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.     

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.     

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.     

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.     

Panitumumab

Panitumumab, previously known as ABX-EGF, is the first fully human monoclonal antibody to be shown to be effective as a treatment for solid-tumor cancers. Its target is the epidermal growth factor receptor (EGFR), which when overactive may contribute to the development and progression of cancer and is expressed in several solid tumors, including colorectal cancer. In a recently reported phase III trial, patients with metastatic colorectal cancer who had failed previous treatment with oxaliplatin- and irinotecan-based therapy were randomized to receive single-agent panitumumab and best-supportive care, or best-supportive care alone. This trial demonstrated a significant improvement in progression-free survival with panitumumab treatment in these patients. A rash similar to that which occurs with the other anti-EGFR antibody, cetuximab, has been observed in up to 100% of patients treated with panitumumab in the various clinical trials. As with other EGFR antagonists, EGFR staining by immunohistochemistry has not been shown to be an effective method of selecting patients for treatment, whereas the severity of the rash appears to be predictive of outcome. Ongoing randomized trials are evaluating the use of panitumumab with combination treatment for the first-line treatment of metastatic colorectal cancer. This review summarizes the rationale for targeting the EGFR and the development of panitumumab in preclinical and early phase trials in several tumor types. Clinical trial results in colorectal cancer, in which the development of this agent is most advanced, will also be discussed, as will the rash associated with treatment.     

Metastatic colorectal cancer: current systemic treatment options

The treatment of colorectal cancer has become increasingly complex over recent years. With the emergence of new chemotherapy drugs and targeted agents, there has been great improvement in the prognosis of patients with metastatic colorectal cancer. This review summarises the evidence supporting the use of combination chemotherapy with oxaliplatin and/or irinotecan with fluorouracil (5-FU) for the treatment of colorectal cancer and outlines the pivotal trials. Phase III trials have demonstrated the superiority of combination chemotherapy over single-agent 5-FU, but the optimal sequencing and combination of treatment is yet to be determined. Oral fluoropyrimidine derivatives have been shown to be equivalent to bolus 5-FU treatment and these offer another option for the treatment of colorectal cancer, but further studies are required to evaluate their use with irinotecan and oxaliplatin. The use of newer targeted therapies, such as bevacizumab and cetuximab, alone and in combination with chemotherapy are discussed, and the most recent data supporting their use is outlined. Bevacizumab-containing regimens have been shown to be superior to those without for the first-line treatment of colorectal cancer, and cetuximab has demonstrated activity in combination with chemotherapy in both the first- and second-line setting. Other targeted agents, such as vatalanib and panitumumab, are discussed and early clinical studies with these agents show promising results.     

Incidence and management of cutaneous toxicities associated with cetuximab

Cetuximab is a human/mouse chimeric monoclonal antibody that binds to the EGF receptor, competitively inhibiting ligand binding, and inducing receptor dimerization and downregulation. Cetuximab has been active in multiple tumors, including colorectal cancer (CRC), head and neck, pancreatic and lung cancers. Cetuximab has been approved by the FDA, in combination with irinotecan, for the treatment of metastatic CRC in patients refractory to irinotecan, and for use as a single agent in the treatment of recurrent metastatic CRC in patients intolerant of irinotecan-based chemotherapy. Most common toxicities are rash, diarrhea, fever, headache, nausea, hypomagnesemia and hypersensitivity reactions. Data from several clinical trials with cetuximab show a positive correlation between rash and response and/or survival. Rash occurred on 90% of patients treated with cetuximab monotherapy and grade 3 or 4 skin reactions occurred on as many as 16% of patients in the trials using cetuximab. A rash usually presents as pustular or maculopapular follicular eruption, often referred to as acneiform. Cetuximab will engage in productive dimerization complexes in human skin causing significant disruption of the normal development and maintenance of the hair follicle, which leads to follicular response and inflammatory response. At this time there are no standard or evidence-based treatment plans for the rash. Most of the evidence is based on institutional or personal experiences. The most commonly used agents are topical antibiotics, oral antibiotics, topical steroids, systemic immunomodulatory agents, topical immunomodulatory agents and anti-inflammatory preparations. As cetuximab is becoming widely used in general oncology practice, it is important to understand the toxicity of rash to develop practice guidelines for their management. This review addresses recommendations for toxicity management of rash caused by cetuximab in treatment of metatstatic CRC.     

