Low-dose Irinotecan Research Articles

Pharmacogenetics: Global Clinical Markers

Sharon Marsh Washington University School of Medicine, Campus Box 8069, 660 S. Euclid Ave., St. Louis, MO 63110, USA Tel.: +1 314 747 5186; Fax: +1 314 362 3764; E-mail: smarsh@ im.wustl.edu ‘Allele frequencies for most polymorphisms show significant differences between populations, and within common population classifications.’ The release of the first working draft of the human genome was quickly followed by the prediction that approximately 1.42 million SNPs would be identified in the human genome [1]. This estimate was rapidly exceeded. Currently, the National Center for Biotechnology Information (NCBI) polymorphism repository dbSNP, has well over 4 million polymorphisms [101]. Endeavours, such as the International HapMap project [102], have provided insights into not only the quantity of polymorphisms, but also the variability in polymorphism frequency between world populations (specifically Europe, Yoruba, Japan and China) [2]. The available data set for pharmacogenetics research will be further expanded with the 1000 Genomes Project [103], which aims to sequence the entire genome of 1000 individuals from multiple populations (chiefly the extended HapMap sample set). This will provide a highly detailed map of polymorphisms that occur at a frequency of 1% or more in the human genome. The ultimate goal of pharmacogenetics is to define robust markers that can be used in the clinical setting to aid in individualized treatment selection. However, despite the plethora of genetic information at our fingertips the true number of established pharmacogenetic markers ready for integration into clinical practice is remarkably small [3,4], and their usefulness may be geographically limited. The lack of robust clinical pharmacogenetic markers could be owing to a multitude of reasons, including environmental factors, diet, concurrent medications, sample size, treatment regimen, population variation in allele frequencies and the lack of available sample sets to perform validation analyses. In addition to the reasons above, commonly published polymorphisms often suffer from contradictory results, making their role in the clinic unclear. Sometimes this can be clarified by taking a closer look at the studies. For example, conflicting data for UGT1A1*28, an FDA approved marker for predicting toxicity in patients receiving the chemotherapy drug irinotecan, can be clarified by including irinotecan dose in the analysis [5]. The polymorphism appears to be a marker for neutropenia in patients receiving high-dose irinotecan, but is a less useful marker for patients receiving low-dose irinotecan. Another factor involved in the use of UGT1A1*28 as a clinical marker is the allele frequency difference between populations. Although UGT1A1*28 is a functional polymorphism and has been associated with irinotecan toxicity in multiple populations [6], the allele frequency is lower in Asian populations (approximately 15% compared with 30–45% in Caucasian and African populations) [7]. Other potentially functional variants in UGT1A1 (e.g., UGT1A1*6) are prevalent in Asian populations and also demonstrate an association with irinotecan toxicity [8]. So although UGT1A1*28 appears to be a relevant clinical marker for all populations, some information would be missed by screening this alone in every patient. There is still work needed to define a panel of markers for irinotecan toxicity in all populations.

B-005 Modulation of the therapeutic efficacy of low-dose irinotecan by celecoxib against neuroblastoma xenografts(Oral Presentation Oncology 1,Better Life for Sick Children, Better Future for Pediatric Surgery,the 45th Annual Meeting of Japanese Society of Pediatric Surgeons)

B-005 Modulation of the therapeutic efficacy of low-dose irinotecan by celecoxib against neuroblastoma xenografts(Oral Presentation Oncology 1,Better Life for Sick Children, Better Future for Pediatric Surgery,the 45th Annual Meeting of Japanese Society of Pediatric Surgeons)

UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose Matters

The Food and Drug Administration and Pfizer changed the package insert for irinotecan to include a patient's UGT1A1*28 genotype as a risk factor for severe neutropenia on the basis of the findings of four pharmacogenetic studies, which found that irinotecan-treated patients who were homozygous for the UGT1A1*28 allele had a greater risk of hematologic toxic effects than patients who had one or two copies of the wild-type allele (UGT1A1*1). Findings of subsequent irinotecan pharmacogenetic studies have been inconsistent. In a meta-analysis, we reviewed data presented in nine studies that included a total of 10 sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III-IV) for patients with a UGT1A1*28/*28 genotype. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.52 to 6.81; P = .008) and high (OR = 27.8, 95% CI = 4.0 to 195; P = .005) doses of irinotecan. However, risk was similar at lower doses (OR = 1.80, 95% CI = 0.37 to 8.84; P = .41). Low doses of irinotecan (100-125 mg/m2) are in the commonly used therapeutic range. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered.

