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Introduction: Fluoropyrimidines such as 5-fluorouracil (5-FU) and its orally active prodrug, capecitabine, are widely used in the treatment of gastrointestinal cancer, including colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) plays an important role in the 5-FU metabolism. Dihydropyrimidine dehydrogenase gene (DPYD) is a highly polymorphic gene with several hundreds of reported genetic variants and DPD activity levels vary considerably among individuals, with different 5-FU-related efficacy and toxicity. About 5% of the population is deficient in DPD enzyme activity. The most well studied DPYD variant is the IVS14+1G>A, also known as DPYD *2A. In this report, we present a case of a patient with a double heterozygote DPYD variant (DPYD activity score: 0,5 according to Clinical Pharmacogenetics Implementation Consortium) who experienced a severe fluoropyrimidine-related toxicity resolved without any consequence., Patient Concerns: A 46-years-old Caucasian man with diagnosis of left colon adenocarcinoma underwent left hemicolectomy on July 2017: pT3 G3 N1c M0. According to the disease stage, he started an adjuvant therapy with XELOX using capecitabine at 50% of total dose, because of his DPYD IVS14+1G>A variant, detected before the treatment., Diagnosis: After few days, despite of this dose reduction, he experienced life-threatening adverse events such as mucositis G3, diarrhea G3, neutropenia G4, thrombocytopenia G4, and hyperbilirubinemia G3 according to Common Terminology Criteria for Adverse Events v 5.0., Interventions: As first, we set up an intensive rehydration therapy, antibiotic and antifungal prophylaxis, Granulocyte-Colony Stimulating Factors, and supportive blood transfusions. Additional genetic tests revealed a double heterozygote variant of DPYD gene (DPYD IVS14+1G>A and 2846A>T) which is a very rare situation and only 3 cases are described in literature, all of them concluded with patient's death., Outcomes: After 3 weeks of intensive therapy, the patient was fully recovered. Furthermore, all the whole-body CT scans performed since discharge from the hospital until now, have confirmed no evidence of disease., Conclusions: Recent studies demonstrated that screening strategy for the most common DPYD variants allowed for avoiding toxicities and saving money. This report underlines the importance of genotyping DPYD before treatment and emphasizes the role of genotype-guided dose individualization.

Background: Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols., Methods: Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated., Results: A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters., Conclusions: Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.

Aim: The goal of this work was to investigate the associations of genetic and environmental factors with gemcitabine disposition and toxicity from genomewide data using a novel information theoretic approach., Methods: We utilized the information theoretic K-way interaction information (KWII) metric to detect gene-gene and gene-environment interactions associated with gemcitabine disposition and gemcitabine-induced neutropenia in genomic and clinical data from Japanese cancer patients., Results: The information theoretic KWII analyses identified age and four genes - DMD, HEXDC, CNTN4, and ALOX5AP - to be associated with gemcitabine pharmacokinetics (PK). The rs4769060 single-nucleotide polymorphism in the ALOX5AP gene was associated with all PK parameters studied. For gemcitabine-induced neutropenia, multiple associations with long intergenic noncoding RNA regions were detected. Pathway analysis identified leukotriene and eoxin synthesis, platelet homeostasis, and L1CAM interactions as potential pathways associated with gemcitabine disposition., Conclusion: The KWII analyses detected novel associations with gemcitabine PK and toxicity. These results could be used to inform future investigations involving gemcitabine efficacy in clinical settings.

Objective: To describe the pharmacokinetics of tenofovir and emtricitabine in the third trimester of pregnant HIV-infected women and at postpartum., Design: A nonrandomized, open-label, multicentre phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe., Methods: HIV-infected pregnant women treated with the nucleotide/nucleoside analogue reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF 300 mg; equivalent to 245 mg tenofovir disoproxil) and/or emtricitabine (FTC 200 mg) were included in the study. Twenty-four-hour pharmacokinetic curves were recorded in the third trimester (preferably week 33) and postpartum (preferably week 4-6). Collection of a cord blood sample and maternal sample at delivery was optional. Pharmacokinetic parameters were calculated using WinNonlin software version 5.3. Statistical analysis was conducted using SPSS version 16.0., Results: Thirty-four women were included in the analysis. Geometric mean ratios of third trimester vs. postpartum [90% confidence interval (CI)] were 0.77 (0.71-0.83) for TDF area under the curve (AUC0-24 h); 0.81 (0.68-0.96) for TDF Cmax and 0.79 (0.70-0.90) for TDF C24 h and 0.75 (0.68-0.82) for FTC AUC0-24 h; and 0.87 (0.77-0.99) for FTC Cmax and 0.77 (0.52-1.12) for FTC C24 h. The viral load close to delivery was less than 200  copies/ml in all but one patient, the average gestational age at delivery was 38 weeks. All children were tested HIV-negative and no congenital abnormalities were reported., Conclusion: Although pharmacokinetic exposure of the NRTIs TDF and FTC during pregnancy is approximately 25% lower, this was not associated with virological failure in this study and did not result in mother-to-child transmission.

