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ABSTRACT: BACKGROUND: Nilotinib is a BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). The UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism UGT1A1*28 (*28)/*28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib. Beside *28, UGT1A1*6 (*6) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan, metabolized by UGT1A1. We retrospectively investigated the association between severe toxicity of nilotinib and UGT1A1 polymorphisms (*6 and*28) in Japanese patients with CML. PATIENTS AND METHODS: Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of UGT1A1 polymorphisms with severe nilotinib-related toxicity. Genotyping analyses were determined for *6 and *28. RESULTS: All 3 patients with the *6/*6 or *6/*28 genotype had severe toxicity, including QT interval prolongation (grade 3), elevated lipase levels (grade 3) plus hyperbilirubinemia (grade 2), and anemia (grade 3) plus hepatic cyst hemorrhage (grade 2) in 1 patient each. Among the 5 patients with the *6/*1 or *1/*1 genotype, 1 had elevated lipase levels (grade 3) and another had severe pain in the lower extremities (grade 3). CONCLUSION: These findings suggest that UGT1A1 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients.
International Journal of Clinical Oncology 04/2013; · 1.41 Impact Factor
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Tomoyo Oguri,
Ayako Mitsuma,
Megumi Inada-Inoue,
Sachi Morita,
Takashi Shibata,
Tomoya Shimokata,
Mihoko Sugishita,
Goro Nakayama,
Keisuke Uehara,
Yoshinori Hasegawa, Yuichi Ando
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ABSTRACT: Objective: Pharmacogenomic associations between severe oxaliplatininduced chronic peripheral neurotoxicity (OXCPN) (Grade 2 lasting for > 7 days or Grade 3) and 9 single nucleotide polymorphisms (SNPs) in 8 genes (TAC1, FOXC1, ITGA1, ACYP2, DLEU7, BTG4, CAMK2N1, and FARS2) were reported by the genomewide association study (GWAS) in Korean patients. The present study was designed to explore reliable predictors of OXCPN and thereby improve the management of metastatic colorectal cancer (CRC). Methods: We retrospectively investigated pharmacogenomic characteristics of OXCPN in 70 Japanese patients with CRC who received oxaliplatin-based chemotherapy and updated the results of our previous analysis of ERCC1 (C118T, rs11615 and C8092A, rs3212986) and GSTP1 (Ile105Val, rs1695) polymorphisms. Results: Univariate analysis suggested potential associations of severe OXCPN with rs843748 in ACYP2 and rs17140129 in FARS2, as well as with the absence of diabetes mellitus (DM) (p = 0.056, 0.072, and 0.029, respectively). There was no association between severe OXCPN and any of the 7 other SNPs. Multiple logistic regression analysis showed that an increased risk of severe OXCPN was related to rs17140129 and the absence of DM (p = 0.034 and 0.030, respectively). On updated analysis, polymorphisms of ERCC1 (C118T, rs11615) and rs10486003 in TAC1 were associated with time to the onset of Grade 1 OXCPN (p = 0.024 and 0.049, respectively). Conclusions: Severe OXCPN is significantly related to rs17140129, found in the GWAS of Korean patients, in Japanese patients. Patients without DM are more likely to have OXCPN. The association between ERCC1 polymorphism and time to the onset of OXCPN was significant on updated analysis.
