Association of cetuximab with adverse pulmonary events in cancer patients: a comprehensive review
Journal of Experimental & Clinical Cancer Research volume 28, Article number: 113 (2009)
Compounds derived from biologic sources, or biologicals, are increasingly utilized as therapeutic agents in malignancy. Development of anti-cancer targeted therapies from biologics is increasingly being utilized. Cetuximab, a chimeric monoclonal antibody, is one such anti-cancer targeted therapeutic that has shown efficacy in quelling the rate of patient decline in colorectal, head/neck, and non-small cell lung cancer. However, due to the relatively recent addition of biologic compounds to the therapeutic arsenal, information related to adverse reactions is less well known than those seen in traditional chemotherapeutics. Dermatologic reactions have been demonstrated as the most frequent side effect cited during cetuximab therapy for malignancy; however, other effects may lead to greater morbidity. In general, pulmonary complications of therapeutics can lead to significant morbidity and mortality. The purpose of this review is to compile the various pulmonary side effects seen in patients treated with cetuximab for various malignancies, and to compare the incidence of these adverse reactions to standard therapies.
Biologic therapies, or biologicals, are those produced or extracted from a biological source. Based upon the specific agent, biologicals have a myriad of activities and have been used to modulate immunity, increase blood cell production, inhibit tumor growth, and other effects . Over the last 5 years, more than 20% of the compounds approved by United States regulatory authorities were biologics . Despite this explosion in the availability of biologicals, surprisingly limited data exists regarding adverse events associated with their use.
Because these compounds are derived from biologic sources, they have the potential for significant immune activation. Although extensively reported in clinical trials, adverse events are rarely compiled in the medical literature. Giezen and coauthors examined adverse event reporting post-approval for biologicals and suggested that there was a need for increasing awareness to certain risks associated with the therapeutic use of biologicals .
One such biologic therapy used in the treatment of malignancy is cetuximab (Erbitux®, ImClone, Branchburg, NJ). Cetuximab is a chimeric monoclonal antibody with inhibitor effects on the epidermal growth factor receptor (EGFR). Cetuximab has been extensively studied and approved  for the treatment of metastatic colorectal cancer (MCRC) and squamous cell head/neck cancers (SCCHN), and growing data supports its use in the treatment of other malignancies including non-small cell lung cancer (NSCLC). Cetuximab has been evaluated in the setting of combination therapy or as a single agent in conventional therapy failures. Moreover, cetuximab has been studied for the treatment of various other malignancies including breast cancer and ovarian cancer, hepatocellular cancer, pancreatic cancer, and others.
Through binding to the extracellular domain of EGFR, cetuximab interrupts the signaling cascade resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production . EGFR, a member of the ErbB-1 family of receptors, is closely related structurally to other tyrosine kinase receptors including HER2/c-neu (ErbB-2), Her 3 (ErbB-3), and Her 4 (ErbB-4). Over expression or increased activity of EGFR as seen in some mutations can result malignancy .
Cetuximab efficacy has been studied as a single agent as well as in combination with other chemotherapeutic modalities. A randomized controlled clinical trial with 329 patients was conducted using cetuximab plus irinotecan or cetuximab alone in treatment of EGFR-expressing MCRC . Cetuximab was shown to lengthen the time to disease progression by 4.2 months in the monotherapy arm and 5.7 months in combination arm. In patients with EGFR-positive NSCLC a phase II study by Rosell showed that combination cisplatin/vinorelbine plus cetuximab resulted in an overall response rate of 32%, compared to 20% with cisplatin/vinorelbine alone . The continuing research of cetuximab is helping to determine which populations of patient will benefit most from Anti-EGFR therapy. Currently most evidence points towards the use of cetuximab in combination with other chemotherapeutic regimens as the best option for treatment in EGFR positive tumors.
