La iponatremia in oncologia

NICOLETTA ZILEMBO

Fondazione IRCCS“Istituto Nazionale dei Tumori”

9 marzo 2017 ISTITUTO NAZIONALEPER LO STUDIO

E LA CURA DEI TUMORI

UN PROBLEMA CLINICO RILEVANTE

IPONATREMIA NEL 15‐30%  DEI PAZIENTI RICOVERATIRobinson AG & Verbalis JG 2002 Williams Textbook of Endocrinology 10th, 300–313 

Causa principaleFino al 30% 

delle iponatremiein pazienti con tumore

INCIDENZA E CAUSE DI IPONATREMIA

Modificata da Liamis G, et al. Am J Kidney Dis. 52: 144-153, 2008

FARMACI ED IPONATREMIA

May 11, 2016

Risk of HIGH- GRADE HYPONATREMIA with targeted agents (brivanib(RR =5.2), sorafenib (RR= 2.4), vorinostat (RR= 2.1)

anti VEGF (RR= 2.69) - anti EGFR (RR= 1.12)

DEFINIZIONE E CLASSIFICAZIONE

• Headache• Irritability• Nausea / vomiting• Mental slowing• Unstable gait / falls• Confusion / delirium • Disorientation

• Stupor / coma• Convulsions• Respiratory arrest

Symptomatic butless impaired;usually chronic (>48 h)

Life‐threatening; usually acute (<48 h)

The degree of symptomotologyis a surrogate for the duration

of hyponatremia

SINTOMI DELL’ IPONATREMIA

• Objective: to determine the frequency and severity ofhyponatremia in patients with cancer and examine itseffect on length of hospital stay andmortality

• 3.357 pz with cancer: hyponatremia was noted in 47 %(Na< 135 mmol/l), mild in 36% (134‐130 mmol/l)moderate/severe in 11% (< 129 mmol/l)

IPONATREMIA E MORTALITA’ IN PAZIENTI ONCOLOGICI

Analisi retrospettiva di tutti i pazienti ammessi all’M.D. Anderson CancerCentre (Università del Texas) in un periodo di 3 mesi (n=3357)

Doshi SM, et al. Am J Kidney Dis 2012

0

5

10

15

20

25

Haematologic(n=587)

Genitourinary(n=614)

Gastrointestinal(n=488)

Head, neck &lung (n=538)

Others (n=1130)

Severe (<120 mEq/L)Moderate (120-129 mEq/L)

Patie

nts

with

hyp

onat

raem

ia

at fi

rst h

ospi

talis

atio

n (%

)

*Others includes melanoma, breast, and thyroid malignancies

Doschi S.M.  et al. AJKD, 2012

Doschi S. M.et al. AJKD, 2012

Strong and indipendent association betweenhyponatremia and longer length of stay and…………..

283(8.4%) deaths during the 90 days:significantly decreased rates of survival in patients with

hyponatremia compared with patients with eunatremia (P<0.01)

…………..higher mortality

Doschi S.M. et al. AJKD, 2012

44% dei paz. con iponatriemia

• median OS 11.2 mos in patients with normal PNaand 7.1 mos in patients with subnormal values (P=0.0001)

IPONATREMIA FATTORE PROGNOSTICO INDIPENDENTEIPONATREMIA FATTORE PROGNOSTICO INDIPENDENTE

Hansen O. et al. Lung Cancer 2010

Tiseo M, et al. Lung Cancer 2014

Ruolo prognostico dell’iponatremia in 564 pazienti con SCLC trattati con topotecan

IPONATREMIA E MORTALITA’ IN PAZIENTI ONCOLOGICI

Berardi R et al. Support Care Cancer 2014

Survival proba

bility (%

)

Time

Sodium ≥135 mEq/L

Sodium <135 mEq/L

Low serum sodium is a new, validated, indipendent prognostic, and predictivefactor in patients with mRCC

Median OS 4.8/5.5  months vs 16.9/18.6  months (p<0,001)

Pazienti di 18/20 centri afferenti al International Multicenter Renal Cell Consortium trattati con agenti anti VEGF o inibitori di mTOR

Schutz FA, et al. Eur Urol 2014

OS

prob

abilit

y

IPONATREMIA E MORTALITA’ IN PAZIENTI ONCOLOGICI

Impact of Hyponatriemia in a Tertiary Cancer Center: A one-year-Survey at National Cancer Institute of Milan

Agustoni F(1), Fucà G(1), Corrao G(1), Vernieri C(1), Cavalieri S(1), Raimondi A(1), Peverelli G(1), Prisciandaro M(1), Indelicato P(1), Lo Russo G(1), Signorelli D(1), Proto C(1), Vitali M(1), Imbimbo M(1), Zilembo N(1), Garassino MC(1), Morelli D(2), Procopio G(1), de Braud F(1) and Platania M(1)

(1)Medical Oncology 1 - Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, IT; (2)Medicine Laboratory Unit - Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, IT

Background

Material and methods

Results

Conclusions

Bibliography

Hyponatremia (HN), defined as a serumsodium lower than 135 mmol/l, is themost common electrolyte disorder inhospitalized patients. Etiology isheterogeneous and a large differenceexists in terms of symptoms andtreatments. The aim of this study is todetermine the incidence of HN in aTertiary Cancer Center evaluatingpossible influence in terms of prognosisand length of hospitalization.

