Management del paziente dializzato Roberto Sabbatini Azienda Ospedaliero Universitaria Policlinico di Modena

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1 Management del paziente dializzato Roberto Sabbatini Azienda Ospedaliero Universitaria Policlinico di Modena AIOM incontra SIN Milano 9 marzo 2017

2 Renal Cell Carcinoma and Renal Impairment Up to 15% of patients with renal cell carcinoma (RCC) present moderate/severe impaired renal function 10% required dialysis at some time during symptom progression

3 Serum Creatinine and MAG3 renal scintigraphy data before and after nephrectomy Variable N. Pts Baseline Postoperative Overall 30 1 mo 1yr Serum creatinine (mg/dl) * * MAG3 clearance (ml/min/1.73 m 2 Percentage increase (%) *= p<.05 Shirasaki Y, Urology 2004

4 Comparison of renal function detriments after local tumor ablation or partial nephrectomy for RCC Local tumor ablation (LTA) and partial nephrectomy (PN) Larcher A, World J Urol 2015

5 Most common AEs induced by targeted anticancer agents Proteinuria Might occur owing to drug-related toxic effects or concomitant non-cancer-related causes VEGF and VEGFR-targeting agents are the most common (but not only) causes Acute Kidney Injury (AKI) AKI in cancer patients may worsen morbidity and mortality Multiple concomitant causes contribute to AKI pathogenesis AKI often occurs due to indirect effects of the anticancer treatment (for example, dehydration due to diarrhoea, malnutrition due to dysgeusia or stomatitis) Hypertension VEGF and VEGFR-targeting agents are the most common causes As an on-target toxic effect, it is considered a marker of treatment efficacy Short-term morbidity should be reduced to maintain effective dose of cancer treatment Fluctuations in hypertension due to intermittent schedules of anticancer agents might be troublesome Electrolyte disturbances Hyponatraemia, hypercalcaemia and other electrolyte disturbances might occur in patients receiving anticancer therapy Previously unrecognized AEs Severity can vary substantially Porta C., Nat Rev Nephrol 2015 Worsening of pre-existing CKD CKD (and dialysis) might be a risk factor for cancer CKD and cancer share common risk factors, and cancer can cause CKD, either directly or indirectly Nephrologists usually encounter CKD in cancer patients when they are asked to assess kidney function for dose adjustment of anticancer drugs; thorough knowledge of the pharmacokinetic properties and metabolism of targeted agents, including in the setting of dialysis, is mandatory Prevention of additional kidney damage from other causes (for example, contrast medium) is important Thrombotic microangiopathies Rare but potentially severe complication in cancer patients receiving anticancer drugs VEGF and VEGFR-targeting agents are the most frequent causes Clinical presentation is not uniform, but kidney alterations are predominant

6 Decreased GFR was not associated with inability to receive VEGF-targeted therapy and did not have an impact on ORR or OS Retrospective analysis on 529 pts with mrcc who received sunitinib (323 pts), sorafenib (165 pts), or bevacizumab (41 pts) was performed. Patient characteristics included: 74% male, median age 61 years, and median GFR 60.1 ml/min/1.73 m2 (range, ) Macfarlane R, Cancer 2011

7 Efficacy and toxicity of sunitinib in pts with mrcc with renal insufficiency mpfs: 12.2 mos (34 pts) (95% CI: ) mos: 26.3 (95% CI: ). clinicians should not hesitate to treat pts with mrcc with renal insufficiency with sunitinib Kim KH, EJC 2014

Impact of sunitinib pharmacokinetic monitoring in a pt with mrcc undergoing hemodialysis Phase I study has shown that potentially active target plasma concentrations need to be 50 ng/ml.

8 Impact of sunitinib pharmacokinetic monitoring in a pt with mrcc undergoing hemodialysis Phase I study has shown that potentially active target plasma concentrations need to be 50 ng/ml. Most patients with dose-limiting toxicity had combined (sunitinib plus SU012662) trough plasma concentrations 100 ng/ml. Two patients sunitinib concentration was monitored by one initial evaluation of sunitinib AUC and then by regular evaluations of its Cmin. With modified schedule, we achieved optimal trough plasma concentrations. Thiery-Vuillemin A, Ann Oncol 2011

9 Authors n. patient TKi Dose reduction Response (after 3 mos) Toxicity (G3 4) Rey PM, Sunitinib Sorafenib No yes SD SD 0 0 Ruppin S, Sorafenib no PR 0 Zastrow S, Sunitinib yes no CR SD Amylase/lipase; 0 Ferraris E, Sorafenib No yes PR SD No Fatigue, dyspnea Hilger RA, Sorafenib Yes NR NR Vickers MM, Sunitinib yes PR Hypothyroidism, fatigue 1 no SD Park CY, Sunitinib No CR 0 Reckova M, Sunitinib yes PR Thrombocytopenia, HTN, EF Izzedine H, Sunitinib no no SD NR 0 0 Castagneto B, Sorafenib Yes PR 0 Shinsako K, Sorafenib No SD 0 Sang Hyun Yoo, Sunitinib Yes PR 0 Park, Sunitinib Yes SD Mucositis, anorexia, fatigue Josephs D, Sunitinib Yes PR Fatigue, stomatitis, HFS, diarrhea Kennoki T, Sorafenib Yes CR, PR, SD subarachnoid hemorrhag, cerebellar hemorrhage Casper, Sunitinib Yes CR, PR, SD Asthenia, nausea, vomiting, diarrhoea, thrombocytopenia, hypertension, hypotension, left systolic ventricular dysfunction Ibrahim Y, Sunitinib No PD Acute pulmonary edema, hypertension Shetty AV, Pazopanib Sunitinib Sorafenib Yes PR, SD Fatigue, HFS, increase LTF

