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.     

西妥昔单抗联合替吉奥治疗老年转移性结直肠癌的临床观察

目的 探讨西妥昔单抗联合替吉奥治疗老年转移性结直肠癌的疗效及安全性.方法 收集一线解救化学治疗(化疗)不能耐受及拒绝一线化疗方案的32例老年患者的临床资料.按K-Ras基因表型分为联合用药组(16例),对照组(16例).联合用药组患者采用西妥昔单抗联合替吉奥方案治疗,西妥昔单抗首次剂量为400mg/m2,以后每周剂量为250mg/m2,每周1次.替吉奥根据体表面积来确定初始剂量,体表面积＜1.25 m2,40mg;体表面积1.25～1.5 m2,50mg;体表面积＞1.5m2,60mg.用法:2次/d,早饭后和晚饭后分别口服1次,连续服用14d,停药7d,3周为1个周期;对照组根据体表面积服用相应剂量的西妥昔单抗.至少给予2个周期治疗.观察疗效及不良反应.结果 联合用药组完全缓解3例(18.75％),部分缓解4例(25.00％),病情稳定5例(31.25％),病情进展4例(25.00％),有效率43.75％ (7/16),疾病控制率75.00％(12/16).对照组完全缓解3例(18.75％),部分缓解3例(18.75％),病情稳定3例(18.75％),病情进展7例(43.75％),有效率37.50％ (6/16),疾病控制率56.25％(9/16).联合用药组的疾病控制率均优于对照组,差异均有统计学意义(P＜0.05);2组有效率比较,差异无统计学意义(P＞0.05).联合用药组和对照组常见的不良反应为色素沉着、皮疹,其发生率分别为87.50％ (14/16)和56.25％(9/16),恶心呕吐的发生率分别为62.50％(10/16)和56.25％(9/16).2组不良反应发生率差异无统计学意义(P＞0.05).结论 西妥昔单抗联合替吉奥治疗老年转移性结直肠癌较对照组更有效,不良反应可耐受.     

西妥昔单抗联合化疗治疗转移性结直肠癌的临床观察

目的观察西妥昔单抗与奥沙利铂/5-FU/FA联合治疗转移性结直肠癌的近期疗效及毒性反应。方法对11例转移性结直肠癌(MCRC)患者采用西妥昔单抗与奥沙利铂/5-FU/FA化疗联合方案,应用2周期后评价近期疗效及毒性反应。西妥昔单抗首次推荐剂量为400 mg/m~2,以后每周剂量为250 mg/m~2,奥沙利铂/5-FU/FA化疗剂量采用FOLFOX4方案。结果11例患者均完成西妥昔单抗连续6周用药,奥沙利铂/5-FU/FA化疗2周期(每2周重复1次),无CR病例,2例PR(18.18%),4例SD(36.36%),5例PD(45.45%),疾病控制(PR SD)率54.55%。治疗过程中出现的毒性反应为3～4度的痤疮样皮疹,另外有恶心、呕吐、腹痛和虚弱,2～3度白细胞下降。全组患者无过敏反应。结论西妥昔单抗可提高肿瘤对放化疗的敏感性。采用西妥昔单抗与奥沙利铂联合治疗11例转移性结直肠癌患者,取得初步疗效和安全性观察,且不因联合化疗而增加毒性反应,耐受性良好。     

