Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-line treatment in advanced colorectal cancer.

PURPOSE: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting. PATIENTS AND METHODS: Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m(2) plus irinotecan 175 mg/m(2) or raltitrexed 3 mg/m(2) given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected. RESULTS: Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P =.0025) and longer progression-free survival (median, 7.1 v 5.0 months; P =.0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P =.3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m(2), tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%). CONCLUSION: Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.     

Grade 3/4 neutropenia is a limiting factor in second-line FOLFIRI following FOLFOX4 failure in elderly patients with metastatic colorectal cancer

Previous studies have reported improved outcomes for elderly patients with metastatic colorectal cancer (mCRC) treated with oxaliplatin or irinotecan as first-line chemotherapy. However, few studies regarding second-line chemotherapy with oxaliplatin or irinotecan are currenlty available. We analyzed retrospectively the efficacy and toxicity in elderly patients (median age, 74 years) treated with second-line FOLFIRI following first-line FOLFOX4 failure. From March 2005 to January 2008, 35 elderly patients with mCRC received first-line FOLFOX4 comprising leucovorin, 5-FU and oxaliplatin followed by second-line FOLFIRI comprising leucovorin, 5-FU and irinotecan. The median number of treatment courses with FOLFIRI was 5 (range 2-32). One patient responded to the treatment. The disease control rate was 38.2%. The median time to treatment failure was 3 months, and the median overall survival (OS) time from the beginning of first-line chemotherapy was 20.7 months. The incidence of grade 3/4 neutropenia was 71.4%, while febrile neutropenia was 11.4%. The incidence of non-hematological toxicity was low. The use of the three active drugs, 5-FU, oxaliplatin and irinotecan, in mCRC produced the longest OS in elderly as well as in younger patients. However, the elderly patients treated with second-line FOLFIRI had a high rate of hematological toxicity. Second-line FOLFIRI may therefore be used with caution in the elderly.     

Current status of second-line therapy for metastatic colorectal cancer

Decisions regarding the optimal systemic therapy for patients with metastatic colorectal cancer (CRC) have become more complex with the identification and development of multiple effective agents for this disease. Multiple treatment options are now available in the second-line setting for patients with metastatic CRC who have progressed despite prior chemotherapy. The exact choice of second-line therapy depends on the first-line treatment that was administered. Irinotecan as a salvage therapy for patients with metastatic CRC who have progression following front-line 5-fluorouracil (5-FU)-based therapies was confirmed in a number of phase II/III studies. Many patients who received irinotecan/5-FU-based therapy as first-line treatment benefit from the combination of oxaliplatin and 5-FU/leucovorin (FOLFOX) in terms of response, time to progression, and relief of tumor-related symptoms. Other considerations include the integration of targeted therapies into chemotherapy regimens. The results of a randomized phase II trial have demonstrated that the addition of cetuximab to irinotecan in patients with irinotecan-resistant tumors represents another active treatment option for these patients. The activity of bevacizumab as part of second-line therapy is currently under investigation and results from phase III trials are expected within the next year. In summary, the availability of 5 drugs that are active in CRC provides us, for the first time, with choice--and dilemma--regarding optimal second-line therapy in patients with metastatic CRC.     

Second-line therapy for advanced colorectal carcinoma

The past decade has witnessed considerable advances in the treatment of colorectal cancer (CRC). The emergence and integration into clinical practice of new cytotoxic agents, such as irinotecan and oxaliplatin, has had a significant impact on outcomes from advanced CRC with median survivals of 18 to 21 months now achievable. Improvements in survival as a consequence of using these drugs as salvage therapies ultimately led to demonstration of efficacy for both in the first-line treatment of CRC. As the importance of second-line therapy is increasingly recognized, key issues, such as optimal schedules, chemotherapy combinations, and sequential therapy, need to be addressed. The integration of newer biologic agents, such as cetuximab and bevacizumab, for which recent data have emerged, has further added to the complexities of delivering therapy to patients with advanced CRC, heralding a new treatment era for this disease.     

