Sorafenib alone vs. sorafenib plus GEMOX as 1st-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial.

BACKGROUND: Sorafenib remains one major first-line therapeutic options for advanced hepatocellular carcinoma (aHCC), with modest efficacy. We investigated the addition of gemcitabine and oxaliplatin (GEMOX) to sorafenib in aHCC patients. METHODS: Our multicentre phase II trial randomised aHCC first-line patients to sorafenib (400 mg BID) or sorafenib-GEMOX every 2 weeks (1000 mg/m2 gemcitabine; 100 mg/m2 oxaliplatin). Primary endpoint was the 4-month progression-free survival (PFS) rate. RESULTS: Ninety-four patients were randomised (sorafenib-GEMOX: n = 48; sorafenib: n = 46). Median age was 64 years, PS 0 (69%) or 1 (31%), 63% patients had cirrhosis, 29% portal vein thrombosis and 70% extra-hepatic disease. Median duration of sorafenib treatment was 4 months (1-51); median number of GEMOX cycles was 7 (1-16). The 4-month PFS rates were 64% and 61% in the sorafenib-GEMOX and sorafenib arms, respectively; median PFS and OS were 6.2 (95% CI: 3.8-6.8) and 13.5 (7.5-16.2) months, and 4.6 (3.9-6.2) months and 14.8 (12.2-22.2), respectively. The ORR/DCR were 9%/70% and 15%/77% in the sorafenib-GEMOX and sorafenib alone arms, respectively. Main toxicities were (sorafenib-GEMOX/sorafenib) neutropenia (23%/0), thrombocytopenia (33%/0), diarrhoea (18%/9), peripheral neuropathy (5%/0) and hand-foot syndrome (5%/18). CONCLUSIONS: Addition of GEMOX had an inpact on ORR and was well-tolerated as frontline systemic therapy. The benefit on PFS seems moderate; no subsequent study was planned.

Intraperitoneal administration of novel doxorubicin loaded polymeric delivery systems against peritoneal carcinomatosis: experimental study in a murine model of ovarian cancer.

OBJECTIVE: Peritoneal spread is an adverse outcome in ovarian cancer. Despite clinical efficiency, intraperitoneal (i.p.) chemotherapy after cytoreductive surgery is associated with high systemic and local toxicity. Two polymer-drug delivery systems (P-HYD1-DOX and P-HYD2-DOX) were developed for i.p. administration by conjugating doxorubicin (DOX) to a poly(l-Lysine citramide) polymer carrier with a hydrazone-based degradable spacer. The aim of this study was to assess the antitumoral efficacy of these two conjugates in a xenograft model of human ovarian carcinomatosis. METHODS: Peritoneal carcinomatosis was generated in athymic mice by i.p. injection of SKOV3-Luc cells. Free DOX, P-HYD1-DOX and P-HYD2-DOX solutions were administered i.p. at the same dose of 10 mg/kg (DOX eq.). For each treatment, tumor load and therapeutic efficacy were compared to untreated mice and assessed by bioluminescence imaging and survival rates. Toxicity profiles in each group and biodistribution of P-HYD2-DOX after i.p. administration were also determined. RESULTS: P-HYD-1-DOX and P-HYD-2-DOX demonstrated significant antitumoral efficacy against peritoneal carcinomatosis. Compared to untreated group, P-HYD1-DOX improved median survival times from 58 to 105 days. For P-HYD2-DOX, median survival was not reached after a follow-up of 120 days. Bioluminescence showed high efficacy of P-HYD-2-DOX compared to free DOX but the difference was not significant. Biodistribution study confirmed that free and active DOX were successively released from P-HYD2-DOX in vivo. P-HYD-DOX conjugates were well tolerated by mice after i.p. injection. CONCLUSION: P-HYD-DOX conjugates demonstrated significant activity against peritoneal carcinomatosis in a xenograft model of ovarian carcinomatosis and their ability to release active DOX in i.p. deposits and tumor. These features are of clinical interest for i.p. administration in the treatment of ovarian peritoneal carcinomatosis after cytoreductive surgery.

Pregnane X Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation.