Purpose of Review: Pre-exposure prophylaxis (PrEP) clinical trial results using antiretrovirals can seem confusing, if not conflicting. We review recent antiretroviral pharmacokinetic studies to help explain PrEP trial results., Recent Findings: Pharmacokinetic studies indicate that topical dosing, compared with oral dosing, achieves far higher colon and vaginal tissue drug concentrations, and far lower drug concentrations in blood. After oral dosing, higher tenofovir diphosphate concentrations are found in colon tissue than cervico-vaginal tissue, but the reverse is the case for emtricitabine triphosphate, although it does not persist as long. Vaginal dosing achieves measurable tenofovir concentrations in the rectum and vice versa. Within and among oral PrEP trials, increased drug concentration is associated with increased HIV protection, with drug concentration differences best explained by adherence, rather than pharmacokinetics. The poor level of protection in topical studies is not consistent with concentration-response in oral studies indicating unknown variables in need of further investigation., Summary: Sparse pharmacokinetic sampling in large trials combined with more intensive sampling in smaller pharmacokinetic-focused studies help explain trial outcome differences due largely to differences in adherence, tissue pharmacokinetics, and type of HIV exposure. Pharmacokinetic analysis can identify protective drug concentration targets, guide dose optimization, and inform future trials.

Purpose of Review: HIV infection among MSM remains a significant issue. Data relevant to MSM populations from animal models, pharmacokinetic studies and clinical trials are summarized and challenges and potential consequences of use of preexposure prophylaxis (PrEP) by MSM are discussed., Recent Findings: Rectal simian-human immunodeficiency virus transmission in macaque models can be prevented by intermittent PrEP dosing. The Preexposure Prophylaxis Initiative (iPrEx) study found that daily oral emtricitabine-tenofovir disoproxyl fumarate (TDF/FTC) decreased HIV infection by 44% among 2499 high-risk MSM. Men with detectable levels of TDF or FTC in plasma and peripheral blood mononuclear cells experienced more than 90% protective effect, emphasizing the importance of adherence. In iPrEX and other studies, PrEP was generally safe and well tolerated. However, it appears that TDF use is associated with a small but significant decrease in mean bone mineral density. No risk compensation has been demonstrated, but this remains an area of potential concern when PrEP is used outside the setting of a placebo-controlled trial. Numerous PrEP trials in MSM are currently underway., Summary: Oral FTC/TDF is effective in preventing HIV infection among MSM. Optimal PrEP agents and dosing regimens now need to be identified. Understanding the patterns of and impediments to PrEP use among MSM is vital and these should be monitored in ongoing demonstration projects and open-label studies.

The term "Pseudocellulitis" can be used to describe an uncomplicated nonnecrotizing inflammation of the dermis and hypodermis from a noninfectious etiology. Chemotherapeutic agents have been associated with a variety of cutaneous reactions, including radiation recall dermatitis, hypersensitivity reactions, and erysipeloid reactions. Gemcitabine (2,2-difluorodeoxycytidine) is currently being used for treatment of a variety of solid malignancies, including carcinoma of the lung. The dermatitis involved with gemcitabine is typically a radiation recall reaction whereby an inflammatory reaction occurs in the area previously treated with radiotherapy. We describe here a case of Gemcitabine-induced pseudocellulitis that was unrelated to radiation exposure and manifested in an area of lymphedema. The pseudocellulitis in such cases could be related to the drug's pharmacokinetics and may last until the drug is displaced from the subcutaneous tissue of the affected area. Antibiotics have no role in the treatment, and diphenhydramine with nonsteroidal anti-inflammatories may be used for symptomatic management.

