Management del paziente dializzato

(1)

AIOM incontra SIN Milano 9 marzo 2017

Roberto Sabbatini

Azienda Ospedaliero Universitaria Policlinico di Modena

Management del paziente

dializzato

(2)

• 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

Renal Cell Carcinoma and

Renal Impairment

(3)

Serum Creatinine and MAG3 renal scintigraphy data before and after

nephrectomy

Variable N.

Pts

Baseline Postoperative

1 mo 1yr

Overall 30

Serum creatinine (mg/dl) 0.82±0.05 1.16±0.07* 1.09±0.06*

MAG3 clearance (ml/min/1.73 m

²

155.4±7.6 209.2±10.3 211.3±9.9

Percentage increase (%) - 39.5±7.5 40.5±6.6

*= p<.05

Shirasaki Y, Urology 2004

(4)

Local tumor ablation (LTA) and partial nephrectomy (PN)

Comparison of renal function detriments after local tumor ablation or partial nephrectomy for RCC

Larcher A, World J Urol 2015

(5)

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

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

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)

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

Most common AEs induced by targeted anticancer agents

Porta C., Nat Rev Nephrol 2015

(6)

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, 6.5-174.2)

Decreased GFR was not associated with inability to receive VEGF-targeted therapy and did not

have an impact on ORR or OS

Macfarlane R, Cancer 2011

(7)

…………. clinicians should not hesitate to treat pts with mRCC with renal insufficiency with sunitinib

Kim KH, EJC 2014

Efficacy and toxicity of sunitinib in pts with mRCC with renal insufficiency

mPFS: 12.2 mos (34 pts) (95% CI: 10.2-14.2)

mOS: 26.3

(95% CI: 17.1-35.3)

(8)

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

Impact of sunitinib pharmacokinetic monitoring in

a pt with mRCC undergoing hemodialysis

(9)

Authors

n.

patient TKi

Dose reduction Response

(after 3 mos) Toxicity (G3‐4)

Rey PM, 2008 1

1

Sunitinib Sorafenib

No yes

SD SD

0 0

Ruppin S, 2008 1 Sorafenib no PR 0

Zastrow S, 2009 1

1

Sunitinib

“

yes no

CR SD

Amylase/lipase;

0

Ferraris E, 2009 1

1

Sorafenib

“

No yes

PR SD

No

Fatigue, dyspnea

Hilger RA, 2009 2 Sorafenib Yes NR NR

Vickers MM, 2009 1

1

Sunitinib

“

yes no

PR SD

Hypothyroidism, fatigue

Park CY, 2009 1 Sunitinib No CR 0

Reckova M, 2009 1 Sunitinib yes PR Thrombocytopenia, HTN, EF

Izzedine H, 2009 1

1

Sunitinib no

no

SD NR

0 0

Castagneto B, 2010 1 Sorafenib Yes PR 0

Shinsako K, 2010 1 Sorafenib No SD 0

Sang Hyun Yoo, 2010 2 Sunitinib Yes PR 0

Park, 2010 6 Sunitinib Yes SD Mucositis, anorexia, fatigue

Josephs D, 2011 10 Sunitinib Yes PR Fatigue, stomatitis, HFS, diarrhea

Kennoki T, 2011 10 Sorafenib Yes CR, PR, SD subarachnoid hemorrhag, cerebellar

hemorrhage

Casper, 2011 21 Sunitinib Yes CR, PR, SD Asthenia, nausea, vomiting, diarrhoea,

thrombocytopenia, hypertension, hypotension, left systolic ventricular

dysfunction

Ibrahim Y, 2014 2 Sunitinib No PD Acute pulmonary edema, hypertension

Shetty AV, 2014 24 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)

“…...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”

Sequential molecularly targeted drug therapy

including axitinib for a pt with end-stage renal failure and mRCC

Nishida H, Hemodialysis Int 2016

(12)

“…...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”

Drug

Pts with renal function impairment

included in pivotal trial

Renal excretion

Most frequente

renal AEs Dose reduction required

Pts with mild to moderate CKD

Pts with severe CKD

Pts receiving

dialysis

Everolimus No 2% Proteinuria,

AKI, electrolyte disorders

No No (no

data);

suspend if AKI

No

Temsirolimus No 4.6% Proteinuria,

AKI, electrolyte disorders

No No (no

data);

suspend if AKI

No

Renal toxicities of mTOR inhibitors and management indications

Porta C., Nat Rev Nephrol 2015

Acute Kidney Injury

(13)

Temsirolimus in mRCC patients on dialysis

Lunardi G., Clin Ther. 2009

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

(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 Number of pts

Primary tumor

Dose reduction

Toxicity G3/4

Thiery-Vuillemin et al,

Ann of Oncology 2012 2 kidney Yes ^Asthenia,

hyperglycemia, Mucitis

J Syrios et al., BMC

Nephrology 2013 2 kidney No ^none

Shetty AV et al.,

Clinical genitourinary cancer 2014

7 kidney Yes Cardiovascular,

pneumonitis

(16)

Kaplan-Meir estimate of overall survival Kaplan-Meir estimate of progression-free survival

Retrospective analysis on safety and efficacy of

everolimus in treatment of mRCC pts receiving dialysis

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)

Predictors of cancer specific survival Comparison of CSS time between RCC-HD and those in the general

population

Comparison of prognosis between patients with RCC on hemodialysis and those with RCC in the

general population

Hashimoto Y, Int J clin Oncol 2015

Comparison of CSS)time between RCC-HD and those in the general population as stratified by stage

(19)

(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

roberto.sabbatini@unimore.it

(23)

Safety and efficacy of molecularly targeted agents in pts with mRCC with renal dysfunction

Gupta A, AntiCancer Drugs 2011

(24)

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