Prospective multicenter phase II study of irinotecan as third-line therapy in metastatic colorectal cancer and progression after bolus and infusional 5-fluorouracil

Irinotecan has proven anti-tumor activity as induction treatment in combination with 5-fluorouracil (5-FU) or as second-line treatment after 5-FU in patients with metastatic colorectal cancer. The aim of the present phase II study was to evaluate irinotecan as third-line chemotherapy in patients with colorectal cancer after sequential treatment with bolus 5-FU followed by an infusional 5-FU regimen. Patients pretreated with bolus 5-FU/folinic acid and the infusional 5-FU/folinic acid regimen were treated with 350 mg/m irinotecan i.v. once every 3 weeks in a multicenter phase II study. Tumor size was measured every cycle and treatment with irinotecan was continued until the occurrence of progressive disease or unacceptable toxicity. A total of 50 pretreated patients were included. Of the 45 evaluable patients, 13.3% [n=6, 95% confidence interval (CI) 5.1-26.8] attained a response (complete/partial response) to treatment lasting 5.6 months (95% CI 4.2-6.3) and in four patients response has been confirmed (8.9%, 95% CI 2.5-21.2). Disease stabilization was noted in 51.1% of the patients (n=23, 95% CI 35.8-66.3). The median duration of response/disease stabilization was 4.2 months (95% CI 3.2-6.0). Median overall survival was 7.9 months (95% CI 6.1-11.1), corresponding to a calculated 1-year survival of 28.3% (95% CI 15.2-41.3). Severe neutropenia occurred in 14% (n=7) and anemia grade III in 6% of the patients (n=3). The most frequent non-hematological toxicity grade III/IV related to treatment was diarrhea in 24% of the patients (n=12), followed by vomiting in 8% (n=4) and constipation as well as infection in two patients each (4%) (evaluable n=50). We conclude single-agent irinotecan is an effective and well-tolerable treatment in pretreated patients with metastatic colorectal cancer after failure of bolus and infusional 5-FU/folinic acid regimens. Elderly patients had the same probability to respond.     

西妥昔单抗联合化疗治疗转移性结直肠癌的观察

目的 观察西妥昔单抗联合化疗方案治疗转移性结直肠癌的近期疗效及不良反应.方法 11例经病理组织学确诊的转移性结直肠癌患者,给予西妥昔单抗联合FOLFOX方案治疗,西妥昔单抗首次给予负荷剂量400 mg/m2,每周给予维持剂量为250 mg/m2.结果 全组11例患者中,完全缓解1例,部分缓解5例,稳定2例,进展3例,有效率54.5％ (6/11),疾病控制率为72.7％ (8/11),中位肿瘤进展时间为8.4个月.主要不良反应为痤疮样皮疹(9例)和腹泻(6例).5例合并肝转移患者中经治疗后1例转化为可切除病灶.患者耐受良好,无治疗相关死亡.结论 西妥昔单抗联合FOLFOX方案治疗转移性结直肠癌疗效较好,不良反应多可耐受.     

