Download file (Chemotherapy Induced Peripheral Neuropathy Drug

Hannah Allegretto
Block 6- Chartwell Home Infusions
Drug Information Question 1
Question: “What is chemotherapy induced peripheral neuropathy and how is it managed?”
Answer:
Chemotherapy is a treatment for cancer involving several powerful antineoplastic agents either
alone or in combination to stop the growth of cancerous cells. Although chemotherapy is successful for
numerous patients, the therapy can be limited by several factors for other patients. Although bone marrow
suppression and renal toxicity are common side effects of these medications leading to discontinuation,
the most significant factor contributing to chemotherapy cessation is neurotoxicity.1
Chemotherapy induced peripheral neuropathy (CIPN) results from damage to the nerves in the
peripheral nervous system as a result from these highly active antineoplastic agents. In many cases, this
damage is only partially reversible, with irreversible damage occurring in severe cases. CIPN can be
disabling with a negative impact on the quality of life of the patient. The degree of CIPN is a result of the
specific chemotherapy agents, doses used to treat the patient, and infusion rates administered to the
patient.2 CIPN can have several manifestations, but is most frequently associated with damaged sensory
axons leading to axonal degeneration.3 The clinical presentation of CIPN differs between patients, but the
most common symptoms include numbness, pain, and parasthesias.3,4 Symptoms are related to the
components of the PNS that are injured, with small fiber damage causing burning/loss of temperature
senses and large fiber damage leading to more severe side effects such as loss of reflexes, muscle
weakness, and slowed nerve conduction.2 CIPN presents symmetrically, with the toes of both feet usually
the first area affected. It then progresses to the ankles and lower legs, and then moves to the fingertips and
fingers.
The degree of axonal degeneration will determine if the CIPN can be reversed, with mild cases
having the best reversal prognosis. Axonal degeneration can occur weeks to months after initiation of the
chemotherapy agent and can persist after the medication is withdrawn. “Coasting” is the term used to
describe CIPN that worsens after certain medications have been stopped.2,3 In order to manage these
symptoms as successfully as possible, it is important to understand which chemotherapy agents hold the
highest risk for causing CIPN when used as monotherapy or in conjunction with other chemotherapy
agents.
Several chemotherapy agents have been implicated in causing dose-limiting CIPN such as
platinum compounds, vinca alkaloids, and taxanes1,3,4 The platinum compounds such as cisplatin,
carboplatin, and oxaliplatin damage DNA leading to premature neuronal cell death. Commonly, the
platinum compounds exhibit coasting, with the full effect of neuropathy not being realized until the drugs
are discontinued. Platinum compounds cause neurotoxicity that is usually sensory, with numbness and
paresthesias in the feet and hands that spread with dose accumulation. Unlike other platinum compounds,
oxaliplatin may induce acute syndromes of cold-induced paresthesias, which can give the patient the
sensation of not being able to breathe when exposed to cold temperatures. For the vinca alkaloids,
vincristine is the most neurotoxic agent. Other agents in this class include vinblastine, vindesine, and
vinorelbine. Paresthesias occur early after initiating treatment with the vinca alkaloids, followed by
autonomic neuropathy. Coasting also occurs with these agents, and recovery can take up to two years.
Paclitaxel and docetaxal, taxane derivatives, lead to primarily sensory neuropathies. Patients receiving
paclitaxel experience dose-related toxicity soon after treatment is started. If treatment doses are not
adjusted before the next cycle, weakness may develop. Commonly, taxanes are combined with
carboplatin for increased efficacy. The combination of these medications will lead to amplified
neurotoxicity.2,5 Along with recognizing the specific agents that may place a patient at a higher risk for
CIPN, it is crucial to become familiar with methods used to alleviate or potentially prevent the occurrence
of CIPN.
