The role of cancer nurses in cancer-related pain management in Europe.

Cancer pain is a common symptom in patients with cancer and can largely affect their quality of life. Pain management is important to minimize the impact of pain on daily activities. Cancer nurses are significantly involved in all steps of pain management and contribute to the success of therapy through their knowledge and expertise. While they generally play an important role in the screening, assessment, diagnosis, treatment and follow-up of patients and their (pain) symptoms, this varies from country to country in Europe. An important aspect is their role in educating patients and their families about what pain is, what impact it can have, how it can be treated pharmacologically or non-pharmacologically and what effects or problems can occur during treatment. While there is a great discrepancy between education and training opportunities for cancer nurses in different European countries, there is a continued need for education and training in pain management. Cancer is increasingly becoming a chronic disease, and the management of pain in cancer survivors will be crucial to maintain an adequate quality of life. With this, the crucial role of cancer nurses is becoming even more important.

Early dose reduction/delay and the efficacy of liposomal irinotecan with fluorouracil and leucovorin in metastatic pancreatic ductal adenocarcinoma (mPDAC): A post hoc analysis of NAPOLI-1.

BACKGROUND: Chemotherapy dose modification to manage adverse events is commonplace in clinical practice. This exploratory analysis evaluates the impact of liposomal irinotecan dose modification on overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 clinical trial (NCT01494506). METHODS: Analysis includes only patients enrolled under protocol version 2 who received at least the first 2 scheduled doses of study drug. Within the liposomal irinotecan +5 fluorouracil/leucovorin (5 FU/LV) arm, patients were grouped according to whether or not they had a dose modification within the first 6 weeks. Dose reduction was defined as any decrease from initial dose; dose delay was any dosing delay >3 days from target date. OS and PFS (Kaplan-Meier estimates) were compared within the liposomal irinotecan+5-FU/LV arm and between treatment arms. Unstratified hazard ratios (HRs) were calculated using Cox regression analysis. RESULTS: Of the 93 patients from the liposomal irinotecan+5 FU/LV arm included in the analysis, 53 experienced a dose modification (both delay and reduction, n = 30; delay only, n = 19; reduction only, n = 4). No apparent difference in median OS or PFS was observed between patients who did versus patients who did not have a dose modification (OS: 8.4 vs 6.7 months; HR, 0.89; PFS: 4.2 vs 3.1 months; HR, 0.74). CONCLUSION: An early dose reduction or delay of liposomal irinotecan+5-FU/LV in the first 6 weeks does not significantly impact OS or PFS compared to patients without dose modifications. This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes.

Phase I study of imalumab (BAX69), a fully human recombinant antioxidized macrophage migration inhibitory factor antibody in advanced solid tumours.

AIM: Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using '3 + 3' dose escalation. METHODS: In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non-small-cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent. RESULTS: Fifty of 68 enrolled patients received imalumab. The most common treatment-related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose-limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients). CONCLUSIONS: Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.

Liposomal irinotecan and 5-fluorouracil/leucovorin in older patients with metastatic pancreatic cancer - A subgroup analysis of the pivotal NAPOLI-1 trial.

OBJECTIVES: Pancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial (NCT01494506) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients. MATERIALS AND METHODS: This exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. RESULTS: Of 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [<65 versus ≥65 years], 0.89/0.88 [<70 versus ≥70 years] and 1.04/0.98 [<75 versus ≥75 years]; P > .25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69% <75 years required a dose delay or reduction due to toxicities (43% versus 32% dose reductions). DISCUSSION: Results suggest that older patients with metastatic pancreatic adenocarcinoma that progressed on prior gemcitabine-based treatment can benefit from second-line therapy, supporting nal-IRI + 5-FU/LV treatment in older patients.

NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors.

BACKGROUND: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ≥1 year) in the NAPOLI-1 trial. PATIENTS AND METHODS: Patients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ≥1 year. Through 16th November 2015, 382 overall survival events had occurred. RESULTS: The overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57-0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ≥90, age ≤65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ≤5 and no liver metastases. No new safety concerns were detected. CONCLUSIONS: The survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified. CLINICAL TRIAL REGISTRATION NUMBER: NCT01494506.

Quality of life in metastatic pancreatic cancer patients receiving liposomal irinotecan plus 5-fluorouracil and leucovorin.

