Shunsuke Kondo

Population pharmacokinetics of gemcitabine and its metabolite in Japanese cancer patients: impact of genetic polymorphisms.

Background and ObjectiveGemcitabine (2′,2’-difluorodeoxycytidine) is an anticancer drug, which is effective against solid tumours, including non-small-cell lung cancer and pancreatic cancer. After gemcitabine is transported into cells by equilibrative and concentrative nucleoside transporters, it is phosphorylated by deoxycytidine kinase (DCK) and further phosphorylated to its active diphosphorylated and triphosphorylated forms. Gemcitabine is rapidly metabolized by cytidine deaminase (CDA) to an inactive metabolite, 2′,2′-difluorodeoxyuridine (dFdU), which is excreted into the urine. Toxicities of gemcitabine are generally mild, but unpredictable severe toxicities such as myelosuppression and interstitial pneumonia are occasionally encountered. The aim of this study was to determine the factors, including genetic polymorphisms of CDA, DCK and solute carrier family 29A1 (SLC29A1 [hENT1]), that alter the pharmacokinetics of gemcitabine in Japanese cancer patients.Patients and Methods250 Japanese cancer patients who received 30-minute intravenous infusions of gemcitabine at 800 or 1000mg/m2 in the period between September 2002 and July 2004 were recruited for this study. However, four patients were excluded from the final model built in this study because they showed bimodal concentration-time curves. Two patients who experienced gemcitabine-derived life-threatening toxicities in October 2006 and January 2008 were added to this analysis. One of these patients received 30-minute intravenous infusions of gemcitabine at 454 mg/m2 instead of the usual dose (1000 mg/m2).Plasma concentrations of gemcitabine and dFdU were measured by high-performance liquid chromatography-photodiode array/mass spectrometry. In total, 1973 and 1975 plasma concentrations of gemcitabine and dFdU, respectively, were used to build population pharmacokinetic models using nonlinear mixed-effects modelling software (NONMEM® version V level 1.1).Results and DiscussionTwo-compartment models fitted well to plasma concentration-time curves for both gemcitabine and dFdU. Major contributing factors for gemcitabine clearance were genetic polymorphisms of CDA, including homozygous CDA*3 [208G>A (Ala70Thr)] (64% decrease), heterozygous *3 (17% decrease) and CDA -31delC (an approximate 7% increase per deletion), which has a strong association with CDA*2 [79A>C (Lys27Gln)], and coadministered S-1, an oral, multicomponent anti-cancer drug mixture consisting of tegafur, gimeracil and oteracil (an approximate 19% increase). The estimated contribution of homozygous CDA*3 to gemcitabine clearance provides an explanation for the life-threatening severe adverse reactions, including grade 4 neutropenia observed in three Japanese patients with homozygous CDA*3. Genetic polymorphisms of DCK and SLC29A1 (hENT1) had no significant correlation with gemcitabine pharmacokinetic parameters. Aging and increased serum creatinine levels correlated with decreased dFdU clearance.ConclusionA population pharmacokinetic model that included CDAgenotypes as a covariate for gemcitabine and dFdU in Japanese cancer patients was successfully constructed. The model confirms the clinical importance of the CDA*3 genotype.

Spontaneous regression of hepatocellular carcinoma

We report four patients with hepatocellular carcinoma (all men, with liver cirrhosis and hepatitis C virus infections) who showed spontaneous regression of the tumor. When the spontaneous regression occurred all of the patients were over age 67 years. They showed a rapid increase of serum alpha-fetoprotein levels just before the spontaneous regression of hepatocellular carcinoma. In all the patients, the alpha-fetoprotein level decreased to within normal limits and the tumor was partially to completely reduced in size. One patient revealed regression after bleeding of esophageal varices and blood transfusion. Another showed spontaneous regression after taking several complementary and alternative medicines. However, the mechanisms underlying this intriguing phenomenon remain unknown.

Do Recurrent and Metastatic Pancreatic Cancer Patients Have the Same Outcomes with Gemcitabine Treatment

Background: Whether recurrence after surgery and primary metastatic pancreatic cancer should be included in the same category when conducting gemcitabine-based clinical trials remains controversial. Objective: To clarify the outcomes of recurrent and metastatic pancreatic cancers. Methods: 326 patients who received gemcitabine monotherapy as a first-line treatment for advanced pancreatic cancer between 2001 and 2007 were reviewed. Multivariate analysis was performed to determine the prognostic relevance of recurrence or metastasis in relation to other factors possibly influencing treatment outcomes with respect to overall survival. Differences in response to chemotherapy, drug delivery and adverse events were also analyzed. Results: There were 65 recurrent and 261 metastatic cancer patients. Recurrent cancer patients had a significantly longer time to treatment failure and survival (respective medians 138 and 77 days, p = 0.017) than the metastatic patients (respective medians 270 and 185 days, p = 0.0003). Multivariate analysis revealed poor Karnofsky performance status (<80), presence of liver or peritoneal metastasis, elevated lactate dehydrogenase (>220 U/l), elevated alkaline phosphatase (>330 U/l) and elevated C-reactive protein (>1.0 mg/dl) to be significantly correlated with short survival, while neither recurrent nor metastatic status were related to survival (hazard ratio 0.76, 95% CI 0.53–1.09, p = 0.14). The response rates and dose intensities of gemcitabine were similar in these groups, although leukopenia was more frequently observed in the recurrence group (p = 0.008). Conclusion: When conducting clinical trials, it appears to be acceptable to treat recurrent pancreatic cancer after surgery and pancreatic cancer with primary metastasis under the same category.

Utility of Assessing the Number of Mutated kras , cdkn2a , tp53 , and smad4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer

Objectives KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcinogenesis. We examined somatic mutations in 50 cancer-related genes, including the four above-mentioned driver genes, to identify genomic biomarkers for predicting the outcome of patients with pancreatic cancer. Methods Genomic DNA was extracted from fresh-frozen specimens obtained from 100 patients with pancreatic cancer who had undergone a pancreatectomy with curative intent. The mutation profile was obtained using a single targeted deep sequencing assay performed with a next-generation sequencer, and the associations with clinicopathological factors were analyzed. Results Mutations in the KRAS, CDKN2A, TP53, and SMAD4 genes were detected in 96% (96/100), 42% (42/100), 13% (13/100), and 7% (7/100) of all patients, respectively. Among the 71 patients who underwent a radical operation followed by adjuvant chemotherapy, patients with fewer mutations among the four driver genes tended to have a better outcome. A multivariate analysis using the Cox proportional hazard model showed that the presence of 0 to 2 mutated driver genes was an independent predictor of a better overall survival (hazard ratio for death, 0.20; P = 0.0040). Conclusions The number of mutated driver genes assessed using a targeted deep sequencing assay was a promising prognostic biomarker for pancreatic cancer.

Multicenter cooperative case survey of hepatitis B virus reactivation by chemotherapeutic agents

The purpose of this multicenter cooperative study was to elucidate the clinical features of hepatitis B virus (HBV) reactivation by chemotherapeutic agents and the patient outcomes after HBV reactivation by a retrospective review of accumulated patients’ medical records.