Irinotecan-related Toxicities Research Articles

Predictive Value of ABCC2 and UGT1A1 Polymorphisms on Irinotecan-Related Toxicities in Patients with Cancer.

Background: There is extensive interindividual variability in response and tolerance to anticancer drugs. This heterogeneity provides a major limitation to the "rational" use of cytotoxic drugs, and it becomes a major problem in oncology giving a narrow therapeutic window with a vital risk. Among these anticancer drugs, irinotecan can cause dose-limiting toxicities, commonly diarrhea and neutropenia. Interaction among pathways of activation/inactivation (UGT1A1) and hepatobiliary transport of irinotecan and its metabolites could, in part, explain its interindividual variability. The objective of this study was to perform an exploratory analysis to evaluate the correlation between the genetic polymorphisms of UGT1A1 and ABCC2 with the different toxicities associated with irinotecan treatment. Materials and Methods: Seventy-five patients with solid cancers were included, all were administered an irinotecan-based regimen in both Mission Bay Medical Center; and Zuckerberg San Francisco General Hospital from May 2016 to December 2016. The patients' genotyping was performed for both the UGT1A1*28 polymorphism, and the ABCC2 - 1549G>A, and ABCC2 - 1249G>A single nucleotide polymorphism. Comparisons among qualitative data were assessed using the χ2-test, and Fisher's exact test in the case of small group sizes. Results: Diarrhea was observed in 40 patients (53.3%), among them only 9 patients had high grades diarrhea (grades III and IV). Grades III/IV of nausea were more frequently associated with the ABCC2-1549 AA genotype (83.3% p = 0.004) in patients with colorectal cancer. In pancreatic cancer, a significant absence of diarrhea grades III-IV was noted in patients with the ABCC2 1249 GG genotype compared to the other ABCC2 1249 genotypes.

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.

ObjectiveThe 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.MethodsThe present study enrolled a total of 44 patients aged younger than 18 years at Sun Yat-sen University Cancer Center between 2014 and 2017.ResultsThere 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.ConclusionIn 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.

P1.03-015 The Relationship between the UGT1A1*27 and UGT1A1*7 Genetic Polymorphisms and Irinotecan-Related Toxicities in Patients with Lung Cancer

P1.03-015 The Relationship between the UGT1A1*27 and UGT1A1*7 Genetic Polymorphisms and Irinotecan-Related Toxicities in Patients with Lung Cancer

Abstract 5032: The relationship between the UGT1A1*27 and UGT1A1*7 genetic polymorphisms and irinotecan-related toxicities in patients with lung cancer

Abstract Background: Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1), UGT1A7, and UGT1A9 genes are associated with interindividual differences in irinotecan toxicities. The UGT1A1*7, *27, and *29 gene polymorphisms occur within the common exons of UGT1A1 isoforms and cause substantial reductions in their functional activity; however, few clinical studies have examined the effects of these polymorphisms. Purpose: To evaluate the effects of gene polymorphisms, including UGT1A1*7, *27, and *29, on the safety of irinotecan therapy. Patients and methods: The eligibility criteria were as follows: lung cancer patients who were scheduled to undergo irinotecan therapy, aged ≥20 years, and had a performance status of 0-2. After informed consent had been obtained, patients were enrolled, and their blood was collected and used to examine the frequency of the UGT1A1*6, *7, *27, *28, and *29 polymorphisms and the drug concentrations of irinotecan, SN-38, and SN-38G after irinotecan therapy. Results: Thirty-one patients were enrolled. The patients’ characteristics were as follows: male/female = 25/6, median age (range) = 71 (55-84), stage IIB/IIIA/IIIB/IV = 2/6/11/12, and Ad/Sq/Sm/Oth = 14/10/3/4. The -/-, *6/-, *7/-, *27/-, *28/-, and *29/- UGT1A1 gene polymorphisms were observed in 10 (32%), 10 (32%), 2 (6%), 2 (6%), 7 (23%), and 0 (0%) cases, respectively. There were no homozygous or complex heterozygous polymorphisms. The UGT1A1*27 polymorphism occurred separately from the UGT1A1*28 polymorphism. The lowest leukocyte counts of the patients with the UGT1A1*27 and UGT1A1*6 gene polymorphisms were lower than those seen in the wild-type patients. SN-38 tended to remain in the blood for a prolonged period after the infusion of irinotecan in patients with the UGT1A1*27 or UGT1A1*28 polymorphism. No severe myelotoxicity was seen in the patients with UGT1A1*7. Conclusions: UGT1A1*27 and UGT1A1*7 are both rare gene polymorphisms. UGT1A1*27 can occur separately from UGT1A1*28 in some circumstances and is related to leukopenia during irinotecan treatment. UGT1A1*7 is less relevant to irinotecan-induced toxicities, and UGT1A1*29 seems to have little clinical impact. Citation Format: Minoru Fukuda, Manabu Okumura, Tomomi Iwakiri, Arimori Kazuhiko, Shinnosuke Takemoto, Takaya Ikeda, Takuya Honda, Hiroyuki Yamaguchi, Katsumi Nakatomi, Kazuma Kobayashi, Mitsuko Masutani, Mikio Oka, Kazuto Ashizawa, Hiroshi Mukae. The relationship between the UGT1A1*27 and UGT1A1*7 genetic polymorphisms and irinotecan-related toxicities in patients with lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5032. doi:10.1158/1538-7445.AM2017-5032