International journal of clinical pharmacology and therapeutics 04/2013; · 1.18 Impact Factor
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Yutaka Fujiwara, Yuichi Ando,
Toru Mukohara,
Naomi Kiyota,
Naoko Chayahara,
Ayako Mitsuma,
Megumi Inada-Inoue,
Masataka Sawaki,
Robert Ilaria,
P Kellie Turner,
Jumpei Funai,
Kaijiro Maeda,
Hironobu Minami
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ABSTRACT: PURPOSE: This phase I study was designed to determine the maximum tolerated dose (MTD) and the dose to be recommended for a future phase II study of tasisulam sodium in Japanese patients with advanced, refractory solid tumors. Safety, pharmacokinetics and preliminary anti-tumor activities were assessed. Due to high-affinity albumin binding, an albumin-tailored dose to reduce the variability in tasisulam exposure was also studied. METHODS: A dose escalation scheme of tasisulam was used over 4 dose levels. Dose levels 1-3 targeted the maximum plasma concentration (C (max)) of 300, 340, and 360 μg/mL. Dose level 4 used an albumin-tailored range of C (max)-targeted doses to achieve an albumin-corrected exposure (AUCalb) of 1,200-6,400 μg h/mL, the range chosen for global tasisulam studies. Tasisulam was administered intravenously on day 1 of each 21-day (dose levels 1 and 2) or 28-day (dose levels 3 and 4) cycle. RESULTS: The major adverse events were related to bone marrow suppression, particularly neutropenia and thrombocytopenia. Dose-limiting toxicities (DLTs) were not observed until dose level 4, where 3 out of 6 patients experienced DLT, despite a tendency toward lower AUCalb variability (CV %) in the albumin-tailored dose group (38 %) compared with the targeted C (max) groups (50-236 %). CONCLUSIONS: Tasisulam in doses up to dose level 3 (target C (max) 360 μg/mL) was well tolerated. Although albumin-tailored dosing provided less AUCalb variability, a MTD that aligns with other global tasisulam studies was not identified. A lower AUCalb range may be required for the Japan population.
Cancer Chemotherapy and Pharmacology 02/2013; · 2.83 Impact Factor
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Folia Pharmacologica Japonica 02/2013; 141(2):62-5.
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ABSTRACT: PURPOSE: Bevacizumab, a monoclonal antibody that binds to VEGF, has a well-known toxic effect of hypertension. We studied possible associations between bevacizumab-related hypertension and gene polymorphisms to assure safer cancer therapy. METHODS: We retrospectively studied 60 Japanese patients with metastatic colorectal cancer who had received bevacizumab-based chemotherapy. Genotypes were determined for five well-known functional single-nucleotide polymorphism of the VEGF gene at positions C-2578A, T-1498C, G-1154A, G-634C, and C936T. Hypertension was graded according to CTCAE v4.0 on the basis of home blood pressure. RESULTS: The VEGF-2578 C/C and -1498 T/T genotypes were associated with significantly less hypertension during the first 2 months of bevacizumab-based chemotherapy (p = 0.004, p = 0.025, respectively). During the treatment period as a whole, the VEGF-2578 C/C and 936 C/C genotypes were associated with less hypertension (p = 0.031, p = 0.043, respectively). Preexisting hypertension was not associated with bevacizumab-related hypertension. CONCLUSIONS: This study demonstrated a significant relation between a lower incidence of grade 2 or higher bevacizumab-related hypertension and the VEGF-2578 C/C genotype for the entire treatment period in Japanese patients with metastatic colorectal cancer. This genotype might be useful for ensuring safer treatment of patients who receive bevacizumab-based chemotherapy.
Cancer Chemotherapy and Pharmacology 11/2012; · 2.83 Impact Factor
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ABSTRACT: This pharmacokinetic study of S-1 was conducted in patients in whom glomerular filtration rate (GFR) was directly measured to explore the possibility of adjusting the S-1 dose on the basis of GFR in patients with normal or nearly normal renal function.
S-1 was given to 12 patients twice daily for 28 consecutive days followed by 14 days of rest, repeated every 6 weeks. GFR was measured on the basis of inulin clearance (CLin) before the first day of treatment.
The area under the time-concentration curve (AUC) of 5-fluorouracil (5-FU) correlated with that of 5-chloro-2,4-dihydroxypyridine (CDHP, r = 0.750, p = 0.005). The AUC of CDHP correlated with the measured 24-hour creatinine clearance (CLcr) per subject (r = -0.620, p = 0.032), but not with the CLin (r = -0.356, p = 0.257). The AUC of 5-FU did not correlate with either the 24-hour CLcr per subject (r = -0.401, p = 0.187) or with the CLin (r = -0.300, p = 0.351).
Dosage adjustment based on the GFR does not reduce individual variations in 5-FU concentrations among patients with normal or nearly normal renal function who receive S-1.