BACKGROUND: Clinical efficacy of chemotherapy in colorectal cancer is subjected to broad inter-individual variations leading to the inability to predict outcome and toxicity. The topoisomerase I inhibitor irinotecan (CPT-11) is worldwide approved for the treatment of metastatic colorectal cancer and undergoes extensive peripheral and tumoral metabolism. PXR is a xenoreceptor activated by many drugs and environmental compounds regulating the expression of drug metabolism and transport genes in detoxification organs such as liver and gastrointestinal tract. Considering the metabolic pathway of irinotecan and the tissue distribution of Pregnane x Receptor (PXR), we hypothesized that PXR could play a key role in colon cancer cell response to irinotecan. RESULTS: PXR mRNA expression was quantified by RT-quantitative PCR in a panel of 14 colon tumor samples and their matched normal tissues. PXR expression was modulated in human colorectal cancer cells LS174T, SW480 and SW620 by transfection and siRNA strategies. Cellular response to irinotecan and its active metabolic SN38 was assessed by cell viability assays, HPLC metabolic profiles and mRNA quantification of PXR target genes. We showed that PXR was strongly expressed in colon tumor samples and displayed a great variability of expression. Expression of hPXR in human colorectal cancer cells led to a marked chemoresistance to the active metabolite SN38 correlated with PXR expression level. Metabolic profiles of SN38 showed a strong enhancement of SN38 glucuronidation to the inactive SN38G metabolite in PXR-expressing cells, correlated with an increase of UDPglucuronosyl transferases UGT1A1, UGT1A9 and UGT1A10 mRNAs. Inhibition of PXR expression by lentivirus-mediated shRNA, led to SN38 chemoresistance reversion concomitantly to a decrease of UGT1A1 expression and SN38 glucuronidation. Similarly, PXR mRNA expression levels correlated to UGT1A subfamily expression in human colon tumor biopsies. CONCLUSION: Our results demonstrate that tumoral metabolism of SN38 is affected by PXR and point to potential therapeutic significance of PXR quantification in the prediction of irinotecan response. Furthermore, our observations are pharmacologically relevant since many patients suffering from cancer diseases are often exposed to co-medications, food additives or herbal supplements able to activate PXR. A substantial part of the variability observed among patients might be caused by such interactions.

Carmustine and methotrexate in combination after whole brain radiation therapy in breast cancer patients presenting with brain metastases: a retrospective study.

BACKGROUND: Since 1999, patients presenting with brain metastases (BM) from breast cancer (BC) are treated in our institution with a carmustine (BCNU)--methotrexate (MTX) combination. We report here our clinical experience regarding this combination. PATIENTS AND METHODS: Patients were treated by a combination of BCNU 100 mg/m(2) on day 1 and MTX 600 mg/m(2) on day 1 and 15 of a 28 day cycle. Treatment was continued until progression or unacceptable toxicity. RESULTS: 50 patients were treated between 1999 and 2007. 94% of the patients presented with concomitant extra-cerebral disease. Median number of previous metastatic setting chemotherapy regimens was 2 (0-5). Median number of cycles was 3 (1-20). There were 11 objective responses (23% [95%CI 12-37]) among 48 evaluable patients. Median progression-free survival and overall survival (OS) were 4.2 (95%CI: 2.8-5.3) and 6.9 (4.2-10.7) months respectively, with a one-year OS rate of 32% (20-46). Median Relative Dose Intensity for BCNU and MTX were 0.98 (0.31-1.1) and 0.96 (0.57-1.66) respectively. There were 2 presumed treatment-related deaths. One patient developed febrile neutropenia. Performance status, BS-BM score and presence of liver metastases were associated with OS in univariate analysis. CONCLUSIONS: This combination appears to be effective and well tolerated in good performance status BC patients presenting with BM.

Multicentre phase II study using increasing doses of irinotecan combined with a simplified LV5FU2 regimen in metastatic colorectal cancer.

