The potential for oral combination chemotherapy of 5'-deoxy-5-fluorouridine, a 5-FU prodrug, and cyclophosphamide for metastatic breast cancer

Preclinical studies have demonstrated the synergistic anti-tumour activity of combination therapy with the oral cytostatics, 5'-deoxy-5-fluorouridine (5'-DFUR) and cyclophosphamide (CPA), in human breast cancer xenograft models. This study was performed to evaluate the efficacy and safety of this oral combination chemotherapy in the treatment of metastatic breast cancer. In all, 101 patients with metastatic breast cancer were enrolled in the study, and the data for 94 eligible patients of these were evaluated. The patients received twice daily oral combinations of 5'-DFUR (1200 mg/body/day) and CPA (100 mg/body/day) for 2 weeks, followed by a 1-week rest period. After a median of 19 treatment cycles (range 1-66 cycles), 16 patients (17.0%) had a complete response, and 40 patients (42.6%) had partial responses. The response rate was 59.6% (95% CI, 49.0-69.6%). The median time to progression and overall survival times were 11.7 and 40.3 months, respectively. The toxicity was mild and tolerable, and the related grade 3/4 clinical adverse effects consisted of haematological toxicity in 21 patients (22%) and nonhaematological toxicity in five patients (5%). These results suggest that the oral combination chemotherapy of 5'-DFUR and CPA has low toxicity and is a novel, very convenient and effective treatment for metastatic breast cancer.     

Intermittent weekly high-dose capecitabine in combination with oxaliplatin: a phase I/II study in first-line treatment of patients with advanced colorectal cancer.

BACKGROUND: The aim of this phase I study was to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of an intermittent weekly capecitabine regimen in combination with oxaliplatin. Furthermore, we intended to explore its safety at the recommended dose, and to assess its principal antitumor activity in patients with advanced colorectal cancer. PATIENTS AND METHODS: Thirty patients with measurable metastatic colorectal cancer who previously were unexposed to palliative chemotherapy were enrolled on to this disease-oriented phase I trial. They were treated with a fixed dose of oxaliplatin (85 mg/m(2) administered as a 2-h intravenous infusion on day 1) plus escalating doses of capecitabine (given at two divided daily doses from days 1 to 7), repeated every 2 weeks. The dose of oral fluoropyrimidine was escalated in consecutive cohorts of three to six patients from 2500 to 4000 mg/m(2)/day. After having defined the toxic dose, nine additional patients were entered at the MTD/recommended dose to confirm its safety profile, and assure suitability for future phase II/III studies. RESULTS: In the phase I part of the study, 21 patients were enrolled, and a total of 222 courses were administered through four dose levels of capecitabine combined with oxaliplatin 85 mg/m(2). Gastrointestinal toxicities, predominantly diarrhea, were the principal DLTs. Other severe adverse events included grade 3 asthenia, acute neurological symptoms and skin toxicity. The combination was not myelosuppressive, eliciting only sporadically grade 3/4 neutropenia and/or thrombocytopenia. There was no alopecia, and only a few patients experienced mild symptoms of hand-foot syndrome. Externally reviewed objective responses were noted in 15 of all 30 evaluable patients (overall response rate, 50%; 95% confidence interval 31% to 69%) including three complete remissions and median progression-free survival was 8.8 months (range 7-14+ months). CONCLUSIONS: Overall results of this study indicate that the administration of clinically relevant single-agent doses of both capecitabine and oxaliplatin is feasible and seems to result in promising therapeutic activity in patients with advanced colorectal cancer. On the basis of the toxicological profile of the combination regimen shown in the present study, oxaliplatin 85 mg/m(2) as a 2-h intravenous infusion every 2 weeks administered in combination with capecitabine 3500 mg/m(2)/day x7 in two divided doses is recommended for further evaluations.     

Phase I and pharmacokinetic study of docetaxel in combination with epirubicin and cyclophosphamide in advanced cancer: dose escalation possible with granulocyte colony-stimulating factor, but not with prophylactic antibiotics.

