Assessing Neuropathy

Neuropathy

Health care professionals play a major role in educating patients and their families about chemotherapy and management of related adverse effects. One important area of concern is neuropathy. Points to cover include:

Important Safety
Information Including
Boxed Warning

Anaphylactic-like reactions to ELOXATIN have been reported and may occur within minutes of ELOXATIN administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

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Numbness and tingling in extremities
Subjective sensations of having trouble breathing or swallowing
Muscle cramping
Clumsiness, difficulty picking up small objects, buttoning clothing, or problems walking
Neurologic pain
Efforts to manage symptoms and minimize their impact on a patient's daily living routine

In this section, you will find the following:

Eloxatin and 2 types of neuropathy: acute and persistent
Symptoms of acute, reversible primarily peripheral sensory neuropathy
General management recommendations for acute neuropathy
Specific management recommendations for acute pharyngolaryngeal dysesthesia
Symptoms of persistent (>14 days), primarily peripheral, sensory neuropathy
Dose modification recommendations for acute and persistent sensory neuropathy

Eloxatin and 2 types of neuropathy: acute and persistent

Peripheral sensory neuropathy (all grades) was reported during treatment in 92% of stage II and III colon cancer patients receiving Eloxatin plus infusional 5-FU/LV. Grade 3 neuropathy was reported in 13% of these patients during treatment. Overall, neuropathy (all grades) was reported in 82% and 74% of previously untreated and treated patients with advanced colorectal cancer, respectively.

Grade 3/4 neuropathy occurred in 19% and 7% of previously untreated and treated patients with advanced colorectal cancer, respectively.

In phase III trials, neurotoxicity was predictable and manageable in the majority of patients.¹

In the adjuvant setting, persistent neuropathy was generally reversible, with only 0.5% of patients continuing to experience symptoms at the 18-month follow-up.
In metastatic colorectal cancer (MCRC), the median time to recovery from grade 3 neurotoxicity was 13 weeks after treatment withdrawal.

Symptoms of acute, reversible, primarily peripheral sensory neuropathy

Symptoms usually present as transient paresthesia, dysesthesia, and hypoesthesia, characterized by numbness and tingling in the hands, feet, perioral area, or throat when exposed to cold temperatures or cold objects; muscle cramping may occur in the hand or forearm
Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed, but are less common
An acute syndrome of pharyngolaryngeal dysesthesia seen in 1% to 2% (grade 3/4) of patients with advanced colorectal cancer, characterized by subjective sensations of dysphagia or dyspnea without any laryngospasm or bronchospasm (no stridor or wheezing), may also occur (see below for management recommendations)
These symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects
Symptoms of acute neuropathy are early in onset, occurring within hours or 1 to 2 days of dosing, resolving within 14 days, and frequently recurring with further dosing

General management recommendations for acute neuropathy

Instruct patients to avoid cold drinks and the use of ice, to cover skin before exposure to cold or cold objects, and to use gloves before picking up cold objects
Prolongation of infusion time for Eloxatin from 2 hours to 6 hours decreases the C_max by an estimated 32% and may reduce acute toxicities
Infusion times for 5-FU and leucovorin should not be changed

Specific management recommendations for acute pharyngolaryngeal dysesthesia

Instruct patients to help alleviate symptoms by warming themselves (e.g., drinking warm beverages and running their extremities under warm water).
Pharyngolaryngeal dysesthesia, though rare, can be frightening. Inform patients that this symptom does not impair oxygenation, and the symptom usually subsides spontaneously in a few minutes.
Instruct patients to avoid triggers such as cold air and cold beverages in order to limit future episodes of acute neuropathy.

