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.     

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 the first fully human monoclonal antibody: from the bench to the clinic

Panitumumab (formerly known as ABX-EGF) is the first fully human monoclonal antibody to epidermal growth factor receptor to enter clinical trials for the treatment of solid tumors. Like cetuximab (Erbitux; BMS), it is directed against the extracellular ligand-binding domain of the receptor and results in blockade of the essential downstream signaling pathways that are known to govern apoptosis, proliferation and differentiation of both normal and neoplastic cell types in a wide array of tissues. It has a very high affinity for epidermal growth factor receptor and has been generally well tolerated and associated with very few infusion reactions. As a fully human agent, panitumumab has not been associated with the formation of any antibodies directed against it that has been evidenced by a very reliable pharmacokinetic profile with possible dosing schedules ranging from 1 to 3 weeks. Similar to other agents targeting the epidermal growth factor receptor pathway, a rash has been the primary toxicity and is dose dependent up to 2.5 mg/kg at which dose 100% of all patients have been affected. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal. It has been efficacious and well tolerated both as monotherapy and in combination with other chemotherapeutic agents. Several phase I trials, two phase II trials and most recently a phase III trial in pretreated colorectal cancer have been carried out to date. Currently, there is also a randomized phase III trial (Panitumumab Advanced Colorectal Cancer Evaluation Study) investigating the role of panitumumab in the first-line treatment of colorectal cancer. No unfavorable drug-drug interactions have been observed nor has there been any effect on the pharmacokinetics of drugs with which it is being used. Recent progress in preclinical and clinical studies of panitumumab is reviewed.     

Panitumumab: the evidence of its therapeutic potential in metastatic colorectal cancer care

Introduction:

Colorectal cancer is the fourth most common malignant disease. Of newly diagnosed patients, 40% have metastatic disease at diagnosis, and approximately 25% of patients with localized disease at diagnosis will ultimately develop metastatic disease. The benefits of systemic chemotherapy in the treatment of metastatic colorectal cancer over best supportive care have been established. Panitumumab (ABX-EGF) is the first fully human monoclonal antibody developed for use in colorectal cancer that targets the extracellular domains of epidermal growth factor receptor.

Aims:

The goal of this article is to review the published evidence for the use of panitumumab in the treatment of metastatic colorectal cancer to define its therapeutic potential.

Evidence review:

The major evidence of panitumumab activity in colorectal cancer has appeared in meeting report abstracts. One phase II study in monotherapy, one in combination with chemotherapy, and one phase III study have included only patients with metastatic colorectal cancer.

Clinical potential:

To date, in phase II clinical studies panitumumab has demonstrated antitumor activity in advanced, refractory colorectal cancer. As monotherapy it resulted in a 10% response rate with 38% of patients having stable disease, and a 36% response rate with 46% stable disease when combined with chemotherapy. A phase III study indicates a clinically significant advantage of panitumumab as third-line monotherapy over best supportive care. Panitumumab appears to have a good tolerability profile, with no maximum tolerated dose yet defined.     

Panitumumab

In December 2007 the European Medicines Agency (EMEA) approved panitumumab (Vectibix) for the treatment of metastatic colorectal cancer. Panitumumab has a conditional approval as monotherapy for the treatment of patients with EGFR-expressing tumours with non-mutated (wild-type) K-ras genes after failure of standard chemotherapy regimens. This specific subgroup of patients showed a more favourable outcome in a controlled, open-label, randomized phase III study. Patients treated with panitumumab plus best supportive care had a significantly prolonged progression-free survival compared to patients receiving best supportive care alone.     

