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Abnormalities of magnesium homeostasis in patients with chemotherapy-induced alimentary tract mucositis

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Purpose: Hypomagnesemia contributes to morbidity in a significant proportion of hospitalized and severely ill patients, but it could also have beneficial anticancer effects. Alimentary tract mucositis is a frequent complication of cytotoxic chemotherapy. The aim of this study was to determine frequency and severity of hypomagnesemia in patients with different grades of chemotherapy-induced alimentary tract mucositis and to assess its clinical manifestations. Methods: Multicentric observational study included 226 adult patients with alimentary mucositis treated at 3 different institutions. Patients were evaluated for severity of mucositis and the presence of hypomagnesemia, symptoms associated with hypomagnesemia, hypocalcemia, ECG changes and granulocytopenia. Subgroup analysis related to mucositis severity and presence of hypomagnesemia was performed. Results: Patients with grade 3 or 4 alimentary mucositis expectedly had more frequent and more severe granulocytopenia than patients with milder mucositis (49.6% vs. 35.4%, P = 0.043), but there were no differences in rate of hypomagnesemia (24.8% vs. 26.5%). When compared to patients with normal magnesium levels, patients with hypomagnesemia had higher rates of hypocalcemia (50.0% vs. 32.7%, P = 0.026), QTc prolongation (15.5% vs. 3.0%, P = 0.002) and granulocytopenia (77.6% vs. 39.9%, P < 0.001), while there was no difference in symptoms or other ECG features among these subgroups. Conclusions: Hypomagnesaemia is not associated with the severity of chemotherapy-induced mucositis. However, hypomagnesaemia was associated with higher rates of granulocytopenia and hypocalcemia. Our study failed to identify the link between hypomagnesaemia and chemotherapy-induced mucositis.
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Barsic et al.
12 Endocrine Oncology and Metabolism
ORIGINAL INVESTIGATION
Abnormalities of magnesium homeostasis
in patients with chemotherapy-induced
alimentary tract mucositis
1Department of gastroenterology and hepatology, Sestre milosrdnice University hospital center, University of Zagreb, Croatia
2Department of oncology, Šibenik County hospital, Šibenik, Croatia
Neven Baršić
1
, Filip Grubišić-Čabo
2
, Marko Nikolić
1
, Neven Ljubičić
1
Abstract
Purpose: Hypomagnesemia contributes to morbidity in a signicant
proportion of hospitalized and severely ill patients, but it could also have
benecial anticancer eects. Alimentary tract mucositis is a frequent
complication of cytotoxic chemotherapy. The aim of this study was to
determine frequency and severity of hypomagnesemia in patients with
dierent grades of chemotherapy-induced alimentary tract mucositis and to
assess its clinical manifestations.
Methods: Multicentric observational study included 226 adult patients
with alimentary mucositis treated at 3 dierent institutions. Patients were
evaluated for severity of mucositis and the presence of hypomagnesemia,
symptoms associated with hypomagnesemia, hypocalcemia, ECG changes
and granulocytopenia. Subgroup analysis related to mucositis severity and
presence of hypomagnesemia was performed.
Results: Patients with grade 3 or 4 alimentary mucositis expectedly had
more frequent and more severe granulocytopenia than patients with milder
mucositis (49.6% vs. 35.4%, P = 0.043), but there were no dierences in rate
of hypomagnesemia (24.8% vs. 26.5%). When compared to patients with
normal magnesium levels, patients with hypomagnesemia had higher rates
of hypocalcemia (50.0% vs. 32.7%, P = 0.026), QTc prolongation (15.5% vs.
3.0%, P = 0.002) and granulocytopenia (77.6% vs. 39.9%, P < 0.001), while
there was no dierence in symptoms or other ECG features among these
subgroups.
Conclusions: Hypomagnesaemia is not associated with the severity of
chemotherapy-induced mucositis. However, hypomagnesaemia was
associated with higher rates of granulocytopenia and hypocalcemia.
