Use of iron sucrose and red blood cell transfusions in anaemic cancer patients in France (OncoFer study).

PURPOSE: This report describes the results of an observational, retrospective cohort study, evaluating the use of iron sucrose (IS) and red blood cell (RBC) transfusions in patients with cancer in routine clinical practice in France. A parallel investigated cohort treated with ferric carboxymaltose (FCM) has been reported earlier. METHODS: Data of patients with a solid tumour or haematological malignancy who have received IS or an RBC transfusion during 2010 from 3 months prior (M-3) to 3 months post first treatment (M+3) were analysed. RESULTS: Data from 46 patients who had received IS (400 mg median total iron dose) and 357 patients who had received RBC transfusions as first treatment (baseline) were included. Median haemoglobin levels improved from 9.9 g/dL (interquartile range 9.2; 11.0 g/dL) at baseline to 12.4 g/dL (11.4; 13.1 g/dL) at M+3 in IS-treated patients and from 8.2 g/dL (7.8; 8.8 g/dL) at baseline to 10.1 g/dL (8.8; 11.1 g/dL) in transfused patients. An erythropoiesis-stimulating agent was given to 54.3 and 28.9% of patients in the IS and the RBC transfusion groups, respectively, resulting in slightly better mean haemoglobin increase in both groups (2.4 vs 1.5 g/dL and 2.0 vs 1.6 g/dL, respectively). No severe nor serious adverse reaction and no hypersensitivity reactions were reported. CONCLUSION: Both IS and RBC transfusions effectively increased Hb levels in patients with cancer. IS was safe and well tolerated in this population. Considering prior reported results with FCM, using FCM may reduce ESA dose requirements and the required number of infusions.

Clinical use of ferric carboxymaltose in patients with solid tumours or haematological malignancies in France.

PURPOSE: This study collected data on the use of ferric carboxymaltose (FCM) in a cancer patient population in France to evaluate the feasibility and the conditions of use of FCM in routine clinical practice beyond the limiting criteria of clinical trials. METHODS: This observational, prospective study of patients with a solid tumour or a haematological malignancy who have received treatment with FCM after 01 July 2011 evaluated data about the circumstances of iron administration, concomitant medication and laboratory tests in the period from 3 months prior to the first FCM administration (baseline) until 3 months post-baseline. RESULTS: Data from 367 FCM-treated patients were analysed. FCM was mainly given as a single dose at baseline (69.2%) and without additional erythropoiesis-stimulating agent (ESA, 64.3%). The median total iron dose was 1000 mg per patient. Median haemoglobin (Hb) levels of FCM-treated patients improved from 10.3 g/dL (interquartile range 9.5, 11.1 g/dL) at baseline to 11.8 g/dL (11.1, 13.0 g/dL) until the end of the 3-month observational period. Patients treated with FCM alone or additional ESA achieved similar median Hb increase (1.3 [0.4, 2.1] g/dL and 1.4 [0.4, 2.5] g/dL, respectively). Patients with baseline Hb up to 11.0 g/dL and serum ferritin up to 500 ng/mL and beyond achieved stable median Hb levels ≥11.0 g/dL without signs of iron overload. No severe or serious adverse reaction and no hypersensitivity reactions were reported. CONCLUSIONS: The results of this observational study confirm the effectiveness and tolerability of FCM when given in clinical routine practice alone or in combination with an ESA.

Combination chemotherapy of vinorelbine and cisplatin: a phase I pharmacokinetic study in patients with metastatic solid tumors.

BACKGROUND: Vinorelbine (VRL)-cisplatin (CDDP) is an active doublet for advanced non-small cell lung cancer. CDDP has a narrow therapeutic index and may produce a cumulative nephrotoxicity over the treatment period. This study was to assess the risks of drug-drug interaction (DDI) over 3 consecutive cycles of VRL-CDDP combined treatments. PATIENTS AND METHODS: An open-label, nonrandomised, phase I study was carried out. Patients with normal hepatic/renal functions. D1: CDDP 100 mg/m2--D1, D8: oral VRL 60 mg/m2 q3w. Pharmacokinetics (PK) over the first 3 cycles. PK comparison between cycles and between study vs. literature. RESULTS: Thirteen patients were evaluable for safety and PK. Adverse events were those frequently observed with CDDP or VRL, and consisted of hematological toxicities, nausea, vomiting and constipation. Concerning VRL and CDDP PK, no difference was detected between the 3 administrations nor between the study and reference values. CONCLUSION: The absence of DDI between CDDP and oral VRL was demonstrated over 3 consecutive cycles of therapy.

Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5-fluorouracil and folinic acid: results of a randomised phase III trial.

PURPOSE: The quality of life (QL) of advanced gastric cancer patients receiving irinotecan, folinic acid and 5-fluorouracil (5-FU) (IF arm) or cisplatin with 5-FU (CF arm) is presented. METHODS: Patients with measurable or evaluable advanced gastric cancer received IF weekly for 6/7 weeks or CF q4 weeks. QL was assessed using the EORTC QLQ-C30 at baseline, subsequently every 8 weeks until progression and thereafter every 3 months until death. The QL data were analysed using several statistical methods including summary measures and pattern-mixture modelling. RESULTS: A total of 333 patients were randomised and treated (IF 170, CF 163). The time-to-progression for IF and CF was 5.0 and 4.2 months (P = 0.088), respectively. The overall compliance rates for QL questionnaire completion were 60 and 56% in the IF and CF arms, respectively. Significant treatment differences were observed for the physical functioning scale (P = 0.024), nausea\vomiting (P = 0.001) and EQ-5D thermometer (P = 0.020) in favour of the IF treatment arm. CONCLUSION: There was a trend in favour of IF over CF in time-to-progression. The IF group also demonstrated a better safety profile than CF and a better QL on a number of multi-item scales, suggesting that IF offers an alternative first-line platinum-free treatment option for advanced gastric cancer.

The Impact of a Small Private Online Course as a New Approach to Teaching Oncology: Development and Evaluation.

BACKGROUND: Oncology involves complex care and multidisciplinary management of patients; however, misinformation and ineffective communication remain problematic. OBJECTIVE: The educational objective of our study was to develop a new teaching method to improve cancer treatment and management by emphasizing the link between hospitals (inpatients) and their surrounding communities (outpatients). METHODS: A team of 22 professionals from public and private institutions developed a small private online course (SPOC). Each offering of the course lasted 6 weeks and covered 6 topics: individual health care plans, cancer surgery, ionizing radiation, cancer medicines, clinical research, and oncological supportive care. For participants in the course, we targeted people working in the cancer field. The SPOC used an active teaching method with collaborative and multidisciplinary learning. A final examination was offered in each session. We evaluated participants' satisfaction rate through a questionnaire and the success of the SPOC by participants' completion, success, and commitment rates. RESULTS: Of the total participants (N=1574), 446 completed the evaluation form. Most participants were aged 31 to 45 years. Participants included 56 nurses, 131 pharmacists, 80 from the medical field (including 26 physicians), 53 from patients' associations, 28 health teachers, and 13 students (medical and paramedical). Among the participants, 24.7% (90/446) had an independent medical practice, 38.5% (140/446) worked in a public institution, and 36.8% (134/446) worked in a private institution. After completing the SPOC sessions, 85.9% (384/446) thought they had learned new information, 90.8% (405/446) felt their expectations were met, and 90.4% (403/446) considered that the information had a positive impact on their professional practice. The completion rate was 35.51% (559/1574), the success rate was 71.47% (1025/1574), and the commitment rate was 64.67% (1018/1574). Concerning the cost effectiveness of SPOC compared with a traditional classroom of 25 students, online education became more effective when there were more than 950 participants. CONCLUSIONS: SPOCs improved the management of oncology patients. This new digital learning technique is an attractive concept to integrate into teaching practice. It offered optimal propagation of information and met the students' expectations.

Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study.

