Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Capecitabine (Xeloda) is an oral prodrug that is enzymatically converted to fluorouracil (5-FU) within cancer cells. Data from two large phase III trials performed in patients receiving first-line chemotherapy for metastatic colorectal cancer showed that capecitabine yielded higher objective response rates and equivalent median time to tumor progression and overall survival rates as 5-FU/leucovorin. In these studies, capecitabine demonstrated lower rates of diarrhea, stomatitis, nausea, and severe neutropenia than bolus 5-FU/leucovorin, but a higher rate of hand-foot syndrome and hyperbilirubinemia. The natural extension of this work has been to evaluate substitution of capecitabine for 5-FU/leucovorin in combination chemotherapy trials with irinotecan (CPT-11, Camptosar) or oxaliplatin (Eloxatin). This is especially important due to concerns regarding toxicities observed with regimens that combine bolus 5-FU/leucovorin with irinotecan or oxaliplatin. Phase I/II and phase II trials of capecitabine in combination with irinotecan or oxaliplatin in patients with advanced disease indicate that the combinations are well tolerated and produce response rates that are in the range of those that would be expected with infusional 5-FU/leucovorin combined with irinotecan or oxaliplatin. Phase III trials have been initiated in the advanced disease and adjuvant settings and should help determine the efficacy, toxicity, and tolerability of the capecitabine/irinotecan or capecitabine/oxaliplatin combination in direct comparison to intravenous 5-FU/leucovorin and irinotecan or oxaliplatin.
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PMID:Current status of capecitabine in the treatment of colorectal cancer. 1252 Jun 35

We hypothesized that hand-foot syndrome is an inflammatory phenomenon mediated by the overexpression of cyclooxygenase 2 (COX-2). Therefore, a specific COX-2 inhibitor such as celecoxib (Celebrex) could attenuate both the incidence and severity of hand-foot syndrome. We undertook a retrospective study comparing the incidences of hand-foot syndrome in 67 patients with metastatic colorectal cancer who took capecitabine (Xeloda) with or without celecoxib. Surprisingly, celecoxib seemed to attenuate capecitabine-induced diarrhea as well. Capecitabine/celecoxib was also associated with increased tumor response, proportion of stable disease (62.5% vs 22.8%, P = .001), and increase in median time to tumor progression (6 vs 3 months, P = .002) compared with capecitabine alone, despite the fact that patients on capecitabine/celecoxib had less favorable disease characteristics (age, performance status, and prior chemotherapies). Overexpression of COX-2, implicated in promoting angiogenesis, enhanced tumor invasiveness, evasion of apoptosis, and immune suppression, is a bona fide molecular target for many solid tumors, including colorectal cancer. Combining capecitabine with celecoxib in the treatment of colorectal cancer has strong preclinical rationales. A prospective study is being designed to evaluate capecitabine and celecoxib with or without epidermal growth factor receptor antagonist ZD1839 in the frontline treatment of metastatic colorectal cancer. These regimens under study are orally based and may significantly impact quality of life in the frontline treatment of metastatic colorectal cancer.
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PMID:Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity. 1252 Jun 38

Capecitabine is a novel fluoropyrimidine carbamate which is selectively activated after oral administration to 5-fluorouracil (5-FU) by a sequential triple enzyme pathway in liver and tumor cells. The cytotoxic activity of the metabolized 5-FU depends on thymidylate synthase (TS) inhibition, leading to defective DNA synthesis. Capecitabine has shown promising activity in all tumor types sensitive to 5-FU and is therefore investigated in many clinical trials. Since we observed an increase of mean corpuscular volume (MCV) of red blood cells under therapy with capecitabine, the current investigation aimed to quantitate this effect and to elucidate the underlying mechanisms. A total of 154 patients suffering from advanced cancer received capecitabine (2500 mg/m2/day for 14 days every 21 days) either as monotherapy, or in combination with other antineoplastic agents or biological response modifiers. During 3 consecutive cycles of therapy a complete blood cell count including the red cell indices MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration was performed before each application of capecitabine. In addition, vitamin B12, folic acid and homocysteine were determined to define their role in increasing MCV. Restaging was performed after 9 weeks. Within 9 weeks, a statistically significant increase of MCV (without other hematologic abnormalities or clinical symptoms) could be observed (p<0.0001). Vitamin B12, folic acid and homocysteine levels did not change significantly during the observation period. When comparing the different increases of MCV during 9 weeks (deltaMCV) with respect to tumor response, deltaMCV tended to higher values in patients with tumor remission or stable disease than in patients with tumor progression. We conclude that serum levels within the normal range rule out severe deficiencies of vitamin B12, folic acid or homocysteine as an account of macrocytemia. We therefore hypothesize that an increased MCV (without concomitant anemia) in patients receiving capecitabine might be due to the 5-FU-induced TS inhibition also in erythroid precursor cells. Whether this increase in MCV might serve as a surrogate marker for tumor response has to be evaluated in further investigations.
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PMID:Capecitabine treatment results in increased mean corpuscular volume of red blood cells in patients with advanced solid malignancies. 1256 98

