Asia-Pacific Journal of Oncology Nursing

: 2019  |  Volume : 6  |  Issue : 4  |  Page : 318--332

Characterization of Internal Validity Threats to Phase III Clinical Trials for Chemotherapy-Induced Peripheral Neuropathy Management: A Systematic Review

Deborah Lee1, Grace Kanzawa-Lee2, Robert Knoerl3, Gwen Wyatt1, Ellen M. Lavoie Smith2,  
1 Michigan State University, School of Nursing, East Lansing, Ann Arbor, MI, USA
2 University of Michigan, School of Nursing, Ann Arbor, MI, USA
3 Phyllis F. Cantor Center for Research in Nursing and Patient Care Services, Dana-Farber Cancer Institute, Boston, MA, USA

Correspondence Address:
Deborah Lee
MSN, FNP.C, ACNP.BC Michigan State University, School of Nursing, East Lansing, MI


Objective: The recent American Society of Clinical Oncology (ASCO) Clinical Guidelines for chemotherapy-induced peripheral neuropathy (CIPN) management (48 Phase III trials reviewed) only recommend duloxetine. However, before concluding that a CIPN intervention is ineffective, scientists and clinicians should consider the risk of Type II error in Phase III studies. The purpose of this systematic review was to characterize internal threats to validity in Phase III CIPN management trials. Methods: The PubMed, CINAHL, EMBASE®, and Scopus databases were searched for Phase III clinical trials testing interventions for CIPN management between 1990 and 2018. The key search terms were neoplasms, cancer, neuropathy, and CIPN. Two independent researchers evaluated 24 studies, using a modified Joanna Briggs Institute Checklist for Randomized Control Trials developed by the authors specific for CIPN intervention trials. Results: Two studies exhibited minimal or no design flaws. 22/24 Phase III clinical trials for CIPN have two or greater design flaws due to sample heterogeneity, malapropos mechanism of action, malapropos intervention dose, malapropos timing of the outcome measurement, confounding variables, lack of a valid and reliable measurement, and suboptimal statistical validity. Conclusions: Numerous CIPN interventions have been declared ineffective based on the results of Phase III trials. However, internal validity threats to numerous studies may have resulted in Type II error and subsequent dismissal of a potentially effective intervention. Patients may benefit from rigorous retesting of several agents (e.g., alpha-lipoic acid, duloxetine, gabapentin, glutathione, goshajinkigan, lamotrigine, nortriptyline, venlafaxine, and Vitamin E) to expand and validate the evidence regarding ASCO's recommendations for CIPN management.

How to cite this article:
Lee D, Kanzawa-Lee G, Knoerl R, Wyatt G, Smith EM. Characterization of Internal Validity Threats to Phase III Clinical Trials for Chemotherapy-Induced Peripheral Neuropathy Management: A Systematic Review.Asia Pac J Oncol Nurs 2019;6:318-332

How to cite this URL:
Lee D, Kanzawa-Lee G, Knoerl R, Wyatt G, Smith EM. Characterization of Internal Validity Threats to Phase III Clinical Trials for Chemotherapy-Induced Peripheral Neuropathy Management: A Systematic Review. Asia Pac J Oncol Nurs [serial online] 2019 [cited 2020 Jul 7 ];6:318-332
Available from:

Full Text


Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and debilitating toxicities of cancer treatment that can negatively impact patients' quality of life and functional status[1],[2] and healthcare costs.[3],[4] Several agents may cause CIPN, including platinums, taxanes, vinca alkaloids, epothilones, bortezomib, and thalidomides.[5] These neurotoxic drugs cause sensorimotor nerve damage, leading to symptoms of weakness, numbness, tingling, and pain in the hands and feet, which can persist far beyond the completion of chemotherapy. To reduce CIPN progression, oncologists may limit or discontinue patients' chemotherapy treatment altogether.

