Influence of UGT1A1 *6/*28 Polymorphisms on Irinotecan-Related Toxicity and Survival in Pediatric Patients with Relapsed/Refractory Solid Tumors Treated with the VIT Regimen

Abstract

The association between UGT1A1*6/*28 polymorphisms and treatment outcomes of irinotecan in children remains unknown. This retrospective study investigated the influence of UGT1A1*6/*28 polymorphisms on irinotecan toxicity and survival of pediatric patients with relapsed/refractory solid tumors. Methods: The present study enrolled a total of 44 patients aged younger than 18 years at Sun Yat-sen University Cancer Center between 2014 and 2017. Results: There were 26 boys and 18 girls; the median age at first VIT course was six years (range: 1-18 years). The tumor types included neuroblastoma (n = 25), rhabdomyosarcoma (n = 11), Wilm's tumor (n = 4), medulloblastoma (n = 2), and desmoplastic small round cell tumor (n = 2). Overall, 203 courses of VIT regimens were prescribed. Neither UGT1A1*6 nor *28 polymorphisms were associated with the incidence rates of severe (grade III-IV) irinotecan-related toxicities, but tended to reduce the patient overall survival (UGT1A1*6, P = 0.146; UGT1A1*28, P = 0.195). Moreover, patients with mutant UGT1A1*6 genotypes were more likely to develop grade I-IV irinotecan-related diarrhea (P = 0.043) and anemia (P = 0.002). Overall, the UGT1A1*28 polymorphism may play a protective role against irinotecan-related diarrhea and abdominal pain. Conclusion: In relapsed/refractory pediatric solid tumors, the UGT1A1*6 polymorphism was a risk factor of irinotecan-related diarrhea and anemia. The UGT1A1*28 polymorphism may serve a protective role in irinotecan-related abdominal pain and diarrhea. Both mutations had a tendency to be risk factors for survival. Nevertheless, prospective studies are required to verify such conclusions.

Combination chemotherapy consisting of irinotecan, etoposide, and carboplatin for refractory or relapsed neuroblastoma

“… 23 Meanwhile, the VIT (oncovin, irinotecan, and temozolomide) regimen in 44 pediatric patients with relapsed/refractory solid tumors was associated with increased irinotecan‐related toxicity but tended to reduce the patient overall survival. 24 In our study, patients with UGT1A1 polymorphisms had an increased frequency of grade 4 leukopenia after IREC therapy but had no increase in FN or BSI compared with wild‐type patients. Meanwhile, four of the six patients with OR had a UGT1A1 polymorphism.…”

“…In contrast, an irinotecan‐containing chemotherapy regimen (carboplatin, dexamethasone, etoposide, and irinotecan [CDE‐11]) for adult diffuse large B‐cell lymphoma has been shown to improve prognosis in patients with the UGT1A1 *6 polymorphism 23 . Meanwhile, the VIT (oncovin, irinotecan, and temozolomide) regimen in 44 pediatric patients with relapsed/refractory solid tumors was associated with increased irinotecan‐related toxicity but tended to reduce the patient overall survival 24 . In our study, patients with UGT1A1 polymorphisms had an increased frequency of grade 4 leukopenia after IREC therapy but had no increase in FN or BSI compared with wild‐type patients.…”

Individual Irinotecan Therapy Under the Guidance of Pre-Treated UGT1A1*6 Genotyping in Gastric Cancer

“…Ethnic differences in UGT1A1 gene polymorphism are closely associated with AEs of irinotecan, 21 – 23 but its efficacy remains uncertain. 15 , 24 , 25 Most studies believed that patients with homozygous UGT1A1*28 mutation would have serious toxic reactions, and it was suggested to reduce the dosage of irinotecan. 23 , 24 , 26 , 27 To reduce the toxicity of irinotecan, FDA proposed that patients should be genotyped for UGT1A1*28 polymorphism before treatment with irinotecan.…”

“… 11 , 12 Multiple meta-analyses showed that the polymorphisms of UGT1A1 * 6 and UGT1A1 * 28 genes were significantly associated with irinotecan-induced severe diarrhea and neutropenia, but this conclusion is still controversial due to the different frequencies of UGT1A1 genotypes in eastern and western countries. 13 – 16 …”

Importance of pharmacologic considerations in the development of targeted anticancer agents for children

“…Additionally, UGT1A1 is an enzyme that conjugates the active metabolite of irinotecan to glucuronic acid to facilitate elimination [24]. Several variants have been recognized, with the UGT1A1∗6 and UGT1A1∗28 forms potentially contributing to worse chemotherapy associated side effects [31,32]. Studies have attempted to assess the value of genotyping for patients receiving irinotecan, with a benefit in cost and toxicity noted in several [33,34 ▪ ].…”