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Background Peritoneal metastases (PM), corresponding to tumor implants into the peritoneal cavity, are associated with impaired prognosis and low responsiveness to systemic chemotherapy. A new therapeutic approach has dramatically changed the prognosis of patients with PM from colorectal cancer (CRC), consisting in the association of a complete cytoreductive surgery followed by intraperitoneal chemotherapy associated to hyperthermia (HIPEC). Many drugs have been administered intraperitoneally, but no clear consensus has been approved. Therefore, relevant preclinical models are essentials for the efficient translation of treatments option into affected patients. Method Organoids, the last generation of preclinical models, were used to rationalize and improve intraperitoneal chemotherapy. We tested several cytotoxics, combination, effect of hyperthermia, exposure duration and frequency. Results Organoids were a representative model of response to chemotherapies used for the treatment of PM from CRC; 460 mg/m 2 of oxaliplatin being the most efficient cytotoxic treatment. Repeated incubations with oxaliplatin; mimicking cycles of intraperitoneal treatment, resulted in an increased efficacy. Conclusion & discussion Organoids are relevant models to study the chemosensitivity of peritoneal metastases from CRCs. These models could be used for large scale drug screening strategies or personalized medicine, for colorectal carcinoma but also for PM from other origins.

Mitotane (o,p′-DDD) is the standard treatment for advanced adrenocortical carcinoma (ACC). Monitoring of plasma mitotane levels is recommended to look for a therapeutic window between 14 and 20mg/L, but its positive predictive value requires optimization. We report the case of an ACC patient with a history of dyslipidemia treated with mitotane in whom several plasma mitotane levels >30mg/L were found together with an excellent neurological tolerance. This observation led us to compare theoretical or measured o,p′-DDD and o,p′-DDE levels in a series of normolipidemic and dyslipidemic plasma samples to explore potential analytical issues responsible for an overestimation of plasma mitotane levels. We demonstrate an overestimation of mitotane measurements in dyslipidemic patients. Mitotane and o,p′-DDE measurements showed a mean 20% overestimation in hypercholesterolemic and hypertriglyceridemic plasma, compared with normolipidemic plasma. The internal standard p,p′-DDE measurements showed a parallel decrease in hypercholesterolemic and hypertriglyceridemic plasma, suggesting a matrix effect. Finally, diluting plasma samples and/or using phospholipid removal cartridges allowed correcting such interference. Learning points Hypercholesterolemia (HCH) and hypertriglyceridemia (HTG) induce an overestimation of plasma mitotane measurements. We propose a routine monitoring of lipidemic status. We propose optimized methodology of measurement before interpreting high plasma mitotane levels. Background Monitoring plasma mitotane levels is recommended in the follow-up of patients with unresectable adrenocortical carcinoma (ACC) to look for a therapeutic window of 14–20mg/L to optimize benefit over risk and avoid toxicities (1). Mitotane is a lipophilic drug that accumulates in lipoproteins and induces dyslipidemia (hypercholesterolemia (HCH) and/or hypertriglyceridemia (HTG)) (2, 3, 4, 5). Previous studies suggested that the lipoprotein profile may influence mitotane drug distribution (6). Moreover, high plasma mitotane levels have been described in dyslipidemic patients who did not exhibit any side effects, suggesting either methodological issues, or that plasma mitotane distribution in lipoprotein subtypes is a major determinant of its distribution in tissues (7). Indeed, we recently reported that plasma mitotane level was correlated with o,p′-DDD measured in HDL and LDL fractions (8). Here, we report the case of an ACC patient with a severe dyslipidemia. Plasma mitotane monitoring revealed very high levels, that is, >30mg/L, while our patient did not present any neurological side effects. Considering this observation, we demonstrate that dyslipidemia causes an overestimation of plasma mitotane levels explained by a so-called matrix effect.