Introduction: Bortezomib, a proteasome inhibitor, has synergistic antitumor activity with gemcitabine, an antimetabolite, in preclinical and clinical studies. The safety of this combination has not yet been established in elderly patients; therefore, this dose-escalation study was designed to assess the maximum-tolerated dose of bortezomib and gemcitabine in patients aged 70 years or older with advanced-stage solid tumors., Patients and Methods: Gemcitabine was administered intravenously (800 to 1000 mg/m) over 30 minutes on days 1 and 8, followed 60 minutes later by bortezomib administered as an intravenous push over 3 to 5 seconds (1.0 to 1.8 mg/m) on a 21-day cycle. This study used a standard phase 1 dose-escalation design with 3 or 6 patients per dose level., Results: Seventeen patients with stage IV solid tumors were treated. Median age was 73 years (range: 70 to 87 y). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status less than 2. Median number of earlier chemotherapy regimens was 2 (range: 0 to 6). Dose-limiting toxicities were seen in 2 of 8 patients enrolled at the second dose level of gemcitabine (1000 mg/m) and bortezomib (1.0 mg/m), which consisted of grade ≥3 lower extremity edema, thrombocytopenia, fatigue, and dehydration. The most common grade ≥3 toxicities included thrombocytopenia (n=9), neutropenia (n=6), and anemia (n=5). Partial response (n=3) or disease stabilization (n=3) was seen in 6 of 14 evaluable patients., Conclusions: Concurrent weekly gemcitabine (800 mg/m) and bortezomib (1 mg/m) is the recommended schedule for future phase 2 trials in elderly patients with stage IV solid tumors.

5-Fluorouracil (5-FU) is the most widely used agent for the management of colorectal cancer. Capecitabine is metabolized by three enzymatic actions, the last of which is mediated by thymidine phosphorylase, to produce 5-FU. Given the oral bioavailability of capecitabine as well as in-vitro and in-vivo findings showing higher expression of thymidine phosphorylase in tumor cells and xenografts compared with normal tissue, capecitabine is an evolving candidate in the management of colorectal cancer with antimetabolite-based therapy. An ideal radiosensitizing agent must balance oncological outcomes with adverse effects and feasibility of administration. This discussion addresses the evolving role of 5-FU in the management of rectal cancer in the neoadjuvant setting in combination with ionizing radiation.

Gemcitabine (2',2'-difluorodeoxycytidine) is a major antimetabolite cytotoxic drug with a wide spectrum of activity against solid tumors. Hepatic elimination of gemcitabine depends on a catabolic pathway through a deamination step driven by the enzyme cytidine deaminase (CDA). Severe hematologic toxicity to gemcitabine was reported in patients harboring genetic polymorphisms in CDA gene. High-resolution melting (HRM) analysis of polymerase chain reaction amplicon emerges today as a powerful technique for both genotyping and gene scanning strategies. In this study, 46 DNA samples from gemcitabine-treated patients were subjected to HRM analysis on a LightCycler 480 platform. Residual serum CDA activity was assayed as a surrogate marker for the overall functionality of this enzyme. Genotyping of three well-described single nucleotide polymorphisms in coding region (c.79A>C, c.208G>A and c.435C>T) was successfully achieved by HRM analysis of small polymerase chain reaction fragments, whereas unknown single nucleotide polymorphisms were searched by a gene scanning strategy with longer amplicons (up to 622 bp). The gene scanning strategy allowed us to find a new intronic mutation c.246+37G>A in a female patient displaying marked CDA deficiency and who had an extreme toxic reaction with a fatal outcome to gemcitabine treatment. Our work demonstrates that HRM-based methods, owing to their simplicity, reliability, and speed, are useful tools for diagnosis of CDA deficiency and could be of interest for personalized medicine.

In an earlier report, we demonstrated the superior anticancer efficacy of orally administered squalenoyl gemcitabine (SQdFdC) nanomedicine over its parent drug gemcitabine on rats bearing RNK-16 large granular lymphocytic (LGL) leukemia. In the present communication, we investigated the mechanisms behind this observation both at the cell and tissue level. The mechanisms were investigated by performing cytotoxicity, cell uptake, and biodistribution experiments. In the presence of cytidine deaminase, SQdFdC nanoassemblies resisted deamination and exerted significant anticancer activity in vitro against RNK-16 LGL leukemia cells, whereas the cytotoxicity of free gemcitabine decreased by approximately 83-fold, indicating its degradation due to deamination. Additionally, the SQdFdC showed considerably higher intracellular accumulation and retention compared with gemcitabine (P<0.05). Unlike gemcitabine, the cellular access to SQdFdC was not influenced by nucleoside transporters. When administered orally to rats, unlike H-gemcitabine, the H-SQdFdC absorbed slowly, but exhibited an improved pharmacokinetics and tissue distribution profile, particularly in the lymphoid organs (the major organs of metastasis). The resistance to deamination, followed by the improved pharmacokinetic and tissue distribution, and greater accumulation and retention at the level of cancer cells, are the key factors for the superiority of SQdFdC nanoassemblies over free gemcitabine against RNK-16 LGL leukemia in rats.

