Role of microRNAs in fluoropyrimidine-related toxicity: what we know
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European Review for Medical and Pharmacological Sciences 2021; 25: 3306-3315
Role of microRNAs in fluoropyrimidine-related
toxicity: what we know
A.L. DEAC1, C.C. BURZ1,2, C. MILITARU3, I.C. BOCȘAN3, R.M. POP3,
P. ACHIMAȘ-CADARIU1,4, A.D. BUZOIANU3
1
“Prof. Dr. Ion Chiricuţă” Oncology Institute, Cluj-Napoca, Romania
2
Department of Immunology and Allergology, Faculty of Medicine, “Iuliu Haţieganu” University of
Medicine and Pharmacy, Cluj-Napoca, Romania
3
Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, “Iuliu
Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
4
Department of Surgery, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and
Pharmacy, Cluj-Napoca, Romania
Abstract. – Although more than half a cen- used in Asia, and TAS-102 is used in subsequent
tury has passed since the discovery of fluoro- treatment lines upon the failure of classical fluo-
pyrimidines, they are still used in the treatment ropyrimidines and targeted therapy.
of many types of cancer, and it is estimated that
annually two million patients undergo fluoropy-
The prodrugs Capecitabine, TAS-102, S-1, and
rimidine-based chemotherapy. The toxicity re- Tegafur are converted to 5-FU, which is sub-
sulting from the use of fluoropyrimidines affects sequently activated in several steps to FdUMP
about 30-40% of patients, which in some cases (fluorodeoxyuridine monophosphate), which is an
may prove to be lethal. The key player in fluoro- inhibitor of TS (thymidylate synthase)1,2. TS inhi-
pyrimidine toxicity is DPD activity, and patients bition leads to the depletion of dTMP (deoxythy-
with deficits are more likely to develop signifi-
midine monophosphate) but an accumulation of
cant adverse events. In addition to genotyping
DPYD variants associated with DPD deficiency, dUMP (deoxyuridine monophosphate). FdUMP
overexpression of miR-27 has also been shown and dUMP can be phosphorylated to FdUTP
to be a predictive factor for fluoropyrimidine tox- (fluorodeoxyuridine triphosphate) and dUTP (de-
icity. This review aims to relate what we know so oxyuridine triphosphate), respectively, and incor-
far about the involvement of miRNA in fluoropy- porated into DNA1,2. TAS-102 is the combination
rimidine toxicity and to open new perspectives of TFT (trifluridine) and TPI (tipiracil hydrochlo-
in this field.
ride). TFT can be phosphorylated to TF-thymine,
Key Words: which can be inhibited by TPI. TFT is phosphor-
Fluoropyrimidine, Chemotherapy, Toxicity, Pharma- ylated to TFT-MP (trifluridine-monophosphate),
cogenetics. which is a reversible inhibitor of TS, while upon
phosphorylation to TFT-TP (trifluridine-triphos-
phate), it can also be incorporated into DNA.
Substitution of dTTP (deoxythymidine triphos-
Introduction phate) by either TFT-TP or dUTP or FdUTP leads
to DNA damage and cell death3.
Fluoropyrimidines are antimetabolite drugs Capecitabine and Tegafur are converted to
widely used in the treatment of head and neck 5-FU by thymidine-phosphorylase (TP) and
cancer, breast cancer, esophageal cancer, gastric CYP2A6. 1-5% of 5-FU is transformed into
cancer, pancreatic cancer, hepatobiliary cancer, cytotoxic metabolites FdUMP, FdUDP (fluoro-
colorectal cancer, anal cancer, and vulvar cancer1. deoxyuridine diphosphate), FdUTP and FUTP
The fluoropyrimidines used in clinical practice (fluorouridine triphosphate)1,2. 5-FU is directly
are 5-fluorouracil (5-FU), Capecitabine, Tega- transformed to FUMP (fluoridine monophos-
fur, S-1 (tegafur/gimeracil/oteracil), and TAS-102 phate) by OPRT (orotate phosphoribosyltrans-
(trifluridine/tipiracil). 5-FU and its oral prod- ferase) or indirectly through FUR (fluorouri-
rug, Capecitabine, are the most commonly used dine) by UP (uridine phosphorylase) and UK
fluoropyrimidines, Tegafur and S-1 are mostly (uridine kinase). FUMP is then phosphorylated
3306 Corresponding Author: Andrada Larisa Deac, MD; e-mail: andrada.deac@gmail.comRole of microRNAs in fluoropyrimidine-related toxicity: what we know
to FUDP (fluorouridine diphosphate), which is variants in the gene encoding DPD (DPYD) are
phosphorylated to FUTP. FUDP can also be known to be related to severe and lethal fluoropy-
converted to FdUDP by ribonucleotide reduc- rimidine toxicity5.