Cost Evaluation of Irinotecan-Related Toxicities Associated With the UGT1A1*28 Patient Genotype.

The adoption of a preemptive UGT1A1*28 genotyping to increase irinotecan safety in clinical practice is still limited. This is the first actual study of costs associated with the management of irinotecan-related toxicities, and their association with UGT1A1*28 genotype. A retrospective analysis of the cost of toxicity management was conducted on 243 metastatic colorectal cancer patients enrolled in a clinical trial and treated with standard of care FOLFIRI (5-fluorouracil combined with irinotecan). The mean predicted cost per patient was higher for *28/*28 (€4,886), vs. *1/*1 (€812), (regression coefficient 1.79, 95% confidence interval (CI) = 1.31-2.28; P < 0.001) and for *1/*28 (€1,119) vs. *1/*1 (regression coefficient 0.32, 95% CI = 0.04-0.60; P = 0.024). This is consistent with a different grade 4 toxicity profile among the three genotypes, and a higher frequency of costly interventions like hospitalization among patients with the *28 allele. A differential toxicity management cost by *28 genotype is herein demonstrated, representing a first step towards the demonstration of the test clinical utility.

Associations between UGT1A1*6 or UGT1A1*6/*28 polymorphisms and irinotecan-induced neutropenia in Asian cancer patients

Neutropenia is a life-threatening side effect of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan-related toxicities. Many studies have demonstrated that patients bearing UGT1A1*28 have a higher risk of severe neutropenia on toxicity of irinotecan. However, UGT1A1 (TA7/TA7) was very rare in Asian populations. Some researches reported that UGT1A1*28 and/or UGT1A1*6 could predict irinotecan-induced toxicities in Asian populations, but controversial conclusions still remained. This study aims to investigate the association between UGT1A1 gene polymorphisms *6, *6/*28 and irinotecan-related neutropenia in Asian cancer patients receiving irinotecan regimen chemotherapy. Meta-analyses were done to assess the relationship between UGT1A1*6 or UGT1A1*6/*28 and irinotecan-induced neutropenia. The risk of neutropenia was significantly higher among patients with a UGT1A1*6 genotype than among those carrying the UGT1A1*1 allele(s) [odds ratio (OR) 3.276; 95 % confidence interval (CI) 1.887-5.688; P = 0.000 (*6/*6 vs. *1/*6 or *1/*1)], [OR 1.542; 95 % CI 1.180-2.041; P = 0.001 (*6/*6 or *1/*6 vs. *1/*1)]. Also, the risk was significantly higher among patients with a UGT1A1*6/*28 than among those carrying the UGT1A1*1 allele(s) [OR 3.275; 95 % CI 2.152-4.983; P = 0.000 (*6/*6 or *28/*28 or *6/*28 vs. *1/*6 or *1/*28 or *1/*1)]. In conclusion, the UGT1A1*6 and UGT1A1*6/*28 genotypes were associated with an increased risk of irinotecan-induced neutropenia in Asian cancer patients.

