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Oral Calcium Ameliorating Oxaliplatin-Induced Peripheral Neuropathy

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					Oral Calcium Ameliorating
Oxaliplatin-Induced Peripheral
Neuropathy
Muhammad Wasif Saif, MD
University of Alabama at Birmingham, Birmingham, Alabama



KEY WORDS: oxaliplatin,                        we also were able to administer a cumu-
neuropathy, colon cancer, calcium,             lative dose of 2500 mg/m2 (990 mg/m2
magnesium                                      with oral calcium). Although the current
                                               recommendations for the management
ABSTRACT                                       of the acute and cumulative neurotoxic-
Oxaliplatin has become an integral part        ity from oxaliplatin with the use of infu-
of the standard treatment for advanced         sion of Ca/Mg remain valid, our case is
colorectal cancer. While oxaliplatin has       the first report demonstrating the role
only mild hematologic and gastrointesti-       of oral minerals in ameliorating neuro-
nal side effects, its dose-limiting toxicity   toxicity from oxaliplatin. Future studies
is a cumulative sensory neurotoxicity.         to evaluate the role of oral Ca/Mg are
Oxaliplatin causes a unique, but fre-          warranted, since they could prove to be
quent, acute sensory neuropathy that is        an effective, less expensive and more
triggered or aggravated by exposure to         convenient way to treat and prevent
cold but is rapidly reversible, without        oxaliplatin-associated toxicity.
persistent impairment of sensory func-
tion. Various strategies have been pro-        INTRODUCTION
posed to prevent or treat                      Oxaliplatin is a third generation plat-
oxaliplatin-induced neurotoxicity. One         inum compound that differs both struc-
such strategy is the “Stop-and-Go” con-        turally and in its spectrum of activity
cept, which uses the reversibility of neu-     from the related and widely used
rologic symptoms to aim at delivering          chemotherapeutic agents cisplatin and
higher cumulative oxaliplatin doses, as        carboplatin. Platinum compounds exert
long as the therapy is still effective and     their cytotoxic effects through the for-
the other is the administration of neuro-      mation of DNA adducts that block both
modulatory agents (ie, calcium-magne-          DNA replication and transcription,
sium infusions, carbamazepine,                 resulting in cell death in actively divid-
gabapentin, amifostine, alpha-lipoic acid,     ing cells, as well as through the induc-
and glutathione) that could limit the          tion of apoptosis. Unlike these
neurotoxic effects of oxaliplatin. Among       cis-diamine platinums, oxaliplatin con-
all of the agents, intravenous calcium         tains a 1,2 diaminocyclohexane carrier
and magnesium have shown the most              ligand. This structural alteration results
promise in prophylaxis and treatment of        in formation of bulkier platinum-DNA
oxaliplatin-induced neurotoxicity. We          adducts that may be more difficult to
report a case of a patient, in which oral      repair, leading to increased inhibition of
calcium supplements not only were suc-         DNA synthesis and induction of
cessful in treating his neurotoxicity, but     apoptosis.1

