[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.

Impact of acute kidney injury on anticancer treatment dosage and long-term outcomes: a pooled analysis of European Organisation for Research and Treatment of Cancer trials.

BACKGROUND: The impact of kidney dysfunction on long-term outcomes of patients with advanced cancer remains unclear. METHODS: Patients with advanced cancer included in trials conducted by the European Organisation for Research and Treatment of Cancer were eligible for this retrospective analysis. Acute kidney injury (AKI) was identified using serum creatinine levels and using adverse events reported by investigators. The impact of baseline estimated glomerular filtration rates (eGFRs) on progression-free survival (PFS) and overall survival (OS) was investigated. Pooled estimates of the impact of AKI on dose intensity, treatment duration, PFS and OS were obtained following a meta-analytic process. RESULTS: Nine trials were included in this study, totalling 2872 metastatic patients with various tumour types and various systemic treatment types. Baseline eGFR had homogeneously no impact on PFS or OS. Most Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) events occurred early during the course of the treatment. AKI was not associated with an increased rate of treatment discontinuation, while it decreased the study treatment dose intensity. Occurrence of a first RIFLE event significantly and homogeneously reduced PFS (pooled hazard ratio = 1.18, 95% confidence interval 1.07-1.30; P = 0.0012), while its impact on OS was more heterogeneous across trials. CONCLUSION: AKI is associated with reduced treatment dose intensity and reduced PFS. Therefore, close monitoring of the kidney function during the first months of treatment should be included in clinical trial protocols and probably also in daily practice to enable early AKI diagnosis and management. Collaboration between oncologists and nephrologists is needed to reduce the risk of undertreatment of patients experiencing AKI.

[Clarification of the method used for drug dosage adjustment in patients with renal failure: The CLEAR study]. / Clarification de la méthode utilisée pour adapter la posologie des médicaments chez les patients insuffisants rénaux : étude CLEAR.

INTRODUCTION: The French National Authority for health recommends that the adjustment of the dosage of drugs in patients with renal insufficiency be carried out on the basis of an estimate of renal function using the Cockcroft-Gault formula, while the estimation of the glomerular filtration rate using the Modification of Diet in Renal Disease or CKD-EPI formula is recommended for the diagnosis and monitoring of renal insufficiency. The argument put forward is that the recommendations for dosage adjustment of the summaries of product characteristics would have been established on the basis of the use of this formula. Service ICAR aimed at verifying the evidence supporting this argument. METHODS: In all, 2447 summaries of product characteristics were analyzed to identify the renal function criterion specified for dose adjustment recommendations. When no formulas were found in the summary of product characteristics, the firms were contacted to obtain information on renal function estimation methods used in developmental studies. Their responses were analyzed. RESULTS: Of the 2447 summaries of product characteristics studied, 438 (17.9%) propose a dosage adjustment in case of renal insufficiency. No formula is mentioned in the summarie of product characteristics for 90.0% of them. The Cockcroft-Gault and Modification of Diet in Renal Disease/CKD-EPI formulas are found in 8.7% and 0.7% respectively of these 438 summaries of product characteristics. After contacting pharmaceutical companies and analysis of the data available in the studies on which the summaries of product characteristics were based, the information cannot be found for 63.0% of the summaries of product characteristics, in spite they mention the need to adjust the dosage in case of renal insufficiency. CONCLUSION: The majority of summaries of product characteristics do not mention the Cockcroft-Gault formula and in the majority of cases it is not possible to identify the formula or technique used in the studies on which is based the reference to dosage adjustment in the summarie of product characteristics. In addition, there are discrepancies between the wording of the summaries of product characteristics and the data from development studies. The use of Cockcroft-Gault for dosage adjustment is to be questioned, especially since the Isotope-dilution mass spectrometry, or IDMS, standardization of creatinine dosage makes obsolete studies based on Cockcroft-Gault formula and a non-standardized dosage, and thus the use of Cockcroft-Gault not transposable to current clinical practice.

[Antineoplastic drug induced nausea and vomiting: What is the clinical practice in 2018? An update of AFSOS clinical guidelines]. / Nausées-vomissements induits par les traitements anti-cancéreux (NVITAC) : quelle prise en charge en 2018 ? Mise à jour du référentiel AFSOS.