Epidermal growth factor receptors are ubiquitous, thus potential for exuberant reactions including adverse events is high. Moreover, due to the diverse tissues expressing EGRF, adverse reactions manifest in many ways. Although dermatologic reactions represent the vast majority of adverse events, occurring in between 30-90% of patients depending on the severity and study examined [6, 7], many other side effects occur with cetuximab therapy. Other adverse events increased above control groups included gastrointestinal complaints (19-59%) and headache (19%) . Cextuximab infusion reactions took place in between 15 and 20% of subjects .
There have only been rare reports of pulmonary side effects with cetuximab. Interstitial lung disease was reported in 4 of 1,570 (0.25%) patients with advanced colorectal cancer . There have also been reports of interstitial pneumonitis with non-cardiogenic pulmonary edema . The use of cetuximab in combination regimens potentially clouds side effect profiles.
Pulmonary complications in the setting of chemotherapy lead to increased morbidity and severe reactions are associated with mortality. Cetuximab, like many other cancer therapies, has been demonstrated to cause a wide range of respiratory effects from mild dyspnea to a fatality due adverse pulmonary events. The purpose of this investigation is to compile a comprehensive list of pulmonary adverse events in the setting of therapy with cetuximab published in the literature in order to better characterize the true incidence of these reactions. A better understanding of the prevalence may help the clinician respond appropriately to specific symptom changes during the therapeutic window with a hope of improving patient care.
We performed a MEDLINE™ search of the English language literature using the search terms: "cetuximab" or "Erbitux" with limits to include only human studies to develop a complete index of trials or reports. Inclusion criteria were clinical trials, meta-analyses, or randomized controlled trials that included the search terms and cited adverse events. The reference lists from each of these manuscripts were scanned to isolate articles not obtained in the MEDLINE® search to complete our database. Studies were excluded if they did not list adverse events.
Data extracted from each report included number of patients, controls, type of cancer, coincident chemotherapy administration, and information regarding pulmonary complications. Pulmonary complications included the incidence of symptoms related to the respiratory system including dyspnea, cough, wheezing, pneumonia, hypoxemia, respiratory insufficiency/failure, pulmonary embolus, pleural effusion, and non-specific respiratory disorders. Incidences of these pulmonary complications were obtained from each study's control group if available and compared between the patients that received cetuximab and those who did not. Infusion reactions were treated as a separate complication to cetuximab and were not included in this analysis, although in many individuals, symptoms of shortness of breath and chest tightness may be encompassed by this type of reaction .
Data Analysis and Statistics
Data is presented as the number of patients and percentage receiving the study medication as well as means (± SD) where appropriate. Comparisons between groups were made using Chi-Square or students t-test where appropriate, and statistical significance was set as p < 0.05.
Using our search criteria defined above, a total of 245 articles were obtained for review. From this complete group, 192 articles were excluded for not meeting inclusion criteria. Reasons for exclusion were: non-pulmonary focus (dermatologic side effects), duplicate patient populations, case reports not relevant to pulmonary side effects, focus on pharmacokinetics, omission of side effects, or non-cetuximab trials. A total of 53 studies (Table 1) met inclusion and were included in the analysis [5, 8, 10–60].
The majority of clinical trials focused on the treatment of colorectal cancers with head/neck, lung, and hepatobiliary or pancreatic making up the next largest groups (Table 1). Similarly, most of the studies examined were completed as Phase I or II trials with the focus on refractory and metastatic disease (Table 2).
A total of 7,411 patients were included in the 53 studies reviewed including 4,436 (59.8%) patients who received cetuximab either alone or in conjunction with other chemotherapeutic medications or radiation therapy. 2,596 (41.4%) patients were in the control groups from these investigations who received the same chemotherapy or radiation therapy without cetuximab (Table 3).
A total of 459 patients (10.3%) in the cetuximab group had adverse pulmonary reactions compared to 221 (8.5%) who received standard, non-cetuximab therapy (p < 0.02). Studies focusing on colorectal cancer, lung cancer, and head-neck cancer had sufficient numbers in both the cetuximab and control groups to compare pulmonary complications; however, hepatobiliary, pancreatic, breast, ovarian, and cutaneous cancer studies lacked adequate numbers of control patients to compare these complications.