BACKGROUND: The NAPOLI-1 study (NCT01494506) reported that liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) improved overall survival vs 5-FU/LV with manageable toxicity in patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy. Yet, clinicians need treatment strategies that also maintain the patient's health-related quality of life (HRQOL). Here, we report the HRQOL data. METHODS: Patients completed the European Organisation for Research and Treatment of Cancer QOL core questionnaire C30 (EORTC QLQ-C30) at baseline, every 6 weeks, and at 30 days after discontinuation of study treatment. Patient-reported outcomes (PROs) were scored according to EORTC guidelines. nal-IRI+5-FU/LV HRQOL was compared with 5-FU/LV. The PRO population comprised intent-to-treat patients who completed baseline and at least one subsequent assessment on the EORTC QLQ-C30. Data were also analysed for missingness. RESULTS: Of 236 patients in the intent-to-treat population, 128 (54.2%) comprised the PRO population (71 in the nal-IRI+5-FU/LV arm; 57 the in 5-FU/LV arm). Of the remaining 108 patients (45.8%) not included in the PRO population, most progressed rapidly, making participation difficult. Median change from baseline was ≤10 points at weeks 6 and 12 in global health status or functional and symptom scale scores, except for fatigue, which deteriorated by 11.1 points with nal-IRI+5-FU/LV but did not change vs 5-FU/LV. The proportion of patients whose HRQOL improved or deteriorated was not significantly different between the arms. CONCLUSION: In the NAPOLI-1 study, HRQOL was maintained with nal-IRI+5-FU/LV in patients with metastatic pancreatic adenocarcinoma previously treated with a gemcitabine-based regimen, while survival was significantly extended.

Survival with nal-IRI (liposomal irinotecan) plus 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in per-protocol and non-per-protocol populations of NAPOLI-1: Expanded analysis of a global phase 3 trial.

BACKGROUND: In the phase 3 randomised NAPOLI-1 clinical study, a 45% increase in median overall survival (OS) was shown with liposomal irinotecan, 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) versus 5-FU/LV in patients with metastatic pancreatic cancer progressing after gemcitabine-based therapy. Here, we report data from a pre-specified, expanded analysis of outcomes in the per-protocol (PP) population. MATERIALS AND METHODS: The PP population comprised patients receiving ≥80% of planned treatment during the first 6 weeks, with no major protocol violations. A post-hoc analysis of the non-PP population was also performed. RESULTS: For PP patients, median OS was 8.9 (95% confidence interval: 6.4-10.5) months with nal-IRI+5-FU/LV (n = 66) vs 5.1 (4.0-7.2) months with 5-FU/LV (n = 71; unstratified hazard ratio [HR] 0.57, p = 0.011). For non-PP patients, it was 4.4 (3.3-5.3) months with nal-IRI+5-FU/LV (n = 51) vs 2.8 (1.7-3.2) months with 5-FU/LV (n = 48; unstratified HR 0.64, p = 0.0648). CONCLUSION: A statistically significant survival advantage was observed with nal-IRI+5-FU/LV vs 5-FU/LV in the PP patient population.

Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis.

BACKGROUND: In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). METHODS: Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. RESULTS: Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). CONCLUSIONS: Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

Post-gemcitabine therapy for patients with advanced pancreatic cancer - A comparative review of randomized trials evaluating oxaliplatin- and/or irinotecan-containing regimens.

A systematic review and critical evaluation of randomized trial evidence for oxaliplatin- or irinotecan-containing regimens in patients with advanced pancreatic cancer previously treated with gemcitabine has not yet been published. We conducted a comparative systematic review of randomized trials evaluating oxaliplatin- or irinotecan-based therapies in patients with advanced pancreatic cancer previously treated with gemcitabine to assess trial similarity and the feasibility of performing an indirect treatment comparison (ITC). Studies were identified through PubMed and key oncology conference abstracts. The following trials met our criteria: NAPOLI-1 (nanoliposomal irinotecan [nal-IRI] or nal-IRI+5-fluorouracil [5-FU]/leucovorin [LV] vs 5-FU/LV), CONKO-003 (oxaliplatin+5-FU/LV [OFF] vs 5-FU/LV), PANCREOX (oxaliplatin+5-FU/LV [mFOLFOX6] vs 5-FU/LV), and Yoo et al. (2009) (irinotecan+5-FU/LV [mFOLFIRI3] vs mFOLFOX). Fundamental differences were identified in study design (i.e., number of study sites, number of countries), patient (i.e., locally advanced vs metastatic disease, stratification variables, prior and subsequent treatments) and treatment (i.e., regimens, dose intensity) characteristics, and primary and secondary outcomes (i.e., primary vs secondary outcomes, overall survival [OS], progression-free survival [PFS]) among the 4 included trials. Our comparative review demonstrated significant dissimilarity across trials, which precluded conducting an ITC. In the absence of head-to-head nal-IRI- and/or oxaliplatin-based therapy trials, clinicians are advised to interpret these studies separately within the context of their individual patient population.

Management of fatigue in patients with cancer -- a practical overview.

