OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 03 October 2017

• Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91.

  (Review of hepatotoxicity of immunosuppressive agents mentions rituximab and problems of reactivation of hepatitis B, but also states that "the biological immunosuppressants are largely free from hepatotoxicity, with the exception of the TNF alpha antagonists").
• Chabner BA, Barnes J, Neal J, Olson E, Mujagiv H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-53.

  (Textbook of pharmacology and therapeutics).
• Two new drugs for colon cancer. Med Lett Drugs Ther 2004; 46 (1184):46-8. [PubMed: 15184808]

  (Concise review of mechanism of action, clinical efficacy, and cost of bevacizumab and cetuximab, two antineoplastic monoclonal antibodies, shortly after their approval in the US; adverse effects of cetuximab include acne [which is common and can be severe], infusion reactions, asthenia, diarrhea, nausea, vomiting and abdominal pain and rarely interstitial pneumonitis; no mention of hepatotoxicity).
• Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351 337-45. [PubMed: 15269313]

  (Among 329 patients with metastatic colorectal cancer treated with cetuximab and irinotecan or cetuximab alone, side effects included acne like rash [89%], but no mention of ALT elevations or hepatotoxicity).
• Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004; 22 (7): 1201-8. [PubMed: 14993230]

  (Among 57 patients with EGFR expressing, metastatic refractory colorectal cancer treated with cetuximab, common adverse events included acne-like skin rash [86%], fatigue [56%] and allergic reactions; no mention of ALT elevations or hepatotoxicity).
• Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, Knecht R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007; 25: 2171-7. [PubMed: 17538161]

  (Among 103 patients with metastatic or recurrent head and neck cancer treated with cetuximab, adverse events included rash, acne and fatigue, and there were 6 infusion related reactions, including one death; no mention of ALT elevations or hepatotoxicity).
• Pinto C, Di Fabio F, Siena S, Cascinu S, Rojas Llimpe FL, Ceccarelli C, Mutri V, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 2007; 18: 510-7. [PubMed: 17164226]

  (Among 38 patients with advanced gastric carcinoma who received FOLFIRI chemotherapy and intravenous cetuximab [weekly], adverse events include in acne in 31 [82%], hypomagnesemia in 13 [34%], and elevated ALT levels in 10 [26%] which were above 5 times ULN in 2 [5%]).
• Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006; 24: 4914-21. [PubMed: 17050875]

  (Among 346 patients with metastatic, advanced colorectal cancer treated with cetuximab, adverse events included rash [90%], fatigue [20%], headache [20%], diarrhea [13%], nausea [12%] and hypersensitivity reactions [7%]; no mention of ALT elevations or hepatotoxicity).
• Cleary JM, Tanabe KT, Lauwers GY, Zhu AX. Hepatic toxicities associated with the use of preoperative systemic therapy in patients with metastatic colorectal adenocarcinoma to the liver. Oncologist 2009; 14: 1095-105. [PubMed: 19880627]

  (Review of toxicities of preoperative chemotherapy for metastatic colorectal cancer including steatohepatitis after irinotecan [4-20%] and sinusoidal dilatation after oxaliplatin [10-78%]; the effects of cetuximab on the liver are not well described, but there is little to suggest that it interferes with hepatic regeneration).
• Nie F, Shen J, Tong JL, Xu XT, Zhu MM, Ran ZH. Meta-analysis: the efficacy and safety of monoclonal antibody targeted to epidermal growth factor receptor in the treatment of patients with metastatic colorectal cancer. J Dig Dis 2009; 10: 247-57 . [PubMed: 19906103]

  (Systematic review of efficacy and safety of monoclonal antibodies to EGFR in metastatic colorectal cancer; summarized 7 randomized trials with 4186 patients using cetuximab or panitumumab, reported similar rates of response and adverse events with the two agents; no mention of ALT elevations or hepatotoxicity).
• Ettinger DS. Emerging profile of cetuximab in non-small cell lung cancer. Lung Cancer 2010; 68: 332-7. [PubMed: 19783064]

  (Review of the efficacy of cetuximab in non-small cell cancer does not mention ALT elevations or hepatotoxicity).
• Baumgaertner I, Ratziu V, Vaillant JC, Hannoun L, Poynard T, André. [Hepatotoxicity of metastatic colorectal cancer chemotherapy: systematic review]. Bull Cancer 2010; 97 (5): 559-69. [PubMed: 20167564]