Chemotherapy of metastatic colorectal cancer

Without treatment, patients with inoperable or metastatic colorectal cancer have a median life expectancy of about 8 months. The following article is an update of our 2005 review of chemotherapy regimens used in metastatic colorectal cancer, based on the standard Prescrire methodology. In 2005, the de Gramont protocol, based on fluorouracil (always combined with folinic acid) plus either oxaliplatin (Folfox protocol) or irinotecan (Folfiri protocol), was the standard first-line chemotherapy in this setting. Four trials comparing monotherapy versus combination therapy in previously untreated patients showed that initial fluorouracil (or fluorouracil precursor) monotherapy, followed by the Folfox or Folfiri protocol in case of failure, was not associated with shorter overall survival. Two trials compared first-line treatment with the Folfiri regimen versus the Folfoxiri regimen (fluorouracil + oxaliplatin + irinotecan). One of these studies showed an increase in median survival with the Folfoxiri protocol (24 versus 17 months), but at a cost of greater neurotoxicity. The only tangible advantage of capecitabine and tegafur, two oral fluorouracil precursors, is their convenience of use. Pemetrexed was less effective and more toxic than the Folfiri protocol in one trial. Bevacizumab and panitumumab have yielded disappointing results in previously untreated patients. Neither of these monoclonal antibodies has yet been shown to improve overall survival. Three trials have assessed the addition of cetuximab to combinations consisting of fluorouracil or capecitabine plus oxaliplatin or irinotecan. In two of these trials, the median survival time of patients whose tumours carried the wild-type KRAS gene was about 3 months longer in the cetuximab arms, although the increase was statistically significant in only one trial. Cetuximab had no impact on survival time in the third trial. In two trials, an anti-EGFR antibody (panitumumab or cetuximab) reduced median survival when added to bevacizumab in previously untreated patients. When progression occurs after treatment with the Folfiri protocol (or equivalent), a combination of the Folfox protocol and bevacizumab seems to increase median survival time by about 2 months versus Folfox alone, but it is also more toxic. In patients who progress after receiving the fluorouracil + oxaliplatin combination (Folfox) or the fluorouracil+ irinotecan combination (Folfiri), neither panitumumab nor cetuximab has been shown to provide a clinically meaningful increase in overall survival. It remains to be shown whether these drugs are more effective in patients with the wild-type KRAS gene than in patients with KRAS mutations. In early 2010, the standard cytotoxic drugs for treatment of metastatic colorectal cancer are fluorouracil (combined with folinic acid), oxaliplatin and irinotecan. Initial combination therapy may be beneficial when the metastases are borderline operable. When the metastases are inoperable and are unlikely to become operable after chemotherapy, it seems best to begin treatment with single-agent fluorouracil (+ folinic acid) or capecitabine. The use of monoclonal antibodies in first-line treatment of patients with colorectal cancer is not justified. Further trials of these drugs are warranted as second-line treatment for patients with KRAS wild-type tumours.     

Phase II study of second-line oxaliplatin, irinotecan and mitomycin C in patients with advanced or metastatic colorectal cancer

The aim of this phase II study was to investigate the therapeutic value of second-line treatment with oxaliplatin, irinotecan (CPT-11) and mitomycin C (MMC) in patients with metastatic colorectal cancer pretreated with 5-fluorouracil (5-FU)-based chemotherapy. A total of 10 patients with metastatic colorectal cancer, all of whom had developed progressive disease from advanced or metastatic colorectal cancer while receiving or within 6 months after discontinuing first-line chemotherapy with 5-FU and leucovorin, were entered in this study. At the time of relapse, cytotoxic chemotherapy consisting of oxaliplatin 80 mg/m2 plus CPT-11 80 mg/m2 given i.v. on therapeutic day 1, and MMC 6 mg/ m2 given i.v. on day 15, respectively, was initiated. Treatment courses were repeated every 4 weeks for a total of six courses unless there was prior evidence of progressive disease. The overall response rate was 30% with three partial responses for all 10 assessable patients. Two additional patients (20%) had stable disease and five patients (50%) progressed. The median overall survival duration has not been reached yet and is longer than 7.1 months (range 2-23.5+) from the beginning of second-line therapy. Four patients are currently alive with progressive disease. The tolerance of second-line treatment was generally mild to moderate and easy to treat. Our data suggest that the combination of oxaliplatin, CPT-11 and MMC in patients with metastatic colorectal cancer pretreated with 5-FU-based chemotherapy is feasible and has substantial antitumor activity. Further evaluation of this regimen seems warranted.     

Biweekly oxaliplatin plus irinotecan and folinic acid-modulated 5-fluorouracil: a phase II study in pretreated patients with metastatic colorectal cancer

Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. On the basis of sensitivity to previous treatment, 19 patients were considered as chemo-resistant and 14 patients as chemo-refractory. OXA 110 mg/m (over 2 h) and IRI 175 mg/m (over 1 h) were delivered on day 1, followed by LFA 250 mg/m (2-h infusion) plus 5FU 800 mg/m as intravenous bolus on day 2. Cycles were repeated every 2 weeks. A total of 348 cycles were delivered, with a median of nine cycles per patient (range, 1-12 cycles per patient). Five complete and 13 partial responses were reported on 40 assessable patients, giving a response rate of 45% [95% confidence interval (CI), 29-62%]; eight of 19 (42%) resistant patients and five of 14 (36%) refractory patients achieved a major response, which was also obtained in four of eight (50%) patients pretreated with IRI and in three of eight (38%) patients pretreated with OXA. Grade 3 or higher neutropenia occurred in 68% of patients, but febrile neutropenia or infections affected only seven (17%) patients. No episodes of grade 3 or higher thrombocytopenia or anemia were recorded. Occurrence of severe non-hematologic toxicities by patients were: diarrhea, 34%; vomiting, 17%; peripheral cumulative neuropathy, 15%; stomatitis, 10%; acute cholinergic syndrome, 7%. Actually delivered dose intensities of all three drugs resulted in about two-thirds of the planned ones. After a follow-up of 39 months, median progression-free survival was 7.5 months. Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.     