BACKGROUND: The objective of this phase I trial was to determine the maximally tolerated doses of the combination of docetaxel, epirubicin and cyclophosphamide. PATIENTS AND METHODS: Patients with advanced cancer, World Health Organization (WHO) performance status 0 to 2, who had received up to one prior chemotherapy regimen were treated with docetaxel, epirubicin and cyclophosphamide repeated every 21 days. The cyclophosphamide dose was fixed at 600 mg/m(2) and the dose levels studied were: docetaxel/epirubicin; 60/60, 75/60, 75/75, 75/90, 85/90 and 85/105 mg/m(2). There was provision for the addition of prophylactic ciprofloxacin and granulocyte colony-stimulating factor (G-CSF) in separate steps if dose-limiting toxicity (DLT) was neutropenia related. RESULTS: Forty-three patients were entered and all were assessable for toxicity. Dose-limiting toxicity, predominantly febrile neutropenia, was surprisingly seen at the first dose level. The addition of prophylactic ciprofloxacin did not permit dose escalation, but dose escalation was possible with the addition of G-CSF. The highest administered dose level with G-CSF was docetaxel 85 mg/m(2) and epirubicin 105 mg/m(2) with DLTs in five of six patients. Treatment was well tolerated in 10 patients treated at the recommended dose level (85/90) with only one patient experiencing DLT. Responses were seen in a range of malignancies including breast and anaplastic thyroid cancers. No significant pharmacokinetic interaction was observed, but a transient increase in epirubicinol plasma concentration occurred during and after docetaxel infusion. CONCLUSIONS: The recommended dose level of docetaxel 85 mg/m(2), epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) with G-CSF support has a favorable toxicity profile and is suitable for further investigation in phase II and III trials.     

A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer

The purpose of the study was to determine the maximum-tolerated dose (MTD) of oral capecitabine, combined with concurrent, standard preoperative pelvic radiotherapy, when given twice daily, from Monday to Friday throughout the course of radiotherapy, for locally advanced potentially resectable rectal cancer. Maximum-tolerated dose was defined as the total (given in two equally divided doses) oral dose of capecitabine that caused treatment-related grade 3 or 4 toxicity in one-third or more of the patients treated. Radiotherapy involved 50.4 Gy given in 28 fractions in 5 weeks and 3 days. Eligible patients had a newly diagnosed clinical stage T3-4 N0-2 M0 rectal adenocarcinoma located within 12 cm of the anal verge suitable for curative resection. Surgery was performed 4-6 weeks from completion of preoperative chemoradiotherapy. In all, 28 patients were enrolled in the study at predefined dose levels: 850 mg m(-2) day(-1) (n=3), 1000 mg m(-2) day(-1) (n=6), 1250 mg m(-2) day(-1) (n=3), 1650 mg m(-2) day(-1) (n=3), 1800 mg m(-2) day(-1) (n=8) and 2000 mg m(-2) day(-1) (n=5). The mean age was 62.3 years (range: 33-80 years). Five patients were female and 23 male. The median distance of tumour from the anal verge was 6 cm (range: 1-11 cm). Endorectal ultrasound was performed in 93% of patients. A total of 26 patients (93%) had T3 disease and two patients had resectable T4 disease. Dose-limiting toxicity (DLT) developed in one patient at dose level 1000 mg m(-2) day(-1) (RTOG grade 3 cystitis). Two of the five patients at dose level 2000 mg m(-2) day(-1) had a total of three DLT (grade 3 perineal skin reaction, grade 3 diarrhoea and grade 3 dehydration). Dose escalation of capecitabine was ceased at 2000 mg m(-2) day(-1) after reaching MTD. None of the eight patients at dose level 1800 mg m(-2) day(-1) developed DLT. All except one patient underwent surgery. A total of 15 patients had the clinical T stage reduced by at least one stage in pathologic specimens. Five patients (19%) achieved a pathologic complete response. We conclude that the MTD of capecitabine was reached at a dose level of 2000 mg m(-2) day(-1), given as 1000 mg m(-2) twice daily, from Monday to Friday throughout the course of preoperative pelvic irradiation of 50.4 Gy. For patients with resectable rectal cancer receiving concurrent, full dose radiotherapy, the recommended dose of capecitabine for further study is 1800 mg m(-2) day(-1) when given in this schedule.     

