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.     

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: 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.     

Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer

Treatment of metastatic colorectal disease has evolved over the last decade. Two epidermal growth factor receptor (EGFR) monoclonal antibodies--cetuximab and panitumumab--have been developed in an effort to provide yet another therapeutic option. The EGFR is a transmembrane glycoprotein, expressed constitutively throughout the body and found on many epithelial tissues. The monoclonal antibodies bind to and inhibit the activation of the receptor in the body. This inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. Cetuximab and panitumumab exhibit nonlinear pharmacokinetics. Both monoclonal antibodies are approved for the treatment of refractory metastatic colorectal cancer. Cetuximab in combination with irinotecan has significantly better response rates and progression-free survival compared with those of cetuximab or irinotecan alone. Cetuximab and panitumumab as monotherapy have shown significantly better response rates and progression-free survival compared with best supportive care in patients refractory to irinotecan and oxaliplatin. In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-na?ve patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI) or FOLFIRI alone; the difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone (8.9 vs 8 mo, p=0.036). Results of a preplanned analysis of the first 231 events in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial favored the control group (chemotherapy regimen with folinic acid [leucovorin], fluorouracil, and oxaliplatin [FOLFOX] plus bevacizumab) instead of the control group plus panitumumab. For clinical consideration, many trials have shown that the intensity or absence of EGFR expression is not a clinically significant predictor of outcomes. Development and intensity of a rash are suggested to be a positive predictor of outcomes in patients. The most common adverse events of EGFR monoclonal antibody therapy are rash, diarrhea, and hypomagnesemia. Other serious but not common adverse events include hypersensitivity reactions and pulmonary toxicity. The availability of EGFR monoclonal antibodies has provided another weapon in the arsenal to treat refractory metastatic colorectal cancer. They have shown safety and efficacy in combination with other chemotherapy regimens and as monotherapy; however, their use as metastatic colorectal cancer therapy needs to be further explored.     

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.     

抗表皮生长因子受体单克隆抗体——西妥昔单抗在结直肠癌治疗中的临床进展

最近,一些临床试验的结果肯定了西妥昔单抗（cetuximab）作为一种表皮生长因子受体（EGFR）单克隆抗体在结直肠肿瘤的治疗作用。本文从转移性结直肠癌治疗的角度综述西妥昔单抗这一EGFR抗体的临床观察结果,回顾分析了多篇近年发表的关于西妥昔单抗在结直肠癌和其它恶性肿瘤临床应用的文献。西妥昔单抗在转移性结直肠肿瘤的无进展生存期的延长上获得了肯定的疗效（3.9月vs2.56月,P〈0.01）。然而,在作为第二线治疗时,西妥昔单抗与依立替康的联合治疗对比依立替康单药治疗并没有使平均生存期得到延长。在副作用方面,痤疮样皮疹的严重程度可以预示肿瘤对西妥昔单抗的应答强弱,外用糖皮质激素和润肤剂可以治疗这一副作用。低镁血症是该药引起的一个比较特殊的副作用,使用静脉补镁是治疗低镁血症的有效方法。     

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.     

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 role of cetuximab in the treatment of colorectal cancer

CRC is the fourth most frequently diagnosed tumor and the second leading cause of cancer death in the United States. KRAS mutations occur in 35-45% of metastatic-CRC and preclude responsiveness to cetuximab or panitumumab. However, less than 20% of KRAS wild-type (wt) patients achieve objective response. Alterations of BRAF/NRAS/ PIK3CA/PTEN, have independently been found to give rise to resistance. The first-line trials with cetuximab chemotherapy are conflicting, because of the many differences among prospective and retrospective evaluations. In neoadjuvant regimens, cetuximab with CT obtained a significant and early increase of the RR. In second-line studies cetuximab improved RR and PFS. In third-line studies cetuximab-irinotecan is associated with a significant advantage in ORR, mTTP and OS. Cetuximab has not reported any benefit neither in adjuvant nor in trials with bevacizumab. In third-line studies cetuximab-irinotecan is associated with a significant advantage in ORR, mTTP and OS. Value of KRAS is questioned, since a high percentage of KRAS-wt patients has no benefit with cetuximab. More and more data on the molecular patterns of these tumors underline their biological complexity. Cetuximab treatment is usually well tolerated. Moreover, toxicity seems to correlate with response to treatment. This patents review focuses on recent advances in the treatment of CRC with cetuximab including several novel therapeutic protocols of intervention.     