CIPN risk can be decreased by administering mediations over a longer period of time as well as
the “stop and go” method, which involves the patient stopping therapy at a predetermined dose or when
the patient progresses to a particular grade of CIPN.3 Along with altering the infusion schedules for
chemotherapy, there are several agents that have been investigated for preventing/alleviating symptoms of
CIPN. Chemoprotectants are agents developed to alleviate the toxicity associated with these
chemotherapy medications. The goal of a chemoprotectant is to target the affected area of damage without
compromising the antitumor effect of the chemotherapy agent. Amifostine, a chemoprotectant, has been
shown beneficial at times in protecting against cisplatin and paclitaxel induced neurotoxicities when
administered before the chemotherapy infusion. Further studies are needed to have a strong clinical
recommendation for the use of this agent.2,3
Along with amifostine, infusions of calcium and magnesium were investigated. This method is
beneficial for patients receiving oxaliplatin, because increased extracellular calcium concentrations
facilitates sodium channel closing which would decrease the oxaliplatin-induced hyperexcitability of
peripheral neurons. The infusion does not interfere with the antitumor effects of oxaliplatin, making this
method desirable for those on oxaliplatin based regimens. Studies have shown that patients treated with
CA++/Mg++ infusions were less likely to experience acute or moderate/severe cumulative CIPN or to
withdraw from oxaliplatin therapy than those patients not treated with the infusion. Larger doses of
oxaliplatin were successfully used in patients receiving the infusion than those with no pretreatment,
which could lead to a better quality of life and positive therapeutic outcomes for patients.2,3,6
Several other chemoprotective agents have been studied in trials in order to better understand how
to control this severe adverse effect from chemotherapy. Glutathione, a natural thiol tripeptide, prevents
the initial accumulation of platinum compounds in the dorsal root ganglia and has shown promising
results for the prevention of oxaliplatin-induced neuropathy. In a randomized, double-blind, placebocontrolled study, IV glutathione administered before oxaliplatin was superior to placebo for recuding the
incidence and severity of CIPN. With glutathione, the incidence of CIPN was 43% as compared to 79%
with placebo. Tumor response rates were similar between both groups, proving glutathione dose not
reduce the effectiveness of platinum compounds.2,3,6 Along with glutathione, glutamine, vitamin E, and
xaliproden are agents currently being tested for the prophylaxis of CIPN. Glutamine has been investigated
in trials using both paclitaxel and oxaliplatin. With paclitaxel, patients who received glutamine has a
significant reduction in the severity of CIPN as measured by numbness in fingers and toes. With
oxaliplatin, dose reductions were lower in glutamine groups than in placebo, and lower incidences of
severe neuropathy were reported.2,3 Vitamin E, a fat soluble vitamin, may also decrease incidence/severity
of CIPN. In a trial involving cisplatin, patients receiving vitamin E reported significantly decreased
incidence of CIPN as compared to those with placebo. In a separate trial with cisplatin, paclitaxel, or a
combination of both, vitamin E patients reported significantly less neurotoxicity than those on placebo
(25% vs 73% respectively).3,6 Xaliproden, an oral neurotrophic and neuroprotective agent, is a promising
drug to help with alleviating symptoms of CIPN. In a randomized, double blind study, patients received
oral xaliproden for 14 days starting on the day of oxaliplatin-based chemotherapy administration and
repeated for a median of 12 cycles. For those patients receiving xaliproden, incidence of severe CIPN
(grade 3-4) was 39% less than those with placebo. Xaliproden was not shown to alter cancer response to
oxaliplatin, warranting further studies.3,6
Unfortunately, there is no treatment algorithm for patients experiencing CIPN. Several agents are
being investigated currently for this issue, but there are no set guidelines on the treatment of CIPN.
Although many of these agents look promising, there has not been sufficient trials and evidence backing
up the positive findings from small studies, and results will have to be repeated in order to make strong
clinical recommendations for the use of these products.
References:
1. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002; 249:917.
2. Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral neuropathy: pathogenesis and emerging
therapies. Support Care Cancer. 2004; 12:619-25.
3. Wickham R. Chemotherapy-induced peripheral neuropathy: a review and implications for
oncology nursing practice. Clin J Oncol Nurs. 2007; 11:361-76.
4. Kaley TJ, DeAngelis LM. Therapy of chemotherapy-induced peripheral neuropathy. Br J
Haematol. 2009; 145:3-14.
5. Malik B, Stillman M. Chemotherapy-induced peripheral neuropathy. Curr Neur Neurosci Rep.
2008; 8:56-65.
6. Wolf S, Barton D, Kottschade L et al. Chemotherapy-induced peripheral neuropathy: Prevention
and treatment strategies. Eur J Cancer. 2008; 44:1507-15.