Colorectal cancer studies demonstrate a low rate of pulmonary complications overall with 3.41% incidence in the cetuximab group versus 2.56% in the control patients (p = NS). The most common side effect was dyspnea in these studies making up more than 90% of the adverse reactions.
Pulmonary adverse events were much more common, as would be expected in NSCLC trials with an incidence of 18.7% in the cetuximab group versus 12.2% in the control arms (p < 0.001). Similarly, dyspnea made up the majority of pulmonary adverse events (13.2% vs 9.2%, p < 0.02) with other significant differences occurring in the incidence of pneumonitis (1.1% versus 0.0%, p < 0.001) being worse in the cetuximab groups.
For head-neck cancer studies, the overall rates of pulmonary complications were similar between the cetuximab and control groups (17.9% versus 20.1%, p = NS), but favored the cetuximab group. Dyspnea was more common in the cetuximab group (8.7%) than the control group (5%, p < 0.02) in Head and Neck Cancer Trials. Conversely, there were fewer patients with increased sputum production (3.0% versus 6.6%, p < 0.01) and cough (4.5% versus 7.8%, p < 0.01) in the control group compared to the cetuximab group. From all studies, the difference in other pulmonary adverse events appears to be similar (Table 4).
Overall, cetuximab seems to increase the incidence of adverse pulmonary reactions compared to controls, although the absolute difference between groups is low (<2%). The severity of the pulmonary complications was not well described in most of the included studies, but did not increase mortality rates. To the contrary, if survival benefits were not demonstrated, almost universally, there was an increase in progression free survival or stability of malignancy in these trials. To this point, the difference between statistical significance and clinical significance should also be examined in relation to the pulmonary reactions. For all clinical trials except NSCLC, the differences in pulmonary adverse events between those treated with and without cetuximab are small. Dyspnea and cough, though increased in the cetuximab groups, did not appear to limit the therapeutic course.
The observation of increased pulmonary adverse events in patients with NSCLC when compared to controls was striking. Again, most of the adverse reactions in these patients were dyspnea or respiratory insufficiency, and were not noted to be treatment limiting. Although the mechanism for increased symptoms in patients with NSCLC is not well defined, it is not surprising that those with a site of action in the lung would suffer from exuberant local effects. Pneumonitis was seen in most patients (71%) treated with cetuximab in combination with radiation therapy for NSCLC, although there was no control group in this study for comparison . These patients had advanced disease and were treated with a radiation dose of 64Gy to the lungs, which is well above the threshold for pneumonitis with radiation alone As expected, treatment of head/neck cancers in these trials had high overall rates of pulmonary adverse events, although there were no significant differences between those who received cetuximab and those who did not.
Severe adverse reactions were not common in clinical trials using cetuximab. Interstitial lung disease, cited as a rare complication in the medication's package insert, was not described in the clinical trials included in this review with the exception of a case report of two post-lung transplantation patients treated with cetuximab for cutaneous malignancy. Obviously, there are likely confounding factors which may have predisposed this select population to the development of diffuse alveolar damage. For those described in the cetuximab package insert, interstitial lung disease was present before the institution of cetuximab therapy for malignancy. Arguably, the increase in pulmonary symptoms in these patients may have been more a manifestation of ILD progression than as an effect of the therapeutic. However, the presence of antecedent parenchymal lung disease may abrogate the utility of cetuximab in select patients. Pulmonary embolism, also considered a severe reaction, occurred in small numbers of patients in the groups analyzed herein.
An association between the presence of malignancy in the lung, regardless of primary origin, and pulmonary adverse events could not be determined from this investigation. Of the 43 non-lung cancer studies included in our series only 9 reported the location of metastatic disease. When combined with studies of lung cancer, 17% of this cohort reported direct pulmonary involvement of cancer. In those defining the sites of metastatic foci, the lungs were involved in 46.0 ± 10% of patients. Primary or metastatic involvement of the lung with any cancer could account for patients experiencing pulmonary adverse events when treated with Cetuximab. Unfortunately, a more clear relationship is limited by the presentation of the data in the original studies.
