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De Mattia et al. Cancer Drug Resist 2019;2:116-30 I http://dx.doi.org/10.20517/cdr.2019.04 Page 117

INTRODUCTION
The development of adverse drug reactions related to a pharmacological treatment is a pivotal phenomenon
burdening patients quality of life as well as the national health systems for the related economical expenses.
Adverse drug reactions were reported to account for about 5% of all the hospital admissions in the UK in
[1]
2004 with an economic burden of about half a billion of pounds every year. About a 0.3% rate of adverse
[2]
drug reactions were estimated to lead to patients death accounting for 100,000 death annually in the US ,
[1]
similarly to the UK . Other Europe-based studies reported an estimate of 1,058 billion Euros per year as
the estimated economic burden related to the hospital costs required to manage adverse drug reaction in
[3]
Germany ; and 21 million dollars per year every 100,000 adult inhabitants in Sweden .
[4]
When the attention is focused on the adverse drug reactions related to cancer therapy, these numbers
dramatically increase. A revision of the adverse events occurred after one drug administration in more
than 4,000 colorectal cancer (CRC) patients treated in the US in 2016 pointed out that more than 90% of the
[5]
patients developed at least one toxic event of any grade of severity with a significant economic burden .
The backbone of the pharmacological treatment of CRC patients is still represented by fluoropyrimidines
(FP) [i.e., 5-fluorouracil (5-FU) and capecitabine], that have been used for more than 50 years in several
combination regimens (mainly for the treatment of the advanced disease) or in monotherapy (in neo-
adjuvant and early tumor stage adjuvant patients) in all the disease stages. FP are used not only in the
treatment of CRC but also in a wide range of solid tumors including breast, head and neck and gastric
cancer. Adverse drug reactions related to the use of FP are quite common, becoming very severe or even
[6,7]
life-threatening in 10%-26% of treated patients . In a significant minority (3%-5%) of patients, early, severe
[8]
side effects occur even with conventional moderate doses of the drug . The most frequently reported severe
adverse events linked to the FP administration, both for the metastatic disease and in the adjuvant setting,
are hematologic (neutropenia in the 40%-56% of patients) and gastrointestinal (diarrhea in the 10%-15% of
patients). Occurrence of such events can lead to a dose reduction, treatment delay and/or therapy suspension
potentially compromising the therapy efficacy . We have recently revised the toxicity data of 743 CRC
[9]
patients enrolled in prospective pharmacogenetic studies in our center (Experimental and Clinical Unit of
CRO Aviano), all treated with FP-based regimens. The revision pointed out that 15.7% (95 patients) developed
a severe to lethal toxicity (grade 3 to 5 according to NCI-CTC vs. 3.0). The large majority of these patients
(55.7%) were treated in neo-adjuvant or adjuvant setting and 3 of them died due to toxicity. Moreover, the
23.3% of the study population (178 patients) developed at least one event of dose-limiting-toxicity (DLT,
grade 3 or higher non-hematological or grade 4 or higher hematological toxicity) during therapy. The most
common DLTs were non-hematological ones (154 patients), mostly represented by diarrhea, vomiting and
hand-foot syndrome (HFS). On the other hand, the 38 patients reporting grade 4 or higher hematological
[10]
toxicities suffered from neutropenia in the majority of cases .

In this review the issue of patients genetic profiling to identify in advance CRC patients at risk of FP-related
toxicity will be addressed.

PHARMACOGENOMIC GUIDELINES AND THEIR IMPLEMENTATION IN THE CLINICAL
PRACTICE
The debate on the opportunity to implement pharmacogenetic variants screening in the clinical practice is
still ongoing and specifically the use of dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) testing
to spare FP-related toxic events occurrence is not yet mandatory. Particularly, the publication of European
Society for Medical Oncology guidelines for the management of CRC patients , not recommending an
[11]
upfront DPYD genotyping for FP administration recently rekindled the debate [12,13] .