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Association of cetuximab with adverse pulmonary events in cancer patients: a comprehensive review

Association of cetuximab with adverse pulmonary events in cancer patients: a comprehensive review 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. Because these compounds are derived from biologic Background Biological Therapies sources, they have the potential for significant immune Biologic therapies, or biologicals, are those produced or activation. Although extensively reported in clinical trials, extracted from a biological source. Based upon the specific adverse events are rarely compiled in the medical litera- agent, biologicals have a myriad of activities and have ture. Giezen and coauthors examined adverse event been used to modulate immunity, increase blood cell pro- reporting post-approval for biologicals and suggested that duction, inhibit tumor growth, and other effects [1]. Over there was a need for increasing awareness to certain risks the last 5 years, more than 20% of the compounds associated with the therapeutic use of biologicals [2]. approved by United States regulatory authorities were bio- logics [2]. Despite this explosion in the availability of bio- Cetuximab (Erbitux ) One such biologic therapy used in the treatment of malig- logicals, surprisingly limited data exists regarding adverse events associated with their use. nancy is cetuximab (Erbitux , ImClone, Branchburg, NJ). Cetuximab is a chimeric monoclonal antibody with Page 1 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 inhibitor effects on the epidermal growth factor receptor There have only been rare reports of pulmonary side (EGFR). Cetuximab has been extensively studied and effects with cetuximab. Interstitial lung disease was approved [3] for the treatment of metastatic colorectal reported in 4 of 1,570 (0.25%) patients with advanced cancer (MCRC) and squamous cell head/neck cancers colorectal cancer [3]. There have also been reports of inter- (SCCHN), and growing data supports its use in the treat- stitial pneumonitis with non-cardiogenic pulmonary ment of other malignancies including non-small cell lung edema [8]. The use of cetuximab in combination regi- cancer (NSCLC). Cetuximab has been evaluated in the set- mens potentially clouds side effect profiles. ting of combination therapy or as a single agent in con- ventional therapy failures. Moreover, cetuximab has been Pulmonary complications in the setting of chemotherapy studied for the treatment of various other malignancies lead to increased morbidity and severe reactions are asso- including breast cancer and ovarian cancer, hepatocellular ciated with mortality. Cetuximab, like many other cancer cancer, pancreatic cancer, and others. therapies, has been demonstrated to cause a wide range of respiratory effects from mild dyspnea to a fatality due Through binding to the extracellular domain of EGFR, adverse pulmonary events. The purpose of this investiga- cetuximab interrupts the signaling cascade resulting in tion is to compile a comprehensive list of pulmonary inhibition of cell growth, induction of apoptosis, and adverse events in the setting of therapy with cetuximab decreased matrix metalloproteinase and vascular published in the literature in order to better characterize endothelial growth factor production [3]. EGFR, a mem- the true incidence of these reactions. A better understand- ber of the ErbB-1 family of receptors, is closely related ing of the prevalence may help the clinician respond structurally to other tyrosine kinase receptors including appropriately to specific symptom changes during the HER2/c-neu (ErbB-2), Her 3 (ErbB-3), and Her 4 (ErbB- therapeutic window with a hope of improving patient 4)[4]. Over expression or increased activity of EGFR as care. seen in some mutations can result malignancy [4]. Methods Cetuximab efficacy has been studied as a single agent as We performed a MEDLINE™ search of the English lan- well as in combination with other chemotherapeutic guage literature using the search terms: "cetuximab" or modalities. A randomized controlled clinical trial with "Erbitux" with limits to include only human studies to 329 patients was conducted using cetuximab plus irinote- develop a complete index of trials or reports. Inclusion cri- can or cetuximab alone in treatment of EGFR-expressing teria were clinical trials, meta-analyses, or randomized MCRC [3]. Cetuximab was shown to lengthen the time to controlled trials that included the search terms and cited disease progression by 4.2 months in the monotherapy adverse events. The reference lists from each of these man- arm and 5.7 months in combination arm. In patients with uscripts were scanned to isolate articles not obtained in EGFR-positive NSCLC a phase II study by Rosell showed the MEDLINE search to complete our database. Studies that combination cisplatin/vinorelbine plus cetuximab were excluded if they did not list adverse events. resulted in an overall response rate of 32%, compared to 20% with cisplatin/vinorelbine alone [5]. The continuing Data extracted from each report included number of research of cetuximab is helping to determine which pop- patients, controls, type of cancer, coincident chemother- ulations of patient will benefit most from Anti-EGFR ther- apy administration, and information regarding pulmo- apy. Currently most evidence points towards the use of nary complications. Pulmonary complications included cetuximab in combination with other chemotherapeutic the incidence of symptoms related to the respiratory sys- regimens as the best option for treatment in EGFR positive tem including dyspnea, cough, wheezing, pneumonia, tumors. hypoxemia, respiratory insufficiency/failure, pulmonary embolus, pleural effusion, and non-specific respiratory Epidermal growth factor receptors are ubiquitous, thus disorders. Incidences of these pulmonary complications potential for exuberant reactions including adverse events were obtained from each study's control group if available is high. Moreover, due to the diverse tissues expressing and compared between the patients that received cetuxi- EGRF, adverse reactions manifest in many ways. Although mab and those who did not. Infusion reactions were dermatologic reactions represent the vast majority of treated as a separate complication to cetuximab and were adverse events, occurring in between 3090% of patients not included in this analysis, although in many individu- depending on the severity and study examined [6,7], als, symptoms of shortness of breath and chest tightness