Introduction Cisplatin, a platinum-based antineoplastic agent, is the cornerstone for the treatment of many malignancies. Nephrotoxicity is the primary dose-limiting toxicity, and various hydration regimens and supplementation strategies are used to prevent cisplatin-induced kidney injury. However, evidence-based recommendations on specific hydration regimens are limited. A systematic review was performed to evaluate clinical studies that have examined hydration and supplementation strategies to prevent cisplatin-induced nephrotoxicity. Materials and methods PubMed and Excerpta Medica databases were searched from 1966 through October 2015 for clinical trials and other studies focused on hydration regimens to prevent nephrotoxicity in cancer patients treated with cisplatin. The University of Oxford Centre for Evidence-Based Medicine criteria were used to grade level of evidence. Results Among the 1,407 identified studies, 24 were included in this systematic review. All studies differed on type, volume, and duration of hydration. Among the 24 studies, 5 evaluated short-duration hydration, 4 evaluated low-volume hydration, 4 investigated magnesium supplementation, and 7 reviewed forced diuresis with hydration. Short-duration and lower-volume hydration regimens are effective in preventing cisplatin-induced nephrotoxicity. Magnesium supplementation may have a role as a nephroprotectant, and forced diuresis may be appropriate in some patients receiving cisplatin. Conclusion Hydration is essential for all patients to prevent cisplatin-induced nephrotoxicity. Specifically, short-duration, low-volume, outpatient hydration with magnesium supplementation and mannitol forced diuresis (in select patients) represent best practice principles for the safe use of cisplatin. The Oncologist 2017;22:609-619 IMPLICATIONS FOR PRACTICE: The findings contained within this systematic review show that (a) hydration is essential for all patients to prevent cisplatin-induced nephrotoxicity, (b) short-duration, low-volume, outpatient hydration regimens appear to be safe and feasible, even in patients receiving intermediate- to high-dose cisplatin, (c) magnesium supplementation (8-16 milliequivalents) may limit cisplatin-induced nephrotoxicity, and (d) mannitol may be considered for high-dose cisplatin and/or patients with preexisting hypertension. These findings have broad implications for clinical practice and represent best practice principles for the prevention of cisplatin-induced nephrotoxicity.

A Systematic Review of Strategies to Prevent Cisplatin‐Induced Nephrotoxicity

Advances in cancer drug therapy have led to improvements in the outcomes of cancer patients, as well as increasing numbers of patients undergoing anticancer chemotherapy and molecularly targeted drug therapy. One adverse event associated with cancer drug therapy is nephrotoxicity, which impedes effective cancer therapy and diminishes the quality of life of cancer patients. Consequently, onco-nephrology has emerged as a new clinical field concerned with the management of nephrotoxicity in cancer drug therapy, creating expectations for advanced expertise and the accumulation of accurate evidence. However, while patients with renal impairment have heretofore undergone planning regarding administration of cancer drug therapy, procedures for nephropathy prevention, and measures for treatment of drug-induced nephrotoxicity in clinical settings based on tradition, experimental rules, and information from clinical trials, the soundness of the evidence for these practices has been uncertain.

Over the past 10 years, estimated glomerular filtration rate (eGFR) has replaced creatinine clearance in the assessment of renal function; in addition, research has revealed the pathologies of and risk factors for chronic kidney disease (CKD) and acute kidney injury (AKI). The objectives of the guidelines presented here are to support improvements in the results of cancer drug therapy and the quality of life of cancer patients through application of these advances in clinical nephrology and the practice of evidence-based treatment.

For these guidelines, we have assembled a group of Japanese experts on cancer drug therapy and nephrology to select highly important clinical questions that are frequently encountered in everyday practice. These guidelines ultimately comprise 16 clinical questions in two chapters regarding assessment of renal function and prevention of nephropathy during cancer drug therapy, thereby determining the level of evidence to support clinical assessments and elucidating the nature of current standard treatments. However, in drafting these guidelines, we discovered a number of clinical issues (evidence gaps) regarding cancer drug therapy and renal impairment. For example, 1) there is very little clinical research on cancer drug therapy and nephropathy to begin with; 2) many clinical trials continue to use creatinine clearance to assess renal function; 3) in assessments of renal function in large populations, there is a vast discrepancy between eGFR and measured values of GFR; and 4) it remains unknown whether body surface area corrections of drug doses are appropriate for elderly patients (who have reduced muscle mass) or obese patients. These and other evidence gaps must be resolved for the sake of future research.