Metastatic breast cancer develops in approximately 50% of women diagnosed with breast cancer. The optimal treatment for patients with metastatic breast cancer has yet to be defined, owing to the heterogeneity of this group and the available agents. Patients with metastatic breast cancer often receive single-agent treatment in sequence as it is unclear whether combination therapy with cytotoxic drugs offers an overall disease-free survival benefit and single agents may offer less toxicity. The advantages of combination cytotoxic therapies have included higher response rates. However, such trials have not stratified on rapidity of disease progression or on tumor bulk. In previous studies, docetaxel is one of the few cytotoxic agents to demonstrate a survival benefit in anthracycline-resistant patients and thus it has become a vital component of cytotoxic therapy. Capecitabine is also an important oral drug and has demonstrated activity in patients pretreated with anthracyclines and taxanes. Recent preclinical and clinical trials of this combination have demonstrated an increased time to tumor progression and overall survival benefit. Paclitaxel combined with gemcitabine has been compared with docetaxel plus capecitabine, with similar response rates and survival benefits. As patients on these trials have not received uniform crossover to the other active agent, whether or not the combination therapy offers an advantage for the entire cohort of metastatic patients or may be indicated for specific subgroups remains uncertain. Combination treatments may be preferable to sequential therapy for patients requiring urgent reduction in their tumor burden. Combinations of cytotoxic agents in combination with biological agents are currently being defined.
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PMID:Capecitabine-docetaxel combination treatment. 1702 Apr 52

The objective of this multicenter phase II trial was to evaluate the efficacy and tolerability of capecitabine in patients with cisplatin-refractory or relapsed germ cell tumors. Between March 2003-June 2004, 14 patients refractory to at least two regimens of cisplatin-based chemotherapy or with relapse after high-dose chemotherapy and autologous peripheral blood stem cell transplantation received 1250 mg/qm capecitabine orally twice daily for 14 days in 3-week cycles. Treatment was continued until tumor progression. All patients were heavily pretreated with a median number of four previous lines of chemotherapy (range, 2-11) and 86% had relapsed after high-dose chemotherapy with peripheral blood stem cell transplantation. No patient responded to study treatment. Nine patients (64%) had progressive disease after two cycles. Two patients already stopped treatment after one cycle, because of a clinically overt tumor progression. One patient died of his tumor progression at the end of the second cycle. Two patients received four cycles of capecitabine, as progression was less than 30%. The median survival time was 4 months (range, 0-10). The toxicity profile was favorable. Eighty-six percent of the cycles could be applied without dose modifications or delay. Grade III/IV toxicities (diarrhea and anorexia in one patient each) occurred in 7% of the cases. No hematotoxicity grade III/IV was observed. Neutropenia grade I/II was documented in 21%, anemia in 35% and thrombocytopenia in 14% of the patients. Capecitabine was well tolerated, but is not effective in heavily pretreated patients with cisplatin-refractory or relapsed germ cell tumors.
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PMID:An open-label, multicenter phase II trial of capecitabine in patients with cisplatin-refractory or relapsed germ cell tumors. 1726 58

