How to manage the dose of drugs in cancer patients with acute kidney injury, practical recommendations.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are common in cancer patients. AKI is a brutal and reversible condition which makes it hard to manage from a pharmacological perspective when patients are receiving anticancer regimens and other supportive care drugs, such as anticoagulants, analgesics and other drugs. In contrast to CKD, which is a slow progressive disease, there is no clear guidance on how to manage and/or modify the dosage of drugs during AKI. Indeed, the slow progression of CKD allows physicians to monitor the renal function by using the glomerular filtration rate. Consequently, publications have explored the management of drugs in cancer patients with CKD, which is currently not the same for AKI. There are no recommendations or suggestions on how to manage drug doses in case of AKI in cancer patients. This commentary explores the different options to manage drugs (anticancer drugs, anticoagulants, and other supportive care drugs) during AKI in cancer patients.

Incidence, risk factors, and management of bleeding in patients receiving anticoagulants for the treatment of cancer-associated thrombosis.

Updated clinical practice guidelines recommend the long-term use of low-molecular-weight heparins or direct oral anticoagulants as the preferred option for the treatment of cancer-associated thrombosis (CAT), using a personalized approach matching the right drug to the right patient. In most cases, the benefit of anticoagulant therapy outweighs the risk. However, the long-term use of anticoagulants is associated with a non-negligible risk of bleeding, which constitutes a rare but serious adverse effect. Bleeding complications have been reported to be overall 2 to 3 times more frequent in cancer patients with CAT receiving anticoagulation than in non-cancer patients, with a reported incidence of major bleeding ranging from 2.4 to 16.0% in randomized controlled trials (RCT). In the absence of validated risk assessment model to predict the risk of bleeding in these patients, a careful evaluation of each individual profile, with adequate selection of the most appropriate anticoagulant for each individual patient, is warranted for overcoming management challenges, taking in account the numerous factors which may potentiate the overall bleeding risk in these complex patients, such as advanced or metastatic disease, older age, anemia, thrombocytopenia, renal impairment, liver dysfunction, and concomitant anticancer therapies. The purpose of this review is to call for awareness on bleeding complications as a major safety issue of CAT treatment and to summarize data from recent RCT and real-world studies on the incidence and risk factors for bleeding in this unique and challenging population to further help clinicians in decision-making.

[Renal toxicity of anticancer drugs]. / Toxicité rénale des anticancéreux.

The renal toxicity of anticancer drugs is a clinical challenge because of the intrinsic toxicity of some anticancer drugs and because the cancer itself. Indeed, cancer patients are exposed to all types of renal disorders (obstructive, functional, organic because of radiotherapy, paraneoplastic glomerulopathy, thrombotic microangiopathy…). The therapeutic index of anticancer drugs is often narrow and the doses used for optimal efficacy are high. Improving safety requires a better dose adjustment, which depends on the correct evaluation of the renal function. Prevention remains important as the mortality associated with acute renal failure is very high.

Are Patients with Active Cancer and Those with History of Cancer Carrying the Same Risks of Recurrent VTE and Bleeding While on Anticoagulants?

Direct oral anticoagulants (DOAC) are now recommended for the treatment of cancer-associated thrombosis (CAT) based on the results of dedicated trials demonstrating that DOAC are non-inferior to low molecular weight heparins in preventing recurrent venous thromboembolism (VTE) in this population. The definition of "cancer patient" differs substantially among studies. Whether patients with active cancer and those with a history of cancer (HOC) carry the same risks of recurrent VTE and bleeding remains unclear. Few studies reported data on the efficacy and safety of anticoagulants according to active cancer or HOC categories. While in subgroup analyses of EINSTEIN and HOKUSAI the rates of recurrent VTE and bleeding did not differ between these categories, results from a subgroup analysis of AMPLIFY, from HOKUSAI-Cancer, and from the COMMAND cohort suggest that HOC patients might have a lower bleeding risk than active cancer patients. Whether the inclusion of HOC patients in CAT studies might introduce some bias by decreasing the rates of both recurrent VTE and bleeding remains an unanswered issue since no dedicated prospective study addressed this question. A strict definition of active cancer should be used in further trials.

[Non-iodinated contrast media nephrotoxicity]. / Toxicité rénale des produits de contraste non iodés.