Morphine and meperidine in Patient-Controlled Analgesic devices are commonly used to treat chronic pain patients. These devices deliver a programmed amount of drug and allow self-administration by the patient depending on the pain. In our department of pharmacy, 300 devices were manufactured in 2003. The aim of this study was to assess their shelf-life. The devices were filled aseptically and without preservatives with 1 and 40 mg/ml morphine solution and 5 and 20 mg/ml meperidine and stored over 30 days at room temperature and protected from light. Culture assay of the solutions showed that they remained sterile for 30 days. No turbidity of any solutions from samples collected twice a week was noticed. pH and osmolarity remained constant. Drug concentrations were determined using stability indicating HPLC method, as we showed that degradation products can be separated from the drugs. Little loss of meperidine occurred within 21 days (

Objective: The opportunity to apply a sampling plan was evaluated. Costs were computed by a microcosting study. Setting: In 2003, a sampling plan was defined to reduce the number of chemotherapy quality controls while preserving the same level of quality. Recent qualitative and quantitative changes led us to define a second sampling plan supplemented by an economic evaluation to determine the cost and cost-savings of quality control. Methods: The study considers preparation produced during four semesters classified into three groups. The first one includes drugs produced below 200 batches a semester. Group 2, those for which the lot of preparation lots would have been rejected twice among these four semesters. Group 3, those would have been accepted (≥3 ‘acceptable lot’). A single sampling plan by attributes was applied to this group with an acceptance quality level of 1.65% and a lot tolerance percent defective below 5%. A micro-costing study was conducted on quality control, from the sampling to the validation of the results. Results: Among 39 cytotoxic drugs, 11 were sampled which enabled to avoid a mean of 17,512 control assays per year. Each batch of the 28 non-sampled drugs was however analyzed. Costs were estimated at 2.98€ and 5.25€ for control assays depending of the analytical method. The savings from the application of the sampling plans was 153,207€ in 6 years. Conclusion: The sampling plan allowed maintaining constancy in number of controls and the level of quality with significant costsavings, despite a substantial increase in drugs to assay and in the number of preparations produced.

Context The use of patient-controlled analgesia (PCA) allows patients to be managed at home and may increase the quality of life of patients with regard to drug administration. To ensure that intact drug is delivered to the patient in this setting, it is important to study its microbiological and physicochemical stability. Although these factors have been widely studied for many parenteral opioids, very few authors have investigated oxycodone stability associated with long-duration infusion in cancer patients. Objectives The aim of this study was to assess the microbiological and physicochemical stability of oxycodone hydrochloride solution in PCA devices and thereby to determine the feasibility of extending the expiration dates after mixing. Methods Sixteen CADD® reservoirs and 32 Rythmic® reservoirs were filled aseptically with pure (10mg/mL) and diluted (1mg/mL) oxycodone solution. Three different vehicles (0.9% sodium chloride, water for injection, and 5% dextrose) were used for dilution. Among the PCA systems stored over 28 days at room temperature, 16 Rythmic® reservoirs were protected from light. Microbiological stability was assessed by performing sterility tests. The physicochemical study was performed by determining aspect, pH, osmolality evolution, and weight. Drug concentrations were determined using the stability-indicating high performance liquid chromatography combined to ultraviolet detection technique. Results There was no significant change in pH, weight, and osmolality values of any solutions. No precipitation or change in color was observed in any of the sample solutions. There was no significant loss of oxycodone, and no trace of degradation products was detected. Conclusion This study indicates that pure and diluted oxycodone solutions in the PCA systems are stable for 28 days at room temperature when prepared aseptically.

