Chemotherapy for metastatic colorectal cancer

Of the 30,000 people in the UK who develop colorectal cancer each year, around 70-80% undergo potentially curative surgery. Even so, around a half of all patients eventually die from metastatic disease, typically within 5 years of diagnosis. Many patients who develop metastases are offered systemic chemotherapy to try to extend survival and maintain or improve quality of life. How effective is such intervention?     

Chemotherapy of colorectal cancer.

Advanced colorectal cancer belongs to the most chemotherapy-resistant human malignancies. The cytotoxic agent with the most consistent antitumor activity has been 5-fluorouracil (5-FU). With this drug, response rates vary between 15% (with conventional weekly or 5-day bolus injection) and 30% (with continuous infusions of 24 h to 12 weeks); survival advantages of the latter approach have not been demonstrated. Combinations of 5-FU with other cytotoxic agents with some activity have been found unsuccessful. Because of its complex metabolism the efficacy-toxicity ratio of 5-FU can be positively influenced by biochemical modulation with agents leading to decreased availability of competing substrates, increased availability of co-substrates or more efficient interactions with target substances. Superior response rates (20-40%) have been observed upon the addition of leucovorin, methotrexate and N-(phosphonacetyl)-L-aspartic acid; survival was modestly prolonged (2-3 months) in two leucovorin and one methotrexate study. Interferon-alpha, inactive as a single agent, appears to synergize with 5-FU at the cost of considerable toxicity; results from randomized trials of this combination are awaited. 5-FU has also been the mainstay of adjuvant treatments; in poor-prognosis rectal cancer it appears to improve survival if added to radiotherapy, whereas in combination with levamisole the survival of node-positive colonic carcinoma patients can be prolonged.     

Chemotherapy of metastatic colorectal cancer: fluorouracil plus folinic acid and irinotecan or oxaliplatin

(1) Following the recent introduction of several new cytotoxic agents, a new look at the role of chemotherapy in metastatic colorectal cancer is needed. (2) In one clinical trial of first-line treatment, fluorouracil + folinic acid infusion, after an initial bolus (LV-5FU2 protocol), was more effective and better tolerated than bolus administration alone (Mayo Clinic protocol). (3) Five comparative trials failed to show that raltitrexed was more effective than fluorouracil + folinic acid in first-line treatment, and it has more serious adverse effects. (4) There are no comparative trials of capecitabine or tegafur + uracil versus fluorouracil + folinic acid (LV-5FU2 protocol) in first-line treatment. (5) In three comparative randomised trials involving previously untreated patients, adjunction of oxaliplatin to the fluorouracil + folinic acid combination (FOLFOX protocol) increased both tumour response rate and progression-free survival (by about 2 months), but it also caused more neuropathies, severe diarrhea and severe neutropenia. (6) In two comparative trials of first-line treatment, adjunction of irinotecan to fluorouracil + folinic acid (FOLFIRI protocol) increased the median survival time by about 3 months, to 15-17 months, but increased the incidence of diarrhea, neutropenia, serious cardiovascular disorders and severe thrombosis. (7) In second-line treatment, irinotecan is the only properly assessed drug with a positive impact, prolonging survival compared with appropriate palliative care (34 months after diagnosis, versus 27 months). (8) In one comparative trial, first-line treatment with the FOLFOX protocol, followed by the FOLFIRI protocol, resulted in the same median survival time (21 months) as the reverse sequence. (9) In practice, the first-line treatment for metastatic colorectal cancer appears to be the fluorouracil + folinic acid combination (LV-5FU2 protocol) plus either oxaliplatin (FOLFOX protocol) or irinotecan (FOLFIRI protocol). The reference second-line treatment is the FOLFIRI protocol (or the FOLFOX protocol if the FOLFIRI protocol has already been used). These treatments were associated with the longest survival in one trial.     

治疗转移性结直肠癌的Ziv-阿柏西普的临床研究进展

针对特异性分子靶点的靶向药物治疗已成为转移性结直肠癌(m CRC)治疗的新方向。2012年Ziv-阿柏西普被美国食品和药物管理局批准用于m CRC患者,Ziv-阿柏西普是一种作用于血管生成信号通路的重组融合蛋白,通过与血管内皮生长因子(VEGF)受体结合,从而阻断肿瘤的生长和转移。一项Ⅲ期临床研究结果显示Ziv-阿柏西普能显著延长m CRC患者的生存期。本文结合国内外最新研究报道,对Ziv-阿柏西普治疗m CRC的研究进展作一综述。     

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--西妥昔单抗

西妥昔单抗是一种嵌合型单克隆抗体,可与结直肠癌肿瘤细胞上的表皮生长因子受体(EGFR)特异性结合,从而诱导有益的细胞反应,提高肿瘤对放化疗的敏感性.西妥昔单抗已在瑞士和美国上市,治疗表达EGFR的转移性结直肠癌.推荐剂量为首次负荷量400 mg·m-2,每周维持剂量250 mg·m-2.西妥昔单抗单独治疗最常见的3/4级不良反应有痤疮样皮疹、虚弱、腹痛和恶心/呕吐等.     