PURPOSE: To evaluate response rate and toxicity of irinotecan and oxaliplatin plus fluorouracil (FU) and leucovorin (Folfirinox) in advanced pancreatic adenocarcinoma (APA). PATIENTS AND METHODS: Chemotherapy-naive patients with histologically proven APA and bidimensionally measurable disease were treated with Folfirinox therapy every 2 weeks, which comprised oxaliplatin 85 mg/m(2) and irinotecan 180 mg/m(2) plus leucovorin 400 mg/m(2) followed by bolus FU 400 mg/m(2) on day 1, then FU 2,400 mg/m(2) as a 46-hour continuous infusion. Quality of life (QOL) was assessed using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). RESULTS: Forty-seven patients were entered, and 46 received treatment. Thirty-five patients (76%) had metastatic disease. A total of 356 cycles were delivered, with a median of eight cycles per patient (range, one to 24 cycles). All patients were assessable for safety. No toxic death occurred. Grade 3 to 4 neutropenia occurred in 52% of patients, including two patients with febrile neutropenia. Other relevant toxicities included grade 3 to 4 nausea (20%), vomiting (17%), and diarrhea (17%) and grade 3 neuropathy (15%; Levi's scale). The confirmed response rate was 26% (95% CI, 13% to 39%), including 4% complete responses. Median time to progression was 8.2 months (95% CI, 5.3 to 11.6 months), and median overall survival was 10.2 months (95% CI, 8.1 to 14.4 months). Between baseline and end of treatment, patients had improvement in all functional scales of the EORTC QLQ-C30, except cognitive functioning. Responders had major improvement in global QOL. CONCLUSION: With a good safety profile, a promising response rate, and an improvement in QOL, Folfirinox will be further assessed in a phase III trial.

Phase-I study of a new schedule based on increasing days of topotecan administration associated with dose individualisation.

BACKGROUND: The most commonly prescribed schedule of topotecan administration is daily for five days, every 21 days. Both pre-clinical and clinical studies suggest that a more protracted schedule may increase its therapeutic index. The current study was undertaken to determine the maximum tolerated number of days with 30-minute i.v. infusion of topotecan daily at fixed area under the plasma concentration-time curve (AUC) (i.e., 35 microg/Lxh). PATIENTS AND METHODS: Topotecan was administered i.v. over 30 min. The planned levels of number of days of administration were: 7, 10, 13, 15 and 17. The dose was individualized according to the patient's individual topotecan clearance observed after the first infusion of each cycle. RESULTS: Twenty-three patients were enrolled and received 71 cycles of therapy. The 13-day level was defined as the maximum number of days of administration. The main side effects were thrombocytopenia and anaemia, whereas neutropenia was infrequent. The mean (coefficient of variation) observed AUC was 34.6 (21%), and 33.4 (19%) microg/Lxh, for the last day of cycle 1, and of cycle 2, respectively. Confirmed partial responses were observed in one patient with metastatic desmoplastic tumour and in two patients with small round metastatic endocrine carcinoma. CONCLUSION: The recommended number of topotecan administration is 10 days. Beyond the potential clinical interest of topotecan administered for a 10-day period, this is the first trial showing the feasibility of a phase-I study exploring a number of administrations of daily AUC rather than a total dose in mg/m(2).

In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR.

This study aimed to assess the effect of cetuximab (C225, Erbitux, a chimeric anti-epidermal growth factor receptor (EGFR) monoclonal antibody) in combination with oxaliplatin in vitro and in vivo on four colon cancer cell lines (HCT-8; HT-29, SW620, HCT-116) expressing different levels of EGFR. In vitro, cetuximab combined with oxaliplatin significantly decreased the IC50 values of oxaliplatin in HCT-8 (EGF-R moderate) and HT-29 (EGF-R weak) cell lines, while SW620 (EGF-R negative) and HCT-116 (EGFR strong) cell lines remained unresponsive. This combination was synergistic in HCT-8 and HT-29 cell lines while cetuximab induced no major modification of the IC50 of oxaliplatin in HCT-116 or SW620 cell lines. We then determined the effect of cetuximab on the EGF-induced EGFR phosphorylation and we highlight a correlation between the basal level of phospho-EGFR and the response to the combination. In vivo, the combination of cetuximab plus oxaliplatin significantly inhibited tumor growth of HCT-8 and HT-29 (tumor delay or Td = 21.6+/-2.9 and 18.0+/-2.9 days respectively, synergistic effect) compared to either oxaliplatin (Td=12.6+/-2.3 and 14.4+/-3.2 days respectively) or cetuximab (Td=13.4+/-2.9 and 14.5+/-2.4 days, respectively) alone in xenograft models. The combination had no effect on HCT-116 and SW-620 cell lines. The observed responses are strictly dependent on the cell type, and are not correlated with the level of EGFR expression but related to the basal level of phospho-EGFR. This study provides promising preclinical results for a possible clinical investigation of the combination of oxaliplatin plus cetuximab in chemorefractory colorectal tumors.