Weekly low dose irinotecan and daily oral anticancer drug chemotherapy for metastatic colorectal cancer (MCRC) patients more than 75 years old

14594 Background: The percentage of CRC patients more than 75 years old is expected to rise in Japan, too. However we have little data on the efficacy and toxicity of chemotherapy in elderly MCRC patients. The aim of this study was to evaluate the objective tumor response rates and toxicities in elderly MCRC patients treated weekly low dose irinotecan and daily oral anticancer drug (UFT or S-1) chemotherapy. Methods: Patients with MCRC were treated on an out-patient treatment basis with irinotecan 60mg/m(2) as an intravenous 90 minutes infusion on weekly plus UFT 300 mg/m(2) or S-1 60 mg/m(2) in 2 divided doses given orally on day 1 to 5 in every week. All the lesions were evaluated with CT and/or MRI scan. Results: From 2001 to 2005, we treated 20 elderly MCRC patients. There were 13 men and 7 women. Fourteen patients were 75∼79 years old and 6 patients were 80 years or more. Chemotherapy was given more than 3 months (3∼30M). To date, 495 cycles (median 24, range 7–98) have been administered. There were 8 PR, 10 SD and 2 PD. The overall response rate was 40% and disease control rate (PR + SD) was seen 90% of pts. Progression free survival time of this regimen is 9.3 months. Median survival time was 16.0 months. One and 2 years survival rates were 72% and 13%. No toxic death was reported. There was no grade III/IV toxicity and all adverse events were manageable. All patients were treated on an out-patient clinic. Conclusions: These results confirmed that this chemotherapy combination is active with acceptable tolerability and QOL maintenance in elderly patients with MCRC. Chemotherapy in elderly patients with MCRC should not be influenced by the chronologic age of the patient. No significant financial relationships to disclose.

Phase I study of oral irinotecan, temozolomide, and vincristine for children with refractory solid tumors: A Children's Oncology Group study

9563 Background: Both temozolomide (TEM) and vincristine (VCR) can increase the preclinical activity of low-dose protracted irinotecan (IRN) against pediatric solid tumors. Because these drugs have different dose-limiting toxicities (DLTs) and mechanisms of action, we combined these three agents and sought to determine the maximum tolerated dose (MTD) of orally administered IRN when given with fixed- dose TEM and VCR in children with relapsed or refractory solid tumors, using the antibiotic cefixime to reduce IRN-associated diarrhea. Methods: We studied two dose levels of oral IRN (35 or 50 mg/m2) administered on days 1–5 and 8–12, combined with oral TEM 100 mg/m2 on days 1–5 and intravenous VCR 1.5 mg/m2 on days 1 and 8. Courses were repeated every 21 days. Oral cefixime was started 5 days before chemotherapy and continued daily. Results: Of 21 patients enrolled, 17 (ages 3–21, median 14 yrs) were evaluable for toxicity and have to date received 46 courses (range 1–8, median 2). At the IRN dose of 50 mg/m2/d, 4 of 12 patients had DLT, including elevated ALT/AST (1), abdominal pain (1), hypokalemia (1), anorexia (1), thrombocytopenia (1), and fatal liver failure in a patient with metastatic disease in the liver and porta hepatis (1). In contrast, none of 5 patients treated at the dose of 35 mg/m2/d experienced first-course DLT, defining this dose as the MTD. UGT1A1 genotype did not correlate with DLT in this small trial. The median SN-38 lactone area under the curve (0–6h) at the IRN dose of 50 mg/m2/day was 13.5 ng/ml*h (range 3.8 to 30.9); pharmacokinetic analysis of patients treated at 35 mg/m2/day is ongoing. Six patients with the following tumors received more than 2 courses: neuroblastoma, ependymoma, hepatoblastoma, fibrillary astrocytoma, osteosarcoma, and Ewing sarcoma. Central review of response data is underway. Three patients continue on therapy at the MTD. Conclusions: Oral administration of IRN together with TEM and VCR was feasible and well tolerated at the MTD of 35 mg/m2 given dx5x2. Further study using a shorter 5-day course of oral IRN is planned. No significant financial relationships to disclose.

