Irinotecan Toxicity Research Articles

Anti-EGFR (cetuximab) combined with irinotecan for treatment of elderly patients with metastatic colorectal cancer (mCRC)

This study was conducted to test the efficacy and toxicity of cetuximab and irinotecan as a biweekly regimen in treatment of elderly patients with metastatic colorectal cancer (mCRC). Forty-nine elderly patients (≥65years) with mCRC who progressed after at least one previous line of treatment were enrolled into this study from May 2008 to January 2011. All recruited patients received cetuximab 500mg/m(2) and irinotecan 180mg/m(2) every 2weeks. Thirty-seven patients (76%) were men, and 76% of patients had colonic cancer in origin. Median age was 69years. Median overall survival time was 7months, and median progression-free survival was 4months. Grade 3-4 skin rash occurred in 20% of patients, grade 3-4 diarrhea in 18% of patients, and neutropenia in 28% of patients. Cetuximab combined with irinotecan when administered biweekly is safe and effective for treatment of pretreated elderly patients with mCRC.

Phase II study of EZN-2208 (PEG-SN38) with or without cetuximab in patients with metastatic colorectal cancer (CRC).

448 Background: EZN-2208 is a water-soluble, parenterally-delivered PEGylated conjugate of SN38 that increases solubility, exposure, and apparent half-life of SN-38. Methods: Patients with metastatic or locally recurrent CRC previously treated with fluoropyrimidines, oxaliplatin and irinotecan, and no more than 2 distinct progressions, were screened for K-Ras mutation and stratified accordingly. Patients with K-Ras tumor mutation (Mut) were treated with EZN-2208 (9mg/m2 SN-38 equivalents) over 1-h IV on days 1, 8, 15 in 4-wk cycles (Arm A). Patients with K-Ras wild type (WT) tumors were randomized (2:1) to EZN-2208 (as above) and cetuximab (250mg/m2 weekly following 400mg/m2 on D1) (Arm B) or to irinotecan (125mg/m2) over 90min IV days 1, 8 in 3 week cycles and cetuximab (as above) (Arm C). The primary objectives of the study were to determine the overall response rates (ORR) and progression free survival (PFS) (Arm A) and compare PFS (Arms B and C). A comparison of safety and toxicity of EZN-2208 and irinotecan was planned as well. Results: Demographic and efficacy parameters are summarized in the table . Common adverse events (Arms A%, B%, C%), observed in > 25% of patients in at least one arm of the study, were diarrhea (45%, 64%, 55%), fatigue (56%, 56%, 39%), nausea (43%, 59%, 47%), vomiting (31%, 46%, 39%), constipation (27%, 26%, 37%), abdominal pain (25%, 28%, 32%), anemia (33%, 21%, 21%), dermatitis acneiform (0%, 28%, 26%), hypokalemia (17%, 28%, 26%), and alopecia (12%, 28%, 3%). Conclusions: EZN-2208 in combination with cetuximab is active in patients in the 3rd line setting of CRC and comparable to irinotecan in combination with cetuximab. EZN-2208 monotherapy did not result in responses in patients with CRC following progression on irinotecan. EZN-2208 has an acceptable safety and tolerability profile as monotherapy, and in combination with cetuximab. [Table: see text]

Ugt1a is required for the protective effect of selenium against irinotecan-induced toxicity

Irinotecan (CPT-11) is widely used for the treatment of patients with colorectal cancer. However, the adverse effects associated with the treatment have hindered the efficacies of irinotecan. We have shown that organic selenium compounds could significantly attenuate irinotecan-associated toxicity and enhance antitumor activity in xenograft tumor models. The objective of this study is to determine the role of a specific group of uridine diphosphate glucuronosyltransferases, which is coded by UGT1A, in detoxification process of irinotecan as well as selenium-associated protective effect against irinotecan-induced toxicity. In this study, the toxicities of irinotecan, docetaxel and cisplatin in the Ugta1 mutant rats and their wild-type controls were compared. The plasma concentrations of irinotecan and SN-38 were measured. The modulatory effect of a selenium compound on irinotecan-induced toxicity was analyzed in these rats. We demonstrated that the maximum tolerated doses of irinotecan in the homozygous mutant rats were significantly lower than those in wild-type rats, 25 mg/kg × 1 versus 200 mg/kg × 1 and 3 mg/kg/day × 3 versus 100 mg/kg/day × 3, respectively. The enhanced sensitivity was specific to irinotecan and was not observed with other chemotherapeutic agents, such as docetaxel and cisplatin, where Ugt1a is not required for their metabolism. Our results also showed that selective protection against irinotecan-induced toxicity by 5-methylselenocysteine was achieved in the wild-type rats but not in the Ugt1a null rats. These data support the hypothesis that expression of UGT1A is critical for 5-methylselenocysteine to exert its protective effect against irinotecan-induced toxicity.

