1 Support Care Cancer (2015) 23: DOI /s ORIGINAL ARTICLE Hyponatraemia is a predictor of clinical outcome for malignant pleural mesothelioma R. Berardi M. Caramanti I. Fiordoliva F. Morgese A. Savini S. Rinaldi M. Torniai M. Tiberi C. Ferrini M. Castagnani F. Rovinelli A. Onofri S. Cascinu Received: 1 May 2014 /Accepted: 11 August 2014 /Published online: 21 August 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract Purpose Hyponatraemia is one of the most common tumourrelated electrolyte disorders. Several clinical, histological and serum factors have been found to influence prognosis, but, to date, there are no studies focusing on the prognostic role of hyponatraemia in mesothelioma. The aim of this study was to assess the prognostic role of hyponatraemia in malignant pleural mesothelioma. Methods We analysed 62 consecutive patients with histologically or cytologically proven advanced malignant pleural mesothelioma undergoing chemotherapy at our institution between January 2003 and September Results All patients received a first-line pemetrexed-based chemotherapy. A second-line chemotherapy was administered to 29 patients. The onset of hyponatraemia (serum sodium <135 meq/l) during the treatment was significantly related to a worsened median overall survival (7.93 vs months; p=0.0069). The occurrence of hyponatraemia during first-line chemotherapy (cutoff 135 and 130 meq/l) was significantly associated to a shorter median progression-free survival (p=0.0214). Results were also similar in the subgroup receiving a second-line treatment. At the multivariate analysis, including haemoglobin and sodium level at the beginning of first-line chemotherapy, age, gender, smoking habit, job exposure and performance status, only hyponatraemia was found to be an independent factor (p=0.029). Hyponatraemia was also found to be a predictive factor for both first-line chemotherapy, being R. Berardi (*): M. Caramanti : I. Fiordoliva : F. Morgese : A. Savini: S. Rinaldi : M. Torniai : M. Tiberi : C. Ferrini : M. Castagnani: F. Rovinelli : A. Onofri : S. Cascinu Medical Oncology Unit, Università Politecnica delle Marche Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I GM Lancisi G Salesi, Via Conca 71, Ancona, Italy related to poorer response to pemetrexed-based chemotherapy (p=0.047) and second-line chemotherapy (p=0.044). Conclusion Our results show that hyponatraemia might be considered a negative prognostic parameter in malignant pleural mesothelioma patients. To our knowledge, this is the first study to evaluate the association of hyponatraemia with the outcome of malignant pleural mesothelioma patients. Keywords Chemotherapy. Hyponatraemia. SIADH. Malignant pleural mesothelioma. Prognostic factor Introduction Hyponatraemia is the most common electrolyte disorder in hospitalized patients (15 50 % of hospitalizations in several surveys), although it is underestimated due to heterogeneous presentations defined by a sodium level <135 meq/l in serum. It can be classified into three levels: mild ( meq/ L), moderate ( meq/l) and severe (<125 meq/l) . Depending on the severity and spread of this alteration, symptoms can vary from aspecific headache and mental impairment to confusion, nausea and vomit and, finally, to coma; however, most patients remain asymptomatic. Cancer-related hyponatraemia could adversely affect the performance status, the quality of life and the prognosis of cancer patients [2 4]. Furthermore it may delay time-critical treatments, such as systemic chemotherapy . In some cases, these effects do not appear to be attributable only to the electrolyte disorders itself. In fact, above all neurological symptoms may have an adverse impact, for example increasing the risk of falls or worsening underlying diseases . In cancer patients, hyponatraemia is often caused by the inappropriate antidiuretic hormone syndrome (SIADH), due to ectopic production of antidiuretic hormone, by extracellular fluid depletion or renal toxicity of chemotherapy, especially
2 622 Support Care Cancer (2015) 23: platinum-based . These conditions are commonly associated with small cell lung cancer (SCLC), but not rarely with non-small cell lung cancer (NSCLC), lymphomas, gastrointestinal cancers and mesothelioma . Malignant pleural mesothelioma (MPM) is a poor-prognosis tumour, with a median overall survival of 1 year . Therapy is based on different combinations of chemotherapy, radical/palliative surgery and radiotherapy, with limited benefit due to the advanced stage at diagnosis and the elderly age . Several clinical, histological and serum factors were found to influence prognosis in mesothelioma , but, to date, there are no studies focusing on the prognostic role of hyponatraemia in this tumour. However, it has been shown that a reduction in serum sodium has negative effects on hospitalization length, quality of life and prognosis, both in neoplastic and in non-neoplastic