PURPOSE: Irinotecan at 180 mg/m2 combined with an infusional 5-fluorouracil/leucovorin (5-FU/LV) regimen (FOLFIRI) is a standard first line therapy for metastatic colorectal cancer (mCRC). This phase II study aimed to assess whether increasing the irinotecan dose in the first line FOLFIRI regimen would benefit mCRC patients. PATIENTS AND METHODS: Patients received FOLFIRI every 2 weeks for up to six cycles, comprising a 5-FU/LV regimen combined with irinotecan at 180 mg/m2 (cycle 1), increasing to 220 mg/m2 (cycle 2) and 260 mg/m2 (cycle 3 and subsequent cycles) dependent on toxicity. Efficacy and safety were determined in the intention to treat (ITT) population and in patients able to receive irinotecan at 260 mg/m2 for at least four cycles [high-dose (HD) population]. RESULTS: Fifty-four eligible patients were included. Among them, 44 (81.5%) formed the HD population. The ITT objective response rate was 48% (90%CI: 36-60) with 25/26 of the responses in the HD population. The disease control rate was 76% (90%CI: 65-85) and median overall survival was 20.4 months (90%CI: 6.4-27.1). The main grade 3/4 toxicities (ITT/HD populations) were neutropenia (61%/59%), and diarrhoea (18%/11%), respectively. CONCLUSIONS: This study confirms the feasibility of increasing the standard dose of the irinotecan component of FOLFIRI to 260 mg/m2, for more than 80% of patients but does not support a clear advantage of this strategy on unselected mCRC patients.

A limited sampling strategy to estimate the pharmacokinetic parameters of irinotecan and its active metabolite, SN-38, in patients with metastatic digestive cancer receiving the FOLFIRI regimen.

In this study we propose for the first time a limited sampling strategy to estimate the individual pharmacokinetic parameters of both irinotecan and SN-38 in patients treated with the irinotecan plus 5-fluorouracil (FOLFIRI) regimen. The pharmacokinetics of irinotecan and SN-38 were studied in 74 patients with advanced inoperable digestive cancer. Plasma concentrations were taken during and up to the 42 h following a 90-min infusion of irinotecan (180-225 mg/m(2)). Data splitting was used to create model-building and validation data sets, and data were analysed with the NONMEM program. The disposition of SN-38 was dependent on the disposition of irinotecan. The estimated pharmacokinetic parameters of irinotecan [terminal half-life (t(1/2)), 11.5 h; total clearance (CL), 25.0 l h(-1); area under curve (AUC), 14.9 mg x h l(-1)] and SN-38 (terminal t(1/2), 32.2 h; AUC, 0.42 mg x h l(-1)) were similar to those determined in other studies. The protocol involving two sampling times, at 1 and 24 h following the beginning of the infusion, allowed for a precise and accurate determination of the individual pharmacokinetic parameters of the two drugs. The limited sampling strategy developed in this study ought to facilitate future studies on the pharmacology and toxicity of irinotecan-based therapy.

Biodistribution of doxorubicin-alkylated poly(L-lysine citramide imide) conjugates in an experimental model of peritoneal carcinomatosis after intraperitoneal administration.

Peritoneal spread is a common manifestation in ovarian and gastrointestinal cancer. Intraperitoneal (i.p.) chemotherapy after cytoreductive surgery is associated with high systemic or local toxicity. A macromolecular drug delivery system was evaluated with the aim of improving the therapeutic index of i.p. chemotherapy. Peritoneal carcinomatosis was generated in BDIX rats (n=55) by i.p. injection of 2 million DHDK12 cells. Fourteen days later, doxorubicin (DOX) and two DOX-alkylated poly(L-lysine citramide imide) conjugates bearing 9.5% and 20.5% (w/w) chemically bound drug, respectively, were given i.p. to rats at a single 2 mg DOX/kg dose. Free and polymer-bound DOX were assessed in plasma, peritoneal fluid, abdominal tissues and heart, 15 min, 2, 6, 24, 48 and 168 h after injection. According to pharmacokinetic profiles, the peritoneal fluid areas under the concentration versus time curves (AUCs) were 2 and 2.6 times greater for the conjugates (P-DOX20 and P-DOX10, respectively) than for the free drug, respectively. Conjugates crossed the peritoneal barrier slower than the free drug. For the tumor, AUCs were, respectively, 3 and 7 times higher for the conjugates than for free DOX. The elimination half-lives of the conjugates were higher than that calculated for the free drug. Only very small concentrations were detected in peripheral organs and in the heart. In contrast, significant retention and accumulation of the conjugates were found in abdominal organs, particularly in the tumor. There was no sign of macroscopic chemical peritonitis after injection of the polymer-DOX conjugates. In conclusion, the conjugates have higher elimination half-lives than free DOX and were preferentially retained in abdominal organs and in the peritoneal carcinomatosis. This feature is of clinical interest to target tumor deposits.