tase (RR)1,2. In an alternative activation path- Not all severe fluoropyrimidine adverse events
way, 5-FU is converted to FUDR (fluorodeoxy- can be explained by DPYD variants; sometimes,
uridine) by thymidine phosphorylase. FUDR carriers of a DPYD variant associated with an
is converted through thymidine phosphate in increased risk of severe adverse events may toler-
FdUMP, which is phosphorylated to FdUDP, ate well the treatment with fluoropyrimidine and
which is phosphorylated to FdUTP. Eighty per- may not experience major toxicity6. As such, the
cent of the 5-FU is catabolized by dihydropy- intervention of other factors capable of affecting
rimidine dehydrogenase into the non-cytotoxic DPYD expression may influence fluoropyrimi-
metabolites DHFU (5-fluoro-5,6-dihydroura- dine metabolism in patients both with and with-
cil), which is then converted to FUPA (flu- out DPYD variants.
oro-beta-ureidopropionate) and FUBA (fluo- MicroRNAs (miRNAs) are endogenous, short
ro-beta-alanine), which are eliminated through non-coding RNA molecules, about 20-22 nucleo-
urine. To modulate the activity of fluoropyrim- tides in length, which are found in all eukaryotic
idines, inhibitors of DPD can be administrat- cells and assist in regulating post-transcription-
ed, which slow the degradation of 5-FU and al gene expression by binding to 3’untranslated
improve the response rate1,2 (Figure 1). regions or 5’untranslated regions of target mes-
The rate-limiting enzyme of 5-FU catabo- senger RNAs. This also leads to the inhibition
lism is dihydropyrimidine dehydrogenase (DPD), of translation of messenger RNA degradation7,8.
which metabolizes almost 80% of the dose of Almost 30% of human genome proteins are regu-
5-FU and Capecitabine4. DPD is the essential en- lated by miRNAs, with half of these genes being
zyme for the 5-fluorouracil catabolism, and there- associated with cancer7,8. MicroRNAs regulate
fore the amount of 5-FU converted in cytotoxic the gene expression involved in essential biolog-
metabolites depends on the systemic activity of ical processes such as cell proliferation, cell dif-
DPD4. Some of the severe side effects that occur ferentiation, apoptosis, metastasis, and immune
during fluoropyrimidine treatment are due to response9-11. Many studies have tried to prove that
metabolism through the DPD. Deleterious genetic miRNAs can be used as diagnostic tools, predic-
Figure 1. Fluoropyrimidine metabolic pathways
3307A.L. Deac, C.C. Burz, C. Militaru, I.C. Bocșan, R.M. Pop, P. Achimaș-Cadariu, A.D. Buzoianu
tive biomarkers of disease progression, prognos- elosuppression, severe diarrhea, and rare events
tic biomarkers, survival rate, progression-free such as acute cardiac ischemia following the first
survival, treatment responsiveness, and chemo- or second cycle of 5-FU, hepatitis, and encepha-
therapy-related toxicity12-14. The importance of lopathy22.
microRNAs regarding chemotherapy toxicity is DPD expression varies from tissue to tissue
less well known. and exerts its activity predominantly in the liver,
In our review, we summarize the role of miR- peripheral blood mononuclear cells, and inflam-
NAs in fluoropyrimidine toxicity, the relation matory and tumor tissues.
with DPD, and how miRNAs may be a tool in The DPD activity is also influenced by the
selecting patients who will benefit from the ef- circadian rhythm, which DPD activity follows:
ficacy of fluoropyrimidines without developing DPD activity peaks near midnight, and through
major toxicities. DPD activity in the early afternoon; this was dis-
covered during the administration of continuous
Fluoropyrimidine-Related Toxicity 5-FU infusions23.
