[Chemotherapy using gemcitabine hydrochloride for malignant lymphoma].

This report summarizes the use of gemcitabine for the treatment of malignant lymphoma. Gemcitabine is a deoxycytidine antagonist that has characteristics different from those of the deoxycytidine antagonist cytarabine(Ara-C). International guidelines based on the results of recent clinical studies recommend the use of gemcitabine as monotherapy and in combination therapy, particularly for relapsed and refractory malignant lymphomas. Clinical studies on gemcitabine monotherapy up to 2012 reported response rates of 51-75% for peripheral T -cell lymphoma and cutaneous T-cell lymphoma. Regarding combination therapy, the GDP regimen consisting of gemcitabine, dexamethasone, and cisplatin was associated with response rates of 62-70% for relapsed or refractory Hodgkin lymphoma and 45-53% for relapsed or refractory non-Hodgkin lymphoma, thereby displaying comparable efficacy to existing salvage chemotherapy regimens. The GDP regimen has a favorable safety profile and is also associated with favorable autologous transplantation rates, which suggests its potential as induction chemotherapy before autologous transplantation. Concerning adverse reactions requiring clinical caution, lung disorder was reported in 8 of 27 patients(30%)who received a regimen of gemcitabine in combination with bleomycin.

Safety and effectiveness of gemcitabine in 855 patients with pancreatic cancer under Japanese clinical practice based on post-marketing surveillance in Japan.

OBJECTIVE: When gemcitabine was approved as an anti-cancer drug, there were limited data for Japanese patients treated with gemcitabine. Generally, advanced or metastatic pancreatic cancer patients experience poor prognosis and suffer from debilitating disease-related symptoms. Reports and information on gemcitabine use within a large patient pool will be beneficial to aid physicians. Therefore, this post-marketing surveillance was conducted as a non-interventional, observational study on the use of gemcitabine in a clinical practice setting in Japan. METHODS: Patients had no previous treatment with gemcitabine and were diagnosed with pancreatic cancer by an attending physician. Patients were registered between May 2001 and December 2003 in Japan. The patients were treated with gemcitabine. Data such as patient background, treatment details, adverse events, tumor response, serum CA19-9 levels and drug-related symptom improvement were assessed. RESULTS: Of the 890 patients registered for the study, 855 were included in the analysis of gemcitabine for safety. Four hundred and forty-three (51.9%) patients reported drug-related adverse events, with 97 patients (11.4%) experiencing serious adverse events. The incidence of interstitial lung disease was 0.7% (six patients). Six hundred patients were evaluated for tumor response. The overall response rate was 6.0% and the disease control rate was 54.0%. CA19-9 decreased in 63.6% of the 335 evaluable patients, with a ≥75% decrease seen in 19.4% of the total group. Drug-related symptom improvement was observed in 27.0% of the 686 evaluable patients. CONCLUSIONS: This large-scale surveillance could confirm the safety of gemcitabine for Japanese pancreatic cancer patients as well as elucidate the efficacy profile, measured by drug-related symptom improvement, for Japanese pancreatic cancer patients.

Safety and effectiveness of gemcitabine in 260 patients with biliary tract cancer in a Japanese clinical practice based on post-marketing surveillance in Japan.

OBJECTIVE: Gemcitabine was approved for the treatment of biliary tract cancer in 2006 in Japan. While biliary tract cancer is usually associated with patients 70 years of age or older and/or those who tend to have underlying liver dysfunction, data on this population were limited in the Japanese Phase II study of gemcitabine. Thus, further evaluation of safety and effectiveness in this population was planned. This special post-marketing surveillance was conducted as an observational study on the use of gemcitabine in a clinical practice setting. METHODS: Gemcitabine-naïve patients with biliary tract cancer were enrolled from 2006 to 2008 and observed over 12 months; one or more doses of gemcitabine were administered during the period. Data such as patient background, treatment details, adverse events occurring during the observational period, laboratory values of liver enzyme and survival status were collected 3 and 12 months after the start of therapy. RESULTS: Of the 285 patients registered for the study, 260 were included in the analysis. The mean age was 66.9 years. There were 120 patients (46.2%) classified as elderly (70 years or older). Haematotoxicities were the most common adverse drug reactions. In the elderly and the non-elderly, adverse drug reactions (serious) occurred in 48.3% (20.8%) and 50.7% (12.9%), respectively. The overall estimated 1-year survival rate was 52.5% (95% confidence interval, 45.9-58.7%). CONCLUSIONS: In line with previous clinical and post-marketing studies conducted in Japan, the results of this study suggest that gemcitabine could be used safely and effectively for biliary tract cancer patients including the elderly.

[Drug interactions in medical oncology].

Cytotoxic anti-neoplastic drugs are some of the strongest acting drugs. They have a complex pharmacological profile, narrow therapeutic window, steep dose-toxicity curve, and many pharmacokinetic and pharmacodynamic differences both within and between patients. This makes it difficult to avoid adverse effects. These drugs are approved for usage based on their clinical benefit to risk ratio. The recommended dose is usually close to the maximally-tolerated dose in order to achieve maximum therapeutic effect. Therefore, there is more concern about drug interactions affecting the pharmacokinetics of anti-neoplastic drugs than drugs in general. Any physician taking care of oncology patients must understand not only the pharmacokinetic profile(absorption, protein binding, metabolism and excretion)of the anti-neoplastic drugs their using, but also the many factors that affect the pharmacokinetic profile such as hepatic and renal function, and co-administered drugs. Expertise to achieve a good balance between safety and efficacy in medical treatment with proper knowledge in supportive care as well as an understanding of pharmacokinetics, pharmacodynamics and pharmacogenomics is essential for medical oncologists. In this review, we have summarized the drug-drug interactions important for the management of cancer patients. The types of interactions covered are pharmaceutical interactions and interactions at the level of absorption, protein binding, metabolism and excretion.