Oncology 06/2012; 83(1):38-44. · 2.27 Impact Factor
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Ayako Mitsuma,
Masataka Sawaki,
Takashi Shibata,
Sachi Morita,
Megumi Inada,
Tomoya Shimokata,
Mihoko Sugishita,
Koichi Kitagawa,
Masaki Sawada,
Akihiro Nawa, Yuichi Ando
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ABSTRACT: A massive extravasation of pegylated-liposomal doxorubicin (Doxil) accidentally occurred, affecting the right forearm of a 54-year-old woman with metastatic ovarian cancer who was receiving an intravenous infusion of the drug. In accordance with the institutional guidelines for vesicant drugs, a corticosteroid preparation was immediately injected subcutaneously into the surrounding tissues. Clobetasol propionate and an ice pack were then topically applied to the affected region. There were no serious complications at the extravasation site, such as tissue necrosis or severe pain, and only a transient erythema of the skin and desquamation remained after 2 months.
Nagoya journal of medical science 02/2012; 74(1-2):189-92.
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ABSTRACT: Purpose Sagopilone has recently been identified and preferentially used for the treatment of taxane-resistant cancer. The purpose of this dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics (PK) of sagopilone in refractory solid tumors. Methods A total of 17 Japanese patients received sagopilone in this Phase I study. Sagopilone was given as a 30-min intravenous infusion once every 3 weeks (one course) with an initial dose of 12.4 mg/m(2) up to 22.0 mg/m(2) for a maximum of 6 courses. Results The maximum tolerated dose (MTD) was determined to be 16.5 mg/m(2). The major dose-limiting toxicity (DLT) was peripheral sensory neuropathy. The PK data demonstrated that sagopilone did not accumulate after repeated administration. Two patients had stable disease (SD) over a period of 12 weeks. Conclusions Our study demonstrated clinically favorable safety, tolerability, and efficacy of sagopilone, which will help define the treatment of advanced tumors in more extensive clinical trials.
Investigational New Drugs 12/2011; · 3.36 Impact Factor
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Sachi Morita,
Satoshi Oizumi,
Hironobu Minami,
Koichi Kitagawa,
Yoshito Komatsu,
Yutaka Fujiwara,
Megumi Inada,
Satoshi Yuki,
Naomi Kiyota,
Ayako Mitsuma,
Masataka Sawaki,
Hiromi Tanii,
Junko Kimura, Yuichi Ando
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ABSTRACT: Panobinostat (LBH589) is a potent pan-histone deacetylase inhibitor. As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of a phase I study to evaluate intravenous panobinostat given on days 1 and 8 of a 21-day cycle in patients with solid tumors. The primary objective was to characterize the safety and tolerability of panobinostat by evaluating the occurrence of dose-limiting toxicity (DLT) and determining the maximum tolerated dose (MTD) in Japanese patients with advanced solid tumors. Secondary objectives included characterizing the pharmacokinetics and assessing antitumor activity. Fourteen patients were assigned to three dose levels (Cohort 1: 10 mg/m(2) [three patients], Cohort 2: 15 mg/m(2) [three patients], Cohort 3: 20 mg/m(2) [eight patients]), according to a standard "3 + 3" design. One patient who received 20 mg/m(2) had a DLT (grade 3 elevation of γ-glutamyl transpeptidase for >7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for ≥4 months was observed in six patients; however, there were no complete or partial responses. It is feasible to conclude that 20 mg/m(2) was the MTD and recommend as the starting dose for phase II clinical trials.
Investigational New Drugs 10/2011; 30(5):1950-7. · 3.36 Impact Factor
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Hiroo Ishida,
Ken-Ichi Fujita,
Yuko Akiyama,
Yu Sunakawa,
Keishi Yamashita,
Keiko Mizuno,
Keisuke Miwa,
Kaori Kawara,
Wataru Ichikawa, Yuichi Ando,
Shigehira Saji,
Yasutsuna Sasaki
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ABSTRACT: We examined the feasibility of regimen selection for first-line irinotecan, 5-fluorouracil and leucovorin or oxaliplatin, 5-fluorouracil and leucovorin in Japanese patients with advanced colorectal cancer based on UDP-glucuronosyltransferase 1A1 genotype as well as physical status of patients related to diarrhea.