Severe toxicity in chemotherapy is usually as- The activity of DPD has high interindividual
sociated with interruption or treatment discontin- variability, but the most important are variants of
uation and often requires hospitalization. Fluoro- the DPYD gene, the gene that encodes the DPD
pyrimidine-related toxicity is a well-recognized enzyme24.
clinical problem that impacts patients’ quality of The DPYD gene allelic variants most fre-
life and, in some cases, can be life-threatening. quently associated with toxicity during the
5-FU and Capecitabine can induce grade 3 or treatment with fluoropyrimidine are DPY-
4 toxicity in 10-30% of patients and fatal tox- D*2A (IVS14+1G>A, c.1905+1G>A), DPYD*9B
icity in 0.3-2% of patients15. When we compare (c.2846A>T), DPYD*13 (c.1679T>G), HapB3
5-FU to Capecitabine, data from the Adverse (c.1129-5923C>G)24-28.
Event Reporting System (AERS) of the Food In addition to DPYD gene polymorphisms,
and Drug Administration (FDA) have shown polymorphisms of other genes such as thymi-
that certain side effects are more common for dylate synthase (TYMS), methylenetetrahydro-
one or the other, such as myelosuppression has folate reductase (MHTFR), enolase superfami-
been shown to be more common in patients ly member 1 (ENOSF1), ATP-binding cassette
receiving 5-FU and diarrhea or hand-foot syn- subfamily B member 1 (ABCB1), and cytidine
drome in patients receiving Capecitabine16. The deaminase (CDA) appear to be involved in fluo-
lower prevalence of adverse effects of S-1 and ropyrimidine toxicity29-34.
TAS-102, compared to 5-FU and Capecitabine, Fluoropyrimidine toxicity, especially of 5-flu-
is due to them carrying a DPD inhibitor in their orouracil, can be manifested through hemato-
composition, which increases the bioavailabil- logical non-cumulative toxicity most common in
ity of 5-FU3. bolus infusion (neutropenia, thrombocytopenia,
5-FU has a narrow therapeutic index; there- anemia), immediate digestive toxicity (nausea,
fore, there is a small limitation between efficacy vomiting, diarrhea, stomatitis, ileitis), alopecia
and toxicity17. Adverse events are likely the re- in case of continuous perfusion, thrombophlebi-
sults of genetic variation, especially ones such tis and photosensitivity along the vein pathway,
as DPD. Decreased DPD activity implies a de- neurological toxicity from high doses (cerebellar
creased clearance and an increased half-time of ataxia), ophthalmological toxicity through tear
5-FU, resulting in an increased risk of toxicity18,19. excretion (conjunctivitis, tear hypersecretion),
More than 80% of the 5-FU dose is converted skin toxicity usually aggravated by sun exposure
to inactive metabolite 5-fluoro-5,6-dihydrouracil (hand-foot syndrome, hyperpigmentation, rash,
by DPD19. DPD deficiency accounts for 20-60% hives) and reversible cardiac toxicity caused by
of fluoropyrimidine-related severe toxicity, and continuous perfusion (angina, myocardial infarc-
20-30% can be explained by DPYD deleterious tion, myocardial necrosis, coronary dissection,
variants19,20. It is estimated that 3-5% of Cauca- heart failure, arrhythmia, cardiogenic shock, car-
sians are carriers of a partial DPD deficiency diac arrest, and sudden cardiac death)35-38. Se-
and that 0.1-0.3% present complete deficiency20. vere adverse events may appear within the first
Overall, 5% of the general population present a chemotherapy cycle – a fact that supports the
DPD deficiency21. This pharmacogenetic “DPD importance of treatment personalization before
syndrome” manifests as mucositis/stomatitis, my- treatment initiation37.
3308Role of microRNAs in fluoropyrimidine-related toxicity: what we know
Fluoropyrimidine cardiotoxicity represents cardiac tissue, and (4) TAS-102 is not catabolized
one of the most severe fluoropyrimidine-induced by DPD, which consequently means a reduced
toxicities. The incidence ranges from 1% to 18%, formation of FBAL and a lower risk of cardio-
and chest pain is the most frequent symptom36,37. toxicity due to FBAL accumulation39. A reduced
The incidence variability is due to various man- level of cardiotoxic metabolites also explains the
ifestations of cardiotoxicity, but the risk is in- lack of cardiac toxicity of S-1 due to the presence
fluenced by the schedule and route of admin- in its composition of gimeracil, a DPD-inhibitor.
istration of 5-FU, the use of concurrent chest
radiotherapy or anthracycline administration, How to Assess Fluoropyrimidine Toxicity?