UGT1A1Promoter Genotype Correlates With SN-38 Pharmacokinetics, but Not Severe Toxicity in Patients Receiving Low-Dose Irinotecan

To study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks). Seventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy. The frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios. Severe toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.

Pharmacogenetics of Irinotecan: Clinical Perspectives on the Utility of Genotyping

Depending upon the UDP glucuronosyltransferase 1A1 (UGT1A1) genotype, patients are more or less susceptible to the risk of severe toxicity of irinotecan. As the US FDA-approved label of irinotecan (CPT-11, Camptosar) has been recently revised to include UGT1A1 genotype among potential risk factors for toxicity, it is expected that UGT1A1 genotyping will be increasingly used in patients undergoing irinotecan treatment. At present, the label states that *28/*28 (7/7) genotype patients are at higher risk of neutropenia and should be treated at a lower dose of irinotecan. Although effective alternative drugs (i.e., oxaliplatin) exist for metastatic colorectal cancer (the main indication of irinotecan), recent studies have confirmed that irinotecan has an important place in the management of this disease. We feel that now is the time for addressing questions around the UGT1A1*28 testing that many oncologists might have had but remained unanswered. For example, does the test have adequate sensitivity/specificity? Can the test results be effectively utilized to guide therapy of metastatic colorectal cancer patients? Is it possible that the *1/*1 (6/6) patients are underdosed? How can the genetic prediction of irinotecan toxicity be improved? Is the UGT1A1*28 test fully predictive of the UGT1A1 deficiency in patients who are not of Caucasian origin? Clinicians and investigators interested in a discussion of each of these points could find this article a useful source.

Phase II trial of concomitant low dose temozolomide with external beam radiation (EBRT) followed by 12 months of temozolomide and irinotecan for newly diagnosed glioblastoma (GBM): Preliminary results of RTOG 04–20

1510 Background: Irinotecan and temozolomide compare favorably to regimens tested in recurrent GBM. RTOG 04–20 intensifies the Stupp R, et al. (N Engl J Med. 2005 Mar 10;352(10):987–96) adjuvant regimen, using irinotecan and temozolomide in place of temozolomide alone. Methods: Adult patients with newly diagnosed histologically confirmed, supratentorial GBM were eligible. Subjects began temozolomide 75mg/m2 daily the night before initiation of EBRT, and continued until the final day of RT. Pneumocystis prophylaxis was begun prior to RT and for 2 weeks following RT. Within 6 wks after EBRT, subjects with stable or improved MRI were scheduled to receive temozolomide 150mg/m2 on days 1–5, and irinotecan 200mg/m2 on days 1 and 15 of 28 day cycles × 12. Clinical assessments and post contrast MRI are required prior to EBRT, after RT, and after every 2 treatment cycles. Only nonenzyme inducing anticonvulsants were allowed. Results: Accrual of 170 patients was completed in September 2005 with 140 patients currently evaluable. Median age is 57yr, 80% were RPA class III or IV. Prior to cycle 1 of adjuvant therapy, 32 subjects withdrew (20 progressed, 4 toxicity). Of the first 25 subjects receiving irinotecan, 10 suffered grade 3–4 hematologic toxicities in the initial 3 cycles. The protocol was modified by dose reducing irinotecan to 100mg/m2 in cycle 1, escalating to 150 and 200mg/2 in subsequent cycles only if no dose limiting hematologic toxicity occured. No data is yet available on patients who started adjuvant therapy at the lower dose of irinotecan. Diarrhea and constitutional symptoms are the most common nonhematologic toxicies Conclusions: Irinotecan 200mg/m2 days 1 and 15 with temozolomide 150mg/m2 days 1–5 of 28 day cycles was well tolerated treating recurrent GBM, but this regimen was too myelosuppressive when given after concomitant low dose temozolomide and EBRT. Primary outcome data should be available in late 2006. [Table: see text]