Our study failed to identify the link between hypomagnesaemia and
chemotherapy-induced mucositis.
Key words: hypomagnesemia, alimentary tract mucositis, chemotherapy-
induced mucositis
Corresponding author:
Neven Baršić, MD, PhD
Department of gastroenterology and
hepatology
Sestre milosrdnice University hospital
center, Vinogradska cesta 29, Zagreb,
Croatia
e-mail: neven.barsic@gmail.com
DOI: 10.21040/eom/2016.2.1.
Received: January 5th 2016
Accepted: February 21st 2016
Published: March 14th 2016
Copyright: © Copyright by Association
for Endocrine Oncology and Metabolism.
This is an Open Access article distributed
under the terms of the Creative
Commons Attribution Non-Commercial
License (http://creativecommons.org/
licenses/by-nc-nd/4.0/) which permits
unrestricted non-commercial use,
distribution, and reproduction in any
medium, provided the original work is
properly cited.
Funding: None.
Conict of interest statement: The
authors declare that they have no conict
of interest.
Data Availability Statement: All
relevant data are within the paper.
Endocrine Oncology and Metabolism 13
Barsic et al.
1. Introduction
Magnesium is the fourth most prevalent mineral in
human body and the second intracelullar cation just
aer potassium [1]. It is a key cofactor in all biochem-
ical reactions involving adenosine triphosphate, and
its depletion is oen associated with other electrolite
abnormalities such as hypokalemia, hypocalcemia,
and metabolic alkalosis. Hypomagnesemia occurs in
more than 10% of hospitalized patients, and in up to
60% of patients in intensive care units, contributing
to overall morbidity and mortality [2,3]. e most
important clinical manifestations of hypomagnese-
mia are neurologic/neuromuscular disturbances, ECG
changes and cardiac arrhythmias, changes in calcium
metabolism leading to hypocalcemia and hypokale-
mia. Serum magnesium concentration is usually not a
standard part of routine blood tests. erefore, detec-
tion of patients with hypomagnesemia usually requires
increased clinical awareness in high risk patients.
Chemotherapy-induced alimentary tract (gastroin-
testinal and oral) mucositis is dened as inamma-
tory and/or ulcerative lesions of the oral cavity and/
or gastrointestinal tract induced by chemotherapeutic
agents. It is an important dose-limiting side eect of
chemotherapy and one of the most common causes
of morbidity. It occurs in 20 - 60% of patients with
solid tumors who are receiving chemotherapy [4].
Manifestations of oral mucositis include erythema,
soreness and ulcers of the oral mucosa. Gastrointestinal
mucositis is usually diagnosed indirectly based on the
presence of diarrhea. Grade 3 – 4 oral and gastrointes-
tinal mucositis is dened by severe symptoms interfer-
ing with oral intake of food, which occurs in 2-15% of
patients [5].
Malapsorption of various nutrients, including mag-
nesium, is one of the consequences of gastrointestinal
tract inammation and dysfunction induced by che-
motherapy. However, published studies on magne-
sium abnormalities in patients receiving chemother-
apy have been mostly focused on hypomagnesemia
associated with renal wasting [6-9]. ere are no stud-
ies that analyzed the impact of chemotherapy-induced
mucositis on hypomagnesemia.
e aim of our study was to establish the frequency and
severity of hypomagnesemia in patients with dierent
grades of chemotherapy-induced gastrointestinal
mucositis, evaluate presence of its clinical manifesta-
tions (symptoms, electrocardiogram changes, calcium
level abnormalities), and assess its relation to occur-
rence of other side eects of cytotoxicity.
2. Patients and methods
is mu
lticentric observational study included 226
adult patients with symptoms of chemotherapy-in-
duced alimentary mucositis treated at 3 dierent
institutions in the period from September 2010 to
November 2012. One hundred and thirteen patients
had grade 3 or 4 alimentary mucositis and the second
group consisted of 113 patients with grade 1 or 2 ali-
mentary mucositis.