diseases [10, 11]. Treatments for hyponatraemia (Table 1) seem to improve clinical discomfort and chemotherapy response, but further research is needed to confirm these data . The aim of this study was to assess the prognostic role of hyponatraemia in MPM, by examining the association between its onset during chemotherapy and overall survival (OS) and progression-free survival. Patients and methods Patient selection This study includes consecutive patients with histologically or cytologically proven advanced or metastatic MPM undergoing chemotherapy at our institution between January 2003 and September Table 1 Treatments for hyponatraemia Euvolemic or hypervolemic hyponatraemia Asymptomatic patients Remove cause-specific predisposing factors Discontinued, whenever possible, drugs note to cause hyponatraemia Fluid restriction±nacl supplementation±furosemide Symptomatic patients Saline (0.9 %) or hypertonic (3 %) saline (possible addition of loop diuretic) Selective vasopressin receptor antagonists (vaptans, i.e. tolvaptan) Demeclocycline/urea/lithium are available in some countries Hypovolemic hyponatraemia Remove cause-specific predisposing factors Isotonic (0.9 %) saline The rate of correction of sodium should not exceed 12 mmol/l/24 h. Excessively rapid correction of hyponatraemia can predispose to the development of cerebral oedema, central pontine myelinolysis, coma and death Eligibility criteria included: Age >18 years Cytological/histological evidence of MPM Locally advanced or metastatic stage No primary mesothelioma in other sites No others types of cancer We collected data regarding age, sex, smoking, asbestos exposure, staging, histology, performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) system, chemotherapy and levels of serum sodium before, during and after chemotherapy. We evaluated tumour objective response to treatments according to the modified RECIST criteria, validated by Byrne and Nowak in MPM patients . Data management and statistical analysis The aim of this study was to evaluate the prognostic role of hyponatraemia in MPM. OS was defined as the time between histological diagnosis and last follow-up visit or death, while progression-free survival (PFS) was calculated from the start of first- and secondline chemotherapy treatment until the date of disease progression or death. Patients who were not reported as dead at the time of the analysis were censored at the date they were last known to be alive. Survival distribution was estimated using the Kaplan- Meier method, and differences in probability of surviving were evaluated by log-rank test. We chose a significant level of 0.05 to assess statistical significance. The Cox multivariate proportional hazard regression model was used to evaluate the effects of the prognostic factors on PFS and OS. Statistical analysis was performed using the MedCalc package (MedCalc v ). Results Patients were predominantly males (79 %), and median age at diagnosis was 68.5 years (range years). Underlying risk factors were the following: smoking (59.7 %) and asbestos exposure (66.1 %). Forty-two out of 62 patients had epithelioid malignant mesothelioma. Main clinical characteristics are summarized in Table 2. Seven patients (24.2 %) were treated with radical surgery and subsequently underwent postoperative radiotherapy alone or in combination with chemotherapy. All patients received a first-line pemetrexed-based chemotherapy (in monotherapy or combined with cisplatin or carboplatin) (Table 3). Only one patient showed a complete response (1.6 %), while we observed a partial response in nine (14.5 %) patients and a progressive disease in 23 patients
3 Support Care Cancer (2015) 23: Table 2 Patient characteristics Characteristics Number of patients (%): total number=62 (100 %) Age (22.6 %) >60 48 (77.4 %) Sex Male 49 (79 %) Female 13 (21 %) Smoking Yes 37 (59.7 %) No 25 (40.3 %) Asbestos exposure Yes 41 (66.1 %) No 21 (33.9 %) PS at diagnosis (ECOG) 0 33(53.2 %) 1 24(38.7 %) 2 4 (6.5 %) 3 1 (1.6 %) Staging Locally advanced 51 (82.3 %) Metastatic 11 (17.7 %) Histology Epithelioid 42 (67.7 %) Sarcomatoid 9 (14.5 %) Desmoplastic 1 (1.6 %) Biphasic 5 (8.1 %) Unknown 5 (8.1 %) Table 3 Type of therapies and response to treatments Characteristics Number of patients (%): total number=62 (100 %) First-line chemotherapy Carboplatin+pemetrexed 24 (38.7 %) Cisplatin+pemetrexed 16 (25.8 %) Pemetrexed 16 (25.8 %) Other 6 (9.7 %) Best response to treatment Progression 23 (37.1 %) Stable disease 18 (29 %) Partial response 9 (14.5 %) Complete response 1 (1.6 %) Not assessable 11 (17.7 %) Characteristics Number of patients (%): total number=29 (100 %) Second-line chemotherapy MMM 11 (37.9 %) Gemcitabine 9 (31 %) Pemetrexed 4 (13.8 %) Carboplatin+pemetrexed 2 (1.6 %) Other 3 (10.3 %) Best response to treatment Progression 13 (44.8 %) Stable disease 4 (13.8 %) Partial response 1 (3.4 %) Complete response 0 Not assessable 