Objectives: Cycloxygenase-2 (COX-2) is overexpressed in pancreatic tumors where it may be involved in inflammation, carcinogenesis, and the regulation of neoangiogenesis. The purpose of this trial was to evaluate the combination of intravenous gemcitabine with selective COX-2 inhibitor, celecoxib for effect on survival, disease progression, and tolerability in patients with advanced pancreatic cancer. In addition, limited pharmacokinetic and pharmacodynamic analyses were preformed., Materials and Methods: Eligible patients included those with locally advanced or metastatic pancreatic cancer with no prior chemotherapy and ECOG performance status 0-2. The treatment consisted of intravenous gemcitabine 1000 mg/m weekly x 7 weeks and concurrent daily oral celecoxib 400 mg orally twice a day. Daily oral low-dose aspirin 81 mg was administered throughout the study as a precaution for increased risk of thrombotic events. Those with stable or responsive disease were continued on intravenous gemcitabine 1000 mg/m weekly x 3 weeks and concurrent oral celecoxib., Results: Twenty five patients have been enrolled at 3 centers. Five patients had locally advanced cancer; 20 had metastatic disease. The most common grade 3/4 hematological toxicities were neutropenia (32%) and anemia (20%). Four patients (17%) had partial response and 7 (35%) demonstrated stable disease. The estimated 12-month survival rate was 15%, which did not reach the predetermined efficacy end point. There was a trend suggestive of correlation between a decrease in serum vascular endothelial growth factor and patient survival., Conclusion: The addition of celecoxib to gemcitabine therapy did not demonstrate significant improvement in measured clinical outcomes, in patients with advanced pancreatic cancer. Higher doses of celecoxib may be needed to observe significant antitumor activity.

5-Fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy is used in rectal cancer to prolong survival, downsize tumors prior to surgery, and allow for sphincter-sparing surgery. Capecitabine is an oral fluoropyrimidine that generates 5-FU preferentially within the tumor. It has been shown to be as effective as 5-FU and well tolerated in the metastatic and adjuvant settings in colorectal cancer. Capecitabine is more convenient for patients than 5-FU, and it avoids the risks of infection and thromboembolism associated with intravenous administration. It was also shown to reduce the use of medical resources, healthcare professionals' time, and cost of therapy. Emerging data from Phase II trials of neoadjuvant regimens in which capecitabine has been substituted for 5-FU are encouraging.

Objective: To understand the impact of protein kinase B (PKB; Akt) signaling on growth and protection from apoptosis in pancreatic ductal adenocarcinoma models demonstrating differences in PKB activity., Methods: Gemcitabine sensitivity was investigated in a panel of cell lines, characterized by differences in levels of activated PKB. Suppression of PKB activity was achieved with an inhibitor of phosphatidylinositol 3-kinase (wortmannin) and silencing RNA., Results: Enhanced gemcitabine (2',2'-difluoro-2'-deoxycytidine)-induced cytotoxicity in vitro was achieved with suppression of high PKB activity with wortmannin in BxPC-3, PK-1, and PK-8 cells and silencing RNA targeted to total PKB, rather than PKBbeta, in PANC-1 cells. Opposite to gemcitabine sensitivity levels in vitro, the growth of PANC-1 xenografts was inhibited with gemcitabine treatment, whereas BxPC-3 became drug resistant. Monolayer cell cultures reestablished from solid tumors behaved similarly to original cultures, suggesting that the tumor microenvironment has a critical role in determining drug sensitivity. A comparison of transcript profiles of the models indicated that PKB signaling might be modulated by a number of pathways responsive to the tumor hypoxia microenvironment., Conclusions: These results suggested that gemcitabine efficacy involving the PKB pathway depends on PKB activity, its mechanisms of enhanced activity, as well as its function in a signaling network.

Objectives: To describe first dose and steady state antiretroviral drug exposure in the female genital tract., Design: Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women., Method: Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA)., Results: For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%)., Conclusions: This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates.

HAART has decreased the incidence of AIDS and death among HIV-infected individuals dramatically. This approach often becomes cumbersome to patients, involving multiple drugs administered on varying schedules. We investigated the pharmacokinetics, efficacy, and tolerability of a once-daily regimen of fosamprenavir, tenofovir, emtricitabine and ritonavir in HIV-infected treatment-naive subjects. No clinically significant interaction between the drugs was noted, and the regimen showed good efficacy and tolerability over the course of 48 weeks.