Panitumumab: in the treatment of metastatic colorectal cancer

Panitumumab is a fully human immunoglobulin G2 monoclonal antibody highly selective for the epidermal growth factor receptor (EGFR), which is overexpressed in 25-77% of colorectal cancers. This overexpression is frequently associated with a poor prognosis. In a large, randomised, nonblind, multicentre phase III study in pretreated adult patients with metastatic colorectal cancer and EGFR staining in >or=1% tumour cells, panitumumab 6 mg/kg every 2 weeks plus best supportive care (BSC) was significantly (p < 0.0001) more effective in improving progression-free survival than BSC alone; recipients of panitumumab plus BSC had a 46% lower disease progression rate than those receiving BSC alone after a median follow-up of 19 weeks. Panitumumab 6 mg/kg every 2 weeks or 2.5 mg/kg/week, administered as monotherapy, produced partial response rates of 8-13% and stable disease rates of 21-30% in pretreated patients with metastatic colorectal cancer in three noncomparative, multicentre phase II studies. Preliminary phase II results also suggest a potential role for panitumumab as first-line therapy in combination with fluorouracil, folinic acid and irinotecan in patients with metastatic colorectal cancer. Panitumumab was generally well tolerated. Grade 3/4 skin-related toxicities were reported in 14% of patients receiving panitumumab plus BSC in the phase III study (versus 0% of patients receiving BSC alone). An analysis of pooled data found that high-affinity binding antibodies to panitumumab were detected in <1% of patients.     

Oral drugs in the treatment of metastatic colorectal cancer

Introduction: Intravenous administration of fluoropyrimidine-based chemotherapy has been the cornerstone of treatment in metastatic colorectal cancer (mCRC) for decades. The availability of oral capecitabine has improved the tolerability in monotherapy schedules, and has simplified combination schedules. Since then, other oral drugs have proven efficacy in this setting.

Areas covered: We review the available evidence and most recent data concerning oral drugs with proven efficacy in mCRC, including capecitabine, S-1, trifluridine-tipiracil (TAS-102) and regorafenib.

Expert opinion: The use of capecitabine is widely implemented in the care of mCRC. However, with recent data supporting its prolonged use, the relatively high incidence of hand-foot syndrome (HFS) may impair quality of life. In Asian populations, S-1 is associated with equivalent efficacy but lower incidence of HFS compared to capecitabine. Further studies evaluating the effects of S-1 in Western populations are needed. Both regorafenib and TAS-102 improve the overall survival of patients in whom all other treatment options have failed. Since only a subset of patients appears to benefit, future studies to identify predictive biomarkers are needed.     

转移性结肠癌药物治疗的研究进展

已有转移灶的转移性结肠癌(CRC)病人的5年生存率小于10%。接受氟尿嘧啶(FU)/亚叶酸(LV)治疗的中位生存期大约为12 mo。以FU/LV为基础制剂,联合不同抗肿瘤药物(奥沙利铂、伊立替康、卡培他滨、贝伐单珠抗)的新联合疗法对晚期结肠癌的疗效、中位生存期、生活质量等在不同程度上有所改善和提高。本文就转移结肠癌的治疗进展作一综述。     

Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer

Cetuximab (Erbitux) is a human-mouse chimeric monoclonal antibody, which competitively binds to the accessible extracellular domain of the epidermal growth factor receptor (EGFR) to inhibit dimerisation and, subsequently, inhibit tumour growth and metastasis. In the EU and the US, cetuximab has been approved for use with concomitant radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) and in combination with irinotecan for the treatment of metastatic colorectal cancer (mCRC) in patients with EGFR-expressing tumours who are refractory to irinotecan-based therapy. In the US, cetuximab has also been approved as monotherapy in patients with recurrent or metastatic SCCHN for whom platinum-based therapy has failed and in patients with mCRC who are intolerant of irinotecan-based regimens.In treatment-naive patients with locoregionally advanced SCCHN, cetuximab plus radiotherapy was more effective than radiation therapy alone in prolonging locoregional disease control. In addition, more limited noncomparative data from a large trial indicated a 13% overall objective response rate (ORR) in platinum-refractory patients with SCCHN. In patients with EGFR-expressing mCRC, cetuximab plus irinotecan improved ORR more than cetuximab monotherapy in a trial in irinotecan-refractory patients; however, there was no difference in overall survival (OS) between cetuximab plus irinotecan and cetuximab monotherapy in oxaliplatin-refractory recipients in another trial. In an ongoing trial, progression-free survival (PFS) exceeded 50% after 12 weeks in irinotecan-refractory patients receiving three different dosages of cetuximab plus irinotecan. In another large trial, cetuximab monotherapy prolonged OS compared with best supportive care (BSC) in heavily pretreated patients. Overall, cetuximab treatment had an acceptable tolerability profile, with the majority of adverse events being mild or moderate in severity and clinically manageable. In particular, cetuximab therapy did not exacerbate toxicities commonly associated with chemo- or radiotherapeutic regimens. Albeit occurring with high incidence, adverse cutaneous reactions appear to be a marker for response. Results of ongoing head-to-head comparative trials comparing cetuximab with other biological agents will help to establish definitively the role of cetuximab in the management of SCCHN and mCRC. In the meantime, cetuximab, with its highly targeted mechanism of action and synergistic activity with current treatment modalities, is a valuable treatment option in patients with SCCHN and mCRC.     

