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.

inhibitor effects on the epidermal growth factor receptor (EGFR). Cetuximab has been extensively studied and approved [3] 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 [3]. 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) [4]. Over expression or increased activity of EGFR as seen in some mutations can result malignancy [4].
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 [3]. 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 [5]. 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 3090% 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 (1959%) and headache (19%) [3]. Cextuximab infusion reactions took place in between 15 and 20% of subjects [3].
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 [3]. There have also been reports of interstitial pneumonitis with non-cardiogenic pulmonary edema [8]. 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.

Methods
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 [9].

Data Analysis and Statistics
Data is presented as the number of patients and percentage receiving the study medication as well as means (±

Results
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 noncetuximab trials. A total of 53 studies (Table 1) met inclusion and were included in the analysis [5,8,.
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).

Pulmonary Reactions
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).

Discussion
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.  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 [56]. 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 [61] 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. 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. 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.

Conclusion
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.

Competing interests
The authors declare that they have no competing interests.

Authors' contributions
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.  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.