The development of interventional radiology techniques regularly exposes patients to the potential renal toxocity of iodinated contrast media. Faced with this risk of nephrotoxicity, gadolinium-based contrast agents have long been considered as a safe alternative to iodinated contrast media, especially in sensitive or at risk patients. However, these gadolinium-based contrast agents are not devoid of nephrotoxicity and present another risk, a complication related to renal failure, the nephrogenic systemic fibrosis. European and US recommendations from health agencies have recently come closer, defining groups of patients at risk of nephrogenic systemic fibrosis according to their level of renal function and the type of gadolinium-based contrast agent used. What are the real renal risks for these products? How to evaluate the benefit-risk balance of the patient to choose a radiological examination in an informative, effective and safe way? This article focuses on the description of the risks of gadolinium-based contrast agents, reviews existing recommendations and best practices to guide the choice of clinicians.

Course of chronic kidney disease in French patients.

BACKGROUND: In 1998, a French survey showed that the referral of patients with chronic kidney disease to a nephrologist was delayed, resulting in many emergency initiations of dialysis. In 2009, the ORACLE study aimed to describe the renal course of dialysis patients from their first nephrology visit to their first dialysis session. METHODS: The ORACLE study was a multicentre retrospective study of all patients who started chronic dialysis. Data were collected at the first nephrology visit and at the first dialysis session. RESULTS: In total, 720 patients were included (69 centres). At the first nephrology visit, the mean Cockcroft-Gault (CG) indicator was 31.8 mL/min (22.7 in 1998) and 52.4% of patients (73% in 1998) had a CG <30. The mean time between the first nephrology visit and the first dialysis session was 48 months (35 months in 1998). CONCLUSION: In 2009, most patients were referred a long time before dialysis initiation, which likely allowed them to benefit from the impact of nephrology care on early outcomes when on dialysis. However, 34.2% of the dialysis sessions were still initiated under emergency conditions.

Pharmacokinetic/pharmacodynamic considerations for cancer patients undergoing hemodialysis.

INTRODUCTION: The increased incidence of cancer in hemodialysis patients has been discussed since the mid-70s. Today, physicians regularly encounter situations where they must manage the prescription of anticancer drugs in hemodialysis patients. Areas covered: Hemodialysis patients are at risk of dose-related toxicities due to pharmacokinetic modifications. Hemodialysis patients are at risk of therapeutic drug removal during their hemodialysis session, which may result in a loss of efficacy. In the advent of novel immunotherapies, particularly tumor vaccines, there is an increased theoretical risk of pharmacodynamic modification. Indeed, pharmacodynamic modifications have already been reported for viral vaccines. Expert opinion: It is important to consider all of the potential pharmacokinetic/pharmacodynamic modifications before prescribing anticancer drugs in hemodialysis patients. However, pharmacokinetic/pharmacodynamic modification should not be considered a contraindication for anticancer drug use in hemodialysis patients, rather, clinicians should be aware of the need individualize treatment according to available recommendations.

Renal insufficiency and cancer treatments.

Renal insufficiency has been shown to be highly prevalent in patients with cancer. This renal insufficiency has been reported to be associated with reduced overall survival and increased cancer-related mortality. Therefore, it is important to screen patients with cancer for renal insufficiency, using an adequate and reliable method of estimation of the renal function. Renal insufficiency may influence 1 or several of the 4 pharmacokinetic phases (absorption, distribution, metabolism, elimination/excretion), potentially resulting in marked modifications of the pharmacokinetic profile of a drug in patients with renal insufficiency. Consequently, it is potentially necessary to adjust the dosage of anticancer drugs in case of renal insufficiency in order to avoid drug accumulation and in order to reduce overdosage-related side effects. This dosage adjustment of anticancer drugs should be performed according to the level of renal function and with an appropriate and validated method. It is not always easy to find clear information on anticancer drug handling in these patients. However, several guidelines, publications and handbooks are available on how to adjust anticancer drug dosages in patients with renal insufficiency and will help practitioners to manage anticancer drugs in such patients.

Is Tenofovir Alafenamide Safer than Tenofovir Disoproxil Fumarate for the Kidneys?

Tenofovir disoproxil fumarate is currently the cornerstone of HIV treatment. Although it shows an overall good safety profile, numerous cases of nephrotoxicity have been reported. Tenofovir alafenamide is a novel tenofovir prodrug that has been developed to improve renal safety. Pharmacokinetic studies suggest a better renal tolerance of tenofovir alafenamide than tenofovir disoproxil fumarate, probably because tenofovir plasma concentrations are lower after tenofovir alafenamide administration. Consistently in clinical trials, renal tolerance seems to be improved in patients treated with tenofovir alafenamide. However, some questions remain. First, whether tenofovir can accumulate and lead to nephrotoxicity under specific circumstances after tenofovir alafenamide administration is unknown. Second, only "real-world practice" will inform us on the long-term renal safety of tenofovir alafenamide. Last, tenofovir alafenamide renal safety in patients with chronic kidney disease has not been studied in any randomized clinical trial. In conclusion, tenofovir alafenamide appears as a very promising drug and long-term safety will be an important determinant of its expanded use.