Patients had received chemotherapy for various solid
malignant tumors and had received chemotherapy
within 3 weeks prior to inclusion. Patients with pos-
itive bacterial culture stool test were excluded from
the study. All patients have signed the informed con-
sent, and the study was approved by local ethics com-
mittees. Grading of severity of chemotherapy side
eects was made according to Common Terminology
Criteria for Adverse Events, Version 4.0 [10].
Study protocol included: serum biochemis-
try and blood count tests, detailed medical his-
tory, physical examination and electrocardiogram.
Hypomagnesaemia was dened as magnesium levels
below the lower limit of normal (0.65 mmol/L).
Presence of symptoms and signs usually associated
with hypomagnesemia including weakness and neu-
romuscular hyperexcitability was meticulously exam-
ined and noted. Electrocardiogram was analyzed for
widening of the QRS complex, peaking or diminution
of T waves, prolongation of the PR interval, corrected
QT interval, atrial and ventricular premature systoles,
and atrial brillation. Collected data included details
on current oncologic disease and treatment, as well
as history of earlier side eects and adverse events
related to chemotherapy. Diagnosis and grading of
chemotherapy-induced gastrointestinal mucositis
was made based on examination of oral cavity, pres-
ence of diarrhea, and possibility of food intake.
Barsic et al.
14 Endocrine Oncology and Metabolism
2.1. Statistical analyses
Patient characteristics were assessed using descriptive
statistics presented as a mean with standard deviations.
Independent continuous variables were compared using
Mann-Whitney test and categorical variables were com-
pared using Fishers exact test. Soware SPSS 20.0 for
Windows was used to perform all the analyses. P value
<0.05 was considered signicant.
3. Results
We included 226 patients with symptoms of chemother-
apy-induced gastrointestinal mucositis: 113 patients
with grade 1 or 2, and 113 with grade 3 or 4 alimen-
tary mucositis. Mean age of the studied population was
63.8 ± 10.6 years, and 131/226 (58%) were females.
Characteristics of the study population divided based on
the severity of mucositis is presented in Table 1. ere
Table 1. Anthropometric and laboratory parameters in the study population divided based on severity
of alimentary tract mucositis. Continous variables are presented as mean ± standard deviation.
Grade 1 or 2 alimentary
mucositis
(n=113)
Grade 3 or 4
alimentary mucositis
(n=113)
P value
Age (years)
64.8
±
9.8 62.9
±
10.3 0.288
Gender n(%)
Male
Female
52 (46%) 43 (38%) 0.225
Magnesium (mmol/L) mean
±
SD
Hypomagnesemia n(%)
0.72
±
0.16
30 (26.5%)
0.76
±
0.16
28 (24.8%)
>0.3
>0.3
Leukocyte levels
mean
±
SD (x109/L)
Granulocytopenia
<2.06 x10/L n(%)
<1.0 x10/L n(%)
7.12
±
4.88
40 (35.4%)
14 (12.4%)
6.35
±
6.17
56 (49.6%)
33 (29.2%)
0.028
0.043
0.003
Calcium levels
mean
±
SD (mmol/L)
Hypocalcemia n(%)
2.25
±
0.16
39 (34.5%)
2.12
±
0.21
45 (39.8%)
>0.3
>0.3
Fatigue/weakness n(%) 21 (18.6%) 84 (74.3%) <0.001
Endocrine Oncology and Metabolism 15
Barsic et al.
were no signicant dierences in demographic data
between the groups. Granulocytopenia was observed
in 96/226 (42.5%) of patients. Patients with grade 3/4
alimentary mucositis had higher rates and more severe
forms of granulocytopenia than patients with grade 1/2
mucositis. We found no dierence in serum magnesium
and calcium levels, nor the rates of hypomagnesae-
mia and hypocalcemia between the two groups (Tab l e
1). In 67.9% of patients who had hypomagnesaemia, it
was mild (magnesium level 0.5-0.65 mmol/L), and in
the remainder it was in the range between 0.4 and 0.5
mmol/L. Fatigue and weakness were more frequently
noted in patients with severe forms of alimentary muco-
sitis (74.3% vs. 18.6%).