As first-line irinotecan, 5-fluorouracil and leucovorin is a little bit superior to oxaliplatin, 5-fluorouracil and leucovorin with respect to efficacy and toxicity, patients without risk factors of irinotecan-induced toxicity were first assigned to irinotecan, 5-fluorouracil and leucovorin. Patients with UDP-glucuronosyltransferase 1A1 28/ 28, 6/ 6, 28/ 6 or 28/ 27 and those with ascites, peritoneal dissemination or diarrhea first received oxaliplatin, 5-fluorouracil and leucovorin to avoid the irinotecan-induced neutropenia and diarrhea, respectively. We retrospectively evaluated the feasibility of this strategy by assessing toxicity and total progression-free survival in first- and subsequent second-line therapies in all patients studied.
In the first-line irinotecan, 5-fluorouracil and leucovorin (n = 61), Grade 4 neutropenia, febrile neutropenia and Grade 3 diarrhea occurred in 8.2, 3.3 and 3.3% of patients, respectively. In the first-line oxaliplatin, 5-fluorouracil and leucovorin (n = 26), Grade 4 neutropenia, febrile neutropenia, Grade 3 thrombocytopenia and Grade 3 neuropathy were observed in 11.5, 3.8, 3.8 and 7.7% of patients, respectively. In the second-line oxaliplatin, 5-fluorouracil and leucovorin (n = 38), Grade 3 diarrhea occurred in 2.6% of patients. In the second-line irinotecan monotherapy (n = 11), Grade 4 or febrile neutropenia occurred in 18% of patients and Grade 3 diarrhea in 9.1% of patients. In second-line S-1 (n = 9), Grade 3 anemia occurred in 2 patients. Median total progression-free survival in all 87 patients was 11.5 months.
Present regimen selection strategy would be feasible, since it causes less toxicity and similar efficacy comparing to previous studies. Determination of appropriate reduced dose in the second-line irinotecan monotherapy or other standard second-line therapy for patients with high-risk to irinotecan-induced toxicity might make this strategy more effective.
Japanese Journal of Clinical Oncology 02/2011; 41(5):617-23. · 1.78 Impact Factor
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ABSTRACT: In Japan, biological safety cabinets (BSCs) are normally used by medical staff while handling antineoplastic agents. We have also set up a class II B2 BSC at the Division of Chemotherapy for Outpatients. The air temperature inside this BSC, however, decreases in winter. We assumed that this decrease is caused by the intake of open-air. Therefore, we investigated the effects of low open-air temperature on the BSC temperature and the time of admixtures of antineoplastic agents.
The studies were conducted from January 1 to March 31, 2008. The outdoor air temperature was measured in the shade near the intake nozzle of the BSC and was compared with the BSC temperature. The correlation between the outdoor air temperature and the BSC temperature, the dissolution time of cyclophosphamide (CPA) and gemcitabine (GEM), and accurate weight measurement of epirubicin (EPI) solution were investigated for low and normal BSC temperatures.
The BSC temperature was correlated with the open-air temperature for open-air temperatures of 5-20°C (p < 0.0001). The dissolution of CPA and GEM at these temperatures was significantly delayed as compared to that at 25°C (p < 0.01 and p < 0.0001, respectively). The weight measurement of EPI solution using a syringe method lacks accuracy because of its high coefficient of viscosity at low temperatures (p < 0.01).
These results suggest that the BSC temperature decreases below room temperature in winter when air is drawn from outdoors. We showed that the BSC temperature affects the dissolution rate of antineoplastic agents. Further, we suggested that the BSC temperature drop might delay the affair of the admixtures of antineoplastic agents and increase the waiting time of outpatients for chemotherapy.
Journal of Oncology Pharmacy Practice 02/2011;
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ABSTRACT: Inhibition of the UDP-glucuronosyltransferase (UGT) 1A1 by nilotinib was examined in vitro with SN-38 as a substrate, to estimate the possibility of drug-drug interaction of nilotinib with other medicines predominantly detoxified by UGT1A1.