Although the negative effects of CIPN on quality of life and chemotherapy administration are well documented, little is known about optimal CIPN prevention and/or treatment strategies. The American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines for CIPN management, informed by a review of over 48 Phase II/III clinical trials of 19 agents for the prevention and six agents for the treatment of CIPN,[5] determined that only duloxetine 60 mg/day can be recommended to treat chronic painful CIPN. No interventions can be currently recommended for CIPN prevention.[5],[6] Additional testing was recommended for antidepressants (e.g., nortriptyline HCl and desipramine), gabapentin, and a compounded topical gel with baclofen, amitriptyline HCl, and ketamine (BAK). No further testing was recommended for acetyl-L-carnitine (ALC), amifostine, calcium/magnesium, diethyldithio-carbamate (DDTC), glutathione, nimodipine, Org 2766, all-trans retinoic acid, rhuLIF, or Vitamin E.[5]

While strong evidence demonstrates the inefficacy of some agents (e.g., calcium/magnesium and ALC),[7],[8] the abandonment of testing some agents could be premature given the underdeveloped and potentially biased state of the evidence. For example, the recommendations to no longer test DDTC, nimodipine, and retinoic acid were each based on one trial[9],[10],[11] that were categorized by Hershman et al.[5] as having an intermediate or high risk of bias. Some agents, such as goshajinkigan, were not listed as agents requiring further testing even though at least one trial with a low risk of bias had supported their efficacy. Finally, the ASCO's Clinical Practice Guidelines were informed by one individual's review of the studies' risks of bias. This individual was not blinded to the study authors and had not done calibration exercises with the research team.[5]

Validity involves the degree to which the study design controls for extraneous variables, thus allowing causal inference to be made between the independent variable (e.g., pharmacological intervention) and the dependent variable (e.g., CIPN severity).[12] [Table 1] defines important internal threats to validity to consider when designing and evaluating CIPN management trials. One cannot eliminate the possibility that an extraneous variable influenced the observed results of a study with multiple threats to validity, thus leading to specious conclusions.[12] Thus, the rigorous evaluation of threats to internal validity of previously conducted Phase III CIPN clinical trials is needed to determine the agents that require further testing and to guide the development of future Phase III CIPN intervention trials. The purpose of this systematic review was to describe the internal threats to validity in Phase III CIPN management trials.{Table 1}


The PubMed, CINAHL, EMBASE®, and Scopus databases were searched for Phase III clinical trials, published between 1990 and 2018, that tested interventions for CIPN prevention or treatment. The search dates were selected to (1) capture all the Phase III clinical trials referenced in the ASCO recommendations and (2) extend the findings of the ASCO recommendations by including recently conducted Phase III trials. The key search terms were neoplasms, cancer, neuropathy, and CIPN. The reference lists of the included articles and other CIPN treatment reviews were hand-searched to identify additional articles.

Eligibility criteria

To increase the comparability of our findings, the eligibility criteria set forth by the ASCO review[5] were used for this review. Specifically, eligible articles reported the results of a Phase III RCT (2) that tested the efficacy of pharmacological interventions for the prevention and treatment of CIPN.[5] Articles were excluded if they (1) reported the findings of Phase I or II studies, (2) used nonexperimental designs, (3) included nonhuman subjects, (4) did not include cancer patients, (5) were not published in English, or (6) had a sample size of <10 subjects.

Data extraction

Data extraction was conducted based on the PRISMA guidelines.[13] Two authors independently scanned the article titles and abstracts to identify relevant studies that met the inclusion criteria. Questions about article inclusion were resolved through discussion among the co-authors. The following information was extracted from the included trials: design (prevention vs. treatment; single- vs. multi-site), sample size, population of interest, drug dosage, control condition, outcome measurement time points, and CIPN-related outcomes (e.g., CIPN severity and associated physical function, neurophysiological changes).

Data evaluation

The quality of the Phase III studies was evaluated using a modified version of the Joanna Briggs Institute (JBI) Checklist for Randomized Control Trials.[14] [Table 1] describes the criteria of the modified JBI checklist that was adapted specifically for CIPN intervention trials. Studies were evaluated as having low risk of bias (<two validity threats) or high risk of bias (>two validity threats). [Table 2] identifies the specific threats to validity of each study included. Descriptive statistics were used to quantify the number (n) of prevention and treatment studies that failed to meet each specific internal validity criteria. Recommendations for or against further testing specific agents for CIPN management were based on studies' risks of bias and findings (the efficacy and safety of the tested agents).{Table 2}


The database search provided 1199 records. After duplicates were removed and additional records were identified by hand-searching, 1108 abstracts were screened. After full-text review, 24 Phase III trials were selected. [Figure 1] presents a diagram of the article selection process.{Figure 1}