576                                Vol. 4, No. 4, 2004 • The Journal of Applied Research
      Oxaliplatin combined with 5-fluo-       and intensity of acute oxaliplatin-
rouracil (5FU) is now considered a stan-      induced symptoms and might delay
dard treatment for metastatic colorectal      cumulative neuropathy, especially in 85
cancer2,3 and on November 4, 2004, the        mg/m2 oxaliplatin dosage.9
FDA approved oxaliplatin for injection            We describe a patient with advanced
for use in combination with infusional        colon cancer, who was able to receive a
5-fluorouracil/leucovorin (5-FU/LV) for       cumulative dose of 2500 mg/m2 of oxali-
adjuvant treatment of stage III colon         platin with intravenous, and later oral
cancer patients who have undergone            calcium. This is the first case of oral cal-
complete resection of the primary             cium ameliorating neurotoxicity.
tumor.4 The combination of oxaliplatin
with oral fluorouracil prodrugs, such as      CASE REPORT
capecitabine,5 is currently being evaluat-    A 62-year-old white male with metastat-
ed. Its overall hematologic and gastroin-     ic colon cancer received oxaliplatin-
testinal side effects profile is good, but    based chemotherapy as a second line
neurotoxicity is a frequent dose-limiting     chemotherapy after unsuccessful treat-
toxicity. The peculiar acute neurotoxicity    ment with bIFL (bolus 5-FU, irinotecan,
of oxaliplatin is manifested as a cold-       and leucovorin). The patient received 8
related dysesthesia and sometimes             cycles of FOLFOX-4 regimen (oxali-
accompanied by muscle contractions,           platin/5FU/LV), initiated on November
which may occur shortly after drug            25, 2002. He tolerated the treatment
administration. These clinical manifesta-     with only grade 1 neuropathy, which
tions of this acute neurotoxicity differ      manifested as tingling, numbness, and
greatly from cisplatin neurotoxicity and      paraesthesias in the lower extremity, and
are not explained by morphological            lasted for 3 to 4 days (Table 1). In March
damage of the nerve,4,6 and resemble          2003, the patient moved to Wisconsin
those described in patients with congeni-     but decided to continue his treatment in
tal myotonia or tetany.6,7 Therefore, it is   Birmingham, Alabama. Therefore, due
hypothesized that oxaliplatin has a           to responding disease and no significant
unique direct effect on nerve excitabili-     toxicities, his regimen was changed to
ty. It is postulated that oxalate, one of     CAPOX (capecitabine with oxaliplatin)
the oxaliplatin metabolites, is responsi-     primarily because it was more conven-
ble for the acute neurotoxic effects of       ient for the patient. The patient tolerat-
oxaliplatin via Ca and/or Mg chelation;8      ed the first two cycles with minimal
which is based on the fact that oxalate is    toxicity, but developed grade 2 neuropa-
also responsible for the acute neurotoxic     thy following cycle 2. An infusion of cal-
effects of ethylene glycol poisoning8 and     cium and magnesium was added to cycle
is a known chelator of both Ca and Mg.        3, but he continued to experience grade
Based on this belief, the effectiveness of    2 neuropathy, hence, the dose of oxali-
both Ca and Mg infusions has been eval-       platin was reduced to 110mg/m2 in cycle
uated in a retrospective cohort of 161        4 (June 2003, Table 1).
patients treated with oxaliplatin, 5-fluo-         He received oxaliplatin at the
rouracil, and leucovorin for advanced         reduced dose through September 2, 2003
colorectal cancer, with 3 regimens of         without any complications or worsening
oxaliplatin (85 mg/m2 (every 2 weeks),        of neuropathy. During cycle 8, he com-
100 mg/m2 (every 2 weeks), 130mg/m2           plained of a severe itch all over his body
(every 3 weeks).9 This study demon-           following the infusion of calcium and
strated that intravenous infusion of          magnesium. The itch was so severe that
Ca/Mg seems to reduce the incidence           intravenous benadryl, ranitidine,

The Journal of Applied Research • Vol. 4, No. 4, 2004                                 577
Table 1. Patient’s Dose and Administration of Oxaliplatin
Date of administration             Dose of oxaliplatin (mg/m2)     Ca/Mg given (+)/not given (-)
11-25-02                                       85                                -
12-19-02                                       85                                -
12-30-02                                       85                                -
1-13-03                                        85                                -
1-27-03                                        85                                -
2-10-03                                        85                                -
2-24-03                                        85                                -
3-10-03                                        85                                -
3-24-03                                       130                                -
4-14-03                                       130                                -
5-20-03                                       130                               +
6-09-03                                       110                               +
6-30-03                                       110                               +
7-21-03                                       110                               +
8-11-03                                       110                               +
9-02-03                                       110                               +/-
9-29-03                                       110                                -
10-20-03                                      110                                -
11-10-03                                      110                                -
12-01-03                                      110                                -
12-22-03                                      110                                -
1-12-04                                       110                                -
2-02-04                                       110                                -
2-16-04                                       110                                -