伊立替康联合靶向药物在晚期结直肠癌治疗中的应用

伊立替康是转移性结直肠癌的主要治疗药物,本文阐述了伊立替康在多项Ⅱ期、Ⅲ期临床研究中的研究结果,表明伊立替康与西妥昔单抗、贝伐珠单抗、帕尼单抗等靶向药物联合在一线、二线、多重耐药转移性结直肠癌治疗中有较好的疗效。但伊立替康与酪氨酸激酶抑制药、舒尼替尼等小分子靶向药物联合疗效不佳。而具体的药物的分子生物学机制与临床疗效及毒副反应的关系,尚需进一步研究。     

Cetuximab: in the treatment of metastatic colorectal cancer

Cetuximab is a chimeric monoclonal antibody highly selective for the epidermal growth factor receptor (EGFR), which is over-expressed by 25-80% of colorectal cancer tumours and associated with advanced disease. Cetuximab induces a broad range of cellular responses in tumours expressing EGFR, enhancing sensitivity to radiotherapy and chemotherapeutic agents. In a large, randomised, open-label, multicentre study in adult patients with irinotecan-refractory, metastatic colorectal cancer expressing EGFR, cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 weekly plus irinotecan (various doses) produced a greater rate of partial response and disease control (partial response plus stable disease), and increased time to disease progression, compared with cetuximab monotherapy; survival was similar in both groups. The same dosage of cetuximab combined with irinotecan, fluorouracil and folinic acid (various regimens) produced partial responses in 43-58% of patients, a complete response in 5% of patients (one study only) and stable disease in 32-52% of patients with treatment-naive metastatic colorectal cancer expressing EGFR in three small, open-label trials. The most common grade 3/4 adverse events associated with cetuximab monotherapy were acne-like rash, asthenia, abdominal pain and nausea/vomiting. In patients receiving cetuximab plus irinotecan, these were diarrhoea, asthenia, leucopenia and neutropenia.     

西妥昔单抗联合化疗方案治疗晚期结直肠癌的临床疗效

目的评价西妥昔单抗联合化疗方案治疗晚期结直肠癌的疗效及不良反应。方法选择我院2007年1月-2010年6月单用或联合化疗使用西妥昔单抗治疗晚期或转移性结直肠癌患者35例,采用RF,cISr 1.1版实体肿瘤客观疗效评定标准进行临床疗效评价。并采用美国毒性反应评价标准(CIE 3.0)进行不良反应评价。结果共有31例纳入疗效评价。其中完全缓解l例,部分缓解9例,疾病稳定14例,疾病进展7例,有效率32.3%,疾病控制率75.O%;K-RAS基因野生型的患者有效率(40.0%)明显高于未检测组(18.2%)。33例发生了不良反应,发生率94.3%,主要为I～Ⅱ级(占74.1%)。结论西妥昔单抗联合放化疗方案治疗晚期结直肠癌可获得较高有效率,延长了疾病进展时间。     

Cetuximab: new drug. Metastatic colorectal cancer: an inappropriate evaluation

(1) In patients with metastatic colorectal cancer initially treated with irinotecan combination therapy, second-line therapy with a combination of fluorouracil, folinic acid and oxaliplatin resulted in a median survival time of 21 months after the start of first-line chemotherapy, in one clinical trial. (2) Cetuximab, an antibody directed against the epidermal growth factor receptor (EGFR), is indicated for patients with EGF-expressing metastatic colorectal cancer, after failure of irinotecan-based chemotherapy. (3) A comparative trial involving 329 patients showed that the cetuximab + irinotecan combination was more effective than cetuximab monotherapy in terms of progression-free survival time (4.1 versus 1.5 months). Three non comparative trials did not show that adding cetuximab to irinotecan improved the efficacy of irinotecan. (4) Nearly 90% of patients taking cetuximab developed cutaneous adverse effects (usually acne), which were severe in about 15% of cases. About 5% of cetuximab infusions were associated with occasionally severe hypersensitivity reactions. (5) More pertinent comparative trials are underway, but no detailed results were available on 29 April 2005. (6) The cetuximab packaging is somewhat impractical. (7) In practice, given its known toxicity and unproven efficacy, cetuximab currently has no place in the second-line treatment of colorectal cancer.     