  (Review of the hepatotoxicity of agents used for metastatic colorectal cancer mentions that the anti-EGFR monoclonal antibodies have not been reported to cause liver injury).
• Pessaux P, Panaro F, Casnedi S, Zeca I, Marzano E, Bachellier P, Jaeck D, Chenard MP. Targeted molecular therapies(cetuximab and bevacizumab) do not induce additional hepatotoxicity: preliminary results of a case-control study. Eur J Surg Oncol 2010; 36: 575-82. [PubMed: 20452168]

  (Among 36 patients with colorectal cancer undergoing hepatic resection after chemotherapy, steatohepatitis was less frequent in 21 patients who received bevacizumab than matched controls [5% vs 33%], and sinusoidal obstruction syndrome was less frequent in 15 patients given cetuximab than controls [0% vs 33%]).
• Pessaux P, Marzano E, Casnedi S, Bachellier P, Jaeck D, Chenard MP. Histological and immediate postoperative outcome after preoperative cetuximab: case-matched control study. World J Surg 2010; 34: 2765-72. [PubMed: 20652697]

  (Among 26 patients with metastatic colorectal cancer undergoing preoperative chemotherapy who also received cetuximab, serum enzyme and bilirubin elevations were similar to 26 matched control patients and liver histology showed no differences in rates of steatohepatitis, sinusoidal obstruction syndrome or fibrosis).
• Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 2012; 30: 1755-62. [PubMed: 22473155]

  (Among 571 patients with metastatic colorectal cancer treated with continuous or intermittent fluorouracil, leucovorin and oxaliplatin, progression free and overall survival were similar with or without added cetuximab, and adverse events were similar except for rash [22% and 29% vs 1%]; no mention of ALT elevations or hepatotoxicity).
• Stremitzer S, Sebio A, Stintzing S, Lenz HJ. Panitumumab safety for treating colorectal cancer. Expert Opin Drug Saf 2014; 13: 843-51. [PubMed: 24766434]

  (Review of mechanism of action and safety of panitumumab therapy of metastatic colorectal cancer discusses skin toxicity, hypomagnesemia, diarrhea and infusion reactions [which are less with panitumumab than cetuximab], but not hepatotoxicity or ALT elevations).
• Pujol JL, Pirker R, Lynch TJ, Butts CA, Rosell R, Shepherd FA, Vansteenkiste J, et al. Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer 2014; 83: 211-8. [PubMed: 24332319]

  (In a metaanalysis of results on 1970 patients from 4 controlled trials of cetuximab, severe adverse events that were more common with cetuximab were acne like rash, leucopenia, febrile neutropenia, septic events, fatigue, diarrhea and infusion reactions; no mention of ALT elevations or hepatotoxicity).
• Satoh T, Gemma A, Kudoh S, Sakai F, Yamaguchi K, Watanabe T, Ishiguro M, et al. Incidence and clinical features of drug-induced lung injury in patients with advanced colorectal cancer receiving cetuximab: results of a prospective multicenter registry. Jpn J Clin Oncol 2014; 44: 1032-9. [PMC free article: PMC4214246] [PubMed: 25210144]

  (Among 2006 Japanese adults with colorectal cancer treated with cetuximab, 24 developed drug induced lung injury, but no mention of concurrent liver injury or ALT elevations).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 were attributed to antineoplastic agents, but none to cetuximab).
• Enzinger PC, Burtness BA, Niedzwiecki D, Ye X, Douglas K, Ilson DH, Villaflor VM, et al. CALGB 80403 (Alliance)/E1206: a randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers. J Clin Oncol 2016; 34: 2736-42. [PMC free article: PMC5019745] [PubMed: 27382098]

  (Among 245 patients with metastatic esophageal cancers treated with cetuximab and one of 3 chemotherapeutic regimens, adverse events were common, but there were no hepatic related deaths).
• Bossi P, Miceli R, Locati LD, Ferrari D, Vecchio S, Moretti G, Denaro N, et al. A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2017; 28 (11): 2820-6. [PubMed: 28950305]

  (Among 201 patients with recurrent or metastatic head and neck cancer treated with cetuximab and cisplatin with or without paclitaxel, the medial progression-free and overall survival were similar, and ALT or AST elevations above 5 times ULN occurred in 4.4% vs 5.0%).