THERAPY UPDATE Chemotherapy-induced peripheral neuropathy
THERAPY UPDATE
Prevention and treatment of chemotherapy-induced peripheral neuropathy
C
Jennifer Piccolo and Jill M. Kolesar
hemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting toxicity of many anticancer agents, including platinum compounds, taxanes, vinca alkaloids, thalidomide, lenalidomide, bortezomib, and ixabepilone, that significantly affects the quality of life of patients with cancer and cancer survivors. CIPN occurs in 30–40% of patients receiving chemotherapy but can be seen to some degree in up to 70% of patients.1-3 CIPN typically causes sensory symptoms such as paresthesias, numbness, tingling and burning, hyperalgesia, a loss of tendon reflexes, vibration sensation, and proprioception that starts in the fingers and toes and spreads progressively to the extremities as it worsens.2,3 The severity of CIPN is dependent on the chemotherapy agent, duration of therapy, cumulative dose, and concomitant use of other neurotoxic agents. Advanced age and any preexisting conditions that could cause nerve damage (e.g., diabetes, alcohol use) can contribute to a patient’s risk of developing CIPN.2 This article reviews the available pharmacologic options for the prevention and treatment of CIPN.
Purpose. The prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN) are reviewed. Summary. A number of agents, including amifostine, glutathione, and vitamin E, were evaluated as prevention strategies for CIPN, with no agent demonstrating efficacy. Calcium and magnesium are effective for the prevention of CIPN; however, concerns regarding reduced chemotherapy efficacy linger. Venlafaxine, a serotonin– norepinephrine reuptake inhibitor (SNRI), was evaluated for the prevention of neuropathy in a randomized, double-blind, placebo-controlled Phase III trial of patients receiving an oxaliplatin-based regimens every two weeks and demonstrated significantly less acute neurotoxicity compared with the control group. Treatment options for CIPN include reducing the dosage of the chemotherapy, changing the chemotherapy, and treating CIPN with adjunct therapy. Adjunct therapy with topical agents, tricy-
Prevention strategies The two primary mechanisms of neurotoxicity are direct toxic effects on the nervous system and indirect toxicity from drug-induced metabolic derangements. 1 Many prevention strategies targeting these mechanisms have been explored with minimal evidence of efficacy.
Jennifer Piccolo, Pharm.D., is Clinical Oncology Pharmacist, Froedert and The Medical College of Wisconsin, Milwaukee. Jill M. Kolesar, Pharm.D., BCPS, FCCP, is Professor of Pharmacy, School of Pharmacy, University of Wisconsin–Madison, and Director, 3P Analytical Laboratory, University of Wisconsin Carbone Comprehensive Cancer Center, Madison.
clic antidepressants, and anticonvulsants, such as pregabalin and gabapentin, have shown limited efficacy. However, a randomized, double-blind, crossover, Phase III trial of duloxetine versus placebo for the treatment of CIPN caused by paclitaxel or oxaliplatin found that patients treated with duloxetine 60 mg daily had a larger average decrease in pain score than those receiving placebo, regardless of the chemotherapy used. Conclusion. Calcium and magnesium infusions and venlafaxine are effective in preventing CIPN but are not routinely used because of concerns related to decreased chemotherapy efficacy. Adjunct treatment options for CIPN include a topical analgesic, a tricyclic antidepressant, an anticonvulsant, or an SNRI. Duloxetine is more effective than placebo in treating oxaliplatin- or paclitaxel-induced CIPN, is well tolerated, and should be considered to be a first-line treatment option for CIPN. Am J Health-Syst Pharm. 2014; 71:19-25
Amifostine. Amifostine is thought to prevent the direct toxic effects of platinum compounds and alkylating agents by binding to the toxic metabolites and protecting the normal tissue from cytotoxic effects. Two randomized controlled trials illustrated a significant decrease in the rate of neurotoxicity in patients receiving
Address correspondence to Dr. Kolesar ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0101-0019$06.00. DOI 10.2146/ajhp130126
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cisplatin and paclitaxel4,5 who were treated with amifostine; however, further studies demonstrated no significant difference in neurotoxicity with amifostine.6-8 In addition to conflicting evidence, amifostine has significant adverse cardiovascular, neurologic, and dermatological effects that limit its use.4-8 Glutathione. Glutathione may prevent the accumulation of platinum compounds by detoxification and protection of tissue from oxidant injury. In two small, randomized, placebo-controlled trials enrolling a total of 79 patients receiving oxaliplatin, fewer cases of grade II–IV neuropathy were reported in patients receiving glutathione versus placebo.9,10 In a larger randomized, double-blind, placebo-controlled trial of 151 patients receiving cisplatin, there was a nonsignificant trend toward less neurotoxicity; however, the attrition rate was high, with only 39% of patients in the control group and 58% of patients in the glutathione group completing therapy.11 Long-term follow-up was lacking in all of the glutathione trials.3 Vitamin E. The antioxidant effects of vitamin E were theorized to prevent tissue damage induced by cytotoxic agents; however, no benefit in improving neurotoxicity over placebo was reported in a randomized, double-blind, Phase III trial of 207 patients receiving chemotherapy.1,12 Erythropoietin. Erythropoietin has been shown to prevent cisplatinand docetaxel-induced impaired sensory nerve conduction in animal studies without compromising the efficacy of these chemotherapeutic agents, though no clinical trials have been conducted in humans to date.13,14 I.V. calcium and magnesium. Calcium gluconate and magnesium sulfate have been proposed to increase the concentration of extracellular calcium and decrease the hyperexcitability of neurons exposed to oxaliplatin.3 The Combined Oxaliplatin Neurop20
athy Prevention Trial (CONcePT) was the first prospective study conducted to evaluate the safety and efficacy of i.v. calcium gluconate and magnesium sulfate in the prevention of oxaliplatin-induced neuropathy.15 The trial was designed to test if an intermittent oxaliplatin schedule of FOLFOX (a regimen containing fluorouracil, leucovorin, and oxaliplatin) was more tolerable than the conventional oxaliplatin schedule of FOLFOX. Patients were randomized to receive intermittent or conventional oxaliplatin. The study utilized a 2 × 2 factorial design whereby patients were also randomized to receive i.v. calcium gluconate plus magnesium sulfate or placebo. This trial was terminated prematurely in 2007 after the recruitment of 140 patients based on tumor response data that indicated lower response rates among patients receiving i.v. calcium and magnesium compared with those receiving placebo (17.3% versus 32.9%, respectively). The decision to terminate the study was based on investigator-read computed tomography (CT) scans. An independent, central, blinded radiology review of the CT scans of 118 evaluable patients in early 2008 contradicted the earlier results, finding no significant difference in response rates between groups.16 The interim results from CONcePT also led to the premature termination of two other prospective clinical trials.17,18 To date, the study conducted by Grothey et al.18 is the only one to be published as a full manuscript; the results from the other studies are published as abstracts14,15 and letters to the editor.16,17 The trial conducted by Grothey et al.18 included patients with stage II and III colon cancer treated with FOLFOX. Patients were randomized to receive 1 g of calcium gluconate plus 1 g of magnesium sulfate or placebo before and after oxaliplatin administration. The primary endpoint was the percentage of patients with grade 2 or higher
