REVIEW URRENT C OPINION
Adverse events of targeted therapies Jean A. Klastersky
Purpose of review There is currently an explosion in the number of so-called targeted therapies. As new indications for these agents multiply, there is also an increase of new and less new side-effects. Recent findings Given this rapidly evolving field, any literature on that topic is rapidly obsolete and needs re-evaluation. Summary Targeted therapies are associated with a wide spectrum of adverse events, which cannot always be easily separated from the complications linked to cancer, its therapy, and comorbidities. A high awareness of these events might improve the patient’s quality of life and contribute to the recognition of new syndromes. Keywords adverse events, cancer treatment, supportive care, targeted therapies
INTRODUCTION The development of targeted therapy is extremely fast and concerns a variety of agents as far as structure and mechanisms of action are concerned. It has been linked with novel and less novel sideeffects. A review of the complications linked with the use of targeted therapies is by nature fragmentary and subject to rapid modifications as new agents are used and as experience with older agents increases. An appraisal of these side-effects is also complicated by two additional factors. Firstly, targeted therapies are often used in combination with other anticancer treatments, namely chemotherapy; it is therefore difficult to ascribe a complication to a specific agent. Secondly, these agents are applied, most often, in patients with metastatic disease who have frequent comorbidities related to age, intrinsic illnesses, and multiple medications. Therefore, relatively nonspecific manifestations may be occasionally difficult to recognize and be linked wrongly to the administration of a specific agent. In this review, we attempted to describe the most common side-effects caused by targeted therapies that are in use today [1 ], in a way that might be helpful to the practicing oncologist. We focused on the studies in which the different targeted therapies were used without another concomitant anticancer treatment, in order to try and define specific aspects linked to these agents. We also discussed the sideeffects from a practical standpoint potentially useful to the clinician.
Our approach has obvious limitations as we restricted the analysis to a few recently published studies. Consequently, there is considerable variation in the methodology used in these different investigations. It remains that the evaluation of side-effects, namely those considered possibly associated with a study drug, is relatively well standardized and as reasonably homogeneous among the studies that we have considered. It should also be stressed that, although we tried to review comprehensively the side-effects in all the studies, it is possible that some aspects have been more developed in some studies than in others. We also limited our investigation to one study for each of the targeted therapies, provided it was devoted to a drug used alone (i.e. without another anticancer agent) and published recently. The targeted therapies considered in this review were bevacizumab [2], sorafenib [3], axitinib [3], sunitinib [4], pazopanib [4], aflibercept [5], tivozanib [6], carbozantinib [7], regorafenib [8], vandetanib [9], cetuximab [10], trastuzumab [11–13], panitumumab [11,14], pertuzumab [15], lapatinib [16,17],
&
Institut Jules Bordet, Centre des Tumeurs de l’Universite´ Libre de Bruxelles, Brussels, Belgium Correspondence to Jean A. Klastersky, MD, PhD, Professor and Chief of Medicine (emeritus), Institut Jules Bordet, 1 Rue He´ger-Bordet, 1000 Brussels, Belgium. e-mail: [email protected] Curr Opin Oncol 2014, 26:395–402 DOI:10.1097/CCO.0000000000000096
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KEY POINTS The most common manifestations linked to the administration of targeted therapy are systemic manifestation (fever, arthralgia, etc.), nephrovascular involvement, skin and mucosal toxicity, and digestive side-effects. These manifestations and those which are less common are relatively nonspecific and may be associated not only with the administration of any drug, but also with cancer and other morbid conditions common in patients with advanced cancer. Overall targeted therapies are associated with a wide spectrum of adverse events that are neither very frequent nor severe (with important exceptions) if taken individually, but they can significantly alter the quality of life of the treated patients. A high awareness of the possibility of targeted-therapyrelated adverse effects might improve the supportive approach for the patients and contribute to the recognition of new syndromes.
gefitinib [18], erlotinib [18], crizotinib [19,20], olaparib [21], imatinib [22], vemurafenib [23], vismodegib [24], everolimus [25], ipilimumab [26], and lambrolizumab [27].
MOST COMMON SIDE-EFFECTS WITH TARGETED THERAPIES As indicated in Table 1, we identified four main clinical syndromes associated with the use of targeted therapies and we estimated their relative frequency, as reported from studies not using targeted therapies with other anticancer treatment. The four most common manifestations linked to the administration of targeted therapy were systemic manifestations, nephrovascular involvement, skin and mucosal toxicity, and digestive side-effects.
SYSTEMIC MANIFESTATIONS These manifestations are not specific and may be associated not only with the administration of any drug, but also with cancer and other morbid conditions that are common in patients with advanced cancer. Fatigue or asthenia, a symptom difficult to critically evaluate, was reported for most agents considered here, with the possible exception of trastuzumab and ipilimumab. The overall frequency of fatigue is shown in Table 1; with the exception of erlotinib, it was not severe (grades 3 and 4) in most instances. Other general manifestations such as 396
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arthralgia, myalgia, or headache were also reported in a significant proportion of the patients, but were rarely severe. A series of possible side-effects could not be taken into consideration because of lack of specificity and infrequent reporting; this is the case for cough, dyspnea, chills, insomnia, back pain, dry skin, dry mouth, abdominal distension, dizziness, and gastroesophageal reflux. Other manifestations more likely to be potentially related to targeted therapy were dysphonia, dysgeusia, hypothyroidism, hypoglycemia or hyperglycemia, hypoalbuminemia, hot flushes, muscle spasms, and various other less specific symptoms that were reported with different, but always low, frequencies and were never severe. These miscellaneous aspects will not be further discussed here.
HYPERTENSION AND NEPHROTOXICITY These complications are clearly associated with the administration of agents that have an anti-vascular endothelial growth factor (VEGF) activity such as bevacizumab, sunitinib, sorafenib, and others (see Table 1), but they are rarely observed with the other targeted therapies. Arterial hypertension is the commonest manifestation and although it may be severe occasionally and lead to serious complications (malignant hypertension, posterior reversible leucoencephalopathy, and stroke), it is usually manageable with classical antihypertensives and actually does not interfere often with the main treatment of cancer. Nephrotoxicity, mainly manifested as proteinuria, is neither very frequent nor severe, although serious manifestations such as nephrotic syndrome, renal failure, interstitial nephritis, or thrombotic microangiopathy have been reported.