Combining capecitabine,oxaliplatin, and gemcitabine (XELOXGEM) for colorectal carcinoma patients pretreated with irinotecan: a multicenter phase I/II trial

Purpose  

Capecitabine plus oxaliplatin (XELOX) is an effective second-line regimen for advanced colorectal carcinoma (CRC) patients pretreated with irinotecan. Previous studies have shown supra-additive anti-tumor activity of gemcitabine (GEM) when administered with oxaliplatin. We investigated the dose, toxicity, and efficacy of a second-line XELOXGEM regimen in CRC patients pretreated with irinotecan.     

Review of the role of CPT-11 in the treatment of colorectal cancer

Colorectal cancer (CRC) is the second leading cause of cancer death in Western countries, and although the treatment of advanced CRC has progressed substantially, the improvements in response rates have not always been translated into a significant survival benefit. Until recently, the standard therapy for advanced CRC was a variety of biomodulated 5-fluorouracil (5-FU) regimens. 5-FU was used as first- or second-line therapy, and a different 5-FU regimen was used second line if first-line 5-FU therapy failed. Typically, the survival times for these patients were short and their quality of life poor. In recent years, a variety of new agents have emerged that have demonstrated activity in the treatment of advanced CRC. Of these, irinotecan (CPT-11) and oxaliplatin in combination with 5-FU and folinic acid (FA) have yielded the most promising results. However, only CPT-11 combined with either bolus or high-dose infusional 5-FU/FA, in randomized phase III studies, has demonstrated an increased response rate and median time to progression, producing a significant and clinically relevant survival advantage. In 2 randomized phase III studies, oxaliplatin/5-FU/FA demonstrated a clear increase in response rate over 5-FU/FA alone but failed to demonstrate a survival advantage. CPT-11 was approved by the Food and Drug Administration in April 2000 for the first-line treatment of advanced CRC in combination with 5-FU/FA.     

Randomised study of sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer, an interim safety analysis. A Dutch Colorectal Cancer Group (DCCG) phase III study.

BACKGROUND: Results on overall survival in randomised studies of mono- versus combination chemotherapy in advanced colorectal cancer patients may have been biased by an imbalance in salvage treatments. This is the first randomised study that evaluates sequential versus combination chemotherapy with a fluoropyrimidine, irinotecan and oxaliplatin. PATIENTS AND METHODS: A total of 820 patients were randomised between first-line capecitabine, second-line irinotecan and third-line capecitabine + oxaliplatin (arm A) versus first-line capecitabine + irinotecan, and second-line capecitabine + oxaliplatin (arm B). The primary end point was overall survival. We present the results of an interim analysis on the safety data in the first 400 patients. RESULTS: In first-line the incidence of grade 3-4 diarrhoea, nausea, vomiting and febrile neutropenia was significantly higher in arm B. However, when toxicity over all lines was considered only grade 3 hand-foot syndrome occurred more frequently in arm A (12% versus 6%, respectively, P = 0.041). The incidence of cardiovascular toxicity was low. In two out of five patients with sudden death (one in arm A, four in arm B) cardiovascular risk factors were present. CONCLUSIONS: Both treatment arms had an acceptable safety profile. These data imply that the results on survival will be the major determinant for the selection of either strategy. Capecitabine plus irinotecan appears to be a feasible first-line treatment for patients with advanced colorectal carcinoma.     

