Neurotoxicity
Quick Facts
- Neuropathy takes 2 forms: acute and chronic
- Acute symptoms occur as peripheral sensory neurotoxicity in 90% of patients
- Chronic form occurs as cumulative sensory neuropathy: Dose-limiting toxicity and cumulative in 57% of patients
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Background
Neurotoxicity is a dose-limiting side effect of many different agents used in chemotherapy treatments; in particular, platinum drugs, including oxaliplatin, are associated with neurotoxicity. Oxaliplatin is an integral part of chemotherapy for colorectal cancer (CRC) in the adjuvant and metastatic setting. However, neurotoxicity is a dose-limiting side effect of this agent, limiting its use in select patients. The incidence of oxaliplatin-associated neurotoxicity has been estimated to be 82% to 92% (all grades), with 7% to 19% grade 3.1 The unique presentation of oxaliplatin-induced neurotoxicity can make it a challenge for oncology nurses to manage. Oxaliplatin can cause acute and cumulative neurotoxicity, with cumulative toxicity serving as the dose-limiting effect.
Acute Neurotoxicity
- Time course is acute, usually appearing immediately after the infusion of drug
- Characterized by cold-exacerbated paresthesias
- Usually transient and occurs in most patients
- Distal sensory and motor toxicity may occur; the sensory component can appear as paresthesias and/or dysesthesias in the distal extremities or perioral region
- 1% to 2% of patients will report a transient cold-induced pharyngolaryngeal dysesthesia, which can create a feeling of difficulty in breathing
- Jaw tightness or pain
- Muscle spasms, contractions, and fasciculations may occur
Cumulative Neurotoxicity
- Time course is delayed, and it can lead to sensory ataxia and functional impairment
- Seen in 10% to 15% of patients after cumulative doses of 780 to 850 mg/m2 are reached
- Symptoms similar to cisplatin toxicity
- Generally persists between cycles and begins to increase in intensity with higher cumulative doses
- Impaired sensation, sensory ataxia, and or deficit in fine sensory motor coordination may occur
- Can be significant enough to interfere with activities of daily living (ADL)
- Consistently reversible, with most patients recovering from grade 3 neurotoxicity to grade = 1 within 6 to 12 months of discontinuing therapy
Pathophysiology
The acute neurotoxicity seen with oxaliplatin can mimic other conditions, suggesting that hyperexcitability of motor neurons may be the mechanism of action. However, the true mechanism of action is not yet completely understood. The working hypothesis is that sodium channels are affected by the oxalate released intracellularly from oxaliplatin by bicarbonate ions.2
A prospective analysis of oxaliplatin-induced neurotoxicity was conducted by Park et al,3 who examined the role of clinical excitability testing to identify early changes in nerve function associated with development of severe presentations of neurotoxicity.3 The study showed that administration of oxaliplatin directly modulated peripheral nerve excitability and that sodium channel alterations occurred after infusion, which supports a role for sodium channel dysfunction in patients receiving oxaliplatin.3 This study also showed that alterations were more obvious in early treatment, because chronic nerve dysfunction occurs at higher cumulative doses. Because of the correlation between immediate sodium channel dysfunction and chronic neuropathy effects, reducing immediate neurotoxicity may help in reducing chronic neuropathy; early intervention with neuroprotective agents may assist in lessening overall toxicity.3
Nursing Assessment and Management Strategies for Neurotoxicity
Nerve conduction studies are the gold standard in measurement of peripheral nerve damage; however, by the time conduction study results show a decline, damage to the nerves is likely to have already occurred.3 Improved measurement strategies are needed to aid clinicians in the assessment of neurotoxicity with chemotherapy and specifically oxaliplatin in the care of the patient with CRC. Grading of neurotoxicity with oxaliplatin is specifically addressed in Tables 1 and 2 of the Eloxatin package insert.4 The National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 (CTCAE) for sensory and motor neuropathy are listed below.
Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Sensory
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Asymptomatic: loss of deep tendon reflexes or paresthesia (including tingling) but not interfering with function
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Sensory alteration or paresthesia (including tingling), interfering with function but not interfering with ADL
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Sensory alteration or paresthesia, interfering with ADL
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Disabling
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Death
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Motor
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Symptomatic: weakness on exam/testing only
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Symptomatic: weakness interfering with function but not interfering with ADL
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Weakness interfering with ADL; bracing or assistance needed to walk indicated
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Life-threatening; disabling (eg, paralysis)
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Death
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Data from National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v4.0 (CTCAE).5
Various strategies have been utilized in an effort to reduce neurotoxicity associated with oxaliplatin. Specific selected positive studies with oxaliplatin and neuroprotective agents are shown in the table below. Since there have been mixed results in terms of efficacy with these strategies, more research is needed to definitively determine the best practice approach to reducing neurotoxicity with oxaliplatin. Initial results of vitamin E treatment of taxane and cisplatin neuropathy are promising, but additional studies are needed to confirm the safety and effectiveness of this treatment with oxaliplatin.
Study Author Study Design Results Recommendations
Wang et al, 20076
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Randomized pilot study with 86 patients receiving FOLFOX and either glutamine or no glutamine (15 g bid for 7 consecutive days every 2 weeks starting with oxaliplatin infusion)
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Lower percentage of grade 1-2 neuropathy noted in glutamine group vs control (16.7% vs 38.6%); after 4 cycles of therapy, a significantly lower incidence of grade 3-4 neuropathy noted in glutamine group (48% vs 18.2%); no effect on efficacy of therapy
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Oral glutamine significantly reduces the incidence and severity of peripheral neuropathy in patients with metastatic CRC receiving oxaliplatin, without affecting response to chemotherapy or survival
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Gamelin et al, 20047
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Retrospective study of 161 patients receiving oxaliplatin (FOLFOX), with 96 of those receiving Ca/Mg 1 g (before and after oxaliplatin infusion)
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Tumor response similar in both groups. Percentage of patients with grade 3 distal paresthesia lower in Ca/Mg group (7% vs 26%;P= 0.001). Patients with Ca/Mg also recovered more rapidly from neuropathy vs those who did not receive the infusion
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Ca/Mg infusion seems to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy, especially in 85 mg/m2dosage of oxaliplatin
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Cascinu et al, 20028
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Randomized, double-blinded placebo-controlled trial of
52 patients to assess glutathione (GSH) (1,500 mg/m2over a 15-minute infusion period before oxaliplatin) or normal saline
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At the 4th cycle, 7patients showed neuropathy in the GSH arm vs 11 patients in placebo arm; at 8th cycle, 9 of 21 assessable patients in the GSH arm had neurotoxicity vs 15 of 19 in the placebo arm; at cycle 12, 3 in the GSH arm had grade 2-4 neurotoxicity vs 8 in the placebo arm. No reduction in efficacy of therapy noted.
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Study provides evidence that GSH is a promising drug for oxaliplatin-associated neurotoxicity and does not interfere with clinical activity of oxaliplatin
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Cassidy et al, 20069
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Phase III trial of 649 patients on FOLFOX randomized to either xaliproden (neuroprotective agent) or placebo; xaliproden administered from 1st day of chemotherapy until 15 days postinfusion
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Severe peripheral neuropathy was reported by 16.7% of the placebo patients vs 11.1% of the xaliproden group
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Xaliproden was shown to be efficient in reducing the risk of grade 3-4 oxaliplatin-induced peripheral sensory neuropathy without affecting antitumor activity; larger trials are needed to confirm activity of this agent, and a large multinational trial is ongoing.