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sensory neurotoxicity. A total of 102 patients were available for analysis. Study results revealed a significant decrease in the incidence of chronic, cumulative, grade 2 or higher neurotoxicity in patients treated with calcium gluconate plus magnesium sulfate versus placebo (p = 0.038). The investigators did not report on the difference in response rates to chemotherapy between the groups. The use of calcium and magnesium for the prevention of oxaliplatininduced CIPN remains controversial. While the majority of data suggest that calcium and magnesium are effective in preventing oxaliplatininduced neuropathy, how these drugs influence patients’ response to chemotherapy remains undefined. Data are limited due to small sample sizes and incomplete reporting of study results. Until the true impact of this treatment on patients’ response to chemotherapy is determined, calcium and magnesium should be used cautiously, if at all, for the prevention of CIPN. Glutamine and acetyl-l-carnitine. Glutamine depletion develops during long periods of stress caused by malignancy and has negative effects on tissue function. In a randomized, open-label trial, lower rates of neuropathy were reported in patients receiving glutamine after four cycles (4.8% versus 18.2%, p = 0.05) and six cycles (11.9% versus 31.8%, p = 0.04) of oxaliplatin compared with patients not receiving glutamine, with no significant difference between groups in the rate of abnormalities seen on electrophysiologic examination.19 A randomized, double-blind, placebo-controlled study in patients receiving paclitaxel found that glutamine was ineffective with no difference over placebo.20 Acetyl-lcarnitine was shown to decrease the grade of sensory neuropathy by 60% and motor neuropathy by 79% after the discontinuation of chemotherapy in a small Phase I trial of 25 patients receiving cisplatin and paclitaxel21;
THERAPY UPDATE Chemotherapy-induced peripheral neuropathy
however, larger randomized trials are needed to confirm this finding. Serotonin–norepinephrine reuptake inhibitors. Both serotonin and norepinephrine maintain important roles in analgesia. It has been shown that analgesia is greater when both neurotransmitters are increased simultaneously rather than by increasing either neurotransmitter alone.22 Venlafaxine was evaluated for the prevention of neuropathy in a randomized, double-blind, placebocontrolled, Phase III trial of 54 patients with histologically proven cancer receiving oxaliplatin-based regimens every two weeks.23 Patients who reported symptomatic acute neurotoxicity after the administration of oxaliplatin-based therapy were eligible for study inclusion. Patients with preexisting neuropathy or predisposing characteristics, such as diabetes, were excluded. A total of 6 patients were excluded from the study; the remaining 48 were randomized to receive venlafaxine or placebo. Patients were given 50 mg of venlafaxine orally one hour before the oxaliplatin infusion on day 1, and extended-release venlafaxine 37.5 mg was administered twice daily on days 2–11. The primary endpoint was the percentage of patients with no acute neurotoxicity, which was significantly higher in the venlafaxine-treated group compared with patients receiving placebo (31.3% versus 5.3%, respectively; p = 0.03). The secondary endpoint was the occurrence of cumulative permanent neurosensory toxicity evaluated three months after the end of treatment. After three months, there were more patients with no neuropathy (38.5% versus 5.6%, p = 0.06) and significantly fewer patients with grade 3 neurotoxicity (0% versus 33.3%, p = 0.03) in the venlafaxine group. Taken together, these data suggest that venlafaxine is effective in preventing oxaliplatininduced CIPN. This study also found that no patients experienced grade 3 or 4
toxicities related to venlafaxine, with the most frequently reported adverse effects being nausea, vomiting, and somnolence.23 Patients had received the immediate-release dosage form of venlafaxine, which is associated with a higher frequency of nausea and vomiting. The incidence of nausea and vomiting may be decreased with the use of a long-acting formulation. The influence of venlafaxine on oxaliplatin anticancer activity was not reported. Preclinical models suggest that venlafaxine modulates oxidative stress, which can affect oxaliplatin anticancer efficacy, though this has not been clinically evaluated.24 None of these prevention strategies are recommended by the National Comprehensive Cancer Network task force report due to the small studies with variable results and lingering concerns over the impairment of antitumor activity of chemotherapy.1 Treatment options Patients with cancer often take opioids to manage cancer-related pain. Unfortunately, high doses of opioids are often required to achieve adequate neuropathic pain relief, and these doses may be accompanied by intolerable adverse effects. While standard opioid doses may dull the pain associated with CIPN, they often do not effectively treat the pain. The use of adjuvant analgesics, including topical agents, antidepressants, and anticonvulsants, in combination with standard opioid doses can provide adequate relief from CIPN without significant toxicity (Table 1).25 Topical agents. Topical creams are often used in the localized treatment of CIPN. These creams can contain a variety of agents, including lidocaine, baclofen, amitriptyline, and ketamine. As no standard formula for topical creams exists, these creams are often compounded in various combinations and concentrations. The mechanism of neuropathy pain
relief of the topical agents is based on localized anesthetic properties of the individual agents. They can provide pain relief within minutes of application; however, they often need to be reapplied frequently due to a short duration of action. Barton et al.26 conducted a randomized, placebo-controlled study in 208 patients with CIPN to evaluate the efficacy of a topical gel containing baclofen, amitriptyline, and ketamine in relieving neuropathic pain. Patients were randomized to receive a compounded gel containing 10 mg of baclofen, 40 mg of amitriptyline, and 20 mg of ketamine or placebo. Patients in the treatment group experienced a slight but nonsignificant improvement in their sensory neuropathy over those treated with placebo. The authors indicated that the improvement may have been insignificant due to patients receiving lower doses of the drugs, since data on their systemic absorption are lacking.1,2,26 Adverse effects are infrequent with topical products, as systemic absorption is minimal, though local irritation and rashes have been reported. Despite little efficacy data, a trial of topical cream is usually warranted. Topical agents can also be combined with systemic agents. Tricyclic antidepressants. Amitriptyline, desipramine, and nortriptyline are considered first-line agents for the treatment of other neuropathic pain syndromes. Two studies have evaluated the efficacy of amitriptyline in the treatment of CIPN. Neither study had sufficient power to show benefit of amitriptyline over placebo.27,28 A Phase III crossover study evaluated the safety and efficacy of nortriptyline versus placebo in the treatment of CIPN in 51 patients with cancer receiving cisplatin.29 The study consisted of two four-week treatment periods, which were separated by a one-week washout period. After the first treatment period, patients receiving nor-
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22
Mechanism of Action
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Inhibit reuptake of serotonin and norepinephrine. Venlafaxine inhibits serotonin more strongly at lower doses, and norepinephrine at higher doses, while duloxetine inhibition is more balanced.