11 (37.9 %) MMM mitoxantrone/methotrexate/mitomycin (37.1 %). In 18 cases (29 %), a tumour stabilization was reported. A second-line therapy with mitoxantrone/methotrexate/mitomycin (MMM) or with gemcitabine in monotherapy or with pemetrexed alone or in combination with carboplatin (in selected cases responsive to first-line pemetrexed-based chemotherapy) was administered to 29 patients (Table 3). No complete responses were obtained. In the second-line setting, we observed one partial response, four (13.8 %) stable diseases and 13 (44.8 %) progressions. Fifteen out of 62 patients (24.2 %) received adjuvant or palliative radiotherapy. The median OS was months and the median PFS was 4.98 months (range ) after first-line chemotherapy and 3.38 months (range ) in the subgroup receiving a second-line therapy. The onset of hyponatraemia (serum sodium <135 meq/ L) during the treatment was observed in 14 patients (22.6 %), and it was significantly related to a worsened median OS (7.93 vs months; p=0.0069). Among hyponatraemic group of patients, only one had low sodium value before receiving chemotherapy. The remaining 13 patients developed hyponatraemia after 1 to 2 cycles of chemotherapy (after an average time of 1 month). With the exception of chemotherapy, no relevant concomitant medications can be related to the onset of hyponatraemia. The occurrence of hyponatraemia during first-line chemotherapy (cutoffs 135 and 130 meq/l) was significantly associated with a shorter median PFS (p=0.0214). In patients with normal serum sodium levels, the median PFS was 6.16 months; patients with hyponatraemia with serum sodium levels 135 and 130 meq/l showed a median PFS of 3.87 and 2.26 months, respectively (Table 4; Fig. 1). Treatment of hyponatraemia included saline i.v. infusion and hypertonic (3 %) saline i.v. infusion. Among hyponatraemic patients, only four (28.5 %cme) received a second-line treatment, while 17 out of 38 patients with no hyponatraemia (44.7 %) underwent a second-line chemotherapy. Results were also similar in the subgroup receiving a secondline treatment (Table 5). In this setting, the median PFS was 3.67 months in patients with normal serum sodium, 3.21 months and 1.51 months in patients with mild hyponatraemia
4 624 Support Care Cancer (2015) 23: Table 4 Prognostic value of hyponatraemia after first-line chemotherapy (total number: 62 patients) Hyponatraemia during therapy Yes 14 (22.6 %) <135 meq/l meq/l 3 No 38 (61.3 %) Unknown 10 (16.1 %) Median OS (months) (p=0.0069) 135 meq/l <135 meq/l 7.93 Median PFS (months) (p=0.0214) 135 meq/k 6.16 < meq/l meq/l 2.26 OS overall survival, PFS progression-free survival ( 135 meq/l) and severe hyponatraemia ( 130 meq/l), respectively (p=0.0386). The multivariate analysis, including haemoglobin and sodium level at the beginning of first-line chemotherapy, age, gender, smoking habit, job exposure and performance status, found only hyponatraemia to be an independent factor (p =0.029). Hyponatraemia was also foundtobeapredictivefactorbothinfirst-linechemotherapy, being related to poorer response to pemetrexedbased chemotherapy (p=0.047), and in second-line chemotherapy (p=0.044). Table 5 Prognostic value of hyponatraemia after second-line chemotherapy (total number: 29 patients) Hyponatraemia during therapy Yes 9 (31 %) <135 meq/l meq/l 1 No 14 (44.8 %) Unknown 6 (20.7 %) Median PFS (months) (p=0.0386) 135 meq/l 3.67 < meq/l meq/l 1.51 PFS progression-free survival Discussion Hyponatraemia is one of the most common electrolyte disorders associated with tumour-related conditions. Abundant literature is available for hyponatraemia in patients with no cancer conditions but very little is known about hyponatraemia in patients with cancer. The incidence of hyponatraemia varies largely (1 40 %), depending on the cancer type, clinical setting and serum sodium cutoff level . Risk factors for hyponatraemia include chemotherapy or its toxicities, such as diarrhoea or vomiting, hydration and narcotic drugs [6, 14 16]. The main cause of hyponatraemia in malignancy, affecting 1 to 2 % of the entire cancer population, is SIADH which may result from ectopic production of Fig. 1 Kaplan-Meier overall survival curves for patients stratified on the basis of the serum sodium level at first-line chemotherapy (p=0.0069)