Irinotecan,oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer

Out of every 17 – 18 individuals in the US, one develops colorectal cancer (CRC) in their lifetime. Of individuals diagnosed with CRC, > 50% present or develop metastatic disease, which, if untreated, is associated with 6 – 9 months median survival. Although surgical resection is the primary treatment modality for CRC, chemotherapy is the mainstay of treatment for metastatic or unresectable disease. For nearly three decades, 5-fluorouracil (5-FU) has been the chemotherapy of choice for treatment of CRC. However, the response rates to single 5-FU therapy have been suboptimal with an objective tumour response of 10 – 20%. Attempts have been made to improve the efficacy of 5-FU by either schedule alteration (protracted infusion versus intravenous push) or biochemical modulation with leucovorin (LV). Continuous infusion induced more tumour regression and prolonged the time-to-disease progression with some significant impact on survival (11.3 versus 12.1 months; p < 0.04). 5-FU/LV resulted in a significant increase in overall response rates and in the prolongation of disease-free survival in the adjuvant setting, although severe toxicities represent a major clinical problem. The last 10 years have seen the addition of several new agents such as irinotecan, oxaliplatin, raltitrexed, bevacizumab and cetuximab. The prognosis has significantly improved with the addition of these agents, with median survivals now > 20 months. This review paper focuses on irinotecan, oxaliplatin and raltitrexed when used alone and in combination.     

Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer

Out of every 17-18 individuals in the US, one develops colorectal cancer (CRC) in their lifetime. Of individuals diagnosed with CRC, > 50% present or develop metastatic disease, which, if untreated, is associated with 6-9 months median survival. Although surgical resection is the primary treatment modality for CRC, chemotherapy is the mainstay of treatment for metastatic or unresectable disease. For nearly three decades, 5-fluorouracil (5-FU) has been the chemotherapy of choice for treatment of CRC. However, the response rates to single 5-FU therapy have been suboptimal with an objective tumour response of 10-20%. Attempts have been made to improve the efficacy of 5-FU by either schedule alteration (protracted infusion versus intravenous push) or biochemical modulation with leucovorin (LV). Continuous infusion induced more tumour regression and prolonged the time-to-disease progression with some significant impact on survival (11.3 versus 12.1 months; p < 0.04). 5-FU/LV resulted in a significant increase in overall response rates and in the prolongation of disease-free survival in the adjuvant setting, although severe toxicities represent a major clinical problem. The last 10 years have seen the addition of several new agents such as irinotecan, oxaliplatin, raltitrexed, bevacizumab and cetuximab. The prognosis has significantly improved with the addition of these agents, with median survivals now > 20 months. This review paper focuses on irinotecan, oxaliplatin and raltitrexed when used alone and in combination.     

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。     

DNA copy number profiles correlate with outcome in colorectal cancer patients treated with fluoropyrimidine/antifolate-based regimens

For decades 5-fluorouracil (5-FU) has remained the treatment of choice in the adjuvant and palliative setting of colorectal cancer (CRC). The combinations of 5-FU or its oral prodrug capecitabine with irinotecan/oxaliplatin and the novel agents bevacizumab/cetuximab increased responses. However, the overall prognosis is poor, and predictive biomarkers of cytotoxic drugs activity are missing. Pharmacogenetic studies focused on candidate determinants of drug activity/metabolism, such as thymidylate synthase or dihydropyrimidine dehydrogenase, but reported controversial results. Given the heterogeneous and complex nature of CRC, it is likely that many aberrations underlying its progression can also affect therapeutic response. Therefore, high-throughput arrays for genome-wide-DNA aberrations play a pivotal role for new markers discovery by moving from hypothesis-driven, targeted-research to unbiased screening of the whole genetic spectrum. Chromosomal aberrations are critical events in tumorigenesis, and genomic regions harbouring DNA gains/losses have been identified in 85% of CRC patients. These aberrations change the expression of many genes, which might explain the differential effects of specific chemotherapeutic agents. In particular, recent studies reported correlations between DNA copy-number profiles and response to fluoropyrimidine-based regimens, such as leucovorin-modulated-5-FU+irinotecan (FOLFIRI), capecitabine+irinotecan (CAPIRI) and pemetrexed+irinotecan (ALIRI). Genome-wide profiling by oligonucleotide-based array-comparative-genomic-hybridization (aCGH) revealed genomic loci, of which the copy-number status may serve as marker for outcome after FOLFIRI and CAPIRI. Larger randomized and prospective trials of these aCGH platforms in CRC patients treated with fluoropyrimidine-based regimens are ongoing, and will ultimately demonstrate whether these findings can be of actual value to predict clinical outcome and direct the choice of therapy.     