DIGESTIVE TRACT INVOLVEMENT Digestive tract involvement can be seen with all the agents used for targeted therapy, with diarrhea being the most common manifestation, although it is severe (grade 3 or 4) in relatively few patients. The precise pathophysiological mechanism that is responsible for it is yet unclear. Other less specific digestive complications such as anorexia, nausea, dyspepsia, vomiting, or constipation have also been reported, but are usually relatively mild; in addition, such relatively common manifestations in cancer patients, who are receiving multiple therapies for their neoplasia and comorbid conditions, may be sometimes difficult to ascribe to a single agent. With the agents with an antiangiogenic potential, perforation of the digestive tract has been described although rarely. With ipilimumab and Volume 26 Number 4 July 2014
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63 (19)
55 (11)
67 (7)
29 (3)
63 (16)
28 (4)
24 (6)
9 (0)
Sunitinib
Pazopanib
Aflibercept
Tivozanib
Cabozantinib
Regorafenib
Vandetanib
Cetuximab
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33 (3)
Everolimus
20 (2)
68 (4)
19 (0)
36 (4)
Vismodegib
30 (1)
11 (2)
Vemurafenib
12 (0)
Lambrolizumab
35 (1)
Imatinib
37 (0)
48 (6)
Olaparib
(8)
(7)
32 (1)
30 (3)
28 (2)
19 (2)
15 (3)
Arthralgia/ myalgia
Ipilimumab
60 (30)
27 (2)
30 (6)
Gefitinib
Crizotinib
19 (0)
Lapatinib
Erlotinib
12 (1)
Pertuzumab
Trastuzumab
24 (4)
37 (10)
Axitinib
Panitumumab
20 (4)
28 (4)
Sorafenib
Targeted therapy
Bevacizumab
Fatigue/ asthenia
14 (0)
19 (1)
4 (1)
18 (0)
9 (0)
5 (0)
(4)
(7)
26 (0)
42 (7)
23 (3)
22 (1)
11 (1)
7 (0)
22 (3)
Headache
Systemic manifestations
14 (1)
32 (9)
30 (1)
22 (12)
45 (11)
51 (13)
46 (16)
41 (15)
42 (17)
30 (12)
36 (8)
Hypertension
64 (3)
48 (11)
18 (4)
14 (4)
13 (3)
8 (1)
5 (0)
Proteinuria
Renovascular
2 (1)
70 (1)
32 (1)
46 (1)
" Creatinine
Table 1. Main adverse reactions – % all severity grades and ( ) grades at least 3 and 4
21 (2)
25 (1)
36 (1)
10 (8)
31 (0)
9 (0)
94 (65)
62 (32)
29 ()
19 (0)
64 (5)
18 (12)
45 (4)
18 (1)
23 (1)
13 (1)
31 (4)
10 (3)
Rash and similar
8 (0)
11 (9)
4 (4)
20 (1)
7 (0)
40 (19)
30 (8)
29 (6)
50 (11)
28 (6)
51 (17)
(3)
Hand and foot syndrome
Skin and mucosa
56 (8)
17 (3)
3 (1)
2 (0)
6 (0)
56 (8)
36 (2)
19 (1)
14 (1)
27 (1)
15 (1)
12 (1)
Stomatitis/ mucositis
4 (1)
29 (1)
23 (3)
32 (0)
18 (0)
37 (11)
8 (3)
10 (1)
2 (0)
22 (3)
5 (0)
26 (1)
26 (2)
54 (6)
21 (0)
37 (1)
37 (3)
31 (4)
26 (2)
Anorexia
29 (1)
29 (11)
7 (1)
28 (1)
68 (2)
55 (1)
14 (7)
7 (1)
28 (0)
19 (0)
22 (1)
6 (0)
29 (1)
49 (5)
12 (0)
45 (2)
46 (2)
30 (2)
19 (1)
6 (0)
Nausea/ dyspepsia
14 (1)
3 (1)
16 (3)
31 (2)
47 (1)
18 (0)
7 (1)
18 (2)
6 (0)
14 (1)
28 (4)
2 (0)
28 (2)
27 (3)
18 (1)
13 (0)
Vomiting
Gastrointestinal symptoms
36 (4)
30 (2)
22 (1)
5 (1)
31 (4)
23 (2)
60 (0)
17 (14)
36 (15)
48 (7)
24 (7)
(6)
21 (1)
30 (0)
30 (2)
32 (8)
51 (3)
33 (2)
11 (0)
63 (9)
57 (8)
13 (1)
52 (8)
5 (2)
Diarrhea
Adverse events of targeted therapies Klastersky
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lambrolizumab, colitis because of autoimmune reactions can occur. There is no clear indication that drugs used for targeted therapy are hepatotoxic, although slight elevations of transaminase levels are often reported; however, again, in these multidrug-treated patients, relatively mild biologic alterations may be difficult to be related with the use of a specific agent. Mucositis and stomatitis are relatively frequent with some targeted therapies, namely those targeting epithelial growth factor receptor (EGFR). Most of these manifestations are comparable to those described with conventional anticancer chemotherapy, but novel presentations have been described as well, calling perhaps for further research into their mechanisms, prevention, and therapy. Concomitant radiotherapy with some targeted therapies (e.g. cetuximab) may increase radiotherapy-induced mucositis (and skin reactions, sometimes as ‘recall’ manifestations).
