Editorial :
Cancer
is one of the prevalent medical problems among people especially in more developed
and industrialized population. Now a day, it is considered as the third leading
cause of death following cardiovascular problems and accidents. Moreover, the
therapeutic approach to malignanttumors has been developed significantly compared with 70s and 80s. Many
immunotherapies and targeted therapies have been developed and approved for
both solid tumors and hematologic malignancies. Curable approach has been
available for many deadly malignancies and multipletreatment lines have been proposed and validated based on the clinical
trials in the majority of cancers. Innovative technologies such as nanotechnology
have been proposed and developed to optimize the bioavailability of the therapeutic
agents within the tumor. However, adverse events associated with these novel
therapeutic approaches have been inevitable. Many of these adverse events
present acutely during or shortly after the completion of the chemotherapy
and resolve spontaneously or with short term palliative approach or even
reducing the dose and schedule of the chemotherapy protocol. Few adverse events
however, might last for longer periods of time and even life long and show a
significantly negative impact on the patients quality of life despite the
application of palliative approach. Although availability of multiple
combination chemotherapy protocols and variety in the type of therapeutic
approach might play a role in reducing these adverse events, it is not able to
completely eliminate these unwanted effects. Besides, relapsing nature of
cancers that necessitates multiple lines of treatment lead to additive
and sometimes synergic adverse events that might further debilitate the
patients. Chemotherapy associated neurotoxicity is one of
these adverse effects of cancer treatment that has a long history. Vinca
alkaloids, such as vincristine and vinblastine, as well as platinum compounds,
namely cisplatin and carboplatin are among the oldest chemotherapeutic agents
that has been introduced and served in cancer treatment since 50s and 60s.
Taxanes are another group of chemotherapeutic agents with potential neurotoxicitythat in spite of their later development, have gained multiple therapeutic indications
among different types of solid tumors. Neurological adverse events are not
limited to chemotherapeutic agents. Newer generations of targeted therapies and
even antibody-drug conjugate innovative medications have also shown
neurological adverse events. Imids, such as thalidomide and lenalidomide
(Revelmide) and proteasome inhibitors, such as bortezomib (Velcade) are the
prototypes of targeted therapies with prominent neurotoxicity as adverse events.
Even blinatumomab, a CD19 targeting monoclonal antibody that has gained approval
for treatment of acute lymphoblastic leukemia has been associated with neurotoxicity,
presenting as seizure and leukoencephalopathy.
Neurotoxicity associated with cancer treatment
modalities has a wide spectrum not only in clinical presentation, signs and
symptoms, but regarding the natural history, prognosis and proposed efficient
therapeutic modalities. Neuropsychiatricproblems, such as somnolence, mood changes and depression and even organic focal
CNS abnormalities are the other side of this neurotoxicity spectrum that might be
indistinguishable from signs and symptoms associated with the cancer itself or psychological
reactions of the patients to the potentially deadly diagnosis [1-3]. Incidence and prevalence of chemotherapy induced
neurotoxicity is difficult to estimate. Neuropsychiatric symptoms might be referred
to other causes, such as primary cancer itself or other medications that are
taken concurrently by the patients. However, peripheral neuropathy as one the
most prominently encountered adverse event has been reported in up to 68% of
patients who have received neurotoxic chemotherapeutic agents. Symptoms of
chemotherapy associated neuropathy might become chronic in about 30% of these
patients, respectively [4-6]. From clinical point of view, neurotoxicity of
chemotherapeutic agents might be divided in to two main categories of
peripheral and central nervous neurotoxicity. Peripheralneuropathy may present as either sensory or motor or even a combination of
both sensory and motor neuropathy. Signs and symptoms of central nervous system
neurotoxicity on the other hand are less defined compared to peripheral
neuropathies. They might present as common cancer associated symptoms, such as
somnolence, mood changes, depression and even seizure to more complicated
scenarios such as focal neurologic deficits, and leukoencephalopathies.
Peripheral neuropathy of sensory type is by far the most frustrating feature of
cancer associated neurotoxicity with a negative impact on patients quality of
life. Type of involvement is correlated to the type of the chemotherapeutic
agent. However, sensory symptoms such as tingling, burning sensation and
dysesthesia are common. Proprioception, vibration, light touch and position are
generally impaired with devastating consequences. Motor and even autonomic
involvement might also present in severe cases. Different mechanisms have been proposed for
chemotherapy associated neurotoxicity based on the type of the responsible chemothttp://edelweisspublications.com/journals/43/Neurophysiology-and-Rehabilitation-(ISSN:-2641-8991)herapeutic
agent. Vinca alkaloids, and taxanes mainly inhibit microtubule formation and
proteasome inhibitor bortezomib shows tubular toxicity, hence, interfering with
neuron energy delivery mechanisms leading to neurotoxicity. Platinum compounds
generally damage the dorsal root ganglia (DRG) due to its vulnerability and
lack of efficient blood- nerve barrier. Other possible explanations are
vascular damage of peripheral nerves. In general, larger peripheral nerves are
involved and small nerves are spared. However, these mechanisms are not
specific to the type of chemotherapeutic agent and more than one mechanism is
usually involved for each specific type of the drug [7-10]. Central
nervous system associated toxicity, on the other hand has also been
reported with different type of chemotherapeutic agents, such as ifosfamide,
cytarabine, methotrexate, 5-FU and even therapeutic cytokines such as
interferon alfa and interleukin-2. Multiple mechanisms and pathogenesis has
been suggested and observed for this type of neurotoxicity, such as
chemotherapy associated direct toxicity to myelin, vascular endothelial damage,
and even thrombotic microangiopathy.