P3-018 - Concomitant Polypharmacy is Associated with Irinotecan-Induced Adverse Drug Reactions in Patients with Cancer

ABSTRACT Background Patients with cancer are often given chemotherapeutic agents concurrently with other medications to treat comorbidity. The practical effects of concomitant medicines, especially polypharmacy, on adverse drug reactions induced by irinotecan-based chemotherapy were not well documented. Methods Associations of adverse drug reactions related to irinotecan monotherapy or a combination of irinotecan, 5-fluorouracil, and l-leucovorin (FOLFIRI) with concomitant medicines used to treat comorbidity were retrospectively investigated in Japanese patients with cancer. Concomitant medications were defined as therapeutic drugs which were given to manage comorbid conditions besides cancer, and those continuously administered at least from the last visit before the start of irinotecan-based chemotherapy until after day 1 of the chemotherapy. Results Among the 172 patients, 118 received concomitant medications. Almost all concomitant medications were continuously administered from the last visit before starting irinotecan-containing chemotherapy to until the end of the first cycle. Twenty one patients had grade 4 neutropenia and/or grade 3 or 4 diarrhea. Univariate and multivariate analyses revealed that concomitant medications were significantly associated with irinotecan-related severe neutropenia and/or diarrhea (P = 0.023 and 0.044). Multiple concomitant medications were significantly related to severe irinotecan-related toxicity in patients given monotherapy or FOLFIRI (P = 0.01). The incidence of severe irinotecan-related toxicities increased in parallel to the number of concomitant medications. Conclusion We thus demonstrated that multiple concomitant medications were significantly associated with irinotecan-related severe toxicity in patients with cancer who received irinotecan-based chemotherapy, indicating that polypharmacy must be effectively managed to decrease the risk of adverse drug reactions.

Concomitant polypharmacy is associated with irinotecan-related adverse drug reactions in patients with cancer

Patients with cancer often receive chemotherapeutic agents concurrently with other medications to treat comorbidity. The practical effects of concomitant medications, especially polypharmacy, on adverse drug reactions related to irinotecan-based chemotherapy are not well documented. Associations of adverse drug reactions related to irinotecan monotherapy or a combination of irinotecan, 5-fluorouracil, and L-leucovorin (FOLFIRI) with concomitant medicines used to treat comorbidity were retrospectively investigated in Japanese patients with cancer. Of the 172 patients, 118 received concomitant medications. Twenty-one patients had grade 4 neutropenia and/or grade 3 or 4 diarrhea. Univariate and multivariate analyses revealed that concomitant medications were significantly associated with irinotecan-related severe neutropenia and/or diarrhea (P = 0.023 and 0.044). Multiple concomitant medications were significantly related to severe irinotecan-related toxicity in patients given monotherapy or FOLFIRI (P = 0.01). The incidence of severe irinotecan-related toxicities increased in parallel with the number of concomitant medications. We found that multiple concomitant medicines were significantly associated with severe irinotecan-related toxicity, indicating that polypharmacy must be effectively managed to decrease the risk of adverse drug reactions in patients with cancer who received irinotecan-based chemotherapy.

Abstract 1866: Genome-wide association study for irinotecan-related severe toxicities in patients with advanced non-small cell lung cancer