Cancer-related fatigue (CRF) is a serious clinical problem and is one of the most common symptoms experienced by cancer patients. CRF has deleterious effects on many aspects of patient quality of life including their physical, psychological and social well-being. It can also limit their ability to function, socialise and participate in previously enjoyable activities. The aetiology of CRF is complex and multidimensional, involving many potentially contributing elements. These include tumour-related factors and comorbid medical/psychological conditions and also side effects associated with anti-cancer therapies or other medications. Barriers to the effective management of CRF exist both on the side of physicians and patients, and as a result CRF often remains unrecognised and undiscussed in clinical practice. A change of approach is required, where fatigue is treated as central to patient management during and after systemic anti-cancer treatment. In this review we summarise factors involved in the aetiology of CRF and the barriers to its effective management, as well as factors involved in the screening, diagnosis and treatment of cancer patients experiencing fatigue. Pharmacological and non-pharmacological approaches to its management are also reviewed. We suggest an algorithm for the process of managing CRF, guided by our experiences in The Netherlands, which we hope may provide a useful tool to healthcare professionals dealing with cancer patients in their daily practice. Although CRF is a serious and complex clinical problem, if it is worked through in a structured and comprehensive way, effective management has the potential to much improve patient quality of life.

A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients.

PURPOSE: Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib. EXPERIMENTAL DESIGN: Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging. RESULTS: After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P < 0.01). For every 100 cm(3) increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed. CONCLUSIONS: This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future "trough level - clinical benefit" analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance.

Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: a prospective cross-over drug-drug interaction study.

BACKGROUND: Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan. METHODS: Fourteen patients were treated with single agent irinotecan (600mg i.v., 90min) followed 3weeks later by a second cycle with concurrent use of omeprazole 40mg once daily, which was started 2weeks prior to the second cycle. Plasma samples were obtained up to 55h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS. RESULTS: The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole. CONCLUSION: Omeprazole 40mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.

Effects of methimazole on the elimination of irinotecan.

PURPOSE: To study the possible pharmacokinetic and pharmacodynamic interactions between irinotecan and methimazole. METHODS: A patient treated for colorectal cancer with single agent irinotecan received methimazole co-medication for Graves' disease. Irinotecan pharmacokinetics and side effects were followed during a total of four courses (two courses with and two courses without methimazole). RESULTS: Plasma concentrations of the active irinotecan metabolite SN-38 and its inactive metabolite SN-38-Glucuronide were both higher (a mean increase of 14 and 67%, respectively) with methimazole co-medication, compared to irinotecan monotherapy. As a result, the mean SN-38 glucuronidation rate increased with 47% during concurrent treatment. Other possible confounding factors did not change over time. Specific adverse events due to methimazole co-treatment were not seen. CONCLUSIONS: Additional in vitro experiments suggest that these results can be explained by induction of UGT1A1 by methimazole, leading to higher SN-38G concentrations. The prescribed combination of these drugs may lead to highly toxic intestinal SN-38 levels. We therefore advise physicians to be very careful in combining methimazole with regular irinotecan doses, especially in patients who are prone to irinotecan toxicity.

Effects of mannose-binding lectin polymorphisms on irinotecan-induced febrile neutropenia.

OBJECTIVE: Mannose-binding lectin (MBL) is important in the innate immune response. MBL2 gene polymorphisms affect MBL expression, and genotypes yielding low MBL levels have been associated with an elevated risk for infections in hematological cancer patients undergoing chemotherapy. However, these reported associations are inconsistent, and data on patients with solid tumors are lacking. Here, we investigated the effects of MBL2 genotypes on irinotecan-induced febrile neutropenia in patients with solid tumors. PATIENTS AND METHODS: Irinotecan-treated patients were genotyped for the MBL2 gene. Two promoter (-550 H/L and -221 X/Y) and three exon polymorphisms (52 A/D, 54 A/B, and 57 A/C) were determined, together with known risk factors for irinotecan-induced toxicity. Neutropenia and febrile neutropenia were recorded during the first course. RESULTS: Of the 133 patients, 28% experienced severe neutropenia and 10% experienced febrile neutropenia. No associations were found between exon polymorphisms and febrile neutropenia. However, patients with the H/H promoter genotype, associated with high MBL levels, experienced significantly more febrile neutropenia than patients with the H/L and L/L genotypes (20% versus 13% versus 5%). Moreover, patients with the HYA haplotype encountered significantly more febrile neutropenia than patients without this high MBL-producing haplotype (16% versus 4%). In the subgroup with wild-type exon polymorphisms (A/A), patients with the high MBL promoter phenotype had the highest incidence of febrile neutropenia, regardless of known risk factors. CONCLUSION: Patients with high MBL2 promoter genotypes and haplotypes seem more at risk for developing febrile neutropenia. If confirmed, these preliminary findings may contribute to more individualized approaches of irinotecan treatment.

