Capecitabine treatment patterns in patients with gastroesophageal cancer in the United States

AIM： To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer （GEC） in a real-world treat- ment setting. METHODS： Patients with claims between 2004 and 2005 were identified from the Thomson Reuters MarketScan databases. Capecitabine regimens were compared with 5-fluorouracU （5-FU） and other chemotherapy regimens, and were stratified by treatment setting. RESULTS： We identified 1013 patients with GEC： approximately half had treatment initiated with a 5-FU regimen, whereas 11% had therapy initiated with a capecitabine regimen. The mean capecitabine dose overall was 2382 ± 1118 mg/d, and capecitabine was used as monotherapy more often than in combination. Overall, 5-FU regimens were the most common treat- ment option in neoadjuvant and adjuvant settings, while other non-capecitabine regimens were used more widely in first- and second-line settings. The overall unadjusted complication rate for capecitabine regimens was about half of that seen with 5-FU regimens. In multivariate analyses, capecitabine recipients had a 51% （95% CI： 26%-81%） lower risk of developing any complication than 5-FU recipients did. The risk of developing bone marrow, constitutional, gastrointestinal tract, infectious, or skin complications was lower with capecitabine therapy than with 5-FU.CONCLUSION： Capecitabine appeared to have a favorable side effect profile compared with 5-FU, which indicates that it may be a treatment option for GEC.     

伊立替康联合卡培他滨治疗晚期结直肠癌的临床观察

目的观察伊立替康联合卡培他滨治疗晚期结直肠癌的疗效和安全性。方法回顾性分析62例复发或转移性结直肠癌患者,接受伊立替康联合卡培他滨治疗：伊立替康125mg／m^2 d1、d8、d15静脉滴注90min;卡培他滨（希罗达）2500mg/m^2,分早晚2次,第1—14天,每28天重复。治疗至少2个周期,按照WHO标准进行疗效和不良反应评价,并观察至疾病进展时间及总生存期。结果62例患者中,可评价疗效的有59例。其中一线治疗28例,RR42．8％,DCR71．4％,TTP 8．6个月,MST18．8个月;二线治疗31例,RR32．3％,DCR61．2％,TTP 7．2个月,MST13．2个月。不良反应主要为恶心与呕吐、迟发性腹泻、粒细胞减少,多为Ⅰ-Ⅱ度,且一线和二线治疗的不良反应无统计学差异。结论伊立替康联合卡培他滨治疗晚期结直肠癌疗效高,不良反应可耐受,值得扩大样本进一步观察。     

紫杉醇联合卡培他滨治疗进展期胃癌的临床观察

目的：观察紫杉醇联合卡培他滨（希罗达）作为二线方案治疗晚期胃癌的有效性和安全性。方法：采用紫杉醇１７５ｍｇ／ｍ２,静脉滴注３ｈ,第ｌ天;希罗达１０００ｍｇ／ｍ２,每天２次,第１～１４天,２１天为１个周期,连用２个周期后评价疗效。结果：３０例中,获得完全缓解（ＣＲ）２例,占６.７％;部分缓解（ＰＲ）１２例,占４０.０％;稳定（ＳＤ）１１例,占３６.７％;进展（ＰＤ）５例,占１６.７％。总有效率（ＣＲ＋ＰＲ）为４６.７％。不良反应主要为恶心呕吐、骨髓抑制、腹泻、手足综合征及脱发等。结论：紫杉醇联合卡培他滨二线治疗晚期胃癌疗效较高,安全性好。     

重组人血管内皮抑素联合卡培他滨、草酸铂治疗结肠癌肝转移的临床观察

目的：评价重组人血管内皮抑素（恩度）联合卡培他滨、草酸铂治疗结肠癌肝转移的有效性和安全性。方法：经临床明确诊断的结肠癌肝转移患者１６例,均接受恩度联合卡培他滨、草酸铂的治疗。恩度３０ｍｇ加生理盐水５００ｍｌ匀速缓慢静脉滴注,ｄ１～ｄ１４,间歇１４天,重复给药;草酸铂２００ｍｇ加５％葡萄糖水５００ｍｌ静脉滴注,ｄ１;卡培他滨每日３０００ｍｇ分早、中、晚３次口服,ｄ１～ｄ１４,休息１４天。２８天为１周期。以ＲＥＣＩＳＴ标准评价近期疗效,以ＮＣＩＣＴＣ３.０评价毒性反应。结果：１６例患者均可评价客观疗效和毒副反应。共完成４０个周期,平均为２５个周期,获得ＣＲ３例,ＰＲ５例,ＳＤ３例,ＰＤ５例。客观有效率（ＲＲ）５０.０％（８／１６）,疾病控制率（ＤＣＲ）６８８％（１１／１６）,３、４级毒性主要与化疗药物有关,白细胞减少４例,血小板减少１例,恶心呕吐４例。结论：恩度联合卡培他滨、草酸铂治疗结肠癌肝转移的疗效较好,毒性低,安全可靠。     

Combined treatment of oxaliplatin and capecitabine in patients with metastatic esophageal squamous cell cancer