FIVB plus GM-CSF in metastatic colorectal cancer

The response rate of patients with metastatic colorectal cancer to the 4-drug combination [5-Fluorouracil (5-FU), dacarbazine, vincristine and bis-chloronitrosourea given 5 weekly (FIVB)] was better than the response rate to 5-FU. The dose limiting toxicity of the FIVB was myelosuppression. The present study investigates the effect of FIVB given with GM-CSF so that drug cycles could be given every 4 weeks.Thirty-five ambulatory patients with measurable metastatic colorectal cancer were treated with FIVB plus GM-CSF 4 weekly. All patients were evaluable for toxicity. Among the 163 cycles given only 4 were delayed because of leucopenia and 8 cycles were delayed because of gastrointestinal (GI) toxicity. A 50% dose reduction was given to 10 patients who had Grade 2 and 3 GI toxicity. Four of the 35 patients developed thromboembolic complications, 2 of which were lethal. Two patients were not evaluable for response as they were removed from study early because of toxicity. There were 2 complete responses and 6 partial responses. The median time to treatment failure was 3.8 months and median survival time 9.9 months.The addition of GM-CSF to FIVB decreased the expected leucopenia allowing drug treatment to be given 4 weekly to most patients. GI toxicity was dose limiting. Despite the increased dose intensity that could be delivered (to two thirds of patients), response rates were not definitely increased, no survival benefit was seen and important thromboembolic complications occurred.     

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。     

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.     

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.     

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。     

Optimal management of metastatic colorectal cancer: current status

Colorectal cancer remains one of the most common causes of cancer death in the US, with approximately a quarter of patients presenting with metastatic disease at the time of diagnosis. Recent advances over the past 2 decades have increased the repertoire of chemotherapeutic agents for this disease and extended median overall survival to more than 20 months. An increasing body of evidence also supports the addition of targeted agents, those directed towards vascular endothelial growth factor and epidermal growth factor receptors, to expand treatment options for patients with metastatic disease. Ongoing trials are exploring the optimal combinations of these drugs as well as promising new investigational agents that take advantage of the genetic aberrations that drive tumour biology. This review aims to summarize the pertinent data on available cytotoxic and biological agents used to extend survival in metastatic colorectal cancer patients and provide a modern approach to treatment strategies while acknowledging the areas of controversy on which future clinical trials should be based.     

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.     

KRAS inhibition in metastatic colorectal cancer: An update

About half of colorectal cancers harbor mutations in the KRAS gene. The presence of these mutations is associated with worse prognosis and, until now, the absence of matched targeted therapy options. In this review, we discuss clinical efforts to target KRAS in colorectal cancer from studies of downstream inhibitors to recent direct inhibitors of KRAS^G12C and other KRAS mutants. Early clinical trial data, however, suggest more limited activity for these novel inhibitors in colorectal cancer compared to other cancer types, and we discuss the role of receptor tyrosine kinase signaling and parallel signaling pathways in modulating response to these inhibitors. We also review the effect of KRAS mutations on the tumor-immune microenvironment and efforts to induce an immune response against these tumors.     

Advanced therapies on BRAF-mutated and KRAS-mutated metastatic colorectal cancer

Colorectal cancer(CRC) is one of the most-diagnosed cancer worldwide, and 30% of patients with CRC have showed a metastatic situation. Monoclonal antibodies(mAbs) that target vascular endothelial growth factor(VEGF) and the epidermal growth factor receptor(EGFR) can achieveantitumor efficacy via antivascular and anticellular effects respectively and have been added into first-line chemotherapy for patients with metastatic colorectal cancer(mCRC). Investigations found that unlike VEGF inhibitors, the efficacy of EGFR inhibitors,such as Cetuximab and panitumumab, is limited to patients with wild-type-KRAS tumors without BRAF mutant. Studies revealed that resistance to EGFR inhibitors result in the poor response to anti-EGFR therapiesthrough acquired mutations of KRAS and BRAF.Considering this situation, in this review, we will focus onresistance mechanism to anti-EGFR therapies and advanced therapies for BRAF-mutated and KRAS-mutated mCRC patients.     

转移性结直肠癌3种一线化疗方案的药物经济学评价

目的：探讨转移性结直肠癌（mCRC）3种一线化疗方案的药物经济学效果及影响因素。方法：采用回顾性调查方法,纳入2012年1月1日-2015年10月30日期间符合纳入标准的mCRC患者,根据化疗方案不同分为FOLFOX组、CapeOx组和FOLFIRI组。以总住院费用为成本,无进展生存时间（PFS）为效果,对3种化疗方案进行成本-效果分析和敏感度分析,并评价化疗药物是否国产及医保支付对结果的影响。结果：共纳入678名患者,FOLFOX组（136例）、CapeOx组（392例）和FOLFIRI组（150例）间基本情况无统计学差异（P>0.05）,具有可比性。FOLFOX组、CapeOx组和FOLFIRI组PFS分别为154.15 d、156.16 d和165.84 d,不良反应各组间无统计学差异,总治疗费用分别为63 956.11元、73 826.06元和79 259.20元,成本-效果比分别为414.90、472.76和477.93。在FOLFOX方案的基础上,每增加一天PFS,FOLFIRI方案和CapeOx方案所追加的成本分别为57.86元和59.69元。敏感度分析结果与成本-效果分析一致。亚组分析表明,国产药物的效果略低于进口药物,成本均高于进口药物,成本-效果比低于进口药物,药物经济学效果好。3种方案患者自付费用成本-效果比FOLFOX方案 < CapeOx方案 < FOLFIRI方案,医保支付费用成本-效果比FOLFOX < FOLFIRI < CapeOx。结论：mCRC 3种一线化疗方案中,成本最低的为FOLFOX方案,效果最佳的为FOLFIRI方案,经济学效果最优为FOLFOX方案。     

A novel antimetabolite: TAS-102 for metastatic colorectal cancer

TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI). TAS-102 has been shown to significantly improve overall survival and progression-free survival in patients with refractory metastatic colorectal cancer (mCRC) in placebo-controlled randomized phase II and III trials. The current review summarizes mechanisms of action, pharmacokinetics/dynamics and preclinical and clinical data of TAS-102 in colorectal cancer. TAS-102 is a new salvage-line treatment option for patients with mCRC. TAS-102 is well tolerated and has great potential in future clinical drug combination therapies.     

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.