Inhibition of UGT1A1-catalyzed SN-38 glucuronidation by nilotinib was examined with human liver microsomes (HLM) and recombinant human UGT1A1 as enzyme sources. Inhibition constants (K(i)) were estimated with kinetic analysis.
Nilotinib potently inhibited the SN-38 glucuronidation by human liver microsomal UGT1A1 and recombinant UGT1A1 in a noncompetitive manner, with K(i) values of 0.286 ± 0.0094 and 0.079 ± 0.0029 μM, respectively. If a drug that serves as a substrate of UGT1A1 is administered with nilotinib, the area under the plasma concentration-time curve of a drug estimated by using these K(i) values would be two times or higher than that without nilotinib, suggesting drug-drug interactions involving UGT1A1. These in vitro data and the prediction of drug-drug interaction are helpful for the clinical management of the nilotinib use.
We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.
Cancer Chemotherapy and Pharmacology 01/2011; 67(1):237-41. · 2.83 Impact Factor
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ABSTRACT: The Calvert formula, that is, carboplatin dose (mg) = target area under the concentration versus time curve (AUC) × (glomerular filtration rate [GFR] + 25), has not been validated in Japanese subjects in whom the GFR was accurately measured. The purpose of this study is to evaluate the validity of this formula for Japanese patients with cancer and modify it for this population. The GFR was measured on the basis of inulin clearance, which is considered to reflect the accurate GFR. Inulin clearance was measured in 28 patients with cancer. The adjusted 24-h creatinine clearance (24-h Ccr) was unbiased (mean prediction error [MPE] ± SE = -2.3 ± 4.5%) and acceptably precise (root mean squared error = 23.7%) for GFR assessment. The pharmacokinetics of carboplatin were analyzed in 21 patients with a GFR of 17.2-91.4 mL/min. The original Calvert formula overestimated carboplatin clearance, resulting in an MPE of 14.3%. When we revised the Calvert formula for Japanese patients by substituting a non-renal clearance of 15 for 25, that is, dose = target AUC × (GFR + 15), the MPE decreased to -0.1% (P < 0.001). We conclude that the adjusted 24-h Ccr is acceptably precise for GFR assessment, and the non-renal clearance of carboplatin is suggested to be lower in Japanese patients with cancer than in their Western counterparts.
Cancer Science 12/2010; 101(12):2601-5. · 3.33 Impact Factor
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Yu Sunakawa,
Wataru Ichikawa,
Ken-Ichi Fujita,
Fumio Nagashima,
Hiroo Ishida,
Keishi Yamashita,
Keiko Mizuno,
Keisuke Miwa,
Kaori Kawara,
Yuko Akiyama,
Kazuhiro Araki,
Wataru Yamamoto,
Toshimichi Miya,
Masaru Narabayashi, Yuichi Ando,
Takashi Hirose,
Shigehira Saji,
Yasutsuna Sasaki
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ABSTRACT: Differences in efficacy and toxicity between UDP-glucuronosyltransferase (UGT) 1A1*1/*1 and *1/*6 or *1/*28 genotypes remain unclear in Japanese patients.
Patients with advanced colorectal cancer who received irinotecan combined with 5-fluorouracil plus l-leucovorin (FOLFIRI) as first-line therapy were divided into two groups: those with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Efficacy and toxicity were compared between these groups retrospectively.
Forty-two patients (24 *1/*1 and 18 *1/*6 or *1/*28) were evaluated. The response rate was 48% in *1/*1 group and 56% in *1/*6 or *1/*28 group (P = 0.847). Median progression-free survival was 8.6 months in *1/*1 group and 8.5 months in *1/*6 or *1/*28 group (P = 0.888). No hematologic or non-hematologic toxic effects were clearly related to UGT1A1*1/*6 or *1/*28 during the first cycle or throughout the entire course of chemotherapy.
There were no significant differences in the efficacy or toxicity of FOLFIRI between patients with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Our results suggest that patients with the latter genotypes can receive FOLFIRI at the same dose of irinotecan as those with the UGT1A1*1/*1 genotype receive.