SNRIsb
Use of MAOIs within past 14 days; use during acute recovery phase after myocardial infarction
None
Use of MAOIs within past 14 days; uncontrolled narrow-angle glaucoma
Caution with other serotonergic drugs (risk of serotonin syndrome); caution with medications that prolong Q-T interval; warfarin (increased INR); primarily substrate of CYP2D6; avoid strong CYP2D6 inhibitors Nonsteroidal antiinflammatory drugs may decrease effectiveness; caution with other medications that can cause sedation
Caution with other serotonergic drugs (risk of serotonin syndrome); caution with anticoagulants or antiplatelets (increased risk of bleeding); duloxetine is a substrate of CYP2D6 and 1A2; venlafaxine is a substrate of CYP2D6 Caution with CYP2D6 and 1A2 inhibitors, this may result in increased plasma concentrations and increased toxicity
Common: anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention), sedation, confusion Rare but serious: cardiac arrhythmias, bone marrow suppression Common: somnolence and fatigue, dizziness, peripheral edema, weight gain Rare but serious: hypersensitivity reactions (including StevensJohnson syndrome and angioedema), seizure, suicidal thoughts Common: hypertension, headache, insomnia, somnolence Rare but serious: seizure, hepatitis, suicidal thoughts, serotonin syndrome
Amitriptyline: 25–100 mg/day, up to max of 200 mg/day Desipramine: 10–25 mg/day initially, increase to a max of 150 mg/day Nortriptyline: 10–25 mg/day initially titrated to effect (usual dose 75 mg/day) Gabapentin: 300–900 mg/day initially, increase to 3600 mg/day Pregabalin: 150 mg/day initially, increase to max of 600 mg/day
Venlafaxine: initial starting dose of 75 mg of immediate-release or 37.5 mg of extended-release formulation daily; may be increased to 225 mg/day Duloxetine: 30 mg/day initially, increase to 60 mg/day after 1 wk
Contraindications
Drug Interactions
Toxicity
Dosing
b
a
INR = International Normalized Ratio, CYP = cytochrome P-450 isoenzyme, MAOI = monoamine oxidase inhibitor, SNRI = serotonin–norepinephrine reuptake inhibitor. Venlafaxine is the only agent that has demonstrated efficacy in the prevention of chemotherapy-induced peripheral neuropathy (CIPN); duloxetine is used for the treatment of CIPN.
Block calcium channels on presynaptic neurons and prevent the release of excitatory neurotransmitters
Anticonvulsants
Tricyclic Block reuptake of antidepressants serotonin and norepinephrine
Drug Class
Oral Agents for Chemotherapy-Induced Peripheral Neuropathy27,28,a
Table 1.
THERAPY UPDATE Chemotherapy-induced peripheral neuropathy
THERAPY UPDATE Chemotherapy-induced peripheral neuropathy
triptyline reported a 5% higher rate of paresthesias over placebo as measured weekly using a visual analog scale (VAS). At the end of the second treatment period after the crossover, patients on nortriptyline reported a 38% lower pain score than those receiving placebo; however, there was a significant dropout rate during the study. Patients receiving placebo reported significantly greater satisfaction with treatment over those using nortriptyline due to the higher rate of adverse events in the nortriptyline group. The anticholinergic, antihistaminergic, and antiadrenergic effects produce adverse effects that many patients cannot tolerate, such as dry mouth, drowsiness, weight gain, and hypotension.1,2 Given the lack of efficacy and significant adverse effects, tricyclic antidepressants are not considered first-line agents for CIPN. Anticonvulsants. Gabapentin and pregabalin are often used for the treatment of CIPN. Gabapentin is widely used to treat many types of neuropathic pain, such as diabetic neuropathy, postherpetic pain, and neuropathic cancer pain caused by direct malignant nerve infiltration or compression.30 Gabapentin was evaluated in a double-blind, placebocontrolled crossover trial of 115 patients with symptomatic CIPN.31 The dosage of gabapentin was adjusted to a maximum of 2700 mg/day in three divided doses. The primary efficacy measure was the patient-reported average pain score per day, which was calculated using a numerical rating scale and the Eastern Cooperative Oncology Group neuropathy scale. The results showed no significant differences in patients’ daily pain scores between the two groups. Pregabalin has a mechanism of action similar to that of gabapentin and has a similar adverse-effect profile.32 Despite benefits seen in smaller trials, a Phase IV study conducted to assess the efficacy of pregabalin in treatment of CIPN was terminated early due to insufficient power to detect a difference in
treatment groups during an interim analysis, suggesting pregabalin is ineffective in the treatment of CIPN.33 Both gabapentin and pregabalin have a modest adverse-effect profile, including drowsiness, dizziness, and fatigue.30,32 Peripheral edema, weight gain, constipation, and dry mouth are more prevalent with pregabalin than gabapentin. 30,32 The clinical evidence does not support the use of gabapentin and pregabalin for CIPN despite their efficacy in treating other forms of neuropathy, tolerability, and low cost. Duloxetine. Duloxetine was approved by FDA in 2004 for the treatment of major depressive disorder and diabetic peripheral neuropathy.22 Duloxetine’s FDA-approved indications expanded in 2007 to include the treatment of generalized anxiety disorder34 and in 2008 for the treatment of fibromyalgia.35 Three studies have been conducted to evaluate the efficacy of duloxetine for the treatment of CIPN. Yang et al.36 conducted an open-label pilot study to evaluate the role of duloxetine in the treatment of oxaliplatin-induced peripheral neuropathy in 39 patients with colorectal cancer reporting grade 1 through 3 neuropathies. The dose of duloxetine was started at 30 mg once daily, and, if tolerated, the dose was escalated to 60 mg once daily after one week of therapy. The level of neuropathic pain was assessed using VAS scores and the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE). A total of 9 patients (28.1%) discontinued duloxetine due to intolerable adverse events, including dizziness, nausea, somnolence, restlessness, insomnia, and urinary hesitancy. Improvements in VAS scores were seen in 19 of the remaining 30 patients (63.3%). Of these, 9 (47.4%) demonstrated an improvement in their NCI-CTCAE adverse-event grade; the remaining 10 patients maintained a stable grade. Matsuoka et al. 37 conducted a retrospective analysis of 15 cancer
patients with neuropathic pain who were nonresponsive to pregabalin. Duloxetine was initiated at 20 mg daily and escalated to 40 mg daily if the pain was not reduced by 33% or more from baseline after three to seven days. Duloxetine was administered concomitantly with pregabalin when the adverse effects were tolerable. Of the 15 patients evaluated, duloxetine was effective in 11 patients based on the reduction of pain in 7 patients and a decrease in sleepiness and lightheadedness in 4 patients. The adverse events reported were mild and did not require treatment discontinuation. A randomized Phase III doubleblind, crossover trial of duloxetine versus placebo for the treatment of CIPN was conducted in patients with persistent painful neuropathy grade 1 or greater secondary to treatment with paclitaxel or oxaliplatin.38 All patients were using analgesics at baseline. A total of 231 patients were enrolled in the study, with 185 patients completing the initial six-week treatment period for the preliminary review. Duloxetine dosing was initiated at 30 mg daily for one week, followed by 60 mg daily thereafter. Individuals receiving duloxetine had a larger mean decrease in their pain scores (calculated using the Brief Pain Inventory—Short Form) than those receiving placebo (–1.06 versus –0.34, p =0.003), with no significant difference observed based on the specific neurotoxic agent received. Patients receiving duloxetine also had improvements in daily functioning and quality of life compared with patients receiving placebo. Fatigue, insomnia, and nausea were reported in 5–7% of patients receiving duloxetine, while 5–8% of patients receiving placebo reported somnolence, insomnia, and fatigue, suggesting no significant differences between duloxetine and placebo in terms of adverse effects. However, more patients in the duloxetine group had moderate adverse effects,