Metronomic oral low-dose treosulfan chemotherapy combined with cyclooxygenase-2 inhibitor in pretreated advanced melanoma: a pilot study

Purpose The safety and efficacy of oral metronomic low-dose treosulfan chemotherapy in combination with the cyclooxygenase-2 (COX-2) inhibitor rofecoxib as a compound with antiangiogenic potential, a therapeutic regimen optimally targeting endothelial cells instead of tumor cells, were assessed in pretreated advanced melanoma patients.Methods Endothelial cells were analyzed for proliferation, apoptosis and cytotoxicity in response to increasing concentrations of treosulfan, either in the absence or presence of COX-2 inhibitor, to determine whether inhibition of COX-2 enhanced the effect of treosulfan on cell function. In a clinical pilot study, 12 consecutive patients with pretreated advanced melanoma, meeting the eligibility criteria were enrolled. Patients received combined daily treosulfan chemotherapy (500 mg) with rofecoxib (25 mg). Metastatic lesions were assessed every 12 weeks. Patients with responsive or stable disease were eligible for a further 12-week treatment period. Response criteria according to the WHO handbook for reporting results of cancer treatment were applied. Side effects were classified according to the National Cancer Institute's Common Toxicity Criteria v2.0.Results At noncytotoxic concentrations, treosulfan inhibited endothelial cell proliferation in a dose-dependent fashion. Simultaneous inhibition of COX-2 significantly increased the extent to which treosulfan suppressed cell proliferation, without inducing cytotoxicity. In the pilot study in which 12 patients were treated, toxicity was mild; only hematologic toxicity of grade II was seen. An objective response was noted in one patient, and four patients showed stabilization of their disease for 24 weeks (one) and 36 weeks (three). The patient who had a partial response subsequently showed stable disease for 48 weeks. The median survival time was 13 months.Conclusions As increases in response rates following polychemo- or biochemotherapy have not been shown to correlate with prolongation in overall survival, more durable control of metastatic melanoma represents an attractive therapeutic goal. Thus, regimens scheduled to primarily target endothelial cells may potentially provide a palliative alternative that preserves quality of life in the absence of significant treatment-related toxicity.     

Multicenter phase II study of oral capecitabine (Xeloda(")) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy.

BACKGROUND: Capecitabine is a rationally designed oral, tumor-activated fluoropyrimidine carbamate with high activity in metastatic breast cancer. This multicenter phase II study was designed to evaluate further the efficacy and safety of capecitabine in patients with metastatic breast cancer previously treated with a taxane-containing regimen. PATIENTS AND METHODS: All patients had to have documented progression after paclitaxel- or docetaxel-containing chemotherapy. Treatment comprised 3-week cycles of oral capecitabine 1250 mg/m(2) twice-daily for 14 days followed by a 7-day rest period. RESULTS: One hundred and thirty-six patients were enrolled. Disease stabilization occurred in 63 patients (46%) and the overall response rate was 15% (95% confidence interval 10% to 23%), providing an overall tumor control rate of 62%. Median time to progression was 3.5 months, median duration of response was 7.5 months and median overall survival was 10.1 months. Capecitabine was generally well-tolerated: most treatment-related adverse events were grade 1/2 in intensity; grade 3/4 treatment-related adverse events were hand-foot syndrome (13%), diarrhea (8%), vomiting (4%) and nausea (3%). There were no treatment-related deaths. CONCLUSIONS: This study confirms that capecitabine achieves a high tumor control rate in heavily pretreated patients with metastatic breast cancer. Due to its favorable safety profile and convenient oral administration, capecitabine can be given as an outpatient therapy. Capecitabine should be considered the reference treatment in this setting based on consistently high efficacy and good tolerability.     