Medical care consumption in a phase III trial comparing irinotecan with infusional 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer after 5-FU failure

We evaluated economic implications of treatment with irinotecan, following a RCT which demonstrated significantly increased survival at 1 year with irinotecan (45%) compared to infusional 5-fluorouracil (5-FU) (32%) in patients with metastatic colorectal cancer. Medical care consumption data were collected prospectively alongside the trial, with 256 patients followed for a median of 10 months. Follow-up was prolonged beyond treatment failure and medical care consumption was not protocol driven, enabling a realistic evaluation of economic implications. Medical care consumption associated with chemotherapy administration was lower with irinotecan as compared with infusional 5-FU. The cumulative number of days in hospital due to treatment toxicity and cancer complications, which is the key cost driver, was 14.4 (95% CI: 10.7-18.1) with irinotecan versus 17.5 (95% CI: 11.7-23.3) with infusional 5-FU. Thus, the survival benefit with second-line irinotecan compared to infusional 5-FU in patients with advanced colorectal cancer was achieved without increasing medical care consumption.     

A phase II study of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin (IFLUX) for advanced, previously untreated colorectal cancer

Our objectives were to determine response rate, time to progression, overall survival and tolerability of novel combination chemotherapy, consisting of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin in advanced previously untreated colorectal cancer. Thirty-eight patients with advanced colorectal cancer were treated at Sylvester Comprehensive Cancer Center, University of Miami, from 2000 to 2004, and received weekly intravenous infusion of irinotecan at 110 mg/m with a combination of 120 mg/kg floxuridine and 500 mg/m leucovorin administered as a 24-h continuous intravenous infusion. The treatment cycle consisted of 4 weeks of consecutive therapy followed by 2 weeks of rest. Five (13%) patients achieved complete response, 10 (26%) patients achieved partial response, 17 (45%) patients attained stable disease and six (16%) patients progressed. The overall response rate was 39% in this study. This chemotherapy regiment was well tolerated; the most common grade 3 toxicities were neutropenia (16%), anemia (16%), vomiting (24%), diarrhea (16%), and hand-and-foot syndrome (26%). The median time to progression was 11.5 months (347.5 days) with 95% confidence intervals of 6.8-12.9 months (206-389 days). The time to progression ranged from 1.8 to 34 months. The median survival of the patients in this trial was 31.28 months (952 days) with a confidence interval of 20.9-38.0 months (629-1141 days). Intravenous infusion of floxuridine and leucovorin is beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged time to progression and overall survival with acceptable tolerability and manageable toxicity profile.     

Weekly treatment with irinotecan, folinic acid and infusional 5-fluorouracil (ILF) in patients with advanced gastric cancer

Although 5-fluorouracil remains the mainstay of treatment for advanced gastric cancer (AGC), no standard chemotherapy regimen exists. Combinations of irinotecan with folinic acid and infusional 5-fluorouracil (5-FU) (ILF) have shown good efficacy with acceptable toxicity in patients with metastatic colorectal cancer. At present, only sparse data on ILF are available for AGC. Therefore we conducted a prospective study of this combination in 25 consecutive patients with metastatic gastric cancer. Median age was 63 years, 10 had received prior chemotherapy and 13 presented initially with peritoneal carcinosis. Treatment consisted of irinotecan 80 mg/m2, folinic acid 500 mg/m2 and infusional 5-FU 2.0 g/m2 over 24 h, given weekly for 6 weeks followed by a 1-week rest. Grade 3/4 hematologic toxicity occurred in six patients (anemia = 4, neutropenia = 1 and leukopenia = 1). Non-hematologic toxicity consisted mainly of nausea/vomiting (grade 3/4 in six patients) and diarrhea (grade 3/4 in 10 patients). The overall response rate was 20% for first- and second-line treatment, with two complete and three partial responses. Another nine patients (36%) had stable disease, for a tumor control rate of 56%. Median time to progression was 4 months, median overall survival and survival for patients with tumor control was 7 and 13 months, respectively. We conclude that ILF is a feasible outpatient regimen with manageable toxicity that provides tumor control in a high proportion of patients with advanced gastric cancer, even among those with unfavorable prognostic features.     

