Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent trials comparing single-agent vs combination therapy in metastatic breast cancer suggest that it may be time to reconsider the belief that combination chemotherapy is the gold standard of treatment. Based on the limited randomized trial data available to date, high-dose chemotherapy with stem-cell rescue should not be viewed as "state-of-the art" treatment for metastatic disease and should be used only in the context of clinical trials. Recent trials have explored the optimal dosing and scheduling of the taxanes, as well as the possible role of these agents in combination regimens. Capecitabine (Xeloda), a new oral fluoropyrimidine, appears to be comparable in efficacy to CMF (cyclophosphamide, methotrexate, and fluorouracil), and preclinical data suggest possible synergy between this agent and the taxanes. Other promising agents under study include liposome-encapsulated doxorubicin (TLCD-99), an immunoconjugate linking a chimeric human/mouse monoclonal antibody to doxorubicin molecules; MTA (LY231514), a multitargeted antifolate; and marimistat, a broad-spectrum matrix metalloproteinase inhibitor. Tamoxifen (Nolvadex) remains the most important hormonal agent, but new antiestrogens and selective estrogen receptor modulators (SERMs) may provide alternatives. The potential role of new aromatase inhibitors as first-line hormonal agents requires further study. Finally, the possible synergy between trastuzumab (Herceptin), a recombinant humanized monoclonal antibody to the HER-2/neu protein, and paclitaxel (Taxol) is being studied in two clinical trials.
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PMID:Update on the management of advanced breast cancer. 1035 85

Although 5-fluorouracil (5-FU) has been used to treat breast and colorectal cancers for several decades, bolus 5-FU has disappointing efficacy. Prolonged infusion schedules and biomodulation with leucovorin have resulted in improved response rates, but these have not translated into significant improvements in survival in patients with metastatic disease. Furthermore, prolonged infusion is inconvenient for patients and can result in medical complications. New oral fluoropyrimidines, including capecitabine, are promising alternatives to i.v. 5-FU. Capecitabine generates 5-FU preferentially within tumors through exploitation of the high intratumoral activity of thymidine phosphorylase. The tumor selectivity of capecitabine has been confirmed in a clinical study of colorectal cancer patients. Clinical trials have shown that capecitabine is an effective, well-tolerated treatment for breast and colorectal cancer, with response rates of 20-26% in anthracycline- and taxane-pretreated metastatic breast cancer. As first-line monotherapy, capecitabine produces response rates of 25-27% in metastatic colorectal cancer and 30% in metastatic breast cancer. In all studies to date, capecitabine has been well tolerated, with adverse events typical of infusional 5-FU and manageable with treatment interruption/dose modification. Myelosuppression and alopecia are rare. Capecitabine is also being investigated in other solid tumors (including ovarian, pancreatic and gastric cancers) as adjuvant monotherapy in breast and colorectal cancer, and in combination with other cytotoxic agents. Results of ongoing trials are eagerly awaited.
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PMID:Capecitabine: a novel agent for the treatment of solid tumors. 1160 50

Results from two phase II studies in metastatic breast cancer have shown that the novel, tumour-selective fluoropyrimidine capecitabine provides an effective and well tolerated therapy in patients with metastatic breast cancer failing or resistant to anthracycline and taxane therapy. Response rates of between 20 and 25% have been observed, with median survival of 12.2-12.6 months. In addition, there was an acceptable incidence of adverse events including diarrhoea and hand-foot syndrome, which can be controlled with a dose reduction. Promising results from two further randomised, phase II studies have indicated that capecitabine may also play a role in first- and second-line treatment of metastatic breast cancer. Capecitabine compared favourably with paclitaxel in anthracycline-resistant patients and with intravenous (i.v.) CMF (cyclophosphamide/methotrexate/5-fluorouracil (5-FU)) in post-menopausal women who had received no prior chemotherapy for metastatic disease, with high efficacy and good tolerability. The results of these four phase II studies demonstrate that capecitabine is active and well tolerated in a range of settings for metastatic breast cancer.
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PMID:Clinical experience of capecitabine in metastatic breast cancer. 1184 30

