La iponatriemia in oncologia

La iponatremia in oncologia

NICOLETTA ZILEMBO

Fondazione IRCCS

“Istituto Nazionale dei Tumori”

9 marzo 2017

PER LO STUDIO E LA CURA DEI TUMORI

UN PROBLEMA CLINICO RILEVANTE

IPONATREMIA NEL 15‐30%  DEI PAZIENTI RICOVERATI

Robinson AG & Verbalis JG 2002 Williams Textbook of Endocrinology 10th, 300–313 

Causa principale

Fino al 30% 

delle iponatremie in 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 but less impaired;

usually chronic (>48 h)

Life‐threatening; 

usually acute (<48 h)

The degree of symptomotology is a surrogate for the duration

of hyponatremia

SINTOMI DELL’ IPONATREMIA

• Objective: to determine the frequency and severity of hyponatremia in patients with cancer and examine its effect on length of hospital stay and mortality

• 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 Cancer Centre (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)

Patients with hyponatraemia at first hospitalisation (%)

*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 between

hyponatremia 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 PNa

and 7.1 mos in patients 

with subnormal values 

(P=0.0001)

IPONATREMIA FATTORE PROGNOSTICO INDIPENDENTE IPONATREMIA 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

Sur viv al  p ro bability  (%)

Time

Sodium ≥135 mEq/L

Sodium <135 mEq/L

Low serum sodium is a new, validated, indipendent prognostic, and predictive factor 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 probability

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 serum sodium lower than 135 mmol/l, is the most common electrolyte disorder in hospitalized patients. Etiology is heterogeneous and a large difference exists in terms of symptoms and treatments. The aim of this study is to determine the incidence of HN in a Tertiary Cancer Center evaluating possible influence in terms of prognosis and length of hospitalization.

This study includes all cancer patients hospitalized at our Institution from January 2015 to December 2015 for all causes otherwise than HN. We analyzed retrospectively data regarding HN and correlation to age, sex, staging, histology. Survival distribution was estimated by Kaplan-Meyer method, differences in probability of surviving were evaluated by chi-square test.

Patients were affected by lung cancer in 21.7%, breast cancer in 19.5%, colorectal cancer in 13.0% (others in 45.8%) [Fig.2]. Most patients had Stage IV disease (93.4%), male 44.7%, female 54.3%. Median age was 62.9 years.

Concomitant diagnosis of SIADH was performed in 4 patients (8.8%).

HN represents a frequent occasional finding in hospitalized cancer patients, although in most cases it’s of mild degree. SIADH represents a small percentage of cases. In our experience HN is not associated to discharge delays. Moderate and severe HN are related with advanced stage disease with poor prognosis. Independently by the underlying disease, moderate and severe HN identify a particular group of patients with poor prognosis, probably reflecting very advanced disease and palliative care needs.

Resolution of HN after specific treatments was observed in 19 patients (41.3%). Median lenght of hospitalization was 10.7 days, without significant differences for patients who corrected HN or not, except to patients with SIADH treated with tolvaptan (7.25 days). OS was lower in patients with moderate/severe HN versus mild (2.72 vs6.81 months) [Fig.3].

A total of 1.071 patients were included in the analysis. 243 (22.7%) with at least one episode of HN. 197 (81.1%) showed mild 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 in patients with corrected HN compared to not (52.6 vs 81.5%; p: 0.08), while no statistically significant difference was observed in OS (2.89 vs 2.63 months; p:

0.85) [Fig.4].

Fig.1 Grading of hyponatriemia observed in all cancer patients hospitalized at our Institution from January 2015 to December 2015

Fig.2 Most common tumor sites in cancer patients with hyponatriemia hospitalized at our Institution from January 2015 to December 2015

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

1. Abu Zwìeinah GF, Al-Kindi SG, Hassan AA et al:

Hyponatriemia in cancer: association with type of cancer and mortality. Eur J Cancer Care 24 (2):

224-31, 2015.

2. Berghmans T, Paesmans M, Body JJ: A prospective study on hyponatriemia in medical cancer patients: epidemiology, aetiology and differential diagnosis. Supp Care Cancer 8: 192- 97, 2000.

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

4. Verbalis JG, Goldsmith SR, Greenberg A, et al:

Diagnosis, evaluation, and treatment of hyponatriemia: expert panel recomandation. Am J Med126: S1-4, 2013.

Fig.4 Kaplan-Meier estimates of Overall Survival for patients 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 cancer Patients in Italy

2. Tolvaptan schedule

3. Correlation with outcome 4. Differences in outcome and

duration of hospitalization in patients treated with Tolvaptan vs. other options.

Hyponatraemia in cancer – Rossana Berardi

Linee Guida ‐ NCCN

“Position paper on electrolyte

disorders in cancer patients” 

www.aiom.it 

QUINDI LA IPONATREMIA NEL PAZIENTE ONCOLOGICO………

Peggiora la prognosi

Peggiora le condizioni generali Ritarda dell’inizio dei trattamenti

Peggiora 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