SKIN TOXICITY Targeted therapies against EGFR are often associated with acneiform rashes, but other dermatologic manifestations are also common: xerosis, eczema, telangiectasias, hyperpigmentation, pyogenic granuloma, and others. These manifestations are rarely severe, except with gefitinib and erlotinib. Overall, these skin lesions appear within 1 or 2 weeks after the onset of targeted therapy and usually tend to diminish with time. They may be a surrogate for antitumor effectiveness. These skin lesions require close surveillance as superinfection occurs often and can be very extensive. Local and systemic therapies have now been developed and accepted recommendations should be followed. A peculiar skin manifestation frequently reported with some of the targeted therapies is the so-called ‘hand and foot syndrome’ that can be very incapacitating; it is mainly associated with the anti-VEGF and anti-EGFR drugs. This manifestation is also seen with the administration of chemotherapy namely capecitabine; there is no universally effective prevention or treatment.
LUNG TOXICITY Pulmonary toxicity of targeted therapy is rare overall and may take several clinical features: interstitial pneumonia, hypersensitivity pneumonitis, pleural effusion, or hemoptysis. Once again, these features are not specific for drug-related reactions, and frequent pulmonary infection or pulmonary embolus in the cancer population may be confounding factors. There are no specific diagnostic tests, although 398
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imaging but bronchoalveolar lavage testing may be useful. Most of these drug-associated pneumonias regress once therapy is discontinued and when corticosteroid treatment is initiated. Gefitinib and erlotinib are typically associated with interstitial pneumonitis; imatinib has been linked to pleural effusions; cetuximab and panitumumab can cause asthma and bronchiolitis; bevacizumab has been associated to hemoptysis and pulmonary emboli, especially in squamous cell lung cancer.
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME Posterior reversible encephalopathy syndrome is rare and has been reported mainly in bevacizumabtreated patients, and also with other anti-VEGF agents. It is an acute central nervous system syndrome with headache, confusion, visual disturbances, and seizures. Most patients have an increase in blood pressure from baseline. Usually, the clinical manifestations resolve promptly after withdrawal of the causative agent and normalization of the blood pressure. Clearly, the differential diagnosis encompasses various neoplastic and infectious possibilities.
VISION PROBLEMS Various ophthalmologic complications have been reported: xerophthalmia, blepharitis, conjunctivitis, keratitis, and corneal ulcerations, namely with gefitinib, erlotinib, crizotinib, and vemurafenib. Sudden loss of vision, because of arterial obliteration, has been reported with vemurafenib.
ARTERIAL AND VENOUS THROMBOEMBOLISM An increase of arterial thrombosis, leading mainly to myocardial infarction and stroke, has been associated with the administration of bevacizumab and other anti-VEGF agents. Patients treated with bevacizumab were reported to have also a significantly increased risk of venous thrombophlebitis, although it is well known that cancer itself and cancer chemotherapy predispose to thrombotic events. Excessive bleeding (epistaxis, from digestive or gynecological sources) has been described in 35% of patients receiving bevacizumab, 8% being severe (grade 3 or 4). There are also reports of increased bleeding in patients receiving simultaneously bevacizumab and anticoagulation, although it is difficult to demonstrate a significant aggravating role of the targeted therapy. Volume 26 Number 4 July 2014
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Adverse events of targeted therapies Klastersky
WOUND HEALING VEGF plays an important role in the healing of surgical wounds and the use of bevacizumab (and related agents, presumably) can lead to an increase of wound-healing complications, namely lack of cicatrization, fistulization, necrosis, and bleeding. These complications have been reported in patients undergoing digestive, thoracic, and brain surgery. Although these complications are relatively rare, it is recommended to perform surgery more than 28 days after the last administered dose of bevacizumab, whenever possible.
JAW OSTEONECROSIS In the absence of bisphosphonates or denosumab administration, it has been occasionally reported with bevacizumab, sunitinib, and cabozantinib.
IMMUNE-RELATED ADVERSE EVENTS They are commonly seen with ipilimumab and consist mostly of immune-mediated hepatitis (30%) and immune-mediated enterocolitis (5%). These adverse events are usually reversible within a few weeks and do respond to corticosteroid therapy. No serious sequelae have been reported in most cases. Immune-related rash and pruritus has also been observed with ipilimumab administration (in 20% of the patients), but it is rarely severe. Autoimmune manifestations have also been described with lambrolizumab, namely pneumonitis in 4% of the patients; hypothyroidism in 8% of the patients; and renal failure, potentially immunemediated and responding to glucocorticoid therapy, occurred in some patients.
INFECTION Although neutropenic infection remains a common problem in a substantial proportion of chemotherapy-treated patients, it has not been reported with a significant frequency in those receiving targeted therapies. Nonetheless, the use of several biologics has been associated with an increased risk of infection: the tumor necrosis factor antagonists can cause serious infections with intracellular organisms such as mycobacteria, listeria, fungi, and pneumocystis; B-cell antagonists like rituximab can cause progressive multifocal leucoencephalopathy; and IL-6 antagonists are associated with increased rates of common bacterial infection and eculizumab with meningococcal sepsis [28 ]. As far as the anticancer targeted therapy agents are concerned, no significant excess of infection was &
observed, except for cetuximab and trastuzumab. In a study comparing cetuximab and best supportive care to best supportive care alone, it was found that cetuximab was associated with 13% of nonneutropenic infections, whereas the corresponding rate with best supportive care alone was 5%. In patients with head and neck cancer, there was a 2.3-fold increased risk of infection in patients treated with cetuximab and older patients were at particular risk. In a comparative trial, also in patients with head and neck tumors, a higher comparable increase in the rate of high-grade infections was noted with the use of cetuximab in addition to chemotherapy compared with chemotherapy alone [29]. In patients receiving trastuzumab for breast cancer, it was found that patients receiving trastuzumab had a higher incidence of infection (4%) than those receiving docetaxel alone [30]. Other studies showed a higher rate of infection in the trastuzumab and docetaxel arm compared with the docetaxel alone regimen. Still in two studies, it was found that the addition of trastuzumab to an anthracycline-based chemotherapy resulted in a slight increase of infections. In a very large study (3387 patients), it was found that trastuzumab increased the risk of severe (grades 3 and 4) infections by 2% [31 ]. More recently, it was found that the addition of pertuzumab to trastuzumab increased the risk of neutropenic infection by 2%; the increase was particularly marked in patients from Asia [32]. With respect to bevacizumab, a study in lung cancer patients showed a 6–10% increase in the number of infections. Similarly, in a study of patients with metastatic colorectal cancer, a 5– 20% increase in the rate of infection was reported in the bevacizumab-containing treatment arm. However, the rate of severe infections, in those two studies, was similar with or without bevacizumab and no increased mortality related to infectious complications was noted [33,34]. &
DISCUSSION Our review has clear limitations in terms of methodology; on the other hand, data limited to the targeted therapies used without another anticancer drug are not very frequent and represent an interesting approach. Such information could also be obtained from the data provided by the manufacturers; however, that kind of information is often clouded by the extremely high number of reported side-effects and by a lack of clinical judgment regarding their relative importance. Therefore, our approach, based on the clinical trials published in reputed journals, makes sense from the clinician’s point of view.