Oxaliplatin combined with 5-FU in second line treatment of advanced pancreatic adenocarcinoma. Results of a phase II trial.

BACKGROUND: The efficacy and benefit of second-line chemotherapy in advanced pancreatic adenocarcinoma has never been demonstrated although it is regularly used. PATIENTS AND METHODS: A randomized phase II study evaluating oxaliplatin alone (OXA), infusional 5-fluorouracil alone (5-FU) and an oxaliplatin/infusional 5-FU combination (OXFU) in untreated advanced pancreatic adenocarcinoma has been conducted. In this trial, a second-line treatment with the OXFU regimen (OXA 130 mg/m2 2-h intravenous (i.v.) infusion combined with 5-FU (1000 mg/m2/day, continuous i.v., days 1-4), every 3 weeks) was offered to patients progressing after single agent treatment. RESULTS: Eighteen out of 32 patients (12 males, median age 57 years) treated in the single agent arms received the OXFU combination in second-line treatment. WHO performance status was at least 2 in 61% of the patients. There was no objective response and 3 patients (17%) had a disease stabilisation. Median time to progression from the start of second-line treatment was 0.9 months. Median overall survival was 4.9 months from the start of front-line therapy and 1.3 months from the start of second-line therapy. CONCLUSION: The results of this trial bring arguments to support a modest value of second-line chemotherapy for advanced pancreatic adenocarcinoma.

Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site.

PURPOSE: To identify clinical and biologic variables with significant impact on survival in patients with carcinomas of an unknown primary site and to develop a simple prognostic model for the selection of patients in prospective clinical trials. PATIENTS AND METHODS: Univariate and multivariate prognostic factor analyses were conducted in a population of 150 unselected patients and led to the construction of two successive classification schemes. An external data set of 116 patients enrolled onto two prospective trials was used for validation. RESULTS: When studying clinical variables only, poor performance status (2 or 3) and presence of liver metastases were retained in the multivariate analysis. The first classification scheme consisted of three subgroups of patients with median survivals of 10.8, 6.0, and 2.4 months, according to the number of adverse prognostic factors. With the introduction of serum lactate dehydrogenase (LDH) levels in a further step, liver metastases were no longer significant. The second classification scheme therefore included poor performance status (relative risk [RR], 2.1) and elevated serum LDH level (RR, 2.1). Good-risk and poor-risk patients were identified, with median survivals of 11.7 months and 3.9 months, respectively (P <.0001). The 1-year survival rates were 45% and 11%, respectively. This second classification scheme was validated in an external data set: the median survival rates of patients assigned to the good-risk group and the poor-risk group were 12 months and 7 months, respectively (P =.0089). The 1-year survival rates were 53% and 23%, respectively. CONCLUSION: A simple prognostic model using performance status and serum LDH levels was developed and validated. It allows the assignment of patients into two subgroups with divergent outcome. Further prospective trials will be designed using this prognostic model.

Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01).