underlying coronary artery disease, and how fre- Over time, many studies have focused on
quently the patients were monitored36,37. Several studying the mechanisms involved in fluoropy-
mechanisms for fluoropyrimidine cardiotoxicity rimidine toxicity. Most strategies have tried to de-
have been proposed, such as (1) vasoconstric- termine the DPD deficiency through genotyping
tion, (2) direct myocardial injury with systolic and phenotyping method (Table I).
dysfunction, (3) accumulation of alpha-fluoro-be- The fact that DPD activity can affect 5-FU
ta-alanine (FBAL), a metabolite of 5-FU, which efficacy through the development of important
is first converted to fluoroacetate and later to adverse events was demonstrated in many stud-
fluorocitrate leading to citrate accumulation and ies, and therefore an upfront screening for func-
downstream depletion of ATP resulting in isch- tionally relevant DPYD genes and treatment ad-
emia, (4) dysfunction of vascular endothelium, justment in patients with related toxicity allelic
(5) hypercoagulable status leading to thrombosis, variants to avoid severe toxicity is justified. The
(5) changes in the shape of erythrocyte mem- first functional mutation related to fluoropyrim-
brane leading to increased blood viscosity and idine toxicity was DPYD*2A. Deenen et al40
decreased ability to carry and release oxygen, demonstrated in a prospective study the clinical
and (6) an acute coronary syndrome caused by validity and utility of DPYD*2A genotype-guid-
an allergic reaction also known as Kounis syn- ed dosing40. However, due to the low frequency
drome3. 5-FU and Capecitabine have the same of DPYD*2A, less than 1% in Caucasian patients,
frequency of cardiac adverse events, while on attention was focused on identifying other DPYD
the other hand, TAS-102 is considered to be a variants associated with DPD deficiency41. Until
“cardio-gentle” fluoropyrimidine. The following now, four variants have demonstrated their utility
mechanism seems to be responsible for the lack and clinical validity based on high-level evidence
of TAS-102 cardiotoxicity: (1) trifluorothymidine from meta-analyses42.
(TFT), an analogue of thymidine and one of the There are situations in which the DPD defi-
components of TAS-102, induces a higher level ciency is not explained by the presence of DPYD
of cell death and does not obtain an autophagic variants or by phenotypic methods. These cases
survival response in cancer cell lines, (2) a dif- are in part explained by a variability in the reg-
ferent oncological target – DNA synthesis, (3) ulation of DPD at the post-transcriptional lev-
the incorporation of the molecule into the DNA el by microRNA. The 3’-untranslated region of
of tumor tissues is higher than the incorporation DPYD is directly targeted by mir-27a, miR-27b,
into DNA of normal tissues, thereby sparing the miR-134, miR-494, miR-582-5p, and in the cod-
Table I. Available methods to identify patients at risk for severe fluoropyrimidine toxicity24-28,42-44,48-53.
Stategies Methods Evidence
Phenotyping methods DPD activity in PBM’s Clinical validity established
Clinical utility in research
Endogenous uracil serum concentration Clinical validity and utility established
2-13C uracil breath test Clinical validity and utility in research
Uracil dose test Clinical validity and utility in research
Genotyping methods DPYD mutation Clinical validity and utility for
DPYD*2A, 13, 9B and HapB3
miRNA mutation Clinical validity and utility in research
DPD – dihydrodioyrimidine dehydrogenase, DPYD – dihydrodioyrimidine dehydrogenase gene, miRNA – microRNA.