[Table 3] lists the 24 randomized, placebo-controlled, double-blind, Phase III trials (17 prevention and 7 treatment) that had tested 14 different agents for CIPN in adults. The prevention trials tested antioxidants (and an herbal supplement), an ion channel blocker, and a tricyclic antidepressant. The treatment trials tested gabapentinoids, serotonin-norepinephrine reuptake inhibitors, antiepileptics, and topical amitriptyline/ketamine-containing agents. Nine prevention and two treatment trials demonstrated a significant treatment effect on the primary outcome; however, 22 studies (16 prevention and 6 treatment) were considered to have a high risk of bias because of two or more identified threats to validity. [Table 4] summarizes the findings and limitations by indication (prevention or treatment), then by agent.{Table 3}{Table 4}

Prevention trials

The most common threats to validity in CIPN prevention trials were lack of valid and reliable measurement (n = 15), confounding variables (n = 13), and suboptimal statistical validity (n = 12). Specifically, only one prevention study utilized both clinical assessment and a patient-reported outcome (PRO) measure with strong psychometric properties.[29] Three studies[18],[19],[20] used either a CIPN clinical examination or PRO with adequate validity and reliability. Physician-graded (the NCI-CTCAE or WHO) scales were the primary CIPN measure in nine studies.[16],[17],[18],[22],[23],[24],[27],[30],[41] Eligibility criteria were not reported in four studies,[16],[22],[25],[29] and various studies lacked control for peripheral neuropathy-associated comorbidities, chemotherapy regimen and dose received,[17],[24],[27],[28],[30] previous receipt of chemotherapy,[17],[19],[29],[30] and concomitant analgesics/psychotropics/neuroleptics.[16],[17],[19],[22],[23],[24],[25],[27],[29] Finally, several studies may have utilized an inadequate drug dosage[22],[30] or a drug that mechanistically would possibly not lead to meaningful benefits in the outcome.[23],[30]

Treatment trials

Three of the CIPN treatment trials may have been biased by lack of valid and reliable measurement,[31],[33],[34] malapropos intervention's mechanism of action and dose,[31],[37],[38] confounding variables,[31],[33],[37] sample heterogeneity,[31],[37],[38] and/or suboptimal statistical validity.[34],[37] The primary threats that could have diluted the observed treatment effects were associated with CIPN instability (coasting effects) and low baseline CIPN severity (lack of room for improvement). Only one study addressed these potential threats.[6] One study may have utilized an inadequate drug dosage,[31] and three studies tested a drug that mechanistically would possibly not lead to meaningful benefits in the outcome.[37],[38],[40]

[Table 5] provides a comparison between the recommendations of the ASCO Clinical Guidelines and of this review based on the evaluation of the Phase III trial threats to validity.{Table 5}


This systematic review described the threats to validity of Phase III clinical trials that tested pharmacological agents for CIPN management. Three of the 24 trials reviewed had a low risk of bias.[6],[8],[40] The remaining studies were compromised by at least two threats to their validity: most commonly, measurement flaws, confounding factors, malapropos intervention's mechanism of action and dosage, inadequate sample size, recruitment, and retention.

Consistent with previous literature, our review suggests that the primary limitation among Phase III CIPN management trials is the use of CIPN measures that lacked sufficient reliability and validity.[42],[43],[44],[45] Specifically, the capability to detect clinically significant changes between groups may have been limited by the use of physician-graded scales – the NCI-CTCAE, WHO, and ECOG scales – as the primary outcome measures (used in 1/3 of reviewed studies). Physician-graded scales are known to lack reliability and sensitivity[46],[47],[48] and often demonstrate floor effects.[49],[50] In treatment trials measuring painful CIPN, the primary outcome measure should assess pain. Consistent with a review by Gewandter et al.,[51] the duloxetine trial by Smith et al.[6] was the only study that used a measure consistent with the primary pain outcome.[51] Further, the lack of a gold standard, reliable, and valid CIPN measure has made comparison among CIPN clinical trials difficult. Ideally, CIPN should be measured using a PRO survey and objective measures of physical findings (e.g., deep tendon reflexes and vibration sensation). The EORTC QLQ-CIPN20 and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Peripheral Neuropathy scale[52] are the examples of PRO measures with demonstrated reliability and validity, sensitivity, and responsiveness that could be used to improve measurement validity in the future CIPN trials. The total neuropathy score (TNS) is an example of an objective measure with demonstrated reliability, validity, sensitivity, and responsiveness that could be used. Moreover, when pain is the primary outcome,[6],[31],[33],[38] a validated pain measure should be used, such as the Brief Pain Inventory-Short Form.[53]