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400 Wound healing complications
Venous thrombosis PE
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Olaparib
8
38
IC, intracranial; ILD, interstitial lung disease; Mg, magnesium (serum); MI, myocardial infarction; PE, pulmonary embolus; RPLE, reversible posterior leucoencephalitis.
10
15
4
12
12
68
14
Hyperglycemia
Lambrolizumab
14
18
16
Hypercholesterolemia
30
21
41
78
Immune-related effects
Ipilimumab
Everolimus
2
0
7
Keratoacanthoma skin cancers
51
41
20
Photosensitivity
Vismodegib
69
17
26
36
53
Muscle spasms
Vemurafenib
Imatinib
26
3
0
6
13
Vision disorders
Crizotinib
0
Erlotinib
4
8
ILD
6
12 13
1
Gefitinib
10
Lapatinib
14 10
13
11
Pertuzumab
31
92
17
60
40
Trastuzumab
40
60
Infection
10
5
11
17
# Mg
Panitumumab
49
15
9
18
Infusion problems
Cetuximab
29
12
24
QT prolongation
Vandetanib
Regorafenib
22 29
7
1
Cabozantinib
1
Tivozanib
Aflibercept
26
Epistaxis
36
Peripheral edema
2
Anemia, leucopenia, and thrombocytopenia
4
8 20
" Transaminases
Pazopanib
8
11
Cardiac dysfunction
Sunitinib
28
2 12
1
Dysphonia
1
GI perforation 2
RPLE
2
Hemorrhage IC
4
Dysgeusia
Axitinib
2
Bevacizumab
Hypothyroidism
Sorafenib
Arterial thrombosis MI
Targeted therapy
Table 2. Selected adverse reactions – % with severity at least grades 3 and 4
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Adverse events of targeted therapies Klastersky
Clearly, the spectrum of adverse events reported for targeted therapies is very different from that described for classical anticancer treatments. The two most common complications of cytostatic therapy, that is, neutropenia-related infections and severe emesis, are not common with targeted therapies. As a matter of fact, neutropenic infection is rarely reported, and nonneutropenic infection is a relatively uncommon and mild side-effect with trastuzumab or cetuximab. Severe nausea and vomiting occur in not more than 30% of the patients and are rarely severe (grade 3–4 in 0–4%). We (and others) have identified several main toxicities associated with the use of targeted therapies: systemic inflammatory reactions, nephrovascular complications, skin and mucosal adverse reactions, and gastrointestinal symptoms. As can be seen in Table 1, these toxicities are, to some extent but not entirely, related to the type of class of the targeted therapy drugs. For instance, hypertension and proteinuria are mainly seen with the VEGF-targeting agents, but rarely with others. It remains that other manifestations such as fatigue or asthenia, skin rash, or diarrhea are seen with practically all agents discussed here. Table 1 indicates the relative frequency of the main adverse events and their severity (grades 3 and 4). A general conclusion that can be made at this point is the relatively rare occurrence of severe reactions, as overall, grades 3 and 4 adverse reactions are seen in less than 20% of the patients. In addition, with the exception of severe hypertension, most of these common adverse reactions are not life-threatening. This does not mean, however, that these sideeffects cannot alter significantly the quality of life of the treated patients; clearly, there is a need for effective prevention and optimal treatment for these complications. Data on discontinuation of targeted therapies because of the adverse events were not available for all the agents discussed here; actually, the discontinuation rates ranged from 2 to 20%, with regorafenib, olaparib, and vemurafenib having higher rates of discontinuation. Regarding the selected adverse reactions, as shown in Table 2, there is a wide range of these adverse events, with some clustering in relationship with the class of targeted therapy. As already said, there is not always a clear relationship between the administration of a given drug and a specific adverse event; many of these side-effects can be related to the neoplastic disease and comorbidities and their therapy. Overall, it should be stressed that these complications, with the possible exception of alterations of
hematological parameters or liver function tests, are not very frequent and rarely severe.
CONCLUSION In conclusion, targeted therapies are associated with a wide spectrum of adverse events that are neither very frequent nor severe (with important exceptions) if taken individually, but which can significantly alter the quality of life of the treated patients, especially if several adverse events coexist in a given patient. Obviously, although not evaluated here, adverse events of targeted therapies are made worse by concomitant chemotherapy. A high awareness of the possibility of adverse events in patients treated with targeted therapies might improve these patients’ quality of life and contribute to the recognition of new syndromes. Acknowledgements The efficacious help of Marie-Aline Echterbille for the preparation of this article is fully acknowledged. Conflicts of interest There is no conflict of interest.
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23. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507–2516. 24. Sekulic A, Midgen MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366:2171–2179. 25. Paplomata E, Zelnak A, O’Regan R. Everolimus: side effect profile and management of toxicities in breast cancer. Breast Cancer Res Treat 2013; 140:453–462. 26. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364:2517– 2526. 27. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369:134– 144. 28. Issacs D. Infectious risks associated with biologics. Adv Exp Med Biol 2013; & 764:151–158. A comprehensive review of the topic. 29. Lee CC, Ho HC, Hsiao SH, et al. Infectious complications in head and neck cancer patients treated with cetuximab: propensity score and instrumental variable analysis. PLos One 2012; 7:e50163. 30. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005; 23:4265–4274. 31. Rafailidis PI, Kakisi OK, Vardakas K, et al. Infectious complications of mono& clonal antibodies used in cancer therapy. Cancer 2007; 109:2182–2189. A well documented analysis of the infections associated with monoclonal antibodies. 32. Baselga J, Corte´s J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012; 366:109– 119. 33. Narita Y. Drug review: safety and efficacy of bevacizumab for glioblastoma and other brain tumors. Jpn J Clin Oncol 2013; 43:587–595. 34. Dai F, Shu L, Bian Y, et al. Safety of bevacizumab in treating metastatic colorectal cancer: a systematic review and meta-analysis of all randomized clinical trials. Clin Drug Investig 2013; 33:779–788.