Our investigation suffers from several limitations which should be pointed out. First, it is a compilation of clinical trials, most of which are early phase, with limited numbers including control populations available for comparison of pulmonary adverse events. Most of the studies examined only cited positive adverse events, omitting negative responses to pulmonary symptom changes. This may lead to an over-estimation of the absolute incidence of pulmonary-specific complications. Conversely, transfusion reactions and sepsis which often include symptoms such as dyspnea or respiratory insufficiency were not included in the present analysis due to lack of a clear definition. There were significant differences in the duration of Cetuximab therapy before pulmonary complications were reported in the clinical trials, ranging from 1 week into therapy to more than several months. This also limits the generalizability of the summation data. Finally, although there appears to be an increase in the incidence of pulmonary adverse events with cetuximab therapy, there is no clearly defined causal relationship that can be proven as mechanistic understandings are lacking. Despite these limitations, we believe that this investigation adds to the sparse literature describing the pulmonary adverse events related to cetuximab therapy.
Cetuximab (Erbitux® ImClone, Branchburg, NJ) therapy, in combination or as monotherapy, is efficacious in the treatment of colorectal, head/neck, lung and possibly other cancers. Although there is an overall increase in the incidence of pulmonary adverse events with this treatment, there seems to be sparse evidence suggesting treatment limitations related to these complications. Particular attention should be given to cetuximab recipients with underlying parenchymal lung disease and those with NSCLC, in particular in conjunction with radiation therapy, as these groups may have more severe pulmonary reactions.
Interstitial lung disease
Non-small cell lung cancer
Squamous cell cancer/head and neck.
Walsh G: Biopharmaceutical benchmarks 2006. Nat Biotechnology. 2006, 24: 769-776. 10.1038/nbt0706-769.
Giezen T, Mantel-Teeuwisse A, Straus S, Schellekens H, Leufkens H, Egberts A: Safety-related regulatory actions for biologicals approved in the United States and the European Union. JAMA. 2008, 300: 1887-1896. 10.1001/jama.300.16.1887.
Inclone Syetems Incorporated NYN, Bristol-Myers Squibb Co PN: Erbitux (Cetuximab) Package Insert. 2008
Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, Greene M: ErbB receptors: from oncogenes to targeted cancer therapies. Journal Clinical Investigation. 2007, 117: 2051-2058. 10.1172/JCI32278.
Rosell R, Robinet G, Szczesna A, Ramlau R, Costenla M, Mennecier B, Pfiefer W, O'Bryne K, Welte T, Kolb R, Pirker R, Chemaissani A, Perol M, Ranson M, Ellis P, Pilz K, Reck M: Randomized pahse II study of cetuximab plus cisplatin/vinorelbine compasred with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small cell lung cancer. Ann Oncology. 2008, 19: 362-369. 10.1093/annonc/mdm474.
Monti M, Motta S: Clinical management of cutaneous toxicity of anti-EGFR agents. Int J Biol Markers. 2007, 22: S53-S61.
Saif MW, Kim R: Incidence and management of cutaneous toxicities associated with cetuximab. Expert Opin Drug Saf. 2007, 6: 175-182. 10.1517/14740322.214.171.124.
Leard L, Cho B, Jones K, Hays S, Tope W, Golden J, Hoopes C: Fatal diffuse alveolar damage in two lung transplant patients treated with cetuximab. J Heart Lung Transplant. 2007, 26: 1340-1344. 10.1016/j.healun.2007.09.019.
Patel D, Goldberg R: Cetuximab-associated infusion reactions: pathology and Management. Oncology. 2006, 20: 1373-1382.
Arnold D, Hohler T, Dittrich C, Lordick F, Seufferlein T, Riemann J, Woll E, Herrmann T, Zubel A, Schmoll H: Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group. Ann Oncology. 2008, 19: 1442-1449. 10.1093/annonc/mdn150.