奥沙利铂一线治疗后再引入与雷替曲塞联合二线治疗晚期结直肠癌的临床观察*

目的:评估奥沙利铂一线用于治疗晚期结直肠癌后与雷替曲塞联合再引入二线治疗的疗效及安全性。方法:收集2010年5 月至2014年12月广西中医药大学附属瑞康医院收治的48例晚期结直肠癌患者,根据一线应用奥沙利铂的情况分为两组:A 组（一线使用不含奥沙利铂方案）20例;B 组（一线使用含奥沙利铂方案）28例。二线治疗方案:雷替曲塞3 mg/m2,静脉滴注,d1;奥沙利铂100～130 mg/m2,静脉滴注,d1;每21天1 次。结果:48例均可评价疗效,两组有效率分别为30.0%（6/ 20）、32.1%（9/ 28）;疾病控制率分别为80.0%（16/ 20）、75.0%（21/ 28）;中位无进展生存期分别为6.5 个月、7.0 个月;中位总生存期分别为10个月、13个月;两组有效率、疾病控制率、中位无进展生存期及中位总生存期比较差异均无统计学意义（P = 0.264,0.514,0.713,0.788）。 主要不良反应为骨髓抑制、转氨酶异常和胃肠道反应,以Ⅰ～Ⅱ级为主;两组感觉神经异常Ⅰ～Ⅱ级发生率相近。结论:奥沙利铂再引入联合雷替曲塞二线化疗对曾使用过奥沙利铂一线化疗的患者仍然有效,无耐药性,安全可行,对不能接受伊立替康二线治疗的晚期结直肠癌患者是较好选择。      

晚期胃癌不同一线及后线治疗方案的疗效对比分析北大核心

目的:分析晚期胃癌(advanced gastric cancer, AGC)一线及后线治疗方案的疗效及生存情况,为指导AGC的系统治疗及全程管理提供依据。方法:收集我院肿瘤科2015年01月至2019年12月收治的AGC患者的临床特征、辅助检查资料、治疗相关资料、疗效评估、疾病转归等相关临床资料,建立数据库,分析不同一线及后线治疗方案的疗效,以及不同人群、进行不同线数化疗的患者总生存期(overall survival, OS)的差异。结果:一线治疗总体客观缓解率(objective response rate, ORR)为37.6%,疾病控制率(disease control rate, DCR)为83.9%;二线治疗ORR为9.5%,DCR为44.6%;三线及以上治疗ORR为0%,DCR为15.2%。总体人群一线治疗中位无进展生存(median progression-free survival, mPFS)时间为7.0个月,中位总生存(medianoverall survival,mOS)时间为15.6个月;二线治疗mPFS时间为3.0个月,mOS时间为7.2个月。一线化疗采取含铂方案与含紫杉方案对比,mPFS分别为7.0个月、4.5个月(P=0.041),mOS分别为16.0个月、9.0个月(P=0.061);二线含紫杉方案与含伊立替康方案对比,mPFS分别为2.6个月、4.0个月(P=0.531),mOS分别为7.0个月、6.5个月(P=0.822)。仅进行一线治疗、一线+二线治疗、一线+二线+三线及以上治疗的AGC患者mOS分别为14.0个月、14.0个月及20.0个月,进行三线及以上治疗的患者mOS优于进行一线+二线治疗的患者(P=0.001)。一线方案中采用两药或三药及以上、有无免疫治疗对患者的mPFS及mOS无影响,且二线治疗中有无联合免疫治疗对患者的mPFS及mOS也无影响。结论:含铂双药方案疗效较佳,应作为AGC患者一线治疗的优选方案;二线及后线化疗有效率较低,二线化疗方案紫杉类与伊立替康疗效无差异;在非选择AGC人群中,一线及二线治疗中联合免疫治疗未见改善生存,化疗仍然是基石。     

女性晚期非小细胞肺癌患者的临床特点及预后分析

目的分析女性晚期非小细胞肺癌(NSCLC)患者的临床特点及其与预后的关系。方法收集218例初治女性晚期NSCLC患者的病历资料,随访3年,观察患者的总生存时间(0S)。结果218例患者中,腺癌占78.9%(172/218),中位OS为16个月(95%CI 13.257-18.743)。多因素分析结果显示,一线治疗方案、二线治疗方案与OS明显相关(P<0.05)。亚组分析显示,一线酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)治疗有效率为75.0%,中位OS为16个月;二线TKI有效率为35.9%,中位OS为23个月;老年患者(≥65岁)二线化疗或口服TKI与OS明显相关(P<0.05)。病理类型、肝转移、放疗与否与治疗转归相关。结论女性晚期NSCLC患者以腺癌为主,一线、二线治疗方案效果是女性晚期NSCLC患者的独立预后因素。一线TKI有效率较二线TKI有效率高,但OS无明显差异。老年患者二线化疗或口服TKI均能改善OS。非腺癌、肿瘤负荷大是临床治疗不易获益患者的临床特点。     

Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers

Combination protocols of 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan or oxaliplatin have demonstrated high activity in metastatic colorectal cancer. Capecitabine, an oral 5-FU prodrug, may replace infusional 5-FU/LV in combination protocols with irinotecan or oxaliplatin. We therefore initiated a phase II study with capecitabine plus either irinotecan or oxaliplatin to determine the efficacy and toxicity of specific combination protocols in patients with advanced gastrointestinal (GI) tumors. Capecitabine 1000 mg/m(2) taken orally twice a day on days 1-14, plus oxaliplatin 70 mg/m(2) on days 1 and 8, or irinotecan 100 mg/m(2) on days 1 and 8; repeated every 3 weeks in an outpatient setting. Patient and tumor characteristics were as follows: median age, 68 years (range, 34-77 years); sex: 10 women, 33 men; tumor types: 35 colorectal cancer; 8 other GI tumors including 5 gastric, 2 pancreatic, and 1 duodenal cancer. All 43 patients treated were evaluable for toxicity (capecitabine/oxaliplatin, 24 patients; capecitabine/irinotecan, 19 patients), and 39 were evaluable for efficacy (capecitabine/oxaliplatin, 22; capecitabine/irinotecan, 17). Grade 3/4 toxicities (National Cancer Institute Common Toxicity Criteria Version 2.0) were limited to diarrhea, 9 patients (capecitabine/irinotecan, n = 5; capecitabine/oxaliplatin, n = 4); hand-foot syndrome, 1 patient (capecitabine/irinotecan); nausea, 2 patients (capecitabine/oxaliplatin); vomiting, 1 patient (capecitabine/oxaliplatin); and peripheral neuropathy, 1 patient (capecitabine/oxaliplatin). No grade 3/4 myelosuppression was noted for either protocol. Capecitabine/irinotecan and capecitabine/oxaliplatin demonstrated significant clinical activity in colorectal cancer and other GI cancers as first-line and salvage therapy. Capecitabine/oxaliplatin and capecitabine/irinotecan show an excellent safety profile and clinical activity in colorectal cancer and other advanced GI tumors. The main toxicity in both arms was manageable diarrhea. This trial served as basis for a randomized multicenter phase II study comparing capecitabine/oxaliplatin and capecitabine/irinotecan as first-line therapy in patients with advanced colorectal cancer.     

晚期结直肠癌内科治疗进展

晚期转移性结直肠癌的5年生存率低于10％。5-FU／LV方案治疗的中位生存期大约12个月。最近化疗方案的更新延长了患者的中位生存期。研究发现奥沙利铂、伊立替康联合5-FU／LV或者卡培他滨等化疗方案使中位生存期延长到20个月。奥沙利铂，伊立替康联合5-FU／LV比传统的单药5-FU／LV使生活质量改善时间延长。目前转移性结直肠癌标准的一线治疗方案为FOLFOX和FOLFIRI。正在进行的研究关注新的分子靶向药物（molecular targeted therapy）联合化疗治疗转移性结直肠癌，且部分试验取得了较好的疗效。本文将对5-FU、新一代化疗药物以及分子靶向药物在转移性结肠癌治疗的演进及新进展作一综述。     