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Research studies have addressed strategies in drug administration schedules to reduce neurotoxicity. The OPTIMOX (STOP and GO) trial developed a dosing scheme in which oxaliplatin is held intermittently.10 The drug is then reintroduced after a 6-month break; this strategy showed lower rates of grade 3 neurotoxicity (13% vs 19%, respectively). The use of oxaliplatin given intermittently in the CONcePT trial showed that intermittent schedules can reduce grade 3-4 neurotoxicity, with a more than 50% reduction in the incidence of severe neurotoxicity. However, an additional randomization in the trial with patients receiving Ca/Mg salts or placebo initially showed that the addition of the salts decreased treatment efficacy.11 Subsequent analysis showed that the actual response rates were similar between the Ca/Mg arm and the placebo arm, with a trend toward improved efficacy in the Ca/Mg patients.12 Further trials are needed to confirm the neuroprotective effect of Ca/Mg; although the N04C7 study demonstrated protective benefit against neurotoxicity, a trial reported in 2009 at the American Society of Clinical Oncology gastrointestinal symposium by Choo and colleagues13 showed that Ca/Mg did not provide such benefit. Oncology nurses must continue to remain knowledgeable regarding the latest data on Ca/Mg and oxaliplatin-associated neuropathy.
Nurses should conduct a baseline neurologic assessment before the start of oxaliplatin therapy and repeat it before each subsequent cycle. This strategy will identify preexisting symptoms of neuropathy and assess for worsening function with each cycle of therapy.14 If patients are receiving therapy for metastatic disease, nurses should assess for previous therapy with oxaliplatin. Although many oncology nurses will not have access to nerve conduction studies or other formalized assessment techniques, practical measurement of neurotoxicity can consist of observing the patient’s gait when walking into the examination room, watching patients write their signature with each treatment, having patients unbutton or unzip their clothing in the examination room, having patients identify coins held in their hands with their eyes closed, and by rapidly assessing a patient’s ability to discriminate between sharp and dull by using a safety pin.14
Nursing Management Strategies2,15,16
- Education of patients is crucial, including both physician and nursing staff
- Patients should be told to avoid exposure to cold objects, environment, and liquids
- Sipping warm fluids with a straw may help
- Reassurance that the acute symptoms of oxaliplatin-induced neurotoxicity are short-lived is important
- Assessment should involve questioning the patient regarding the nature of the symptoms, including location, time course, and severity
- Dosing modifications and change in drug scheduling are published. Prolonging the duration of infusion time from 2-6 hours can help reduce the recurrence of pharyngolaryngeal dysesthesia
- Patients should be cautioned regarding the need for safe environments; potential for thermal injury or ambulation problems should be discussed
- For most patients, oxaliplatin-associated peripheral neuropathy is reversible
- Although not rigorously studied, exercise can help to increase muscle strength and improve coordination and sensory integration
Pain Management Strategies
Pharmacologic management of chemotherapy-induced neurotoxicity has included the use of various pharmacologic agents. Although gabapentin and tricyclic antidepressants were found to be helpful in some trials with diabetic neuropathy, their effectiveness with chemotherapy-induced neurotoxicity effects have been unsuccessful.17 Pharmacologic management of chemotherapy-induced neuropathy has not been systematically studied.16 Management typically involves the use of opioids and adjuvant analgesics.16 Venlafaxine was found to be helpful in one small trial of 12 patients, but larger trials are needed to confirm its effectiveness in this setting.18 Acupuncture has also been studied with HIV-related peripheral neuropathy, and in one small trial found to be helpful in neurotoxic chemotherapy patients (n = 5).15 However, it is important to realize that large randomized controlled trials are needed to confirm the role of selected therapies that appear promising and that better pain strategies are needed to combat this often troubling and common side effect.
Clinical Practice Guidelines
The National Comprehensive Cancer Network (NCCN) cancer pain treatment guidelines for health care professionals are available at the following link:http://www.nccn.org/professionals/physician_gls/PDF/pain.pdf.
Web Site Resources
Oncology Nursing Society Web site for symptom management: www.cancersymptoms.org
A patient information Web site sponsored by the American Society of Clinical Oncology (ASCO) that discusses peripheral neuropathy in detail, its multiple causes, and current treatments may be found at www.cancer.net
The ONS Putting Evidence into Practice (PEP) card may be obtained at the following link:http://www.ons.org/outcomes/volume2/peripheral/pdf/PEPCardDet_peripheral.pdf
References
- Wilkes G. Oxaliplatin: third-generation platinum analog. Clin J Oncol Nurs. 2003;7:353-356.