many other side effects occur with cetuximab therapy. may be encompassed by this type of reaction [9]. Other adverse events increased above control groups included gastrointestinal complaints (1959%) and head- Data Analysis and Statistics ache (19%) [3]. Cextuximab infusion reactions took place Data is presented as the number of patients and percent- in between 15 and 20% of subjects [3]. age receiving the study medication as well as means (± Page 2 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 Table 1: Studies included in the analysis including first author, year of publication, type of trial and combined therapy, and pulmonary adverse reactions. Number Ref: Author Year Study Type Cancer Type Combined Agents Pulmonary Reactions 1 51 Vermorken 2008 Phase II SCCHN platinum dyspnea, Pneumonia 2 29 Koo 2007 Phase II Colorectal FOLFIRI, irinotecan dyspnea 3 8 Leard 2007 case SCCHN DAD 4 16 Burtness 2005 Phase III SCCHN cisplatin dyspnea, hypoxia 5 15 Bourhis 2006 Phase I/II SCCHN cisplatin, carboplatin/5- respiratory symptoms fluorouracil 6 12 Baselga 2005 Phase II SCCHN platinum respiratory disorder 7 50 Vermorken 2007 review SCCHN cisplatinum, carboplatin dyspnea, infusion rxn 8 20 Cunningham 2004 Prospective Colorectal irinotecan dyspnea 9 53 Xiong 2004 Phase II Pancreatic gemcitabine Pneumonia, Sepsis, PE, Pulm Insufficeincy 10 19 Chan 2005 Phase II Nasopharyngeal carboplatin Pleural Effusion, Dyspnea, Pneumonia 11 40 Robert 2005 Phase I/II NSCLC gemcitibine, carboplatin Pulmonary Embolism 12 23 Hanna 2006 Phase II NSCLC Dyspnea 13 54 Zhu 2007 Phase II HCC Cough 14 31 Machiels 2007 Phase I/II Colorectal capecitabine, ExBR Pulmonary Embolism, Pulm Infetion 15 13 Bonner 2006 RCT SCCHN ExBR cough, increased sputum 16 32 Martin-Martorell 2008 Phase II Colorectal irinotecan none 17 28 Konner 2008 Phase II Ovarian carboplatin, paclitaxel Dyspnea 18 56 Hughes 2008 Phase I/II NSCLC platinum, ExBR 64 Gy dyspnea, pneumonitis, pulm embolism, pneumonia 19 11 Asnacios 2008 Phase II HCC oxaliplatin, gemcitabine none 20 18 Cascinu 2008 Phase II Pancreatic cisplatin, gemcitabine none 21 35 Paule 2007 Phase II Cholangiocarcinoma oxaliplatin, gemcitabine none 22 47 Tabernero 2007 Phase II Colorectal oxaliplatin, 5-fluorouracil Dyspnea 23 27 Jonker 2007 rescue Colorectal prev-oxal, irinotecan, dyspnea flouropyrimidine 24 42 Safran 2008 phase II Espohageal carboplatin, paclitaxel, ExBR Pneumonia 25 26 Ibrahim 2007 phase II Colorectal oxaliplatin, irinotecan none 26 38 Pinto 2007 phase II Gastric/GE irinotecan, 5-fluorouracil none 27 46 Souglakos 2007 phase II Colorectal oxaliplatin, capecitabine none 28 30 Lenz 2006 phase II Colorectal prev-oxaloplatin, irinotecan, none flouropyrimidine 29 25 Hofheinz 2006 phase I Colorectal capecitabine, irinotecan, none ExBR 30 24 Herbst 2005 phase II SCCHN cisplatin none 31 43 Saltz 2004 phase II Colorectal previous irinotecan none 32 52 Vincenzi 2006 phase II Colorectal irinotecan none 33 37 Pfister 2006 phase II SCCHN cisplatin, ExBR pneumonia 34 39 Robert 2001 phase I SCCHN ExBR none 35 48 Thienelt 2005 Phase I/II NSCLC carboplatin, paclitaxel pulmonary embolism 36 34 Neyns 2008 Phase II Colorectal oxaloplatin or irinotecan Interstitial pneumonitis 37 10 Arnold 2008 Phase Ib/II Colorectal oxaliplatin, 5-fluorouracil None 38 45 Sobrero 2008 Phase III Colorectal irinotecan None 39 44 Secord 2008 Phase II Ovarian carboplatin Pulmonary rxn 40 14 Borner 2008 Phase II Colorectal oxaliplatin, capecitabine none 41 21 Gamucci 2008 Phase II Colorectal irinotecan none 42 49 Tol 2008 Phase III Colorectal capecitabine, Oxaliplatin + Pulmonary embolism, Bevacizumab Respiratory Insuffiency 43 17 Butts 2007 Phase II NSCLC gemcitabine, Cisplatin, dyspnea, Cough, Pneumonia Carboplatin 44 36 Pessino 2008 Phase II Colorectal none none 45 5 Rosell 2008 Phase II NSCLC cisplatin, vinorelbine resp symptoms 46 41 Rodel 2008 Phase I/II Colorectal capecitabine, ExBR, none Oxaliplatin 47 33 Modi 2006 Phase I Breast paclitaxel none 48 22 Gebbia 2006 retrospect rev Colorectal irinotecan none Page 3 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 Table 1: Studies included in the analysis including first author, year of publication, type of trial and combined therapy, and pulmonary adverse reactions. (Continued) 49 58 Pirker 2009 Phase III NSCLC cisplatin, vinorelbine dyspnea, respiratory failure, pulmonary embolism 50 57 Belani 2008 Phase II NSCLC carboplatin, docetaxel none 51 55 Gridelli 2009 Phase II NSCLC gemcitibine pulmonary symptoms 52 59 Shin 2001 Phase I SSCHN Cisplatin Shortness of Breath 53 60 Baselga 2000 Phase I SSCHN/NSCLC Cisplatin Dyspnea (Abbreviations: SCCHN squamous cell cancer of the head and neck, NSCLC non-small cell lung cancer, ExBR external beam radiation) SD) where appropriate. Comparisons between groups these studies making up more than 90% of the adverse were made using Chi-Square or students t-test where reactions. appropriate, and statistical significance was set as p < 0.05. Pulmonary adverse events were much more common, as Results would be expected in NSCLC trials with an incidence of Using our search criteria defined above, a total of 245 arti- 18.7% in the cetuximab group versus 12.2% in the control cles were obtained for review. From this complete group, arms (p < 0.001). Similarly, dyspnea made up the major- 192 articles were excluded for not meeting inclusion crite- ity of pulmonary adverse events (13.2% vs 9.2%, p < 0.02) ria. Reasons for exclusion were: non-pulmonary focus with other significant differences occurring in the inci- (dermatologic side effects), duplicate patient populations, dence of pneumonitis (1.1% versus 0.0%, p < 0.001) case reports not relevant to pulmonary side effects, focus being worse in the cetuximab groups. on pharmacokinetics, omission of side effects, or non- cetuximab trials. A total of 53 studies (Table 1) met inclu- For head-neck cancer studies, the overall rates of pulmo- sion and were included in the analysis [5,8,10-60]. nary complications were similar between the cetuximab and control groups (17.9% versus 20.1%, p = NS), but The majority of clinical trials focused on the treatment of favored the cetuximab group. Dyspnea was more com- colorectal cancers with head/neck, lung, and hepatobil- mon in the cetuximab group (8.7%) than the control iary or pancreatic making up the next largest groups group (5%, p < 0.02) in Head and Neck Cancer Trials. (Table 1). Similarly, most of the studies examined were Conversely, there were fewer patients with increased spu- completed as Phase I or II trials with the focus on refrac- tum production (3.0% versus 6.6%, p < 0.01) and cough tory and metastatic disease (Table 2). (4.5% versus 7.8%, p < 0.01) in the control group com- pared to the cetuximab group. From all studies, the differ- A total of 7,411 patients were included in the 53 studies ence in other pulmonary adverse events appears to be reviewed including 4,436 (59.8%) patients who received similar (Table 4). cetuximab either alone or in conjunction with other chemotherapeutic medications or radiation therapy. Discussion 2,596 (41.4%) patients were in the control groups from Overall, cetuximab seems to increase the incidence of these investigations who received the same chemotherapy adverse pulmonary reactions compared to controls, or radiation therapy without cetuximab (Table 3). although the absolute difference between groups is low (<2%). The severity of the pulmonary complications was Pulmonary Reactions not well described in most of the included studies, but did A total of 459 patients (10.3%) in the cetuximab group not increase mortality rates. To the contrary, if survival had adverse pulmonary reactions compared to 221 benefits were not demonstrated, almost universally, there (8.5%) who received standard, non-cetuximab therapy (p was an increase in progression free survival or stability of < 0.02). Studies focusing on colorectal cancer, lung can- malignancy in these trials. To this point, the difference cer, and head-neck cancer had sufficient numbers in both between statistical significance and clinical significance the cetuximab and control groups to compare pulmonary should also be examined in relation to the pulmonary complications; however, hepatobiliary, pancreatic, breast, reactions. For all clinical trials except NSCLC, the differ- ovarian, and cutaneous cancer studies lacked adequate ences in pulmonary adverse events between those treated numbers of control patients to compare these complica- with and without cetuximab are small. Dyspnea and tions. cough, though increased in the cetuximab groups, did not appear to limit the therapeutic course. Colorectal cancer studies demonstrate a low rate of pul- monary complications overall with 3.41% incidence in The observation of increased pulmonary adverse events in the cetuximab group versus 2.56% in the control patients patients with NSCLC when compared to controls was (p = NS). The most common side effect was dyspnea in striking. Again, most of the adverse reactions in these Page 4 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 Table 2: Number and type of trials broken into groups according to cancer type. Trial Type Cancer Type Colorectal NSCLCa Head-Neck HB-Panc Breast-Ov-Skin TOTAL Phase I/II 20 9* 10* 5 3 47 Phase III 2 1 1 0 0 4 Case Series/Review 1 0 1 0 1 3 TOTAL 23 10 12 5 4 53 First-Line 5 2 0 0 2 9 Refractory Disease 18 8* 12* 5 2 44 (NSCLCa nonsmall cell lung cancer, HB-Panc hepatobiliary or pancreatic, Breast-Ov-Skin Breast or Ovarian or Cutaneous). * One study contained patients with either Head-Neck or Non-small cell lung cancer and is displayed in both groups. patients were dyspnea or respiratory insufficiency, and described in the cetuximab package insert, interstitial lung were not noted to be treatment limiting. Although the disease was present before the institution of cetuximab mechanism for increased symptoms in patients with therapy for malignancy. Arguably, the increase in pulmo- NSCLC is not well defined, it is not surprising that those nary symptoms in these patients may have been more a with a site of action in the lung would suffer from exuber- manifestation of ILD progression than as an effect of the ant local effects. Pneumonitis was seen in most patients therapeutic. However, the presence of antecedent paren- (71%) treated with cetuximab in combination with radia- chymal lung disease may abrogate the utility of cetuximab tion therapy for NSCLC, although there was no control in select patients. Pulmonary embolism, also considered a group in this study for comparison [56]. These patients severe reaction, occurred in small numbers of patients in had advanced disease and were treated with a radiation the groups analyzed herein. dose of 64Gy to the lungs, which is well above the thresh- old for pneumonitis with radiation alone[61] As expected, An association between the presence of malignancy in the treatment of head/neck cancers in these trials had high lung, regardless of primary origin, and pulmonary adverse overall rates of pulmonary adverse events, although there events could not be determined from this investigation. were no significant differences between those who Of the 43 non-lung cancer studies included in our series received cetuximab and those who did not. only 9 reported the location of metastatic disease. When combined with studies of lung cancer, 17% of this cohort Severe adverse reactions were not common in clinical tri- reported direct pulmonary involvement of cancer. In als using cetuximab. Interstitial lung disease, cited as a those defining the sites of metastatic foci, the lungs were rare complication in the medication's package insert, was involved in 46.0 ± 10% of patients. Primary or metastatic not described in the clinical trials included in this review involvement of the lung with any cancer could account for with the exception of a case report of two post-lung trans- patients experiencing pulmonary adverse events when plantation patients treated with cetuximab for cutaneous treated with Cetuximab. Unfortunately, a more clear rela- malignancy. Obviously, there are likely confounding fac- tionship is limited by the presentation of the data in the tors which may have predisposed this select population to original studies. the development of diffuse alveolar damage. For those Table 3: Number of patients included by trial type. Cancer Type Studies Included Total Patients Number of Cetuximab with Number of Controls with Cetuximab Pulmonary Reaction Controls Pulmonary Reaction nn n n n n Colorectal 23 3731 2227 76 (3.4) 1367 35 (2.6) Head-Neck 10 1749 1004 173 (17.2) 516 104 (20.2) Lung 10 1664 980 189 (19.6) † 671 82 (12.2) Hepatobiliary/ 5 209 167 9 (5.4) 42 0 (0.0) Pancreatic Breast/Ovarian 3 78 78 10 (12.8) 0 0 (0.0) Cutaneous 1 2 2 2 (100) 0 0 (0.0) TOTAL: 52 7433 4458 459 (10.3) † 2596 221 (8.5) Patients were grouped into those who received cetuximab, either alone or in combination with other therapeutics, and controls (those who did not receive cetuximab). † p < 0.05 compared to control group. * One study contained patients with either Head-Neck or Non-small cell lung cancer and is displayed in both groups. Page 5 