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resulting in an 11% dropout rate compared with 1% in the placebo group. Discussion The role of preventive treatments in patients with cancer who are at risk for developing CIPN remains unclear. With the exception of venlafaxine, the studied agents have been found to be either ineffective or potentially associated with a decreased tumor response.1-3 If a preventive agent is desired, venlafaxine is the only agent that has demonstrated effectiveness in preventing oxaliplatin-induced CIPN.23 Whether venlafaxine is effective in preventing neuropathy caused by other agents is unknown, as is the effectiveness of duloxetine in this setting. In addition, the influence of venlafaxine on oxaliplatin’s anticancer activity is unknown; such influence was unreported in the clinical trial and is theoretically possible, as preclinical models suggest that venlafaxine modulates oxidative stress.24 Until concurrent venlafaxine is found not to reduce the anticancer activity of oxaliplatin and other agents, its use should not routinely be recommended for the prevention of CIPN. There are three options for the management of CIPN: reducing the dose of the offending chemotherapy, changing the treatment regimen entirely, or using adjunct medications.1 For patients with advanced or metastatic disease, when weighing the severity of neuropathy compared with the benefits of chemotherapy in the palliative setting, dosage reductions are supported over the alternative options, though alternative chemotherapy options may also be appropriate. Furthermore, the addition of adjunct medications to manage CIPN increases the complexity of the patient’s medication regimen and can introduce new adverse effects and toxicities. For patients with early-stage disease who are receiving curative24
intent chemotherapy, especially for diseases where high-dose chemotherapy is associated with better survival rates, adding an adjunct agent to treat CIPN may be the best option. An alternative chemotherapy regimen may also be an option, especially if there are other effective treatment regimens available. If adjunct therapy for CIPN is to be initiated, topical analgesics, tricyclic antidepressants, anticonvulsants, and serotonin–norepinephrine reuptake inhibitors (SNRIs) are therapeutic options. A trial of topical therapies, with limited systemic absorption, is warranted in most patients and can be combined with other agents.26 Tricyclic antidepressants have little or no efficacy and significant toxicity and should be avoided unless patients have not responded to more-effective therapies.27-29 While their efficacy in CIPN is not substantial, the anticonvulsants gabapentin and pregabalin are well tolerated and may benefit some patients.30-32 Duloxetine has been shown to be more effective than placebo in treating oxaliplatin- or paclitaxelinduced CIPN, is well tolerated, and should be considered to be a first-line treatment option.36-38 Given that duloxetine is administered for existing neuropathy after the completion of chemotherapy, there is less risk of reduced anticancer activity of the chemotherapy. Duloxetine may also be beneficial for patients experiencing symptoms of depression or anxiety about their cancer diagnosis and treatment options. However, duloxetine’s efficacy in CIPN induced by other agents is unknown, as is the efficacy of venlafaxine for treating CIPN. Despite the paucity of data, a trial of duloxetine is a reasonable approach in patients with CIPN caused by other agents, as the mechanisms of chronic neurotoxicity are similar among anticancer agents and duloxetine is well tolerated.
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Conclusion Calcium and magnesium infusions and venlafaxine are effective for preventing CIPN but are not routinely used because of concerns related to decreased chemotherapy efficacy. Adjunct treatment options for CIPN include a topical analgesic, a tricyclic antidepressant, an anticonvulsant, or an SNRI. Duloxetine is more effective than placebo in treating oxaliplatin- or paclitaxel-induced CIPN, is well tolerated, and should be considered to be a first-line treatment option for CIPN. References 1. Stubblefield MD, Burstein HJ, Burton AW et al. NCCN task force: management of neuropathy in cancer. J Natl Compr Canc Netw. 2009; 7(suppl 5):S1-26. 2. Pachman DR, Barton DL, Watson JC et al. Chemotherapy-induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther. 2011; 90:377-87. 3. Beijers AJ, Jongen JL, Vreugdenhil G. Chemotherapy-induced neurotoxicity: the value of neuroprotective strategies. Neth J Med. 2012; 70:18-25. 4. Kemp G, Rose P, Lurain J et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol. 1996; 14:2101-12. 5. Lorusso D, Ferrandina F, Freffi S et al. Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients. Ann Oncol. 2003; 14:1086-93. 6. De Vos FY, Bos AM, Schaapveld M et al. A randomized phase II study of paclitaxel with carboplatin +/– amifostine as first line treatment in advanced ovarian carcinoma. Gynecol Oncol. 2005; 97:60-7. 7. Openshaw H, Beamon K, Synold TW et al. Neurophysiological study of peripheral neuropathy after high-dose paclitaxel: lack of neuroprotective effect of amifostine. Clin Cancer Res. 2004; 10:461-7. 8. Hilpert F, Stähle A, Tomé O et al. Neuroprotection with amifostine in the first-line treatment of advanced ovarian cancer with carboplatin/paclitaxel-based chemotherapy—a double-blind, placebocontrolled, randomized phase II study from the Arbeitsgemeinschaft Gynäkologische Onkologoie (AGO) Ovarian Cancer Study Group. Support Cancer Care. 2005; 13:797-805. 9. 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-
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controlled trial. J Clin Oncol. 2002; 20:3478-83. Milla P, Airoldi M, Weber G et al. Administration of reduced glutathione in FOLFOX4 adjuvant treatment for colorectal cancer: effect on oxaliplatin pharmacokinetics, Pt-DNA adduct formation, and neurotoxicity. Anticancer Drugs. 2009; 20:369-402. Smyth JF, Bowman A, Perren T et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomized trial. Ann Oncol. 1997; 96:4154-7. Kottschasde LA, Sloan JA, Mazurczak MA et al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial. Support Cancer Care. 2011; 19:1769-77. Bianchi R, Gilardini A, RodriguezMenendez V et al. Cisplatin-induced peripheral neuropathy: neuroprotection by erythropoietin without affecting tumour growth. Eur J Cancer. 2007; 43:710-7. Cervellini I, Bello F, Frapolli R et al. The neuroprotective effect of erythropoietin in docetaxel-induced peripheral neuropathy causes no reduction of antitumor activity in 13,762 adenocarcinomabearing rats. Neurotox Res. 2010; 18:15160. Grothey A, Hart LL, Rowland KM et al. Intermittent oxaliplatin administration and time-to-treatment-failure in metastatic colorectal cancer: final results of the Phase III CONcePT trial. http://meeting.ascopubs.org/cgi/content/ abstract/26/15_suppl/4010 (accessed 2013 Sep 23). Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol. 2007; 25:4028-9. Letter. Gamelin L, Boisdron-Celle M, Morel A et al. Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol. 2008; 26:1188-90. Letter.
18. Grothey A, Nikcevich D, Sloan J et al. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol. 2011; 29:421-7. 19. Wang WS, Lin JK, Lin TC et al. Oral glutamine is effective for preventing oxaliplatin- induced neuropathy in colorectal cancer patients. Oncologist. 2007; 12:312-9. 20. Loven D, Levavi H, Sabach G et al. Longterm glutamate supplementation failed to protect against peripheral neurotoxicity of paclitaxel. Eur J Cancer Care. 2009; 18:78-83. 21. Bianchi G, Vitali G, Caraceni A et al. Symptomatic and neurophysiological responses of paclitaxel- or cisplatininduced neuropathy to oral acetyl-lcarnitine. Eur J Cancer. 2005; 41:1746-50. 22. Bellingham GA, Peng PW. Duloxetine: a review of its pharmacology and use in chronic pain management. Reg Anesth Pain Med. 2010; 35:294-303. 23. Durand JP, Deplanque G, Montheil V et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized double-blind, placebocontrolled Phase III trial. Ann Oncol. 2012; 23:200-5. 24. Zafir A, Ara A, Banu N. In vivo antioxidant status: a putative target of antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33:220-8. 25. Vadallouca A, Raptis E, Moka E et al. Pharmacological treatment of neuropathic cancer pain: a comprehensive review of the current literature. Pain Pract. 2011; 12:219-51. 26. Barton DL, Wos EJ, Qin R et al. A doubleblind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer. 2011; 19:833-41. 27. Kautio AL, Haanpää M, Saarto T et al. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage. 2008; 35:31-9.