PURPOSE: To evaluate the efficacy and toxicity of novel chemotherapy combinations including cisplatin with gemcitabine (GC) or irinotecan (IC) for patients with carcinomas of an unknown primary site. PATIENTS AND METHODS: Eighty patients were randomly assigned to receive GC or IC. In the GC arm, chemotherapy consisted of cycles combining gemcitabine 1,250 mg/m2 intravenously (IV) on days 1 and 8, and cisplatin 100 mg/m2 IV on day 1 at 3-week intervals. Patients in the IC arm originally received 3-week cycles of irinotecan 200 mg/m2 IV on day 1 and cisplatin 80 mg/m2 IV on day 1. After the inclusion of 15 patients in that arm, the toxicity profile required the irinotecan doses to be reduced to 150 mg/m2 per cycle. Independent histologic and radiologic reviews were done. RESULTS: A total of 78 patients were assessable for efficacy and toxicity. The median number of cycles was four in each arm. Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). Treatment had to be stopped because of toxicity in seven patients in the GC arm and in eight patients in the IC arm. With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively. CONCLUSION: This study demonstrates the activity of both the GC and IC regimens. There was toxicity associated with both regimens. Additional studies of combination chemotherapy regimens are required.

Cystatin C as a new covariate to predict renal elimination of drugs: application to carboplatin.

BACKGROUND AND OBJECTIVE: The individual dosing of drugs that are mainly eliminated unchanged in the urine is made possible by assessing renal function. Most of the methods used are based on serum creatinine (SCr) levels. Cystatin C (CysC) has been proposed as an alternative endogenous marker of the glomerular filtration rate (GFR). Carboplatin is one of the drugs for which elimination is most dependent on the GFR. A prospective clinical trial including 45 patients was conducted to assess the value of serum CysC as a predictor of carboplatin clearance (CL). METHODS: The patients were receiving carboplatin as part of established protocols. Carboplatin was administered as a daily 60-minute infusion at doses ranging from 290 to 1700mg. A population pharmacokinetic analysis was performed using the nonlinear mixed effect modelling NONMEM program according to a two-compartment pharmacokinetic model. RESULTS: Data from 30 patients were used to test the relationships between carboplatin CL and morphological, biological and demographic covariates previously proposed for prediction of the GFR. The interindividual variability of carboplatin CL decreased from 31% (no covariate) to 14% by taking into account five covariates (SCr, CysC, bodyweight [BW], age and sex). Prospective evaluation of these relationships using the data from the other 15 patients confirmed that the best equation to predict carboplatin CL was based on these five covariates, with a mean absolute percentage error of 13% as an assessment of precision. NONMEM analysis of the whole dataset (n = 45 patients) was performed. The best covariate equation corresponding to the overall analysis was: CL (mL/min) = 110 x (SCr/75)-0.512 x (CysC/1.0)-0.327 x (BW/65)0.474 x (age/56)-0.387 x 0.854sex, with SCr in micromol/L, CysC in mg/L, BW in kilograms, age in years and sex = 0 if male and 1 if female. To put the value of CysC as an endogenous marker of the GFR into perspective, covariate equations without SCr were also evaluated; a better prediction was obtained by considering CysC together with age and BW (interindividual variability of 16.6% vs 23.3% for CysC alone). CONCLUSION: CysC is a marker of drug elimination that is at least as good as SCr for predicting carboplatin CL. The model based on five covariates was superior to those based on only four covariates (with BW, age and sex combined with either SCr or CysC), indicating that CysC and SCr are not completely redundant to each other. Further pharmacokinetic evaluation is needed to determine whether SCr or CysC is the better marker of renal elimination of other drugs.

Pharmacokinetics of platinum after oral or intravenous cisplatin: a phase 1 study in 32 adult patients.