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 Table 4: Combined pulmonary adverse events cited in clinical trials. Colorectal Cancer Control Non-Small Cell Lung Cancer Control Head-Neck Cancer Control Cetuximab Cetuximab Cetuximab N (%) N (%) N (%) N (%) N (%) N (%) Dyspnea/RI 70 (3.1) 35 (2.6) 131 (13.4) † 62 (9.2) 87 (8.7) † 26 (5.0) PE 3 (0.1) 0 (0.0) 32 (3.3) 16 (2.4) 0 (0.0) 0 (0.0) Pneumonia 2 (0.1) 0 (0.0) 4 (0.4) 1 (1.2) 13 (1.4) 4 (0.8) ILD 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Cough 0 (0.0) 0 (0.0) 8 (3.4) 3 (3.6) 42 (4.5) † 40 (7.8) Pneumonitis 1 (0.0) 0 (0.0) 17 (1.7) † 0 (0.0) 0 (0.0) 0 (0.0) Pleural Effusion 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (0.3) 0 (0.0) Increased Sputum 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 28 (3.0) † 34 (6.6) TOTAL: 76 (3.4) 35 (2.6) 192 (19.6) † 82 (12.2) 173 (17.9) 104 (20.2) Patients were grouped into those who received cetuximab, either alone or in combination with other therapeutics, and controls (those who did not receive cetuximab). † p < 0.05 compared to control group. Our investigation suffers from several limitations which Abbreviations should be pointed out. First, it is a compilation of clinical ILD: Interstitial lung disease; NSCLC: Non-small cell lung trials, most of which are early phase, with limited num- cancer; SCCHN: Squamous cell cancer/head and neck. bers including control populations available for compari- son of pulmonary adverse events. Most of the studies Competing interests examined only cited positive adverse events, omitting The authors declare that they have no competing interests. negative responses to pulmonary symptom changes. This may lead to an over-estimation of the absolute incidence Authors' contributions of pulmonary-specific complications. Conversely, transfu- JH conceived and designed the study and participated in sion reactions and sepsis which often include symptoms writing. AA participated in data gathering, study screen- such as dyspnea or respiratory insufficiency were not ing, and study coordination. TD participated in data gath- included in the present analysis due to lack of a clear def- ering, study screening, and study coordination. JL inition. There were significant differences in the duration participated in statistical analysis of the study and study of Cetuximab therapy before pulmonary complications design. RW participated in study design and data analysis. were reported in the clinical trials, ranging from 1 week ML performed oversight of study design, coordination, into therapy to more than several months. This also limits and writing. All authors read and approved the final man- the generalizability of the summation data. Finally, uscript. although there appears to be an increase in the incidence of pulmonary adverse events with cetuximab therapy, References 1. Walsh G: Biopharmaceutical benchmarks 2006. Nat Biotechnol- there is no clearly defined causal relationship that can be ogy 2006, 24:769-776. proven as mechanistic understandings are lacking. 2. 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Martin-Martorell P, Rosello S, Rodriguez-Braun E, Chirivella I, Bosch study of gemcitabine plus cisplatin or carboplatin [cor- A, Cervantes A: Biweekly cetuximab and irinotecan in rected], with or without cetuximab, as first-line therapy for advanced colorectal cancer patients progressing after at patients with advanced or metastatic non small-cell lung least one previous line of chemotherapy: results of a phase II cancer. J Clin Oncol 2007, 25:5777-5784. single institution trial. Br J Cancer 2008, 99:455-458. 18. Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, 33. Modi S, D'Andrea G, Norton L, Yao TJ, Caravelli J, Rosen PP, Hudis Di CF, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani C, Seidman AD: A phase I study of cetuximab/paclitaxel in I, Scartozzi M, Zaniboni A: Cetuximab plus gemcitabine and cis- patients with advanced-stage breast cancer. Clin Breast Cancer platin compared with gemcitabine and cisplatin alone in 2006, 7:270-277. patients with advanced pancreatic cancer: a randomised, 34. Neyns B, Aerts M, Van NY, Fontaine C, De CL, Schallier D, Vander- multicentre, phase II trial. Lancet Oncol 2008, 9:39-44. auwera J, De MF, Vandenbroucke F, Everaert H, Meert V, De MJ, De 19. Chan AT, Hsu MM, Goh BC, Hui EP, Liu TW, Millward MJ, Hong RL, RM, Delvaux G, De GJ: Cetuximab with hepatic arterial infu- Whang-Peng J, Ma BB, To KF, Mueser M, Amellal N, Lin X, Chang AY: sion of chemotherapy for the treatment of colorectal cancer Multicenter, phase II study of cetuximab in combination with liver metastases. Anticancer Res 2008, 28:2459-2467. carboplatin in patients with recurrent or metastatic 35. Paule B, Herelle MO, Rage E, Ducreux M, Adam R, Guettier C, Bralet nasopharyngeal carcinoma. J Clin Oncol 2005, 23:3568-3576. MP: Cetuximab plus gemcitabine-oxaliplatin (GEMOX) in 20. Cunningham D, Humblet Y, Siena S, Khayat D, Blieberg H, Santoro A, patients with refractory advanced intrahepatic cholangi- Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E: ocarcinomas. Oncology 2007, 72:105-110. Cetuximab monotherapy and Cetuximab plus irinotecan in 36. Pessino A, Artale S, Sciallero S, Guglielmi A, Fornarini G, Andreotti irinotecan-refractory metastatic colorectal cancer. New Eng- IC, Mammoliti S, Comandini D, Caprioni F, Bennicelli E, Andretta V, land Journal of Medicine 2004, 351:337-345. Siena S, Sobrero A: First-line single-agent cetuximab in 21. Gamucci T, Nelli F, Cianci G, Grassi G, Moscetti L, Sperduti I, Zeuli patients with advanced colorectal cancer. Ann Oncol 2008, M, Cortesi E, D'Auria G, Pollera C: A phase II study of cetuximab/ 19:711-716. irinotecan in patients with heavily pretreated metastatic 37. Pfister DG, Su YB, Kraus DH, Wolden SL, Lis E, Aliff TB, Zahalsky AJ, colorectal cancer: predictive value of early specific toxicities. Lake S, Needle MN, Shaha AR, Shah JP, Zelefsky MJ: Concurrent Clinical Colorectal Cancer 2008, 7:273-279. cetuximab, cisplatin, and concomitant boost radiotherapy 22. Gebbia V, Del Prete S, Borsellino N, Ferrau F, Tralongo P, Verderame for locoregionally advanced, squamous cell head and neck F, Leonardi V, Capasso E, Maiello E, Bordonaro R, Stinco S, Agostara cancer: a pilot phase II study of a new combined-modality B, Barone C: Efficacy and safety of cetuximab/irinotecan in paradigm. J Clin Oncol 2006, 24:1072-1078. Page 7 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 38. Pinto C, DI FF, Siena S, Cascinu S, Rojas Llimpe FL, Ceccarelli C, Mutri 51. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, V, Giannetta L, Giaquinta S, Funaioli C, Berardi R, Longobardi C, Piana Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso E, Martoni AA: Phase II study of cetuximab in combination M, Vynnychenko I, De RD, Bokemeyer C, Schueler A, Amellal N, Hitt with FOLFIRI in patients with untreated advanced gastric or R: Platinum-based chemotherapy plus cetuximab in head gastroesophageal junction adenocarcinoma (FOLCETUX and neck cancer. N Engl J Med 2008, 359:1116-1127. study). Ann Oncol 2007, 18:510-517. 52. Vincenzi B, Santini D, Rabitti C, Coppola R, Beomonte ZB, Trodella 39. Robert F, Ezekiel MP, Spencer SA, Meredith RF, Bonner JA, Khazaeli L, Tonini G: Cetuximab and irinotecan as third-line therapy in MB, Saleh MN, Carey D, LoBuglio AF, Wheeler RH, Cooper MR, advanced colorectal cancer patients: a single centre phase II Waksal HW: Phase I study of antiepidermal growth factor trial. 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J Clin Oncol 2005, Publish with Bio Med Central and every 23:8786-8793. scientist can read your work free of charge 49. Tol J, Koopman M, Rodenburg CJ, Cats A, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, Mol L, Antonini NF, Punt CJ: A randomised "BioMed Central will be the most significant development for phase III study on capecitabine, oxaliplatin and bevacizumab disseminating the results of biomedical researc h in our lifetime." with or without cetuximab in first-line advanced colorectal Sir Paul Nurse, Cancer Research UK cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol Your research papers will be: 2008, 19:734-738. available free of charge to the entire biomedical community 50. Vermorken JB, Trigo J, Hitt R, Koralewski P, az-Rubio E, Rolland F, Knecht R, Amellal N, Schueler A, Baselga J: Open-label, uncon- peer reviewed and published immediately upon acceptance trolled, multicenter phase II study to evaluate the efficacy cited in PubMed and archived on PubMed Central and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the yours — you keep the copyright head and neck who failed to respond to platinum-based ther- BioMedcentral apy. J Clin Oncol 2007, 25:2171-2177. Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 8 of 8 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Experimental & Clinical Cancer Research Springer Journals

Association of cetuximab with adverse pulmonary events in cancer patients: a comprehensive review

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Springer Journals
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Copyright © 2009 by Hoag et al; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Oncology; Cancer Research
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1756-9966
DOI
10.1186/1756-9966-28-113
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19682368
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Abstract

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. Because these compounds are derived from biologic Background Biological Therapies sources, they have the potential for significant immune Biologic therapies, or biologicals, are those produced or activation. Although extensively reported in clinical trials, extracted from a biological source. Based upon the specific adverse events are rarely compiled in the medical litera- agent, biologicals have a myriad of activities and have ture. Giezen and coauthors examined adverse event been used to modulate immunity, increase blood cell pro- reporting post-approval for biologicals and suggested that duction, inhibit tumor growth, and other effects [1]. Over there was a need for increasing awareness to certain risks the last 5 years, more than 20% of the compounds associated with the therapeutic use of biologicals [2]. approved by United States regulatory authorities were bio- logics [2]. Despite this explosion in the availability of bio- Cetuximab (Erbitux ) One such biologic therapy used in the treatment of malig- logicals, surprisingly limited data exists regarding adverse events associated with their use. nancy is cetuximab (Erbitux , ImClone, Branchburg, NJ). Cetuximab is a chimeric monoclonal antibody with Page 1 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 inhibitor effects on the epidermal growth factor receptor There have only been rare reports of pulmonary side (EGFR). Cetuximab has been extensively studied and effects with cetuximab. Interstitial lung disease was approved [3] for the treatment of metastatic colorectal reported in 4 of 1,570 (0.25%) patients with advanced cancer (MCRC) and squamous cell head/neck cancers colorectal cancer [3]. There have also been reports of inter- (SCCHN), and growing data supports its use in the treat- stitial pneumonitis with non-cardiogenic pulmonary ment of other malignancies including non-small cell lung edema [8]. The use of cetuximab in combination regi- cancer (NSCLC). Cetuximab has been evaluated in the set- mens potentially clouds side effect profiles. ting of combination therapy or as a single agent in con- ventional therapy failures. Moreover, cetuximab has been Pulmonary complications in the setting of chemotherapy studied for the treatment of various other malignancies lead to increased morbidity and severe reactions are asso- including breast cancer and ovarian cancer, hepatocellular ciated with mortality. Cetuximab, like many other cancer cancer, pancreatic cancer, and others. therapies, has been demonstrated to cause a wide range of respiratory effects from mild dyspnea to a fatality due Through binding to the extracellular domain of EGFR, adverse pulmonary events. The purpose of this investiga- cetuximab interrupts the signaling cascade resulting in tion is to compile a comprehensive list of pulmonary inhibition of cell growth, induction of apoptosis, and adverse events in the setting of therapy with cetuximab decreased matrix metalloproteinase and vascular published in the literature in order to better characterize endothelial growth factor production [3]. EGFR, a mem- the true incidence of these reactions. A better understand- ber of the ErbB-1 family of receptors, is closely related ing of the prevalence may help the clinician respond structurally to other tyrosine kinase receptors including appropriately to specific symptom changes during the HER2/c-neu (ErbB-2), Her 3 (ErbB-3), and Her 4 (ErbB- therapeutic window with a hope of improving patient 4)[4]. Over expression or increased activity of EGFR as care. seen in some mutations can result malignancy [4]. Methods Cetuximab efficacy has been studied as a single agent as We performed a MEDLINE™ search of the