diazepam, and decadron did not relieve              he felt 99% better (6 days later). I
it. The patient mentioned that previous-            asked him to show me the “new pill”,
ly, he had developed an itch every time             which was Rolaids (oral calcium supple-
he received the Ca/Mg infusion, but he              ment, over the counter). I asked the
did not mention it because it was not               patient to maintain a diary of his symp-
“bad” and he did not want to stop oxali-            toms and note whenever he took the
platin, which continued to shrink his               oral calcium supplement (Table 2). The
tumor. Post-oxaliplatin infusion of                 patient said that he had not developed
Ca/Mg was not given. He also thought                any itch since infusions were stopped
his itch was caused by Mg and he                    after the last cycle, and that oral calcium
refused to receive an infusion of Ca/Mg             was helping him to ameliorate peripher-
during cycle 9 of CAPOX on September                al neuropathy. Due to his positive
29, 2003. The patient also mentioned                response to oral calcium, we tried oral
that when he went to Wisconsin and                  magnesium (Mg Oxide 400mg PO x
developed neuropathy described as                   BID x 5 days starting on the evening of
numbness, lack of sensation on the feet             oxaliplatin administration), in addition
and tips of fingers of both hands, he               to calcium starting with cycle 11
took a “pill” and “the new pill is really           (November 10, 2003). The patient was
helping me”. On the 29th of September,              able to continue oxaliplatin till February

578                                 Vol. 4, No. 4, 2004 • The Journal of Applied Research
Table 2. Dose of Oral Calcium and Outcome in Improvement of Neurotoxicity
                                    AMOUNT OF
DATE                  TIME         ROLAIDS TAKEN       SYMPTOMS
9/30/03                PM                    4
10/1/03                AM                    3         Noticed improvement in feet
10/1/03                PM                    3
10/2/03              8:30 AM                 3         Reduced numbness considerably
10/2/03              2:30 PM                 3         Numbness started to build up,
                                                        Rolaids reversed
10/3/03                AM                    3         Less severe numbness
10/4/03              9:00 AM                 3         No numbness in Feet
10/4/03              7:00 PM                 3         Numbness was returning
10/5/03              7:45 AM                 3         Numbness improving
10/5/03              2:00 PM                 3
10/5/03              3:00 PM                 2
10/6/03                               Took several     Both palms numb before taking rolaids
107/03                 AM                    3         Helping numbness
10/7/03                PM                    3         Helping numbness
10/8/03                            10 throughout day   Helping numbness
10/9/03              4:45 PM                 3         Less numbness
10/10/03               AM                    3         Helping numbness
10/11/03             4:00 PM                 4         Hands were numb at this point
10/15/03                                               Numbness 50% better. Hardly peeling
10/20/03                                               Patient has an appointment


16, 2004 with a cumulative dose of 2500          tive.2,3 An acute neurosensory toxicity,
mg/m2 of oxaliplatin. He did not devel-          which develops shortly after infusion of
op any severe diarrhea with Mg Oxide,            oxaliplatin, presents as paresthesias and
which was probably counter balanced by           dysesthesias of the hands, feet, and peri-
the calcium. In March 2004, this regimen         oral region; jaw tightness; and unusual
was stopped due to progressive disease.          pharyngo-laryngo-dysesthesias. The
The patient is currently receiving erbitux       pharyngo-laryngo-dysesthesias/syn-
and has no objective or subjective evi-          drome is characterized by a loss of sen-
dence of residual neuropathy.                    sation of breathing without any objective
    Also of note, during the entire peri-        evidence of respiratory distress but may
od of treatment, he continued to work            rarely involve laryngospasm.10 Acute
full days at work and gardened outdoors          neurotoxicity may be triggered or exac-
at home. He denied any fatigue, anorex-          erbated by exposure to cold. These
ia, nausea, vomiting, diarrhea, mucositis,       symptoms occur within hours of expo-
cough, or abdominal pain; his only per-          sure and are usually reversible over the
sistent problem was grade 1 to grade 2           following hours or days, and they may
neuropathy.                                      increase in both duration and severity
                                                 with repeated administration of oxali-
DISCUSSION                                       platin. Cumulative neuropathy is mani-
Neurotoxicity is the principal and dose-         fested as a persistent sensory peripheral
limiting toxicity of oxaliplatin, with two       neuropathy that may develop with pro-
distinct subtypes: acute and cumula-             longed treatment, eventually causing