Efficacy and safety of gemcitabine monotherapy in patients with transitional cell carcinoma after Cisplatin-containing therapy: a Japanese experience.

BACKGROUND: In Japan, the standard chemotherapy for advanced transitional cell carcinoma (TCC) of the urothelium is MVAC (methotrexate, vinblastine, adriamycin, cisplatin). However, a second-line therapy is still required for patients with recurrent TCC who discontinued MVAC because of toxicity or have MVAC refractory tumors. METHODS: We evaluated gemcitabine monotherapy in patients with advanced TCC who were previously treated with a platinum-based regimen. Gemcitabine (1000 mg/m2) was given once a week for three consecutive weeks followed by a week of rest. This cycle was repeated at least three times, or until disease progression or intolerable adverse events were observed. RESULTS: Of the 46 patients entered into this study, 44 received gemcitabine. Performance status (PS) at study entry was: PS 0 (30 patients), PS 1 (12 patients) and PS 2 (2 patients). Stages III/IV were observed in 1/9 patients; the other 34 patients had relapsed after surgery. All 44 patients had been previously treated with a platinum-based regimen. The overall response rate was 25%, 1-year survival rate 52.3%, median survival time 12.6 months and median progression free survival 3.1 months. The major grade 3/4 hematological toxicity was neutropenia (47.7%), and the major grade 3/4 non-hematological toxicity was anorexia (9.1%). All adverse drug reactions seen in the study were manageable. CONCLUSION: Gemcitabine monotherapy is a sufficiently active and well-tolerated therapy for patients who have previously undergone chemotherapy with a platinum-based regimen.

Susceptibility of murine periportal hepatocytes to hypoxia-reoxygenation: role for NO and Kupffer cell-derived oxidants.

Ischemia/reperfusion (I/R) is an important problem in liver resection and transplantation that is associated with hepatocellular dysfunction and injury. This study was designed to investigate whether a difference in hepatocyte susceptibility occurs in the periportal (PP) and/or perivenous (PV) zones in response to hypoxia/reoxygenation (H/R), and to delineate the mechanisms underlying this susceptibility. H/R was induced in an in situ perfused mouse liver model with deoxygenated Krebs-Henseleit buffer followed by oxygenated buffer. Selective destruction of PP or PV sites was achieved by digitonin perfusion into the portal or inferior vena cava, and was confirmed by histological evaluations and zone-specific enzymes. Hepatocellular injury was assessed by alanine aminotransferase (ALT) release. In whole liver, H/R significantly increased perfusate ALT. H/R of PP-enriched zones caused ALT release that was similar to that of whole liver (80 + 10 vs. 70 + 12 U/mg protein), consistent with significant PP hepatocyte injury. Minimal ALT release occurred in PV zones (10 + 5 U/mg protein). Administration of N-acetyl L-cysteine or a chimeric superoxide dismutase (SOD)-SOD2/3, a genetically engineered SOD-abrogated ALT release in H/R-perfused PP zones, implicating a role for superoxide (O(2) (-)). This elevated ALT release was attenuated by gadolinium chloride pretreatment, indicating that Kupffer cells are the O(2) (-) source. Enzymatic inhibition of cellular nitric oxide synthase (NOS) or genetic depletion of endothelial nitric oxide synthase (eNOS) aggravated hypoxia injury while exogenous NO and inducible nitric oxide synthase (iNOS) deficiency abolished reoxygenation injury. In conclusion, PP hepatocytes are more vulnerable to H/R; this injury is mediated directly or indirectly by Kupffer cell derived O(2) (-) and is limited by eNOS-derived NO.

Carbon monoxide stimulates mrp2-dependent excretion of bilirubin-IXalpha into bile in the perfused rat liver.

Although carbon monoxide (CO) has been reported to protect against hepatobiliary dysfunction, mechanisms for its actions remain unknown. This study aimed to examine actions of physiologically relevant concentrations of CO on biliary excretion. The effects of transportal administration of CO on bile output and constituents were examined in perfused rat livers. In livers of fed rats, CO regulated bile output biphasically in a dose-dependent manner; transportal administration of CO at 4 micro mol/L stimulated bile output by 10%. Under these circumstances, CO increased paracellular junctional permeability and consequently decreased biliary excretion of bile salts. Choleresis elicited by 4 micro mol/L CO coincided with significant increases in biliary excretion of bilirubin-IXalpha and glutathione. The CO-induced choleresis occurred independently of cyclic GMP, coincided with elevated excretion of K(+) and HCO(3)(-), and was abolished by tetraethylammonium, suggesting stimulatory effects of the gas on potassium channels. CO-mediated choleresis and increased excretion of organic anions appeared to be mediated by mrp2, because Eisai hyperbilirubinemia rats, which genetically lack the transporter, did not exhibit choleresis upon the CO administration. These results suggest that CO stimulates mrp2-dependent excretion of bilirubin-IXalpha through mechanisms involving potassium channels, serving as a cooperator standing behind the heme oxygenase reaction to facilitate hepatic heme detoxification.