Palliative treatment of unresectable metastatic colorectal cancer

Importance of the field: Treatment options for metastatic colorectal cancer (mCRC) patients have rapidly increased in the past years, but 50 – 70% of mCRC patients are still unlikely to undergo radical resection of metastases and are candidates for palliative therapy only.

Areas covered in this review: Oxaliplatin and irinotecan have widened the chemotherapy alternatives available in this setting and effective targeted agents against vascular endothelial growth factor and epidermal growth factor receptor have further improved treatment efficacy. This review covers the main areas of debate in the optimal treatment of unresectable mCRC patients, focusing on the implications for everyday clinical practice and future research of the most relevant clinical trials and molecular investigations published from 1999 to 2009.

What the reader will gain: Insights into treatment individualization strategies are provided in the review.

Take home message: ‘One size fits all’ can not longer be considered an adequate approach to unresectable mCRC, and treatment with both chemotherapy and biologic agents should be guided by prognostic and predictive factors in order to maximize the benefit while reducing futile toxicities.     

治疗转移性结直肠癌新药:呋喹替尼

呋喹替尼是我国自主研发的新型抗肿瘤药物,于2018年9月经国家药品监督管理局批准上市,用于转移性结直肠癌的治疗。呋喹替尼是一种强效、高选择性血管内皮生长因子受体(VEGFR)抑制剂,与瑞戈非尼相比,呋喹替尼对VEGFR的选择性更高,对转移性结直肠癌的效果更明确。呋喹替尼常见不良反应为手足综合征、高血压、声音嘶哑、蛋白尿和天冬氨酸转氨酶升高等。     

转移性结直肠癌二线治疗的研究进展

结直肠癌在全球范围内都是威胁人们健康的重大疾病。内科治疗是进展期结直肠癌的最主要、也是最有效的治疗措施。近年来,转移性结直肠癌的内科治疗效果得到了很大提高。化疗及分子靶向药物治疗能显著改善转移性结直肠癌患者的二线治疗的预后,延长生存时间、提高生活质量。     

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.     

Emerging tyrosine kinase inhibitors for the treatment of metastatic colorectal cancer

Introduction: Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Over the last decade, the addition of antibodies that block the epidermal growth factor receptor (EGFR) or angiogenesis to the classic chemotherapy backbone has improved overall survival in metastatic colorectal cancer (mCRC). However, the role of the other major targeted therapy, the tyrosine kinase inhibitors (TKIs), is not yet fully clarified.

Areas covered: This review discusses key published and ongoing studies with TKIs in mCRC, the mechanisms of resistance to standard treatments that are potentially targetable with these small molecules, along with the role of biomarkers in therapeutic decision-making process.

Expert opinion: The current effectiveness of TKIs is limited by two principal reasons, firstly the use of combination chemotherapy necessitates lower dose-density to manage the toxicity profile and secondly, development of these drugs has mainly been performed in molecularly unselected populations. mCRC is a heterogeneous and dynamic disease, and clinical trials with TKIs must be designed on the basis of specific molecular alterations targeted by these drugs. Success with this approach relies on identifying mutations at the time of progression, raising the importance of minimally-invasive monitoring tools. Liquid biopsies are a promising option, although this technique remains to be validated. Overall, this approach contributes to the move towards personalized and precision therapeutic strategies.     