多西紫杉醇联合表阿霉素及环磷酰胺治疗晚期乳腺癌的临床观察

目的：观察多西紫杉醇联合表阿霉素及环磷酰胺治疗晚期乳腺癌的疗效与不良反应。方法：采用多西紫杉醇联合表阿霉素及环磷酰胺治疗56例复发或转移的晚期乳腺癌患者,多西紫杉醇75mg/m2,d1,表阿霉素50mg/m2,d1,环磷酰胺500mg/m2,d1,21天为1周期,连续治疗2周期。结果：56例患者TEC方案治疗2周期后CR7例,PR22例,总有效率为51.8%。最常见不良反应为骨髓抑制、消化道反应及脱发,本组无一例发生过敏反应,其不良反应可耐受。结论：TEC方案治疗晚期乳腺癌可作为晚期乳腺癌的一线治疗方案。     

Effective oral chemotherapy for breast cancer: pillars of strength.

Traditionally, anticancer therapy has been dominated by intravenous drug therapy. However, oral agents provide an attractive approach to chemotherapy and use of oral treatments is increasing. We discuss the benefits and challenges of oral chemotherapy from the perspectives of patients, healthcare providers and healthcare funders. Important issues include patient preference, efficacy, compliance, bioavailability, reimbursement, use in special patient populations, financial and staff time savings and flexibility of dosing. We review data for traditional oral agents (e.g. cyclophosphamide, methotrexate), newer oral chemotherapies (e.g. capecitabine), oral formulations of traditionally intravenous agents (e.g. vinorelbine, idarubicin) and new biologic agents under evaluation in breast cancer (e.g. tyrosine kinase inhibitors). Lastly, we review studies of all-oral combination regimens. The wealth of data available and the increasing use of oral agents in breast cancer suggest that many of the concerns and perceptions about oral therapy, including efficacy and bioavailability, have been overcome, and that oral therapy will play a major role in breast cancer management in the future in both the metastatic and adjuvant settings.     

A Prospective Phase I/II Study of Docetaxel,Cisplatin and Continuous Capecitabine in Advanced Oesophago-Gastric Cancer (NWCOG-3)

Aims

This open-label prospective phase I/II dose-escalation study determined the maximum tolerated dose (MTD) and then evaluated response, safety and feasibility of a novel combination of docetaxel, cisplatinum and capecitabine (DCC) in chemotherapy-naive patients with advanced oesophago-gastric carcinoma.

A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer.

PURPOSE: The aim of this study was to determine in patients with previously untreated advanced colorectal cancer the maximum tolerated dose (MTD) and safety profile of irinotecan in combination with capecitabine, to identify a recommended dose and to determine the response rate and time to disease progression. In addition, we aimed to explore the pharmacokinetic parameters of irinotecan and capecitabine when used in different sequences of administration, with irinotecan infusion either prior to or after the first intake of capecitabine. PATIENTS AND METHODS: One hundred patients were included: 43 patients were recruited into an extended phase I trial of alternating escalation in dose of both drugs where irinotecan was administered intravenously (i.v) on day 1 after first intake of capecitabine taken from days 1-14 twice daily, with cycles repeated every 3 weeks. After the determination of recommended dose a further 57 patients were treated in a phase II evaluation with the reverse sequence of drugs on day 1. Pharmacokinetic analysis was performed in patients treated at the recommended dose in two cohorts of patients in which the sequence of the first administration of each drug was reversed. RESULTS: The MTD of the combination was determined as irinotecan 300 mg/m2, with capecitabine 2000 mg/m2/day. Dose limiting toxicities were neutropenia and diarrhoea. The recommended dose is irinotecan intravenous (i.v.) 250 mg/m2 day 1 and capecitabine 2000 mg/m2/day days 1-14, every 3 weeks. Treatment was well tolerated, with diarrhoea the most common serious toxicity. Response rate in the phase II cohort was 42% [95% confidence interval (CI) 29% to 56%]. Median duration of response was 7.7 months (95% CI 7.5-8.9). Median time to progression was 8.3 months (95% CI 5.8-10). No significant effect on irinotecan pharmacokinetics was observed whatever the intake of capecitabine before or after irinotecan infusion. An effect of irinotecan on capecitabine and some capecitabine metabolites was observed, but irinotecan did not effect 5-fluorouracil (5-FU) pharmacokinetics. CONCLUSIONS: Irinotecan in combination with capecitabine is a well tolerated regimen with an activity comparable to, but more convenient than, irinotecan-5-FU i.v. combinations in patients with previously untreated advanced colorectal cancer. The pharmacokinetic data suggest that the sequence of administration does not impact significantly on the metabolism of the two drugs.     

