Capecitabine: an evidence-based review of its effectiveness in the treatment of carcinoma of the pancreas

Introduction:

More than 90% of patients with pancreatic cancer present either with incurable locally advanced or metastatic disease or relapse following surgery. For these patients systemic therapy offers the only prospect of salvage, but pancreatic cancer is one of the most chemoresistant of tumors; current chemotherapy can only delay progression in a limited proportion of patients and survival rates are poor. There is therefore a pressing need for more effective therapy. Capecitabine is a new oral prodrug of fluorouracil, which has shown activity in pancreatic cancer particularly when used in combination with gemcitabine.

Aims:

To review the emerging evidence for the clinical effectiveness of capecitabine in the management of carcinoma of the pancreas.

Evidence review:

There is evidence from phase II testing that capecitabine is active in pancreatic cancer. The Swiss Group for Clinical Cancer Research/Central European Cooperative Oncology Group (SAKK/CECOG) phase III trial found that the combination of gemcitabine and capecitabine did not improve overall median survival as compared with gemcitabine alone (8.4 vs 7.3 months, respectively; P=0.314) but subgroup analysis in patients with good performance score [Karnofsky Performance Scores (KPS) ≥90] revealed a significant survival improvement with the combination arm (10.1 months) compared with single-agent gemcitabine (7.5 months; P=0.033). Preliminary data from the GemCap phase III trial indicated significantly improved response rates and survival for the combination of gemcitabine with capecitabine (7.4 months) compared with gemcitabine alone (6 months; P=0.026) but analysis of the mature data with adequate follow-up awaits reporting.

Clinical potential:

The addition of capecitabine to gemcitabine may represent a small step forward in the management of advanced pancreatic cancer but further data are required in order to determine its full impact.     

A phase II trial of capecitabine (Xeloda) in recurrent ovarian cancer

Oral capecitabine is a highly active, well-tolerated and convenient treatment for breast and colorectal cancer. This trial assessed the efficacy and safety of single-agent capecitabine in patients with previously treated ovarian cancer. A total of 29 patients with platinum-pretreated relapsed ovarian cancer were enrolled in this prospective, open-label, single-centre, phase II study. Patients received oral capecitabine 1250 mg m(-2) twice daily on days 1-14 of a 21-day cycle. Tumour response was evaluated using serum CA125. Out of 29 enrolled patients, 28 were evaluable, and a response was observed in eight patients (29%, 95% confidence interval (CI), 13-49%). Median progression-free and overall survivals were 3.7 (95% CI, 2.8-4.6) and 8.0 (95% CI, 4.1-11.8) months, respectively. After 6 months of treatment, 28% (95% CI, 13-48%) of patients remained progression-free and 62% (95% CI, 42-79%) were still alive. The most common clinical adverse events were hand-foot syndrome (HFS), nausea and diarrhoea. Grade 3 HFS occurred in 14% of patients, grade 3 vomiting in 10%. Efficacy and safety of capecitabine compare favourably with other monotherapies in platinum-refractory epithelial ovarian cancer. The convenience and improved safety profile of capecitabine compared with intravenous. regimens make it an ideal agent for administration in the outpatient setting.     

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.     

Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients

AIMS: To assess the relationship between systemic exposure to capecitabine metabolites and parameters of efficacy and safety in patients with advanced or metastatic colorectal cancer from two phase III studies. METHODS: Concentration-effect analyses were based on data from 481 patients (248 males, 193 females; age range 27-86 years) in two phase III studies. Plasma concentration-time data for 5'-deoxy-5-fluorouridine (5'-DFUR), 5-fluorouracil (5-FU) and alpha-fluoro-beta-alanine (FBAL) were obtained from sparse blood samples collected within the time windows 0.5-1.5 h, 1.5-3.0 h, and 3.0-5.0 h after capecitabine administration (1250 mg m(-2)) on the first day of cycles 2 (day 22) and 4 (day 64), respectively. Systemic exposure based on plasma concentrations of capecitabine and its metabolites was determined using individual parameter estimates derived from a population pharmacokinetic model constructed for this purpose in NONMEM. Logistic regression analysis was conducted for selected safety parameters (all treatment-related grade 3-4 adverse events, treatment-related grade 3-4 diarrhoea, grade 3 hand-foot syndrome (HFS) and grade 3-4 hyperbilirubinaemia) and for tumour response. Cox regression analysis was used for the analysis of time-to-event data (time to disease progression and duration of survival). RESULTS: Statistically significant relationships between covariates and PK parameters were found as follows. A doubling of alkaline phosphatase activity was associated with a 11% decrease in 5-FU clearance and a 12% increase in its AUC. A 50% decrease in creatinine clearance was associated with a 35% decrease in FBAL clearance, a 53% increase in its AUC, a 24% decrease in its volume of distribution, and a 41% increase in its Cmax. A 30% increase in body surface was associated with a 24% increase in the volume of distribution of FBAL and a 19% decrease in its Cmax. There was a broad overlap in systemic drug exposure between patients regardless of the occurrence of treatment-related grade 3-4 adverse events or response to treatment, leading to weak relationships between systemic exposure to capecitabine metabolites and the safety and efficacy parameters. Of 42 concentration-effect relationships investigated, only five achieved statistical significance. Thus, we obtained a positive association between the AUC of FBAL and grade 3-4 diarrhoea (P = 0.035), a positive association between the AUC of 5-FU and grade 3-4 hyperbilirubinaemia (P = 0.025), a negative association between the Cmax of FBAL and grade 3-4 hyperbilirubinaemia (P = 0.014), a negative association between the AUC of 5-FU (in plasma) and time to disease progression (hazard ratio (HR) = 1.626, P = 0.0056), and a positive association between the Cmax of 5'-DFUR and survival (HR = 0.938, P = 0.0048). Additionally, there were inconsistencies when concentration-effect relationships were compared across the two studies. CONCLUSIONS: Systemic exposure to capecitabine and its metabolites in plasma is poorly predictive of safety and efficacy. The present results have no clinical implications for the use of capecitabine and argue against the value of therapeutic drug monitoring for dosage adjustment.     

吉西他滨联合卡培他滨二线治疗晚期乳腺癌

背景与目的：含蒽环类或紫杉类药物的化疗方案是治疗晚期乳腺癌较佳的方案,但临床有20%～30%的患者疗效不佳,对这部分患者二线化疗目前无统一标准方案.本研究探讨既往接受过蒽环类和紫杉类药物治疗失败的晚期乳腺癌患者,使用吉西他滨联合卡培他滨方案治疗的疗效和毒性.方法：吉西他滨1 000 mg/m2,静脉滴注,第1、8天;卡培他滨950 mg/m2口服,每日2次,第1～14天;每3周为一周期,至少应用2疗程,评价临床疗效和毒性,并进行随访.结果：30例女性患者入本研究,疗效均可评价,CR 2例（6.7%）,PR 12例（40.0%）,SD 13例（43.3%）,PD 3例（10.0%）,总有效率（CR﹢PR）46.7%, 中位无进展生存期9个月,中位生存期12.5个月.主要毒性是骨髓抑制和手足综合征.结论：吉西他滨联合卡培他滨化疗方案二线治疗晚期乳腺癌有较好疗效,毒性可耐受.     

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.     