28. Kautio AL, Haanpää M, Leminen A et al. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. Anticancer Res. 2009; 29:2601-6. 29. Hammack J, Michalak J, Loprinzi C et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinuminduced peripheral neuropathy. Pain. 2002; 98:195-203. 30. Neurontin (gabapentin) package insert. New York: Pfizer; revised 2012 Dec. 31. Rao RD, Michalak JC, Sloan JA et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, doubleblind, placebo-controlled, crossover trial (N00C3). Cancer. 2007; 110:2110-8. 32. Lyrica (pregabalin) package insert. New York: Pfizer; revised 2012 Jun. 33. ClinicalTrials.gov. Prevention and treatment of chemotherapy-induced peripheral neuropathy in subjects with advanced colorectal cancer. http://clinicaltr ials.gov/ct2/show/ NCT00380874 (accessed 2013 Sep 26). 34. Lilly. FDA approves Cymbalta for treatment of generalized anxiety disorder. http://newsroom.lilly.com/releasedetail. cfm?releaseid=231196 (accessed 2013 Sep 26). 35. Lilly. FDA approves Cymbalta for the management of fibromyalgia. http:// newsroom.lilly.com/releasedetail.cfm? releaseid=316740 (accessed 2013 Sep 26). 36. Yang Y, Lin J, Chen W et al. Duloxetine improves oxaliplatin-induced neuropathy in patients with colorectal cancer: an open-label pilot study. Support Cancer Care. 2012; 20:1491-7. 37. Matsuoka H, Makimura C, Koyama A et al. Pilot study of duloxetine for cancer patients with neuropathic pain nonresponsive to pregabalin. Anticancer Res. 2012; 32:1805-10. 38. Smith EM, Pang H, Cirrincione C et al. Effect of duloxetine on pain function, and quality of life among patients with chemotherapy-induced peripheral neuropathy: a randomized clinical trial. JAMA. 2013; 309:1359-67.
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THERAPY UPDATE
Prevention and treatment of chemotherapy-induced peripheral neuropathy
C
Jennifer Piccolo and Jill M. Kolesar
hemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting toxicity of many anticancer agents, including platinum compounds, taxanes, vinca alkaloids, thalidomide, lenalidomide, bortezomib, and ixabepilone, that significantly affects the quality of life of patients with cancer and cancer survivors. CIPN occurs in 30–40% of patients receiving chemotherapy but can be seen to some degree in up to 70% of patients.1-3 CIPN typically causes sensory symptoms such as paresthesias, numbness, tingling and burning, hyperalgesia, a loss of tendon reflexes, vibration sensation, and proprioception that starts in the fingers and toes and spreads progressively to the extremities as it worsens.2,3 The severity of CIPN is dependent on the chemotherapy agent, duration of therapy, cumulative dose, and concomitant use of other neurotoxic agents. Advanced age and any preexisting conditions that could cause nerve damage (e.g., diabetes, alcohol use) can contribute to a patient’s risk of developing CIPN.2 This article reviews the available pharmacologic options for the prevention and treatment of CIPN.
Purpose. The prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN) are reviewed. Summary. A number of agents, including amifostine, glutathione, and vitamin E, were evaluated as prevention strategies for CIPN, with no agent demonstrating efficacy. Calcium and magnesium are effective for the prevention of CIPN; however, concerns regarding reduced chemotherapy efficacy linger. Venlafaxine, a serotonin– norepinephrine reuptake inhibitor (SNRI), was evaluated for the prevention of neuropathy in a randomized, double-blind, placebo-controlled Phase III trial of patients receiving an oxaliplatin-based regimens every two weeks and demonstrated significantly less acute neurotoxicity compared with the control group. Treatment options for CIPN include reducing the dosage of the chemotherapy, changing the chemotherapy, and treating CIPN with adjunct therapy. Adjunct therapy with topical agents, tricy-
Prevention strategies The two primary mechanisms of neurotoxicity are direct toxic effects on the nervous system and indirect toxicity from drug-induced metabolic derangements. 1 Many prevention strategies targeting these mechanisms have been explored with minimal evidence of efficacy.
Jennifer Piccolo, Pharm.D., is Clinical Oncology Pharmacist, Froedert and The Medical College of Wisconsin, Milwaukee. Jill M. Kolesar, Pharm.D., BCPS, FCCP, is Professor of Pharmacy, School of Pharmacy, University of Wisconsin–Madison, and Director, 3P Analytical Laboratory, University of Wisconsin Carbone Comprehensive Cancer Center, Madison.
clic antidepressants, and anticonvulsants, such as pregabalin and gabapentin, have shown limited efficacy. However, a randomized, double-blind, crossover, Phase III trial of duloxetine versus placebo for the treatment of CIPN caused by paclitaxel or oxaliplatin found that patients treated with duloxetine 60 mg daily had a larger average decrease in pain score than those receiving placebo, regardless of the chemotherapy used. Conclusion. Calcium and magnesium infusions and venlafaxine are effective in preventing CIPN but are not routinely used because of concerns related to decreased chemotherapy efficacy. Adjunct treatment options for CIPN include a topical analgesic, a tricyclic antidepressant, an anticonvulsant, or an SNRI. Duloxetine is more effective than placebo in treating oxaliplatin- or paclitaxel-induced CIPN, is well tolerated, and should be considered to be a first-line treatment option for CIPN. Am J Health-Syst Pharm. 2014; 71:19-25
Amifostine. Amifostine is thought to prevent the direct toxic effects of platinum compounds and alkylating agents by binding to the toxic metabolites and protecting the normal tissue from cytotoxic effects. Two randomized controlled trials illustrated a significant decrease in the rate of neurotoxicity in patients receiving
Address correspondence to Dr. Kolesar ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0101-0019$06.00. DOI 10.2146/ajhp130126
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THERAPY UPDATE Chemotherapy-induced peripheral neuropathy
cisplatin and paclitaxel4,5 who were treated with amifostine; however, further studies demonstrated no significant difference in neurotoxicity with amifostine.6-8 In addition to conflicting evidence, amifostine has significant adverse cardiovascular, neurologic, and dermatological effects that limit its use.4-8 Glutathione. Glutathione may prevent the accumulation of platinum compounds by detoxification and protection of tissue from oxidant injury. In two small, randomized, placebo-controlled trials enrolling a total of 79 patients receiving oxaliplatin, fewer cases of grade II–IV neuropathy were reported in patients receiving glutathione versus placebo.9,10 In a larger randomized, double-blind, placebo-controlled trial of 151 patients receiving cisplatin, there was a nonsignificant trend toward less neurotoxicity; however, the attrition rate was high, with only 39% of patients in the control group and 58% of patients in the glutathione group completing therapy.11 Long-term follow-up was lacking in all of the glutathione trials.3 Vitamin E. The antioxidant effects of vitamin E were theorized to prevent tissue damage induced by cytotoxic agents; however, no benefit in improving neurotoxicity over placebo was reported in a randomized, double-blind, Phase III trial of 207 patients receiving chemotherapy.1,12 Erythropoietin. Erythropoietin has been shown to prevent cisplatinand docetaxel-induced impaired sensory nerve conduction in animal studies without compromising the efficacy of these chemotherapeutic agents, though no clinical trials have been conducted in humans to date.13,14 I.V. calcium and magnesium. Calcium gluconate and magnesium sulfate have been proposed to increase the concentration of extracellular calcium and decrease the hyperexcitability of neurons exposed to oxaliplatin.3 The Combined Oxaliplatin Neurop20