Our objective was to determine the response to gemcitabine plus docetaxel in advanced urothelial transitional cell carcinoma in a phase II trial, and gemcitabine distribution between plasma and erythrocytes, following docetaxel administration. Patients with locally advanced or metastatic transitional cell carcinoma, following a maximum of one prior chemotherapy regimen, were given gemcitabine 800 mg/m on days 1 and 8 plus docetaxel 85 mg/m on day 8, every 21 days. Gemcitabine was measured in the plasma and erythrocytes of nine patients before and after docetaxel administration. Thirty-four patients (median 63 years; range 49-79 years), of whom seven had prior chemotherapy and 27 were chemotherapy-naive, received a median of six cycles (range 1-6). Complete and partial remissions were observed in two and 16 (including three pretreated) patients, respectively, for an overall response rate of 53%. Median response duration was 5 months (range 1-39+). Haematoxicity was manageable, despite grade 3 infections in 24% of patients, but other toxicities were mostly mild. An apparent shift of gemcitabine from plasma to erythrocytes occurred after docetaxel in five of six patients evaluable for this analysis. We conclude gemcitabine plus docetaxel is tolerable and highly active in treated and untreated patients with advanced transitional cell carcinoma.

We investigated the possible pharmacokinetic interactions of gemcitabine and oxaliplatin in patients with advanced solid tumors. Ten patients with advanced stage solid tumors were treated with gemcitabine (1500 mg/m) as a 30-min intravenous infusion on days 1 and 8, followed by oxaliplatin (130 mg/m) as a 4-h intravenous infusion, on day 8 every 21 days. Pharmacokinetic data for 24 h after dosing were obtained for both day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) during the first cycle of treatment. Gemcitabine levels in plasma were quantified using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection, and total and ultrafiltrated platinum levels by flameless atomic absorption spectrophotometry with deuterium correction. All pharmacokinetic parameters of gemcitabine seemed to be unchanged when coadministered with oxaliplatin (day 8) compared with pharmacokinetic data of gemcitabine given as a single agent (day 1). The mean (maximum) concentration of gemcitabine on days 1 and 8 was 13.57 (+/-7.42) and 10.23 (+/-5.21) mg/l, respectively (P=0.28), and the mean half-life was 0.32 and 0.44 h, respectively (P=0.40). Similarly, the P-values for AUC0-24 and the observed clearance were 0.61 and 0.30, respectively. Plasma total and free platinum levels were in agreement with other published data. Gemcitabine disposition appeared to be unaffected by oxaliplatin coadministration because no significant changes in pharmacokinetics between day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) were observed.

Objectives: To evaluate the efficacy, the toxicity and the pharmacokinetics of a gemcitabine (GEM) and oxaliplatin (OXA) combination in metastatic breast cancer patients (MBC), previously treated with anthracycline and taxanes., Methods: A total of 40 women were enrolled; 37 patients had visceral metastases as dominant site of disease, including 20 patients with liver metastases and 14 with multiple visceral metastases. Three patients received neo-adjuvant chemotherapy, 13 patients adjuvant chemotherapy alone, 24 patients chemotherapy for MBC alone. Gemcitabine was given at 1000 mg/m2 on days 1, 8 followed by oxaliplatin at 100 mg/m2 iv on day 2 every 2 weeks (GEM-OXA sequence). Possible pharmacokinetic interactions were studied in 10 patients, by administering on cycle 1 gemcitabine d1/oxaliplatin d2 (GEM-OXA) and on cycle 2 oxaliplatin d1/gemcitabine d2 (OXA-GEM)., Results: After a median of 8 cycles, 10 partial response (PR) (25%), 16 stable disease (SD) (40%), and 14 progressive disease (PD) (35%) were obtained. The median duration of response was 6 months (3-9) for responding patients and 4.9 months (2-7.5) for patients with stable disease. For PR, SD and PD patients, median survival was 18 (10-23+), 13 (8-18), and 6 months (4-13), respectively. G3-4 neutropenia occurred in 20% of patients (febrile G3 neutropenia in 2.5%), G3-4 thrombocytopenia and anemia in 15% and 7.5%. The most frequent G3-4 nonhematologic toxicity was represented by peripheral neuropathy (20%), always reversible. The GEM-OXA and OXA-GEM schedules showed a similar pharmacokinetic behavior, with no sequence-dependent interaction., Conclusions: The combination gemcitabine plus oxaliplatin has moderate activity in anthracycline and taxanes resistant/relapsed heavily treated patients, mild toxicity and no administration sequence-dependent pharmacokinetic interactions.