Management of Cancer Cachexia and Guidelines Implementation in a Comprehensive Cancer Center: A Physician-Led Cancer Nutrition Program Adapted to the Practices of a Country.

CONTEXT: Cancer-associated cachexia is correlated with survival, side-effects, and alteration of the patients' well-being. OBJECTIVES: We implemented an institution-wide multidisciplinary supportive care team, a Cancer Nutrition Program (CNP), to screen and manage cachexia in accordance with the guidelines and evaluated the impact of this new organization on nutritional care and funding. METHODS: We estimated the workload associated with nutrition assessment and cachexia-related interventions and audited our clinical practice. We then planned, implemented, and evaluated the CNP, focusing on cachexia. RESULTS: The audit showed a 70% prevalence of unscreened cachexia. Parenteral nutrition was prescribed to patients who did not meet the guideline criteria in 65% cases. From January 2009 to December 2011, the CNP team screened 3078 inpatients. The screened/total inpatient visits ratio was 87%, 80%, and 77% in 2009, 2010, and 2011, respectively. Cachexia was reported in 74.5% (n = 2253) patients, of which 94.4% (n = 1891) required dietary counseling. Over three years, the number of patients with artificial nutrition significantly decreased by 57.3% (P < 0.001), and the qualitative inpatients enteral/parenteral ratio significantly increased: 0.41 in 2009, 0.74 in 2010, and 1.52 in 2011. Between 2009 and 2011, the CNP costs decreased significantly for inpatients nutritional care from 528,895€ to 242,272€, thus financing the nutritional team (182,520€ per year). CONCLUSION: Our results highlight the great benefits of implementing nutritional guidelines through a physician-led multidisciplinary team in charge of nutritional care in a comprehensive cancer center.

Neoadjuvant percutaneous 4-hydroxytamoxifen decreases breast tumoral cell proliferation: a prospective controlled randomized study comparing three doses of 4-hydroxytamoxifen gel to oral tamoxifen.

PURPOSE: Two chemoprevention randomized studies using tamoxifen showed drug efficacy; however, adverse effects such as hot flushes, endometrial cancer, and above all, thromboembolism, remain a problem. 4 hydroxytamoxifen (4-OHT) is a very active metabolite of tamoxifen. This randomized study was designed to analyze if 4-OHT gel, administered percutaneously on the breast skin, can inhibit the proliferation of malignant breast cells to the same extent as orally administered tamoxifen. PATIENTS AND METHODS: Fifty-five postmenopausal women with an invasive estrogen receptor-positive breast cancer were randomly assigned to receive (for 2 to 3 weeks) either 4-OHT gel (0.5, 1, or 2 mg/d) or oral tamoxifen (20 mg/d) or no treatment. Response was evaluated using proliferation markers (Ki-67, proliferating cell nuclear antigen) and apoptosis markers in tissue samples obtained by Tru-cut biopsy before treatment, and at surgery after treatment. RESULTS: Administration of 4-OHT gel resulted in reductions in tumor tissue proliferation indexes (Ki-67 and PCNA), with approximate equivalence between the 1.0 mg/d or 2.0 mg/d 4-OHT dose, and oral tamoxifen, but had no effect on apoptotic markers. Plasma levels of 4-OHT were consistently higher in the oral tamoxifen group than in the gel groups. No dose-related pattern was shown for estrogen or progesterone receptor levels, and topical 4-OHT gel appeared to be generally well tolerated. Hot flushes are as common in the two higher gel doses as with tamoxifen. CONCLUSION: Percutaneous 4-OHT gel has a local impact on tumor proliferation. It could be tested in future prospective trials of chemoprevention or ductal carcinoma in situ adjuvant hormonotherapy.