athy Prevention Trial (CONcePT) was the first prospective study conducted to evaluate the safety and efficacy of i.v. calcium gluconate and magnesium sulfate in the prevention of oxaliplatin-induced neuropathy.15 The trial was designed to test if an intermittent oxaliplatin schedule of FOLFOX (a regimen containing fluorouracil, leucovorin, and oxaliplatin) was more tolerable than the conventional oxaliplatin schedule of FOLFOX. Patients were randomized to receive intermittent or conventional oxaliplatin. The study utilized a 2 × 2 factorial design whereby patients were also randomized to receive i.v. calcium gluconate plus magnesium sulfate or placebo. This trial was terminated prematurely in 2007 after the recruitment of 140 patients based on tumor response data that indicated lower response rates among patients receiving i.v. calcium and magnesium compared with those receiving placebo (17.3% versus 32.9%, respectively). The decision to terminate the study was based on investigator-read computed tomography (CT) scans. An independent, central, blinded radiology review of the CT scans of 118 evaluable patients in early 2008 contradicted the earlier results, finding no significant difference in response rates between groups.16 The interim results from CONcePT also led to the premature termination of two other prospective clinical trials.17,18 To date, the study conducted by Grothey et al.18 is the only one to be published as a full manuscript; the results from the other studies are published as abstracts14,15 and letters to the editor.16,17 The trial conducted by Grothey et al.18 included patients with stage II and III colon cancer treated with FOLFOX. Patients were randomized to receive 1 g of calcium gluconate plus 1 g of magnesium sulfate or placebo before and after oxaliplatin administration. The primary endpoint was the percentage of patients with grade 2 or higher
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sensory neurotoxicity. A total of 102 patients were available for analysis. Study results revealed a significant decrease in the incidence of chronic, cumulative, grade 2 or higher neurotoxicity in patients treated with calcium gluconate plus magnesium sulfate versus placebo (p = 0.038). The investigators did not report on the difference in response rates to chemotherapy between the groups. The use of calcium and magnesium for the prevention of oxaliplatininduced CIPN remains controversial. While the majority of data suggest that calcium and magnesium are effective in preventing oxaliplatininduced neuropathy, how these drugs influence patients’ response to chemotherapy remains undefined. Data are limited due to small sample sizes and incomplete reporting of study results. Until the true impact of this treatment on patients’ response to chemotherapy is determined, calcium and magnesium should be used cautiously, if at all, for the prevention of CIPN. Glutamine and acetyl-l-carnitine. Glutamine depletion develops during long periods of stress caused by malignancy and has negative effects on tissue function. In a randomized, open-label trial, lower rates of neuropathy were reported in patients receiving glutamine after four cycles (4.8% versus 18.2%, p = 0.05) and six cycles (11.9% versus 31.8%, p = 0.04) of oxaliplatin compared with patients not receiving glutamine, with no significant difference between groups in the rate of abnormalities seen on electrophysiologic examination.19 A randomized, double-blind, placebo-controlled study in patients receiving paclitaxel found that glutamine was ineffective with no difference over placebo.20 Acetyl-lcarnitine was shown to decrease the grade of sensory neuropathy by 60% and motor neuropathy by 79% after the discontinuation of chemotherapy in a small Phase I trial of 25 patients receiving cisplatin and paclitaxel21;
THERAPY UPDATE Chemotherapy-induced peripheral neuropathy
however, larger randomized trials are needed to confirm this finding. Serotonin–norepinephrine reuptake inhibitors. Both serotonin and norepinephrine maintain important roles in analgesia. It has been shown that analgesia is greater when both neurotransmitters are increased simultaneously rather than by increasing either neurotransmitter alone.22 Venlafaxine was evaluated for the prevention of neuropathy in a randomized, double-blind, placebocontrolled, Phase III trial of 54 patients with histologically proven cancer receiving oxaliplatin-based regimens every two weeks.23 Patients who reported symptomatic acute neurotoxicity after the administration of oxaliplatin-based therapy were eligible for study inclusion. Patients with preexisting neuropathy or predisposing characteristics, such as diabetes, were excluded. A total of 6 patients were excluded from the study; the remaining 48 were randomized to receive venlafaxine or placebo. Patients were given 50 mg of venlafaxine orally one hour before the oxaliplatin infusion on day 1, and extended-release venlafaxine 37.5 mg was administered twice daily on days 2–11. The primary endpoint was the percentage of patients with no acute neurotoxicity, which was significantly higher in the venlafaxine-treated group compared with patients receiving placebo (31.3% versus 5.3%, respectively; p = 0.03). The secondary endpoint was the occurrence of cumulative permanent neurosensory toxicity evaluated three months after the end of treatment. After three months, there were more patients with no neuropathy (38.5% versus 5.6%, p = 0.06) and significantly fewer patients with grade 3 neurotoxicity (0% versus 33.3%, p = 0.03) in the venlafaxine group. Taken together, these data suggest that venlafaxine is effective in preventing oxaliplatininduced CIPN. This study also found that no patients experienced grade 3 or 4
toxicities related to venlafaxine, with the most frequently reported adverse effects being nausea, vomiting, and somnolence.23 Patients had received the immediate-release dosage form of venlafaxine, which is associated with a higher frequency of nausea and vomiting. The incidence of nausea and vomiting may be decreased with the use of a long-acting formulation. The influence of venlafaxine on oxaliplatin anticancer activity was not reported. Preclinical models suggest that venlafaxine modulates oxidative stress, which can affect oxaliplatin anticancer efficacy, though this has not been clinically evaluated.24 None of these prevention strategies are recommended by the National Comprehensive Cancer Network task force report due to the small studies with variable results and lingering concerns over the impairment of antitumor activity of chemotherapy.1 Treatment options Patients with cancer often take opioids to manage cancer-related pain. Unfortunately, high doses of opioids are often required to achieve adequate neuropathic pain relief, and these doses may be accompanied by intolerable adverse effects. While standard opioid doses may dull the pain associated with CIPN, they often do not effectively treat the pain. The use of adjuvant analgesics, including topical agents, antidepressants, and anticonvulsants, in combination with standard opioid doses can provide adequate relief from CIPN without significant toxicity (Table 1).25 Topical agents. Topical creams are often used in the localized treatment of CIPN. These creams can contain a variety of agents, including lidocaine, baclofen, amitriptyline, and ketamine. As no standard formula for topical creams exists, these creams are often compounded in various combinations and concentrations. The mechanism of neuropathy pain
relief of the topical agents is based on localized anesthetic properties of the individual agents. They can provide pain relief within minutes of application; however, they often need to be reapplied frequently due to a short duration of action. Barton et al.26 conducted a randomized, placebo-controlled study in 208 patients with CIPN to evaluate the efficacy of a topical gel containing baclofen, amitriptyline, and ketamine in relieving neuropathic pain. Patients were randomized to receive a compounded gel containing 10 mg of baclofen, 40 mg of amitriptyline, and 20 mg of ketamine or placebo. Patients in the treatment group experienced a slight but nonsignificant improvement in their sensory neuropathy over those treated with placebo. The authors indicated that the improvement may have been insignificant due to patients receiving lower doses of the drugs, since data on their systemic absorption are lacking.1,2,26 Adverse effects are infrequent with topical products, as systemic absorption is minimal, though local irritation and rashes have been reported. Despite little efficacy data, a trial of topical cream is usually warranted. Topical agents can also be combined with systemic agents. Tricyclic antidepressants. Amitriptyline, desipramine, and nortriptyline are considered first-line agents for the treatment of other neuropathic pain syndromes. Two studies have evaluated the efficacy of amitriptyline in the treatment of CIPN. Neither study had sufficient power to show benefit of amitriptyline over placebo.27,28 A Phase III crossover study evaluated the safety and efficacy of nortriptyline versus placebo in the treatment of CIPN in 51 patients with cancer receiving cisplatin.29 The study consisted of two four-week treatment periods, which were separated by a one-week washout period. After the first treatment period, patients receiving nor-
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21
22
Mechanism of Action
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Inhibit reuptake of serotonin and norepinephrine. Venlafaxine inhibits serotonin more strongly at lower doses, and norepinephrine at higher doses, while duloxetine inhibition is more balanced.