The Journal of Applied Research • Vol. 4, No. 4, 2004                                     579
superficial and deep sensory loss, senso-   “Stop-and-Go” concept uses the
ry ataxia, and functional impairment.       reversibility of neurologic symptoms to
Development of sensory neuropathy is        aim at delivering higher cumulative
correlated with the cumulative dose of      oxaliplatin doses as long as the therapy
oxaliplatin. On cessation of drug, the      is still effective, such as OPTIMOX
chronic neurotoxicities improve in the      trial.16
majority of patients within 4 to 6 months         Calcium and magnesium possess the
and will completely resolve in approxi-     ability to modify the properties of the
mately 40% of patients within 6 to 8        voltage-gated sodium channels. In par-
months.11 The likelihood of symptomatic     ticular, increasing extracellu1ar calcium
improvement on discontinuation of           concentration has a hyperpolarizing
oxaliplatin correlates inversely with       effect on the cell membrane. Kinetic
cumulative dose.                            analyses show that increasing calcium
     The differences in symptom onset       concentrations increases the probability
and clinical spectrum suggest a different   of sodium channel closing. In a state of
mechanism for the acute and chronic         extended refractory period like that
forms of oxaliplatin-associated neuro-      observed in the presence of oxaliplatin,
toxicity. Studies have shown patients       increasing extracellular calcium concen-
with acute sensory symptoms display lit-    tration should facilitate sodium channel
tle or no axonal degeneration, suggest-     closing and reduce the oxaliplatin hyper-
ing a specific effect of oxaliplatin on     stimulatory effect. These results provid-
sensory neurons and/or motor neurons        ed the rationale for using calcium and
or muscle cells that is not observed with   magnesium supplementation in patients
other platinum agents. The similarity of    with severe acute neurotoxicity symp-
acute symptoms induced by oxaliplatin       toms. Gamelin L et al9 recently reported
with those caused by several drugs or       a retrospective study of 161 patients
toxins acting on neuronal or muscular       treated with oxaliplatin with 5-fluo-
ion channels suggest that these symp-       rouracil and leucovorin for advanced
toms may result from a specific interac-    colorectal cancer, with 3 regimens of
tion of oxaliplatin with ion channels       oxaliplatin (85 mg/m2/2 weeks, 100
located in the cellular membrane.           mg/m2/2 weeks, 130 mg/m2/3 weeks).
Recent data indicate that oxaliplatin       Ninety-six patients received infusions of
may act on specific isoforms of the volt-   Ca gluconate (1 g) and Mg sulfate (1 g)
age gated sodium (Na+) channel to           before and after oxaliplatin (Ca/Mg
increase the excitability of sensory neu-   group) and 65 did not. Only 4% of
rons, an action inhibited by the Na+        patients withdrew for neurotoxicity in
channel blocker, carbamazepine. This        the Ca/Mg group versus 31% in the con-
contention is supported by recent clini-    trol group (P = 0.000003). The tumor
cal findings indicating that pharmacolog-   response rate was similar in both groups.
ic blockade of Na+ channels may             The percentage of patients with grade 3
prevent and/or repress the acute neuro-     distal paresthesia was lower in Ca/Mg
toxicity of oxaliplatin.12-15 There is no   group (7 versus 26%, P = 0.001). Acute
indication at this time that a common       symptoms such as distal and lingual
cellular mechanism induces both the         paresthesia were much less frequent and
acute and the cumulative neurotoxicity      severe (P = 10(-7)), and pseudolaryn-
of oxaliplatin.                             gospasm was never reported in Ca/Mg
     Various strategies have been pro-      group. At the end of the treatment, 20%
posed to prevent or treat oxaliplatin-      of patients in Ca/Mg group had neu-
induced neurotoxicity. The                  ropathy versus 45% (P = 0.003) in the