[Renovascular effects of antiangiogenic drugs]. / Effets rénovasculaires des antiangiogéniques.

During the last decade, inhibitors of the vascular endothelial growth factor (VEGF) were developed for the treatment of cancer. Many anti-VEGF are available but the issue is still the same: to inhibit the effect of the VEGF on their receptors. There are two main classes, depending on the mechanism of action by blocking the binding of the ligand on the receptor (VEGF trap or monoclonal antibody) or by affecting directly the receptor (tyrosine kinase inhibitor [TKI], monoclonal antibody directed against the VEGF receptor). These selective agents are safe. Nevertheless, side effects were described, in particular renal and vascular effects. In this article, we analyze the frequency of these renovascular complications, their clinical aspects and the interest of these indexes as a marker of treatment efficacy.

Results from the LIDO anemia survey: adherence to EORTC guidelines in cancer patients in France.

PURPOSE: The aim of the LIDOanemia surveys was to assess how anemia in cancer patients is managed by oncologists and hematologists according to the key messages of the EORTC guidelines. METHODS: LIDO 1 and LIDO 2 (Leaning upon International Directives for Optimization: Anemia) were declarative web-based surveys conducted in France. LIDO 1 specifically focused on clinical features triggering the decision to treat anemia, biological indicators of anemia, the hemoglobin (Hb) threshold for initiating treatment and blood transfusion, and the Hb treatment target. In LIDO 2, participants were presented the main messages of the EORTC guidelines and were asked four questions to assess the impact of the guideline's broadcast on their practice. RESULTS: A total of 133 and 319 physicians took part in the LIDO 1 and 2 surveys, respectively. The majority were oncologists (65 and 61 %, respectively). Responses from LIDO 1 showed practice habits that differed from those recommended in the EORTC guidelines. However, LIDO 2 showed that an average of 18 % of the participating physicians were willing to amend their clinical practice after receiving a summary of the EORTC recommendations for anemia management. CONCLUSION: These findings raise the questions of how often and how to most effectively disseminate key guideline messages. With the best interests of patients in mind, the ultimate objective is to improve the understanding of consensus recommendations and to close the gap between them and actual clinical practice.

[Renovascular safety of bevacizumab in breast cancer patients. The prognostic value of hypertension and proteinuria]. / Tolérance rénovasculaire du bévacizumab dans le cancer du sein. Valeur pronostique de l'hypertension et de la proteinuria.

INTRODUCTION: The potential prognostic value of hypertension and proteinuria of anti-vascular endothelial growth factor (VEGF) drugs has not been assessed in routine clinical practice so far in breast cancer. The objectives of the MARS study were to assess the prevalence of proteinuria and hypertension at baseline, their incidence under anti-VEGF treatment, and to evaluate a possible link with overall survival. METHODS: Patients from 8 centres were included between 2009 and 2011 with a follow-up of 1 year. They were naive of any previous anti-VEGF treatment and planned to be started on one. The results of the group of patients with breast cancer receiving bevacizumab are presented. RESULTS: Four hundred and two patients with breast cancer and treated with bevacizumab were included. At inclusion, hypertension prevalence was 12.4%, proteinuria 23.9%. The incidence of de novo proteinuria and hypertension during the follow-up was 61.7% and 16.8%, respectively. Among patients with de novo proteinuria, 62.2% afterwards improved/normalized. No thrombotic microangiopathy was reported. Baseline or de novo proteinuria/hypertension were not associated with overall survival in breast cancer patients treated with bevacizumab. DISCUSSION: These results on the renovascular safety of bevacizumab in breast cancer patients showed that the prevalence of hypertension and proteinuria was high at baseline and, moreover, patients treated with bevacizumab frequently developed de novo hypertension and/or proteinuria. Finally, neither hypertension, nor proteinuria, neither at baseline, nor de novo, were associated with overall survival in our cohort of "real-life'' patients

Anticancer Drugs in End-Stage Kidney Disease Patients.