Background About 26,000 chemotherapeutic batches were produced in 2003 in the Institute Gustave Roussy and 83% were qualitatively and quantitatively assessed in post-production controls via an analytical platform. The rate of non-conformity (outside the specification limits of the target concentration ±10%) decreased from 8.9% to 2.2% between years 2001 and 2003. A cost- and time-saving acceptance sampling plan was applied to assay fewer batches whilst maintaining an accurate estimate of the quality level. Methods The opportunity to apply a single sampling plan by attributes with an acceptance quality level of 2.2% was evaluated. A prognostic study using a logistic regression model was performed for some drugs to identify risk factors associated with the non-conformity rate of preparations. Results Out of 26 drugs, 17 have not been sampled, since they were prepared less than 400 times per year. For six drugs, a reduction of about 50% in the number of assays was estimated. Three drugs were “at risk” of being non-conform: for these drugs, all batches were analysed. Conclusions The sampling plan allowed a reduction of almost 8000 analyses with respect to the number of batches analysed for 6 drugs. For the 3 drugs with the higher risk to be non-conform, associated risk factors were identified to set up corrective actions.

The aim of this study was to assess the microbiological and physicochemical stability of opioid solutions containing fentanyl or sufentanil and thereby determine the feasibility of extending the expiration dates after mixing. Five systems containing fentanyl or sufentanil solutions at 50 microg/mL in portable patient-controlled analgesia (PCA) systems were filled and stored at room temperature for 14 days. They were sampled immediately after preparation, at day 3, and each day of the following weeks. Microbiological stability was assessed by performing sterility tests. The physicochemical study was performed by determining aspect, pH, and osmolality evolution. All samples were tested for appearance, change in color, and loss of concentration using an analytical method. There was no significant change in pH and osmolality values of any solutions. No precipitation or change in color was observed in any of the sample solutions. There was no significant loss of fentanyl or sufentanil over 14 days (4.3% and 4.1%, respectively). This study indicates that both drug solutions in the PCA systems are stable for a minimum of 14 days at room temperature.

The Department of Clinical Pharmacy (DCP) in the Institut Gustave-Roussy (IGR) is equipped with a high-performance thin-layer chromatography (HPTLC) analytical platform. One of the numerous possible uses of HPTLC is post-production quality control of chemotherapy manufacturing. After 3 years of existence, routine validation of manufactured batches has attained considerable maturity: 24 cytotoxic agents can be controlled in terms of identity, purity and concentration. Approximately 50% of the sampled preparations are assessed. More than 97% were within specifications, 1.6% were not, probably due to incorrect homogenization before sampling; and 1% were not evaluable. Using HPTLC in a hospital manufacturing unit contributes to quality assurance programmes such as accreditation to which the IGR DCP is now committed but also ISO 9001:2000 certification concerning the chemotherapy manufacturing unit.

In a context of day hospital care of cancer patients, a protocol combining etoposide and carboplatin is used in paediatrics. Disposable infusion devices can be used to improve patient quality of life and to optimize nursing time. Stability data are available for carboplatin in these devices but not for etoposide. The aim of this study was to determine the stability of etoposide solutions in these devices by monitoring the changing etoposide concentration. To study the changing etoposide concentration, we investigated three different concentrations, each in two different solvents: sodium chloride (NaCl) 0.9 % and dextrose 5 %, in Intermate(®) disposable infusion devices. Quantitative analyses were performed by high-performance liquid chromatography coupled with ultraviolet (UV) detection on samples collected over a 24-h study period. The results showed that 100 mg/L etoposide solutions were stable for 24 h in NaCl 0.9 % and for 12 h in dextrose 5 %, whatever the temperature. The 400-mg/L solutions were stable for 24 h in both diluents, whatever the temperature, whereas the 600-mg/L solutions when diluted in NaCl 0.9 % and dextrose 5 % in water were stable for 8 and 6 h, respectively. We found that precipitation was the main phenomenon responsible for decreased etoposide concentrations. This study allowed us to conclude that etoposide solutions prepared in Intermate(®) infusion devices are stable for day hospital administration in paediatrics. It will also allow us to conduct a future clinical study that will focus on the medico-economic feasibility of this protocol and on the evaluation of patient and nurse satisfaction.