AIM： To investigate the efficacy and side effects of the combined therapy of oxaliplatin and capecitabine in patients with metastatic esophageal squamous cell cancer （ESCC） and the survival of the patients. METHODS： Sixty-four patients （median age of 63 years） with histological or cytological confirmation of ESCC received oxaliplatin 120 mg/m^2 intravenously on day 1 and capecitabine 1000 mg/m^2 orally twice daily on days 1 to 14 in a 21-d treatment cycle as palliative chemotherapy. Each patient received at least two cycles of treatment. The efficacy, side effects and patient survival were evaluated. RESULTS： The partial response （PR） rate was 43.8% （28/64）. Stable disease （SD） rate was 47.9% （26/64）, and disease progression rate was 15.6% （10/64）. The clinical benefit rate （PR ＋ SD） was 84.4%. The main toxicities were leukopenia （50.0%）, nausea and vomiting （51.6%）, diarrhea （50.0%）, stomatitis （39.1%）, polyneuropathy （37.5%） and hand-foot syndrome （37.5%）. No grade 4 event in the entire cohort was found. The median progression-free survival was 4 mo, median overall survival was 10 mo （95% CI： 8.3-11.7 mo）, and the 1- and 2-year survival rates were 38.1% and 8.2%, respectively. High Karnofsky index, single metastatic lesion and response to the regimen indicated respectively good prognosis. CONCLUSION： Oxaliplatin plus capecitabine regimen is effective and tolerable in metastatic ESCC patients. The regimen has improved the survival moderately and merits further studies.     

Concurrent capecitabine and whole-brain radiotherapy for treatment of brain metastases in breast cancer patients

Preclinical data have demonstrated that ionizing radiation acts synergistically with capecitabine. This report retrospectively assessed the use of capecitabine concurrently with whole-brain radiotherapy (WBRT) in patients with brain metastases from breast cancer. From January 2003 to March 2005, five breast cancer patients with brain metastases were referred for WBRT with concurrent capecitabine. Median age was 44 years (range: 38–53). The median dose of capecitabine was 1,000 mg/m² twice daily for 14 days (day1–14). Treatment cycles were repeated every 21 days, concurrently with WBRT (30 Gy, 3 Gy per fraction, 5 days per week). Median survival after starting WBRT plus capecitabine was 6.5 months (range 1–34 months). One patient achieved a complete response. Two patients achieved partial response, including one with local control lasting until most recent follow-up. One patient had stable disease. The remaining patient was not assessable for response because of early death. Most commonly reported adverse events were nausea (n = 2) and headache (n = 2), always grade 1. Other toxicities were grade 3 hand/foot syndrome (n = 1), moderate anemia requiring transfusion and dose reduction of capecitabine (n = 1), and grade 1 mucositis (n = 1). Although promising, these preliminary data warrant further assessment of capecitabine-based chemoradiation in brain metastases from breast cancer and need to be further validated in the setting of a clinical trial. An erratum to this article can be found at     

Early severe toxicities after capecitabine intake: possible implication of a cytidine deaminase extensive metabolizer profile

We report here the case of a 19-year-old female patient who suffered from extremely severe toxicities (G4 mucitis, fever, diarrhea, alteration of general state) while undergoing low-dose capecitabine treatment for her metastatic corticosurrenaloma. The severe toxicities stopped as soon as treatment was suspended. Interestingly, this patient was not deficient in DPD, a pharmacogenetic syndrome usually associated with increased risk of developing severe/lethal toxicities in patients undergoing fluoropyrimidine therapy, and she had been treated previously with 5-FU with a good tolerance. We then hypothesized that cytidine deaminase (CDA) extensive phenotype could be responsible for the severe toxicities observed with capecitabine. CDA is affected by genetic polymorphism, with subsequent acquisition of either deficient or extensive metabolizer profile. Phenotypic investigations confirmed that CDA activity in this patient was +180% higher than the ones usually recorded in the general population. This strongly suggests that the extensive activation of triple-prodrug capecitabine could have occurred in this patient, resulting in overexposure to 5-FU and its cytotoxic metabolites eventually. This case report suggest for the first time that severe toxicities with a capecitabine-containing protocol could be, at least in part, linked with an extensive-CDA syndrome. The case reported here suggests therefore that besides DPD, screening for CDA activity could be of interest to ensure a better safety in the handling of oral capecitabine at the bedside.     