Irinotecan Plus Mitomycin C as Second-Line Chemotherapy for Advanced Gastric Cancer Resistant to Fluoropyrimidine and Cisplatin: A Retrospective Study

Background. S-1 plus cisplatin has been established to be standard first-line chemotherapy for advanced gastric cancer in Japan. The optimal second-line treatment refractory to S-1 plus cisplatin remains unclear. Methods. We retrospectively studied the efficacy, toxicity, and survival of irinotecan plus mitomycin C in patients with advanced gastric cancer refractory to a fluoropyrimidine plus cisplatin. Results. Twenty-four patients were studied. Prior chemotherapy was S-1 plus cisplatin in 15 patients, S-1 plus cisplatin and docetaxel in 8, and 5-fluorouracil plus cisplatin with radiotherapy in 1. The overall response rate was 17.4%. The median overall survival was 8.6 months, and the median progression-free survival was 3.6 months. Grade 3 or 4 toxicities included leukopenia (33%), neutropenia (50%), anemia (33%), thrombocytopenia (4%), anorexia (13%), diarrhea (4%), and febrile neutropenia (13%). Conclusion. A combination of irinotecan and mitomycin C is potentially effective in patients with advanced gastric cancer refractory to a fluoropyrimidine plus cisplatin.

Predictors of Irinotecan Toxicity and Efficacy in Treatment of Metastatic Colorectal Cancer

The colorectal cancer ranks high among the malignant tumours in incidence and mortality and irinotecan is standardly used in palliative treatment of metastatic disease in every therapeutic line. Unfortunately, the treatment with irinotecan is often associated with severe toxicities, especially neutropenia and diarrhea. The majority of the toxic manifestation is caused by the insufficient deactivation (glucuronidation) of irinotecan active metabolite SN-38 by UGT1A enzyme. The elevated SN-38 plasma concentration is responsible for the hematological and gastrointestinal toxicity that can become life-threatening. The patients carrying the mutation of the gene encoding UGT1A enzyme lack the ability of bilirubin glucuronidation, and suffer from the inherited un-conjugated hyperbilirubinemia (Gilbert syndrome, Crigler-Najjar type 1 and 2 syndrome). The mutations in other enzyme systems also play role in the etiopathogenesis of the irinotecan toxicity: CYP3A (cytochrome P-450), ABC family of transmembrane transporters (adenosine-triphosphate binding cassette). The goal of the contemporary research is to determine the predictive factors that will enable the individual adjustment of the individual drug dosage while minimising the adverse effects and maintaining the treatment benefit.

Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer

PurposeThe purpose of this study was to evaluate efficacy and toxicity of irinotecan, leucovorin and 5-fluorouracil (FOLFIRI) as second-line treatment after failure of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) for advanced gastric cancer.Materials and MethodsPatients who received modified FOLFOX-4 as first-line treatment and then received sequential modified FOLFIRI for disease progression were included in this study. The modified FOLFIRI regimen consisted of irinotecan 150 mg/m2 in a 90-minute intravenous infusion on day 1, leucovorin (LV) 20 mg/m2 and 5-fluorouracil (5-FU) 400 mg/m2 as a bolus followed by 600 mg/m2 as a 22-hour infusion on days 1 and 2 with the same dose of 5-FU/LV of modified FOLFOX-4 every 2 weeks.ResultsA total of 32 patients received 126 courses of FOLFIRI chemotherapy. No complete response was achieved. Three patients (9.4%; 95% confidence interval [CI], 0 to 20.1%) achieved partial response, whereas 11 (34.4%; 95% CI, 17.0 to 51.8%) patients showed stable disease. Disease control rate (complete response, partial responses and stable diseases) was 43.8% (95% CI, 25.6 to 61.9%) and median follow up duration was 11.3 months (range, 2.23 to 37.9 months). Median time to progression was 2 months (95% CI, 1.49 to 2.51 months), and median overall survival from the start of FOLFIRI was 5.84 months (95% CI, 4.34 to 7.34 months). Toxicities were tolerable.ConclusionModified FOLFIRI as second-line chemotherapy after failure of the modified FOLFOX-4 in advanced gastric cancer was tolerable but showed a lower response rate. Further study about retrying 5-FU/LV with irinotecan after failure of the 5-FU/LV combined regimen is necessary in advanced gastric cancer.

