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Page 62 Olivera et al. Cancer Drug Resist 2019;2:53-68 I http://dx.doi.org/10.20517/cdr.2018.25

Guidelines from other professional societies
Cisplatin is one of the most efficacious chemotherapeutic agent in pediatrics, widely used in the treatment
of diverse solid tumors such as neuroblastoma, hepatoblastoma, brain tumors, osteosarcoma and germ
[45]
cell tumors . One of the most important complications of this drug is its risk of ototoxicity that produces
[46]
permanent bilateral audition loss in 26% to 90% of the children treated and 10%-25% of adults .
There are several studies that suggest that genetic factors may be involved in ototoxicity, although the results
are contradictory and scarce in children . Studies of gene variants are related to the cytotoxic effect of
[47]
cisplatin, where genes such as GSTP1, SOD2 (rs4880), XPC (rs2228001), XPD (rs1799793), or genes related to
transport are involved such as SLC family (rs4788863) [48-52] .

Currently there are no CPIC nor DPWG guidelines for this drug. However, CPNDS has published a guide
[15]
relating cisplatin ototoxicity with TPMT variants , even if the works they refer to are controversial [53-56] .
The CPNDS elaborated a guide with recommendations based on the levels of classification for clinical
practice. Level A corresponds to high level of evidence (benefits clearly overcome the risks); level B is
a recommendation with lower scientific evidence level based on expert opinion; and level C is mainly
based in experts opinion to be used in research context. This guide recommends with level A to perform
pharmacogenetics tests in pediatric patients with variants *2, *3A, *3B and *3C related with reduced
enzyme activity and audition loss [54,55,57-59] . There are recommendations with evidence level C such as the
consideration to use otoprotectors in those patients with non-functional variants. Also, the prescription
of an alternative treatment when presenting the same efficacy, low toxicity and less ototoxicity [60,61] . More
frequent monitoring and tracing audiometric control after treatment are also recommended. The impact of
these variants related with audition loss is unknown in adult patients [62,63] .

There is also a document for doxorubicin. Anthracyclines, as doxorubicin, are among the most effective
[64]
anticancer treatments, with survival rates over 80% in some kinds of cancer . They are employed in the
treatment of children and adults’ leukemia, lymphoma and some solid tumors such as breast cancer, ovarian
cancer, lung cancer and sarcomas. They act by blocking the synthesis of DNA and RNA by inhibiting
topoisomerase II enzyme, thus interrupting DNA replication and transcription and, hence, the replication
of cancer cells. Anthracyclines also damage the DNA, proteins and membranes of rapid division cells by
creating free oxygen radicals mediated by iron [65,66] .

The clinical use of anthracyclines is mainly limited by the high inter-individual variability in anthracycline-
induced cardiotoxicity (ACT) which is dependent on the cumulative dose of the drug and produces toxic
effects on heart muscles and their conductivity. ACT occurs in 57% of patients treated and is still an
important limitation of chemotherapy based on anthracyclines [67,68] .

[69]
There is a guide for doxorubicin elaborated by the CPNDS in which it is recommended to perform a
pharmacogenetic test for the variants rs2229774 (G> A) in the gene RARG and rs17863783 (G> T) in the
UGT1A6*4, considered of high risk for developing ACT and the variant rs7853758 in the SLC28A3 gene
whose allele A is associated with a reduced risk of ACT [68,70] . This allows a stratification of the patients:
low-risk patients are recommended a routine echocardiogram and according to the long-term follow-up
guidelines of the Children’s Oncology Group (COG), a cardiac follow-up every 5 years . For patients at
[71]
moderate risk, an increase in the frequency of echocardiograms is recommended, such as the monitoring of
cardiotoxicity and, according to the COG, a follow-up every 2 years [71,72] . Finally, for high-risk patients, the
following recommendations should be considered: the increase in the frequency of annual echocardiograms
and monitoring before each administration of anthracyclines as well as the follow-up recommended
[71]
by the COG guidelines ; as well as the “aggressive” detection and the examination of risk factors such