Antineoplastic drug induced nausea and vomiting (ANDINV) (previously named: Chemotherapy-induced nausea and vomiting [CINV]) are one of the most feared adverse effect for patients who begin treatment with anti-cancer treatments and their bad control have a negative impact in the management of these patients. In this review article, it is proposed an update of French-speaking Association for oncologic supportive care (AFSOS) clinical practice of CINV guidelines. This update became necessary for several reasons: newly available anti-emetic drugs; new data published about individual risk factors of CINV; new antineoplastic agents available; changing in emetic risk levels for some molecules in the international guidelines. To address these guidelines, the various clinical presentations of ANDINV and their intensity classification are discussed. Then, the different therapeutic solutions are presented: classes of conventional drug therapies, complementary therapies and advice to patients. Then, the implementation of primary prophylaxis are presented in four steps: (1) to evaluate the emetic risk level of antineoplastic agent; (2) to set the emetic risk level of antineoplastic protocols; (3) to set types of antiemetic drugs to implement; (4) "Outperform" prophylaxis in case of individual risk factors. Finally, implementation of secondary prophylaxis and rescue treatments are adressed.

Treating Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck Unsuitable to Receive Cisplatin-Based Therapy.

Concurrent chemoradiotherapy with high-dose cisplatin (100 mg/m2 every 3 weeks) is the preferred regimen with curative intent for patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). This treatment is associated with acute and late toxicities, including myelosuppression, severe nausea/vomiting, irreversible renal failure, hearing loss, and neurotoxicity. Because of cisplatin's safety profile, treatment adherence to high-dose cisplatin can be suboptimal. Patients commonly receive less than the total cumulative target dose of 300 mg/m2 or the minimum recommended dose of 200 mg/m2, which can have a negative impact on locoregional control and survival. Alternatively, cetuximab plus radiotherapy may be most suitable for patients at high risk of non-adherence to high-dose cisplatin. We discuss the baseline characteristics dictating the unsuitability/borderline unsuitability of cisplatin and the available alternative evidence-based treatment regimens for patients with LA SCCHN. We non-systematically reviewed published phase II and III trials and retrospective analyses of high-dose cisplatin-based chemoradiation in LA SCCHN conducted between 1987 and 2018, focusing on recent key phase III studies. We defined the baseline characteristics and associated prescreening tests to determine unsuitability and borderline unsuitability for high-dose cisplatin in combination with radiotherapy in patients with LA SCCHN. Patients with any pre-existing comorbidities that may be exacerbated by high-dose cisplatin treatment can be redirected to a non-cisplatin-based option to minimize the risk of treatment non-adherence. High-dose cisplatin plus radiotherapy remains the preferred treatment for fit patients with unresected LA SCCHN; patients who are unsuitable or borderline unsuitable for high-dose cisplatin could be identified using available tests for potential comorbidities and should be offered alternative treatments, such as cetuximab plus radiotherapy.

[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.

A quick scoping review of efficacy, safety, economic, and health-related quality-of-life outcomes of short- and long-acting erythropoiesis-stimulating agents in the treatment of chemotherapy-induced anemia and chronic kidney disease anemia.

Erythropoiesis-stimulating agents (ESAs) are man-made forms of erythropoietin used in the treatment of anemia. This quick-scoping review of systematic literature reviews (SLRs) was conducted to define the clinical, economic, and health-related quality of life (HRQoL) outcomes for short-acting and long-acting ESAs in patients with chronic kidney disease-induced anemia (CKD-IA) and patients with chemotherapy-induced anemia (CIA). Embase, Medline, and the Cochrane Database of Systematic Reviews were searched from their establishment until October 2017. SLRs related to the use of short-acting and long-acting ESAs in the treatment of CIA and CKD-IA were included. Forty-eight studies met the inclusion criteria. The evidence suggests little difference in efficacy, HRQoL, and safety outcomes among ESA types. Cost-effectiveness and market price are likely to become determining factors driving the choice of agent. Comparative studies and costing models accounting for the utilization of biosimilars are needed to establish which ESAs are more cost-effective.