Combined paclitaxel and cetuximab achieved a major response on the skin metastases of a patient with epidermal growth factor receptor-positive, estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative (triple-negative) breast cancer

The epidermal growth factor receptor, a transmembrane receptor tyrosine kinase of the erbB family, is expressed in 15-30% of all breast cancers. Anti-epidermal growth factor receptor agent cetuximab is an IgG1 chimeric monoclonal antibody with a potent antitumor activity. Cetuximab competes with ligand binding to the epidermal growth factor receptor ectodomain, resulting in an efficient blockade of tumor-promoting downstream signaling pathways. Large clinical studies recently demonstrated cetuximab synergy with radiotherapy and chemotherapy agent irinotecan. Studies in human breast cancer xenografts showed cetuximab synergy with paclitaxel, a potent mitosis spindle-cell stabilizer. In this report, combined paclitaxel and cetuximab achieved a major reduction of the skin metastases of a heavily pretreated patient with epidermal growth factor receptor-positive, estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative (triple-negative) invasive ductal breast carcinoma. Treatment was well-tolerated overall and response was not correlated with the appearance of major cetuximab-induced acneiform rash.     

Neutrophilic eccrine hidradenitis induced by cetuximab

Cetuximab is an epidermal growth factor receptor inhibitor used in metastatic colorectal cancer, and head and neck cancers. Several cutaneous side effects due to cetuximab such as acne-like rash, pruritus, dry skin, desquamation, hypertrichosis, and paronychia have been reported so far. A 59-year-old male patient with metastatic colon cancer referred to our outpatient clinic for his lesions on the dorsal surfaces of his hands and wrists, and on thighs developing after the chemotherapy. He was diagnosed as neutrophilic eccrine hydradenitis related to cetuximab in the light of clinical and histopathological findings. According to our knowledge, this is the first reported case of neutrophilic ecrine hydradenitis due to cetuximab.     

Neutrophilic eccrine hidradenitis induced by cetuximab

Cetuximab is an epidermal growth factor receptor inhibitor used in metastatic colorectal cancer, and head and neck cancers. Several cutaneous side effects due to cetuximab such as acne-like rash, pruritus, dry skin, desquamation, hypertrichosis, and paronychia have been reported so far. A 59-year-old male patient with metastatic colon cancer referred to our outpatient clinic for his lesions on the dorsal surfaces of his hands and wrists, and on thighs developing after the chemotherapy. He was diagnosed as neutrophilic eccrine hydradenitis related to cetuximab in the light of clinical and histopathological findings. According to our knowledge, this is the first reported case of neutrophilic ecrine hydradenitis due to cetuximab.     

Progress in colorectal cancer chemotherapy: how far have we come, how far to go?

Fluorouracil has been the mainstay of treatment for colorectal cancer (CRC) for almost 40 years. Various schedules and biochemical modulators have been investigated in an attempt to improve the therapeutic efficacy of fluorouracil. To date, fluorouracil plus folinic acid represents the standard therapy in CRC for the adjuvant treatment of patients at high risk for relapse and for the first-line treatment of metastatic disease. To gain clinical acceptance, however, oral fluoropyrimidines must confer at least the same survival advantages associated with the optimal intravenous fluorouracil regimens. Irinotecan and oxaliplatin are 2 other novel agents that have mechanisms of action that are uniquely different from those of fluorouracil, with demonstrated activity in patients with fluorouracil-refractory disease. Recent randomised trials comparing fluorouracil plus folinic acid with combinations of either irinotecan or oxaliplatin and fluorouracil plus folinic acid have shown that response rates are improved and time to progression is increased in patients receiving the combination regimens. These regimens are being rapidly introduced in the adjuvant setting, and the role and acceptance of these combination regimens as first-line therapy needs to be defined. Other novel agents being evaluated in the treatment of patients with advanced CRC include oral edrecolomab (monoclonal antibody 17-1A) and tumour vaccines. Future research is focused on enabling clinicians to individualise treatment strategies in patients with CRC, so as to improve clinical outcomes and reduce drug toxicity.     

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.     

Two cases of acneiform eruption induced by inhibitor of epidermal growth factor receptor

BACKGROUND: Cetuximab is a member of a new family of antineoplastic agents that inhibit the epidermal growth factor receptor (EGF-R), and which are increasingly being used in the treatment of solid tumors. METHODS: We have observed new secondary side effects. We present here 2 patients with acneiform eruption secondary to the administration of cetuximab (IMC-C225, Erbitux). The diagnoses of these patients were adenocarcinoma. RESULTS: Histologically, a superficial purulent folliculitis and disordered differentiation with focal parakeratosis were observed. The follicular eruption responded favorably to treatment with 5% benzoyl peroxide and 4% erythromycin gel. These lesions healed within a few days after treatment. CONCLUSION: The cutaneous adverse effects of cetuximab are similar to other EGF-R-targeted agents and result from direct interference with the functions of EGF-R signaling in the skin.