Adverse reactions to targeted and non-targeted chemotherapeutic drugs with emphasis on hypersensitivity responses and the invasive metastatic switch

Abstract

More than 100 drugs are used to treat the many different cancers. They can be divided into agents with relatively broad, non-targeted specificity and targeted drugs developed on the basis of a more refined understanding of individual cancers and directed at specific molecular targets on different cancer cells. Individual drugs in both groups have been classified on the basis of their mechanism of action in killing cancer cells. The targeted drugs include proteasome inhibitors, toxic chimeric proteins and signal transduction inhibitors such as tyrosine kinase (non-receptor and receptor), serine/threonine kinase, histone deacetylase and mammalian target of rapamycin inhibitors. Increasingly used targeted vascular (VEGF) and platelet-derived endothelial growth factor blockade can provoke a range of pathological consequences. Many of the non-targeted drugs are cytotoxic, suppressing haematopoiesis as well as provoking cutaneous eruptions and vascular, lung and liver injury. Cytotoxic side effects of the targeted drugs occur less often and usually with less severity, but they show their own unusual adverse effects including, for example, a lengthened QT interval, a characteristic papulopustular rash, nail disorders and a hand-foot skin reaction variant. The term hypersensitivity is widely used across a number of disciplines but not always with the same definition in mind, and the terminology needs to be standardised. This is particularly apparent in cancer chemotherapy where anti-neoplastic drug-induced thrombocytopenia, neutropenia, anaemia, vascular disorders, liver injury and lung disease as well as many dermatological manifestations sometimes have an immune basis. The most insidious of all adverse consequences of targeted therapies, however, are tumour adaptation, increased malignancy and the invasive metastatic switch seen with anti-angiogenic drugs that inhibit the VEGF-A pathway. Adverse reactions to 44 non-targeted and 33 targeted, frequently used, chemotherapeutic drugs are presented together with discussions of diagnosis, premedications, desensitizations and importance of understanding the mechanisms underlying the various drug-induced reactions. There is need for wide-ranging acceptance of what constitutes a hypersensitivity reaction and for allergists to be more involved in the diagnosis, treatment and prevention of chemotherapeutic drug-induced hypersensitivity reactions.

Fig. 1

Diagrammatic representation of the aim of signal transduction therapy. Interference with signalling arrests growth of tumour cells irreversibly and promotes apoptosis of many cells. Growth of some normal cells may be arrested, but many retain viability and resume growth once treatment is stopped

Fig. 2

Diagrammatic representation of the proteasome and its role in protein degradation via the ubiquitin–proteasome pathway. Proteins tagged with ubiquitin and unfolded for degradation on the 19S regulatory particles are degraded into small peptide fragments in the 20S catalytic core, a region of β1 caspase-, β2 trypsin- and β5 chymotrypsin-like activities. Ubiquitin molecules are liberated and recycled

Fig. 3

Acral erythema (palmar–plantar erythrodysesthesia; hand–foot syndrome) may manifest as erythema, swelling and desquamation of the palms and soles following treatment with cytotoxic drugs such as capecitabine. Note that acral erythema is a distinct entity from hand–foot skin reaction seen following treatments with some targeted tyrosine kinase inhibitors such as lapatinib, regorafenib, sorafenib (see Fig. 4) and sunitinib [151, 152]. Examples of hand–foot syndrome scored as a severity grade 1. b Grade 2 or moderate severity with characteristic erythema. c Grade 3 severity associated with desquamation, pain and debilitating effects on the patient (reproduced from Son et al. [153], an Open Access article distributed under the terms of the Creative Commons Attribution License)

Fig. 4

Hand–foot skin reaction caused by the multikinase inhibitor sorafenib (compare with Fig. 3). Hyperkeratosis, manifesting as painful yellowish plaques on pressure areas of the soles (b–d) and a defining feature of the condition, usually develops after formation of blisters. The reaction appears to be dose-dependent. The photographs show increasing degrees of severity from grade I (a) to grade II (b) and grade III (c and d) (reproduced with permission from Degen et al. [151])

Fig. 5

Small molecule EGFR tyrosine kinase inhibitors such as erlotinib, gefitinib and sorafenib often provoke characteristic inflammatory papulopustular exanthemas described as acneiform or rosaceaform rashes. These are the most frequently seen cutaneous reactions to these drugs occurring in more than 90 % of patients in the first days–weeks of therapy [152, 154, 155]. The photographs show increasing degrees of severity of rashes based on a scoring system that takes into account colour and distribution of erythema, papulation, pustulation and scaling/crusts: a mild rash; b moderate rash; c severe rash (reproduced from Gerber et al. [154], an Open Access article distributed under the terms of the Creative Commons Attribution License)

Fig. 6

Two-dimensional (a) and three-dimensional CPK space-filling models (b, c) of cilengitide, a cyclic pentapeptide with the structure cyclo(l-arginylglycyl-l-α-aspartyl-d-phenylalanine-N-methyl-l-valyl) (c(RGDf(NMe)V) containing the RGD (Arg-Gly-Asp)-binding motif. Cilengitide is regarded as a promising drug for treatment of glioblastoma and several other tumours. In a and c, the three amino acids of the RGD motif are distinguished by the colours: orange, arginine; blue, glycine and green, aspartic acid. The remaining two amino acids making up the pentapeptide are shown in magenta (phenylalanine) and grey (N-methylated valine). The RGD sequence, the most prominent recognition motif involved in cell adhesion, is also found in fibronectin, fibrinogen, vitronectin and osteopontin each of which bind the pro-angiogenic ανβ3 integrin targeted for cancer therapy. Note that the cilengitide molecule contains the d-isomer of phenylalanine to force adaptation of a βII′ turn in the synthesis of the cyclic peptide and one peptide bond (in the linkage with valine) has been N-methylated to increase the antagonistic activity of the molecule. The guanidino and carboxyl side chain groups of arginine and aspartic acid, respectively, which point in opposite directions may promote ionic interactions with the receptor [291]