3309A.L. Deac, C.C. Burz, C. Militaru, I.C. Bocșan, R.M. Pop, P. Achimaș-Cadariu, A.D. Buzoianu ing sequence by hsa-miR-302b-3p40-43. Of these, 5-fluorouracil, SW480, and SW480/5-FU cells45. miR-27-a and miR-27-b have been shown to So be these meanings, DPYD expression was downregulate DPD expression by targeting an under the control of miR-494, and 5-fluorouracil RNA-induced silencing complex (RISC) protein resistance and toxicity can be associated with to DPYD43. Moreover, miR-27-a functions as an abnormal downregulation of miR-49447. oncogene, and its overexpression has been asso- The gene encoding for thymidylate synthase ciated with poor prognostics, increased risk of (TYMS) has been investigated to highlight the metastasis and disease progression, and chemo- possible role as a biomarker for fluoropyrimidine therapy resistance43. toxicity and effectiveness. Sinicrope et al46 re- The clinical relevance of miR-27a polymor- vealed that the overexpression of TS in colorectal phism has been demonstrated in three studies cancer was related to poor response to 5-flu- on patients undergoing fluoropyrimidine-based orouracil, chemoresistance, and toxicity47. The chemotherapy. Amstutz et al42 showed, in a study TYMS variants associated with fluoropyrimidine with 514 patients who presented fluoropyrimi- toxicity involve tandem repeats of a 28-base- dine-related toxicity after the first two cycles, an pair sequence instead of three in the 5’-untrans- association between rs895819 variant G allele of lated region or a 6-base-pair variation in the miR-27a and increased early-onset toxicity and 3’-untranslated region of TYMS, also known as also the fact that this association is dependent TYMS enhancer region (TSER)47,48. The activity on the DPYD variant related to DPD deficien- of TYMS can also be controlled by microR- cy42. In the same study, another polymorphism, NA. Increased expression of miR-218 suppresses rs11671784, was analyzed, but no association with TYMS-enhanced fluoropyrimidine toxicity and fluoropyrimidine toxicity was observed and no is associated with progression-free survival and significant relation with DPYD mutated variants overall survival in colorectal cancer48. was detected42. Meulendiks et al43 confirmed the Regarding phenotyping methods, the main above information in a study including 1592 pa- methods related to fluoropyrimidine treatment tients in treatment with fluoropyrimidine43. They are the determination of DPD activity in periph- showed that rs895819 polymorphism is mod- eral blood mononuclear cells (PBM), uracil dose erately associated with toxicity, but those who test, pretreatment determination of the endoge- have DPYD mutation also have a significantly nous concentration of dihydrouracil and uracil increased risk grade 3 or 4 toxicity, these facts in plasma, urine, and saliva (UH2/Ura ratio), suggesting the additional role and importance 2-13C uracil breath test49-54. Among all phenotyp- of miR-27-a polymorphism43. The carriers of ic methods, the highest accuracy is assigned to rs11671784 polymorphism showed no significant- pretreatment serum uracil determination54. ly increased risk of toxicity regarding the DPYD status43. In a small study of 64 patients, Falvella et al44 showed in both univariate and multivariate Discussion analysis the association between rs895819 and grade 3 or 4 adverse events44. Side effects are one of the factors that limit Another miRNA that shows promising results the efficacity of chemotherapy, and they usually based on in vitro studies is miR-494. This miR- require either dose reduction or delayed adminis- NA, located in chromosome 14q32.31, works as tration of treatment until remission. an oncogene in breast cancer metastasis and is Due to the multiple indications that fluoro- overexpressed in hepatocellular carcinoma cells, pyrimidines have, they are probably the most although some studies also suggest its tumor sup- commonly used chemotherapeutic agents, and pressor role by repressing the proliferation, mi- therefore it is essential to find ways to prevent gration, and invasion of prostate cancer cells by toxicities that can decrease the efficacity or in- suppression of C-X- C chemokine receptor 4 (CX- terrupt the treatment, or which endanger the CR4) gene, and of gastric cancer cells by target- patient’s life. ing c-myc45,46. Chai et al45 showed in their study Many detection methods are available now- that miR-494 has tumor suppressor function and adays, phenotypic or genotypic, and we know can sensitize colon cancer cells to 5-fluoroura- that the onset of toxicity is influenced by DPD cil by binding to the 3’-untranslated region of activity. At the present time, four variants of DPYD and negatively regulate DPYD expression DPYD have proven their clinical utility and their in modified colon cancer cell lines sensitive to influence on DPD deficiency, but due to the low 3310
Role of microRNAs in fluoropyrimidine-related toxicity: what we know
frequency and the multitude of mutant variants, for colorectal cancer was updated in September
their routine testing has not yet progressed into 2017 and recommended DPYD genotyping in all
clinical practice. It is estimated that almost 3-15% patients before initiating treatment with fluoropy-
of patients present a partial DPD deficiency and rimidine58,59.