AIMS: To develop a population pharmacokinetic model for simultaneous analysis of oral/intravenous cisplatin data in order to estimate the mean population pharmacokinetic parameters, mainly the bioavailability, of cisplatin and to evaluate the influence of covariates on the pharmacokinetic variability. METHODS: Pharmacokinetic and demographic data were collected from 32 adult patients (20 males/12 females, age range 47-76 years) receiving 30-min infusions or an oral formulation of cisplatin, 10-30 mg/m2, for various malignancies. Both total plasma and ultrafilterable or unbound platinum concentrations were determined. RESULTS: Unbound and total platinum concentrations were ascribed to a two-compartment model, with first-order absorption and elimination. The oral bioavailability (F) population estimates were, respectively, 0.39 and 0.30 with associated intersubject variabilities (ISV) of 24% and 26%. Peak concentrations following oral dosing occurred at 1.0 h and 1.6 h for unbound and total platinum, respectively. Clearance (CL) and central distribution volume (V1) of unbound platinum were significantly related to body surface area (BSA). The CL and V1 mean estimates were, respectively, 37 l/h and 23 l with an associated ISV of 15%. The final pharmacokinetic models were validated using 1000 bootstrap samples of the original datasets. CONCLUSIONS: Both unbound and total platinum data allowed a fair evaluation of oral cisplatin disposition, with close estimations for both absorption rates and oral bioavailability. These results also support the conventional dose adjustment of cisplatin based on BSA.

Individual adaptive dosing of topotecan in ovarian cancer.

PURPOSE: To take into account relationships between topotecan area under the plasma concentration (AUC) versus time curve and percentage decrease of neutrophil count previously shown when topotecan is administered on a 5-day, daily schedule. A multicentric clinical trial with individualized dosing of topotecan was performed in patients with platinum-refractory ovarian cancer. The primary goal of this study was to evaluate the toxicity of topotecan when the interindividual variability in plasma drug exposure is decreased. EXPERIMENTAL DESIGN: A total of 39 patients were evaluable. In cycle 1, the daily dose for the last 2 days was dependent on the observed topotecan AUC at day 1; the general objective was to constrain the overall AUC (i.e., from day 1 to day 5) within 37,500-75,000 nM.min. A pharmacokinetic study was also performed on day 5 of cycle 1 and day 1 of cycle 2 to evaluate the intrapatient pharmacokinetic variability both within cycle 1 and between cycles. RESULTS: The dose of topotecan was decreased for 20 patients and increased for only 1 patient within cycle 1. The total administered dose was correlated to the creatinine clearance. The dose adjustments allowed control of the topotecan exposure: mean (+/-SD) observed AUC of 70,697 (+/-12,364) nM.min. Fourteen cases of dose-limiting toxicity were observed, mainly in patients who previously received two different regimens of chemotherapy without a washout period before topotecan treatment. An overall response rate of 21% was observed in the 33 patients evaluable. CONCLUSION: Dose adjustments are required not only in patients with creatinine clearance below 40 ml/min, but also in those with values between 40 and 60 ml/min (recommended starting dose is 1.2 mg/m(2)). By performing drug monitoring and taking into consideration the past treatment of each patient, better dose individualization can be obtained.

Mechanism-based models for topotecan-induced neutropenia.

OBJECTIVE: A semiphysiologic pharmacokinetic-pharmacodynamic model was applied to describe topotecan-induced neutropenia, to quantify interindividual and intraindividual pharmacodynamic variability, and to study the effect of covariates on the model. METHODS: Data were obtained from patients treated with topotecan given either orally (118 patients) or intravenously (71 patients), according to different schedules (5 to 21 consecutive days), with or without cisplatin. The model mimics the maturation chain of neutrophils. Topotecan concentration-time profiles affected the proliferation of neutrophil precursors (sensitive cells) through an inhibitory linear model (topotecan is assumed to induce cell loss by a function, E drug, proportional to the topotecan concentration in the central compartment: E drug = Slope . Concentration). The topotecan plasma concentration versus time profile was generated for each patient by modeling the data according to a 2-compartment pharmacokinetic model and first-order absorption for oral administration by use of NONMEM. RESULTS: The model described the time course of neutrophil values well. Topotecan neutropenic effect exhibited a large interpatient variability (coefficient of variation of 82% for the slope values). The oral route was associated with a 43% lower value for slope, corresponding to a lower toxicity. The combination with cisplatin increased the neutropenic effect compared with topotecan alone by a factor 3.5. The intrapatient variability between cycle 1 and cycle 2 on slope was lower for the intravenous administration than for the oral administration. By application of the model to a new weekly schedule of topotecan, neutrophil values at the nadir were consistent with those observed during a phase I study of this regimen. CONCLUSION: This model can be used to describe both the duration and intensity of neutropenia; the area between the curve of neutrophil count versus time and a critical neutrophil count (such as 0.500 x 10(3) /mm 3 ) would be a better toxic endpoint than the unique observed value of neutrophil at nadir. The model may be used to predict neutropenia corresponding to regimens of topotecan not yet explored.