Review article: panitumumab - a fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer

Background  Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR).
Aim  To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC).
Methods  Available literature identified from PubMed and conference websites was reviewed.
Results  In phase 2–3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8–13% in relapsed/refractory EGFR-expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44–0.66; P  <   0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab – and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild-type KRAS (ORR ≈20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (≈90%) and diarrhoea (<30%). Development of anti-panitumumab antibodies (0.3% by ELISA) and grade 3–4 infusion reactions (<1%) are rare.
Conclusion  Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR-expressing mCRC harbouring 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。     

Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It is indicated for use as monotherapy in the treatment of patients with EGFR-expressing metastatic colorectal cancer after disease progression with standard chemotherapy. The currently indicated dose is 6 mg/kg given every 2 weeks. Panitumumab is mainly distributed into the vascular space and exhibits nonlinear pharmacokinetics that are consistent with target-mediated drug disposition, involving saturable binding to EGFR and subsequent internalization and degradation inside the cells. Panitumumab is also cleared in a linear fashion by the reticuloendothelial system, similarly to other endogenous immunoglobulins. After single-dose administration of panitumumab as a 1-hour intravenous infusion, the area under the serum concentration-time curve increases in a greater-than-dose-proportional manner as the dose increases from 0.75 to 5 mg/kg; however, at doses above 2 mg/kg, the exposure to panitumumab increases in a dose-proportional manner. Panitumumab pharmacokinetics are not meaningfully affected by the tumour type, EGFR membrane expression, tumour KRAS mutation, sex, age, race or renal or hepatic dysfunction. In addition, irinotecan-containing and paclitaxel/carboplatin-containing chemotherapeutic regimens do not appear to affect panitumumab pharmacokinetics. The results of population pharmacokinetic analyses have shown that bodyweight is the most influential covariate on panitumumab exposure, supporting the current use of bodyweight-adjusted doses (mg/kg). The relationship between the weekly dose of panitumumab and skin rash, an on-target pharmacodynamic effect of EGFR inhibition, reaches a plateau at 2.5 mg/kg, indicating that this is the optimal weekly dose. Two less-frequent dosing regimens (6 mg/kg given every 2 weeks and 9 mg/kg given every 3 weeks) achieve steady-state serum trough concentrations similar to those achieved by 2.5 mg/kg given every week, ensuring maximal EGFR coverage. Anti-panitumumab antibody production is uncommon and does not appear to have an impact on the pharmacokinetics of panitumumab.     

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.     

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.     

Risk of anti-EGFR monoclonal antibody-related hypomagnesemia: systematic review and pooled analysis of randomized studies

INTRODUCTION: The typical class side effect of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (panitumumab and cetuximab) is a cutaneous maculopapular rash, although hypomagnesemia is also described to be a frequent adverse event. The purpose of our meta-analysis is to evaluate the frequency and the relative risk of hypomagnesemia in patients treated with cetuximab or panitumumab in randomized trials. AREA COVERED: Eligible studies included prospective randomized Phase III controlled trials in which cetuximab or panitumumab were compared with standard anti-neoplastic therapy or best supportive care. Summary incidence rates and relative risks with 95% confidence intervals were calculated. EXPERT OPINION: The overall incidence of hypomagnesemia was 17% among the patients who received the treatment, whose risk of developing hypomagnesemia turned out to be significantly increased compared with the patients treated with control medication, with an overall relative risk of 5.83 (p < 0.00001), where 3.87 refers to cetuximab and 12.55 to panitumumab. The addition of anti-EGFR monoclonal antibodies to standard anticancer therapy showed a significantly increased risk of hypomagnesemia compared with controls. The risk seems to be even higher for panitumumab, probably correlated with the increased risk of other adverse events (e.g., diarrhea and dehydration). Hypomagnesemia does not seem to be linked with any serious complications.     

