Treatment-related grade 3 hand-foot syndrome (17% v < 1%) and grade 3/4 diarrhea (11% v 4%) occurred more commonly with HTX than HT. One case of congestive heart failure occurred in each arm. CONCLUSION: HTX is an effective and feasible first-line therapy for HER2-positive locally advanced or metastatic breast cancer, although it should be reserved for patients with good performance status who are not receiving long-term steroids.
PMID: 20038734 [PubMed - as supplied by publisher]
Phytomedicine. 2010 Jan 19. [Epub ahead of print] Phase I study of the botanical formulation PHY906 with capecitabine in advanced pancreatic and other gastrointestinal malignancies.
PMID: 20092990 [PubMed - as supplied by publisher]
Tumori. 2007 Mar-Apr;93(2):129-32. Intermittent capecitabine monotherapy with lower dose intensity in heavily pretreated patients with metastatic breast cancer.
Osako T, Ito Y, Takahashi S, Tokudome N, Iwase T, Hatake K.
Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo. tomo.osako@jfcr.or.jp
AIMS AND BACKGROUND: The purpose of the present retrospective study was to evaluate efficacy and safety of a lower dose-intensity capecitabine monotherapy regimen in heavily pretreated patients with metastatic breast cancer. METHODS: Patients with metastatic breast cancer who had been administered capecitabine monotherapy between June 2003 and August 2004 at our hospital were retrospectively reviewed. Oral capecitabine (828 mg/m2) was given twice daily for three weeks followed by a one-week rest period; this was repeated every four weeks. RESULTS: One-hundred and two patients were assessed. Median follow-up of patients was 16.4 months. One hundred patients (98%) had been pretreated with either anthracyclines or taxanes, 81 patients (79%) with both anthracyclines and taxanes. Response rate was 17% (95% CI, 9-24%), and clinical benefit rate was 41% (95% CI, 32-51%). Median time-to-treatment failure was 4.9 months, and median overall survival time was 24.3 months. This regimen was well tolerated. The most frequent grade 3 or 4 adverse event was hand-foot syndrome (6%). Other grade 3 or 4 adverse events were seen in only 1%-3% of patients. CONCLUSIONS: Intermittent capecitabine monotherapy with lower dose intensity achieved a high tumor control rate with low toxicity in heavily pretreated metastatic breast cancer patients.
PMID: 17557557 [PubMed - indexed for MEDLINE]
Breast Cancer. 2009 Jul 25. [Epub ahead of print] Phase II study of 4-weekly capecitabine monotherapy in advanced/metastatic breast cancer.
Kusama M, Nomizu T, Aogi K, Yoshimoto M, Horikoshi N, Tabei T, Noguchi S, Miura S, Yoshimura N, Kimura M, Toyama K, Shin E.
Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan, kusama@breastcenter.jp.
BACKGROUND: A multicenter, phase II study was conducted to evaluate the efficacy and safety of the Japanese intermittent 4-week regimen of capecitabine in patients with advanced/metastatic breast cancer. METHODS: RESULTS: Fifty patients who had received no more than one prior chemotherapy regimen for advanced/metastatic disease were enrolled from 23 centers and received at least two 4-weekly cycles of capecitabine (828 mg/m(2) orally twice daily for 3 weeks followed by a 1-week rest period).The overall response rate assessed by the Independent Review Committee (standard population, n = 46) was 28.3% (95% confidence interval 16.0-43.5%), including complete responses in 6.5%. Stable disease was observed in 20 patients and maintained for more than 6 months in 10 patients. The median duration of response in 13 evaluable responders was 5.3 months. Among evaluable patients (n = 47), median time to disease progression was 5.1 months. Median overall survival was 20.2 months. The most common treatment-related adverse events (all grades) were hand-foot syndrome (66%), nausea (26%), stomatitis (22%) and diarrhea (20%). Grade 3/4 treatment-related adverse events were seen in 23 patients (46%). The most common grade 3/4 adverse events were lymphocytopenia (22%), hand-foot syndrome (18%) and hyperbilirubinemia (10%). CONCLUSIONS: Although the target overall response rate was not reached, the Japanese intermittent 4-week regimen of capecitabine was shown to be an effective and well-tolerated first- or second-line therapy for advanced/metastatic breast cancer.
PMID: 19633909 [PubMed - as supplied by publisher]
Oncology. 2009;77(5):318-27. Epub 2009 Nov 23. First-line capecitabine monotherapy for slowly progressing metastatic breast cancer: do we need aggressive treatment?
Debled M, Madranges N, Trainaud A, Floquet A, Donamaria C, Brouste V, Durand M, Mauriac L.
