Biology Reference
In-Depth Information
Patel et al.
141
showed that high doses of ifosfamide
(14 g/m
2
) could exacerbate underlying neuropathies.
Of interest is the lack of peripheral neuropathy after
ionizing radiation, although there are reports of breast
cancer patients developing brachial plexopathy after
irradiation.
142
e
143
Symptoms in these patients include
paresthesia, hypoesthesia, and pain.
143
In isolated
sensory neurons harvested from rats, ionizing radiation
produces a dose-dependent apoptosis.
144
Ionizing radi-
ation also increases the level of substance P in small
diameter sensory neurons
145
e
146
and decreases the
evoked release of calcitonin gene-related peptide.
147
Because these peptides contribute to neurogenic inflam-
mation
148
and wound healing,
149
decreasing sensory
neuronal function could contribute to radiation-induced
injury.
Chemotherapy-induced peripheral neuropathy has
been widely observed in patients treated with either
cisplatin or oxaliplatin (see review
4
). With cisplatin,
various symptoms of neuropathy occur in up to
approximately half of patients, and the severity of
symptoms is related to the cumulative dose the
patients receive.
120,150
e
152
After cisplatin treatment is
stopped, the neuropathy can persist and even wor-
sen.
151,153
e
154
Combining cancer therapies that produce
CIPN generally increases the incidence of the symp-
toms of neuropathy and thus combined treatments
are not as well tolerated. In one study, the combination
of cisplatin and doxorubicin resulted in neuropathy in
92% of the patients examined.
155
Peripheral nerve
biopsies revealed axonal degeneration in large diam-
eter sensory fibers. Likewise, 10 of 11 patients receiving
cisplatin, cyclophosphamide, and doxorubicin devel-
oped neuropathy.
156
At autopsy, electron micrographs
of peripheral nerves of these patients revealed signifi-
cant axonal degeneration and demyelination. Interest-
ingly, levels of platinum compounds in these patients
were highest in the sural nerve and DRG, which were
similar to levels found in tumors, whereas amounts
in the brain were significantly lower.
156
Treatment
with cisplatin and paclitaxel also resulted in significant
neuropathy and decreased sensory neuronal activity in
a vast majority of patients examined.
157
Thus, much
data supports the notion that agents where the thera-
peutic effect is caused by DNA damage can produce
significant damage to sensory neurons: both large
fibers that convey touch and proprioception
156
and
small fibers that convey temperature and noxious stim-
uli.
158
e
159
The overall consensus in the literature is that
CIPN-induced by carboplatin is less frequent and
less severe than that observed with cisplatin,
160
e
161
although high doses
studying mechanisms of chronic pain use long-term
administration of anticancer drugs in rodents as a model
of neuropathic pain.
137
e
139
Although the neuropathies
can manifest with a variety of symptoms, in general
they can be divided into symptoms that occur acutely
during therapy and those that manifest over time during
repeated treatments. This division may reflect different
mechanisms for acute versus chronic exposure to cancer
therapies.
Peripherally, the cell body of primary sensory
neurons involved with touch, proprioception, pain,
and temperature are localized in the dorsal root ganglia
(DRG). These neurons are pseudounipolar in that an
axon travels from cutaneous and visceral endings in
the periphery to the dorsal horn of the spinal cord.
Touch and proprioception are conveyed by large diam-
eter myelinated sensory neurons, whereas pain and
temperature are conveyed by small diameter lightly
myelinated or unmyelinated fibers. Because the cell
bodies of sensory neurons and a majority of nerves lie
outside the blood
brain barrier, these cells are exposed
to higher concentrations of chemotherapeutic drugs
than neurons in the central nervous system. For
example, in one study measuring postmortem levels
of cisplatin in tissues taken from patients that received
the drug antemortem, the highest concentrations of
the drug were found in the dorsal root ganglia and
dorsal roots, and there was a correlation between high
levels in these tissues and clinical neuropathy.
120
In an
animal study measuring paclitaxel concentrations in
tissues after chronic dosing, the highest concentrations
of the drug were found in the sciatic nerve and the
DRG.
140
With CIPN, the various symptoms that are reported
suggest that toxicity can occur in both myelinated and
unmyelinated fibers. Furthermore, the toxic symptoms
could be the result of either increased or decreased func-
tion in the neurons. For example, the tingling and pain-
ful sensations are generally associated with increased
excitability of myelinated and unmyelinated fibers,
respectively. In contrast, the loss of touch or propriocep-
tion and decreased pain sensitivity suggest a loss of
function of large and small diameter sensory neurons,
respectively. Data in animal studies (see below) clearly
show that all sensory neurons can be affected by cancer
therapies. Determining which symptoms are mediated
by which neurons and the mechanisms for gain or loss
of function remain a challenge.
In general, most CIPN is reported in patients treated
with platinum compounds (see below) or with the
microtubule stabilizing drugs such as paclitaxel or vinca
alkaloids.
19
Peripheral neuropathy is rare as a major side
effect of anticancer treatment with alkylating agents or
doxorubicin. In fact, there are only few reports associ-
ating ifosfamide with peripheral neuropathy but
e
can result
in significant
symptoms.
162
Oxaliplatin treatment presents a unique neurotoxicity
compared to other platinum compounds. In a majority