Symptoms of persistent (>14 days), primarily peripheral, sensory neuropathy

Usually characterized by paresthesias, dysesthesias, and hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (eg, writing, buttoning, swallowing, and difficulty walking from impaired proprioception)
Persistent neuropathy can occur without any prior acute neuropathy event
These symptoms may improve in some patients upon discontinuation of Eloxatin

Dose modification recommendations for acute and persistent sensory neuropathy

	Acute sensory neuropathy^*	Persistant sensory neuropathy
	Any grade	Grade 1	Grade 2	Grade 3 or 4
Stage III colon cancer	Prolong ELOXATIN infusion from 2 h to 6 h^† (optional)	No dose modification recommended	consider reducing ELOXATIN dose to 65 mg/m^2†	Consider discontinuing ELOXATIN tharapy^†
Advanced CRC	Prolong ELOXATIN infusion from 2 h to 6 h^† (optional)	No dose modification recommended	consider reducing ELOXATIN dose to 65 mg/m^2†	Consider discontinuing ELOXATIN tharapy^†

^†The 5-FU/LV doses need not be altered. Prolonging the infusion time for ELOXATIN from 2 hours to 6 hours decreases the C_max by an estimated 32% and may mitigate acute toxicities; infusion times for
5-FU/LV do not need to be changed.

INDICATIONS

Eloxatin^® (oxaliplatin injection), used in combination with infusional 5-FU/LV, is
indicated for

Adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor.
Treatment of advanced carcinoma of the colon or rectum.

Clinical Safety Considerations

ELOXATIN should not be administered to patients with a history of known allergy to ELOXATIN or other platinum compounds. Hypersensitivity and anaphylactic/anaphylactoid reactions to ELOXATIN have been reported and were similar in nature and severity to those reported with other platinum compounds (ie, rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension). These reactions occur within minutes of administration and should be managed with appropriate supportive therapy. Drug-related deaths from this reaction have been reported.
ELOXATIN may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant while receiving ELOXATIN. It is not known whether ELOXATIN or its derivatives are excreted in human milk.
ELOXATIN has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (<1% grade 3, no grade 4) in the ELOXATIN plus 5-FU/LV arm compared to 4.5% (no grade 3, 0.1% grade 4) in the 5-FU/LV alone arm in the adjuvant colon cancer study. In this study, one patient died from eosinophilic pneumonia in the ELOXATIN combination arm. The combined incidence of cough, dyspnea, and hypoxia was 43% (7% grade 3 and 4) in the ELOXATIN plus 5-FU/LV arm compared to 32% (5% grade 3 and 4) in the irinotecan plus 5-FU/LV arm in patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms, ELOXATIN should be discontinued until pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
ELOXATIN is associated with two types of primarily peripheral sensory neuropathy: an acute, reversible type of early onset and a persistent type (>14 days). In patients with advanced colorectal cancer paresthesias occurred in 77% (all grades) and 18% (grade 3/4) of previously untreated patients. In previously treated patients, acute neuropathy occurred in 56% (all grades) and 2% (grade 3/4) of patients; persistent neuropathy occurred in 48% (all grades) and 6% (grade 3/4) of patients. In patients with stage II and III colon cancer, paresthesia was seen in 92% (all grades) and 13% (grade 3/4) of patients; 21% (all grades), 0.5% (grade 3/4) had residual paresthesia at 18-month follow-up.
Hepatotoxicity, as evidenced in the adjuvant study by increase in transaminases and alkaline phosphatase was observed more commonly in the ELOXATIN combination arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis and veno-occlusive lesions. Hepatic vascular disorders should be considered and, if appropriate, investigated in case of abnormal liver function test results or portal hypertension not explained by liver metastases.
Monitoring of white blood cell count with differential, hemoglobin, platelet count and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each ELOXATIN cycle.
The safety and effectiveness of ELOXATIN plus 5-FU/LV in patients with renal impairment have not been evaluated. Since the primary route of platinum elimination is renal, this combination should be used with caution in patients with preexisting renal impairment. Clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds, although this has not been specifically studied.
The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients ≥65 years old.
Extravasation may result in local pain and inflammation that may be severe and lead to complications, including necrosis. Injection site reaction, including redness, swelling and pain, has been reported.
There have been reports of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients receiving ELOXATIN plus 5-FU/LV while on anticoagulants. Patients receiving ELOXATIN plus 5-FU/LV and requiring oral anticoagulants may require closer monitoring.
The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue, and stomatitis. The most common adverse reactions in patients with advanced colorectal cancer were peripheral sensory neuropathy, fatigue, neutropenia, nausea, emesis, and diarrhea.

Click here for additional important information for Eloxatin.

References:

Haller DG. Safety of oxaliplatin in the treatment of colorectal cancer. Oncology (Williston Park). 2000;14 (suppl 11):15-20.

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