5-Fluorouracil/Leucovorin Combined with Irinotecan and Oxaliplatin (FOLFIRINOX) as Second-Line Chemotherapy in Patients with Metastatic Pancreatic Adenocarcinoma

Background: To evaluate the efficacy and toxicity of irinotecan and oxaliplatin plus 5-fluorouracil (FU) and leucovorin (FOLFIRINOX) as second-line therapy in metastatic pancreatic adenocarcinoma (MPA). Patients and Methods: We retrospectively analyzed the medical records of 27 patients with MPA treated with FOLFIRINOX as second-line therapy between January 2003 and November 2009 in our hospital. The recommended schedule was oxaliplatin 85 mg/m² on day 1 + irinotecan 180 mg/m² on day 1 + leucovorin 400 mg/m² on day 1 followed by FU 400 mg/m² as a bolus on day 1 and 2,400 mg/m² as 46-hour continuous infusion biweekly. Results: The median age of the 27 patients (13 males and 14 females) was 63 years (45–83). All patients had progressive disease after first-line chemotherapy by gemcitabine. A total of 167 cycles were administered, with a median number of 6 cycles (1–29) per patient. One toxic death occurred (sepsis). Tolerance of treatment was acceptable, and the relative dose density delivered per patient was 92.8% for oxaliplatin, 89.1% for irinotecan and 96.4% for FU. Grade 3–4 neutropenia occurred in 55.6% of the patients, including 1 febrile neutropenia. The other toxicities were manageable. Regarding efficacy, 22 of the 27 patients were evaluable (WHO and RECIST criteria). Five patients had partial responses and 12 stable disease, resulting in an overall disease control rate of 63%. Median time to progression was 5.4 months (0.7–25.48), and median event-free survival was 3 months (0.5–24.9). Median overall survival was 8.5 months (0–26). A clinical benefit was reported for 55% of the patients. Conclusions: These results confirmed the good safety profile and the efficacy of the FOLFIRINOX regimen as second-line treatment of MPA.

Clinical effects of irinotecan hydrochloride in combination with cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer

Objective To evaluate the toxicity and efficacy of irinotecan plus cisplatin neoadjuvant chemotherapy (NACT) for cervical cancer. Methods A total of 120 cases with cervical cancer were divided into 2 groups and retrospectively reviewed: Sixty FIGO IB2-IIB patients in NACT group were treated with 2 cycles of irinotecan 60 mg/m 2 on days 1 and 8 plus cisplatin 60 mg/m 2 on day 1 followed by surgery. Sixty FIGO IB2-IIB patients in control group were treated directly with surgery. Results The 60 patients in NACT group received a total of 120 cycles. Grades III and IV neutropenia and diarrhea were seen in 15.8% and 11.7%, respectively, of all chemotherapy cycles. Six (10.0%) patients achieved complete remission, 33 (55.0%) achieved partial remission, 21 (35.0%) remained stable, and none had disease progression. Postoperatively the deep cervical stromal invasion and positivity of surgical margins were significantly fewer in the NACT group. The pelvic lymph node metastasis rate of responders to NACT was significantly lower than that of non-responders (12.8% vs 38.1%). With a median follow-up of 29 and 30 months, the intra-pelvic recurrence rate of the NACT group was significantly lower than that of the control group (3/60 vs 11/60, p = 0.023), the 2-year recurrence-free survival and the 2-year overall survival was 82.3% and 86.1% in the NACT group, and 86.3%, 87.9% in the control group with no significant difference. Multivariate analysis showed that response to NACT was the only factor associated with survival ( p = 0.036). Conclusion Irinotecan plus cisplatin NACT for cervical cancer has high efficacy and tolerable toxicity, and can significantly reduce the rates of deep cervical stromal invasion and positive surgical margins. Pelvic lymph node metastasis decreases significantly in responders compared with non-responders. The response to NACT can be considered as an independent prognostic factor.