English lan- well as in combination with other chemotherapeutic guage literature using the search terms: "cetuximab" or modalities. A randomized controlled clinical trial with "Erbitux" with limits to include only human studies to 329 patients was conducted using cetuximab plus irinote- develop a complete index of trials or reports. Inclusion cri- can or cetuximab alone in treatment of EGFR-expressing teria were clinical trials, meta-analyses, or randomized MCRC [3]. Cetuximab was shown to lengthen the time to controlled trials that included the search terms and cited disease progression by 4.2 months in the monotherapy adverse events. The reference lists from each of these man- arm and 5.7 months in combination arm. In patients with uscripts were scanned to isolate articles not obtained in EGFR-positive NSCLC a phase II study by Rosell showed the MEDLINE search to complete our database. Studies that combination cisplatin/vinorelbine plus cetuximab were excluded if they did not list adverse events. resulted in an overall response rate of 32%, compared to 20% with cisplatin/vinorelbine alone [5]. The continuing Data extracted from each report included number of research of cetuximab is helping to determine which pop- patients, controls, type of cancer, coincident chemother- ulations of patient will benefit most from Anti-EGFR ther- apy administration, and information regarding pulmo- apy. Currently most evidence points towards the use of nary complications. Pulmonary complications included cetuximab in combination with other chemotherapeutic the incidence of symptoms related to the respiratory sys- regimens as the best option for treatment in EGFR positive tem including dyspnea, cough, wheezing, pneumonia, tumors. hypoxemia, respiratory insufficiency/failure, pulmonary embolus, pleural effusion, and non-specific respiratory Epidermal growth factor receptors are ubiquitous, thus disorders. Incidences of these pulmonary complications potential for exuberant reactions including adverse events were obtained from each study's control group if available is high. Moreover, due to the diverse tissues expressing and compared between the patients that received cetuxi- EGRF, adverse reactions manifest in many ways. Although mab and those who did not. Infusion reactions were dermatologic reactions represent the vast majority of treated as a separate complication to cetuximab and were adverse events, occurring in between 3090% of patients not included in this analysis, although in many individu- depending on the severity and study examined [6,7], als, symptoms of shortness of breath and chest tightness many other side effects occur with cetuximab therapy. may be encompassed by this type of reaction [9]. Other adverse events increased above control groups included gastrointestinal complaints (1959%) and head- Data Analysis and Statistics ache (19%) [3]. Cextuximab infusion reactions took place Data is presented as the number of patients and percent- in between 15 and 20% of subjects [3]. age receiving the study medication as well as means (± Page 2 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 Table 1: Studies included in the analysis including first author, year of publication, type of trial and combined therapy, and pulmonary adverse reactions. Number Ref: Author Year Study Type Cancer Type Combined Agents Pulmonary Reactions 1 51 Vermorken 2008 Phase II SCCHN platinum dyspnea, Pneumonia 2 29 Koo 2007 Phase II Colorectal FOLFIRI, irinotecan dyspnea 3 8 Leard 2007 case SCCHN DAD 4 16 Burtness 2005 Phase III SCCHN cisplatin dyspnea, hypoxia 5 15 Bourhis 2006 Phase I/II SCCHN cisplatin, carboplatin/5- respiratory symptoms fluorouracil 6 12 Baselga 2005 Phase II SCCHN platinum respiratory disorder 7 50 Vermorken 2007 review SCCHN cisplatinum, carboplatin dyspnea, infusion rxn 8 20 Cunningham 2004 Prospective Colorectal irinotecan dyspnea 9 53 Xiong 2004 Phase II Pancreatic gemcitabine Pneumonia, Sepsis, PE, Pulm Insufficeincy 10 19 Chan 2005 Phase II Nasopharyngeal carboplatin Pleural Effusion, Dyspnea, Pneumonia 11 40 Robert 2005 Phase I/II NSCLC gemcitibine, carboplatin Pulmonary Embolism 12 23 Hanna 2006 Phase II NSCLC Dyspnea 13 54 Zhu 2007 Phase II HCC Cough 14 31 Machiels 2007 Phase I/II Colorectal capecitabine, ExBR Pulmonary Embolism, Pulm Infetion 15 13 Bonner 2006 RCT SCCHN ExBR cough, increased sputum 16 32 Martin-Martorell 2008 Phase II Colorectal irinotecan none 17 28 Konner 2008 Phase II Ovarian carboplatin, paclitaxel Dyspnea 18 56 Hughes 2008 Phase I/II NSCLC platinum, ExBR 64 Gy dyspnea, pneumonitis, pulm embolism, pneumonia 19 11 Asnacios 2008 Phase II HCC oxaliplatin, gemcitabine none 20 18 Cascinu 2008 Phase II Pancreatic cisplatin, gemcitabine none 21 35 Paule 2007 Phase II Cholangiocarcinoma oxaliplatin, gemcitabine none 22 47 Tabernero 2007 Phase II Colorectal oxaliplatin, 5-fluorouracil Dyspnea 23 27 Jonker 2007 rescue Colorectal prev-oxal, irinotecan, dyspnea flouropyrimidine 24 42 Safran 2008 phase II Espohageal carboplatin, paclitaxel, ExBR Pneumonia 25 26 Ibrahim 2007 phase II Colorectal oxaliplatin, irinotecan none 26 38 Pinto 2007 phase II Gastric/GE irinotecan, 5-fluorouracil none 27 46 Souglakos 2007 phase II Colorectal oxaliplatin, capecitabine none 28 30 Lenz 2006 phase II Colorectal prev-oxaloplatin, irinotecan, none flouropyrimidine 29 25 Hofheinz 2006 phase I Colorectal capecitabine, irinotecan, none ExBR 30 24 Herbst 2005 phase II SCCHN cisplatin none 31 43 Saltz 2004 phase II Colorectal previous irinotecan none 32 52 Vincenzi 2006 phase II Colorectal irinotecan none 33 37 Pfister 2006 phase II SCCHN cisplatin, ExBR pneumonia 34 39 Robert 2001 phase I SCCHN ExBR none 35 48 Thienelt 2005 Phase I/II NSCLC carboplatin, paclitaxel pulmonary embolism 36 34 Neyns 2008 Phase II Colorectal oxaloplatin or irinotecan Interstitial pneumonitis 37 10 Arnold 2008 Phase Ib/II Colorectal oxaliplatin, 5-fluorouracil None 38 45 Sobrero 2008 Phase III Colorectal irinotecan None 39 44 Secord 2008 Phase II Ovarian carboplatin Pulmonary rxn 40 14 Borner 2008 Phase II Colorectal oxaliplatin, capecitabine none 41 21 Gamucci 2008 Phase II Colorectal irinotecan none 42 49 Tol 2008 Phase III Colorectal capecitabine, Oxaliplatin + Pulmonary embolism, Bevacizumab Respiratory Insuffiency 43 17 Butts 2007 Phase II NSCLC gemcitabine, Cisplatin, dyspnea, Cough, Pneumonia Carboplatin 44 36 Pessino 2008 Phase II Colorectal none none 45 5 Rosell 2008 Phase II NSCLC cisplatin, vinorelbine resp symptoms 46 41 Rodel 2008 Phase I/II Colorectal capecitabine, ExBR, none Oxaliplatin 47 33 Modi 2006 Phase I Breast paclitaxel