RP101 [(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU)], which supports apoptosis and prevents the acquisition of chemoresistance, was tested in cultured human pancreatic tumor cells. RP101 downregulated uridine phosphorylase, a marker of poor prognosis, and APEX1, which is involved in DNA repair, and repressed Stat3 and its target vascular endothelial growth factor. Furthermore, RP101 activated antitumor immunity as demonstrated by enhanced cytolytic activity of NK-92 natural killer cells. This was concomitant with an enhanced expression of lymphotoxins alpha and beta, natural killer cell transcript 4, tumor necrosis factor LIGHT/TNFSF-14, and intercellular adhesion molecule-1 in pancreas carcinoma cells. These results encouraged us to investigate the effect of RP101 in pancreas cancer patients. Here, we present data from two RP101 combination therapy schemes. In a first pilot study, 13 patients in stage III and VI of the disease were treated with gemcitabine +cisplatin+RP101. RP101 co-treatment enhanced remissions, survival and time to progression. Seventy-seven percent of the patients lived or have lived longer than 1 year, and 23% have lived more than 2 years. Median survival was 447 days, time to progression 280 days and the response rate 33%. A second study with 21 patients in similar stages of disease, treated with RP101+gemcitabine alone, confirmed the results of the pilot study. Eighty-three percent of the presently evaluable patients live or lived 0.5 years or longer and 33% 1 year or longer. Considering both studies, the tumor control was 94%. The data indicate that acquisition of chemoresistance was prevented and the antitumor efficacy of standard chemotherapy was improved. To our knowledge, RP101 co-treatment is more efficient than any other regimen published.

Purpose of Review: Nonmuscle-invasive bladder cancer is a common malignancy, standardly treated by transurethral resection and adjuvant intravesical instillations of chemotherapy or immunotherapy. Adjuvant instillations are needed to reduce recurrence and/or progression. With currently existing adjuvant treatments, however, recurrences still occur, progression is hardly influenced and these treatments induce local or systemic side effects. In search for efficacy improvement and side effect reduction, we reviewed the promising properties of the relatively new intravesical drug, gemcitabine., Recent Findings: The safety of gemcitabine is tested in different instillation schemes, drug concentrations and administered volumes. Its safety profile is excellent, with good tolerability and minimal toxicity up to 2000 mg/50 ml for 2-h instillations. In comparison with other drugs, the ablative efficacy of gemcitabine is good. The first studies on prophylactic efficacy in intermediate-risk, high-risk and bacillus Calmette-Guerin-refractory patients are promising but limited by the small number of patients studied., Summary: The available literature underlines the promising properties of gemcitabine for the intravesical use against nonmuscle-invasive bladder cancer. Exploring phase-II and comparative randomized phase-III studies should provide additional information on gemcitabine and its benefit to clinical practice.

Objectives: This phase 2 study evaluated clinical efficacy, toxicity, and pharmacokinetics of combination gemcitabine (GEM) and oxaliplatin (OXA) in patients with advanced pancreatic adenocarcinoma., Methods: Of 30 eligible patients, 20 had metastatic disease and 10 had nonmetastatic unresectable locally advanced disease. Gemcitabine 1000 mg/m2 as a 10 mg/m2/min intravenous infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour intravenous infusion on day 2 were administered every 2 weeks. Pharmacokinetics were evaluated in 11 patients by administering the 2 drugs in opposing sequences GEM-OXA (GEM day 1, OXA day 2) and OXA-GEM (OXA day 1, GEM day 2)., Results: Of 30 patients evaluated, 9 had a partial response, 11 had disease stabilization, and 10 had disease progression. Median progression-free survival and overall survival were 5.5 and 9.5 months, respectively. The 1-year survival was 37% for all patients. This study revealed no significant pharmacokinetic interaction between the 2 drugs in the GEM-OXA or in the OXA-GEM sequence., Conclusions: The combination of GEM and OXA was well tolerated and showed a promising activity in patients with advanced pancreatic adenocarcinoma; no sequence-dependent pharmacokinetic interaction occurred when comparing the GEM-OXA versus the OXA-GEM sequence, with a 24-hour interval.