Study population was then divided based on the pres-
ence of hypomagnesaemia and the characteristics
are presented in Tabl e 2 . Signicant dierences were
observed in rates of granulocytopenia, hypocalcemia
and QTc prolongation. Granulocytopenia was observed
more frequently in patients with hypomagnesemia.
Moreover, patients with granulocytopaenia had higher
rates of hypomagnesemia (39.3% vs. 10.5%, P<0.001).
Hypocalcemia and QTc prolongation was also more fre-
quent in patients with hypomagnesemia. e presence
of fatigue/weakness was similar in both groups.
4. Discussion
We found no dierence in rates of hypomagnesemia,
when comparing patients with mild (grade 1 or 2) and
severe (grade 3 or 4) alimentary tract mucositis. is
is contrary to what we have initially hypothesized.
Nevertheless, hypomagnesemia was present in approx-
imately one quarter of patients in both groups. To reach
denite conclusions, rates of hypomagnesemia in our
Table 2. Hypomagnesemia-associated symptoms and signs in patients with low and normal
magnesium levels.
Hypomagnesemia
(n=58)
Normal magnesium
levels
(n=168)
P value
Granulocytopenia n(%) 45 (77.6%) 67 (39.9%) <0.001
Symptoms n(%)
(fatigue/weakness) 30 (51.7%) 75 (44.6%) >0.3
ECG changes n(%)
Atrial brillation
PR prolongation
QRS widening
QTc duration >120%
1 (1.7%)
0
7 (12.1%)
9 (15.5%)
12 (7.1%)
0
24 (14.3%)
5 (3.0%)
0.192
NA
>0.3
0.002
Hypocalcemia n(%) 29 (50.0%) 55 (32.7%) 0.026
Barsic et al.
16 Endocrine Oncology and Metabolism
Author contributions
NB participated in statistical analyses, reviewing the
literature, writing the artical and gave the nal aproval.
FGČ gave the idea for the article, participated in data col-
lection, draing the article and gave the nal approval.
MN reviewed the previously published literature, partic-
ipated in draing the article and gave the nal approval.
NLj critically revised the manuscript, gave suggestions
regarding data collection and analyses and gave the nal
aproval.
cohort of patient, should be compared with patients
without any signs of alimentary mucositis. However, our
study suggests that hypomagnesemia may be associated
with chemotherapy-induced granulocytopenia.
As for the clinical manifestations of hypomagnesemia,
in the subgroup of our patients with low magnesium
levels, we have observed higher rates of hypocalcemia
and QTc prolongation, but without any dierence in
symptoms associated with hypomagnesaemia nor other
ECG abnormalities. Absence of specic symptoms is
not unusual, as most patients in our population had
only mild hypomagnesemia and the symptoms usually
occur only with more profound magnesium depletion
[11]. Albeit fatigue or weakness was more common in
patients with severe alimentary mucositis, their preva-
lence was similar in patients with low and normal mag-
nesium levels. erefore, these symptoms are probably
related to other treatment-induced or disease-related
morbidity.
It has been previously reported that decreased magne-
sium levels could have a benecial role in terms of treat-
ment success. is was observed in patients treated with
cetuximab, which induces renal magnesium wasting
[12]. ese observations raise the question if hypomag-
nesemia should be corrected at all, in order to increase
treatment ecacy [13]. Further studies are needed in
order to determine the etiology and impact of hypo-
magnesaemia in patients with chemotherapy-induced
alimentary tract mucositis.
