4. Discussion
Toxicity of irinotecan varies greatly and can be even life-threatening
in some cancer patients. The findings of current analysis indicated that
irinotecan-induced severe toxicities e.g. neutropenia and diarrhea were
significantly associated with the Asian cancer patients who carriedUGT1A1*6 and UGT1A1*28 genetic variants.
Due to strong association of UGT1A1*28 with severe toxicity of
irinotecan as replicated in multiple studies predominantly in Caucasian
cancer patients, the Food and Drug Administration of the United States
(US FDA) has already approved UGT1A1*28 genetic testing before
starting irinotecan therapy and recommended to reduce the starting dose
by at least one level of irinotecan dosage form for cancer patients
carrying UGT1A1*28/*28 genotype [16, 75]. The Dutch
Pharmacogenetics Working Group (DPWG) recommended 30% reduction of the
standard starting dose of irinotecan for patients harboringUGT1A1*28/*28 genotype. Also, the French National Network of
Pharmacogenetics (RNPGx) recommended 25-30% dose reduction in patients
with UGT1A1*28/*28 especially if having other toxicity risk
factors and contraindicated if taking higher doses [75].
The current findings are supporting these recommendations since
toxicities were greatly higher in patients especially when taking high
doses of irinotecan (>150mg/m2) and
suggest that such recommendations should specify the high-risk
population especially Asian patients. This is because, Asian cancer
patients carried either heterozygous or homozygous variant of theUGT1A1*28 were significantly associated with irinotecan induced
neutropenia and diarrhea. Meta-analysis conducted by other research
groups have also established such strong association in Asian cancer
patients [36, 37]. Although some studies did not find such
associations in Asian cancer patients due to claiming low frequency ofUGT1A1*28 [18, 26, 39, 76], however, current analysis has
establised robust evidence for these associations after aggregating data
from large number of studies and sample sizes as well.
Current study also found that UGT1A1*6 genetic variant was
significantly associated with irinotecan induced severe toxicity such as
neutropenia and diarrhea which is consistent with the findings of
previous analyses [36, 37]. However, after assessing the combined
effects of UGT1A1*6 and UGT1A1*28, current study concluded
that patients inherited both of these variants especially with
homozygous variants (UGT1A1*6/*6+UGT1A1*28/28 )
had significant striking effects in experiencing irinotecan-induced
toxicities i.e. neutropenia and diarrhea. The findings of current
analysis suggest that inheriting these genetic variants were probably
associated with reduced function of UGT1A1 which maximize the active
irinotecan concentration in the blood and developing toxicities.
Although genetic testing kit of UGT1A1*6 and UGT1A1*28 has
been recommended in clinical practice in Japan for cancer patients
taking irinotecan [32], however, other parts of Asia are lacking
regulatory consensus for recommending such genetic testing. This may be
partly because many Asian countries are not well positioned for
preceding pharmacogenomics research or may have lack sufficient robust
evidence for the associations of UGT1A1*6 and UGT1A1*28genetic variants with irinotecan induced severe toxicities.
The findings of current analysis may therefore be considered as
sufficiently robust evidence since the pooled risk was measured from
reasonably large number of sample sizes and providing strong evidence
that patients were being at significantly greater risk of irinotecan
induced toxicities i.e. neutropenia and diarrhea when harbored bothUGT1A1*6 and UGT1A1*28 genetic variants especially
homozygous variants. These findings may facilitate translational ofUGT1A1*6 and UGT1A1*28 pharmacogenomics into clinical
practice in the form of precision irinotecan therapy and may reduce
associated severe toxicities profoundly in cancer patients. Drug
regulatory body and poly makers of Asian regions should emphasize such
strong genetic relations with irinotecan induced severe toxicities and
should prepare national guidelines to adhere preemptive screening ofUGT1A1*6 and UGT1A1*28 genetic variants before prescribing
irinotecan.
All ethnic group of Asian patients developed toxicities who carried bothUGT1A1*6 and UGT1A1*28 genetic variants except diarrhea in
Japanese patients. Without knowing specific reason, it is hard to
explain such association although lifestyle, food and comedications may
affect this association. This yet to be elucidated in future studies
explaining why Japanese patients were not significantly associated with
diarrhea who carried both of the UGT1A1*6 and UGT1A1*28genetic variants and taking irinotecan.
The effects of UGT1A1*6 and UGT1A1*28 genetic variants are
applicable in any type of cancer where irinotecan is clinically
warranted since both colorectal and different other cancers were
significantly associated with toxicities. Diarrhea and neutropenia were
observed especially when patients used high doses of irinotecan
>150 mg/m2 with exception of neutropenia
in low doses, however, the results are consistent with a previous
analysis [10]. Although toxicities at low doses are usually
exceptional but confounding factors such as surgery, radiation etc. may
also contribute to irinotecan induced neutropenia. Future clinical
studies are warranted to establish the mechanism for such association.
However, dose dependent analysis of this study suggesting that
irinotecan induced toxicities may be prevented by adjusting doses of
irinotecan and needs further stratification.
Statistically significant associations were not found betweenABCC2 c.3972C>T genetic polymorphism and
irinotecan driven neutropenia in this analysis. This may be partly
because very small number of studies (only three) and sample size were
included in establishing this association which may underpower the
clinical outcomes. Although diarrhea was reduced significantly in
patients carried ABCC2 c.3972C>T genetic
variant, however, the findings are again underpower and should
investigate such association in relatively large sample sizes in
different ethnic groups.
In spite of establishing significant associations of increased risk of
irinotecan induced toxicities e.g. neutropenia and diarrhea in Asian
cancer patients inherited UGT1A1*6 and UGT1A1*28 genetic
variants, nevertheless, there are some limitations in this study.
Firstly, this study did not consider the confounding factors affecting
the toxicity outcomes e.g. chemotherapy regimen, comedications, food,
sex, age etc. Secondly, this analysis only extracted the data from
studies published in English language, which may limit the access to
useful information published in other languages.