The increased incidence of malignancies in patients with chronic kidney patients and especially in end-stage kidney disease (ESKD) patients has been discussed since the mid-1970s. Consequently, oncologists, nephrologists, and pharmacists are increasingly facing challenging situations of cytotoxic drug handling in dialysis patients because of pharmacokinetic modifications. In these patients, two main issues must be considered. First, the absence of renal function in hemodialysis (HD) patients may necessitate drug dosage reduction. Therefore, drug prescription must be cautiously checked before administration with appropriate dosage adjustment whenever necessary to ensure efficacy while avoiding overdosage and related side effects. Second, drug clearance by dialysis session must be taken into account for appropriate chemotherapy timing administration to avoid drug removal, which may result in a loss of efficacy. These two main considerations must not be considered as a contra-indication to chemotherapy in ESKD patients, but more as a need for an individualized prescription according to available recommendations.

Prevalence of renal abnormalities in chronic HBV infection: the HARPE study.

BACKGROUND & AIMS: Few data are available on the prevalence of renal abnormalities in chronic hepatitis B virus (HBV)-infected patients. The multicentric cross-sectional HARPE study evaluated the prevalence of kidney disease indicators, in chronic HBV surface antigen carriers patients (HBsAg+) with active or inactive infection. PATIENTS AND METHODS: Two hundred and sixty-eight HBsAg+ adult patients, naïve of any oral antihepatitis B virus treatment were prospectively included over 2 years. Data for renal assessment were collected once from patient files. Univariate tests and multiple linear regressions were performed with the SAS software, version 8.02 (SAS, Inc., Cary, NC, USA). RESULTS: Among the 260 patients analysed, 58% were men, the mean age was 42 ± 14 years, 59.6% were inactive carriers whereas 47 patients, mostly active, were about to start an antiviral therapy. Prevalence of proteinuria, haematuria, glycosuria, uninfectious leukocyturia was 38.1%, 20.6%, 3.9% and 9% respectively. According to the international definition, a total of 64.6% of patients were found to have kidney disease. Diabetes, hypertension and dyslipidaemia were observed, respectively, in 4.6%, 9.2% and 38.8% patients. There were no significant differences in these results within the three subgroups. CONCLUSION: Renal abnormalities are highly prevalent in our population and pre-exist before the initiation of any antihepatitis B virus treatment. This emphasizes the need for: (i) a baseline renal evaluation in all HBs antigen-positive patients; (ii) a regular renal monitoring before and during antihepatitis B virus treatment to diagnose and manage renal impairment and adjust antihepatitis B virus treatment doses to renal function when necessary.

New therapies for hepatitis C: considerations in patients with renal impairment.

Hepatitis C virus (HCV) is a major public health issue because infection may lead to liver failure, cirrhosis and hepatocellular carcinoma. In patients with renal dysfunction, hepatitis C can also worsen the underlying renal disease. Treating HCV infection is thus mandatory in this population. New therapies for hepatitis C have recently been developed, and some have been launched. Most of them are used in combination with the current standard of care, ribavirin and pegylated interferon alfa. Some of them can be used in regimens without ribavirin and/or pegylated interferon. However, few data are available on dosage adjustment for renal function in patients receiving these very new drugs. We reviewed the literature on this subject and gathered information, although scarce, to propose guidelines for using these drugs in patients with chronic kidney disease.

Renal insufficiency, mortality, and drug management in heart transplant. Results of the CARIN study.

Renal insufficiency (RI) is a frequent complication in heart transplant (HT) patients. The main objectives of the Cardiac trAnsplantation and Renal INsufficiency (CARIN) study were to follow the evolution of renal function after heart transplantation (HTx), to identify the factors associated with the decline of renal function, to describe the impact of RI on mortality during 3 years after the HT, and to observe the renal profile of the prescriptions. CARIN was a French retrospective, multicentric, study. Data were collected for patients who received a HT between 2000 and 2005. Data collection was performed at five time points: before HTx (T0), 1(T1), 6(T6), 12 (T12), and 36 (T36) months after HTx. Glomerular filtration rate (GFR) was estimated with aMDRD formula. RI was defined as GFR < 60 ml/min/1.73 m². Four hundred and forty-one patients from five HT centers were included. The prevalences of RI were 28.8% (T0), 54.0% (T1), 50.4% (T6), 51.6% (T12), and 59.6% (T36). Age and cyclosporine were independently linked to the decline of renal function. Hypertension and GFR < 60 at T0 were independent risk factors of mortality. 48.7-64.7% of the nonimmunosuppressive prescriptions were drugs that required dosage adjustment in RI patients or for which no data were available concerning administration in RI patients. RI is highly frequent after HTx. Because RI is a risk factor of mortality, any sparing renal strategies have to be undertaken.