Contribution of apoptosis in the cytotoxicity of the oxaliplatin-irinotecan combination in the HT29 human colon adenocarcinoma cell line.

Interactions between the topoisomerase I inhibitor irinotecan (CPT-11) and the platinum derivative oxaliplatin (L-OHP) were investigated in HT29 colon cancer cell line. Synergism was observed when cells were simultaneously exposed to drugs or when cells were first exposed to CPT-11. Flow cytometric studies showed a G(2)/M accumulation when cells were exposed to the simultaneous and CPT-11-->L-OHP combinations whereas a persistent S phase delay was observed when cells were first exposed to L-OHP. We characterised the cytotoxic effect by assessing the induction of apoptosis. Irinotecan induced substantial DEVDase activity and poly(ADP-ribose) polymerase cleavage while this activity was moderate and delayed after exposure to L-OHP. Combination experiments showed a sequence-dependent onset of apoptosis, the CPT-11-->L-OHP schedule being the earliest and the most effective; on the other hand the apoptotic signaling generated by CPT-11 was partly inhibited in the simultaneous combination and in the L-OHP-->CPT-11 sequence. Cell death studies using a dual staining technique showed a shift from apoptosis to necrosis when combining these drugs at high concentrations. Synergistic interactions observed using CPT-11 before L-OHP may be linked to an early apoptotic signaling while the L-OHP-induced S phase block could account for the observed additive effect in the reverse sequence. An additional phenomenon might work towards synergism for the simultaneous combination.

All trans retinoic acid enhances CDDP-induced apoptosis: modulation of the CDDP effect on cell cycle progression.

We have previously shown that ATRA potentiates CDDP cytotoxicity in various ovarian carcinoma cell lines. In the present study, we found that the enhanced sensitivity to CDDP was due to an increase of CDDP-induced apoptosis in OVCCR1 and NIH-OVCAR-3 cells. In these cell lines, flow cytometric analysis indicated that CDDP induced an initial accumulation of cells in the S-phase, followed by an increase in the proportion of cells in G2/M phase. Pretreatment of OVCCR1 and NIH-OVCAR-3 cells with ATRA did not modify cell cycle parameters, but delayed S-phase exit of CDDP-treated cells. Bcl-2 over-expression inhibited both delay in S-phase exit and CDDP-induced apoptosis in ATRA-pretreated cells. The CDDP-induced S-phase accumulation of OVCCR1 cells resulted from an activation of CDK2/cyclin A activity. Our results indicate that ATRA-pretreatment modified the CDDP-induced regulation of CDK2 activity by the CDK inhibitors p21 and p27. Taken together, our findings suggest that ATRA potentiates the apoptosis induced by CDDP in ovarian carcinoma cells and that this action is sustained by modulation of the activity of CDK2/cyclin A.

The effects of food on the pharmacokinetic profile of oral vinorelbine.