对比EGFR-TKIs治疗EGFR突变状态未明晚期NSCLC疗效研究

目的探讨对比表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)一线、维持及二线治疗EGFR突变状态未明晚期非小细胞肺癌(non-small-cell lung cancer,NSCLC)的疗效。方法回顾性分析接受EGFR-TKIs治疗的57例EGFR突变状态未明晚期NSCLC,按照接受EGFR-TKIs治疗的时机分为EGFR-TKIs治疗一线组(19例)、维持组(18例)和二线组(20例),按照RECIST标准进行疗效评价。结果一线组、维持组和二线组客观有效率(52.6%vs 38.9%vs 35.0%,P=0.098)、中位无进展生存期(4.0月vs 7.8月vs 2.2月,P=0.417)差异无统计学意义,但一线组患者总生存期较维持组和二线组差(8.7月vs 20.0月vs 19.1月,P=0.009)。结论 EGFR突变状态未明晚期NSCLC EGFR-TKIs一线、维持和二线治疗的客观有效率和中位无进展生存期相似,但EGFR-TKIs一线治疗总生存期较短,建议EGFR-TKIs用于维持或二线治疗EGFR突变状态未明晚期NSCLC。     

Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05)

BackgroundIn Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC.Patients and methodsPatients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40–60 mg/m²) on days 1–14 and intravenous irinotecan (150 mg/m²) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS).ResultsFrom February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78–1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group.ConclusionThe consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy.Clinical Trials.govNCT00639327.     

Cetuximab in previously treated colorectal cancer

Within the past decade, there have been considerable advances in the first- and second-line treatment of colorectal cancer (CRC). For many years, 5-fluorouracil was the only therapeutic option for the first-line treatment of CRC, and virtually no effective salvage therapies were available. However, the advent of oxaliplatin and irinotecan has improved outcomes for advanced CRC, providing increased therapeutic choice in the first-line setting and effective salvage therapies. Many patients are now receiving multiple lines of therapy, and it is in the setting of previously treated CRC that cetuximab, a monoclonal antibody to the epidermal growth factor receptor, has been successfully developed based on sound scientific principles. The ability to integrate new biologic therapies with conventional cytotoxic agents marks a new treatment era for this disease. This review discusses the development of cetuximab in pretreated CRC to date and future directions with this novel therapy.     

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.

PURPOSE: In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). PATIENTS AND METHODS: Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2) or dl-LV 400 mg/m(2) followed by a FU bolus 400 mg/m(2) and 46-hour infusion 2,400 to 3,000 mg/m(2) every 46 hours every 2 weeks, either with irinotecan 180 mg/m(2) or with oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). RESULT: Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P =.99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P =.64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P =.26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. CONCLUSION: Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.     

Role of tyrosine kinase inhibitors in the treatment of advanced colorectal cancer

Colorectal cancer (CRC) is a common health problem in Western countries. In advanced disease, either FOLFOX (oxaliplatin/5-fluorouracil [5-FU]/leucovorin [LV]) or FOLFIRI (irinotecan/LV/5-FU) are accepted first-line chemotherapy regimens, but median survival appears to plateau with a chemotherapy-only approach. The use of epidermal growth factor receptor (EGFR)- and vascular endothelial growth factor (VEGF)-targeting monoclonal antibodies has increased the median survival of patients with advanced CRC beyond 20 months. However, the precise role of cetuximab, panitumumab and bevacizumab in combination with different chemotherapeutic regimens is still being determined in first- and second-line settings. The activity and tolerance of the EGFR tyrosine kinase inhibitors (TKIs), gefitinib erlotinib, and EKB-569, alone or in combination with chemotherapy, have been explored in patients with metastatic CRC. Regarding VEGF receptor TKIs, 2 phase III clinical trials determined the role of vatalanib in combination with FOLFOX. Efficacy of the oral multitargeted TKIs sorafenib and sunitinib is under investigation. This article aims to review the role of TKIs in advanced CRC.     