Our objective was to study the feasibility of schedule- and dose-intensive cisplatin plus gemcitabine in patients with non-small cell lung cancer (NSCLC) when given on 1 day in four 2-weekly cycles. Cisplatin was administered as a 3 h i.v. infusion followed by gemcitabine as a 30-min i.v. infusion on the same day, every 2 weeks. An interval of 1 h between the two infusions was applied. Patients received four courses without any break. An interpatient dose-escalation scheme was used. The starting dose was 87.5 mg/m of cisplatin and 1350 mg/m of gemcitabine. The pharmacokinetics of cisplatin and gemcitabine were determined in plasma and white blood cells. In total, 23 patients were included in the study. Median age of the patients was 56 years (range 27-76) and most patients were in good clinical condition. Thirteen patients received all planned courses. Dose-limiting toxicity was Common Toxicity Criteria grade 2 ototoxicity. The maximum tolerated dose was established at cisplatin 90 mg/m in combination with gemcitabine 1500 mg/m. This short induction schedule is practical and convenient for the patient. We conclude that the combination of cisplatin at a dose intensity of 51 mg/m/week followed by gemcitabine (1500 mg/m) on the same day is clinically feasible in NSCLC patients when given as a 2-weekly cycle.

The purpose of this phase I study was to determine the pharmacokinetics and toxicity of gemcitabine in patients with advanced, recurrent, and/or metastatic cancer and renal impairment. Patients were entered in 4 groups estimated by EDTA-Cr plasma clearance (CLp, mL/min): > or =80; > or =60 and <80; > or =30 and <60; and > or =30 and <80 plus renal insufficiency induced by previous chemotherapy, respectively. Gemcitabine 500 to 1000 mg/m was administered intravenously on days 1, 8, and 15 every 4 weeks. Plasma concentration data were pooled and analyzed using a population pharmacokinetic program (NONMEM). Eighteen white patients (14 females, 4 males) entered the study with a median age of 55 years. Linear regression analyses revealed no significant relationship between gemcitabine CLp and indices of renal impairment (EDTA-Cr CL; p = 0.797 or beta2-microglobulin; p = 0.153). Hematologic and nonhematologic toxicities were mild. Thus, there seems to be no significant impact of mild to moderate renal insufficiency on gemcitabine pharmacokinetics in patients with advanced cancer.

Purpose: The purpose of this study was to determine the maximum tolerated dose, pharmacokinetic profile, and evidence of antitumor activity of CI-994 used in combination with gemcitabine., Methods: This was a dose escalation trial in which gemcitabine (1,000 mg/m2) was given as a 30-minute infusion on days 1, 8, and 15 of a 28-day cycle. CI-994 was taken orally on consecutive days 1-21 at escalating doses of 2, 4, 6, and 8 mg/m2 per cohort (three patients/cohort). Plasma samples were collected on days 1 and 15 of course 1 and analyzed for CI-994 pharmacokinetic assessment., Results: Twenty patients with advanced cancer received a total of 76 courses of treatment. Dose-limitingtoxicity occurred at the 8-mg/ m2 dose. Four of seven patients experienced thrombocytopenia during the first cycle. Grade 4 thrombocytopenia was observed in three of 10 (30%) courses at 8 mg/m2. In contrast, only two of 28 (7%) courses at 6 mg/m2 were associated with grade 4 thrombocytopenia. Pharmacokinetic analysis indicated that absorption of CI-994 was rapid, with peak plasma concentrations occurring at the first sample 2 hours after dosing. Two patients achieved a minor response, 12 had stable disease (median duration, 105 days), four had progressive disease, and two were not evaluable., Conclusions: The 6-mg/m2 dose of CI-994 (p.o. x 21 days) was defined as the maximum tolerated dose that could safely be administered in combination with gemcitabine (1,000 mg/m2 i.v. on days 1, 8, and 15) during a 28-day cycle.

Our objective was to determine the maximum tolerated dose (MTD) of two administration sequences of docetaxel and gemcitabine in cancer patients, and to describe the pharmacokinetics of both drugs. Patients were treated in a 4-weekly schedule at two dose levels: gemcitabine 800 mg/m2 on days 1, 8 and 15, and docetaxel 85 or 100 mg/m2 on day 15 (levels I and II). The protocol was amended to a 3-weekly schedule, testing gemcitabine 800 or 1000 mg/m2 on days 1 and 8, with docetaxel 85 mg/m2 on day 8 given initially (dose levels IIIa and IV). At the recommended dose, an extra cohort of patients initially received gemcitabine (dose level IIIb). Eleven patients were treated with the 4-week schedule; 29% of cycles were delayed predominantly because of hematological toxicity. Four patients developed dose-limiting toxicities (DLTs), predominantly hematological. In the 3-week schedule, 14 patients were treated. At level IV, three of four patients developed DLTs, defining the MTD. With the reverse sequence, three patients received a total of 10 cycles. Overall, nine partial remissions were observed. We conclude the recommended dose for phase II studies is gemcitabine 800 mg/m2 on days 1 and 8, combined with docetaxel 85 mg/m2 on day 8, on a 3-weekly schedule. Gemcitabine distribution is significantly altered upon docetaxel administration.