0.1-5% a complete deficiency54. On 13 March 2020, the European Medicines
The Group of Clinical Pharmacology in Oncol- Agency’s (EMA) Pharmacovigilance Risk As-
ogy (GPCO)-UNICANCER and the French Net- sessment Committee (PRAC) has recommended
work of Pharmacogenetics (RNPGx) recommend testing for DPD deficiency before initiation of
the following regarding the treatment with fluoro- fluoropyrimidine-based chemotherapy; patients
pyrimidine: (1) the screening of DPD deficiency with complete DPD deficiency should not receive
before starting treatment with 5-fluorouracil or any type of fluoropyrimidine, and those with a
Capecitabine, (2) performing DPD phenotyping partial deficiency can receive fluoropyrimidine
by determination of plasma uracil concentra- treatment with a reduced dose and later in the
tions and DPD genotyping (variants DPYD*2A, course of the treatment adjustment of the dose
DPYD*13, DPYD*9, and Haplotype B3), (3) re- depending on the toxicities associated60.
ducing the first cycle dose of fluoropyrimidine ac- In 2015, uridine triacetate (UT, Vistogard) was
cording to DPD status and later in the treatment approved by FDA as an antidote in case of se-
to consider increasing the dose according to each vere fluoropyrimidine toxicities, with a survival
tolerance55. benefit in 96% of cases, based on two open-label,
The Clinical Pharmacogenetics Implementa- single-arm trials61,62. Vistogard can be used in
tion Consortium (CPIC) has formulated a guide- the first 96 hours after the last dose of 5-FU or
line for better interpretation of clinical DPD Capecitabine for life-threatening toxicities such
genotyping tests and how to adjust the treatment. as severe neutropenia, diarrhea, or cardiotoxicity
Based on DPYD genotype and phenotype they unresponsive to drug cessation and antianginal
calculated DPYD activity score (DPYD-AS) and therapy63.
made the following recommendations: (1) in pa- In recent years, miRs are involved and control
tients who are DPYD normal metabolisers with many of the processes involved in cancer, but also
activity score of 2 (AS) and two normal func- in efficacy, resistance, and toxicity to treatment.
tional alleles a dose modification is not recom- So far, in terms of fluoropyrimidine toxicity, only
mended, (2) in DPYD intermediate metabolisers, mir-27 has proven its potential role as a predic-
meaning decreased DPD activity and increased tive factor. Previous studies45-47 have illustrated
risk of toxicity with AS 1 or 1.5, and one normal that the presence of rs895819A>G presents only
functional plus one non-functional allele, or two a moderate risk of toxicity, but the association of
decreased functional alleles, a reduction of 25 rs895819A>G and a DPYD variant are associated
to 50% is recommended (the percentage of dose with an increased risk of early-onset severe fluo-
reduction depends on activity score) and (3) in ropyrimidine toxicity. This fact highlights the im-
DPYD poor metabolisers with complete DPD portant role that microRNAs could play in DPYD
deficiency and very increased risk of toxicity, genotyping and, subsequently, in providing an
with AS 0 or 0.5 and two non-functional alleles or appropriate treatment with limited side effects.
one non-functional plus one decreased functional As mentioned previously, CPIC recommends the
allele, it is recommended to avoid the use of flu- association of phenotyping and genotyping for
oropyrimidine treatment; if AS 0.5 and there is the screening of DPD deficiency, but the com-
no other therapeutic option, 5-fluorouracil should bined determination between polymorphism on
be administered with a significant dose reduction DPYD gene and microRNA can be a method
and under therapeutic drug monitoring56. with greater accuracy and could help us detect
Another working group, the Dutch Pharmaco- more patients who may be suffering from major
genetics Working Group (DPWG), offers some toxicities.
recommendations regarding fluoropyrimidine
treatment. In contrast to the CPIC guideline, DP-
WG also includes Tegafur in their guideline, not Conclusions
only 5-fluorouracil and Capecitabine; they also
recommend patients with AS 0 or 0.5 using a phe- Even today, when target therapy and immuno-
notyping method to initiate the treatment with a therapy, alone or combined with chemotherapy,
fluoropyrimidine57. The Dutch National guideline tend to become the first-line treatment in many
3311A.L. Deac, C.C. Burz, C. Militaru, I.C. Bocșan, R.M. Pop, P. Achimaș-Cadariu, A.D. Buzoianu
types of cancer, fluoropyrimidine is still the cor- 5) Froehlich TK, Amstutz U, Aebi S, Joerger M, Lar-
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Conflict of Interest Bokharaei-Salim F, Karampoor S, Jafari A, Ase-
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