Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature.

BACKGROUND: Capecitabine is active against anthracycline- and taxane-pretreated metastatic breast cancer. Post-marketing use of capecitabine at the FDA-approved dose (2500 mg/m2/day) leads to unacceptable toxicity in many patients. Dose reductions anecdotally improve tolerability without compromising efficacy. This retrospective analysis was designed to verify these anecdotal reports. Patients and methods: We retrospectively reviewed the records of 141 consecutive patients with metastatic breast cancer identified from pharmacy records as receiving capecitabine outside of a clinical trial between May 1998 and February 1999. Responses were defined as clinical improvement (ID), stabilization of disease (SD) for 6 weeks or longer, or progression (PD). Patients were grouped according to the starting dose level of capecitabine: A=2500+/-5% (dose range 2385-2560) mg/m2/day; B=2250+/-5% (range 2130-2350) mg/m2/day; C < or = 2000+5% (range 1000-2100) mg/m2/day. We also reviewed the safety profile of capecitabine at these doses and performed a safety review of capecitabine in phase II and III metastatic breast and colorectal cancer trials. RESULTS: Clinical data were available for 113 patients (105 for response, 106 for toxicity). The median age was 52.5 years and the mean number of prior metastatic chemotherapy regimens was 2 (range 0-7). The mean capecitabine starting dose was 2220 mg/m2/day and the median number of cycles administered was 4 (range 1-19). The mean tolerated dose was 2040 mg/m2/day (range 960-2670). Grade 3/4 toxic effects at dose levels A, B and C, respectively, included palmar-plantar erythrodysesthesia (33%, 63%, 20%), diarrhea (13%, 12%, 3%), stomatitis (8%, 0%, 3%), and nausea/vomiting (4%, 6%, 5%). Forty per cent of all patients required capecitabine dose reductions; fewer patients treated with 2000 mg/m2/day required dose modification (28%). Five per cent of the patients required discontinuation of capecitabine owing to toxicity. Patients started at the lowest doses of capecitabine did not have poorer response rates or shorter time to progression. CONCLUSIONS: This retrospective analysis supports a starting dose of 2000 mg/m2/day because of its superior therapeutic index; however, patients may still have toxic effects and individualization of dosing is necessary. A phase III, multicenter, randomized study to establish the safety and efficacy of different doses of capecitabine is urgently needed.     

Capecitabine and vinorelbine in elderly patients (> or =65 years) with metastatic breast cancer: a phase I trial (SAKK 25/99).

BACKGROUND: Few chemotherapy regimens are suitable for the treatment of elderly patients with advanced breast cancer. With the aim of finding a regimen with a low burden of subjective non-overlapping toxic effects, vinorelbine and capecitabine were chosen to be investigated in a phase I dose-finding study. PATIENTS AND METHODS: Thirty-six patients with advanced breast cancer were stratified for the presence of bone and non-bone involvement and treated at four dose levels from capecitabine 800 mg/m2 orally days 1-14 and vinorelbine 20 mg/m2 intravenously days 1 and 8, to capecitabine 1250 mg/m2 orally days 1-14 and vinorelbine 25 mg/m2 intravenously days 1 and 8, for a maximum of six cycles. None of the patients had received prior chemotherapy for metastatic/advanced disease. Fifty-three per cent of patients with bone metastases and 67% of patients without bone metastases had visceral disease. The median age was 70 years for the 15 with bone involvement patients and 73 years for the 21 without bone involvement patients. RESULTS: Twenty-eight patients were fully evaluable for hematological dose-limiting toxicity (DLT), and all patients for other DLTs and for antitumor activity. One DLT with grade 3 venous thrombosis at dose level 2 and two dose-limiting neutropenia events at level 3 occurred in patients without bone involvement. Two dose-limiting neutropenia events were observed at dose level 2 for patients with bone involvement. Thus, the recommended dose was defined at level 1 (capecitabine 1000 mg/m2 days 1-14 and vinorelbine 20 mg/m2 days 1 and 8) for patients with bone involvement. For patients without bone involvement, the recommended dose was at level 2 (capecitabine 1250 mg/m2 days 1-14 and vinorelbine 20 mg/m2 days 1 and 8). For patients without bone involvement the overall response rate was 48% and the time to progression (TTP) was 4.5 months [95% confidence interval (CI) 3.3-6.9]. For patients with bone involvement the overall response rate was 53% and TTP was 5.3 months (95% CI 2.7-7.8). CONCLUSIONS: This regimen of capecitabine and vinorelbine is well tolerated and effective in elderly patients with metastatic breast cancer. Toxicity was mainly hematological and was observed at a lower dose in patients with bone involvement. A phase II study with the two different dose levels for elderly patients with and without bone involvement is currently being conducted.     