Strain- and Sex-Dependent Circadian Changes in Abcc2 Transporter Expression: Implications for Irinotecan Chronotolerance in Mouse Ileum

BackgroundATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity for ileum mucosa, and further assess whether genetic background or sex modify this relation.Methodology/Principal FindingsIleum mucosa was obtained every 3–4 h for 24 h in male and female B6D2F1 and B6CBAF1 mice synchronized with light from Zeitgeber Time (ZT)0 to ZT12 alternating with 12 h of darkness. Irinotecan (50 mg/kg i.v. daily for 4 days) was administered at the sex- and strain-specific times corresponding to least (ZT11-15) or largest drug-induced body weight loss (ZT23-03-07). Abcc2 expression was determined with qRT-PCR for mRNA and with immunohistochemistry and confocal microscopy for protein. Histopathologic lesions were graded in ileum tissues obtained 2, 4 or 6 days after treatment. Two- to six-fold circadian changes were demonstrated for mRNA and protein mean expressions of abcc2 in mouse ileum (p<0.05). ZT12 corresponded to high mRNA and protein expressions, with circadian waveforms differing according to genetic background and sex. The proportion of mice spared from ileum lesions varied three-fold according to irinotecan timing, with best tolerability at ZT11-15 (p = 0.00003). Irinotecan was also best tolerated in males (p = 0.05) and in B6CBAF1 (p = 0.0006).Conclusions/SignificanceStrain- and sex-dependent circadian patterns in abcc2 expressions displayed robust relations with the chronotolerance of ileum mucosa for irinotecan. This finding has strong potential implications for improving the intestinal tolerability of anticancer drugs through circadian delivery.

An independent, external validation study of proposed genetic biomarkers of irinotecan toxicity and pharmacokinetics.

e14022 Background: Pharmacogenetic studies have proposed a large number of genetic variants as predictors of outcome of chemotherapy. The vast majority of them failed to replicate, leaving very few validated associations. UGT1A1*28 is a validated marker of severe neutropenia of irinotecan. In addition to UGT1A1*28, we proposed other variants in the irinotecan pathway as associated with neutropenia and pharmacokinetics in 85 refractory cancer patients treated with 300-350 mg/m2 three-weekly single-agent irinotecan (Innocenti et al., JCO 2009). These variants were associated with ANC nadir and the pharmacokinetics of irinotecan and its metabolites SN-38 (active) and SN-38G (inactive). In this study, we aimed to independently validate these variants. Methods: 112 refractory cancer patients (Caucasians, 1 African) from The Netherlands were genotyped for 10 variants in ABCC1, ABCC2, SLCO1B1, TCF1, and UGT1A1. In the replication set, patients received irinotecan as 600 mg (flat dose, n=60), 350 mg/m2 (n=33), and 380-1,060 mg (flat dose calculated according to the algorithm of van der Bol JM et al., CCR 2010, n=19). ANC nadir and pharmacokinetic results were already available. After multivariate analysis by linear regression, a p<0.05 and same direction of the effect were used as the validation criteria. Results: For ANC nadir, both UGT1A1*93 (p=0.04) and SLCO1B1*1b (p=0.04) were replicated. SLCO1B1*1b had a protective effect on neutropenia. For irinotecan pharmacokinetics, replicated variants were ABCC2 -24C>T for irinotecan AUC (p=0.04), UGT1A1*93 for SN-38 AUC (p<0.001), and UGT1A1*28 for the SN-38G/SN-38 AUC ratio (p<0.001). The other 7 gene variants failed to replicate. For some variants, the lower significance is due to a higher interpatient phenotypic variation in the replication set. Differences in irinotecan dosing between the two studies did not impact the ability to reproduce associations. Conclusions: This prospective study 1) validated, besides UGT1A1*93, the new marker SLCO1B1*1b for irinotecan neutropenia, 2) failed to confirm previously reported variants, and 3) provided a study framework to conduct external validation in cancer pharmacogenomics.