Endocrine Oncology and Metabolism 17
Barsic et al.
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To assess the incidence of hypomagnesaemia, the influence of different cisplatin dosages on the degree of hypomagnesaemia and the effect of routine magnesium supplementation on magnesium levels. Magnesium levels for 214 consecutive patients receiving cisplatin-based chemotherapy were studied. Twenty different chemotherapy regimens were prescribed. Doses ranged from 7 to 51 mg/m(2)/week. The interval between cycles ranged from 1 to 4 weeks. The number of evaluable cycles ranged from one to eight. Patients receiving bleomycin, etoposide and cisplatin (BEP) chemotherapy routinely received 60 mmol magnesium per cycle; patients receiving cisplatin, vincristine, methotrexate, bleomycin - dactinomycin, cyclophosphamide, etoposide (POMB-ACE) chemotherapy routinely received 20 mmol magnesium per cycle. For all other chemotherapy regimens, magnesium was not routinely prescribed. Baseline magnesium levels were available for 195 patients, 92% were within the normal range. The average level was 0.82 mmol/l. There was a statistically significant decrease in magnesium levels from baseline to the lowest magnesium level (mean = 0.68 mmol/l, standard deviation = 0.13) (P < 0.0005). The incidence of hypomagnesaemia (serum magnesium < 0.7 mmol/l) at any point during chemotherapy was 43%. Multiple regression analysis showed a significant association between dose, frequency, and number of cycles given, and the degree of hypomagnesaemia (P = 0.001, P = 0.03 and P < 0.0005, respectively). Routine magnesium supplementation significantly reduced the degree of hypomagnesaemia if sufficient amounts of magnesium are given: 60 mmol magnesium per cycle for a regimen containing 33 mg/m(2)/week cisplatin is sufficient; 20 mmol magnesium per cycle for a regimen containing 40 mg/m(2)/week cisplatin is insufficient. It is recommended that magnesium levels should be measured routinely in all patients receiving cisplatin and that all cisplatin-based chemotherapy regimens should be supplemented routinely with sufficient doses of magnesium (40-80 mmol magnesium per cycle depending on the regimen).
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Preliminary evidence suggests that magnesium wasting occurs in patients who are treated with epidermal-growth-factor receptor (EGFR)-targeting antibodies for colorectal cancer. The mechanism of this side-effect is unknown, and if all or a subset of patients are affected is also unclear. We aimed to assess the incidence, characteristics, and predictive factors of magnesium wasting during treatment with EGFR-targeting antibodies, and to study the pathophysiology of this phenomenon. We measured prospectively magnesium concentrations in a cohort of 98 patients with colorectal cancer treated with EGFR-targeting antibodies with or without combined chemotherapy. The primary outcome measure was the slope of the serum magnesium concentrations over time. In 35 patients, 24-h urinary magnesium excretion was measured. In a subset of patients (n=5), an intravenous magnesium load test was done. 16 patients who had chemotherapy alone acted as controls. A clinical protocol was written before initiation of the study, but because this was a non-interventional study, the protocol was not formally registered. 95 (97%) patients had decreasing serum magnesium concentrations during EGFR-targeting treatment compared with baseline measurements. The mean serum magnesium slope during EGFR-targeting treatment (with or without combined chemotherapy) was significantly lower compared with chemotherapy alone (-0.00157 mmol/L/day, SD 0.00162 [95% CI -0.00191 to -0.00123] vs 0.00014 mmol/L/day, SD -00076 [-0.00026 to 0.00055]; (t test, p < 0.0001). 24-h urine analysis and intravenous magnesium load tests showed a defect in renal magnesium reabsorption. EGFR-inhibiting antibodies compromised the renal magnesium retention capacity, leading to hypomagnesaemia in most patients. Future studies should address the effects of exposure and target affinity. Our study suggests a pivotal role of the EGFR-signalling pathway in regulating magnesium homoeostasis.