Department of Medical Oncology, Institut Bergonié, South-West Comprehensive Cancer Center, Bordeaux, France. debled @ bergonie.org
BACKGROUND: Primary treatment goals in less aggressive metastatic breast cancer (MBC) are prolonged survival, good quality of life and control of the disease and its symptoms. High activity, oral administration and no alopecia make capecitabine monotherapy attractive in slowly evolving disease. METHODS: We retrospectively analysed 226 patients who had received single-agent capecitabine as 1st-line chemotherapy at our institution. RESULTS: The median interval between breast cancer diagnosis and MBC was 52 months (range 0-479); 76% had received endocrine therapy for MBC, 58% had visceral involvement and 30% had 3 or more metastatic sites. The median starting dose was 1,000 mg/m(2) twice daily. Disease was improved in 56% of the patients (median duration: 13.2 months) and stabilised in 20%. Median time to treatment failure was 8.8 months (95% CI: 7.1-10.5); median overall survival from initiating capecitabine was 23.6 months (95% CI: 19.7-27.4). Prior adjuvant chemotherapy, endocrine therapy for MBC, visceral disease, hormone receptor status and initial capecitabine dose did not influence time to treatment failure. Among 161 patients <75 years, 90% received further chemotherapy. CONCLUSION: Based on these findings, 1st-line capecitabine should be considered in slowly progressing disease, offering an active, well-tolerated oral treatment with minimal toxicity and no alopecia. More toxic treatments may be reserved for more aggressive disease. Copyright 2009 S. Karger AG, Basel.
PMID: 19940523 [PubMed - indexed for MEDLINE]
Clin Breast Cancer. 2007 Dec;7(11):857-60. Safety profile and activity of lower capecitabine dose in patients with metastatic breast cancer.
Rossi D, Alessandroni P, Catalano V, Giordani P, Fedeli SL, Fedeli A, Baldelli AM, Casadei V, Ceccolini M, Catalano G.
Oncology Unit, S. Salvatore Hospital, Pesaro, Italy. d.rossi63@libero.it
PURPOSE: Capecitabine is an orally administered precursor of 5'-deoxy-5-fluorouridine that was rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumor tissue. The drug enables chronic dosing that mimics continuous infusion of 5-FU. Phase II trials of capecitabine at 1250 mg/m2 twice daily for 14 days followed by 7 days of rest, is active in anthracycline- and taxane-pretreated patients; the main toxicity is palmar-plantar erythrodysesthesia, diarrhea, and nausea. To overcome these side effects, the dose has been reduced to 1000 mg/m2 twice daily with a better therapeutic profile and encouraging efficacy. The aim of our study was to confirm safety and activity of capecitabine at lower doses in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Thirty-seven patients with advanced breast cancer entered the study. The first 7 patients were treated with capecitabine 1250 mg/m2 twice daily (for 14 days followed by 7 days of rest) and the next 30 patients with capecitabine 1000 mg/m2. The median age was 62 years (range, 38-87 years). Thirteen patients were chemotherapy naive and 24 were pretreated with chemotherapy (9 patients, 1 line; 15 patients, > or = 2 lines). Anthracyclines and/or taxane schedules were administered in 22 patients. Soft tissue metastases were documented in 36 patients; visceral metastases in 24 patients; visceral and soft tissue metastases in 23 patients. RESULTS: Thirty patients were evaluable for response (5 at "higher" dose and 25 at "lower" dose) and all for toxicity. Overall objective response rate was 57% (5 complete responses and 12 partial responses); 95% CI, 39%-74%; stable disease 20% and progressive disease 23%. Eight of 13 chemotherapy-naive patients (61.5%) and 9 of 24 pretreated patients (37.5%) responded to capecitabine, according to the intent-to-treat principle (6 of 9 responses were obtained at a lower dose). Three responses at the "higher" dose and 14 at the "lower" dose were reported. Median time to progression was 7 months (range, 1-38 months) and median overall survival was 19 months (range, 2-47 months). Toxicity was as follows: grade 2/3 palmar-plantar erythrodysesthesia in 9 patients (24%), grade 2/3 asthenia in 7 patients (19%), grade 2 vomiting in 4 patients (11%), grade 2 renal toxicity in 1 patient, grade 2 skin reaction in 1 patient, and suspected cardiac toxicity in 1 patient. CONCLUSION: Our study confirmed that a lower dose of capecitabine has a good toxicity profile and is active in patients with MBC.
Cancer Chemother Pharmacol. 2010 Mar 5. [Epub ahead of print] DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity.
Yang CG, Ciccolini J, Blesius A, Dahan L, Bagarry-Liegey D, Brunet C, Varoquaux A, Frances N, Marouani H, Giovanni A, Ferri-Dessens RM, Chefrour M, Favre R, Duffaud F, Seitz JF, Zanaret M, Lacarelle B, Mercier C.
Medical Oncology Unit, La Timone University Hospital, 234 Rue St Pierre, 13385, Marseille cedex 05, France.
BACKGROUND: Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy. METHODS: About 65 patients with HNC (59 +/- 9 years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5-FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59 +/- 10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage. RESULTS: Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia + sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P = 0.790). CONCLUSIONS: Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC.
PMID: 20204365 [PubMed - as supplied by publisher]
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.
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