草酸铂联合卡培他滨治疗晚期胃癌的近期疗效分析

目的：探讨草酸铂联合卡培他滨治疗晚期胃癌的近期疗效。方法：对32例晚期胃癌采用草酸铂联合卡培他滨方案治疗共76周期。结果：CR6例，PR16例，NC8例和PD2例，总有效率(CR PR)为68．75％(22／32)。中位缓解期8个月，中位生存期12个月，1年生存率为55％；临床受益者共30例(93．75％)。不良反应可耐受，经积极对症治疗后均见好转，无相关死亡出现。无患者因为不良反应中止治疗。结论：草酸铂加卡培他滨方案而组成的OX方案治疗晚期胃癌疗效较好，毒性反应能够耐受，可作为经济状况好的患者的一线方案在更多的病人中应用，以进一步探讨其疗效。     

卡培他滨联合肝动脉栓塞化疗治疗原发性肝癌

目的 :探讨卡培他滨联合经肝动脉栓塞化疗 (TACE)治疗晚期肝癌的有效性。方法 :6 2例不能手术切除的晚期肝癌患者 (TNM分期Ⅱ～Ⅳ )随机分成两组 :①单纯TACE组 30例 ;②卡培他滨联合TACE组 32例 ,在TACE治疗后第 2天 ,口服给药 14天。全部患者随访两年。比较两组患者的中位生存时间 ,死亡患者平均生存时间、一年生存率、二期手术切除率。结果 :卡培他滨联合TACE治疗组患者的中位生存时间为 14 .5个月 ,一年生存率为 75 .0 % ,二期手术切除率 2 5 .0 % ;而单纯TACE组患者的中位生存时间为 6个月 ,一年生存率为 39.3% ,二期手术切除率 6 .7% ,两组比较有显著差异 (P <0 .0 5 )。结论 :卡培他滨联合TACE治疗晚期原发性肝癌患者的疗效优于单纯TACE。     

Front-line treatment of inoperable or metastatic pancreatic cancer with gemcitabine and capecitabine: an intergroup, multicenter, phase II study.

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (GEM) combined with capecitabine (CAP) in untreated patients with inoperable or metastatic pancreatic cancer. PATIENTS AND METHODS: Fifty-three patients with pancreatic cancer (85% stage IV) were enrolled. Patients were treated with GEM 1000 mg/m2 on days 1 and 8 and CAP 1300 mg/m2 per day PO (per os), divided into two equal doses on days 1-14, in 21-day cycles. RESULTS: In an-intention-to-treat analysis, 10 (18.9%) objective partial responses were achieved (95% confidence interval 8.33% to 29.4%). Twenty-two (42%) patients had stable disease and 15 (28%) had progressive disease. The median response time was 3 months (range 1.5-7.0) and the median time to tumor progression was 6.5 months (range 3.5-15.5). Median overall survival time was 8 months (range 1.0-15.5) and 1-year survival was 34.8%. Pain improvement during treatment was observed in 23 of 43 (53%) patients, and eight of 18 (44%) patients who had been receiving opioids discontinued their use. Weight gain was observed in 12 of 33 (36%) patients. Grade 3 anemia occurred in five (9%) patients and grade 3-4 thrombocytopenia occurred in three (6%). Grade 3-4 neutropenia occurred in 13 (25%) and five (9%) patients, respectively, and two (4%) developed febrile neutropenia. Non-hematological toxicity was mild. CONCLUSION: In patients with pancreatic cancer, the combination of GEM with CAP is an active and well tolerated regimen that merits further evaluation in prospective randomized studies.     

Upregulation of thymidine phosphorylase in rectal cancer tissues by mitomycin C

BACKGROUND AND OBJECTIVES: We have investigated the regulation by mitomycin C (MMC) of thymidine phosphorylase (dThdPase) and dihydropyrimidine dehydrogenase (DPD), which enhances or reduces the efficacy of capecitabine and its metabolite 5'-deoxy-5-fluorouridine (5'-DFUR), in rectal cancer tissues. MATERIALS AND METHODS: In 31 patients with a rectal cancer, tumor biopsies were performed before and after pre-operative venous administration of 4 mg/m2, 6 mg/m2, or 10 mg/m2 of MMC. The dThdPase and DPD levels in the biopsy and surgical specimens were measured using ELISA, and immunostaining for dThdPase was performed. RESULTS: The fitting multiple linear regression models indicated that the dThdPase levels increased after MMC administration, in particular in the patients with a pre-treatment dThdPase level less than 56.2 U/mg protein (median value). The time course analysis indicated that the increase in the dThdPase level by 4 mg/m2 of MMC administration continued for 3 weeks. The dThdPase/DPD ratio was increased after MMC administration in patients with a pre-treatment dThdPase/DPD ratio less than 1.79 (median value). MMC enhanced the expression of dThdPase protein both in the tumor cells and in the stromal cells. The disease free-survival rate in the Dukes B or C patients with a high dThdPase/DPD ratio in surgical specimen who received 5'-DFUR based adjuvant chemotherapy tended to be higher than that in those with a low dThdPase/DPD ratio. CONCLUSION: MMC may upregulate the dThdPase level and the dThdPase/DPD ratio in rectal cancer tissues. Combined use of MMC with capecitabine or 5'-DFUR may offer a more effective colorectal cancer therapy.     

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。     

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.     

1，2，3-O-三乙酰基-5-脱氧核糖的合成工艺研究

目的抗肿瘤药物中间体1，2，3-O-三乙酰基-5-脱氧核糖的合成。方法以肌苷为起始原料经碘化得5＇-碘代-6-羟基-9-β-D-嘌呤核苷，产物氢化得产物5＇-脱氧-6-羟基-9-β-D-嘌呤核苷，然后经酰化共3步反应合成1，2，3-O-三乙酰基-5-脱氧核糖。结果以肌苷为起始原料经3步反应合成了1，2，3-O-三乙酰基-5-脱氧核糖。结论本合成方法原料价廉易得，工艺简便，条件温和，总收率为38．0％，适合于工业制备。     

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。