SNRIsb
Use of MAOIs within past 14 days; use during acute recovery phase after myocardial infarction
None
Use of MAOIs within past 14 days; uncontrolled narrow-angle glaucoma
Caution with other serotonergic drugs (risk of serotonin syndrome); caution with medications that prolong Q-T interval; warfarin (increased INR); primarily substrate of CYP2D6; avoid strong CYP2D6 inhibitors Nonsteroidal antiinflammatory drugs may decrease effectiveness; caution with other medications that can cause sedation
Caution with other serotonergic drugs (risk of serotonin syndrome); caution with anticoagulants or antiplatelets (increased risk of bleeding); duloxetine is a substrate of CYP2D6 and 1A2; venlafaxine is a substrate of CYP2D6 Caution with CYP2D6 and 1A2 inhibitors, this may result in increased plasma concentrations and increased toxicity
Common: anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention), sedation, confusion Rare but serious: cardiac arrhythmias, bone marrow suppression Common: somnolence and fatigue, dizziness, peripheral edema, weight gain Rare but serious: hypersensitivity reactions (including StevensJohnson syndrome and angioedema), seizure, suicidal thoughts Common: hypertension, headache, insomnia, somnolence Rare but serious: seizure, hepatitis, suicidal thoughts, serotonin syndrome
Amitriptyline: 25–100 mg/day, up to max of 200 mg/day Desipramine: 10–25 mg/day initially, increase to a max of 150 mg/day Nortriptyline: 10–25 mg/day initially titrated to effect (usual dose 75 mg/day) Gabapentin: 300–900 mg/day initially, increase to 3600 mg/day Pregabalin: 150 mg/day initially, increase to max of 600 mg/day
Venlafaxine: initial starting dose of 75 mg of immediate-release or 37.5 mg of extended-release formulation daily; may be increased to 225 mg/day Duloxetine: 30 mg/day initially, increase to 60 mg/day after 1 wk
Contraindications
Drug Interactions
Toxicity
Dosing
b
a
INR = International Normalized Ratio, CYP = cytochrome P-450 isoenzyme, MAOI = monoamine oxidase inhibitor, SNRI = serotonin–norepinephrine reuptake inhibitor. Venlafaxine is the only agent that has demonstrated efficacy in the prevention of chemotherapy-induced peripheral neuropathy (CIPN); duloxetine is used for the treatment of CIPN.
Block calcium channels on presynaptic neurons and prevent the release of excitatory neurotransmitters
Anticonvulsants
Tricyclic Block reuptake of antidepressants serotonin and norepinephrine
Drug Class
Oral Agents for Chemotherapy-Induced Peripheral Neuropathy27,28,a
Table 1.
THERAPY UPDATE Chemotherapy-induced peripheral neuropathy
THERAPY UPDATE Chemotherapy-induced peripheral neuropathy
triptyline reported a 5% higher rate of paresthesias over placebo as measured weekly using a visual analog scale (VAS). At the end of the second treatment period after the crossover, patients on nortriptyline reported a 38% lower pain score than those receiving placebo; however, there was a significant dropout rate during the study. Patients receiving placebo reported significantly greater satisfaction with treatment over those using nortriptyline due to the higher rate of adverse events in the nortriptyline group. The anticholinergic, antihistaminergic, and antiadrenergic effects produce adverse effects that many patients cannot tolerate, such as dry mouth, drowsiness, weight gain, and hypotension.1,2 Given the lack of efficacy and significant adverse effects, tricyclic antidepressants are not considered first-line agents for CIPN. Anticonvulsants. Gabapentin and pregabalin are often used for the treatment of CIPN. Gabapentin is widely used to treat many types of neuropathic pain, such as diabetic neuropathy, postherpetic pain, and neuropathic cancer pain caused by direct malignant nerve infiltration or compression.30 Gabapentin was evaluated in a double-blind, placebocontrolled crossover trial of 115 patients with symptomatic CIPN.31 The dosage of gabapentin was adjusted to a maximum of 2700 mg/day in three divided doses. The primary efficacy measure was the patient-reported average pain score per day, which was calculated using a numerical rating scale and the Eastern Cooperative Oncology Group neuropathy scale. The results showed no significant differences in patients’ daily pain scores between the two groups. Pregabalin has a mechanism of action similar to that of gabapentin and has a similar adverse-effect profile.32 Despite benefits seen in smaller trials, a Phase IV study conducted to assess the efficacy of pregabalin in treatment of CIPN was terminated early due to insufficient power to detect a difference in
treatment groups during an interim analysis, suggesting pregabalin is ineffective in the treatment of CIPN.33 Both gabapentin and pregabalin have a modest adverse-effect profile, including drowsiness, dizziness, and fatigue.30,32 Peripheral edema, weight gain, constipation, and dry mouth are more prevalent with pregabalin than gabapentin. 30,32 The clinical evidence does not support the use of gabapentin and pregabalin for CIPN despite their efficacy in treating other forms of neuropathy, tolerability, and low cost. Duloxetine. Duloxetine was approved by FDA in 2004 for the treatment of major depressive disorder and diabetic peripheral neuropathy.22 Duloxetine’s FDA-approved indications expanded in 2007 to include the treatment of generalized anxiety disorder34 and in 2008 for the treatment of fibromyalgia.35 Three studies have been conducted to evaluate the efficacy of duloxetine for the treatment of CIPN. Yang et al.36 conducted an open-label pilot study to evaluate the role of duloxetine in the treatment of oxaliplatin-induced peripheral neuropathy in 39 patients with colorectal cancer reporting grade 1 through 3 neuropathies. The dose of duloxetine was started at 30 mg once daily, and, if tolerated, the dose was escalated to 60 mg once daily after one week of therapy. The level of neuropathic pain was assessed using VAS scores and the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE). A total of 9 patients (28.1%) discontinued duloxetine due to intolerable adverse events, including dizziness, nausea, somnolence, restlessness, insomnia, and urinary hesitancy. Improvements in VAS scores were seen in 19 of the remaining 30 patients (63.3%). Of these, 9 (47.4%) demonstrated an improvement in their NCI-CTCAE adverse-event grade; the remaining 10 patients maintained a stable grade. Matsuoka et al. 37 conducted a retrospective analysis of 15 cancer