Acute renal failure associated with the new BRAF inhibitor vemurafenib: a case series of 8 patients.

BACKGROUND: Vemurafenib is a BRAF inhibitor that has become the cornerstone of metastatic or inoperable melanoma therapy since its approval in 2011 in the United States and 2012 in Europe. This targeted therapy has shown impressive results in terms of increased progression-free and overall survival as compared to dacarbazine. The safety profile did not include any renal manifestations at that time. METHODS: This report is the first case series of 8 patients who experienced significant to severe renal insufficiency under vemurafenib treatment. RESULTS: This case series shows that vemurafenib may induce potentially severe acute renal failure, including renal sequelae and persistent kidney disease in some cases. CONCLUSIONS: Further studies are needed to investigate the effects of vemurafenib on the kidneys. Meanwhile, renal function should be closely monitored in treated patients for early detection of any renal dysfunction occurrence. Cancer 2014;120:2158-2163. © 2014 American Cancer Society.

Incidence of nephrogenic systemic fibrosis in patients undergoing dialysis after contrast-enhanced magnetic resonance imaging with gadolinium-based contrast agents: the Prospective Fibrose Nephrogénique Systémique study.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) has been related to the use of gadolinium-based contrast agents (GBCAs) in patients undergoing dialysis. The Prospective Fibrose Nephrogénique Systémique study, a French prospective study supported by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament) and the French Societies of Nephrology, Dermatology, and Radiology, aimed at determining the incidence of NSF in patients undergoing long-term dialysis. MATERIALS AND METHODS: Adult patients undergoing long-term dialysis receiving a magnetic resonance imaging (MRI) examination prescribed between January 15, 2009 and May 31, 2011, with or without GBCA were included. The methodology was based on a patient form intended to detect any dermatological event (DE) that may occur within 4 months after the examination. Further investigations were planned with their physicians if a DE was reported. RESULTS: A total of 571 patients were included. A total of 50.3% received GBCA. Among them, 93.4% received a macrocyclic GBCA, usually gadoteric acid (88.9%). All in all, 22 patients (3.9%) reported a DE. Dermatological diagnoses did not reveal any evidence of NSF. CONCLUSIONS: The incidence of NSF after a single dose of a macrocyclic GBCA is null in our sample of 268 patients undergoing dialysis (hemodialysis and peritoneal dialysis). This incidence is just lower than 0.5%. When contrast-enhanced MRI can be essential, or even decisive, to the diagnosis, these results are important and reassuring if physicians need to perform contrast-enhanced MRI in patients undergoing dialysis.

Administration of intravenous iron complexes on implantable central venous access port in cancer patients in France: the FERPAC survey.

PURPOSE: Implantable central venous access port (portacath) is used to provide long-term venous access and to deliver chemotherapy in cancer patients. Intravenous iron complexes are frequently prescribed in this setting, and some physicians use a portacath for their administration. The aim of this survey was to assess the frequency of this practice and the reasons supporting it. METHODS: This declarative survey was conducted in France; 497 oncologists/hematologists were contacted to answer a survey on their practices regarding the administration of intravenous iron via a portacath. RESULTS: A total of 141 recipients (29.5 %) completed the questionnaire. The intravenous iron complexes most frequently used were iron sucrose and ferric carboxymaltose, and 55.2 % of the responders reported using a portacath to administer intravenous iron complexes. The main reasons mentioned for this practice were ease of administration (27.9 %) and preservation of venous capital (27.6 %). The main reasons reported for not using a portacath to administer intravenous iron were a history of thrombosis (45.1 %) or potential drug interactions (17.7 %). Efficacy and safety were expected to be similar to those observed with peripheral administration. A 47.6 % of physicians declared that they usually did not observe adverse reactions after use of a portacath for iron administration. Intravenous iron administration was always planned after chemotherapy for 46.6 % of the responders and before chemotherapy for 38.2 %, whereas 15.3 % did not have any preference for either option. CONCLUSIONS: Intravenous iron complexes (mainly iron sucrose and ferric carboxymaltose) are commonly administered through a portacath in cancer patients in France. The choice for this route of administration is supported by clinical considerations, but further studies are needed to confirm the efficacy and safety of this practice.