Incidence and management of cutaneous toxicities associated with cetuximab

Cetuximab is a human/mouse chimeric monoclonal antibody that binds to the EGF receptor, competitively inhibiting ligand binding, and inducing receptor dimerization and downregulation. Cetuximab has been active in multiple tumors, including colorectal cancer (CRC), head and neck, pancreatic and lung cancers. Cetuximab has been approved by the FDA, in combination with irinotecan, for the treatment of metastatic CRC in patients refractory to irinotecan, and for use as a single agent in the treatment of recurrent metastatic CRC in patients intolerant of irinotecan-based chemotherapy. Most common toxicities are rash, diarrhea, fever, headache, nausea, hypomagnesemia and hypersensitivity reactions. Data from several clinical trials with cetuximab show a positive correlation between rash and response and/or survival. Rash occurred on 90% of patients treated with cetuximab monotherapy and grade 3 or 4 skin reactions occurred on as many as 16% of patients in the trials using cetuximab. A rash usually presents as pustular or maculopapular follicular eruption, often referred to as acneiform. Cetuximab will engage in productive dimerization complexes in human skin causing significant disruption of the normal development and maintenance of the hair follicle, which leads to follicular response and inflammatory response. At this time there are no standard or evidence-based treatment plans for the rash. Most of the evidence is based on institutional or personal experiences. The most commonly used agents are topical antibiotics, oral antibiotics, topical steroids, systemic immunomodulatory agents, topical immunomodulatory agents and anti-inflammatory preparations. As cetuximab is becoming widely used in general oncology practice, it is important to understand the toxicity of rash to develop practice guidelines for their management. This review addresses recommendations for toxicity management of rash caused by cetuximab in treatment of metatstatic CRC.     

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.     

The safety of monoclonal antibodies for treatment of colorectal cancer

ABSTRACT

Introduction: Monoclonal antibodies such as bevacizumab, ramucirumab, cetuximab and panitumumab play an important role in the treatment of metastatic colorectal cancer (mCRC). With the introduction of these drugs considerable improvements in both progression-free survival (PFS) and overall survival (OS) were achieved. However these antibodies are associated with a unique side effect profile.

Areas covered: This review provides an overview about drug efficacy of bevacizumab, cetuximab, panitumumab and ramucirumab in the treatment algorithm of mCRC. Additionally, we discuss the most common toxicites of these monoclonal antibodies.

Expert opinion: The most common toxicities associated with the VEGF-A directed antibody bevacizumab are hypertension, proteinuria, thromboembolism, bleeding, gastrointestinal perforation and prolonged wound healing. Similarly, the rate of hypertension and proteinuria is increased during treatment with the VEGFR2 antibody ramucirumab.

On the other hand the most frequent side effects of EGFR targeted antibodies are skin rash, hypersensitivity reactions and hypomagnesemia. Due to the murine portions of cetuximab the incidence of infusion reactions is more frequent compared to panitumumab which is a pure human monoclonal antibody.     

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with every second week cetuximab and irinotecan in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with wild-type KRAS metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. Cetuximab was administered at 500 mg/m(2) biweekly with irinotecan. The primary endpoint was response rate. The pharmacokinetics of cetuximab was also evaluated in 5 patients. From May 2009 to February 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 patients who were treated with biweekly cetuximab plus irinotecan, partial response was observed in 9 patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7%-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95% CI, 57.7%-90.0%). The median progression-free survival was 5.3 months and median overall survival was 10.8 months. Grade 3 skin toxicity was observed in 3 patients (10.0%) and one treatment related death due to pneumonia was observed. Combination chemotherapy with biweekly cetuximab and irinotecan was effective for pretreated metastatic colorectal cancer with wild-type KRAS.     

Cetuximab: an IgG(1) monoclonal antibody for the treatment of epidermal growth factor receptor-expressing tumours

The epidermal growth factor receptor (EGFR) plays an essential role in normal cell growth and differentiation and in the survival of healthy and cancerous cells. EGFR expression is a common feature of non-haematological malignancies and is associated with poor clinical prognosis. Cetuximab is an IgG(1) monoclonal antibody that blocks EGFR activation. It has efficacy alone, and in combination with irinotecan, in the treatment of metastatic colorectal cancer that has progressed on irinotecan-containing therapy. It has been approved for use in combination with irinotecan in both Switzerland and the US and as monotherapy in the US. Cetuximab also has efficacy in cancers of the head and neck and non-small cell lung cancer. Cetuximab is well-tolerated and does not exacerbate the side effects of co-administered cytotoxic chemotherapy.     

