Neurotoxic side effects of chemotherapy occur frequently, and are often a reason to limit the dose of chemotherapy. Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome by growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is allowed, increasing the risk of neurotoxicity.
Chemotherapy may cause both peripheral neurotoxicity, consisting mainly of a peripheral neuropathy, and central neurotoxicity ranging from minor cognitive deficits to encephalopathy with dementia or even coma.
Vincristine (VCR), the platinum analogs, the taxanes and thalidomide are amongst the most important drugs inducing peripheral neurotoxicity. These drugs are widely used for various malignancies like ovarian cancer, breast cancer, and haematological cancers.
Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies or earlier treatment with neurotoxic chemotherapy are thought to be more vulnerable for the development of chemotherapy-induced peripheral neuropathy.
Management mainly consists of cumulative dose-reduction or lower dose-intensities, especially in patients who have a higher risk to develop neurotoxic side-effects.
Table 1. gives an overview from all chemotherapeutic agents commonly used these days, which may cause peripheral neurotoxicity.
In this guideline we will further focus on the most commonly used peripheral neurotoxic cytostatic agents: cisplatin, oxaliplatin, vincristine, paclitaxel and thalidomide.
Table 1
|
Compound |
Peripheral nervous system |
Management# |
|
Cisplatin |
sensory PNP* with often off-therapy worsening, Lhermitte's sign, muscle cramps |
Amifostine and acetyl-L-carnitine might protect in PNP |
|
Carboplatin |
sensory PNP |
caution with high-dose |
|
Oxaliplatin |
post-infusion paresthesias, sensory PNP |
avoid cold drinks post-infusion, carbamazapine might ameliorate PNP, glutamine might protect |
|
Vincristine |
sensorimotor PNP, mononeuropathy, cranial nerve palsy, autonomic neuropathy |
reducing dose-intensity, glutamic acid, gangliosides and NGF** may protect in PNP |
|
Paclitaxel |
sensorimotor PNP, myalgia and proximal muscle weakness |
reducing dose-intensity, longer infusion time, amitriptyline for pain. NGF, glutamine, glutamate, acetyl-L-carnitine and amifostine may protect |
|
Docetaxel |
predominantly sensory PNP, Lhermitte's sign, proximal motor weakness |
dose reduction, pyridoxine for paresthesias |
|
Methotrexate |
lumbosacral radiculopathy |
caution with high-dose |
|
Cytarabine |
rare: painful sensory PNP, brachial plexopathy |
|
|
5-Fluorouracil |
rare: PNP |
|
|
Ifosfamide |
painful axonal PNP |
|
|
Procarbazine |
sensory PNP |
|
|
Thalidomide |
sensory PNP |
Avoid when possible high cumulative doses (cumulative = |
|
Etoposide |
sensory PNP |
dose reduction |
# Thus far, neuroprotective agents are not widely used in every-day clinical practice, agents mentioned in the table are studied in vitro, in vivo and in clinical trials.
* Peripheral neuropathy
** Nerve growth factor
Authors
C. Verstappen MD, PhD
Clinical features
The clinical features consist of symptoms and signs identical to a sensorimotor axonal neuropathy (vincristine1 and paclitaxel2), sensory neuropathy (thalidomide13), or sensory neuronopathy (cisplatin3). Large myelinated fibers are mainly affected, and this may lead to paresthesias and numbness in hands and feet, loss of propriocepsis, decreased vibration-sense and an ataxic gait.
Ankle and patellar reflexes are nearly always diminished or disappeared.
Oxaliplatin induces two different types of peripheral neuropathy: an acute neurotoxicity typically occurring 30-60 minutes after infusion, consisting of paresthesias, cold hypersensitivity, jaw and eye pain, ptosis, leg cramps and visual and voice changes. After a certain Read more
Natural course and prognosis
Chemotherapy-induced neuropathy is usually reversible after discontinuation, but worsening after cessation of therapy (off-therapy worsening) may occur. Cisplatin is well known for its off-therapy worsening and peripheral neuropathic changes may even begin after completion of the chemotherapy course and progress 2.5-5.5 months after withdrawal of cisplatin3. Paclitaxel and vincristine may also progress a few weeks after cessation of therapy9,10, but in general symptoms and signs resolve within 3-4 months.
Long-term effects were troublesome in only 6% of patients who were treated with cisplatin more than 13 years before11. Vincristine-induced neuropathy may persist up to 40 months, but in general has a good prognoses12.
Epidemiology
Cisplatin-induced neuropathy usually develops after cumulative doses of > 400 mg/m2, occurring in 100% of patients, and ranging from mild to moderate severity (= without interference with daily life activities). Dose-limiting peripheral neuropathy may occur with higher doses7.
Vincristine-induced neuropathy usually starts after a cumulative Read more
Pathophysiology / etiology
The mechanisms responsible for the development of peripheral neuropathy are not fully understood. Depending on the cytostatic agent used, a pure sensory neuropathy (cisplatin, carboplatin and oxaliplatin), or a mixed sensorimotor neuropathy with or without involvement of the autonomic nervous system (vincristine, paclitaxel and thallidomide) occurs. Cisplatin affects mainly the sensory neurons in the dorsal root ganglia resulting in a sensory neuronopathy5, whereas vincristine and paclitaxel presumably disrupt axonal transport by inhibiting microtubuli transport, leading to an axonal neuropathy6. Pathological studies in both cases show axonal degeneration with segmental demyelination.
Differential diagnosis
The differential diagnosis consists mainly of other causes of peripheral neuropathy, especially diabetes mellitus, alcohol abuse, renal failure and hereditary neuropathies.
Worsening or even starting of peripheral neuropathic symptoms after completion of the chemotherapy course is a well-known phenomenon of cisplatin,3 and there is no need to look for other causes in this situation.
In general, when a patient, who is treated with neurotoxic chemotherapy, develops a peripheral neuropathy no further diagnostic investigations are warranted.
Ancillary investigations
Ancillary investigations are also not necessary when known neurotoxic chemotherapeutic agents are administered to patients (e.g. cisplatin, vincristine, paclitaxel, oxaliplatin or thalidomide).
Nerve conduction studies are not mandatory, but can be helpful in evaluating new chemotherapeutic regimens and/or potential neuroprotective agents.
When patients develop an unexpected severe peripheral neuropathy, underlying causes need to be investigated (hereditary polyneuropathy, like Charcot Marie Tooth disease, diabetes mellitus, alcohol abuse, leptomeningeal spread of the tumour, and renal failure).
Genetics
A possible genetic basis for chemotherapy-induced neuropathy has not been elucidated thus far.
Therapy
Management of chemotherapy-induced neuropathy mainly consists of cumulative dose reduction or lower dose-intensities of the cytostatic agent. Painful paresthesias can be treated with amitriptyline or carbamazapine.
Neuroprotective agents should ideally protect the nervous system without affecting the anti-tumour effect of the cytostatic agent. For many years now potential neuroprotective agents (eg. Nerve Growth Factor, Org2766, glutamine, amifostine, glutamate, and vitamin E) have been studied, with different results. Thus far, however, none of the above-mentioned agents can be recommended for standard use in daily clinical practise, and further studies are warranted.