Anthracyclines, together with taxanes, are at present the most active agents in metastatic breast cancer, while single-agent, bolus 5-fluorouracil (5-FU) is not very active in this setting. In view of encouraging results and tolerable toxicity of continuous infusion of 5-FU in gastrointestinal cancer, innovative oral 5-FU agents such as capecitabine have been developed. Capecitabine is a prodrug that is converted into the active compound 5-FU preferentially at the tumor site. An intermittent dosing schedule of capecitabine twice daily at a dose of 2510 mg/m2/day on days 1-14 in a 3-week cycle appeared to be feasible and resulted in a high dose intensity. A large phase II study investigating capecitabine in 135 advanced breast cancer patients, pretreated with anthracyclines and taxanes, observed three complete and 24 partial responses (response rate, 20%), with a mean duration of 8.0 months. Preliminary results of a study comparing capecitabine with paclitaxel in 42 breast cancer patients failing anthracyclines indicate that the efficacy of capecitabine is comparable to that of paclitaxel, with response rates of 36% and 21%, respectively. Another study reported a response rate of 25% for capecitabine as first-line therapy for advanced breast cancer in women aged > or = 55 years, which tended to be better than combination chemotherapy with cyclophosphamide/methotrexate/5-FU. In all studies, capecitabine side effects were mainly mild, and treatment-related grade 3/4 toxicity consisted of diarrhea (8%-11%), nausea (4%-11%), hand-foot syndrome (10%-18%), neutropenia (3%-20%), and bilirubin elevation (6%). Capecitabine is clearly an active agent for the treatment of breast cancer. It is currently registered in various countries for use in third-line treatment of metastatic disease. Its further role will have to be defined from data of randomized phase III studies.
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PMID:Capecitabine in breast cancer: current status. 1189 51

Capecitabine, a tumor-selective, oral fluoropyrimidine, has demonstrated significant antitumor activity in patients with metastatic breast cancer. In this open-label monocenter phase II study the efficacy and safety of capecitabine in patients with metastatic breast cancer who relapsed after high-dose chemotherapy was examined. Female patients 18-65 years of age, with a histologically confirmed diagnosis of metastatic breast cancer, who relapsed after high-dose chemotherapy (adjuvant and/or metastatic) followed by autologous peripheral blood stem cell transplantation (PBSCT) and who had been treated in their course of the disease with an anthracycline and/or an anthracycline/taxane containing regimen were included into this clinical study. Capecitabine was applied as the first salvage chemotherapy at relapse after high-dose chemotherapy (1250 mg/m(2) b.i.d. p.o. for 14 days followed by 7 days rest period). Responding patients or those with stable disease after two treatment cycles were offered to continue treatment until tumor progression. Response rate, time to disease progression, survival, toxicity and quality of life were assessed. Fourteen patients between 35 and 60 years (median 45.5 years) entered this study and received a median number of 5 cycles (range 1-19) of capecitabine. All patients were evaluable for response. All patients had been pretreated with 1-2 cycles of high-dose chemotherapy plus PBSCT. Furthermore, 13 patients had additionally received local radiotherapy. On average, the patients showed metastatic disease in two organ sites (range 1-4 sites). One patient obtained a complete response and five patients a partial response, accounting for a response rate of 42.9% [95% confidence interval (17.7%; 71.1%)]. All responses were already achieved at the first observation time point 6 weeks after treatment initiation. Two further patients obtained stable disease for at least 12 weeks. At the time of final analysis all patients have progressed. Median time to progression was 2.8 months (range 0.4-13.3 months). No median survival time was reached (range 3.9-36.5 months, at the time of reporting eight patients were alive and six patients had died). Two patients developed grade III granulocytopenia. Five patients developed grade III hand-foot syndrome. One patient had the combination of nausea, fever and diarrhea grade III. All adverse events were considered manageable. We conclude that capecitabine as single-agent oral chemotherapy is active and well tolerated in heavily pretreated patients with breast cancer. It can be safely used in patients who have been intensively pretreated by myelotoxic chemotherapy or who have even relapsed after high-dose chemotherapy with PBSCT.
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PMID:Capecitabine in patients with breast cancer relapsing after high-dose chemotherapy plus autologous peripheral stem cell transplantation--a phase II study. 1198 86

In the United States, tumors of the central nervous system remain the third leading cancer-related cause of death in young adults with a median survival time of < 1 year. A recent case study suggested that Capecitabine (a novel, fluoropyrimidine prodrug) may be effective in the treatment of brain metastases. Pharmacogenomic studies have correlated the antitumor response to Capecitabine with the expression of the drug metabolizing enzymes thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). In the current study, we examined TP and DPD expression in normal human brain tissues and in glioblastoma multiforme, the most common and malignant type of brain tumor. Because previous reports suggest a tumor necrosis factor (TNF)-alpha-mediated increase in TP expression after irradiation (a current standard of care for glioblastoma multiforme), we also examined the effect of irradiation on the expression of TP, DPD, and TNF-alpha in both irradiated and lead-shielded contralateral U87MG glioma xenografts within the same animal. Expression levels were determined using real-time quantitative PCR as described previously. Results demonstrate an approximately 70-fold increase in TP mRNA levels 4 days after irradiation, relative to initial control levels. Interestingly, TP mRNA in the lead-shielded tumors (contralateral to irradiated tumors) increased approximately 60-fold by day 10 relative to initial control levels. Elevated TP levels were sustained for 20 days in irradiated xenografts but began to decrease after 15 days in the shielded/contralateral tumors, returning to baseline by 20 days. TP mRNA levels in normal mouse liver were unaltered, suggesting a tumor-associated effect. TNF-alpha mRNA levels did not increase after irradiation; therefore, mRNA expression of 11 additional cytokines [interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, and IFN-gamma] in both the irradiated and shielded xenografts was quantitated. Results demonstrated increased levels of IFN-gamma, IL-10, and IL-1 alpha by 6.3-, 3.7-, and 1.6-fold, respectively, in irradiated tumors only. DPD mRNA levels did not change after irradiation. The tumor-associated induction of TP in irradiated and lead-shielded tumors within the same animal may have significant implications for the combined modality treatment of cancer patients with Capecitabine in conjunction with radiotherapy and may apply to the treatment of distant tumors and or metastatic disease.
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PMID:Induction of thymidine phosphorylase in both irradiated and shielded, contralateral human U87MG glioma xenografts: implications for a dual modality treatment using capecitabine and irradiation. 1248 38