Pharmacokinetics and pharmacodynamics of irinotecan and its metabolites from plasma and saliva data in patients with metastatic digestive cancer receiving Folfiri regimen.

PURPOSE: Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic-pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites. METHODS: Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks. The irinotecan-administered dose was 180 mg/m(2); 17 patients participated in a dose-escalating study. Irinotecan and its metabolites (SN-38, SN-38G, APC, NPC) were quantified in plasma and saliva by high-performance liquid chromatography with fluorescence detection. RESULTS: The mean irinotecan systemic clearance and steady-state volume of distribution values were 14.3 l/h/m(2) and 211 l/m(2), respectively. The intrapatient variability (22-28%) was far lower than the interindividual variability (33-88%). Age and weight were the two physiological parameters that influenced drug disposition. For irinotecan, SN-38, APC and NPC, similar pharmacokinetic profiles were observed from plasma and saliva data. The saliva/plasma AUC ratios averaged 1 for irinotecan, 0.3 for SN-38, 0.17 for APC and 0.27 for NPC. Neutropenia, diarrhea and nausea were the main toxicities encountered. From both plasma and saliva data, the percentage decrease in neutrophil count appeared to be related to irinotecan and SN-38 AUCs. CONCLUSIONS: All these findings provide a rationale for an individual adaptation of irinotecan dosing. In case of difficult venous access, the titration of irinotecan and of its active metabolite SN-38 in saliva may prove relevant.

In vitro cytotoxic effect of melphalan and pilot phase II study in hormone-refractory prostate cancer.

The objective of this study was to determine the impact of single versus sequential exposure to melphalan on the proliferation of an androgen-independent prostate cell line, PC-3, and to report the results of a pilot phase II study. For exposure to a single bolus dose, the doses were added at the start of the study and cell culture was continued for 96 h. For sequential exposure, 1/9 of the dose was added every 1.5 h over 12 h, followed by cell culture for 84 h. Cell growth inhibition was determined by the MTT assay. The clinical study was carried out on 14 patients with advanced prostate cancer. Melphalan was infused over a 24-h period. The sequential-dose schedule was more effective than the single-dose exposure, IC50 values: 0.074 versus 0.77/microg/ml. Out of the 14 patients (42 courses) enrolled into the study, two patients were removed within the first 2 weeks because of rapid disease progression. The toxicity profile did not differ greatly from that reported after a 1-h infusion. Four PR and two SD were observed. The median survival of the twelve patients was 23 weeks. Melphalan administered over a 24-h period to patients with androgen-independent prostate cancer appeared to provide some clinical benefits with manageable toxicity.

Population pharmacokinetics of melphalan, infused over a 24-hour period, in patients with advanced malignancies.

PURPOSE: The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies. METHODS: Enrolled in the study were 64 patients (144 courses). The population pharmacokinetic analysis was performed using NONMEM through the graphical interface Visual-NM. Population characteristics were computed from an initial group of 43 patients (99 courses), and 21 additional patients (45 courses) were used for model validation. With the use of a one-compartment model, the influence of demographic and biological characteristics was examined. The basic parameters were total clearance (CL) and volume of distribution (V). The interoccasion variability was taken into account in the model. The drug exposure was estimated for each patient and correlated with markers of efficacy and toxicity. RESULTS: Data analysis was performed using a three-step approach. In step 2, a close relationship was found between creatinine clearance, gender and melphalan CL. The inclusion of this second stage model significantly improved the fit. Melphalan CL was higher in male patients (14.3+/-4.5 l/h per m2) than in female patients (12.3+/-4.5 l/h per m2). CL was also reduced somewhat in patients with decreased creatinine clearance. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 4.4 to 30.6 l/h per m2). The percentage intrapatient variability in clearance between courses was 25.4%. For determining melphalan AUC in clinical routine from one sample drawn at steady state, Bayesian methodology allowed a more accurate estimation of CL than the classical formula. Neutropenia and thrombocytopenia were the main haematological toxicities encountered; grade 4 was observed in 34 and 22 courses over a total of 144 courses, respectively. No significant relationship between AUC and haematological toxicity was found. In patients with prostatic cancer a weak relationship was observed between the decrease in PSA levels and AUC (P=0.0457), while in patients with ovarian cancer no relationship was found between AUC and CA125 levels. CONCLUSION: The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.