Although 5-fluorouracil (5-FU) has been used to treat breast and colorectal cancers for several decades, bolus 5-FU has disappointing efficacy. Prolonged infusion schedules and biomodulation with leucovorin have resulted in improved response rates, but these have not translated into significant improvements in survival in patients with metastatic disease. Furthermore, prolonged infusion is inconvenient for patients and can result in medical complications. New oral fluoropyrimidines, including capecitabine, are promising alternatives to i.v. 5-FU. Capecitabine generates 5-FU preferentially within tumors through exploitation of the high intratumoral activity of thymidine phosphorylase. The tumor selectivity of capecitabine has been confirmed in a clinical study of colorectal cancer patients. Clinical trials have shown that capecitabine is an effective, well-tolerated treatment for breast and colorectal cancer, with response rates of 20-26% in anthracycline- and taxane-pretreated metastatic breast cancer. As first-line monotherapy, capecitabine produces response rates of 25-27% in metastatic colorectal cancer and 30% in metastatic breast cancer. In all studies to date, capecitabine has been well tolerated, with adverse events typical of infusional 5-FU and manageable with treatment interruption/dose modification. Myelosuppression and alopecia are rare. Capecitabine is also being investigated in other solid tumors (including ovarian, pancreatic and gastric cancers) as adjuvant monotherapy in breast and colorectal cancer, and in combination with other cytotoxic agents. Results of ongoing trials are eagerly awaited.

Purpose: (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite. Preclinical tests have shown antiproliferative activity in various human tumor xenograft models and have also indicated that efficacy is greatest with frequent dosing schedules. We conducted a phase I trial of MDL 101,731 infusion in humans with advanced cancer to determine the maximum tolerated dose and the dose-limiting toxicities of this drug when administered on a twice-weekly schedule., Patients and Methods: The drug was administered on a twice-weekly schedule for 3 weeks, followed by a 2-week rest. The initial dose was 16 mg/m2. This was reduced to 12 mg/m2 if persistent neutropenia occurred. All toxicity in the first six patients resolved by the end of the first rest week. The schedule was changed to 3 weeks of therapy followed by 1 rest week for the subsequent four patients., Results: Dose escalation beyond 16 mg/m2 was not feasible because of dose-limiting toxicities, principally hematologic. No irreversible or life-threatening toxicity was seen. Grade 2 noninfectious fever, mucositis, and anorexia were also seen. In patients with stable disease, there was a heavily pretreated patient with rectal cancer in whom a 38% reduction in indicator lesions of 7 months' duration occurred., Discussion: (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite with evidence of anticancer activity in heavily pretreated patients. The maximum tolerated dose when the agent is given twice weekly is 16 mg/m2.

2',2'-difluorodeoxycytidine (known as dFdC, Gemcitabine and LY188011) is a new analog of deoxycytidine which has demonstrated excellent antineoplastic activity against many kinds of solid tumors and leukemic cell lines. We were interested in the comparison of the antineoplastic activity of this new antimetabolite with cytosine arabinoside (ARA-C) against HL-60 myeloid, RPMI-8392 B-lymphoid and Molt-3 T-lymphoid leukemic cell lines. Our in vitro experiments showed that dFdC was a more potent cytostatic drug than ARA-C against all the leukemic lines with IC50 ranging from 3 to 10 nM for dFdC and from 26 to 52 nM for ARA-C for a 48 h exposure. The cytotoxicity of both drugs was evaluated by clonogenic assay and dFdC was found to be 100 times more potent than ARA-C against all the leukemic cell lines for both a 2 h and a 24 h exposure. The recovery of DNA synthesis after drug removal was much slower for dFdC than for ARA-C. However, in contrast to cytostatic and cytotoxicity results ARA-C was a more potent inhibitor of DNA synthesis than dFdC for all the leukemic cell lines for short exposure. Uptake and elimination of the drugs showed that dFdC accumulated to a higher degree in the leukemic cells than ARA-C and that elimination of this difluoro analog was slower than that of ARA-C. These results indicate that dFdC has more potent in vitro antileukemic activity than ARA-C.