Asnacios A, Fartoux L, Romano O, Tesmoingt C, Louafi SS, Mansoubakht T, Artru P, Poynard T, Rosmorduc O, Hebbar M, Taieb J: Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study. Cancer. 2008, 112: 2733-2739. 10.1002/cncr.23489.
Baselga J, Trigo JM, Bourhis J, Tortochaux J, Cortes-Funes H, Hitt R, Gascon P, Amellal N, Harstrick A, Eckardt A: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005, 23: 5568-5577. 10.1200/JCO.2005.07.119.
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006, 354: 567-578. 10.1056/NEJMoa053422.
Bornr M, Koeberle D, Von Moos R, Saletti P, Rauch D, Hess V, Trojan A, Helbling D, Pestalozzi B, Caspar C, Ruhstaller T, Roth A, Kappeler A, Dietrich D, Lanz D, Mingrone W, Swiss Group for Clinical Cancer Research (SAKK) BS: Adding cetuximab to capecitabine plus oxaliplatin (XELOX)in first-line treatment of metastatic colorectal cancer: a rnadomized phase II trial of the Swiss Group for Clinical Research SAKK. Ann Oncology. 2008, 19: 1288-1289. 10.1093/annonc/mdn058.
Bourhis J, Rivera F, Mesia R, Awada A, Geoffrois L, Borel C, Humblet Y, Lopez-Pousa A, Hitt R, Vega Villegas ME, Duck L, Rosine D, Amellal N, Schueler A, Harstrick A: Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol. 2006, 24: 2866-2872. 10.1200/JCO.2005.04.3547.
Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA: Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005, 23: 8646-8654. 10.1200/JCO.2005.02.4646.
Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, Kreisman H, Graze P, Maher J, Ross HJ, Ellis PM, McNulty W, Kaplan E, Pautret V, Weber MR, Shepherd FA: Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol. 2007, 25: 5777-5784. 10.1200/JCO.2007.13.0856.
Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di CF, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A: Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008, 9: 39-44. 10.1016/S1470-2045(07)70383-2.
Chan AT, Hsu MM, Goh BC, Hui EP, Liu TW, Millward MJ, Hong RL, Whang-Peng J, Ma BB, To KF, Mueser M, Amellal N, Lin X, Chang AY: Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol. 2005, 23: 3568-3576. 10.1200/JCO.2005.02.147.
Cunningham D, Humblet Y, Siena S, Khayat D, Blieberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E: Cetuximab monotherapy and Cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine. 2004, 351: 337-345. 10.1056/NEJMoa033025.
Gamucci T, Nelli F, Cianci G, Grassi G, Moscetti L, Sperduti I, Zeuli M, Cortesi E, D'Auria G, Pollera C: A phase II study of cetuximab/irinotecan in patients with heavily pretreated metastatic colorectal cancer: predictive value of early specific toxicities. Clinical Colorectal Cancer. 2008, 7: 273-279. 10.3816/CCC.2008.n.035.
Gebbia V, Del Prete S, Borsellino N, Ferrau F, Tralongo P, Verderame F, Leonardi V, Capasso E, Maiello E, Bordonaro R, Stinco S, Agostara B, Barone C: Efficacy and safety of cetuximab/irinotecan in chemotherapy-refractory metastatic colorectal adenocarcinomas: a clinical practice setting, multicenter experience. Clinical Colorectal Cancer. 2006, 5: 422-428. 10.3816/CCC.2006.n.013.
Hanna N, Lilenbaum R, Ansari R, Lynch T, Govindan R, Janne PA, Bonomi P: Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J Clin Oncol. 2006, 24: 5253-5258. 10.1200/JCO.2006.08.2263.
Herbst RS, Arquette M, Shin DM, Dicke K, Vokes EE, Azarnia N, Hong WK, Kies MS: Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 2005, 23: 5578-5587. 10.1200/JCO.2005.07.120.