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Adverse events of targeted therapies Jean A. Klastersky
Purpose of review There is currently an explosion in the number of so-called targeted therapies. As new indications for these agents multiply, there is also an increase of new and less new side-effects. Recent findings Given this rapidly evolving field, any literature on that topic is rapidly obsolete and needs re-evaluation. Summary Targeted therapies are associated with a wide spectrum of adverse events, which cannot always be easily separated from the complications linked to cancer, its therapy, and comorbidities. A high awareness of these events might improve the patient’s quality of life and contribute to the recognition of new syndromes. Keywords adverse events, cancer treatment, supportive care, targeted therapies
INTRODUCTION The development of targeted therapy is extremely fast and concerns a variety of agents as far as structure and mechanisms of action are concerned. It has been linked with novel and less novel sideeffects. A review of the complications linked with the use of targeted therapies is by nature fragmentary and subject to rapid modifications as new agents are used and as experience with older agents increases. An appraisal of these side-effects is also complicated by two additional factors. Firstly, targeted therapies are often used in combination with other anticancer treatments, namely chemotherapy; it is therefore difficult to ascribe a complication to a specific agent. Secondly, these agents are applied, most often, in patients with metastatic disease who have frequent comorbidities related to age, intrinsic illnesses, and multiple medications. Therefore, relatively nonspecific manifestations may be occasionally difficult to recognize and be linked wrongly to the administration of a specific agent. In this review, we attempted to describe the most common side-effects caused by targeted therapies that are in use today [1 ], in a way that might be helpful to the practicing oncologist. We focused on the studies in which the different targeted therapies were used without another concomitant anticancer treatment, in order to try and define specific aspects linked to these agents. We also discussed the sideeffects from a practical standpoint potentially useful to the clinician.
Our approach has obvious limitations as we restricted the analysis to a few recently published studies. Consequently, there is considerable variation in the methodology used in these different investigations. It remains that the evaluation of side-effects, namely those considered possibly associated with a study drug, is relatively well standardized and as reasonably homogeneous among the studies that we have considered. It should also be stressed that, although we tried to review comprehensively the side-effects in all the studies, it is possible that some aspects have been more developed in some studies than in others. We also limited our investigation to one study for each of the targeted therapies, provided it was devoted to a drug used alone (i.e. without another anticancer agent) and published recently. The targeted therapies considered in this review were bevacizumab [2], sorafenib [3], axitinib [3], sunitinib [4], pazopanib [4], aflibercept [5], tivozanib [6], carbozantinib [7], regorafenib [8], vandetanib [9], cetuximab [10], trastuzumab [11–13], panitumumab [11,14], pertuzumab [15], lapatinib [16,17],
&
Institut Jules Bordet, Centre des Tumeurs de l’Universite´ Libre de Bruxelles, Brussels, Belgium Correspondence to Jean A. Klastersky, MD, PhD, Professor and Chief of Medicine (emeritus), Institut Jules Bordet, 1 Rue He´ger-Bordet, 1000 Brussels, Belgium. e-mail: [email protected] Curr Opin Oncol 2014, 26:395–402 DOI:10.1097/CCO.0000000000000096
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Supportive care
KEY POINTS The most common manifestations linked to the administration of targeted therapy are systemic manifestation (fever, arthralgia, etc.), nephrovascular involvement, skin and mucosal toxicity, and digestive side-effects. These manifestations and those which are less common are relatively nonspecific and may be associated not only with the administration of any drug, but also with cancer and other morbid conditions common in patients with advanced cancer. Overall targeted therapies are associated with a wide spectrum of adverse events that are neither very frequent nor severe (with important exceptions) if taken individually, but they can significantly alter the quality of life of the treated patients. A high awareness of the possibility of targeted-therapyrelated adverse effects might improve the supportive approach for the patients and contribute to the recognition of new syndromes.
gefitinib [18], erlotinib [18], crizotinib [19,20], olaparib [21], imatinib [22], vemurafenib [23], vismodegib [24], everolimus [25], ipilimumab [26], and lambrolizumab [27].
MOST COMMON SIDE-EFFECTS WITH TARGETED THERAPIES As indicated in Table 1, we identified four main clinical syndromes associated with the use of targeted therapies and we estimated their relative frequency, as reported from studies not using targeted therapies with other anticancer treatment. The four most common manifestations linked to the administration of targeted therapy were systemic manifestations, nephrovascular involvement, skin and mucosal toxicity, and digestive side-effects.
SYSTEMIC MANIFESTATIONS These manifestations are not specific and may be associated not only with the administration of any drug, but also with cancer and other morbid conditions that are common in patients with advanced cancer. Fatigue or asthenia, a symptom difficult to critically evaluate, was reported for most agents considered here, with the possible exception of trastuzumab and ipilimumab. The overall frequency of fatigue is shown in Table 1; with the exception of erlotinib, it was not severe (grades 3 and 4) in most instances. Other general manifestations such as 396
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arthralgia, myalgia, or headache were also reported in a significant proportion of the patients, but were rarely severe. A series of possible side-effects could not be taken into consideration because of lack of specificity and infrequent reporting; this is the case for cough, dyspnea, chills, insomnia, back pain, dry skin, dry mouth, abdominal distension, dizziness, and gastroesophageal reflux. Other manifestations more likely to be potentially related to targeted therapy were dysphonia, dysgeusia, hypothyroidism, hypoglycemia or hyperglycemia, hypoalbuminemia, hot flushes, muscle spasms, and various other less specific symptoms that were reported with different, but always low, frequencies and were never severe. These miscellaneous aspects will not be further discussed here.