Abstract Purpose: We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with severe diarrhea and neutropenia in patients treated with irinotecan for advanced non-small cell lung cancer (NSCLC). Patients and Methods: We performed a case-control GWAS using the Affymetrix 5.0 array set in 103 patients enrolled in two phase II studies of with irinotecan and cisplatin. A subsequent replication study was conducted to validate major GWAS findings in an independent series of 146 patients enrolled in another phase II study of irinotecan-based chemotherapy. Cases were defined as patients with grade 3 diarrhea (G3D) or grade 4 neutropenia (G4N) according to the National Cancer institute's Common Terminology Criteria for adverse events v3.0. Results: The GWAS included 11 G3D (control 90) and 24 G4N (control 77). The replication set included 13 G3D (control 133) and 21 G4N (control 125). GWAS identified 49 and 32 SNPs putatively associated with G3D and G4N, respectively. In the replication series, SNPs, rs1517114 (C8orf34), rs1661167 (FLJ41856), and rs2745761 (PLCB1) were confirmed for G3D, and rs11128347 (PDZRN3), rs11979430 and rs7779029 (SEMAC3) were confirmed for G4N. Conclusion: This GWAS screen along with subsequent validation indentified novels SNPs associated with irinotecan-related severe toxicities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1866. doi:1538-7445.AM2012-1866

Clinical implications of polymorphisms in UDP-glucuronosyl transferase (UGT) in patients with metastatic colorectal cancer (mCRC) who were treated with oxaliplatin, irinotecan, and S-1.

503 Background: The three-drug regimen with oxaliplatin, irinotecan and fluoropyrimidine is an effective therapeutic option for patients with mCRC, but is associated with high rate of toxicity. Pharmacogenetic profile might be helpful for selection of proper patients for this intensive regimen. Methods: Forty-two patients were enrolled to our phase II trial and were given irinotecan 150mg/m2 plus oxaliplatin 85mg/m2 on D1 and S-1 80mg/m2/day on D1-14 every 21 days as their front-line therapy for mCRC. Genomic DNA was extracted from peripheral blood, where the presence of germline polymorphisms of UGT including UGT1A1*6, UGT1A1*28, UGT1A1*60, UGT1A6*2, and UGT1A7*3 were tested. Results: Patients with UGT1A1*6 allele had a tendency of more frequent grade 2-3 vomiting (p = 0.06) compared to those without UGT1A1*6. The presence of a haplotype containing UGT1A6*2 and UGT1A7*3 was associated with grade 2-3 vomiting (p = 0.014) and grade 2-3 diarrhea (p = 0.063). Higher objective response rate (18/20, 90%) was noted in patients without UGT1A*60 compared to those with UGT1A1*60 (11/22, 50%; p = 0.008). The absence of UGT1A1*60 was also associated with marginally improved progression-free survival (10.3 mo v 7.7 mo, p = 0.081) and overall survival (26.8 mo v 15.1 mo, p= 0.044) compared to the presence of the variant allele. Conclusions: UGT1A1*6 and a haplotype containing UGT1A6*2 and UGT1A7*3 may be associated with irinotecan-related gastrointestinal toxicities. Phenotypic association of UGT1A1*60 and efficacy of the three-drug regimen requires further investigation.

Abstract 3592: Association of SUMO-1 and UBC9 genotypes with tumor response and toxicity in non-small cell lung cancer patients treated with irinotecan-based chemotherapy