- Saif MW, Reardon J. Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag. 2005;1:249-258.
- Park SB, Goldstein D, Lin CS-Y, et al. Acute abnormalities of sensory nerve function associated with oxaliplatin-induced neurotoxicity. J Clin Oncol. 2009;27:1243-1249.
- Eloxatin (oxaliplatin injection) prescribing information. http://www.eloxatin.com/. Accessed August 25, 2009.
- National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v4.0 (CTCAE), page 53.http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf Accessed August 25, 2009.
- Wang W-S, Lin J-K, Lin T-C, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist. 2007;12:312-319.
- Gamelin L, Boisdron-Celle M, Delva R, et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions. Clin Cancer Res. 2004;10:4055-4061.
- Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002;20: 3478-3483.
- Cassidy,J, Bjarnason GA, Hickish T, et al. Randomized double blind (DB) placebo (Plcb) controlled phase III study assessing the efficacy of xaliproden (X) in reducing the cumulative peripheral sensory neuropathy (PSN) induced by the oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in 1st line treatment of patients (pts) with metastatic colorectal cancer. 2006 ASCO Gastrointestinal Cancers Symposium. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=41&abstractID=385. Abstract 229. Accessed August 25, 2009.
- De Gramont A, Cervantes A, Andre T, et al. OPTIMOX study: FOLFOX7/LV5FU2 compared to FOLFOX4 in patients with advanced colorectal cancer. J Clin Oncol. 2004;22:3525.
- Hochster H, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol. 2004;25:4028-4029.
- Grothey A, Turja JH. Optimizing therapy by minimizing toxicities in the treatment of colorectal cancer: 2008 American Society of Clinical Oncology (ASCO) 44th annual meeting. Medscape Nurses. http://www.medscape.com/viewarticle/577625. Accessed August 25, 2009.
- Choo S, Tan S, Lo H, Ng, K, et al. Use of intravenous calcium and magnesium infusion in preventing oxaliplatin-induced sensory neuropathy. [Abstract 416], ASCO 2009 Gastrointestinal Cancers Symposium. http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=63&abstractID=10345. Abstract 416. Accessed August 25, 2009.
- Viale PH, Sommers R. Nursing care of patients receiving chemotherapy for metastatic colorectal cancer: implications of the treatment continuum concept. Sem Oncol Nurs. 2007;23:22-35.
- Wilkes GM. Therapeutic options in the management of colon cancer: 2005 update. Clin J Oncol Nurs. 2005;9:31-44.
- Bennett GJ, Paice JA. Peripheral neuropathy: experimental findings, clinical approaches. J Support Oncol. 2007; 5: 61-63.
- Wolf S, Barton D, Kottschade L, et al. Chemotherapy-induced peripheral neuropathy: Prevention and treatment strategies. Eur J Cancer. 2008;44:1507-1515.
- Ozdogan M, Samur M, Bozcuk HS, et al. Venlafaxine for treatment of chemotherapy-induced neuropathic pain. Turk J Cancer. 2004;34: 110-113.http://www.turkjcancer.org/pdf/pdf_TJC_373.pdf. Accessed August 25, 2009.
Key Definitions
ataxia—inability to coordinate voluntary muscle movements; unsteady movements and staggering gait
dysesthesia—an unpleasant or painful response to a normal stimulus, eg, pain from being touched lightly
fasciculations—involuntary muscle twitches, usually localized and temporary
paresthesia—abnormal skin sensations (eg, tingling, tickling, itching, or burning), usually associated with peripheral nerve damage
pharyngolaryngeal dysesthesia—a sensation of discomfort or tightness in the back of the throat and the inability to breathe. It may be accompanied by jaw pain and is often precipitated by ingestion of a cold beverage or exposure to cold temperatures
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