HYPERTENSION AND NEPHROTOXICITY These complications are clearly associated with the administration of agents that have an anti-vascular endothelial growth factor (VEGF) activity such as bevacizumab, sunitinib, sorafenib, and others (see Table 1), but they are rarely observed with the other targeted therapies. Arterial hypertension is the commonest manifestation and although it may be severe occasionally and lead to serious complications (malignant hypertension, posterior reversible leucoencephalopathy, and stroke), it is usually manageable with classical antihypertensives and actually does not interfere often with the main treatment of cancer. Nephrotoxicity, mainly manifested as proteinuria, is neither very frequent nor severe, although serious manifestations such as nephrotic syndrome, renal failure, interstitial nephritis, or thrombotic microangiopathy have been reported.
DIGESTIVE TRACT INVOLVEMENT Digestive tract involvement can be seen with all the agents used for targeted therapy, with diarrhea being the most common manifestation, although it is severe (grade 3 or 4) in relatively few patients. The precise pathophysiological mechanism that is responsible for it is yet unclear. Other less specific digestive complications such as anorexia, nausea, dyspepsia, vomiting, or constipation have also been reported, but are usually relatively mild; in addition, such relatively common manifestations in cancer patients, who are receiving multiple therapies for their neoplasia and comorbid conditions, may be sometimes difficult to ascribe to a single agent. With the agents with an antiangiogenic potential, perforation of the digestive tract has been described although rarely. With ipilimumab and Volume 26 Number 4 July 2014
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63 (19)
55 (11)
67 (7)
29 (3)
63 (16)
28 (4)
24 (6)
9 (0)
Sunitinib
Pazopanib
Aflibercept
Tivozanib
Cabozantinib
Regorafenib
Vandetanib
Cetuximab
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33 (3)
Everolimus
20 (2)
68 (4)
19 (0)
36 (4)
Vismodegib
30 (1)
11 (2)
Vemurafenib
12 (0)
Lambrolizumab
35 (1)
Imatinib
37 (0)
48 (6)
Olaparib
(8)
(7)
32 (1)
30 (3)
28 (2)
19 (2)
15 (3)
Arthralgia/ myalgia
Ipilimumab
60 (30)
27 (2)
30 (6)
Gefitinib
Crizotinib
19 (0)
Lapatinib
Erlotinib
12 (1)
Pertuzumab
Trastuzumab
24 (4)
37 (10)
Axitinib
Panitumumab
20 (4)
28 (4)
Sorafenib
Targeted therapy
Bevacizumab
Fatigue/ asthenia
14 (0)
19 (1)
4 (1)
18 (0)
9 (0)
5 (0)
(4)
(7)
26 (0)
42 (7)
23 (3)
22 (1)
11 (1)
7 (0)
22 (3)
Headache
Systemic manifestations
14 (1)
32 (9)
30 (1)
22 (12)
45 (11)
51 (13)
46 (16)
41 (15)
42 (17)
30 (12)
36 (8)
Hypertension
64 (3)
48 (11)
18 (4)
14 (4)
13 (3)
8 (1)
5 (0)
Proteinuria
Renovascular
2 (1)
70 (1)
32 (1)
46 (1)
" Creatinine
Table 1. Main adverse reactions – % all severity grades and ( ) grades at least 3 and 4
21 (2)
25 (1)
36 (1)
10 (8)
31 (0)
9 (0)
94 (65)
62 (32)
29 ()
19 (0)
64 (5)
18 (12)
45 (4)
18 (1)
23 (1)
13 (1)
31 (4)
10 (3)
Rash and similar
8 (0)
11 (9)
4 (4)
20 (1)
7 (0)
40 (19)
30 (8)
29 (6)
50 (11)
28 (6)
51 (17)
(3)
Hand and foot syndrome
Skin and mucosa
56 (8)
17 (3)
3 (1)
2 (0)
6 (0)
56 (8)
36 (2)
19 (1)
14 (1)
27 (1)
15 (1)
12 (1)
Stomatitis/ mucositis
4 (1)
29 (1)
23 (3)
32 (0)
18 (0)
37 (11)
8 (3)
10 (1)
2 (0)
22 (3)
5 (0)
26 (1)
26 (2)
54 (6)
21 (0)
37 (1)
37 (3)
31 (4)
26 (2)
Anorexia
29 (1)
29 (11)
7 (1)
28 (1)
68 (2)
55 (1)
14 (7)
7 (1)
28 (0)
19 (0)
22 (1)
6 (0)
29 (1)
49 (5)
12 (0)
45 (2)
46 (2)
30 (2)
19 (1)
6 (0)
Nausea/ dyspepsia
14 (1)
3 (1)
16 (3)
31 (2)
47 (1)
18 (0)
7 (1)
18 (2)
6 (0)
14 (1)
28 (4)
2 (0)
28 (2)
27 (3)
18 (1)
13 (0)
Vomiting
Gastrointestinal symptoms
36 (4)
30 (2)
22 (1)
5 (1)
31 (4)
23 (2)
60 (0)
17 (14)
36 (15)
48 (7)
24 (7)
(6)
21 (1)
30 (0)
30 (2)
32 (8)
51 (3)
33 (2)
11 (0)
63 (9)
57 (8)
13 (1)
52 (8)
5 (2)
Diarrhea
Adverse events of targeted therapies Klastersky
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Supportive care
lambrolizumab, colitis because of autoimmune reactions can occur. There is no clear indication that drugs used for targeted therapy are hepatotoxic, although slight elevations of transaminase levels are often reported; however, again, in these multidrug-treated patients, relatively mild biologic alterations may be difficult to be related with the use of a specific agent. Mucositis and stomatitis are relatively frequent with some targeted therapies, namely those targeting epithelial growth factor receptor (EGFR). Most of these manifestations are comparable to those described with conventional anticancer chemotherapy, but novel presentations have been described as well, calling perhaps for further research into their mechanisms, prevention, and therapy. Concomitant radiotherapy with some targeted therapies (e.g. cetuximab) may increase radiotherapy-induced mucositis (and skin reactions, sometimes as ‘recall’ manifestations).