Cancer Chemotherapy and Pharmacology 10/2010; 68(2):279-84. · 2.83 Impact Factor
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Ken-ichi Fujita,
Yu Sunakawa,
Keisuke Miwa,
Yuko Akiyama,
Minako Sugiyama,
Kaori Kawara,
Hiroo Ishida,
Keishi Yamashita,
Keiko Mizuno,
Shigehira Saji,
Wataru Ichikawa,
Wataru Yamamoto,
Fumio Nagashima,
Toshimichi Miya,
Masaru Narabayashi, Yuichi Ando,
Takashi Hirose,
Yasutsuna Sasaki
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ABSTRACT: This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) ≤ 20 ml/min] who were undergoing dialysis and received 100 mg/m(2) irinotecan as monotherapy were prospectively compared with those in five 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. The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was approximately one tenth of that in patients with normal renal function (P = 0.025). Approximately 50% of SN-38 was dialyzed with a 2.1-m(2) dialysis membrane, whereas 27% was dialyzed with a 1.5-m(2) membrane. Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure compared with patients with normal renal function. We demonstrated that SN-38 was partly dialyzed.
Drug metabolism and disposition: the biological fate of chemicals 10/2010; 39(2):161-4. · 3.74 Impact Factor
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Keishi Yamashita,
Fumio Nagashima,
Ken-ichi Fujita,
Wataru Yamamoto,
Hisashi Endo,
Toshimichi Miya,
Masaru Narabayashi,
Kaori Kawara,
Yuko Akiyama, Yuichi Ando,
Masahiko Ando,
Yasutsuna Sasaki
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ABSTRACT: This phase I/II study determined the recommended dose of FOLFIRI (irinotecan, infusional 5-fluorouracil and leucovorin) for Japanese patients with advanced colorectal cancer, and evaluated safety at the recommended dose in patients without the UDP-glucuronosyltransferase 1A1*28 allele which caused reduced enzyme expression.
The phase I part assessed the maximum tolerated dose of FOLFIRI to determine the recommended doses of irinotecan and infusional 5-fluorouracil. The doses were escalated from 150 to 180 mg/m(2) (irinotecan) and 2000 to 2400 mg/m(2) (5-fluorouracil). UDP-glucuronosyltransferase 1A1*6 and *28, and pharmacokinetics of irinotecan were observationally examined. In the phase II part, patients without the UDP-glucuronosyltransferase 1A1*28 allele received FOLFIRI at the recommended dose to evaluate safety.
Among 15 patients in the phase I part, dose-limiting toxicity (diarrhea) occurred in one patient who received 150 mg/m(2) irinotecan and 2400 mg/m(2) infusional 5-fluorouracil. The respective recommended doses were 180 and 2400 mg/m(2) for irinotecan and infusional 5-fluorouracil, without reaching the maximum tolerated dose. Twenty-five patients received FOLFIRI at the recommended doses. Grade 3 or 4 neutropenia occurred in 44%, and Grade 3 diarrhea in 4%.
This phase I/II study demonstrates that the recommended doses of irinotecan and infusional 5-fluorouracil in FOLFIRI for Japanese patients with advanced colorectal cancer who do not possess the UDP-glucuronosyltransferase 1A1*28 allele are 180 and 2400 mg/m(2), respectively. Toxicities occurring at the recommended doses are manageable in these patients.
Japanese Journal of Clinical Oncology 10/2010; 41(2):204-9. · 1.78 Impact Factor
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ABSTRACT: To examine the safety of carboplatin-based chemotherapy and the applicability of the Calvert formula in patients with cancer who are undergoing hemodialysis.
We treated two patients who were undergoing hemodialysis and received carboplatin-based chemotherapy to treat non-small-cell lung cancer or ovarian cancer. The dose of carboplatin was calculated by the Calvert formula. Glomerular filtration rate was considered to be 0, and the target area under the plasma concentration versus time curve (AUC) was 4 (carboplatin dose, 100 mg) for patient 1 and 5 (125 mg) for patient 2. Carboplatin was administered as a 1-h intravenous infusion on day 1. Hemodialysis was performed for 3 or 4 h, starting 24 h after the infusion of carboplatin had begun. Heparinized blood samples were collected during the first cycle of chemotherapy.