FOLFIRI方案治疗转移性结直肠癌96例观察

目的观察FOLFIRI方案治疗转移性结直肠癌的疗效、副反应及UGT1A1基因多态性与与副反应的相关性。方法对96例确诊的晚期结直肠癌患者,采用FOLFIRI方案治疗,观察近期疗效和副反应及UGT1A1基因多态性与副反应相关性。结果 96例患者用药后获得PR58例,SD 24例,PD 14例,无1例获得CR。ORR60.4%,DCR85.4%,所有患者均获随访,中位TTP 6.1月。主要毒副反应为骨髓抑制,其中中性粒细胞减少发生率为88.5%;脱发发生率较高,总发生率为83.3%;迟发性腹泻发生率为19.8%,均得到了有效的控制。检测UGT1A1基因多态性12例患者中,(TA)6/(TA)6UGT1A1*1/*1纯合野生基因型9例,发生腹泻为1例,为Ⅰ度。(TA)6/(TA)7UGT1A1*28/*1杂合基因型3例,发生腹泻2例,其中1例为Ⅲ度腹泻。结论 FOLFlRI方案是治疗常规化疗失败晚期结直肠癌的有效化疗方案,缓解率较高,迟发性腹泻和中性粒细胞减少为其主要不良反应。UGT1A1启动子区TATA盒基因多态性(TA)6/(TA)7杂合状态可以增加患者发生严重腹泻的风险。     

阿帕替尼联合化疗治疗转移性结直肠癌的疗效

目的 比较阿帕替尼联合化疗与阿帕替尼单药治疗转移性结直肠癌(mCRC)的疗效和安全性。方法 共纳入62例患者,将其分为阿帕替尼联合化疗组(联合组)和阿帕替尼单药组(单药组)。记录并评估2组的无进展生存期(PFS)、总生存期(OS)、客观反应率(ORR)、疾病控制率(DCR)、治疗前后的实验室检查结果和治疗相关不良事件。此外,进行单因素和多因素Cox回归分析PFS和OS的独立预后因素。结果 与单药组相比,联合组显著延长了OS(8.1 m vs 7.7 m,P=0.021),但2组PFS比较差异无统计学意义(3.65 m vs 3.15 m,P=0.100)。[联合组的ORR为8.3%(3/36),DCR为80.6%(29/36),单药组的ORR和DCR分别为7.7%(2/26)、61.5%(16/26)。多因素分析提示治疗方案[风险比(HR)=1.946,95%CI:1.014～3.738,P=0.045]和原发肿瘤的位置(HR=3.486,95%CI:1.374～8.844,P=0.009)是OS的重要因素。联合组治疗后的平均红细胞体积(MCV)和平均红细胞体积与红细胞比值(MCV/RBC)均高于单药组(P<0.05),而联合组治疗后的淋巴细胞与单核细胞比值(LMR)和血红蛋白、白蛋白、淋巴细胞和血小板计数评分(HALP评分)均低于单药组(P<0.05)。联合组3/4级血小板减少(11.1%)高于单药治疗组(0%),其他不良反应2组比较差异无统计学意义。结论 在mCRC后线治疗中,阿帕替尼联合化疗比单药治疗能延长OS,且未增加不良反应。     

新的抗血管生成药物阿柏西普治疗转移性结直肠癌研究进展

新生血管生成是结直肠癌发生、生长和转移的重要机制之一。阿柏西普作为血管内皮生长因子 (vascular endothelial growth factor,VEGF)的可溶性诱饵受体,作用于靶点VEGF-A、VEGF-B和胎盘生长因子(placental growth factor,PIGF)抑制肿瘤血管的生成。最近多项研究表明阿柏西普对多种实体瘤尤其转移性结直肠癌(metastatic colorectal cancer,mCRC)有明确的抗肿瘤作用。而且美国食品药品监督管理局和欧洲药物管理局已批准阿柏西普联合5-氟尿嘧啶、亚叶酸钙和伊立替康方案(5-fluorouracil,leucovorin,irinotecan,FOLFIRI)可用于二线治疗对奥沙利铂为基础的化疗方案耐药或进展的mCRC患者。该文就阿柏西普抗血管生成的作用机制和在mCRC中的临床试验作一综述。     

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.     