Hofheinz R, Horisberger K, Woernle C, Wenz F, Kraus-Tiefenbacher U, Kahler G, Dinter D, Grobholz R, Heeger S, Post S, Hochhaus A, Willeke F: Phase I trial cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer. Int Journal Radiation Oncology Biol Phys. 2006, 66: 1384-1390. 10.1016/j.ijrobp.2006.07.005.
Ibrahim E, Zeeneldin A, Al-Gahmi A, Sallam Y, Fawzi E, Bahadur Y: Safety and efficacy of cetuximab-chemotherapy combination in Saudi patients with metastatic colorectal cancer. Indian J Cancer. 2007, 44: 56-61. 10.4103/0019-509X.35812.
Jonker D, O'Callaghan C, Karapetis C, Zalcberg J, Tu D, Au H, Berry S, Krahn M, Price T, Simes R, Tebbutt N, van Hazel G, Wierzbicki R, Langer C, Moore M: Cetuximab for the treatment of colorectal cancer. New England Journal of Medicine. 2007, 357: 2040-2048. 10.1056/NEJMoa071834.
Konner J, Schilder RJ, DeRosa FA, Gerst SR, Tew WP, Sabbatini PJ, Hensley ML, Spriggs DR, Aghajanian CA: A phase II study of cetuximab/paclitaxel/carboplatin for the initial treatment of advanced-stage ovarian, primary peritoneal, or fallopian tube cancer. Gynecol Oncol. 2008, 110: 140-145. 10.1016/j.ygyno.2008.04.018.
Koo D, Lee J, Kim T, Chang H, Ryu M, Lee S, Kim M, Sym S, Lee J, Kang Y: A phase II study of cetuximab (Erbitux) plus FOLFIRI for irinotecan and oxaliplatin-refractory metastatic colorectal cancer. J Korean Med Sci. 2007, 22: S98-S103. 10.3346/jkms.2007.22.S.S98.
Lenz H, Van Cutsem E, Khambata-Ford S, Mayer R, Gold P, Stella P, Mirtsching B, Cohn A, Pippas A, Azarnia N, Tsuchihashi Z, Mauro D, Rowinsky E: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clinical Oncology. 2006, 24: 4914-4921. 10.1200/JCO.2006.06.7595.
Machiels JP, Sempoux C, Scalliet P, Coche JC, Humblet Y, Van CE, Kerger J, Canon JL, Peeters M, Aydin S, Laurent S, Kartheuser A, Coster B, Roels S, Daisne JF, Honhon B, Duck L, Kirkove C, Bonny MA, Haustermans K: Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol. 2007, 18: 738-744. 10.1093/annonc/mdl460.
Martin-Martorell P, Rosello S, Rodriguez-Braun E, Chirivella I, Bosch A, Cervantes A: Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008, 99: 455-458. 10.1038/sj.bjc.6604530.
Modi S, D'Andrea G, Norton L, Yao TJ, Caravelli J, Rosen PP, Hudis C, Seidman AD: A phase I study of cetuximab/paclitaxel in patients with advanced-stage breast cancer. Clin Breast Cancer. 2006, 7: 270-277. 10.3816/CBC.2006.n.040.
Neyns B, Aerts M, Van NY, Fontaine C, De CL, Schallier D, Vanderauwera J, De MF, Vandenbroucke F, Everaert H, Meert V, De MJ, De RM, Delvaux G, De GJ: Cetuximab with hepatic arterial infusion of chemotherapy for the treatment of colorectal cancer liver metastases. Anticancer Res. 2008, 28: 2459-2467.
Paule B, Herelle MO, Rage E, Ducreux M, Adam R, Guettier C, Bralet MP: Cetuximab plus gemcitabine-oxaliplatin (GEMOX) in patients with refractory advanced intrahepatic cholangiocarcinomas. Oncology. 2007, 72: 105-110. 10.1159/000111117.