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.     

Cetuximab: an IgG1 monoclonal antibody for the treatment of epidermal growth factor receptor-expressing tumours

The epidermal growth factor receptor (EGFR) plays an essential role in normal cell growth and differentiation and in the survival of healthy and cancerous cells. EGFR expression is a common feature of non-haematological malignancies and is associated with poor clinical prognosis. Cetuximab is an IgG₁ monoclonal antibody that blocks EGFR activation. It has efficacy alone, and in combination with irinotecan, in the treatment of metastatic colorectal cancer that has progressed on irinotecan-containing therapy. It has been approved for use in combination with irinotecan in both Switzerland and the US and as monotherapy in the US. Cetuximab also has efficacy in cancers of the head and neck and non-small cell lung cancer. Cetuximab is well-tolerated and does not exacerbate the side effects of co-administered cytotoxic chemotherapy.     

Bevacizumab: new drug. Metastatic colorectal cancer: good in theory, not in practice

(1) The prognosis for metastatic colorectal cancer is grim. The best treatment results are obtained by adding irinotecan to first-line fluorouracil + folinic acid therapy and then oxaliplatin to second-line fluorouracil + folinic acid therapy (or the reverse sequence), but median survival time still fails to exceed 2 years. (2) Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), a mediator involved in angiogenesis. Bevacizumab is marketed in Europe for first-line treatment of metastatic colorectal cancer, in combination with fluorouracil + folinic acid (with or without irinotecan). (3) The clinical evaluation includes 3 comparative trials. A double-blind trial involving 813 patients compared the American IFL protocol (irinotecan + fluorouracil + folinic acid) + placebo with the IFL protocol + bevacizumab. Median survival time was shorter with IFL + placebo (15.6 versus 20.3 months), but the results are difficult to extrapolate to the situation in Europe, where the FOLFIRI protocol is used (irinotecan + fluorouracil + folinic acid). This protocol is more effective than the IFL protocol. (4) Another double-blind trial, involving 204 patients, compared another American protocol, fluorouracil + folinic acid + placebo, with fluorouracil + folinic acid + bevacizumab. Median survival time did not differ significantly between the groups (12.9 and 16.6 months). (5) A combined analysis of 3 comparative trials showed an increase in median survival time of 3.3 months (17.9 versus 14.6 months) when bevacizumab was added to a fluorouracil + folinic acid combination. An indirect comparison suggests that this is no better than adding irinotecan. (6) In second-line treatment, preliminary data from a trial of bevacizumab + FOLFOX 4 (oxaliplatin + fluorouracil + folinic acid) fail to show a tangible benefit for bevacizumab. (7) Bevacizumab adjunction to current chemotherapy protocols increased the frequency of some potentially serious reactions, such as cardiovascular disorders (hypertension, arterial thrombosis); tumour haemorrhage; intestinal perforation; wound healing; and haematological disorders (severe leukopenia, etc.). (8) In practice, there is no evidence that bevacizumab is any better than current European chemotherapy protocols for first-line treatment of metastatic colorectal cancer.     

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.     

替吉奥联合伊立替康治疗FOLFOX耐药的晚期结直肠癌的临床研究

目的评价替吉奥（S-1）联合伊立替康（CPT-11）治疗FOLFOX耐药的晚期结直肠癌患者的临床疗效和不良反应。方法选择对FOLFOX方案耐药的有可评价病灶的晚期结直肠癌患者144例,将其随机分为实验组（72例）和对照组（72例）。实验组给予替吉奥联合伊立替康（IRIS）方案,对照组给予伊立替康联合亚叶酸钙、5-氟尿嘧啶（FOLFIRI）方案。每2个周期评价疗效及不良反应发生情况。结果 144例患者均可评价疗效,实验组和对照组的CBR分别为54.17%和50.00%,RR分别为19.4%和12.86%,PFS分别为6.8和5.1个月。两组间PFS的差异有统计学意义（P〈0.05）。两组患者主要Ⅲ/Ⅳ度不良反应（血液学毒性、腹泻、手足综合症）的发生率比较,差异均无统计学意义（P〉0.05）。结论替吉奥联合伊立替康治疗FOLFOX耐药的晚期结直肠癌患者,其中位无进展期高于FOLFIRI方案,而毒副反应严重程度无显著差异,可作为转移性结直肠癌晚期二线化疗的一种新的选择。     

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.