These guidelines were drafted with reference to the “Minds Treatment Guideline Creation Companion 2014” using the Minds Guideline Creation support tool “GUIDE”. We would like to express our profound gratitude to Doctors Tsuguya Fukui and Takeo Nakayama of Minds for their roles as advisors in the creation of our guidelines.

We would also like to take this opportunity to express our appreciation to the many young physicians of the systematic review team for their contributions in drafting structured abstracts.

The primary significance of treatment guidelines is their application in daily clinical practice. We would appreciate any criticisms or ideas that would be useful in future revisions of these guidelines.

Shigeo Horie, M.D.

Professor and Chairman,

Department of Urology

Juntendo University, Graduate School of Medicine

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Guidelines for treatment of renal injury during cancer chemotherapy 2016

Background: Cisplatin is still used as a first-line medication for solid tumors. Nephrotoxicity is a serious side effect that can decrease renal function and restrict applicable doses. This research aimed to obtain the profile of cisplatin-induced nephrotoxicity and its associated factors in adult cancer patients at Dharmais National Cancer Hospital (DNCH). Materials and Methods: The design was cross-sectional with data obtained from patient medical records. We retrospectively reviewed adult cancer patients treated with cisplatin ≥60mg/m 2 for at least four consecutive chemotherapy cycles from August 2011 to November 2013. The nephrotoxicity criterion was renal function decline characterized by creatinine clearance <60 ml/min using the Cockroft-Gault (CG) equation. Results: Eighty-eight subjects received at least four chemotherapy cycles of cisplatin. The prevalence of cisplatin nephrotoxicity was 34.1%. Symptoms could be observed after the first cycle of chemotherapy, and the degree of renal impairment was higher with increased numbers of cycles (r=-0.946, r 2 =89.5%). Factors that affected the decline of renal function were patient age (p=0.008, OR=3.433, 95%CI= 1.363-8.645) and hypertension (p=0.026, OR=2.931, 95%CI=1.120-7.670). Conclusions: Cisplatin nephrotoxicity occurred in more than one-third of patients after the fourth cycle of chemotherapy and worsened after each cycle despite preventive strategies such as hydration. The decline of renal function induced by cisplatin ≥60 mg/m 2 was affected by age and hypertension.

http://koreascience.or.kr:80/article/JAKO201510534323775.pdf

Incidence of cisplatin-induced nephrotoxicity and associated factors among cancer patients in Indonesia.

Importance Few multicenter pediatric studies have comprehensively described the epidemiologic characteristics of cisplatin-associated acute kidney injury using standardized definitions. Objective To examine the rate of and risk factors associated with acute kidney injury among children receiving cisplatin infusions. Design, Setting, and Participants This prospective cohort study examined children (aged Exposures Cisplatin infusions. Main Outcomes and Measures The primary outcome was acute kidney injury during cisplatin infusion, defined using a Kidney Disease: Improving Global Outcomes serum creatinine criteria–based definition (stage 1 or higher). The secondary outcome was acute kidney injury defined by electrolyte criteria from the National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1 or higher). Assessments occurred at early (first or second cycle) and late (last or second to last cycle) cisplatin infusions. Results A total of 159 children (mean [SD] age at early cisplatin infusion, 7.2 [5.3] years; 80 [50%] male) participated. The most common diagnoses were central nervous system tumors (58 [36%]), neuroblastoma (43 [27%]), and osteosarcoma (33 [21%]). Acute kidney injury (by serum creatinine level increase) occurred in 48 of 159 patients (30%) at early cisplatin infusions and 23 of 143 patients (16%) at late cisplatin infusions. Acute kidney injury (by electrolyte abnormalities) occurred in 106 of 159 patients (67%) at early cisplatin infusion and 100 of 143 patients (70%) at late cisplatin infusions. Neuroblastoma diagnosis and higher precisplatin GFR were independently associated with acute kidney injury (serum creatinine level increase) at early cisplatin infusions (adjusted odds ratio [aOR] for neuroblastoma vs other, 3.25; 95% CI, 1.18-8.95; aOR for GFR, 1.01; 95% CI, 1.00-1.03) and late cisplatin infusions (aOR for neuroblastoma vs other, 6.85; 95% CI, 1.23-38.0; aOR for GFR, 1.01; 95% CI, 1.00-1.03). Higher cisplatin infusion dose was also independently associated with acute kidney injury (serum creatinine level increase) at later cisplatin infusions (aOR, 1.05; 95% CI, 1.01-1.10). Conclusions and Relevance The findings suggest that acute kidney injury is common among children receiving cisplatin infusions and that rate and risk factors differ at earlier vs later infusions. These results may help with risk stratification with a goal of risk reduction.

