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.