Phase II trial of chemotherapy with high-dose FOLFIRI plus bevacizumab in the front-line treatment of patients with metastatic colorectal cancer (mCRC) and genotype UGT1A1*1/ UGT1A1*1 or UGT1A1*1/ UGT1A1*28 (FFCD 0504 trial): Final results.

3578 Background: The combination of high-dose irinotecan (260mg/m2) with LV5FU2 (FOLFIRI HD regimen) is feasible with an acceptable safety profile and promising efficacy data (Ducreux et al. Oncology 2008;74:17-24). The aim of this phase II study was to evaluate the combination of FOLFIRI HD plus bevacizumab (B) in patients (pts) selected on the UGT1A1 polymorphism, which could be predictive of the irinotecan toxicity and efficacy. Methods: Pts with UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotypes and previously untreated mCRC were treated with bevacizumab 5 mg/kg D1, irinotecan 260 mg/m² D1, LV 400 mg/m² D1, 5FU 400 mg/m² IV bolus D1 and 5FU 2400 mg/m² 46h infusion D1-2 every 2 weeks. Using Bryant & Day design with objective response rate (ORR) (independent review, H0 ≤ 40%; H1 ≥ 60%) and toxicity (gr 4 neutropenia or febrile neutropenia or gr 3-4 diarrhea; H0 ≥ 20%; H1≤ 5%) as primary endpoints; a total of 108 pts, 54 in each group, was required (alpha 5% and power 80%) with a planned interim analysis after the inclusion of 17 pts by group. The trial will be stopped at interim analysis if ≤ 7 pts had an OR and/or ≥ 3 pts had a severe toxicity. All analyses were performed in ITT. Results: At the time of interim analysis, done when the 17th pt of group 1 had a 6-months follow-up, 86 pts were included (group 1: 40 pts, group 2: 46 pts). Results of primary endpoints at the interim analysis are presented in the table. According to interim analysis rules, the trial was closed to inclusion for unacceptable toxicity. Conclusions: The trial was stopped after interim analysis because of unacceptable toxicity according to trial's criteria, even if toxicity was manageable and most of the patients continued the treatment after dose adaptation. Defined toxicity criteria to stop the trial at interim analysis may have been too strict and not clinically adapted. There is however no clear benefit of the FOLFIRI HD - B combination in terms of efficacy. Group 1 Group 2 N 17 17 ORR (%) 52.9 58.8 Toxicity (%) 41.2 18.8

In Situ Intestinal Perfusion of Irinotecan: Application to P-gp Mediated Drug Interaction and Introduction of an Improved HPLC Assay

To determine experimentally the intestinal permeability of the anticancer prodrug irinotecan, and to quantify the amount of its cytotoxic metabolite SN-38 that is intestinally excreted (exsorped) as a predictor of intestinal toxicity, and to assess the effect of p-glycoprotein (p-gp) inhibitors (verapamil as a model) on the permeability and toxicity of irinotecan. Single pass intestinal perfusion of rat's whole length small intestines is applied to assess the permeability of the parent drug and quantify the intestinally excreted metabolite. The perfusion solution contained 30μg/ml of irinotecan (control group) without or with verapamil (verapamil group). A simple reversed phase HPLC method with UV detection is developed and validated for simultaneous determination of irinotecan and SN-38 using camptothecin as an internal standard. HPLC-UV method found to be simple, specific, accurate, and precise. Effective permeability coefficient of irinotecan found to be 4.9±1.7 10-3 mm/min and was doubled in verapamil group (P=0.007). Average cumulative amount of SN-38 exsorped found to be 29 ng/cm over 2 hours perfusion time which was decreased to 15 ng/cm in verapamil group (P=0.016). in situ intestinal perfusion method was successfully applied to quantify the permeability of irinotecan and the exsorption of SN-38 in the same experiment, in a manner that robustly reflects real in vivo situation. P-gp inhibition using verapamil found to significantly enhance the intestinal permeability of irinotecan and potentially decrease the intestinal toxicity due to SN-38 exposure.