Safety and efficacy of nintedanib for the treatment of metastatic colorectal cancer

Introduction: Nintedanib (BIBF 1200) is an oral tyrosine kinase inhibitor that targets the vascular endothelial growth factor (VEGFR), platelet-derived growth factor (PDGFR) and fibroblast growth factor (FGFR) receptors. It is approved in Europe in combination with docetaxel for patients with advanced lung adenocarcinoma who have progressed to first-line chemotherapy. However, its role in the treatment of metastatic colorectal cancer (mCRC) is uncertain. Recent results from the LUME-Colon 1 pivotal phase III trial showed only a marginal increase in progression free survival over placebo in refractory mCRC patients, with a toxicity profile similar to other antiangiogenic agents, and no benefit in overall survival.

Areas covered: The aim of this review is to summarize the pharmacology, efficacy and safety profile of nintedanib in the context of mCRC, and to provide some perspective regarding the role of this drug in clinical practice.

Expert commentary: Nintedanib provides limited clinical benefit in refractory CRC and its use in this clinical setting is not warranted. Efforts shall continue to pursue the identification of predictive biomarkers that allow the selection of subpopulations with a greater likelihood to benefit from this therapeutic approach, in order to improve the benefit-risk and cost-benefit ratios of this and other antiangiogenic agents.     

First-line treatment strategies for elderly patients with metastatic colorectal cancer

Colorectal cancer ranks third in incidence in both men and women after lung, breast and prostate cancer. The prevalence of colorectal cancer increases significantly with age, with 40% of patients in Europe being >75 years of age at the time of initial diagnosis. Furthermore, the number of elderly patients with colorectal cancer is expected to increase significantly over the next two decades. Treatment of advanced colorectal cancer has evolved dramatically over the last decade. Advances in surgery and chemotherapy are effective in prolonging time to disease progression and survival in patients with advanced colorectal cancer. For >40 years, fluorouracil has been the mainstay of chemotherapy for advanced colorectal cancer. Recently, however, newer cytotoxic chemotherapies and biological agents effective against colorectal cancer have been shown to improve overall survival in metastatic disease. Thus, a patient with metastatic colorectal cancer today has an expected median survival of 20 months compared with 10 months only a few years ago. There is evidence that elderly individuals derive as much survival benefit from standard chemotherapy approaches in metastatic colorectal cancer as younger patients. Unfortunately, most older patients who might benefit from chemotherapy are not offered this treatment, and the fraction who are not offered it increases with increasing age. Treatment decisions should not be made on the basis of age. Rather, they should be based on functional status, the presence of co-morbidities, and consideration of drug-specific toxicities that can be aggravated in older individuals because of decreased functional reserve. Although the elderly have been under-represented in clinical trials, studies also support the effectiveness of combination chemotherapy in elderly patients with advanced colorectal cancer. This article reviews current optimal first-line treatment strategies for elderly patients with metastatic colorectal cancer.     

卡培他滨治疗晚期/转移性结直肠癌的成本-效果分析

目的对卡培他滨治疗晚期转移性结直肠癌进行经济学评价。方法基于卡培他滨和5-氟尿嘧啶+亚叶酸钙(5-FU+LV)治疗晚期转移性结直肠癌的Meta分析结果,将各个方案的结局终点分别设为缓解、稳定、无效,通过临床调查天津市三级医院相关的医疗服务价格,利用Treeage软件进行决策树的模型建立,最后进行成本–效果分析以及敏感性分析。结果卡培他滨组的疗效略好于5-FU+LV组,其治疗成本高于5-FU+LV组。通过单因素敏感性分析发现,结局指标稳定,结局未发生逆转。结论与5-FU+LV方案相比,卡培他滨口服使用方便且临床疗效肯定,尽管直接医疗成本–效果分析发现,其无显著经济学优势,但其间接成本和隐性成本费用低,具有一定的临床推广应用价值。