La iponatremia in oncologia NICOLETTA ZILEMBO Fondazione IRCCS Istituto Nazionale dei Tumori 9 marzo 2017 ISTITUTO NAZIONALE 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
INCIDENZA E CAUSE DI IPONATREMIA Causa principale Fino al 30% delle iponatremie in pazienti con tumore
FARMACI ED IPONATREMIA Modificata da Liamis G, et al. Am J Kidney Dis. 52: 144-153, 2008
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
SINTOMI DELL IPONATREMIA 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) The degree of symptomotology is a surrogate for the duration of hyponatremia Life threatening; usually acute (<48 h)
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) 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) Doshi SM, et al. Am J Kidney Dis 2012
Patients with hyponatraemia at first hospitalisation (%) 25 20 15 10 5 Severe (<120 meq/l) Moderate (120-129 meq/l) 0 Haematologic (n=587) Genitourinary (n=614) Gastrointestinal (n=488) Head, neck & lung (n=538) Others (n=1130) *Others includes melanoma, breast, and thyroid malignancies Doschi S.M. et al. AJKD, 2012
Strong and indipendent association between hyponatremia and longer length of stay and.. Doschi S. M.et al. AJKD, 2012
..higher mortality 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) 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 Hansen O. et al. Lung Cancer 2010
IPONATREMIA E MORTALITA IN PAZIENTI ONCOLOGICI Ruolo prognostico dell iponatremia in 564 pazienti con SCLC trattati con topotecan Tiseo M, et al. Lung Cancer 2014
Survival probability (%) Sodium 135 meq/l Sodium <135 meq/l Berardi R et al. Support Care Cancer 2014 Time
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)
IPONATREMIA E MORTALITA IN PAZIENTI ONCOLOGICI Pazienti di 18/20 centri afferenti al International Multicenter Renal Cell Consortium trattati con agenti anti VEGF o inibitori di mtor OS probability Schutz FA, et al. Eur Urol 2014
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 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. Material and methods 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. Results 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]. Fig.1 Grading of hyponatriemia observed in all cancer patients hospitalized at our Institution from January 2015 to December 2015 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%). Fig.2 Most common tumor sites in cancer patients with hyponatriemia hospitalized at our Institution from January 2015 to December 2015 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 vs 6.81 months) [Fig.3]. Fig.3 Kaplan-Meier estimates of Overall Survival for patients with moderate/severe or mild hyponatriemia Fig.4 Kaplan-Meier estimates of Overall Survival for patients with not corrected or corrected hyponatriemia 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]. Conclusions 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. Bibliography 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 Med 126: S1-4, 2013.
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
EFFETTI DELLA CORREZIONE DELL IPONATREMIA mos=16 vs. 9 months, p=0.018 Italy-UK collaboration Berardi R. et al, Oncotarget 2016
Correzione della iponatriemia (da SIADH) Peri A. et al, JEI 2010
Peri A. et al, JEI 2010
LA CORREZIONE DELL IPONATREMIA IN ONCOLOGIA.. limita il tempo di degenza in ospedale permette il pronto inizio del trattamento chemioterapico migliora le condizioni generali ( PS)
HYPONATREMIA DUE TO SIADH NATIONAL RETROSPECTIVE STUDY 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. waiting for the prospective trial Hyponatraemia in cancer Rossana Berardi Poster presentation at ESMO and AIOM 2014
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