Modeling plasma and saliva topotecan concentration time course using a population approach.

The purpose of this study was to develop a pharmacokinetic model simultaneously accounting for topotecan concentrations in plasma and saliva. Thirteen patients with metastatic epithelial ovarian cancer received topotecan. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Data were analyzed using the nonlinear mixed-effect model program. The saliva concentrations were associated to a peripheral compartment while the central compartment described the plasma concentration time course. Thus, a three-compartment model was used; the basic parameters were: total clearance (CL), initial volume of distribution (V1), transfer rate constants (k12/k21 and k13/k31). The interoccasion variability was taken into account in the model. Data analysis was performed using a three-step approach; in step 2, a close relationship was found between creatinine CL and topotecan CL. The inclusion of this second stage model significantly improved the fit. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 10.4 to 23 L/h) while interoccasion variability was limited (6%). Seven additional courses were used for model validation. A limited sampling strategy using Bayesian estimation based on two sampling times (saliva at 25 min and plasma plus saliva at 8.5 h after the start of infusion) was developed. This study shows that salivary concentrations can be effectively used for drug monitoring.

In vitro and in vivo pharmacological characterisation of the antitumour properties of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline.

The anti-tumour activity of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline (PIQ) was investigated in vitro and in vivo with a human tumour model. In vitro PIQ cytotoxicity was evaluated on two different human parental-sensitive cancer cell lines (HL60S and A2780S) and their multidrug-resistant variant sublines (HL60R and A2780R). Proliferation was assessed using the MTT assay and PIQ showed activity, particularly with resistant cell lines. Drug activity was not affected by MDR resistance. After LD50 determination using Swiss mice, in vivo activity with A2780 ovarian carcinoma was carried out using xenografted Swiss nude mice. We performed either a weekly intra-peritoneal injection of 64 mg.kg-1 PIQ or an intra-venous injection of 10 mg.kg-1 PIQ during 2 months. After 60 days of treatment, no toxicologically meaningful differences were observed in macroscopic and microscopic parameters compared to controls. Both regimens demonstrated efficacy against xenografted tumours. However, the decrease in tumoural volume of the xenografted mice was significant only in the PIC i.v. injection group. Pharmacokinetics and the accumulation of PIQ in normal and tumour tissues were also assessed using a chromatographic method. The lack of activity using the i.p. route was explained by the four-fold reduction of its AUC in comparison to the i.v. route. After an i.v. injection, the highest concentrations of PIQ were accumulated in the tumour and spleen. Drug analysis has shown that PIQ intercalates into DNA. PIQ derivatives are effective new antitumour agents in cancer chemotherapy.

Stability of dacarbazine in amber glass vials and polyvinyl chloride bags.

The stability of dacarbazine in commercial glass vials and polyvinyl chloride (PVC) bags in various storage conditions and the emergence of 2-azahypoxanthine, a major degradation product possibly linked with some adverse effects, were studied. Triplicate samples of reconstituted (11 mg/mL) and diluted (1.40 mg/mL) dacarbazine admixtures were prepared and stored at 4 degrees C or at 25 degrees C in daylight, fluorescent light, or the dark. The effect of several light-protective measures (amber glass vials, aluminum foil wrapping, and opaque tubing) on dacarbazine stability in a simulated i.v. infusion system was also evaluated. Dacarbazine quantification and main degradation product determination were performed by high-performance liquid chromatography. Stability was defined as conservation of 90-105% of initial dacarbazine concentration without major variations in clarity, color, or pH and without precipitate formation. Reconstituted dacarbazine solutions were stable for 24 hours at room temperature and during light exposure and stable for at least 96 hours at 2-6 degrees C when stored in the dark. After dilution in PVC bags, stability time increased from 2 hours in daylight to 24 hours in fluorescent light and to 72 hours when covered with aluminum foil. After two hours of simulated infusion, dacarbazine remained stable. Diluted dacarbazine solutions stored at 2-6 degrees C were stable for at least 168 hours. The only degradation product found was 2-azahypoxanthine, which was detected in every sample. The storage and handling of dacarbazine should take into account both the loss of the drug and the production of its potentially toxic degradation product. Dacarbazine must be carefully protected from light, administered using opaque infusion tubing, and, if necessary, refrigerated before administration to reduce 2-azahypoxanthine formation.