The second most frequent threat to validity was lack of control for confounding factors. Numerous disease processes (e.g., alcoholism, diabetes mellitus, and Vitamin B deficiencies) and pharmacological agents can cause peripheral nerve damage. Heterogeneous chemotherapy regimens also lead to varying CIPN symptoms and severity through varying mechanisms. Even chemotherapies of the same-drug class may vary in presentation. For example, oxaliplatin alone (unique from the other platinum-based chemotherapies: cisplatin and carboplatin) may cause both chronic CIPN and acute transient effects of cold-induced or temperature-evoked dysesthesia.[54] Exclusion criteria or statistical analysis should be used to control for these confounding factors.

The third most common threat to validity was associated with malapropos intervention's mechanism of action and dose. The intervention's mechanism of action did not match that of the nerve cell injury underlying the CIPN manifestations. For example, the pathophysiologic mechanisms underlying acute CIPN are peripheral nerve cell injury, whereas chronic painful CIPN is caused by central nervous system plasticity. Thus, central-acting interventions may treat chronic painful CIPN but would not be expected to prevent CIPN or treat acute CIPN due to peripheral nerve damage.[51] In addition, the intervention must be administered for an adequate amount of time to become efficacious; the primary treatment end points should be measured at the time point when a therapeutic effect would be expected based on previous CIPN trials. Rao[31] evaluated gabapentin for the treatment of CIPN. Patients received gabapentin (300 mg capsules) incrementally over 3 weeks to a maximum dose of 2700 mg daily, which was maintained for 3 weeks. Then, patients had a 2-week washout period before switching to the placebo arm. However, evidence from diabetic neuropathy treatment trials suggest that at least 2 months of gabapentin treatment is required before assessing efficacy.[55] In this example, timing of the primary end point measurement may have been too soon, resulting in insignificant results. In clinical practice, providers prescribe gabapentin for CIPN and titrate the dose to the desired effect.

Many trials exhibited high attrition rates (>50%)[15],[20],[23],[29] which lowers the statistical power of a study. Low power results in effect size estimates being less precise; thus, the researchers may incorrectly conclude that there is no effect demonstrated between the intervention group and the control group. High attrition rates may be the result of poor intervention efficacy, other therapy-related toxicities, or disease progression. Three studies[22],[27],[40] had low enrollment rates due to restrictive exclusion criteria that attempted to control for confounding factors which can result in increased risk for Type I errors (i.e., failure to detect no difference) and Type II errors (i.e., failure to detect a treatment effect that truly exists). Finally, inadequate sample size may have biased the results of 10 studies.[15],[20],[22],[23],[27],[28],[29],[34],[37],[40]

As presented in [Table 4], no further testing is recommended of ALC due to findings of worsening CIPN in the intervention group[7] and of calcium/magnesium based on three clinical trials demonstrating no effect for the prevention of CIPN.[8],[20],[22] Amifostine is not recommended for further testing due to side effect profile of the drug which includes hypotension.[16],[17] The clinical trial evaluating alpha-lipoic acid for the prevention of CIPN would have been strengthened with the addition of an objective measure such as the TNS to identify subclinical findings of CIPN in the control group, thus showing an effect in the prevention of CIPN.[15] Vitamin E was shown to be effective in the prevention of CIPN with a valid and reliable measurement tool.[29] However, a later study investigating Vitamin E showed no effect for the prevention of CIPN but used a less valid and reliable tool; thus, further testing would be beneficial.[30] In addition, glutathione should be retested for the prevention of CIPN using a valid and reliable measurement tool that can identify subclinical CIPN. In agreement with the ASCO Clinical Guideline recommendations, venlafaxine and goshajinkigan should be further tested for the prevention of CIPN.