The effects of food on the pharmacokinetics and safety profile of a soft-gel capsule formulation of vinorelbine (Navelbine Oral) were evaluated in fed and fasted patients with solid tumours or lymphomas. A group of 18 patients (12 planned) were entered into a multicentre phase I pharmacokinetic study following a crossover design with a 1-week wash-out period. Patients received the first dose of 80 mg/m(2) oral vinorelbine either after fasting or after ingestion of a standard continental breakfast. The second dose of 80 mg/m(2) was administered 1 week later in the alternate feeding condition to the first dose. Of the 18 patients, 13 were eligible for pharmacokinetic evaluation. The mean time to maximum concentration (T(max)) was shorter in fasted patients (1.63+/-0.98 h in blood, 1.67+/-0.96 h in plasma) than in fed patients (2.48+/-1.40 h in blood, 2.56+/-1.65 h in plasma) but these differences are not likely to modify the safety and/or efficacy of oral vinorelbine. Values for C(max) and AUC were similar in fed and fasted patients and no significant differences were observed. The safety profile of oral vinorelbine observed in this limited number of patients appears to be comparable to that usually reported for vinorelbine, the main toxicity being neutropenia. Only one episode of febrile neutropenia was reported. The main nonhaematological toxicities encountered were gastrointestinal, consisting of nausea, vomiting, diarrhoea and constipation. A tendency for a lower incidence of vomiting was suggested when oral vinorelbine was administered after a standard breakfast. Based on this study, the administration of oral vinorelbine to fasted patients is not mandatory since administration after a standard breakfast does not lead to differences in body exposure to the drug. As the comfort of patients may be improved when the treatment is administered after a light meal, this procedure can be recommended in clinical practice.

Population pharmacokinetics of oxaliplatin.

The objective of this study was to explore correlations between a variety of covariates and oxaliplatin ultrafilterable and blood pharmacokinetic parameters. Data from 40 patients receiving oxaliplatin combined with 5-fluorouracil and levofolinic acid as standard treatment for advanced colorectal cancer were analysed. Plasma ultrafilterable, blood, and urine platinum concentrations were determined by flameless atomic absorption spectrophotometry. Data were analysed according to a population pharmacokinetic method using the NONMEM program. The best fit for oxaliplatin plasma ultrafilterable clearance (CL) was given by the following equation, which considers four covariates: body surface area (BSA, in metres squared), age (in years), sex (0 if male, 1 if female), and serum creatinine (Scr, in micromoles per liter): CL (l/h)=5.49xBSA+4.55xBSAx(140-AGE)x(1-0.15xSEX)/Scr. By taking into account these covariates, the interindividual variability in CL decreased from 43% to 33%. Renal clearance represented 34% of the overall elimination. This value was obtained by recovering urine over only 5 h from the beginning of the infusion and modelling the data using NONMEM. We would recommend the use of this methodology for pharmacokinetic studies in oncology in which renal clearances of the drug are presently rarely explored. The oxaliplatin blood concentrations versus time observed during the three-cycle period were well-described by a three-compartment model with first-order elimination from the central compartment. No significant intrapatient pharmacokinetic variability was observed between cycles. The relationship we obtained using the population approach between oxaliplatin CL and covariates may allow rational reduction of oxaliplatin dose in cases of elevated serum creatinine levels.

Pharmacokinetic linearity of i.v. vinorelbine from an intra-patient dose escalation study design.

As pharmacokinetics represents a bridge between pharmacological concentrations and clinical regimens, the pharmacokinetic exploration of the therapeutic dose range is a major outcome. This study was aimed at assessing pharmacokinetic linearity of i.v. vinorelbine through an open design with intra-patient dose escalation (3 doses/group). Three groups of six patients received either 20-25-30 mg/m2; or 25-30-35 mg/m2; or 30-35-40 mg/m2. The inclusion criteria were: histologically confirmed tumour with at least one assessable target lesion, age 25-75 years, WHO PS < or =2, normal haematology and biochemistry, life expectancy > or =3 months. The pharmacokinetics was evaluated in both whole blood and plasma over 120 h. Twenty-six patients were recruited and 18 were evaluable for pharmacokinetics. The toxicity consisted in grade < or =3 leucopenia and neutropenia (<20% of courses) and two grade 4 constipation with rapid recovery (2/54 courses). Compared to blood, plasma was demonstrated to underestimate the pharmacokinetic parameters. In blood, the drug total clearance was about 0.6 l/h/kg, with minor contribution of renal clearance, steady state volume of distribution close to 13 l/h/kg, and elimination half-life at about 40 h. A pharmacokinetic linearity was demonstrated up to 40 mg/m2, and even up to 45 mg/m2 when pooling data from another study. A pharmacokinetic-pharmacodynamic relationship was evidenced on leucopenia and neutropenia when pooling the data from the two studies.