Gastric cancer is the second most frequent cancer in the world. Approximately 84% of patients with gastric cancer will have advanced disease and median survival of these patients without chemotherapy is only 3-4 months. "Classical" chemotherapy regimens, mainly CF (cisplatin plus infusional 5FU) and ECF (cisplatin plus infusional 5FU plus Epirubicin) obtain responses in 20-40% of the patients and improve quality of life. Nevertheless, duration of these responses is short with very few complete responses. Median time to tumor progression (TTP) with these regimens is only about 4-5 months and median survival does not exceed 7-10 months. Moreover, benefit seems to be limited to patients with good performance status and treatment toxicity and discomfort are not negligible, specially that of regimens with cisplatin or infusional 5FU. Trying to improve these results, the incorporation of new drugs has been explored. Among the new combinations, the more developed ones are those with Docetaxel (DCF), oxaliplatin (EOX, FLO), Capecitabine (EOX, cisplatin-Xeloda) and irinotecan (ILF). We have final results from Phase III trials that suggest that all these regimens could have a role in the treatment of these patients but survival is still very poor and toxicity remains important. It would be interesting to investigate other new combinations and the incorporation of drugs directed against new therapeutic targets in this setting. It would be of utmost interest that these clinical trials would also explore clinical and molecular prognostic and predictive factors.
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PMID:Chemotherapy of advanced gastric cancer. 1737 98

The treatment of metastatic colorectal cancer (mCRC) has evolved significantly over the past 10 years. For nearly 40 years, the fluoropyrimidine 5-fluorouracil (5-FU) was the only agent to be used for advanced metastatic disease. However, since the mid-1990s, the chemotherapy treatment options for patients with mCRC have been greatly facilitated with the introduction of several new cytotoxic and biologic agents. In particular, combination regimens that incorporate infusional schedules of 5-FU in combination with oxaliplatin (FOLFOX) and/or irinotecan (FOLFIRI) have significantly improved clinical efficacy as related to overall response rates, time to tumor progression, and median overall survival. Capecitabine, an oral fluoropyrimidine, has now been shown in several phase III studies to be as effective as infusional 5-FU when combined with oxaliplatin. During this same time frame, intense efforts have focused on integrating novel biologic agents with cytotoxic chemotherapy regimens. These biologic agents target critical signaling pathways such as the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Bevacizumab is a monoclonal antibody targeting VEGF-A, and when combined with fluoropyrimidine-based chemotherapy, which includes oxaliplatin or irinotecan, significantly improves clinical efficacy in the management of patients with mCRC. Cetuximab and panitumumab are monoclonal antibodies targeting EGFR, and each of these agents is approved to treat mCRC patients who have progressed on previous chemotherapy treatments. Recent studies have shown that cetuximab, when combined with cytotoxic chemotherapy, significantly enhances the management of patients with mCRC in the first-, second-, and disease-refractory settings. With these advances in treatment options, much attention is now focused on identifying the critical molecular biomarkers that can predict response and/or toxicity to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with mCRC.
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PMID:An update on treatment advances for the first-line therapy of metastatic colorectal cancer. 1792 24

In addition to the direct cytotoxic effects of chemotherapy agents on tumor cells, the anti-angiogenic activities attained by these agents by targeting proliferating endothelial cells in tumor blood vessels has attracted much research interest. In this study, we examined the antitumor activity of 5-Fluorouracil (5-FU)-based drugs (S-1 [1M tegafur, 0.4M 5-chloro-2,4-dihydroxypyridine and 1M potassium oxonate] and capecitabine) on human colorectal cancer xenografts and evaluated their anti-angiogenic effects. Both drugs showed significant antitumor activities against COL-1 xenografts at a sub-maximum tolerated dose (sub-MTD), which was lower than the maximum tolerated dose (MTD). At the sub-MTD, a significant reduction in the microvessel number and the enhancement of tumor-associated microvessel endothelial cell apoptosis was seen in xenografts treated with S-1. In addition, we found that thrombospondin-1 (TSP-1) expression, known to be a mediator of the anti-angiogenic effects of metronomic chemotherapy, was significantly up-regulated in xenograft tumor tissues and plasma in animals treated with S-1 at a sub-MTD. Capecitabine also showed a trend toward the induction of TSP-1. These results suggest that 5-FU-based drugs inhibit tumor progression through different modes of action, including cytotoxic activity derived from 5-FU and the inhibition of angiogenesis through the induction of TSP-1.
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PMID:Anti-angiogenic effect of 5-Fluorouracil-based drugs against human colon cancer xenografts. 1842 Mar 42

The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2-negative MBC.
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PMID:Capecitabine monotherapy: review of studies in first-line HER-2-negative metastatic breast cancer. 2241 69


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