Salvage chemotherapy with irinotecan and cisplatin in patients with metastatic gastric cancer failing both 5-fluorouracil and taxanes

We conducted a phase II study to assess the efficacy and tolerability of irinotecan and cisplatin as salvage chemotherapy in patients with advanced gastric adenocarcinoma, progressing after both 5-fluorouracil (5-FU)- and taxane-containing regimen. Patients with measurable metastatic gastric cancer, progressive after previous chemotherapy that consisted either of a 5-FU-based regimen followed by second-line chemotherapy containing taxanes or a 5-FU and taxane combination were treated with irinotecan and cisplatin. Irinotecan 70 mg/m(2) was administered on day 1 and day 15; cisplatin 70 mg/m(2) was administered on day 1. Treatment was repeated every 4 weeks. For 28 patients registered, a total of 94 chemotherapy cycles were administered. The patients' median age was 51 years and 27 (96%) had an ECOG performance status of 1 or below. In an intent-to-treat analysis, seven patients (25%) achieved a partial response, which maintained for 6.3 months (95% confidence interval 6.2-6.4 months). The median progression-free and overall survival were 3.5 and 5.6 months, respectively. Major toxic effects included nausea, diarrhea and neurotoxicity. Although there was one possible treatment-related death, toxicity profiles were generally predictable and manageable. We conclude that irinotecan and cisplatin is an active combination for patients with metastatic gastric cancer in whom previous chemotherapy with 5-FU and taxanes has failed.     

K-ras基因突变状态与西妥昔单抗/帕尼单抗治疗转移性结直肠肠癌疗效的系统评价

目的 评价K-ras基因突变状态与西妥昔单抗/帕尼单抗治疗mCRC疗效间的关系。方法 检索Pubmed、CENTRAL(the Cochrane Central Register of Controlledtrials)、EMBASE、中国期刊全文数据库(CNKI)、美国临床肿瘤学会(ASCO)、欧洲肿瘤协会(EMSO)官方网等,公开发表的K-ras基因突变状态与西妥昔单抗/帕尼单抗治疗mCRC疗效间关系的研究(包括前瞻性和回顾性)。应用Stata 11.0统计软件分析K-ras基因突变状态与西妥昔单抗/帕尼单抗治疗mCRC疗效间的关系。结果 共12项研究1 622例受试者纳入分析,合并分析显示：mCRC 患者中K-ras基因突变率为P=39%(95% CI：37%~44%);K-ras野生型和突变型患者西妥昔单抗/帕尼单抗治疗的客观有效率(CR+PR)分别为P=18%(95% CI：15%~26%)和P=9%(95% CI：2%~15%);与K-ras突变型相比,K-ras野生型患者西妥昔单抗/帕尼单抗治疗的客观有效率优势比OR(odds ratio)=5.10(95% CI：2.84~9.14)。结论 mCRC中约有40%的患者存在K-ras基因突变,存在K-ras基因突变的患者对抗EGFR治疗(西妥昔单抗/帕尼单抗)反应较差。     

西妥昔单抗联合化疗治疗消化系统肿瘤的临床研究

目的观察西妥昔单抗联合化疗治疗消化系统肿瘤的疗效及不良反应。方法回顾性分析17例接受西妥昔单抗联合化疗治疗的消化系统肿瘤患者的资料,对其进行疗效评价及安全性分析。合并的化疗方案主要有以奥沙利铂或伊立替康为主的联合化疗以及伊立替康单药化疗。结果全组可评价疗效者13例,有效率（RR）为46.2%,疾病控制率（DCR）为76.9%,中位疾病进展时间（TTP）4.0个月。一线治疗6例,RR为66.7%,DCR为83.3%,中位TTP 4.8个月。13例有8例为结直肠癌,RR为50%,DCR为87.5%,中位TTP 5.0个月,其中一线治疗3例全部获得PR。痤疮样皮疹发生率为52.9%,但未显示出皮疹与有效率的相关性。结论西妥昔单抗联合化疗治疗消化系统肿瘤安全有效,尤其一线治疗效果更佳,值得进一步扩大样本研究。     

伊立替康联合对症支持疗法在转移性结直肠癌治疗中的临床应用

目的 评价伊立替康联合对症支持疗法在不能耐受联合化疗的转移性结直肠癌患者治疗中的临床疗效及不良反应.方法 选取我院原发肿瘤、淋巴结及远处转移(TNM)分期均为Ⅳ期的结直肠癌患者共24例,卡氏行为状态评分为40～ 60分,完全随机将患者分为观察组(13例)和对照组(11例).观察组患者第1、8天给予伊立替康125 mg/m2静脉滴注,30 ～ 90 min内滴完,联合对症支持治疗;对照组患者单纯给予对症支持治疗.观察2组患者临床疗效和不良反应发生情况.结果 观察组治疗有效率为15.4％(2/13),疾病控制率53.8％(7/13);对照组治疗有效率为0,疾病控制率为8.2％(2/11).治疗1年后随访,观察组患者的生存率高于对照组[53.8％(7/13)比27.3％(3/11),P＜0.05].治疗后,观察组生存质量提高患者的比率高于对照组,差异有统计学意义[53.8％(7/13)比27.3％(3/11),P＜0.05].化疗的不良反应大多数患者可耐受,并未因此中断治疗.结论 与单纯给予对症支持治疗相比,伊立替康联合支持治疗可以改善不能耐受联合化疗的转移性结直肠癌患者的疾病控制率,提高患者生存率和生活质量,且患者耐受性和依从性好.     