Phase II study of an all-oral combination of vinorelbine with capecitabine in patients with metastatic breast cancer

Purpose  Combination of intravenous (i.v.) vinorelbine and capecitabine was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience and to prolong infusion-free survival, we investigated in first-line treatment a regimen combining oral vinorelbine and capecitabine in a phase II study. Patients and methods  Fifty-two patients (median age, 60 years) with MBC received the combination consisting of oral vinorelbine 60 mg/m² on days 1, 8 and 15 plus capecitabine 1,000 mg/m² bid given from day 1 to day 14 in an open-label, multicentre phase II study [the recommended doses were established in a phase I study (Nolé et al. in Ann Oncol 17:332–339, 2006)]. Cycles were repeated every 3 weeks. Results  Seventy-nine percent of the patients had received prior adjuvant chemotherapy and 81% presented with visceral involvement. The median number of administered cycles per patient was 7 (range 1–18). Twenty-three responses were documented and validated by an independent panel review, yielding response rates of 44.2% (95% CI, 30.5–58.7) in the 52 enrolled patients and 54.8% (95% CI, 38.7–70.2) in the 42 evaluable patients. Median progression-free survival and median overall survival were 8.4 and 25.8 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, only one patient having experienced febrile neutropenia. Other frequently reported adverse events included, fatigue, nausea, vomiting, diarrhoea and constipation, stomatitis and hand-foot syndrome, which were rarely severe. Conclusions  This regimen combining oral vinorelbine with capecitabine is effective and manageable in the first-line treatment of MBC. Oral vinorelbine on days 1, 8 and 15 with capecitabine from days 1 to 14 every 3 weeks represents a convenient option which offers an all-oral treatment to the patients and prolongs their infusion-free survival.     

Phase I trial of GTI-2040, oxaliplatin, and capecitabine in the treatment of advanced metastatic solid tumors: a California Cancer Consortium Study

Background  GTI-2040 is a 20-mer antisense oligonucleotide targeting the mRNA of ribonucleotide reductase M2. It was combined with oxaliplatin and capecitabine in a phase I trial in patients with advance solid tumors based on previous studies demonstrating potentiation of chemotherapy with ribonucleotide reductase inhibitors. Methods  Patients at least 18 years of age with advanced incurable solid tumors and normal organ function as well as a Karnofsky performance status of ≥60% were eligible. One prior chemotherapy regimen for advanced disease or relapse within 12 months of adjuvant chemotherapy was required. Patients could have received prior fluoropyrimidines, including capecitabine, but not oxaliplatin. Treatment cycles were 21 days. In each cycle, GTI-2040 was given as a continuous intravenous infusion over 14 days, oxaliplatin as a 2-h intravenous infusion on day 1, and capecitabine orally twice a day for 14 days. In cycle 1 only, oxaliplatin and capecitabine were started on day 2 to allow ribonucleotide reductase mRNA levels to be measured with and without oxaliplatin and capecitabine. Doses were escalated in cohorts of three patients using a standard 3 + 3 design until the maximum tolerated dose was established, defined as no more than one first-cycle dose-limiting toxicity among six patients treated at a given dose level. Results  The maximum tolerated dose was estimated to be the combination of GTI-2040 3 mg/kg per day for 14 days, capecitabine 600 mg/m² twice daily for 14 days, and oxaliplatin 100 mg/m² every 21 days. Dose-limiting toxicities were hematologic. GTI-2040 pharmacokinetics, obtained at steady-state on days 7 and 14, showed the high inter-patient variability previously reported. Two of six patients had stable disease at the maximum tolerated dose and one patient, with heavily pre-treated non-small cell lung cancer, had a partial response at a higher dose level. In samples from a limited number of patients, there was no clear decrease in ribonucleotide reductase expression in peripheral blood mononuclear cells during treatment. Conclusion  A combination of GTI-2040, capecitabine and oxaliplatin is feasible in patients with advanced solid tumors. This study was supported by U01 CA062505 and P30 CA033572 from the NCI.     

Phase I clinical and pharmacokinetic study of oxaliplatin, irinotecan and capecitabine

Purpose  To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the combination of weekly oxaliplatin × 4, weekly irinotecan × 4 and capecitabine Monday through Friday for 4 weeks of every 6 week cycle in patients with solid tumors; to determine the pharmacokinetic profile of these agents in this combination; to observe patients for clinical anti-tumor response. Methods  Twenty-two patients with metastatic solid tumors received oxaliplatin 60 mg/m² weekly × 4, irinotecan beginning at a dose of 40 mg/m² weekly × 4, and capecitabine Monday through Friday for 4 weeks of every 6 week cycle, initially at 1,000 mg twice daily (bid). Results  The MTD was oxaliplatin 60 mg/m² weekly × 4, irinotecan 50 mg/m² weekly × 4 and capecitabine 450 mg bid Monday through Friday for 4 weeks of every 6 week cycle. One of six patients at this dose level developed DLT of nausea, vomiting, and diarrhea. Among patients treated with a constant capecitabine dose of 450 mg bid, there was a higher mean AUC of 5-FU in women than in men (mean ± SD: 892 ± 287 nM h vs. 537 ± 182 nM h; Mann–Whitney two-tailed, P = 0.02). There was one complete response in a patient with gastric cancer. Conclusion  The novel schedule of weekly oxaliplatin, weekly irinotecan, and capecitabine Monday through Friday, all administered for 4 weeks of every 6 week cycle, evaluated in this phase I trial is well-tolerated and demonstrated activity in a patient with gastric cancer. Supported in part by NIH grants U01 CA62502, M01-RR-00080, K12 CA76917 (SSK), P30 CA43703, U01-CA099168-01 and P30CA47904. Published in part in: Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 2111.