none 48 22 Gebbia 2006 retrospect rev Colorectal irinotecan none Page 3 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 Table 1: Studies included in the analysis including first author, year of publication, type of trial and combined therapy, and pulmonary adverse reactions. (Continued) 49 58 Pirker 2009 Phase III NSCLC cisplatin, vinorelbine dyspnea, respiratory failure, pulmonary embolism 50 57 Belani 2008 Phase II NSCLC carboplatin, docetaxel none 51 55 Gridelli 2009 Phase II NSCLC gemcitibine pulmonary symptoms 52 59 Shin 2001 Phase I SSCHN Cisplatin Shortness of Breath 53 60 Baselga 2000 Phase I SSCHN/NSCLC Cisplatin Dyspnea (Abbreviations: SCCHN squamous cell cancer of the head and neck, NSCLC non-small cell lung cancer, ExBR external beam radiation) SD) where appropriate. Comparisons between groups these studies making up more than 90% of the adverse were made using Chi-Square or students t-test where reactions. appropriate, and statistical significance was set as p < 0.05. Pulmonary adverse events were much more common, as Results would be expected in NSCLC trials with an incidence of Using our search criteria defined above, a total of 245 arti- 18.7% in the cetuximab group versus 12.2% in the control cles were obtained for review. From this complete group, arms (p < 0.001). Similarly, dyspnea made up the major- 192 articles were excluded for not meeting inclusion crite- ity of pulmonary adverse events (13.2% vs 9.2%, p < 0.02) ria. Reasons for exclusion were: non-pulmonary focus with other significant differences occurring in the inci- (dermatologic side effects), duplicate patient populations, dence of pneumonitis (1.1% versus 0.0%, p < 0.001) case reports not relevant to pulmonary side effects, focus being worse in the cetuximab groups. on pharmacokinetics, omission of side effects, or non- cetuximab trials. A total of 53 studies (Table 1) met inclu- For head-neck cancer studies, the overall rates of pulmo- sion and were included in the analysis [5,8,10-60]. nary complications were similar between the cetuximab and control groups (17.9% versus 20.1%, p = NS), but The majority of clinical trials focused on the treatment of favored the cetuximab group. Dyspnea was more com- colorectal cancers with head/neck, lung, and hepatobil- mon in the cetuximab group (8.7%) than the control iary or pancreatic making up the next largest groups group (5%, p < 0.02) in Head and Neck Cancer Trials. (Table 1). Similarly, most of the studies examined were Conversely, there were fewer patients with increased spu- completed as Phase I or II trials with the focus on refrac- tum production (3.0% versus 6.6%, p < 0.01) and cough tory and metastatic disease (Table 2). (4.5% versus 7.8%, p < 0.01) in the control group com- pared to the cetuximab group. From all studies, the differ- A total of 7,411 patients were included in the 53 studies ence in other pulmonary adverse events appears to be reviewed including 4,436 (59.8%) patients who received similar (Table 4). cetuximab either alone or in conjunction with other chemotherapeutic medications or radiation therapy. Discussion 2,596 (41.4%) patients were in the control groups from Overall, cetuximab seems to increase the incidence of these investigations who received the same chemotherapy adverse pulmonary reactions compared to controls, or radiation therapy without cetuximab (Table 3). although the absolute difference between groups is low (<2%). The severity of the pulmonary complications was Pulmonary Reactions not well described in most of the included studies, but did A total of 459 patients (10.3%) in the cetuximab group not increase mortality rates. To the contrary, if survival had adverse pulmonary reactions compared to 221 benefits were not demonstrated, almost universally, there (8.5%) who received standard, non-cetuximab therapy (p was an increase in progression free survival or stability of < 0.02). Studies focusing on colorectal cancer, lung can- malignancy in these trials. To this point, the difference cer, and head-neck cancer had sufficient numbers in both between statistical significance and clinical significance the cetuximab and control groups to compare pulmonary should also be examined in relation to the pulmonary complications; however, hepatobiliary, pancreatic, breast, reactions. For all clinical trials except NSCLC, the differ- ovarian, and cutaneous cancer studies lacked adequate ences in pulmonary adverse events between those treated numbers of control patients to compare these complica- with and without cetuximab are small. Dyspnea and tions. cough, though increased in the cetuximab groups, did not appear to limit the therapeutic course. Colorectal cancer studies demonstrate a low rate of pul- monary complications overall with 3.41% incidence in The observation of increased pulmonary adverse events in the cetuximab group versus 2.56% in the control patients patients with NSCLC when compared to controls was (p = NS). The most common side effect was dyspnea in striking. Again, most of the adverse reactions in these Page 4 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 Table 2: Number and type of trials broken into groups according to cancer type. Trial Type Cancer Type Colorectal NSCLCa Head-Neck HB-Panc Breast-Ov-Skin TOTAL Phase I/II 20 9* 10* 5 3 47 Phase III 2 1 1 0 0 4 Case Series/Review 1 0 1 0 1 3 TOTAL 23 10 12 5 4 53 First-Line 5 2 0 0 2 9 Refractory Disease 18 8* 12* 5 2 44 (NSCLCa nonsmall cell lung cancer, HB-Panc hepatobiliary or pancreatic, Breast-Ov-Skin Breast or Ovarian or Cutaneous). * One study contained patients with either Head-Neck or Non-small cell lung cancer and is displayed in both groups. patients were dyspnea or respiratory insufficiency, and described in the cetuximab package insert, interstitial lung were not noted to be treatment limiting. Although the disease was present before the institution of cetuximab mechanism for increased symptoms in patients with therapy for malignancy. Arguably, the increase in pulmo- NSCLC is not well defined, it is not surprising that those nary symptoms in these patients may have been more a with a site of action in the lung would suffer from exuber- manifestation of ILD progression than as an effect of the ant local effects. Pneumonitis was seen in most patients therapeutic. However, the presence of antecedent paren- (71%) treated with cetuximab in combination with radia- chymal lung disease may abrogate the utility of cetuximab tion therapy for NSCLC, although there was no control in select patients. Pulmonary embolism, also considered a group in this study for