Opening an onconephrology clinic: recommendations and basic requirements.

Onconephrology is a rapidly evolving subspeciality that covers all areas of renal involvement in cancer patients. The complexity of the field may benefit from well-defined multidisciplinary management administered by a dedicated team. Since there is an increasing need to address the needs of this population in dedicated outpatient clinics, it is critical to highlight basic characteristics and to suggest areas of development. In this brief perspective article, we analyse the requirements of an onconephrology clinic in terms of logistics, critical mass of patients and building a multidisciplinary team. We will further discuss which patients to refer and which conditions to treat. The last part of the article is dedicated to education and performance indicators and to analysis of the potential advantages of applying the hub-and-spoke model to this field. The ultimate aim of this experience-based article is to initiate debate about what an onconephrology outpatient clinic might look like in order to ensure the highest quality of care for this growing population of patients.

Risk factors associated with post-kidney transplant malignancies: an article from the Cancer-Kidney International Network.

In kidney transplant recipients, cancer is one of the leading causes of death with a functioning graft beyond the first year of kidney transplantation, and malignancies account for 8-10% of all deaths in the USA (2.6 deaths/1000 patient-years) and exceed 30% of deaths in Australia (5/1000 patient-years) in kidney transplant recipients. Patient-, transplant- and medication-related factors contribute to the increased cancer risk following kidney transplantation. While it is well established that the overall immunosuppressive dose is associated with an increased risk for cancer following transplantation, the contributive effect of different immunosuppressive agents is not well established. In this review we will discuss the different risk factors for malignancies after kidney transplantation.

Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology.

Therapy for metastatic renal cell carcinoma should be tailored to the circumstances and preferences of the individual patient. Age should not be a barrier to effective treatment. Systematic geriatric screening and assessment contributes to the goal of personalised management, in addition to the involvement of a multidisciplinary team. A task force from the International Society of Geriatric Oncology (SIOG) updated its 2009 consensus statement on the management of elderly patients with metastatic renal cell carcinoma by reviewing data from studies involving recently approved targeted drugs and immunotherapies for this disease. Overall, it seems that age alone does not appreciably affect efficacy. Among the pivotal studies that were included, there is a striking scarcity of analyses that relate toxic effects to patient age. Even if the adverse effects of therapy are no more frequent or severe in elderly patients than in their younger counterparts, the practical, psychological, and functional impact of treatment may be greater, especially if toxic effects are chronic and cumulative.

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.

Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review.

BACKGROUND: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patient's own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers. SUMMARY: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system database were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hyponatremia were toxicities caused by ipilimumab. The main adverse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3-10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2-3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9-29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of immune checkpoint inhibitors is extremely important.

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.

Renal effects of BRAF inhibitors: a systematic review by the Cancer and the Kidney International Network.

Advanced melanoma has been traditionally unresponsive to standard chemotherapy agents and used to have a dismal prognosis. Genetically targeted small-molecule inhibitors of the oncogenic BRAF V600 mutation or a downstream signaling partner (MEK mitogen-activated protein kinase) are effective treatment options for the 40-50% of melanomas that harbor mutations in BRAF. Selective BRAF and MEK inhibitors induce frequent and dramatic objective responses and markedly improve survival compared with cytotoxic chemotherapy. In the past decade after discovery of this mutation, drugs such as vemurafenib and dabrafenib have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of V600-mutated melanomas. While the initial trials did not signal any renal toxicities with the BRAF inhibitors, recent case reports, case series and FDA adverse reporting systems have uncovered significant nephrotoxicities with these agents. In this article, we systematically review the nephrotoxicities of these agents. Based on recently published data, it appears that there are lower rates of kidney disease and cutaneous lesions seen with dabrafenib compared with vemurafenib. The pathology reported in the few kidney biopsies done so far are suggestive of tubulo interstitial damage with an acute and chronic component. Electrolyte disorders such as hypokalemia, hyponatremia and hypophosphatemia have been reported as well. Routine monitoring of serum creatinine and electrolytes and calculation of glomerular filtration rate prior to the first administration when treating with dabrafenib and vemurafenib are essential.

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.