10 Use of TKis in pts with mrcc receiving haemodialysis: a retrospective Italian survey Masini C, BJUI 2012

11 Sequential molecularly targeted drug therapy including axitinib for a pt with end-stage renal failure and mrcc...axitinib is highly bound (> 99%) to human plasma proteins, which indicates the difficulty for filtration of axitinib during hemodialysis sessions. For the reasons mentioned earlier, it can be difficult to determine an appropriate axitinib dose in hemodialysis patients Nishida H, Hemodialysis Int 2016

12 Renal toxicities of mtor inhibitors and management indications Drug Pts with renal function impairment included in pivotal trial Renal excretion Most frequente renal AEs Everolimus No 2% Proteinuria, AKI, electrolyte disorders Temsirolimus No 4.6% Proteinuria, AKI, electrolyte disorders Pts with mild to moderate CKD No No Dose reduction required Pts with severe CKD No (no data); suspend if AKI No (no data); suspend if AKI Pts receiving dialysis No No Acute Kidney Injury...Few reports are available on the use of mtor inhibitors in patients receiving dialysis. Everolimus and temsirolimus, however, are not dialysed by commonly used membranes and do not appear in the dialysate, thus the concentration in plasma is not affected. Unnecessary dose adjustments should, therefore, be avoided Porta C., Nat Rev Nephrol 2015

13 Temsirolimus in mrcc patients on dialysis After single-dose administration of temsirolimus 25 mg as a 30-minute intravenous infusion, neither temsirolimus nor sirolimus concentrations were significantly affected by hemodialysis in these patients with RCC compared with those not receiving dialysis Lunardi G., Clin Ther. 2009

14 Hemodialysis does not affect everolimus pharmacokinetics: two cases of patients with mrcc HD did not modify the blood everolimus concentrations as they were close to the predialysis level No everolimus was detected in the dialysate, confirming its lack of adhesion to the dialysis membrane.the toxic effects observed (Asthenia G2-3, diarrhea G2, hyperglycemia G3, mucitis G2-3, pneumonitis G2) do not seem to be linked to an overdose of everolimus A. Thiery-Vuillemin, Ann Oncol 2012

15 Everolimus in mrcc patients on dialysis Authors Thiery-Vuillemin et al, Ann of Oncology 2012 J Syrios et al., BMC Nephrology 2013 Number of pts Primary tumor Dose reduction Toxicity G3/4 2 kidney Yes Asthenia, hyperglycemia, Mucitis 2 kidney No none Shetty AV et al., Clinical genitourinary cancer kidney Yes Cardiovascular, pneumonitis

16 Retrospective analysis on safety and efficacy of everolimus in treatment of mrcc pts receiving dialysis Kaplan-Meir estimate of progression-free survival Kaplan-Meir estimate of overall survival Guida A, Future Medicine 2015

17 Retrospective analysis on safety and efficacy of everolimus in treatment of mrcc pts receiving dialysis Guida A, Future Medicine 2015

18 Comparison of prognosis between patients with RCC on hemodialysis and those with RCC in the general population Comparison of CSS time between RCC-HD and those in the general population Comparison of CSS)time between RCC-HD and those in the general population as stratified by stage Predictors of cancer specific survival Hashimoto Y, Int J clin Oncol 2015

efficacy of nivolumab in this setting and

20 Response to Nivolumab in a Patient With Metastatic ccrcc and End-stage Renal Disease on Dialysis...Our case demonstrates the safety and efficacy of nivolumab in this setting and exemplifies the pseudoprogression sometimes observed with checkpoint blockade Carlo MI, Eur Urol 2016

21 Conclusions Renal impairment is frequently in metastatic renal cancer patients The use of targetes therapies seem not contraindicated in pts with mrcc and severe renal impairment or on dialysis The need to reduced dose of TKis or mtori was dictated by the little experience of the clinician to avoid severe toxicity Case reports demonstrate the safety and efficacy of checkpoint inhibitors in dialysis patients Toxicity observed was mild/moderate

22 .. Grazie per la Vostra Attenzione

23 Safety and efficacy of molecularly targeted agents in pts with mrcc with renal dysfunction Gupta A, AntiCancer Drugs 2011

Safety and efficacy of molecularly targeted agents in pts with mrcc with renal dysfunction In this retrospective study patients receiving any of the targeted agents seem to have comparable response

24 Safety and efficacy of molecularly targeted agents in pts with mrcc with renal dysfunction In this retrospective study patients receiving any of the targeted agents seem to have comparable response rates, but favorable TTP and OS, than patients with normal renal function It is unclear if this difference is related to longer plasma exposure of the drugs or its metabolites in renal impairment patients Gupta A, AntiCancer Drugs 2011

David N. Robinson, MD

David N. Robinson, MD Background and Treatment of mrcc Background ~ 64,770 new cases of kidney/renal pelvis cancers will be diagnosed in the US in 2012 with an estimated 13,570 deaths [1] ~ 75% are clear-cell