comparison [56]. These patients severe reaction, occurred in small numbers of patients in had advanced disease and were treated with a radiation the groups analyzed herein. dose of 64Gy to the lungs, which is well above the thresh- old for pneumonitis with radiation alone[61] As expected, An association between the presence of malignancy in the treatment of head/neck cancers in these trials had high lung, regardless of primary origin, and pulmonary adverse overall rates of pulmonary adverse events, although there events could not be determined from this investigation. were no significant differences between those who Of the 43 non-lung cancer studies included in our series received cetuximab and those who did not. only 9 reported the location of metastatic disease. When combined with studies of lung cancer, 17% of this cohort Severe adverse reactions were not common in clinical tri- reported direct pulmonary involvement of cancer. In als using cetuximab. Interstitial lung disease, cited as a those defining the sites of metastatic foci, the lungs were rare complication in the medication's package insert, was involved in 46.0 ± 10% of patients. Primary or metastatic not described in the clinical trials included in this review involvement of the lung with any cancer could account for with the exception of a case report of two post-lung trans- patients experiencing pulmonary adverse events when plantation patients treated with cetuximab for cutaneous treated with Cetuximab. Unfortunately, a more clear rela- malignancy. Obviously, there are likely confounding fac- tionship is limited by the presentation of the data in the tors which may have predisposed this select population to original studies. the development of diffuse alveolar damage. For those Table 3: Number of patients included by trial type. Cancer Type Studies Included Total Patients Number of Cetuximab with Number of Controls with Cetuximab Pulmonary Reaction Controls Pulmonary Reaction nn n n n n Colorectal 23 3731 2227 76 (3.4) 1367 35 (2.6) Head-Neck 10 1749 1004 173 (17.2) 516 104 (20.2) Lung 10 1664 980 189 (19.6) † 671 82 (12.2) Hepatobiliary/ 5 209 167 9 (5.4) 42 0 (0.0) Pancreatic Breast/Ovarian 3 78 78 10 (12.8) 0 0 (0.0) Cutaneous 1 2 2 2 (100) 0 0 (0.0) TOTAL: 52 7433 4458 459 (10.3) † 2596 221 (8.5) Patients were grouped into those who received cetuximab, either alone or in combination with other therapeutics, and controls (those who did not receive cetuximab). † p < 0.05 compared to control group. * One study contained patients with either Head-Neck or Non-small cell lung cancer and is displayed in both groups. Page 5 of 8 (page number not for citation purposes) Journal of Experimental & Clinical Cancer Research 2009, 28:113 http://www.jeccr.com/content/28/1/113 Table 4: Combined pulmonary adverse events cited in clinical trials. Colorectal Cancer Control Non-Small Cell Lung Cancer Control Head-Neck Cancer Control Cetuximab Cetuximab Cetuximab N (%) N (%) N (%) N (%) N (%) N (%) Dyspnea/RI 70 (3.1) 35 (2.6) 131 (13.4) † 62 (9.2) 87 (8.7) † 26 (5.0) PE 3 (0.1) 0 (0.0) 32 (3.3) 16 (2.4) 0 (0.0) 0 (0.0) Pneumonia 2 (0.1) 0 (0.0) 4 (0.4) 1 (1.2) 13 (1.4) 4 (0.8) ILD 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Cough 0 (0.0) 0 (0.0) 8 (3.4) 3 (3.6) 42 (4.5) † 40 (7.8) Pneumonitis 1 (0.0) 0 (0.0) 17 (1.7) † 0 (0.0) 0 (0.0) 0 (0.0) Pleural Effusion 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (0.3) 0 (0.0) Increased Sputum 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 28 (3.0) † 34 (6.6) TOTAL: 76 (3.4) 35 (2.6) 192 (19.6) † 82 (12.2) 173 (17.9) 104 (20.2) Patients were grouped into those who received cetuximab, either alone or in combination with other therapeutics, and controls (those who did not receive cetuximab). † p < 0.05 compared to control group. Our investigation suffers from several limitations which Abbreviations should be pointed out. First, it is a compilation of clinical ILD: Interstitial lung disease; NSCLC: Non-small cell lung trials, most of which are early phase, with limited num- cancer; SCCHN: Squamous cell cancer/head and neck. bers including control populations available for compari- son of pulmonary adverse events. Most of the studies Competing interests examined only cited positive adverse events, omitting The authors declare that they have no competing interests. negative responses to pulmonary symptom changes. This may lead to an over-estimation of the absolute incidence Authors' contributions of pulmonary-specific complications. Conversely, transfu- JH conceived and designed the study and participated in sion reactions and sepsis which often include symptoms writing. AA participated in data gathering, study screen- such as dyspnea or respiratory insufficiency were not ing, and study coordination. TD participated in data gath- included in the present analysis due to lack of a clear def- ering, study screening, and study coordination. JL inition. There were significant differences in the duration participated in statistical analysis of the study and study of Cetuximab therapy before pulmonary complications design. RW participated in study design and data analysis. were reported in the clinical trials, ranging from 1 week ML performed oversight of study design, coordination, into therapy to more than several months. This also limits and writing. All authors read and approved the final man- the generalizability of the summation data. Finally, uscript. although there appears to be an increase in the incidence of pulmonary adverse events with cetuximab therapy, References 1. Walsh G: Biopharmaceutical benchmarks 2006. Nat Biotechnol- there is no clearly defined causal relationship that can be ogy 2006, 24:769-776. proven as mechanistic understandings are lacking. 2. 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Vermorken JB, Trigo J, Hitt R, Koralewski P, az-Rubio E, Rolland F, Knecht R, Amellal N, Schueler A, Baselga J: Open-label, uncon- peer reviewed and published immediately upon acceptance trolled, multicenter phase II study to evaluate the efficacy cited in PubMed and archived on PubMed Central and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the yours — you keep the copyright head and neck who failed to respond to platinum-based ther- BioMedcentral apy. J Clin Oncol 2007, 25:2171-2177. Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 8 of 8 (page number not for citation purposes)

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Journal of Experimental & Clinical Cancer ResearchSpringer Journals

Published: Aug 14, 2009

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