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Epidemiologic Characteristics of Acute Kidney Injury During Cisplatin Infusions in Children Treated for Cancer.

Objectives The most serious adverse reaction of cisplatin is acute kidney injury (AKI). Cisplatin-induced acute kidney injury (CIA) has no specific preventive measures. This study aims to explore the characteristics and risk factors for CIA in the elderly and to identify potential methods to reduce CIA. Materials and methods Patients ≥18 years old, with primary tumors, who received initial cisplatin chemotherapy and whose serum creatinine (SCr) values were measured within 2 weeks pre- and postcisplatin treatment and who had complete medical records, were selected from a single center from January 1, 2013 to December 31, 2015. The exclusion criteria included radiotherapy or surgery, recurrent tumors, previous cisplatin treatment, lack of any SCr values before or after cisplatin therapy, and incomplete medical records. Results Out of a total of 527 patients, 349 were elderly. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) use (9.2%) was more prevalent in the elderly than in younger patients (2.8%, p = 0.007). The dosage of cisplatin treatment was lower in the elderly, but the incidence of CIA (9.46%) was higher in the elderly than in younger patients (3.37%). There were significant differences in the SCr levels, estimated glomerular filtration rate, ACEI/ARB use, and whether a single application of cisplatin was administered, between the elderly AKI group and the non-AKI group. Multivariable analysis showed that administration of a single application of cisplatin (OR 2.853, 95% CI: 1.229, 6.621, p = 0.015) and ACEI/ARB use (OR 3.398, 95% CI: 1.352, 8.545, p = 0.009) were predictive factors for developing CIA in the elderly. Conclusion The incidence of CIA in the elderly was higher than in younger patients. ACEI/ ARB usage and administration of a single application of cisplatin were independent risk factors for CIA in the elderly.

/pdf/the-characteristics-and-risk-factors-for-cisplatin-induced-gc19ow86rf.pdf

The characteristics and risk factors for cisplatin-induced acute kidney injury in the elderly

Background Cisplatin is a pivotal drug in combined chemotherapy for non-small cell and small-cell lung cancers (NSCLC or SCLC), but its renal toxicity limits its use. Current guidelines recommend 24 h hydration: thus hospitalization is required. The aim of this retrospective study was to confirm the safety of short hydration before giving an intermediate-to-high dose of cisplatin in an outpatient clinic. Patients and methods Patients eligible had NSCLC or SCLC and were being treated with a chemotherapy regimen that included cisplatin ≥ 75 mg/m 2 . They were given the same short hydration protocol for 1 day. Nephrotoxicity was defined as ≥ grade 1 according to NCIC common toxicity criteria. Predictive factors for nephrotoxicity were analyzed. Results Three hundred and fifty-seven consecutive patients (median age 58 years, range: 25-81) were reviewed. Twenty-one patients (6%) had ≥ grade 1 nephrotoxicity and all except one had grade 1 toxicity according to NCIC criteria for common toxicity (SC  P  = 0.002), initial serum creatinine ≥ 100 μmol/L (OR = 8.3 CI 95% [2.55-27.4] P  = 0.0005), and dose cycle of cisplatin ≥ 100 mg/m 2 (OR = 10.8 CI 95% [3.6-32.5] P Conclusion Rapid outpatient administration of a single dose of cisplatin at ≥ 75 mg/m 2 is feasible without a high risk of nephrotoxicity.

Lise Rosencher

Papers

Routine administration of a single dose of cisplatin ≥ 75 mg/m2 after short hydration in an outpatient lung-cancer clinic.