伊立替康联合靶向药物在晚期结直肠癌治疗中的应用

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

Cetuximab: in the treatment of metastatic colorectal cancer

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

A phase II trial of ZD1839 (Iressa™) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer

Summary Purpose: The epidermal growth factor receptor (EGFR) appears relevant in the pathogenesis and progression of colorectal cancer. After completing a phase I pharmacodynamic trial of ZD1839, we undertook a dose expansion trial to examine the antitumour efficacy and adverse effect profile of this agent in a homogeneous group of patients with metastatic colorectal cancer (CRC). Experimental design: Eligible patients with metastatic or recurrent CRC received ZD1839 750 mg daily by mouth. This dose was selected based on a phase I trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). Treatment was continued until unacceptable toxicity or disease progression. Results: Twenty-eight patients were enrolled at three NCIC CTG centers. Twenty-three patients had received prior chemotherapy; 12 patients had received three or more regimens. No objective responses were observed in 24 evaluable patients, although 8 patients had stable disease (median duration of 2.2 months). The most frequent drug related adverse events were diarrhea, rash and nausea. Eleven patients required dosing modification (hold or reduction), while 3 patients discontinued therapy because of toxicity. There were no treatment related deaths. Conclusions: ZD1839, when given at 750 mg/day to patients with pre-treated metastatic colorectal cancer, does not result in significant tumor regression.This study was supported by the National Cancer Institute of Canada and AstraZeneca Canada     

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.     

Epidermal growth factor receptor and signal transduction: potential targets for anti-cancer therapy

Agents targeting the epidermal growth factor receptor (EGFR) pathway hold particular promise for the treatment of patients with advanced disease, for whom standard chemotherapy is generally palliative. Expression of EGFR on numerous types of solid tumors, and the association of EGFR activation with tumorigenic processes including proliferation, anti-apoptosis and metastatic spread, make this pathway a particularly compelling target for rational drug design. The two classes of anti-EGFR agents in late-stage clinical testing include antibodies directed toward the extracellular EGFR domain (cetuximab, panitumumab) and small molecule tyrosine kinase inhibitors (gefitinib, erlotinib), which inactivate the receptor enzyme activity. However, important issues remain to be addressed. These include the development of appropriate predictive markers for response, such as improved tests for EGFR activity, correlation of rash with response and potential pharmacogenomic approaches; the sequencing and combination of these agents with chemotherapy and irradiation; and the possible role of these agents in the treatment of patients with earlier stage disease.     

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.     

A review of oxaliplatin and its clinical use in colorectal cancer

Colorectal cancer is one of the leading causes of death from malignant diseases in the Western world. Worldwide, ～ 50% of patients who present with colorectal cancer will develop metastatic disease and eventually die from this malignancy. Recently, significant advances have been made in the medical treatment of advanced colorectal cancer with the introduction of novel cytotoxic drugs, such as irinotecan and oxaliplatin. Based on the results of recent Phase III trials, combination regimens of infusional 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX) have emerged as a new standard of care in the palliative and adjuvant treatment of colorectal cancer. The addition of biological agents targeting angiogenesis or oncogenes such as epidermal growth factor receptor (EGFR) to FOLFOX will conceivably further enhance the activity of treatment regimens. Making use of all available active therapeutic options in the course of disease has significantly improved median overall survival of metastatic colorectal cancer into a chronic disease, with implications for treatment strategies and pharmacoeconomic considerations.     

表皮生长因子受体抑制剂相关性皮肤毒性的研究进展

表皮生长因子受体抑制剂包括小分子酪氨酸激酶抑制剂及单抗类,在肺癌、结直肠癌等肿瘤的分子靶向治疗中起着重要作用。其中小分子酪氨酸激酶抑制剂包括吉非替尼、厄洛替尼、埃克替尼等,单抗类包括西妥昔单抗、帕尼单抗等。以痤疮样皮疹为代表的皮肤毒性是表皮生长因子受体抑制剂使用后最常见的不良反应,严重的皮肤毒性导致药物剂量减少与治疗的中断,影响药物的抗肿瘤疗效。但目前临床对于这一类皮肤毒性仍没有十分有效的处理方法。已有临床试验涉及的处理方法包括口服四环素类药物、局部应用维生素K乳剂、局部应用他克莫司、防晒霜以及表皮生长因子凝胶等。本文综述了此类皮疹的发生机制、治疗皮疹药物的临床试验结果及已有的专家共识或指南,以期为这一类不良反应的处理提供临床思路。