Abstract 1302: Delayed elimination of SN-38 and prolonged neutropenia in cancer patients with severe renal failure requiring dialysis who receive irinotecan

Abstract Purpose: We prospectively examined the effects of severe renal failure on the pharmacokinetics and toxicity of irinotecan. Experimental Design: The pharmacokinetics of irinotecan, SN-38 and SN-38 glucuronide (SN-38G), and irinotecan-induced toxicity in 3 cancer patients with severe renal failure (creatinine clearance [Ccr] ≤20 mL/min) who were undergoing dialysis and received 100 mg/m2 irinotecan as monotherapy were compared with those in 5 cancer patients with normal renal function (Ccr ≥60 mL/min). To ensure that the subjects had similar genetic backgrounds of UDP-glucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, *1/*6, or *1/*28 were enrolled. Results: The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was about one tenth that in patients with normal renal function (P=0.025). Consequently, the estimated t1/2 of SN-38 in patients with severe renal failure was roughly 10 times longer than that in patients without renal failure (P=0.025). About 50% of SN-38 was dialyzed with a 2.1-m2 dialysis membrane, whereas 27% was dialyzed with a 1.5-m2 membrane. All patients with severe renal failure experienced neutropenia (grade 2, 3 or 4 at nadir). In two of them experienced grade 2 or 3 neutropenia, the second irinotecan infusion was delayed 10 or 20 days by the prolonged neutropenia. Conclusions: Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure as compared with patients with normal renal function. We demonstrated SN-38 was partly dialyzed. The prolonged neutropenia was seen in patients with severe renal failure. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1302. doi:10.1158/1538-7445.AM2011-1302

Comparison between the effects of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer

To observe and compare the response rate and toxicity of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer. Sixty-three patients with advanced gastric cancer were randomly divided into two groups. The CPT-11 + CAP group consisted of 32 patients who received irinotecan plus capecitabine: CPT-11 100 mg/m(2) was injected in 90 minutes on d 1, 8;capecitabine 2000 mg/m(2), bid, with the first dose in the evening of day 1 and last dose the morning of day 15, repeated for every 21 days. The L-OHP + CAP group consisted of 31 patients who received oxaliplatin plus capecitabine: oxaliplatin 100 mg/m(2) on day 1, capecitabine 2000 mg/m(2), bid, with the first dose in the evening of day 1 and last dose the morning of day 15, repeated for every 21 days. Two or more cycle chemotherapy was completed in each group. In the CPT-11 + CAP group, no patient achieved complete response and 13 patients achieved partia1 response. The overall response rate was 40.6% (13/32), and the median progression-free survival time was 6.3 months. In the L-OHP + CAP group, no patient achieved complete response and 12 patients achieved partial response. The overall response rate was 38.7% (12/31), and the median progression-free survival time was 6.1 months. There was no significant difference between them (P > 0.05). The most common toxicities were gastrointestinal reaction, peripheral neuropathy and myelosuppression in the two groups. Patients in CPT-11 + CAP group experienced more III/IV diarrhea (28.1%/3.2%, P = 0.018). On the contrary, the rate of III/IV neurotoxicity in the group B was higher (25.8%/3.1%, P = 0.027). No chemotherapy-related death occurred. The therapeutic effects of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer are good and comparable, and their toxicities are tolerable.

Concurrence of UGT1A Polymorphism and End-Stage Renal Disease Leads to Severe Toxicities of Irinotecan in a Patient with Metastatic Colon Cancer

Colorectal cancer is one of the most common malignancies in the world, and irinotecan (CPT-11) is useful in its treatment. However, the safety and pharmacokinetics of irinotecan in dialysis patients with metastatic colorectal cancer are unclear. We report the case of a 74-year-old man receiving chronic hemodialysis who had metastatic colorectal cancer. Palliative chemotherapy with irinotecan (80 mg/m2 weekly) was administered after hemodialysis. Blood samples were collected before and 1.5, 3, 6, 9, and 15 hours after administration of irinotecan. The peak serum concentrations (Cmax) of irinotecan and SN-38 in this patient were 1,480 and 17.8 ng/mL, respectively, which were similar to the reported values in patients with normal renal function after a similar dose of irinotecan (75 mg/m2). The area under the serum concentration-time curve (AUC0-∞) was 8,240 ng×h/mL for irinotecan and 619 ng×h/mL for SN-38. The AUC0-∞ for SN-38 was markedly higher than that for patients with normal renal function. Sequencing analysis of the UGT1A genes found that the patient had variant alleles of UGT1A1*28, UGT1A1*60 and UGT1A9*22, which may lead to decreased glucuronidation and excretion of SN-38, and may account for increased irinotecan-related toxicity. The patient developed febrile grade 4 neutropenia on day 7 after chemotherapy and died of septic shock on day 14. UGT1A polymorphisms and renal failure may lead to accumulation of SN-38, which may have played a role in the death of this patient. Irinotecan should be used cautiously in dialysis patients with metastatic colorectal cancer and screening for UGT1A polymorphisms may help in identifying patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan-induced toxicity.