Versatile UCST-based thermoresponsive hydrogels for loco-regional sustained drug delivery.

Poly(N-acryloyl glycinamide) is a neutral polymer that can form gel-sol thermoresponsive systems with upper critical solution temperature in aqueous media. The temperature of the reversible gel-sol transition depends on the molar mass and the concentration of macromolecules. These parameters were combined to adjust the transition temperature slightly above body temperature for the sake of respecting living tissues during the sol form injection using a classical syringe. On contact with local tissues, the injected sol turned rapidly to a gel. The simplicity of the process makes it exploitable to administrate and deliver neutral or ionic drug and especially those that are soluble in aqueous media. The versatility was exemplified from formulations with cobalt acetate, small polymers (MW~2000g/mol), tartrazine and methylene blue dyes and albumin. The model compounds were allowed to diffuse in an isotonic pH=7.4 buffered medium at 37°C. All the release profiles were typical of diffusion control with 100% release within 2 to 3weeks and no obvious burst. The in vitro release of methylene blue from a gel formulation was checked prior to injection in the peritoneal cavity of mice where the release of the dye was monitored visually through tissue and organ colorations. A comparable polymer-free dye solution was used as control. Coloration appeared rapidly in tissues and organs and it was still detectable 52h post injection of the gel whereas it was no longer present at 24h in control mice.

Etoposide, mitomycin, and methotrexate combination in heavily treated breast cancer: a retrospective study.

BACKGROUND: Since 2004, metastatic breast cancer patients pretreated with anthracyclines, taxanes, and capecitabine have been treated in our institution with a combination of mitomycin C, methotrexate, and VP-16 (VMM). We report in this study a retrospective analysis of the activity and safety of the VMM combination. METHODS: Patients were treated with a combination of VP-16 (100 mg/m2 on day 1), mitomycin C (MMC, 10 mg/m2 on day 1), and methotrexate (MTX, 12.5 mg/m2 twice a day on day 2 and 3) in a 21-day cycle. RESULTS: Seventy-five patients were treated. Median age was 48 years. A total of 256 cycles were administered. Median relative dose intensities were 0.87, 0.87, and 0.95 for VP-16, MMC, and MTX, respectively. Objective response rate was 31%, with a clinical benefit rate of 47%. Median response duration was 5.8 months. Median disease stabilization duration was 9.1 months. Median progression-free survival (PFS) was 4.2 months with a 14% 1-year PFS rate. Median overall survival (OS) was 6.2 months, with a 25% 1-year OS rate. Myelosuppression was the most common toxicity. The most commonly reported extra-hematological adverse event (AE) was fatigue. Emesis and alopecia were rarely reported. CONCLUSIONS: This combination appears to be effective and well tolerated in this heavily pretreated metastatic breast cancer population.

Physicochemical stability of oxaliplatin in 5% dextrose injection stored in polyvinyl chloride, polyethylene, and polypropylene infusion bags.

PURPOSE: The physicochemical stability of extemporaneous dilutions of oxaliplatin in 5% dextrose injection stored in polyvinyl chloride (PVC), polypropylene, and polyethylene infusion bags was studied. METHODS: Oxaliplatin 100 mg/20 mL concentrated solution was diluted in 100 mL of 5% dextrose injection in PVC, polypropylene, and polyethylene infusion bags to produce nominal oxaliplatin concentrations of 0.2 and 1.3 mg/mL. The filled bags were stored for 14 days at 20 degrees C and protected from light, at 20 degrees C under normal fluorescent light, and at 4 degrees C. A 1-mL sample was removed from each bag at time 0 and at 24, 48, 72, 120, 168, and 336 hours. The samples were visually inspected for color and clarity, and the pH values of the solutions were measured. High-performance liquid chromatography was used to assay oxaliplatin concentration. Bacterial contamination was assessed on study day 14 after incubation in trypticase soy solution for three days at 37 degrees C. RESULTS: Solutions of oxaliplatin 0.2 and 1.3 mg/mL in 5% dextrose injection were stable in the three container types for at least 14 days at both 4 degrees C and 20 degrees C without regard to light exposure. No color change was detected during the storage period, and pH values remained stable. No microbial contamination was detected in any samples over the study period. CONCLUSION: Oxaliplatin solutions diluted in 5% dextrose injection to 0.2 and 1.3 mg/mL were stable in PVC and PVC-free infusion bags for at least 14 days at both 4 degrees C and 20 degrees C without regard to light exposure.