SKIN TOXICITY Targeted therapies against EGFR are often associated with acneiform rashes, but other dermatologic manifestations are also common: xerosis, eczema, telangiectasias, hyperpigmentation, pyogenic granuloma, and others. These manifestations are rarely severe, except with gefitinib and erlotinib. Overall, these skin lesions appear within 1 or 2 weeks after the onset of targeted therapy and usually tend to diminish with time. They may be a surrogate for antitumor effectiveness. These skin lesions require close surveillance as superinfection occurs often and can be very extensive. Local and systemic therapies have now been developed and accepted recommendations should be followed. A peculiar skin manifestation frequently reported with some of the targeted therapies is the so-called ‘hand and foot syndrome’ that can be very incapacitating; it is mainly associated with the anti-VEGF and anti-EGFR drugs. This manifestation is also seen with the administration of chemotherapy namely capecitabine; there is no universally effective prevention or treatment.
LUNG TOXICITY Pulmonary toxicity of targeted therapy is rare overall and may take several clinical features: interstitial pneumonia, hypersensitivity pneumonitis, pleural effusion, or hemoptysis. Once again, these features are not specific for drug-related reactions, and frequent pulmonary infection or pulmonary embolus in the cancer population may be confounding factors. There are no specific diagnostic tests, although 398
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imaging but bronchoalveolar lavage testing may be useful. Most of these drug-associated pneumonias regress once therapy is discontinued and when corticosteroid treatment is initiated. Gefitinib and erlotinib are typically associated with interstitial pneumonitis; imatinib has been linked to pleural effusions; cetuximab and panitumumab can cause asthma and bronchiolitis; bevacizumab has been associated to hemoptysis and pulmonary emboli, especially in squamous cell lung cancer.
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME Posterior reversible encephalopathy syndrome is rare and has been reported mainly in bevacizumabtreated patients, and also with other anti-VEGF agents. It is an acute central nervous system syndrome with headache, confusion, visual disturbances, and seizures. Most patients have an increase in blood pressure from baseline. Usually, the clinical manifestations resolve promptly after withdrawal of the causative agent and normalization of the blood pressure. Clearly, the differential diagnosis encompasses various neoplastic and infectious possibilities.
VISION PROBLEMS Various ophthalmologic complications have been reported: xerophthalmia, blepharitis, conjunctivitis, keratitis, and corneal ulcerations, namely with gefitinib, erlotinib, crizotinib, and vemurafenib. Sudden loss of vision, because of arterial obliteration, has been reported with vemurafenib.
ARTERIAL AND VENOUS THROMBOEMBOLISM An increase of arterial thrombosis, leading mainly to myocardial infarction and stroke, has been associated with the administration of bevacizumab and other anti-VEGF agents. Patients treated with bevacizumab were reported to have also a significantly increased risk of venous thrombophlebitis, although it is well known that cancer itself and cancer chemotherapy predispose to thrombotic events. Excessive bleeding (epistaxis, from digestive or gynecological sources) has been described in 35% of patients receiving bevacizumab, 8% being severe (grade 3 or 4). There are also reports of increased bleeding in patients receiving simultaneously bevacizumab and anticoagulation, although it is difficult to demonstrate a significant aggravating role of the targeted therapy. Volume 26 Number 4 July 2014
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Adverse events of targeted therapies Klastersky
WOUND HEALING VEGF plays an important role in the healing of surgical wounds and the use of bevacizumab (and related agents, presumably) can lead to an increase of wound-healing complications, namely lack of cicatrization, fistulization, necrosis, and bleeding. These complications have been reported in patients undergoing digestive, thoracic, and brain surgery. Although these complications are relatively rare, it is recommended to perform surgery more than 28 days after the last administered dose of bevacizumab, whenever possible.
JAW OSTEONECROSIS In the absence of bisphosphonates or denosumab administration, it has been occasionally reported with bevacizumab, sunitinib, and cabozantinib.
IMMUNE-RELATED ADVERSE EVENTS They are commonly seen with ipilimumab and consist mostly of immune-mediated hepatitis (30%) and immune-mediated enterocolitis (5%). These adverse events are usually reversible within a few weeks and do respond to corticosteroid therapy. No serious sequelae have been reported in most cases. Immune-related rash and pruritus has also been observed with ipilimumab administration (in 20% of the patients), but it is rarely severe. Autoimmune manifestations have also been described with lambrolizumab, namely pneumonitis in 4% of the patients; hypothyroidism in 8% of the patients; and renal failure, potentially immunemediated and responding to glucocorticoid therapy, occurred in some patients.