Oxaliplatin plus oral fluoropyrimidines in colorectal cancer

The medical treatment of colorectal cancer (CRC) has rapidly evolved in recent years with the introduction of novel cytotoxic drugs into clinical practice such as irinotecan, oxaliplatin, and capecitabine. Combination regimens using infusional 5-fluorouracil (5-FU)/leucovorin (LV) plus either oxaliplatin or irinotecan have demonstrated clinically meaningful, high efficacy in advanced CRC. Based on the results of the Intergroup trial N9741, FOLFOX4, a combination of infusional plus bolus 5-FU/LV and oxaliplatin, has emerged as the standard first-line therapy in the palliative setting. However, infusional 5-FU-based regimens carry the need for use of central venous lines and implantable ports to allow treatment on an outpatient basis and are thus inconvenient and expensive. The use of oral fluoropyrimidines (capecitabine or uracil/tegafur [UFT] plus LV) as substitutes for infusional 5-FU in combination protocols with oxaliplatin offers greater convenience, at the same time conceivably maintaining the high efficacy and tolerability observed with intravenous protocols. Various phase I/II trials have recently been reported that investigated oxaliplatin in combination with either capecitabine or UFT/LV in patients with advanced CRC. This review will detail the results of these trials focused on capecitabine-based combinations.     

Advances in the treatment of metastatic colorectal cancer

The overall 5-year survival rate for patients with metastatic colorectal cancer (CRC) is less than 10%. Median survival with 5-fluorouracil (5-FU)/leucovorin (LV) therapy is approximately 12 months. Recent additions to the chemotherapy armamentarium for this disease have begun to prolong median survival times. In trials in which patients are exposed to all three approved chemotherapy agents, oxaliplatin, irinotecan, and 5-FU/LV, or capecitabine during the course of their disease, median survival has reached 20 months. The addition of oxaliplatin and irinotecan to 5-FU/LV regimens has also led to the maintenance of quality of life for longer intervals than were traditionally observed with 5-FU/LV alone. Current standard first-line regimens for metastatic CRC are FOLFOX (infusional 5-FU/LV with oxaliplatin) and FOLFIRI (infusional 5-FU/LV with irinotecan). The addition of bevacizumab to a two-drug regimen (irinotecan with 5-FU/LV) prolongs median survival to 20 months, with a modest amount of additional toxicity. Improvements in this median survival have not yet been realized with modifications to the current standard regimens; however, the oral agent capecitabine appears to be a reasonable substitute for infusional 5-FU/LV in combination regimens or as a single agent, with the advantage of reducing the inconvenience of the long infusion time. Ongoing investigations will identify a place for capecitabine, epidermal growth factor inhibitors, and new cytotoxics in the treatment of metastatic CRC.     

The role of 5-fluorouracil (5-FU) reintroduction with irinotecan or oxaliplatin in truly 5-FU-refractory advanced colorectal cancer patients

OBJECTIVES: Although several evidences have demonstrated a synergistic activity of 5-fluorouracil with irinotecan and oxaliplatin, thus explaining the use of this drug combination in the first-line treatment of advanced colorectal cancer, the need for the reintroduction of 5-FU in the second-line setting is more questionable. METHODS: We retrospectively evaluated the outcome of patients developing progressive disease while on an infusional 5-FU-based front-line chemotherapy and subsequently treated with one of the four following chemotherapy regimens: irinotecan, oxaliplatin and irinotecan or oxaliplatin both combined with the de Gramont schedule (LV5-FU2). RESULTS: 225 patients (137 males and 88 females), were eligible for analysis. Second-line chemotherapy consisted of irinotecan in 79 patients (35%, group A), oxaliplatin in 47 patients (21%, group B), irinotecan with LV5-FU2 in 53 patients (24%, group C) and oxaliplatin with LV5-FU2 in the remaining 46 cases (20%, group D). The response rate to second-line chemotherapy was obtained in 6/79 patients (8%) in group A, in 4/47 patients (9%) in group B, in 11/53 patients (21%) in group C and in 10/46 patients (22%) in group D (p = 0.04). CONCLUSIONS: These data suggest that reintroduction of 5-FU could increase irinotecan and oxaliplatin activity in patients progressing during a 5-FU-based first-line chemotherapy.