Inter- and intraindividual variabilities in pharmacokinetics of fentanyl after repeated 72-hour transdermal applications in cancer pain patients.

Perception of pain by the patient is frequently one of the early signs preceding a diagnosis of cancer and, later, a sinister sign of disease progression. Among opioid drugs, transdermal fentanyl has been evaluated in the treatment of moderate to severe cancer pain. The objective of this study was to investigate the intra- and interindividual variabilities in pharmacokinetics after fentanyl drug delivery by the transdermal fentanyl patch delivery system in patients with cancer pain. As a first step, a liquid chromatography-mass spectrometry method was developed for the determination of the analgesic fentanyl in human plasma. This method was validated over the concentration range 0.15-100 ng/mL. The study group consisted of 29 inpatients (18 men and 11 women; age range 29-80 years). The initial transdermal fentanyl delivery rate was chosen depending on the patient's analgesic requirements. For 20 patients, the initial TTS fentanyl delivery rate was 25 or 50 microg/h. For 6 patients, the initial delivery rate was 75-150 microg/h. Two patients received up to 300 microg/h fentanyl delivery rate, and 3 patients received up to 350 microg/h fentanyl delivery rate. Fifteen of the 29 patients received rescue doses of subcutaneous or oral morphine, and 26 patients received paracetamol with codeine (30 mg per os). Blood samples were collected at the following intervals: 2-5, 22-26, or 45-47 hours following fentanyl patch application. The severity of pain experienced by the patient was assessed thrice daily using a visual analogue scale. The study period was 46 days. Large patient-to-patient variations in pharmacokinetic parameters occurred, although intraindividual variability was limited. A mean bioavailability of 78% was estimated; the total clearance averaged 41 L/h. From 25 to 100 mug/h fentanyl delivery rate, the pharmacokinetics was linear. At the 2 highest doses, an increase of total clearance was observed (>60 L/h). For the whole group, transdermal fentanyl treatment provided good to excellent pain relief in the majority of patients.

Sensitive HPLC-fluorescence method for irinotecan and four major metabolites in human plasma and saliva: application to pharmacokinetic studies.

BACKGROUND: We developed gradient HPLC methods for quantification of the antimitotic drug irinotecan (CPT-11) and its four metabolites, SN-38, SN-38 G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4amino-1-piperidino]-carbonyloxycamptothecin (NPC), as the sum of the lactone and carboxylate forms, in human plasma and saliva. Camptothecin was used as internal standard. METHODS: The sample pretreatment involved protein precipitation with methanol-acetonitrile (50:50 by volume) followed by acidification with hydrochloric acid to convert the lactone ring-opened form into its lactone form, quantitatively. HPLC separation was performed on a Xterra RP18 column. The excitation wavelength was 370 nm, and the emission wavelength was set at 470 nm for the first 24 min and then at 534 nm for the next 4 min. The stabilities of irinotecan and its four metabolites in plasma, saliva, and acidic extracts were also investigated under various conditions. RESULTS: Assays were linear in the tested range of 0.5-1000 micro g/L. For the five analytes, limits of quantification were 0.5 micro g/L in both matrices. The interassay imprecision (as relative standard deviation) was 3.2-14% in plasma and 2.6-5.6% in saliva. Assay recoveries ranged from 92.8% to 111.2% for plasma and 100.1% to 104.1% for saliva. Mean extraction recovery from plasma or saliva was 90%. CONCLUSION: The developed assay can be used to determine pharmacokinetic parameters for CPT-11, SN-38, SN-38 G, APC, and NPC in plasma and saliva from patients with metastatic colorectal cancer.