INFECTION Although neutropenic infection remains a common problem in a substantial proportion of chemotherapy-treated patients, it has not been reported with a significant frequency in those receiving targeted therapies. Nonetheless, the use of several biologics has been associated with an increased risk of infection: the tumor necrosis factor antagonists can cause serious infections with intracellular organisms such as mycobacteria, listeria, fungi, and pneumocystis; B-cell antagonists like rituximab can cause progressive multifocal leucoencephalopathy; and IL-6 antagonists are associated with increased rates of common bacterial infection and eculizumab with meningococcal sepsis [28 ]. As far as the anticancer targeted therapy agents are concerned, no significant excess of infection was &
observed, except for cetuximab and trastuzumab. In a study comparing cetuximab and best supportive care to best supportive care alone, it was found that cetuximab was associated with 13% of nonneutropenic infections, whereas the corresponding rate with best supportive care alone was 5%. In patients with head and neck cancer, there was a 2.3-fold increased risk of infection in patients treated with cetuximab and older patients were at particular risk. In a comparative trial, also in patients with head and neck tumors, a higher comparable increase in the rate of high-grade infections was noted with the use of cetuximab in addition to chemotherapy compared with chemotherapy alone [29]. In patients receiving trastuzumab for breast cancer, it was found that patients receiving trastuzumab had a higher incidence of infection (4%) than those receiving docetaxel alone [30]. Other studies showed a higher rate of infection in the trastuzumab and docetaxel arm compared with the docetaxel alone regimen. Still in two studies, it was found that the addition of trastuzumab to an anthracycline-based chemotherapy resulted in a slight increase of infections. In a very large study (3387 patients), it was found that trastuzumab increased the risk of severe (grades 3 and 4) infections by 2% [31 ]. More recently, it was found that the addition of pertuzumab to trastuzumab increased the risk of neutropenic infection by 2%; the increase was particularly marked in patients from Asia [32]. With respect to bevacizumab, a study in lung cancer patients showed a 6–10% increase in the number of infections. Similarly, in a study of patients with metastatic colorectal cancer, a 5– 20% increase in the rate of infection was reported in the bevacizumab-containing treatment arm. However, the rate of severe infections, in those two studies, was similar with or without bevacizumab and no increased mortality related to infectious complications was noted [33,34]. &
DISCUSSION Our review has clear limitations in terms of methodology; on the other hand, data limited to the targeted therapies used without another anticancer drug are not very frequent and represent an interesting approach. Such information could also be obtained from the data provided by the manufacturers; however, that kind of information is often clouded by the extremely high number of reported side-effects and by a lack of clinical judgment regarding their relative importance. Therefore, our approach, based on the clinical trials published in reputed journals, makes sense from the clinician’s point of view.
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400 Wound healing complications
Venous thrombosis PE
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Olaparib
8
38
IC, intracranial; ILD, interstitial lung disease; Mg, magnesium (serum); MI, myocardial infarction; PE, pulmonary embolus; RPLE, reversible posterior leucoencephalitis.
10
15
4
12
12
68
14
Hyperglycemia
Lambrolizumab
14
18
16
Hypercholesterolemia
30
21
41
78
Immune-related effects
Ipilimumab
Everolimus
2
0
7
Keratoacanthoma skin cancers
51
41
20
Photosensitivity
Vismodegib
69
17
26
36
53
Muscle spasms
Vemurafenib
Imatinib
26
3
0
6
13
Vision disorders
Crizotinib
0
Erlotinib
4
8
ILD
6
12 13
1
Gefitinib
10
Lapatinib
14 10
13
11
Pertuzumab
31
92
17
60
40
Trastuzumab
40
60
Infection
10
5
11
17
# Mg
Panitumumab
49
15
9
18
Infusion problems
Cetuximab
29
12
24
QT prolongation
Vandetanib
Regorafenib
22 29
7
1
Cabozantinib
1
Tivozanib
Aflibercept
26
Epistaxis
36
Peripheral edema
2
Anemia, leucopenia, and thrombocytopenia
4
8 20
" Transaminases
Pazopanib
8
11
Cardiac dysfunction
Sunitinib
28
2 12
1
Dysphonia
1
GI perforation 2
RPLE
2
Hemorrhage IC
4
Dysgeusia
Axitinib
2
Bevacizumab
Hypothyroidism
Sorafenib
Arterial thrombosis MI
Targeted therapy
Table 2. Selected adverse reactions – % with severity at least grades 3 and 4
Supportive care
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Adverse events of targeted therapies Klastersky
Clearly, the spectrum of adverse events reported for targeted therapies is very different from that described for classical anticancer treatments. The two most common complications of cytostatic therapy, that is, neutropenia-related infections and severe emesis, are not common with targeted therapies. As a matter of fact, neutropenic infection is rarely reported, and nonneutropenic infection is a relatively uncommon and mild side-effect with trastuzumab or cetuximab. Severe nausea and vomiting occur in not more than 30% of the patients and are rarely severe (grade 3–4 in 0–4%). We (and others) have identified several main toxicities associated with the use of targeted therapies: systemic inflammatory reactions, nephrovascular complications, skin and mucosal adverse reactions, and gastrointestinal symptoms. As can be seen in Table 1, these toxicities are, to some extent but not entirely, related to the type of class of the targeted therapy drugs. For instance, hypertension and proteinuria are mainly seen with the VEGF-targeting agents, but rarely with others. It remains that other manifestations such as fatigue or asthenia, skin rash, or diarrhea are seen with practically all agents discussed here. Table 1 indicates the relative frequency of the main adverse events and their severity (grades 3 and 4). A general conclusion that can be made at this point is the relatively rare occurrence of severe reactions, as overall, grades 3 and 4 adverse reactions are seen in less than 20% of the patients. In addition, with the exception of severe hypertension, most of these common adverse reactions are not life-threatening. This does not mean, however, that these sideeffects cannot alter significantly the quality of life of the treated patients; clearly, there is a need for effective prevention and optimal treatment for these complications. Data on discontinuation of targeted therapies because of the adverse events were not available for all the agents discussed here; actually, the discontinuation rates ranged from 2 to 20%, with regorafenib, olaparib, and vemurafenib having higher rates of discontinuation. Regarding the selected adverse reactions, as shown in Table 2, there is a wide range of these adverse events, with some clustering in relationship with the class of targeted therapy. As already said, there is not always a clear relationship between the administration of a given drug and a specific adverse event; many of these side-effects can be related to the neoplastic disease and comorbidities and their therapy. Overall, it should be stressed that these complications, with the possible exception of alterations of
hematological parameters or liver function tests, are not very frequent and rarely severe.
CONCLUSION In conclusion, targeted therapies are associated with a wide spectrum of adverse events that are neither very frequent nor severe (with important exceptions) if taken individually, but which can significantly alter the quality of life of the treated patients, especially if several adverse events coexist in a given patient. Obviously, although not evaluated here, adverse events of targeted therapies are made worse by concomitant chemotherapy. A high awareness of the possibility of adverse events in patients treated with targeted therapies might improve these patients’ quality of life and contribute to the recognition of new syndromes. Acknowledgements The efficacious help of Marie-Aline Echterbille for the preparation of this article is fully acknowledged. Conflicts of interest There is no conflict of interest.
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Volume 26 Number 4 July 2014
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