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

Variation of a short (TA)(n) repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDP-glucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA)(7) and (TA)(8) )) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA)(n) alleles frequencies were highest in equatorial Africa, (TA)(7,) being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA)(n) . Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA)(n) on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.

Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: A prospective cross-over drug–drug interaction study

BackgroundOmeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan. MethodsFourteen patients were treated with single agent irinotecan (600mg i.v., 90min) followed 3weeks later by a second cycle with concurrent use of omeprazole 40mg once daily, which was started 2weeks prior to the second cycle. Plasma samples were obtained up to 55h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS. ResultsThe exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole. ConclusionOmeprazole 40mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.

Abstract ES9-2: Understanding the Role of Botanicals in the Management of Breast Cancer

Abstract Botanical agents have been used for centuries based on empiric observations of salutary effects on a variety of illnesses. A significant portion of our modern pharmacopeia is derived from botanical products and may be attributable to bioactive components that have evolved over time to protect plants from infection and pestilence or even promote health of consumers to better spread seeds or pollinate. However, whole botanicals and combinatorial formulas are still used worldwide and represent a small but growing area of research in Western medicine. One potential advantage of this approach is that synergistic combinations of compounds may have developed over time through natural selection. Drawbacks include lower potency and higher potential for drug interactions with numerous compounds. Many Chinese herbs that have been used historically to treat cancer on an empiric basis do in fact possess anti-proliferative and pro-apoptotic properties. A variety of effects on cell signaling, oxidative stress, and metabolism have been reported. As with any foreign compound, the induction or suppression of metabolism enzymes and membrane transporters can lead to significant drug interactions. Contemporary research strategies for testing botanicals must therefore incorporate hypotheses based on early clinical or laboratory observations as would be the case for a chemical compound. However, complex effects that involve host interactions are not testable via in vitro models, posing a problem with efficient prioritization of clinical trials. Drug interaction models need to be applied early on prior to clinical testing. Investigational new drug (IND) processes for botanicals are still in flux, but becoming more transparent and increasingly requiring proof of product consistency. The botanical BZL101 is an extract of Scutellaria Barbatae (Ban Zhi Lian) that has shown in vitro and in vivo growth inhibition of breast cancer cells, and causes diverse effects including tumor-specific induction of reactive oxygen species, oxidative DNA damage and necrotic cell death mediated by poly (ADP-ribose) polymerase (PARP) activation, NAD consumption, inhibition of glycolysis, ATP depletion and ultimate energetic collapse. Two Phase I trials have shown that this agent can be given safely, with mild gastrointestinal side effects and Phase II trials are planned based on early evidence of clinical benefit. In the area of symptom management, amelioration of acute irinotecan gastrointestinal toxicities has been demonstrated in mice using an ancient 4-herb Chinese formulation termed PHY906, the chemical constituents of which exhibit pleiotropic effects including inhibition of nuclear factor kB, cyclooxygenase-2, and inducible nitric oxide synthase. For menopausal climacteric symptom relief, several modern botanicals have been show to be only marginally effective, and some demonstrate estrogenic activity. A 22-botanical formula called Menerba that induces estrogen receptor-beta specifically has been preliminarily shown to reduce hot flashes to a greater extent compared to placebo, and a Phase III trial is in progress in healthy women with hot flashes. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES9-2.