Pessino A, Artale S, Sciallero S, Guglielmi A, Fornarini G, Andreotti IC, Mammoliti S, Comandini D, Caprioni F, Bennicelli E, Andretta V, Siena S, Sobrero A: First-line single-agent cetuximab in patients with advanced colorectal cancer. Ann Oncol. 2008, 19: 711-716. 10.1093/annonc/mdm516.
Pfister DG, Su YB, Kraus DH, Wolden SL, Lis E, Aliff TB, Zahalsky AJ, Lake S, Needle MN, Shaha AR, Shah JP, Zelefsky MJ: Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol. 2006, 24: 1072-1078. 10.1200/JCO.2004.00.1792.
Pinto C, DI FF, Siena S, Cascinu S, Rojas Llimpe FL, Ceccarelli C, Mutri V, Giannetta L, Giaquinta S, Funaioli C, Berardi R, Longobardi C, Piana E, Martoni AA: 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: 510-517. 10.1093/annonc/mdl459.
Robert F, Ezekiel MP, Spencer SA, Meredith RF, Bonner JA, Khazaeli MB, Saleh MN, Carey D, LoBuglio AF, Wheeler RH, Cooper MR, Waksal HW: Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol. 2001, 19: 3234-3243.
Robert F, Blumenschein G, Herbst RS, Fossella FV, Tseng J, Saleh MN, Needle M: Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer. J Clin Oncol. 2005, 23: 9089-9096. 10.1200/JCO.2004.00.1438.
Rodel C, Arnold D, Hipp M, Liersch T, Dellas K, Iesalnieks I, Hermann RM, Lordick F, Hinke A, Hohenberger W, Sauer R: Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys. 2008, 70: 1081-1086.
Safran H, Suntharalingam M, Dipetrillo T, Ng T, Doyle LA, Krasna M, Plette A, Evans D, Wanebo H, Akerman P, Spector J, Kennedy N, Kennedy T: Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity. Int J Radiat Oncol Biol Phys. 2008, 70: 391-395.
Saltz LB, Meropol NJ, Loehrer PJ, 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: 1201-1208. 10.1200/JCO.2004.10.182.
Secord AA, Blessing JA, Armstrong DK, Rodgers WH, Miner Z, Barnes MN, Lewandowski G, Mannel RS: Phase II trial of cetuximab and carboplatin in relapsed platinum-sensitive ovarian cancer and evaluation of epidermal growth factor receptor expression: a Gynecologic Oncology Group study. Gynecol Oncol. 2008, 108: 493-499. 10.1016/j.ygyno.2007.11.029.
Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kroning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA: EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008, 26: 2311-2319. 10.1200/JCO.2007.13.1193.
Souglakos J, Kalykaki A, Vamvakas L, Androulakis N, Kalbakis K, Agelaki S, Vardakis N, Tzardi M, Kotsakis AP, Gioulbasanis J, Tsetis D, Sfakiotaki G, Chatzidaki D, Mavroudis D, Georgoulias V: Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy. Ann Oncol. 2007, 18: 305-310. 10.1093/annonc/mdl392.
Tabernero J, Van CE, az-Rubio E, Cervantes A, Humblet Y, Andre T, Van Laethem JL, Soulie P, Casado E, Verslype C, Valera JS, Tortora G, Ciardiello F, Kisker O, de GA: Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2007, 25: 5225-5232. 10.1200/JCO.2007.13.2183.
Thienelt CD, Bunn PA, Hanna N, Rosenberg A, Needle MN, Long ME, Gustafson DL, Kelly K: Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. J Clin Oncol. 2005, 23: 8786-8793. 10.1200/JCO.2005.03.1997.
Tol J, Koopman M, Rodenburg CJ, Cats A, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, Mol L, Antonini NF, Punt CJ: A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol. 2008, 19: 734-738. 10.1093/annonc/mdm607.
Vermorken JB, Trigo J, Hitt R, Koralewski P, az-Rubio E, Rolland F, Knecht R, Amellal N, Schueler A, Baselga J: 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: 2171-2177. 10.1200/JCO.2006.06.7447.