A CYP3A4 phenotype-based dosing algorithm for individualized treatment of irinotecan.

PURPOSE: Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test. EXPERIMENTAL DESIGN: Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m(2) (group A) or doses based on an equation consisting of midazolam clearance, gamma-glutamyl-transferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course. RESULTS: Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P > 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P > 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was >4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%). CONCLUSIONS: Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment.

[Medicinal use of cannabis in the Netherlands: towards a responsible pattern of use]. / Medicinale cannabis in Nederland: op weg naar een verantwoord gebruik.

Since 2003, medicinal cannabis has been legally cultivated and distributed in the Netherlands under the auspices of the Dutch Office of Medicinal Cannabis (BMC), part of the Ministry of Health, Welfare and Sport. As a result of this measure, the indication, dosage, administration route, and safety of cannabis can now be investigated, information necessary for justifying its potentially future position as a standard medicinal product. Despite the current lack of reliable scientific efficacy data, standardised medicinal cannabis without microbes has also been made available on prescription. This has led to a safer and more responsible use. However, it is a bridge too far to say that 'it doesn't hurt to try'. The legalization of medicinal cannabis has also stimulated the development of new purified cannabis-based products, although it is claimed that some patients specifically benefit from using cannabis as a whole product. Despite disappointing sales at the end of 2007, the Minister of Health, Welfare and Sport has announced that the current policy will be extended for a further five years. The Minister also indicated that he would consider discontinuing the availability of medicinal cannabis for patients, if new cannabis products are granted market authorization. This might, however, give rise to a new era of illegal cannabis use for medicinal purposes, notably for the use as a whole product.

Lifestyle habits as a contributor to anti-cancer treatment failure.

Lifestyle may have serious consequences for cancer treatment outcome, which is a fact that both physicians and patients are often not explicitly aware of, thereby unwillingly exposing the patient to possible danger. In certain cases, patient behaviour can lead to potentially life-threatening adverse events, whilst in other cases the clinical benefit of anti-cancer therapy can be diminished. In this review, we focus on the role of certain habits (like cigarette smoking, alcohol use and the use of complementary and alternative medicine) and discuss the effects they may have on anti-cancer medication. Also patient compliance to prescribed anti-cancer drugs is a factor frequently overlooked if treatment does not follow the expectations, which gains importance with the increasingly frequent prescription of oral anti-cancer agents.

Medicinal cannabis in oncology.

In The Netherlands, since September 2003, a legal medicinal cannabis product, constituting the whole range of cannabinoids, is available for clinical research, drug development strategies, and on prescription for patients. To date, this policy, initiated by the Dutch Government, has not yet led to the desired outcome; the amount of initiated clinical research is less than expected and only a minority of patients resorts to the legal product. This review aims to discuss the background for the introduction of legal medicinal cannabis in The Netherlands, the past years of Dutch clinical experience in oncology practice, possible reasons underlying the current outcome, and future perspectives.

Irinotecan chemotherapy during valproic acid treatment: pharmacokinetic interaction and hepatotoxicity.

PURPOSE: Because of its supposed inhibiting capacities of uridine-diphosphate glucuronosyltransferase 1A (UGT1A)-mediated glucuronidation in rats, the antiepileptic drug valproic acid has been investigated as modulator of irinotecan-induced delayed-type diarrhea in rats. Here, we report on the pharmacokinetic and pharmacodynamic effects of this combination in a cancer patient. EXPERIMENTAL DESIGN: A patient who used valproic acid was administered irinotecan (600 mg). To investigate dose-limiting hepatotoxicity encountered during the first course, which was clinically attributed to a supposed higher exposure to the active irinotecan metabolite SN-38, valproic acid was tapered off. Blood samples for pharmacokinetic purposes were drawn during a course with and a course without concomitant valproic acid. Plasma-levels of irinotecan, SN-38, and SN-38G were determined using HPLC-assays. RESULTS: When irinotecan was combined with valproic acid, the exposure to SN-38 was 41% lower. Additionally, reversible elevations of the liver enzyme tests were noted. In particular, seven days after irinotecan administration gammaGT and transaminase levels raised up to 5.3-11.3 times the ULN (CTCAE grade 3). CONCLUSIONS: Valproic acid-induced plasma protein binding displacement and/or metabolic modulation of enzymes and drug transporters involved in irinotecan disposition may explain the reduced exposure to SN-38 in the presence of valproic acid. Given the herewith-coupled potential undertreatment, patients should firstly switch to another antiepileptic drug not known to interfere with irinotecan treatment. Additionally, this particular combination should not be implemented in clinical studies without simultaneously adjusting the irinotecan dose, and the risk of (severe) hepatotoxicity should be considered when designing protocols studying valproic acid (as histone deacetylase-inhibitor) in combination with other (anticancer) drugs.