To evaluate the efficacy and toxicity of capecitabine as a salvage chemotherapy regimen in Chinese patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) previously treated with platinum-based chemotherapy, 17 patients with recurrent or metastatic NPC previously treated with platinum-based chemotherapy as adjuvant or palliative treatments received oral capecitabine at a dose of 1.25 G/m(2) twice daily in 3-week cycles consisting of 2 weeks of treatment followed by rest period of 1 week. Seven patients had local recurrence, seven had distant metastases, one had loco-regional recurrence, and two had both local/regional recurrence and distant metastases. Patients received a median number of three cycles of capecitabine (range: 1-6). The median follow-up was 7.5 months (range: 3-25.3). All patients were included in the efficacy and adverse events analysis. Three patients (17.6%) achieved partial response and one patient (5.9%) achieved complete response, with an overall response rate of 23.5% (95% confidence interval, 7-50%). The duration of response's were 4.2, 5, 6+, and 23.1+ months. Nine patients (52.9%) had stable disease whereas four (23.5%) had progressive disease. The median time to progression was 4.9 months. The median survival was 7.6 months. Five patients are still alive with an estimated 1-year survival rate of 35%. Treatment-related adverse events were generally mild except hand-foot syndrome which occurred in 58.8% of patients. Capecitabine is an effective salvage regimen in patients with recurrent and metastatic NPC. Capecitabine as a single agent or in combination with other chemotherapeutic agents or treatment modalities should be further studied in NPC.
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PMID:A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. 1267 55

5-Fluorouracil (5-FU) has been the main chemotherapeutic agent for the treatment of colorectal cancer for four decades with modest efficacy. Modulation of 5-FU by leucovorin or continuous infusion improves the response rate, but overall survival duration remains approximately 12 months. Many oral fluoropyrimidines have been studied, including capecitabine, UFT, S-1, and Eniluracil. Capecitabine has demonstrated equivalent efficacy with 5-FU and has been approved as first line treatment. The combinations of capecitabine with CPT-11 or oxaliplatin are being developed. CPT-11 demonstrated non-crossover resistance with 5-FU and was proven to be effective treatment for patients who received prior 5-FU. CPT-11 in combination with 5-FU has demonstrated improved response rate and overall survival duration over 5-FU or CPT-11. Oxaliplatin plus 5-FU has offered another effective treatment option for colorectal cancer. Both 5-FU plus leucovorin in combination with CPT-11 or oxaliplatin are widely used first-line chemotherapies for advanced colorectal cancer. Optimal combinations and sequences of treatment are being studied, since several effective regimens have become available.
Cancer Metastasis Rev
PMID:Treatment of colorectal cancer metastasis: the role of chemotherapy. 1500 Jan 55

This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m(-2) twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.
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PMID:Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. 1502

Blood-borne metastases to the kidneys from solid tumors have received little attention in the medical literature because they usually occur in a setting of advanced systemic disease, and renal involvement is a relatively minor cause of symptoms. Although the frequency of metastases to the kidney in cancer patients is 7-13% in large autopsy series, incidental discovery of a renal metastasis as the first manifestation of a primary tumor is a very rare event. The most common primary malignancy to involve the kidney is bronchogenic carcinoma,followed by breast and gastrointestinal cancers. In this article, we report a patient with left colon cancer and isolated metastasis to the right kidney at the time of initial diagnosis. Left hemicolectomy and right nephrectomy were performed. Adjuvant systemic chemotherapy consisting of 5-fluorouracil (5-FU) and folinic acid (FA) was given. 5-FU and FA were stopped after four cycles because metastases to the lung and liver occurred about 3 mo after the surgery during adjuvant chemotherapy. Capecitabine was started. The patient died 9 mo after the discovery of the isolated renal metastasis. Nephrectomy is more for diagnostic clarification in the setting of synchronous primary because it has no effect on survival and its effect on quality of life is minimal; as seen in our case, the other organ metastases rapidly occur and the survival is limited. Nephrectomy may also compromise the choice of chemotherapy agents that require renal clearance, thus a careful evaluation of renal functions is necessary if a nephrectomy is performed. In the matter of a decreased renal clearance,the doses of these drugs should be decreased or the choice should be reevaluated.
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PMID:Colon cancer with isolated metastasis to the kidney at the time of initial diagnosis. 1536 38


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