Alteration in thiamine due to the chemotherapeutic agents itself or its
metabolites has also been suggested in specific type of chemotherapeutic
agents, such as ifosfamide [11-15]. Apart from type of the chemotherapeutic
agent and dose and schedule of treatment modality, other factors, such a kidney
and liver function, past history of radiation to CNS or co administration of
other medications such as immunosuppressive therapy may also play a role in
presence, severity and even the outcome of the neurotoxicity. Other important
factors that have been suggested to play a role are the genetic polymorphisms
in folate metabolizing enzymes and apolipoprotein E, as well as in the
blood–brain barrier transporter genes. Leukoencephalopathy, meningitis
(especially associated with intrathecal administration of chemotherapeutic
agents), cerebellar dysfunction, myelitis, visual or hearing impairment, ataxia
and seizure, as well as psychiatric presentations such as mood changes, sleep
pattern changes, or even depression has been reported as clinical presentations
in CNS neurotoxicity. Interestingly, despite the systemic nature of exposure to
neurotoxic substance, focal neurologic symptoms are not uncommon [12, 16,17]. Apart from few chemotherapeutic agents with known
antidots that reverse their toxicity such as methotrexate, approaching neurotoxicity
associated with many chemotherapeutic agents follows identical steps, early
detection of clinical signs and symptoms, co morbidities that might potentiate
these toxicities, such as renal and liver dysfunction, reducing the exposure by
changing the treatment protocol and dose- schedule of treatment if possible,
palliative managements, as well as anti-inflammatory treatments such as
corticosteroids, COX-2 inhibitors, antiaggregation and even anticoagulants
especially when thrombotic microangiopathy is suspected. The prognosis however,
is largely dependent on the causative agents and the extent of damage. From therapeutic point of view, no specific modality
has been proven to resolve the signs and symptoms or even play a preventive role
for both central and peripheral nervous system toxicities associated with
chemotherapy. However, several classifications of treatments have been proposed
and tried. Antioxidants, such as acetyl L-Carnitine, glutathione, glutamine,
vitamin B derivatives such as vitamin B6 and B12, as well as fish oil have been
proposed for peripheral nerve toxicities associated with platinum compounds,
taxanes and even bortezomib. Anti-convulsants
are another classification of therapeutic agents that has been suggested mostly
as a symptomatic management for sensory neuropathy associated symptoms such as
dysesthesia, tingling and burning. Carbamazepine, ethosuximide and newer
generations of this group of treatment modalities such as gabapentin and
pergabalin has also been administered and tried in clinical trial setting. Antidepressants,
such as amitriptyline and duloxetine have also been tried in clinical setting
to control neuropath associated symptoms. Analgesics and anti-inflammatory
drugs, such as COX-2 inhibitors, corticosteroids, opioid analgesics have been
tried in clinical trial setting addressing symptomatic management of
chemotherapy associated peripheral neuropathy. Interestingly, cannabinoids are another
group of therapeutic modalities that has been proposed and tried in clinical
setting based on their ability to control neurologic complications of chronic
degenerative disorders such as multiple sclerosis. Among all the mentioned
medications that has been proposed and applied in clinical trials, none of them
has shown protective role against chemotherapy associated peripheralneuropathy. Moreover, only duloxetine has shown therapeutic effect to
control taxane associated peripheral neuropathy in phase III clinical trials
[18-20]. A variety of
non-pharmacological modalities has also been proposed and tried in clinical
setting of chemotherapy associated peripheral neurotoxicity. Acupuncture has
been the most widely applied treatment by far. It has shown efficacy in limited
clinical trials, however, its efficacy in neurotoxicity associated with
different types of chemotherapeutic agents needs to be further evaluated in clinical
trial settings [21]. In conclusion, despite the
significant progresses in both chemotherapeutic approaches and targeted
therapies in solid tumors and hematologic malignancies, palliative management
of the adverse events associated with treatment and the disease itself is still
one of the unmet clinical needs in cancer patients. Although many cancers are
still considered as the incurable diseases with a limited survival chance, the
list of curable cancers is fortunately growing further. Moreover, availability
of multiple lines of treatment for each cancer type increases the overall
survival of the cancer patients. These progressions necessitate more attention
to be paid to the signs and symptoms brought by the cancer itself or therapeutic
approaches. Among all of the signs and the symptoms associated with cancer and
its treatment, neurotoxicity
is one of the mostly encountered and long lasting symptoms that need special
attention due to its negative impact in quality of life. Both preventive and
therapeutic approaches to this adverse event need to be addressed further in large randomised clinical
trial setting. 1. Sioka C, Krytsis AP. Central
and peripheral nervous system toxicity of common chemotherapeutic agents (2009)
Cancer Chemother Pharmacol. 63:761-767. Cancer, neurotoxicity, peripheral neuropathy, malignant tumors, multiple treatment, nanotechnology, leukoencephalopathy
Neurotoxicity Associated with Cancer Treatment
Ghazaleh Shoja E Razavi
Abstract
Full-Text
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