Capecitabine monotherapy for recurrent and metastatic nasopharyngeal cancer

Background: Capecitabine monotherapy had activity in recurrent/metastaticnasopharyngeal carcinoma (NPC) as demonstrated previously ina small pilot study. We conducted a retrospective review ofpatients who received capecitabine for recurrent and metastaticNPC to further evaluate its clinical benefits. Methods: Forty-nine patients with recurrent and metastatic NPC receivedcapecitabine at a dose of 1–1.25 G/m² twice daily for14 days in 3-week cycles. Disease sites were locoregional in29%, distant in 45% and locoregional plus distant in 26%. Allexcept one had prior platinum-based chemotherapy for relapseor as adjunctive treatment. Median follow-up was 10 months (range:3–41). Results: Treatment was generally well tolerated. Hand-foot syndrome wascommon and occurred in 86% (25% Grade 3). Grade 3 hematologicaltoxicity occurred in 6%. Partial response rate was 31% (95%CI: 18%, 44%) and complete response rate was 6% (95% CI: 0%,13%), for an overall response rate of 37% (95% CI: 23%, 50%).Median time-to-progression was 5 months and median survivalwas 14 months. One- and two-year survival rates were 54 and26%, respectively. Significantly better survival was observedin patients treated for locoregional recurrence and those withsevere hand-foot syndrome. Conclusions: Capecitabine has single agent activity in NPC and severe hand-footsyndrome predicts favorable outcome. Based on our experience,capecitabine monotherapy should be considered in patients withrecurrent/metastatic NPC.     

A phase II trial of cyclophosphamide, epirubicin and vinorelbine in the treatment of advanced breast cancer

Background.Vinorelbine (Navelbin®; N) has proven to be active in patients with advanced breast cancer (ABC) and cyclophosphamide (C) and epirubicin (Epiadriamycin®: E) are still among the main cytostatic agents against this tumor. On this basis was carried out a study to determine the activity and toxicity of the combination of these three agents (CEN). Patients and method.From April 1996 to March 1998, 59 patients with ABC were recruited of whom 56 were found eligible and evaluable for toxicixty and 55 for activity. The treatment regimen was C: 400mg/m², E: 30mg/m² and N: 25mg/m² administered intravenously on days 1 and 8 of a 28-day cycle. Results.The median number of cycles administered was 6 (range: 1–16). The most common hematological toxicity was grade (G) 3 and 4 neutropenia occurring in 36% of patients, associated with fever in 7% of them. Grade 3–4 thrombocytopenia and anemia occurred in 5% and 7%, respectively. Other G2–G3 non hematologic toxicities were: N/vomiting in 34%, alopecia in 73% and mucositis in 11% of patients. An objective response was achieved in 28 of 56 patients (50%) (95% confidence interval (CI): 37–63%): complete response (CR) in 9%, partial response (PR) in 41%. The median duration of response, time to progression and overall survival time was 54, 47 and 90 weeks, respectively. Conclusion.The CEN combination at these doses and treatment schedule appears to have acceptable tolerability but there is no apparent improvement in therapeutic efficacy when compared to other regimens used as first line treatment in ABC.     