580                             Vol. 4, No. 4, 2004 • The Journal of Applied Research
control group. Patients with grade 2 and               2.    de Gramont A, Figer A, Seymour M, et al.
                                                             Leucovorin and fluorouracil with or without
3 neuropathy at the end of the treat-                        oxaliplatin as first-line treatment in advanced
ment, in the 85 mg/m2 oxaliplatin group,                     colorectal cancer. J Clin Oncol. 2000;18:2938-
recovered significantly more rapidly                         2947.
from neuropathy than patients who                      3.    de Gramont A, Vignoud J, Tournigand C, et
were not receiving Ca/Mg. No compari-                        al. Oxaliplatin with high-dose leucovorin and
                                                             5-fluorouracil 48-hour continuous infusion in
son exists at present between this                           pretreated metastatic colorectal cancer. Eur J
approach and other alternatives such as                      Cancer. 1997;33:214-219.
carbamazepine, glutathione, alipoïc acid,              4.    de Gramont A, Boni C, Navarro M,
or amifostine.17-20 The efficacy of such                     Tabernero J. Oxaliplatin/5FU/ LV in adjuvant
neuromodulatory agents is not estab-                         colon cancer: safety results of the internation-
                                                             al randomized MOSAIC trial. Proc Am Soc
lished and they can generate toxic side                      Clin Oncol. 2002;21:132a.
effects and interfere with oxaliplatin effi-           5.    Cassidy J, Tabernero J, Twelves C, et al.
cacy.                                                        XELOX (capecitabine plus oxaliplatin):
     Calcium and magnesium infusions                         active first-line therapy for patients with
                                                             metastatic colorectal cancer. J Clin Oncol.
are nontoxic and well-tolerated, except                      2004;22:2084-2091.
for the itch side effect in our case study
                                                       6.    Wilson RH, Lehky T, Thomas RR, Quinn
patient. Neurotoxic effects are experi-                      MG, Floeter MK, Grem JL. Acute oxali-
enced by a large number of patients;                         platin-induced peripheral nerve hyperex-
whereas the cumulative effects are expe-                     citability. J Clin Oncol. 2002;20:1767-1774.
rienced by a smaller number of patients                7.    Cannon SC. Ion-channel defects and aberrant
and are potentially reversible, even ade-                    excitability. In myotonia and periodic paraly-
                                                             sis. Trends Neurosci. 1996;19:3-10.
quate management of the former may
                                                       8.    Jacobsen D, Mc Martin KE. Methanol and
render oxaliplatin therapy highly tolera-                    ethylene glycol poisonings. Mechanisms of
ble. But now with the addition of target-                    toxicity, clinical course, diagnosis and treat-
ed therapy, such as avastin, to                              ment. Med Toxicol. 1986;1:309-334.
oxaliplatin, it is expected to have longer             9.    Gamelin L, Boisdron-Celle M, Delva R, et al.
time to treatment failure, measures to                       Prevention of oxaliplatin-related neurotoxici-
                                                             ty by calcium and magnesium infusions: a ret-
allow patients to receive higher cumula-                     rospective study of 161 patients receiving
tive doses of oxaliplatin are prudent.                       oxaliplatin combined with 5-Fluorouracil and
Whereas the current recommendations                          leucovorin for advanced colorectal cancer.
                                                             Clin Cancer Res. 2004;10:4055-4061.
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management of the acute and cumula-                    10.   Extra JM, Marty M, Brienza S, Misset JL.
                                                             Pharmacokinetics and safety profile of oxali-
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remain valid, data suggest that oral sup-              11.   Brienza S, Vignoud J, Itzhaki M, et al.
plements need to be explored in this set-                    Oxaliplatin (L-OHP): Global safety in 682
ting. Larger prospective studies to                          patients. Proc Am Soc Clin Oncol.
                                                             1995;14:209. Abstract 513.
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form should be considered. If oral calci-              12.   Adelsberger H, Quasthoff S, Grosskreutz J,
                                                             Lepier A, Eckel F, Lersch C. The chemothera-
um and/or magnesium can be effective                         peutic oxaliplatin alters voltage-gated Na (+)
in ameliorating neurotoxicity induced by                     channel kinetics on rat sensory neurons. Eur
oxaliplatin, then it can lead to a less                      J Pharmacol. 2000;406:25-32.
expensive and more convenient way to                   13.   Grolleau F, Gamelin L, Boisdron-Celle M,
treat and prevent this toxicity.                             Lapied B, Pelhate M, Gamelin E. A possible
                                                             explanation for a neurotoxic effect of the
                                                             anticancer agent oxaliplatin on neural volt-
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