卡培他滨单药治疗老年晚期肿瘤的临床观察

目的：研究单药卡培他滨治疗老年晚期肿瘤的近期疗效及毒副反应。方法：27例老年晚期肿瘤患者，均经病理或临床诊断，治疗以卡培他滨2500mg／m2，每日分2次口服，d1-18，21天1个周期，至少2周期评价疗效。结果：27例完全缓解（CR）2例，部分缓解（PR）12例，无变化（NC）8例，进展（PD）5例，总有效率51．7％，1年生存率67．9％。毒性反应主要为消化道反应，可耐受。结论：对于老年晚期肿瘤患者，卡培他滨单药治疗疗效肯定，值得临床应用。     

Capecitabine and oral cyclophosphamide: A novel oral treatment combination for advanced cancer

Background: This dose escalation study assessed feasibility of a totally oral chemotherapy regimen using cyclophosphamide and capecitabine. The rationale for this combination was based on the observation that preclinical models of cyclophosphamide up‐regulated tumor thymidine phosphorylase and increased the activation of capecitabine. Methods: Eligible patients with advanced cancer were treated with oral cyclophosphamide and capecitabine on a 28‐day cycle. If no dose limiting toxicities (DLT) were encountered during the first two treatment cycles, the next patient group was assigned to the next highest dose level until the maximum tolerable dose (MTD) was determined. Results: Twenty‐seven patients entered treatment. The majority of non‐DLT were grades 1 and 2. DLT experienced in the first 8‐week observation period were grade 3 diarrhea (one patient, level III) and grade 3 emesis (two patients, level V). MTD was observed at level 5, 1331 mg/m²/day capecitabine days 1–28 with 125 mg/m²/day cyclophosphamide days 1–14 of the 28‐day cycle. The recommended phase II dose is therefore 1331 mg/m²/day capecitabine with 100 mg/m²/day cyclophosphamide. The best response evaluation showed four partial responses (breast, colon, ovary and pancreas). Conclusion: Cyclophosphamide and capecitabine can be combined at their full oral single agent dose with promising tolerability and activity.     

卡培他滨引起急性肾衰竭

1名94岁男性直肠腺癌患者接受卡培他滨化疗。在第3周期给予卡培他滨1500mg,2次/d,用药12d后,患者出现嗜睡、心慌、发热,血Cr由145μmol/L上升到173μmol/L,BUN由10.9mmol/L上升到27.4mmol/L,立刻停药。6d后,SCr310μmol/L,BUN62.5mmol/L。给予复方α-酮酸、利尿剂、低蛋白饮食等治疗,SCr及BUN逐渐下降。4个月后复查,SCr及BUN恢复正常。     

Capecitabine plus docetaxel every 3 weeks in first- and second-line metastatic oesophageal cancer: final results of a phase II trial

Capecitabine and docetaxel have single-agent activity in upper gastrointestinal tumours, and have together demonstrated preclinical synergy and a survival benefit in breast cancer, and high response rates in first-line metastatic gastric cancer. This trial assessed the efficacy, safety and feasibility of capecitabine in combination with docetaxel in patients with metastatic oesophageal cancer. In all, 24 patients with advanced disease (17 squamous cell carcinoma and seven adenocarcinoma) received oral capecitabine (1000 mg m(-2) twice daily on days 1-14) plus intravenous docetaxel (75 mg m(-2) on day 1) every 3 weeks as first- (n = 16) or second-line (n = 8) therapy. Patients received a median of four cycles of treatment (range, 0-6). The median follow-up is 16.5 months (range, 7.9-21.4 months). Intent-to-treat efficacy analysis showed an overall response rate of 46%. Of the 11 responders (one complete and 10 partial), nine of 16 (56%) received first-line and two of eight (25%) received second-line therapy. The median time to progression was 6.1 months (95% confidence interval (CI), 4.5-7.7 months). The median survival was 15.8 months (95% CI, 7.8-23.9 months). Severe adverse events (grade 3/4) reported were: neutropenia (42%, including febrile neutropenia 8%), hand-foot syndrome (29%), diarrhoea (13%), sensory neuropathy (13%), anaemia (8%) and fatigue (8%). Capecitabine plus docetaxel has a manageable adverse event profile and very promising activity in metastatic oesophageal cancer, at least comparable to other doublet regimens. Therefore, the combination merits further investigation in this setting.