Open Access

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

  • Jeffrey B Hoag1, 2Email author,
  • Aimel Azizi2,
  • Timothy J Doherty2,
  • Jason Lu2,
  • Rudolph E Willis1 and
  • Mark E Lund1, 2
Journal of Experimental & Clinical Cancer Research200928:113

DOI: 10.1186/1756-9966-28-113

Received: 26 June 2009

Accepted: 14 August 2009

Published: 14 August 2009

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.

Background

Biological 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 [1]. Over the last 5 years, more than 20% of the compounds approved by United States regulatory authorities were biologics [2]. 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 [2].

Cetuximab (Erbitux®)

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 [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 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%) [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 (± 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.

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 non-cetuximab trials. A total of 53 studies (Table 1) met inclusion and were included in the analysis [5, 8, 1060].
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-fluorouracil

respiratory symptoms

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, flouropyrimidine

dyspnea

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, flouropyrimidine

none

29

25

Hofheinz

2006

phase I

Colorectal

capecitabine, irinotecan, ExBR

none

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 + Bevacizumab

Pulmonary embolism, Respiratory Insuffiency

43

17

Butts

2007

Phase II

NSCLC

gemcitabine, Cisplatin, Carboplatin

dyspnea, Cough, Pneumonia

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, Oxaliplatin

none

47

33

Modi

2006

Phase I

Breast

paclitaxel

none

48

22

Gebbia

2006

retrospect rev

Colorectal

irinotecan

none

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)

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).
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.

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).
Table 3

Number of patients included by trial type.

Cancer Type

Studies Included

Total Patients

Number of Cetuximab

Cetuximab with Pulmonary Reaction

Number of Controls

Controls with Pulmonary Reaction

 

n

n

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/Pancreatic

5

209

167

9 (5.4)

42

0 (0.0)

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.

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).
Table 4

Combined pulmonary adverse events cited in clinical trials.

 

Colorectal Cancer Cetuximab

Control

Non-Small Cell Lung Cancer Cetuximab

Control

Head-Neck Cancer Cetuximab

Control

 

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.

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.

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 [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.

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.

Abbreviations

ILD: 

Interstitial lung disease

NSCLC: 

Non-small cell lung cancer

SCCHN: 

Squamous cell cancer/head and neck.

Declarations

Authors’ Affiliations

(1)
Cancer Treatment Centers of America, Eastern Regional Medical Center
(2)
Drexel University College of Medicine

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