Download Hyponatraemia is a predictor of clinical outcome for malignant

Support Care Cancer (2015) 23:621–626
DOI 10.1007/s00520-014-2398-6
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 2013.
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 13.48 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, 60126 Ancona, Italy
e-mail: [email protected]
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 (130–134 mEq/
L), moderate (125–129 mEq/L) and severe (<125 mEq/L) [1].
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 [5].
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 [3].
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
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platinum-based [6]. 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 [4]. Malignant pleural mesothelioma (MPM) is a poor-prognosis tumour, with a median
overall survival of 1 year [7]. 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 [8]. Several clinical, histological
and serum factors were found to influence prognosis in mesothelioma [9], 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 [12].
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 2013.
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
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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 [13].
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 KaplanMeier 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® v9.4.2.0).
Results
Patients were predominantly males (79 %), and median age at
diagnosis was 68.5 years (range 48–81 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
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Table 2 Patient characteristics
Characteristics
Age
≤60
>60
Sex
Male
Female
Smoking
Yes
No
Asbestos exposure
Yes
No
PS at diagnosis (ECOG)
0
1
2
3
Staging
Locally advanced
Metastatic
Histology
Epithelioid
Sarcomatoid
Desmoplastic
Biphasic
Unknown
Table 3 Type of therapies and response to treatments
Number of patients (%):
total number=62 (100 %)
14 (22.6 %)
48 (77.4 %)
49 (79 %)
13 (21 %)
37 (59.7 %)
25 (40.3 %)
41 (66.1 %)
21 (33.9 %)
33 (53.2 %)
24 (38.7 %)
4 (6.5 %)
1 (1.6 %)
51 (82.3 %)
11 (17.7 %)
42 (67.7 %)
9 (14.5 %)
1 (1.6 %)
5 (8.1 %)
5 (8.1 %)
(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 12.46 months and the median PFS was
4.98 months (range 0.23–24.79) after first-line chemotherapy
and 3.38 months (range 0.79–19.38) 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 13.48 months; p=0.0069). Among
hyponatraemic group of patients, only one had low sodium value before receiving chemotherapy. The remaining
Characteristics
First-line chemotherapy
Carboplatin+pemetrexed
Cisplatin+pemetrexed
Pemetrexed
Other
Best response to treatment
Progression
Stable disease
Partial response
Complete response
Not assessable
Characteristics
Second-line chemotherapy
MMM
Gemcitabine
Pemetrexed
Carboplatin+pemetrexed
Other
Best response to treatment
Progression
Stable disease
Partial response
Complete response
Not assessable
Number of patients (%):
total number=62 (100 %)
24 (38.7 %)
16 (25.8 %)
16 (25.8 %)
6 (9.7 %)
23 (37.1 %)
18 (29 %)
9 (14.5 %)
1 (1.6 %)
11 (17.7 %)
Number of patients (%):
total number=29 (100 %)
11 (37.9 %)
9 (31 %)
4 (13.8 %)
2 (1.6 %)
3 (10.3 %)
13 (44.8 %)
4 (13.8 %)
1 (3.4 %)
0
11 (37.9 %)
MMM mitoxantrone/methotrexate/mitomycin
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
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Table 4 Prognostic value of hyponatraemia after first-line chemotherapy
(total number: 62 patients)
Table 5 Prognostic value of hyponatraemia after second-line chemotherapy (total number: 29 patients)
Hyponatraemia during therapy
Yes
<135 mEq/L
≤130 mEq/L
No
Unknown
Median OS (months) (p=0.0069)
≥135 mEq/L
<135 mEq/L
Median PFS (months) (p=0.0214)
≥135 mEq/K
Hyponatraemia during therapy
Yes
<135 mEq/L
≤130 mEq/L
No
Unknown
Median PFS (months) (p=0.0386)
≥135 mEq/L
<135→130 mEq/L
≤130 mEq/L
<135→130 mEq/L
≤130 mEq/L
14 (22.6 %)
11
3
38 (61.3 %)
10 (16.1 %)
13.48
7.93
6.16
3.87
2.26
9 (31 %)
8
1
14 (44.8 %)
6 (20.7 %)
3.67
3.21
1.51
PFS progression-free survival
Discussion
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
found to be a predictive factor both in first-line chemotherapy, being related to poorer response to pemetrexedbased chemotherapy (p=0.047), and in second-line chemotherapy (p=0.044).
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)
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
[4]. 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
Support Care Cancer (2015) 23:621–626
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
[21]. 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 [6]. 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 [11]. 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 [4]. 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].
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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 [29].
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 [30].
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
[10]. 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 [31]. 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.
626
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