A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours

Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1-14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m(-2) twice a day and of docetaxel from 75 to 100 mg m(-2). The dose-limiting toxicity (DLT) was asthenia grade 2-3 at a dose of 1000 mg m(-2) bid of capecitabine combined with docetaxel 100 mg m(-2). Neutropenia grade 3-4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m(-2) twice a day plus docetaxel 100 mg m(-2) was tolerable, as was capecitabine 1250 mg m(-2) twice a day plus docetaxel 75 mg m(-2).     

卡培他滨维持治疗局部晚期鼻咽癌的回顾性研究

目的:回顾性分析中国西北地区非高发区N2³期鼻咽癌根治性放化疗后序贯卡培他滨维持化疗的疗效,以明确卡培他滨维持化疗在局部晚期鼻咽癌治疗中的价值。方法:选取2014年1月至2016年12月空军军医大学第一附属医院初诊初治、经病理确诊为鼻咽癌N2³期的患者,给予诱导化疗2³个周期后联合同期放化疗,研究组(维持化疗组)在根治性放化疗后继续予以卡培他滨维持化疗4个周期,对照组(未维持化疗组)观察随访。比较两组患者的生存差异,评价两种方案的不良反应及顺应性。结果:共179例患者纳入本研究,研究组84例,对照组95例。两组病例一般临床资料均衡。全组中位随访时间44.4(5.97⁷0.26)个月,研究组与对照组3年无远处转移生存率(distant metastasis-free survival,DMFS)分别为79.3%、68.1%(χ²=3.898,P=0.048),3年无病生存率(disease-free survival,DFS)分别为75.6%、64.2%(χ²     

Combination treatment of advanced pancreatic cancer using novel vaccine and traditional therapies

Introduction: Pancreatic cancer is a highly malignant disease with high treatment resistance. Many patients are diagnosed in a very advanced state, and few patients can be curatively resected. With FOLFIRINOX and nab-paclitaxel plus gemcitabine, the prognosis of advanced pancreatic cancer has improved, yet many patients cannot survive longer than a year. Therefore, new therapeutic approaches are needed. Cancer vaccine therapy is characterized by controlling cancer by a cancer-specific immune reaction with few adverse events. Thus, a cancer peptide vaccine is considered promising for pancreatic cancer patients, who are often in poor general condition at diagnosis.

Areas covered: This article reviews available data from recent clinical trials of the novel cancer vaccine therapy in combination with traditional chemotherapy or radiotherapy for pancreatic cancer, and the prospect will be described.

Expert commentary: In clinical trials of the novel cancer vaccine therapy in combination with traditional therapy, many studies have failed to outperform traditional therapy, although some effects were recognized in subgroups. What is necessary in the future for cancer vaccine therapy to improve the prognosis of pancreatic cancer is combination of immune-checkpoint blockade to release immune escape mechanism and combination with strong multi-drug combination chemotherapy.     

Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study.

BACKGROUND: The aim of the study was to evaluate tolerance and efficacy of preoperative treatment with capecitabine in combination with radiation therapy (RT) in patients with locally advanced, resectable, rectal cancer. PATIENTS AND METHODS: Fifty-three patients with potentially resectable T3, N0-2 (87%) and T4, N0-2 (13%) rectal cancer were treated with capecitabine (825 mg/m2, twice daily for 7 days/week) and concomitant RT (50.4 Gy/28 fractions). Patients underwent surgery after 6-8 weeks followed, upon physician's indications, by 4-months adjuvant capecitabine. The primary end point was to determine the rate of pathologic complete response. Secondary end points were to assess the rate of clinical response and the safety profile. RESULTS: All patients but two completed the RT programme and 47 (89%) received 81%-100% of the capecitabine dose (100% of dose in 72% patients, 81%-95% in 17% patients and 48%-74% in 11% of patients). No patient had grade 4 toxicity. Grade 3 toxicity occurred in six patients (11%) and consisted mainly of leucopenia (4%) and hand-foot syndrome (4%). Mild or moderate toxicity was common and included leucopenia (72%), diarrhea (40%), proctitis (34%) and skin toxicity (20%). The overall clinical response rate was 58% and the downstaging rate was 57%, with a pathologic complete response rate of 24%. Among 34 patients with low-lying tumors (相似文献   

Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial

Evaluation of new drug combinations is needed to improve patients' prognosis in advanced hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the safety and efficacy of the capecitabine-oxaliplatine combination (XELOX) in HCC patients. First-line chemotherapy with XELOX regimen consisting of a 3-week cycle of intravenous oxaliplatin (130 mg m(-2)) on Day 1, and oral capecitabine twice daily from Days 1-14 (1000 mg m(-2)) was administered in patients with measurable, unresectable HCC. Fifty patients (male, 88%; median age, 68 years) received a total of 295 cycles (median, 6) of treatment. Disease control (three partial responses, 29 stable diseases) rate was 72% (95% CI 57-83%). Median overall and median progression-free (PFS) survival was 9.3 months and 4.1 months, respectively. Progression-free survival rates at 6 and 12 months were 38% (95% CI 26-52%) and 14% (95% CI 7-26%), respectively. Main grade 3-4 drug-related toxicities included diarrhoea (16%), elevation of aminotransferases and/or bilirubin (16%), thrombocytopenia (12%), and neurotoxicity (6%). Capecitabine plus oxaliplatin regimen showed modest anti-tumour activity with tolerable toxicities in patients with advanced HCC. However, the manageable toxicity profile and the encouraging disease control rate deserve further attention for this convenient, outpatient-based chemotherapy regimen.     

Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation

The main purpose of the present review article was to shed light on the different 5-fluorouracil (5-FU) prodrugs by underlining their respective pharmacological features in terms of metabolic activation, dihydropyrimidine dehydrogenase inhibition, pharmacokinetic profile and biomodulation ability. Oral fluoropyrimidines differ particularly as concerns their pharmacokinetic profile and especially in the delivery of circulating 5-FU. More clinical studies need to be performed incorporating tumour predictive markers during oral fluoropyrimidine-based treatment. The new possibilities are to achieve pharmacomodulation of oral fluoropyrimidines, notably for UFT and capecitabine, that open up the prospect of establishing significant novel treatment protocols based on drug combinations.     

Phase I, dose-finding study of capecitabine in combination with docetaxel and epirubicin as first-line chemotherapy for advanced breast cancer.

PURPOSE: Capecitabine is an oral fluoropyrimidine with considerable activity and minimal myelosuppression and alopecia. This phase I study evaluated the addition of capecitabine to epirubicin/docetaxel combination therapy as first-line treatment for advanced breast cancer. PATIENTS AND METHODS: Twenty-three female patients with advanced breast cancer received capecitabine (765-1060 mg/m2 twice daily on days 1-14 of a 3-week treatment cycle) in combination with epirubicin and docetaxel (75 mg/m2 i.v. on day 1). RESULTS: The maximum tolerated dose of capecitabine was 985 mg/m2 and the principal dose-limiting toxicity was febrile neutropenia. No grade 3/4 anemia or thrombocytopenia occurred. There were no grade 4 non-hematological events and grade 3 events other than alopecia were rare. Alopecia occurred in all patients and treatment cycles, and asthenia occurred in all patients and in 84% of treatment cycles. Other frequent adverse events included nausea, vomiting, fever, paresthesia and elevated transaminase levels. An objective response to treatment was observed in 91% (95% confidence interval 72% to 99%) of patients. CONCLUSIONS: The addition of capecitabine to docetaxel/epirubicin combination therapy provides a well-tolerated and active first-line chemotherapy regimen in patients with advanced breast cancer, and merits phase II/III evaluation.