Gefitinib and irinotecan in patients with fluoropyrimidine-refractory irinotecan-naïve advanced colorectal cancer (CRC): dose-finding, pharmacokinetics, safety and efficacy

13520 Background: Gefitinib (IRESSA) is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has shown supra-additive activity in human CRC xenografts when combined with irinotecan. We have previously established that the recommended dose level (RDL) to be irinotecan 225mg/m2 q3 weeks and gefitinib 250mg daily (Chau et al ASCO 2004). The dose limiting toxicities were neutropenia and diarrhoea. The continuation phase of this study aimed to evaluate the efficacy and safety of this combination. Patients and Methods: Between Jun 2002 and Feb 2005, patients (pts) with advanced CRC progressing on or within 12 weeks of fluoropyrimidines-based chemotherapy, irinotecan-naïve and performance status ≤2 were recruited. Thirty-nine pts were treated with irinotecan and gefitinib in total with 27 treated at the RDL. Results: Median age was 61 years (range: 31–79) and 13 (33.3%) pts were females. All pts were Caucasians (94.9%) and non-oriental Asians (5.1%). Thirteen (33.3%) pts had received (neo)adjuvant chemotherapy and 16 (41.0%) pts had prior oxaliplatin-based chemotherapy for metastatic disease. Grades 3–4 toxicities were anaemia 2.6%, neutropenia 15.4%, febrile neutropenia 10.3%, diarrhoea 35.9%, nausea 2.6%, vomiting 5.1%, lethargy 15.4% and skin rash 7.7%. For the pts treated at RDL, the objective tumour response rate was 11.1% (3 partial responses [PRs]; 95% confidence interval [CI]: 2.4–29.2%) and the disease control rate was 40.7% (3PRs, 8 stable diseases lasting for ≥12 weeks). The median time to progression was 4.2 months and median survival was 9.3 months. Six-month progression free survival was 22.2% (95% CI: 6.5–37.9%) and 6-month overall survival was 73.4% (95% CI: 56.5–90.3%). Preliminary pharmacokinetic data suggested that the addition of irinotecan to gefitinib resulted in an average of 14–33% increase in exposure to gefitinib (p<0.05). Conclusions: Irinotecan and gefitinib at this dose schedule was tolerable. Gefitinib did not appear to add substantial efficacy to irinotecan. The relative low dose of irinotecan at the RDL and the rarity of EGFR somatic mutation in CRC may be contributory to the modest activity of irinotecan and gefitinib combination. [Table: see text]

Irinotecan Therapy in a 12-year-old Girl with Recurrent Brain Stem Glioma and without Functional Polymorphisms in UGT1A1 Activity: Case Report

A 10-year-old girl was diagnosed with astrocytoma grade 2. Immuno-chemo-radiotherapy (interferon, ranimustine, and radiation), second-line chemotherapy (carboplatin and etoposide, 7 cycles) and third-line chemotherapy (ifosfamide, carboplatin, and etoposide) was given to treat progressive disease. Finally, irinotecan therapy was initiated and led to dramatic clinical improvement. Irinotecan is metabolized by carboxylesterase to form an active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) to yield its beta-glucuronide. The polymorphic UGT isoenzyme, UGT1A1 has genetic variants which decrease in SN-38 glucuronidating capacity and could help predict irinotecan-associated toxicity. The patient suffered excessive toxicity with low-dose irinotecan although no functional polymorphism in UGT1A1 was identified. We suggest that irinotecan offers an effective treatment option for children with recurrent brain stem glioma and other genetic variants except UGT1A1 may be a risk factor for irinotecan-induced toxicity.

Successful salvage therapy of continuous low-dose irinotecan for a patient with relapsed and refractory diffuse large B-cell lymphoma

Successful salvage therapy of continuous low-dose irinotecan for a patient with relapsed and refractory diffuse large B-cell lymphoma