For the treatment of acute CIPN, topical amitriptyline and ketamine should not be retested based on the mechanism of action. Concordant with the ASCO Clinical Guidelines recommendations, gabapentin, nortriptyline, and topical BAK should be retested for the treatment of CIPN. To date, there are no Phase III clinical studies evaluating oral amitriptyline. As suggested in the ASCO Clinical Guidelines, oral amitriptyline should be evaluated based on its efficacy in the treatment of polyneuropathy in diabetic and nondiabetic patients.[39] The ASCO Clinical Guidelines suggest no further testing of lamotrigine for the treatment and venlafaxine for the prevention of CIPN. However, this review suggests that lamotrigine should be retested for the treatment of painful CIPN using a valid and reliable measurement tool such as the EORTC CIPN20 or the FACT-GOG-NTX. Venlafaxine should be retested for acute painful CIPN using a valid and reliable measurement tool with a study design that can increase enrollment rates to demonstrate statistical validity.


We analyzed articles describing the trials for CIPN; thus, our results relied on the detail of the authors' study documentation. Lack of documentation was interpreted as a negative finding. Although evidence-based, the CIPN-specific critical appraisal criteria were developed by the authors and may not be comprehensive. Finally, the two researchers who evaluated the risks of bias for this review were not blinded to the study authors.

Implications for practice or research

The quality of studies included in a systematic review is important to consider when deciding whether review findings should guide practice and guidelines. This review conveys the complex challenges researchers face when designing Phase III CIPN trials. Despite the rigorous designs of Phase III CIPN clinical trials (e.g., randomization, double-blinding, and placebo-controlling), clinicians should carefully evaluate CIPN intervention trials for threats to validity before implementing changes in protocols or order sets. Only strong and consistent evidence should be used to inform clinical practice. This review can aid clinicians and scholars in identifying design flaws, analysis, or reporting of Phase III CIPN clinical trials.

Financial support and sponsorship

This study was funded by Jonas Nurse Scholar Program 2016–2018 cohort; Jonas Center for Nursing and Veterans Healthcare; Predoctoral Fellowship from the Rita and Alex Hillman Foundation.

Conflicts of interest

There are no conflicts of interest.