5 Support Care Cancer (2015) 23: arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) by the tumour tissue [17 19]. It is most common in patients with lung cancer (11 15 %), head and neck cancer (3 %), breast cancer and less frequent in other type of malignancies [6, 17, 19, 20]. Perks et al. first described SIADH in a patient with a MPM . Hyponatraemia in cancer patients has been reported to adversely affect survival: in a prospective study on a general cancer population, Berghmans et al. found that hyponatraemic patients had an increased mortality compared to those with normal serum sodium levels . Recently, another study reported a high frequency of hyponatraemia in hospitalized patients with cancer and a strong and independent association between hyponatraemia, longer length of stay and higher mortality . In our group of 62 patients with mesothelioma receiving first-line treatment, 12 (19.4 %) presented hyponatraemia; in the second-line setting, hyponatraemia was detected in eight patients (27.6 %). A significant lower median OS and median PFS were observed in patients with a serum sodium level 135 meq/l compared with eunatraemic patients. Furthermore, among hyponatraemic patients, we found a worse lower median OS in the subgroup with serum sodium levels 130 meq/l. Hyponatraemia was significantly related to survival in both first-line setting and during the second-line of treatment. Our results seem to indicate that, in malignant pleural mesothelioma patients, the occurrence of hyponatraemia under chemotherapy may represent a significant factor influencing the outcome. Previous studies analysed prognostic factors in MPM patients in order to select the best therapeutic management; however, none of them evaluated the role of natraemia in predicting survival. The most important scoring systems were assessed by European Organisation for Research and Treatment of Cancer (EORTC) and Cancer and Leukemia Group B (CALGB). These scores included age, gender, performance status, histology and site of disease, as well as laboratoristic parameters such as haemoglobin, LDH levels, blood count of platelets and leucocytes. Both EORTC and CALGB systems were validated in following series of patients, and they represent, to date, the reference for prognostication in MPM [22 24]. Our findings are consistent with several studies analysing the impact of low serum sodium level on survival outcomes in patients with different cancer types, although in previous studies the cutoff points used in the definition of hyponatraemia were not homogeneous. In a systematic review of published studies, Castillo et al. found that in SCLC patients, hyponatraemia was an independent risk factor for poor outcome in six of the 13 analysed studies . Furthermore, a low serum sodium level was identified as a negative prognostic factor also in patients with other malignancies, although evaluated only in a limited number of studies [25 28]. In a retrospective study of 453 SCLC patients undergoing chemotherapy, Hansen et al. demonstrated that patients with hyponatraemia at diagnosis had a lower median OS compared to eunatraemic patients. The authors also suggested that patients whose serum sodium value did not fully normalize within the first two cycles of chemotherapy had a worse prognosis than patients with hyponatraemia whose serum sodium value did . Recently, Petereit et al. investigated the prognostic value of hyponatraemia in 2,100 lung cancer patients. They reported that the median survival in lung cancer with hyponatraemia was shorter compared to normonatraemic patients, and the correction of serum sodium above the level of 138 meq/l was correlated with an improved survival . Again, cancer-related hyponatraemia has been hypothesized to adversely affect the response to treatment: in a recent study, hyponatraemia was reported to be a prognostic factor for short survival and a predictive factor for lack of response in metastatic renal cell cancer patients treated with cytokines . Similarly, another recent study investigated the association of hyponatraemia on treatment outcome in metastatic renal cell cancer patients treated with anti-vegf and mtor-targeted agents. Hyponatraemia was found to be an independent predictor of OS, time to treatment failure and disease control rate . The mechanisms underlying this resistance to treatment are not known. Conclusion In conclusion, hyponatraemia is a common condition in cancer patients. Our results show that it could be considered a negative prognostic parameter also in malignant pleural mesothelioma patients. Most of the studies have evaluated the prognostic value of hyponatraemia at baseline: in our study, we found a prognostic significance of hyponatraemia arising during chemotherapy. The early detection, monitoring and management of hyponatraemia might improve the patient s prognosis. To our knowledge, this is the first study to evaluate the association of hyponatraemia on outcome of malignant pleural mesothelioma patients. However, further investigations are needed to examine the effect of treating hyponatraemia on the outcome of cancer patients. Funding This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. Conflict of interest All authors disclose no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work or that could be perceived as prejudicing the impartiality of the research reported. The authors have full control of all primary data and do agree to allow the journal to review their data if requested.
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