Abstract Purpose: As the molecular target of irinotecan, TOP1 is a plausible predictive marker for irinotecan chemotherapy. Recently clinical studies have demonstrated that high TOP1 expression in cancer cells was predictive for benefit from irinotecan chemotherapy. Because sumoylation has been implicated in the regulation of protein stability and activity, TOP1 sumoylation may competitively inhibit TOP1 ubiquitination and degradation and lead to increased sensitivity to irinotecan. Thus, we investigated whether SUMO1 and UBC9 genotypes affect tumor response and toxicities in patients with advanced non-small cell lung cancer (NSCLC) treated with irinotecan and cisplatin (IP) chemotherapy. Experimental design: SUMO1 and UBC9 SNPs were selected based on Japanese Hapmap genotyping data (http://www.hapmap.org) and tagging SNP selection were performed with Tagger program (http://www.broad.mit.edu/mpg/tagger) with linkage disequilibrium bin tagging approach. Genomic DNA was extracted from blood samples and genotyped for SUMO1 −8348A&amp;gt;T, −1901C&amp;gt;G, −150G&amp;gt;A, and UBC9 390C&amp;gt;A, −207G&amp;gt;A, 10920C&amp;gt;G. To clarify the independent effects of those polymorphisms on tumor response and toxicities, well known genotypes such as UGT1A1*6, UGT1A1*28, UGT1A9*22, SLCO1B1 521T&amp;gt;C, ABCC2 −24C&amp;gt;T, ABCC2 3972C&amp;gt;T, ABCG2 34G&amp;gt;A genotypes were also examined and correlated with tumor response and toxicities. Immunohistochemistry for SUMO1 and UBC9 was performed on 42 tumor samples and correlated with genotypes. Results: There were 147 patients included in this analysis, including 115 men and 32 women with a median age of 61 (range, 29 to 77 years). Of 147 patients, 143 were assessable for tumor responses to IP chemotherapy. The overall response rate (ORR) was 43%; 61 had partial responses; 47 had stable diseases; and 35 had progressive diseases. Among SUMO1 and UBC9 polymorphisms examined, only the UBC9 10920C&amp;gt;G was associated with tumor responses. Patients with the UBC9 10920CG genotype had a significantly higher ORR than those with homozygous CC (81% v 37%, P = 0.0002). In a multivariate logistic analysis using the associated factors with P&amp;lt;0.1 as predictive variables, only the UBC9 10920CG variant maintained its predictive value on tumor response to IP chemotherapy (OR =8.5, 95% CI; 2.1 to 34.6, P=0.003). Moreover, tumors arising from the UBC9 10920CG genotype were associated with higher prevalence of SUMO1 overexpression compared with those with CC genotype (78% v 31%, P=0.021). However, none of SUMO1 and UBC9 polymorphisms was significantly predictive for irinotecan-related severe toxicities. Conclusions: This finding suggests that the UBC9 10920CG genotype enhances sensitivity to irinotecan chemotherapy in advanced NSCLC through upregulation of SUMO1 in tumor cells (This study was supported by a grant from National Cancer Center 0810130-2). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3592.

Phase Ib study of recombinant human Apo2L/TRAIL plus irinotecan and cetuximab or FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts): Preliminary results

4129 Background: Preclinical data suggest that recombinant human Apo2 ligand/TNF-related apoptosis-inducing ligand (rhApo2L/TRAIL) induces tumor cell death through pro-apoptotic receptors DR4 and DR5. In specific mouse xenograft colon cancer models, tumors regressed in the majority of mice given rhApo2L/TRAIL and irinotecan. In this ongoing study of rhApo2L/TRAIL in previously treated mCRC pts, the primary objectives are to assess the safety and pharmacokinetics of rhApo2L/TRAIL combined with irinotecan and cetuximab or FOLFIRI. Methods: As of 12/12/08, 30 pts have received rhApo2L/TRAIL (on Days 1–5) with irinotecan (on Day 1) and cetuximab (on Days 1, 8, and 15) in 21-day cycles; rhApo2L/TRAIL dose cohorts range from 1.5–8 mg/kg/day. 5 pts have received rhApo2L/TRAIL 9 mg/kg (on Days 1–3) with FOLFIRI (leucovorin, 5-FU, and irinotecan on Day 1) in 14-day cycles. Results: In the first cohort, rhApo2L/TRAIL was given at 4 mg/kg/d with irinotecan (350 mg/m2) and cetuximab; the first 3 pts developed Grade 3–4 neutropenia. The study was amended to allow irinotecan dose reductions to 300 mg/m2 for pts at risk for irinotecan-related toxicities and patients were started on a lower dose of Apo2L/TRAIL at 1.5 mg/kg/d. An additional 32 pts received rhApo2L/TRAIL at 1.5–9 mg/kg/d. The most common adverse events thus far are diarrhea, fatigue, and nausea. A pt with anemia at screening developed Grade 4 anemia DLT. 2 pts (1 with progressive liver disease) discontinued therapy due to elevated ALT. Conclusions: Preliminary data indicate that rhApo2L/TRAIL can be safely combined with irinotecan-based regimens. Full data will be available by June 2008. A phase II study of rhApo2L/TRAIL with FOLFIRI should provide more information on safety, efficacy, and a potential diagnostic for rhApo2L/TRAIL. [Table: see text]