盐酸伊立替康的不良反应及其预防处理

伊立替康(irinotecan,CPT-11)是喜树碱的半合成衍生物,是选择性拓扑异构酶Ⅰ抑制剂,本品及其体内代谢物SN-38可诱导单链DNA损伤,从而阻断DNA复制,产生细胞毒作用。CPT-11于1998年获FDA批准用于标准化疗方案治疗后转移性结肠直肠癌复发和恶化的二线治疗;于2000年3月获FDA批准联合氟尿嘧啶(5-FU)和亚叶酸钙(CF)用于转移性结肠直肠癌的一线治疗。本品单药有效率在18%左右,联合5-FU和CF的有效率约为50%。CPT-11主要不良反应有迟发性腹泻、恶心、呕吐、中性粒细胞减少症、急性胆碱能综合征等,现就其不良反应的表现类型及预防处理方法进行概述。     

Lack of usefulness of epidermal growth factor receptor expression determination for cetuximab therapy in patients with colorectal cancer

In patients with metastatic colorectal cancer, the use of cetuximab currently requires a documented tumoral epidermal growth factor receptor positivity. Responses to cetuximab, however, have been described in patients with epidermal growth factor receptor-negative tumors. We have used cetuximab in all eligible patients with metastatic colorectal cancer, whether their tumor expressed epidermal growth factor receptor or not. We assessed the cetuximab efficacy with regard to tumoral epidermal growth factor receptor expression. Twenty patients with metastatic colorectal cancer were treated off study with cetuximab and irinotecan after failure of oxaliplatin- and irinotecan-based regimens. Tumors were analyzed in all patients for epidermal growth factor receptor expression by immunohistochemistry. Tumors were positive for epidermal growth factor receptor in 12 cases and negative in eight cases. An objective response to cetuximab-based therapy was obtained in four patients (20%). Tumors of these four patients were negative for epidermal growth factor receptor expression. These results provide further evidence for the lack of usefulness of epidermal growth factor receptor detection by immunohistochemistry for cetuximab therapy in patients with metastatic colorectal cancer.     

Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer: a pooled analysis

KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified as representing a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question of whether first-line treatment of p.G13D mCRCs should include cetuximab or bevacizumab. Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic first-line treatment with a fluoropyrimidine and oxaliplatin/irinotecan that was combined with either cetuximab or bevacizumab. The analysis of cetuximab-based and bevacizumab-based regimens in mCRC patients with p.G13D-mutated tumours indicated comparable data for the overall response rate (58 vs. 57%) and progression-free survival (8.0 vs. 8.7 months; hazard ratio: 0.96, P=0.9). Overall survival (OS) was 20.1 months in patients treated with cetuximab-based first-line therapy compared with 14.9 months in patients receiving bevacizumab-containing regimens (hazard ratio: 0.70, P=0.29). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate with a poor outcome (P=0.03). Moreover, a strong trend in favour of capecitabine compared with infusional 5-FU (P=0.06) was observed. Response to treatment correlated with OS in patients receiving cetuximab-based, but not bevacizumab-based regimens. This retrospective pooled analysis suggests comparable efficacy of cetuximab-based and bevacizumab-based first-line therapy in patients with p.G13D mutant mCRC. The combination with capecitabine and irinotecan was associated with a more favourable outcome compared with infusional 5-FU and oxaliplatin.     

Treatment of advanced or recurrent colorectal cancer with irinotecan in Japan and elsewhere

BACKGROUND: Dramatic prolongation of the survival of patients with advanced or recurrent colorectal cancer has been achieved by multi-drug chemotherapy using agents such as continuous 5-fluorouracil and leucovorin, irinotecan (CPT-11), L-OHP, bevacizumab and cetuximab. OBJECTIVE: To explain the background of CPT-11 and to discuss its role in the treatment of advanced or recurrent colorectal cancer in Japan and elsewhere together with the authors' own experience.