The AUCs in patients 1 and 2 were 4.7 and 6.1 (mg/ml min), which were about 20% higher than the target values (4 and 5 mg/ml min, respectively). In the absence of hemodialysis, the hypothetical AUCs were 6.2 and 7.6 (mg/ml min), respectively. The pre-dialysis body clearances of carboplatin were 16.1 and 16.5 ml/min, with elimination half-lives of 17.5 and 13.8 h, respectively.
By performing hemodialysis 24 h after the start of chemotherapy, we obtained reproducible and robust AUC data. Use of the Calvert formula allowed carboplatin-based chemotherapy to be performed safely. Our results suggest that the non-renal clearance of carboplatin is lower in Japanese patients than in non-Asian patients.
Cancer Chemotherapy and Pharmacology 09/2010; 66(4):813-7. · 2.83 Impact Factor
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Kenji Kawada,
Koichi Kitagawa,
Sachi Kamei,
Megumi Inada,
Ayako Mitsuma,
Masataka Sawaki,
Toyone Kikumori,
Yasushi Fujimoto,
Hiroshi Arima,
Tsuneo Imai, Yuichi Ando
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ABSTRACT: There is no established chemotherapy for anaplastic thyroid cancer. We conducted a prospective feasibility study at a single center to explore the antitumor activity of docetaxel against anaplastic thyroid cancer. Docetaxel was administered intravenously at a dose of 60 mg/m(2) over the course of 1 h every 3 weeks in patients with anaplastic thyroid cancer who had received no prior chemotherapy. A total of seven patients with anaplastic thyroid cancer were enrolled over the course of 30 months and received docetaxel. The treatment response was complete response in one patient, stable disease in two and progressive disease in four. The response rate was 14%, and the disease control rate (complete response plus stable disease) was 43%. The median time to progression was 6 weeks (range, 1-50). Toxicity was tolerable. Docetaxel could be an effective drug for the treatment of anaplastic thyroid cancer, with tolerable toxicity.
Japanese Journal of Clinical Oncology 03/2010; 40(6):596-9. · 1.78 Impact Factor
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ABSTRACT: In order to promote the appropriate control of cancer pain by opioids, we distributed a pocket-sized protocol pamphlet on cancer pain control and opioid prescription to the medical staff of Nagoya University Hospital. In this study, we examined whether the prescription rate of opioids for rescue use, antiemetics for preventing adverse effects, and the rate of increase of regular opioid dosage were increased after distribution to evaluate its utility. Rescue opioid prescriptions, increase of regular opioid dosage and antiemetic prescription rate after distribution were all significantly increased, compared with before distribution. Furthermore, the frequency of nausea and vomiting was reduced by the use of prophylactic antiemetics. These results suggest that distribution of this protocol for cancer pain control may contribute to appropriate pain management.
Gan to kagaku ryoho. Cancer & chemotherapy 02/2010; 37(2):285-90.
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Ken-ichi Fujita, Yuichi Ando,
Wataru Yamamoto,
Toshimichi Miya,
Hisashi Endo,
Yu Sunakawa,
Kazuhiro Araki,
Keiji Kodama,
Fumio Nagashima,
Wataru Ichikawa,
Masaru Narabayashi,
Yuko Akiyama,
Kaori Kawara,
Mari Shiomi,
Hiroyasu Ogata,
Hiroyasu Iwasa,
Yasushi Okazaki,
Takashi Hirose,
Yasutsuna Sasaki
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ABSTRACT: To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients.
We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and μ-opioid receptor 1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets.
The T/T genotype at 1236 or TT/TT diplotype at 2677 and 3435 in ABCB1 was associated with significantly lower frequency of fatigue (grades 1-3) (P = 0.012 or 0.011, Fisher’s exact test). The UGT2B7*2 genotype was associated with the frequency of nausea (grades 1-3) (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2677 and 3435 in ABCB1 was associated with the frequency of vomiting (grades 1-3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2677 and 3435 suffered from vomiting.
Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.
Cancer Chemotherapy and Pharmacology 06/2009; 65(2):251-8. · 2.83 Impact Factor