patients with neuropathic pain who were nonresponsive to pregabalin. Duloxetine was initiated at 20 mg daily and escalated to 40 mg daily if the pain was not reduced by 33% or more from baseline after three to seven days. Duloxetine was administered concomitantly with pregabalin when the adverse effects were tolerable. Of the 15 patients evaluated, duloxetine was effective in 11 patients based on the reduction of pain in 7 patients and a decrease in sleepiness and lightheadedness in 4 patients. The adverse events reported were mild and did not require treatment discontinuation. A randomized Phase III doubleblind, crossover trial of duloxetine versus placebo for the treatment of CIPN was conducted in patients with persistent painful neuropathy grade 1 or greater secondary to treatment with paclitaxel or oxaliplatin.38 All patients were using analgesics at baseline. A total of 231 patients were enrolled in the study, with 185 patients completing the initial six-week treatment period for the preliminary review. Duloxetine dosing was initiated at 30 mg daily for one week, followed by 60 mg daily thereafter. Individuals receiving duloxetine had a larger mean decrease in their pain scores (calculated using the Brief Pain Inventory—Short Form) than those receiving placebo (–1.06 versus –0.34, p =0.003), with no significant difference observed based on the specific neurotoxic agent received. Patients receiving duloxetine also had improvements in daily functioning and quality of life compared with patients receiving placebo. Fatigue, insomnia, and nausea were reported in 5–7% of patients receiving duloxetine, while 5–8% of patients receiving placebo reported somnolence, insomnia, and fatigue, suggesting no significant differences between duloxetine and placebo in terms of adverse effects. However, more patients in the duloxetine group had moderate adverse effects,
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resulting in an 11% dropout rate compared with 1% in the placebo group. Discussion The role of preventive treatments in patients with cancer who are at risk for developing CIPN remains unclear. With the exception of venlafaxine, the studied agents have been found to be either ineffective or potentially associated with a decreased tumor response.1-3 If a preventive agent is desired, venlafaxine is the only agent that has demonstrated effectiveness in preventing oxaliplatin-induced CIPN.23 Whether venlafaxine is effective in preventing neuropathy caused by other agents is unknown, as is the effectiveness of duloxetine in this setting. In addition, the influence of venlafaxine on oxaliplatin’s anticancer activity is unknown; such influence was unreported in the clinical trial and is theoretically possible, as preclinical models suggest that venlafaxine modulates oxidative stress.24 Until concurrent venlafaxine is found not to reduce the anticancer activity of oxaliplatin and other agents, its use should not routinely be recommended for the prevention of CIPN. There are three options for the management of CIPN: reducing the dose of the offending chemotherapy, changing the treatment regimen entirely, or using adjunct medications.1 For patients with advanced or metastatic disease, when weighing the severity of neuropathy compared with the benefits of chemotherapy in the palliative setting, dosage reductions are supported over the alternative options, though alternative chemotherapy options may also be appropriate. Furthermore, the addition of adjunct medications to manage CIPN increases the complexity of the patient’s medication regimen and can introduce new adverse effects and toxicities. For patients with early-stage disease who are receiving curative24
intent chemotherapy, especially for diseases where high-dose chemotherapy is associated with better survival rates, adding an adjunct agent to treat CIPN may be the best option. An alternative chemotherapy regimen may also be an option, especially if there are other effective treatment regimens available. If adjunct therapy for CIPN is to be initiated, topical analgesics, tricyclic antidepressants, anticonvulsants, and serotonin–norepinephrine reuptake inhibitors (SNRIs) are therapeutic options. A trial of topical therapies, with limited systemic absorption, is warranted in most patients and can be combined with other agents.26 Tricyclic antidepressants have little or no efficacy and significant toxicity and should be avoided unless patients have not responded to more-effective therapies.27-29 While their efficacy in CIPN is not substantial, the anticonvulsants gabapentin and pregabalin are well tolerated and may benefit some patients.30-32 Duloxetine has been shown to be more effective than placebo in treating oxaliplatin- or paclitaxelinduced CIPN, is well tolerated, and should be considered to be a first-line treatment option.36-38 Given that duloxetine is administered for existing neuropathy after the completion of chemotherapy, there is less risk of reduced anticancer activity of the chemotherapy. Duloxetine may also be beneficial for patients experiencing symptoms of depression or anxiety about their cancer diagnosis and treatment options. However, duloxetine’s efficacy in CIPN induced by other agents is unknown, as is the efficacy of venlafaxine for treating CIPN. Despite the paucity of data, a trial of duloxetine is a reasonable approach in patients with CIPN caused by other agents, as the mechanisms of chronic neurotoxicity are similar among anticancer agents and duloxetine is well tolerated.
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Conclusion Calcium and magnesium infusions and venlafaxine are effective for preventing CIPN but are not routinely used because of concerns related to decreased chemotherapy efficacy. Adjunct treatment options for CIPN include a topical analgesic, a tricyclic antidepressant, an anticonvulsant, or an SNRI. Duloxetine is more effective than placebo in treating oxaliplatin- or paclitaxel-induced CIPN, is well tolerated, and should be considered to be a first-line treatment option for CIPN. References 1. Stubblefield MD, Burstein HJ, Burton AW et al. NCCN task force: management of neuropathy in cancer. J Natl Compr Canc Netw. 2009; 7(suppl 5):S1-26. 2. Pachman DR, Barton DL, Watson JC et al. Chemotherapy-induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther. 2011; 90:377-87. 3. Beijers AJ, Jongen JL, Vreugdenhil G. Chemotherapy-induced neurotoxicity: the value of neuroprotective strategies. Neth J Med. 2012; 70:18-25. 4. Kemp G, Rose P, Lurain J et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol. 1996; 14:2101-12. 5. Lorusso D, Ferrandina F, Freffi S et al. Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients. Ann Oncol. 2003; 14:1086-93. 6. De Vos FY, Bos AM, Schaapveld M et al. A randomized phase II study of paclitaxel with carboplatin +/– amifostine as first line treatment in advanced ovarian carcinoma. Gynecol Oncol. 2005; 97:60-7. 7. Openshaw H, Beamon K, Synold TW et al. Neurophysiological study of peripheral neuropathy after high-dose paclitaxel: lack of neuroprotective effect of amifostine. Clin Cancer Res. 2004; 10:461-7. 8. Hilpert F, Stähle A, Tomé O et al. Neuroprotection with amifostine in the first-line treatment of advanced ovarian cancer with carboplatin/paclitaxel-based chemotherapy—a double-blind, placebocontrolled, randomized phase II study from the Arbeitsgemeinschaft Gynäkologische Onkologoie (AGO) Ovarian Cancer Study Group. Support Cancer Care. 2005; 13:797-805. 9. 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-
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