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De RD, Bokemeyer C, Schueler A, Amellal N, Hitt R: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008, 359: 1116-1127. 10.1056/NEJMoa0802656.
Vincenzi B, Santini D, Rabitti C, Coppola R, Beomonte ZB, Trodella L, Tonini G: Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial. Br J Cancer. 2006, 94: 792-797. 10.1038/sj.bjc.6603018.
Xiong HQ, Rosenberg A, LoBuglio A, Schmidt W, Wolff RA, Deutsch J, Needle M, Abbruzzese JL: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. J Clin Oncol. 2004, 22: 2610-2616. 10.1200/JCO.2004.12.040.
Zhu AX, Stuart K, Blaszkowsky LS, Muzikansky A, Reitberg DP, Clark JW, Enzinger PC, Bhargava P, Meyerhardt JA, Horgan K, Fuchs CS, Ryan DP: Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer. 2007, 110: 581-589. 10.1002/cncr.22829.
Gridelli C, Morabito A, Gebbia V, Mencoboni M, Carrozza F, Vigano MG, Verusio C, Bollina R, Mattioli R, Valerio MR, Valmadre G, Maione P, Rossi A, Cascone T, Morgillo F, Di MM, Piccirillo MC, Gallo C, Perrone F, Ciardiello F: Cetuximab and gemcitabine in elderly or adult PS2 patients with advanced non-small-cell lung cancer: The cetuximab in advanced lung cancer (CALC1-E and CALC1-PS2) randomized phase II trials. Lung Cancer. 2009
Hughes S, Liong J, Miah A, Ahmad S, Leslie M, Harper P, Prendiville J, Shamash J, Subramaniam R, Gaya A, Spicer J, Landau D: A brief report on the safety study of induction chemotherapy followed by synchronous radiotherapy and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRATCH study. J Thorac Oncol. 2008, 3: 648-651. 10.1097/JTO.0b013e3181757a60.
Belani CP, Schreeder MT, Steis RG, Guidice RA, Marsland TA, Butler EH, Ramalingam SS: Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced-stage nonsmall cell lung cancer: a multicenter phase 2 study. Cancer. 2008, 113: 2512-2517. 10.1002/cncr.23902.
Pirker R, Pereira JR, Szczesna A, von PJ, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de MF, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009, 373: 1525-1531. 10.1016/S0140-6736(09)60569-9.
Shin DM, Donato NJ, Perez-Soler R, Shin HJ, Wu JY, Zhang P, Lawhorn K, Khuri FR, Glisson BS, Myers J, Clayman G, Pfister D, Falcey J, Waksal H, Mendelsohn J, Hong WK: Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res. 2001, 7: 1204-1213.
Baselga J, Pfister D, Cooper MR, Cohen R, Burtness B, Bos M, D'Andrea G, Seidman A, Norton L, Gunnett K, Falcey J, Anderson V, Waksal H, Mendelsohn J: Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol. 2000, 18: 904-914.
Park K, Chung F, Chun M, Suh F: Radiation-Induced Ling Disease and the impact of Radiation Methods in Imaging Features. RadioGraphics. 2000, 20: 983-998.
The authors declare that they have no competing interests.
JH conceived and designed the study and participated in writing. AA participated in data gathering, study screening, and study coordination. TD participated in data gathering, study screening, and study coordination. JL participated in statistical analysis of the study and study design. RW participated in study design and data analysis. ML performed oversight of study design, coordination, and writing. All authors read and approved the final manuscript.
About this article
Cite this article
Hoag, J.B., Azizi, A., Doherty, T.J. et al. Association of cetuximab with adverse pulmonary events in cancer patients: a comprehensive review. J Exp Clin Cancer Res 28, 113 (2009). https://doi.org/10.1186/1756-9966-28-113
- Epidermal Growth Factor Receptor
- Interstitial Lung Disease
- Pulmonary Complication
- Vascular Endothelial Growth Factor Production