Jean Gary W, Shah Sachin R
School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, Texas 75216, USA.
Pharmacotherapy. 2008 Jun;28(6):742-54. doi: 10.1592/phco.28.6.742.
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-naïve 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.
在过去十年中，转移性结直肠癌的治疗方法不断演变。为了提供更多治疗选择，人们研发了两种表皮生长因子受体（EGFR）单克隆抗体——西妥昔单抗和帕尼单抗。EGFR是一种跨膜糖蛋白，在全身组成性表达，存在于许多上皮组织中。单克隆抗体与体内的受体结合并抑制其激活。这种抑制作用可防止肿瘤细胞生长、血管生成、侵袭和转移，并诱导细胞凋亡。西妥昔单抗和帕尼单抗呈现非线性药代动力学。两种单克隆抗体均被批准用于治疗难治性转移性结直肠癌。与单独使用西妥昔单抗或伊立替康相比，西妥昔单抗联合伊立替康的缓解率和无进展生存期显著更高。与最佳支持治疗相比，西妥昔单抗和帕尼单抗单药治疗在对伊立替康和奥沙利铂难治的患者中显示出显著更高的缓解率和无进展生存期。在“西妥昔单抗联合伊立替康一线治疗转移性结直肠癌（CRYSTAL）”试验中，初治患者接受西妥昔单抗联合化疗方案（静脉输注亚叶酸钙、氟尿嘧啶和伊立替康[FOLFIRI]）或单独接受FOLFIRI治疗；无进展生存期的差异具有统计学意义，但仅显示出比单独使用FOLFIRI有适度益处（8.9个月对8个月，p = 0.036）。“帕尼单抗晚期结直肠癌评估（PACCE）”试验对前231例事件的预先计划分析结果显示，对照组（含亚叶酸钙[甲酰四氢叶酸]、氟尿嘧啶和奥沙利铂[FOLFOX]加贝伐单抗的化疗方案）优于对照组加帕尼单抗。从临床角度考虑，许多试验表明EGFR表达的强度或缺失并非临床结局的显著预测指标。皮疹的发生及严重程度被认为是患者预后的阳性预测指标。EGFR单克隆抗体治疗最常见的不良事件是皮疹、腹泻和低镁血症。其他严重但不常见的不良事件包括过敏反应和肺部毒性。EGFR单克隆抗体的出现为治疗难治性转移性结直肠癌提供了又一武器。它们与其他化疗方案联合及单药治疗均显示出安全性和有效性；然而，其作为转移性结直肠癌治疗方法的应用仍需进一步探索。