This study includes all cancer patientshospitalized at our Institution fromJanuary 2015 to December 2015 for allcauses otherwise than HN. We analyzedretrospectively data regarding HN andcorrelation to age, sex, staging,histology. Survival distribution wasestimated by Kaplan-Meyer method,differences in probability of survivingwere evaluated by chi-square test.

Patients were affected by lung cancer in21.7%, breast cancer in 19.5%,colorectal cancer in 13.0% (others in45.8%) [Fig.2]. Most patients had StageIV disease (93.4%), male 44.7%, female54.3%. Median age was 62.9 years.Concomitant diagnosis of SIADH wasperformed in 4 patients (8.8%).

HN represents a frequent occasionalfinding in hospitalized cancer patients,although in most cases it’s of milddegree. SIADH represents a smallpercentage of cases. In our experienceHN is not associated to dischargedelays. Moderate and severe HN arerelated with advanced stage disease withpoor prognosis. Independently by theunderlying disease, moderate andsevere HN identify a particular group ofpatients with poor prognosis, probablyreflecting very advanced disease andpalliative care needs.

Resolution of HN after specifictreatments was observed in 19 patients(41.3%). Median lenght of hospitalizationwas 10.7 days, without significantdifferences for patients who correctedHN or not, except to patients with SIADHtreated with tolvaptan (7.25 days). OSwas lower in patients withmoderate/severe HN versus mild (2.72vs 6.81 months) [Fig.3].

A total of 1.071 patients were included inthe analysis. 243 (22.7%) with at leastone episode of HN. 197 (81.1%) showedmild hyponatriemia (135-130 mmol/l), 44(18.1%) moderate (130-125 mmol/l), 2(0.8%) severe (< 125 mmol/l) [Fig.1].

Mortality rate was significantly lower inpatients with corrected HN compared tonot (52.6 vs 81.5%; p: 0.08), while nostatistically significant difference wasobserved in OS (2.89 vs 2.63 months; p:0.85) [Fig.4].

Fig.1 Grading of hyponatriemia observedin all cancer patients hospitalized at ourInstitution from January 2015 to December2015

Fig.2 Most common tumor sites in cancerpatients with hyponatriemia hospitalized atour Institution from January 2015 toDecember 2015

Fig.3 Kaplan-Meier estimates of Overall Survival forpatients with moderate/severe or mild hyponatriemia

1. Abu Zwìeinah GF, Al-Kindi SG, Hassan AA et al:Hyponatriemia in cancer: association with type ofcancer and mortality. Eur J Cancer Care 24 (2):224-31, 2015.

2. Berghmans T, Paesmans M, Body JJ: Aprospective study on hyponatriemia in medicalcancer patients: epidemiology, aetiology anddifferential diagnosis. Supp Care Cancer 8: 192-97, 2000.

3. Doshi SM, Shah P, Lei X, et al: Hyponatriemia inhospitalized cancer patients and its impact onclinical outcome. Am J Kidney Dis 59: 222-28,2012.

4. Verbalis JG, Goldsmith SR, Greenberg A, et al:Diagnosis, evaluation, and treatment ofhyponatriemia: expert panel recomandation. Am JMed 126: S1-4, 2013.

Fig.4 Kaplan-Meier estimates of Overall Survival forpatients with not corrected or corrected hyponatriemia

COSTS:128% FOR MODERATE HN 299% FOR SEVERE 

HN 

COSTS:128% FOR MODERATE HN 299% FOR SEVERE 

HN 

OS significativamente più lunga in pazienti in cui si correggeva la iponatriemia (13.6 mesi vs 16 giorni, p<0.001) con possibilità di ricevere più linee di trattamento antineoplastico

Italy-UK collaboration

Berardi R. et al, Oncotarget 2016

EFFETTI DELLA CORREZIONE DELL’ IPONATREMIA

mOS=16 vs. 9 months, p=0.018

Correzione della iponatriemia (da SIADH)

Peri A. et al, JEI 2010

Peri A. et al, JEI 2010

permette il pronto inizio del trattamento chemioterapico

migliora le condizioni generali ( PS)

limita il tempo di degenza in ospedale

LA CORREZIONE DELL’IPONATREMIA IN ONCOLOGIA…………..

HYPONATREMIA DUE TO SIADH – NATIONAL RETROSPECTIVE STUDY

…waiting for the prospective

trial…

Poster presentation at ESMO and AIOM 2014

1. SIADH epidemiology in cancerPatients in Italy

2. Tolvaptan schedule

3. Correlation with outcome

4. Differences in outcome and duration of hospitalization in patientstreated with Tolvaptan vs. otheroptions.

Hyponatraemia in cancer – Rossana Berardi

Linee Guida ‐ NCCN

“Position paperon electrolytedisordersin cancerpatients” 

www.aiom.it 

QUINDI LA IPONATREMIA NEL PAZIENTE ONCOLOGICO……………

Peggiora la prognosiPeggiora le condizioni generaliRitarda dell’inizio dei trattamentiPeggiora l’outcome del trattamento oncologico

DA RICORDARE ………

• Le terapie “target “ possono aumentarne la incidenza

• Si associa a sintomi che aumentano la durata di degenza

• Importante l’approccio multidisciplinare per una corretta

diagnosi di SIADH (non sottovalutare valori di Na inferiori

alla norma!)

• La pronta correzione dei valori di Na impatta sulla prognosi