Abstract P6-11-09: Pilot Study of Irinotecan and S-1 for Advanced and Metastatic Breast Cancer

Abstract Patients with metastatic breast cancer (MBC) are often treated with multiple regimens, and viable options may soon be exhausted. Irinotecan (CPT-11), a topoisomerase 1 inhibitor, is rarely used in this setting, however. Approved for advanced breast cancer in Japan, S-1 is a pyrimidine derivative comprising the combination of tegafur, gimeracil and oteracil. Irinotecan is combined with S-1 (IRIS) to obtain an additive effect, even in the presence of high thymidylate synthase in breast cancer cells. This combination has also been successfully used for gastro-intestinal malignancies in Japan. Method: This study was divided into two steps: step 1, in which the safety profile of the regimen was determined; and step 2, in which tumor response was evaluated if the safety profile was considered acceptable. Irinotecan was given intravenously at a dose of 80 mg/m2 on days 1 and 8 and S-1 orally at 80-120 mg/day depending on body surface area for 2 weeks. The cycle was repeated every 3 weeks. Results: A total of 21 patients were registered in the study. Median age was 50 years (range, 26 -69 years). Performance status was 0 and 1 in 20 and 1 patients, respectively. Six patients were enrolled in step 1. Grade (G) 3 fatigue and vomiting were observed in 1 patients, G 3-4 neutropenia in 4 and G 3 anemia in 1. The toxicity profile in step 1 was determined acceptable to move on to step 2. Step 2 included 15 patients treated with IRIS. Grade 3-4 neutropenia occurred in 7 out of these 15 patients, fatigue in 1, diarrhea in 3 and anorexia in 1. All patients had previously received anthracyclines and taxanes. Eighteen patients, including 3 patients in step 1, were evaluable for response. A partial response was obtained in 5 patients (27.8%), including in 1 patient who had a history of 4 previous treatments. Progression-free survival in these patients was 137+, 147, 168+, 304+ and 364+ days; no progressive disease was observed in 4 of them. In addition, stable disease was obtained in 5 patients (27.8%) in whom 2 patients experienced SD for longer than 6 months. Conclusion: These results indicate that the IRIS regimen has an acceptable safety profile and modest activity against breast cancer in patients who have been heavily treated with chemotherapy for MBC. We believe the patients responded to the IRIS regimen because irinotecan has a different mechanism of action as compared to other drugs commonly used for breast cancer and complete cross-resistance may not exist between S-1 and capecitabine. This regimen is commonly used for gastric or colorectal cancer in Japan and is considered to be highly tolerable. Therefore, we conclude that this regimen has potential as an option to treat advanced and metastatic breast cancer, although attention must be paid to diarrhea, the dose-limiting toxicity of irinotecan and S-1. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-09.

Toxicity, Response Rates and Survival Outcomes of Induction Cisplatin and Irinotecan Followed by Concurrent Cisplatin, Irinotecan and Radiotherapy for Locally Advanced Esophageal Cancer

Cisplatin-based chemoradiotherapy is standard treatment for locally advanced esophageal and gastroesophageal cancers; however, the optimal chemotherapy regimen remains to be defined. Retrospective single institution analysis of toxicities, response rates and survival outcomes in patients with cT3-4 or N1/M1a esophageal squamous cell or adenocarcinoma treated with induction cisplatin and irinotecan followed by concurrent cisplatin, irinotecan and radiotherapy. Secondary analysis for association of disease control and outcomes with demographic, tumor and treatment factors (including histology). Fifty-three patients were eligible for the present analysis. All patients underwent endoscopic ultrasonography and were either cT3-4 and/or cN1 disease. Fifty patients completed radiotherapy as planned (median dose 50.4 Gy, range 0-61.2), and 35 patients completed four cycles of chemotherapy as planned (range 1-4). Severe acute toxicities included Grade ≥ 3 neutropenia and esophagitis in 13 and 12 patients, respectively. There were no Grade 5 (fatal) toxicities noted. At mean survivor follow-up of 24.5 months (range 2.7-63), 17 patients were alive (8 without disease) and 36 deceased. Forty patients experienced disease recurrence, with initial loco-regional, distant or both failures in 28, 9 and 3 patients, respectively. Estimated 2-year overall survival and freedom from failure were 42 and 9%, respectively, without significant difference by histology. Cisplatin/irinotecan chemoradiotherapy is tolerable, demonstrating similar efficacy for squamous cell and adenocarcinoma esophageal cancers.