1Meyer-Rosberg K, Kvarnström A, Kinnman E, Gordh T, Nordfors LO, Kristofferson A. Peripheral neuropathic pain – A multidimensional burden for patients. Eur J Pain 2001;5:379-89.
2Mols F, Beijers T, Vreugdenhil G, van de Poll-Franse L. Chemotherapy-induced peripheral neuropathy and its association with quality of life: A systematic review. Support Care Cancer 2014;22:2261-9.
3Bakitas MA. Background noise: The experience of chemotherapy-induced peripheral neuropathy. Nurs Res 2007;56:323-31.
4Sasane M, Tencer T, Beusterien K. PCN63 review of the economic impact of chemotherapy induced peripheral neuropathy. Value Health 2009;12:A268.
5Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2014;32:1941-67.
6Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA 2013;309:1359-67.
7Hershman DL, Unger JM, Crew KD, Minasian LM, Awad D, Moinpour CM, et al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol 2013;31:2627-33.
8Loprinzi CL, Qin R, Dakhil SR, Fehrenbacher L, Flynn KA, Atherton P, et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance). J Clin Oncol 2014;32:997-1005.
9Arrieta Ó, Hernández-Pedro N, Fernández-González-Aragón MC, Saavedra-Pérez D, Campos-Parra AD, Ríos-Trejo MÁ, et al. Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer. Neurology 2011;77:987-95.
10Cassidy J, Paul J, Soukop M, Habeshaw T, Reed NS, Parkin D, et al. Clinical trials of nimodipine as a potential neuroprotector in ovarian cancer patients treated with cisplatin. Cancer Chemother Pharmacol 1998;41:161-6.
11Gandara DR, Nahhas WA, Adelson MD, Lichtman SM, Podczaski ES, Yanovich S, et al. Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities. J Clin Oncol 1995;13:490-6.
12Flannelly KJ, Flannelly LT, Jankowski KR. Threats to the internal validity of experimental and quasi-experimental research in healthcare. J Health Care Chaplain 2018;24:107-30.
13Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. Ann Intern Med 2015;162:777-84.
14The Joanna Briggs Institute. New JBI Levels of Evidence. The Joanna Briggs Institute; 2014. Available from: [Last accessed on 2017 Feb 17].
15Guo Y, Jones D, Palmer JL, Forman A, Dakhil SR, Velasco MR, et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled trial. Support Care Cancer 2014;22:1223-31.
16Kemp G, Rose P, Lurain J, Berman M, Manetta A, Roullet B, 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.
17Lorusso D, Ferrandina G, Greggi S, Gadducci A, Pignata S, Tateo 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.
18Gobran NS. Role of calcium and magnesium infusion in prevention of oxaliplatin neurotoxicity. A phase III trial. Chin Ger J Clin Oncol 2013;12:232-6.
19Grothey A, Hart LL, Rowland KM, Ansari RH, Alberts SR, Chowhan NM, et al. Intermittent oxaliplatin (oxali) administration and time-to-treatment-failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONcePT trial. J Clin Oncol 2008;26 Suppl 15:4010.
20Grothey A, Nikcevich DA, Sloan JA, Kugler JW, Silberstein PT, Dentchev T, et al. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol 2011;29:421-7.
21Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol 2007;25:4028-9.
22Ishibashi K, Okada N, Miyazaki T, Sano M, Ishida H. Effect of calcium and magnesium on neurotoxicity and blood platinum concentrations in patients receiving mFOLFOX6 therapy: A prospective randomized study. Int J Clin Oncol 2010;15:82-7.
23Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, 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;20:3478-83.
24Cascinu S, Cordella L, Del Ferro E, Fronzoni M, Catalano G. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: A randomized double-blind placebo-controlled trial. J Clin Oncol 1995;13:26-32.
25Smyth JF, Bowman A, Perren T, Wilkinson P, Prescott RJ, Quinn KJ, 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, randomised trial. Ann Oncol 1997;8:569-73.
26Leal AD, Qin R, Atherton PJ, Haluska P, Behrens RJ, Tiber CH, et al. North central cancer treatment group/Alliance trial N08CA-the use of glutathione for prevention of paclitaxel/carboplatin-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled study. Cancer 2014;120:1890-7.
27Oki E, Emi Y, Kojima H, Higashijima J, Kato T, Miyake Y, et al. Preventive effect of goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): A placebo-controlled, double-blind, randomized phase III study. Int J Clin Oncol 2015;20:767-75.
28Zimmerman C, Atherton PJ, Pachman D, Seisler D, Wagner-Johnston N, Dakhil S, et al. MC11C4: A pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy. Support Care Cancer 2016;24:1071-8.
29Pace A, Giannarelli D, Galiè E, Savarese A, Carpano S, Della Giulia M, et al. Vitamin E neuroprotection for cisplatin neuropathy: A randomized, placebo-controlled trial. Neurology 2010;74:762-6.
30Kottschade LA, Sloan JA, Mazurczak MA, Johnson DB, Murphy BP, Rowland KM, et al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: Results of a randomized phase III clinical trial. Support Care Cancer 2011;19:1769-77.
31Rao RD, Michalak JC, Sloan JA, Loprinzi CL, Soori GS, Nikcevich DA, et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer 2007;110:2110-8.
32Moore RA, Wiffen PJ, Derry S, Toelle T, Rice AS. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2014;(4):CD007938.
33Rao RD, Flynn PJ, Sloan JA, Wong GY, Novotny P, Johnson DB, et al. Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer 2008;112:2802-8.
34Hammack JE, Michalak JC, Loprinzi CL, Sloan JA, Novotny PJ, Soori GS, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain 2002;98:195-203.
35Harvey BH, Slabbert FN. New insights on the antidepressant discontinuation syndrome. Hum Psychopharmacol 2014;29:503-16.
36Dworkin RH, Turk DC, Peirce-Sandner S, Burke LB, Farrar JT, Gilron I, et al. Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. Pain 2012;153:1148-58.
37Barton DL, Wos EJ, Qin R, Mattar BI, Green NB, Lanier KS, et al. Adouble-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer 2011;19:833-41.
38Gewandter JS, Mohile SG, Heckler CE, Ryan JL, Kirshner JJ, Flynn PJ, et al. Aphase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy (CIPN): A University of Rochester CCOP study of 462 cancer survivors. Support Care Cancer 2014;22:1807-14.
39Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindström T, Thorell LH, et al. Acomparison a amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain 1997;13:313-23.
40Durand JP, Deplanque G, Montheil V, Gornet JM, Scotte F, Mir O, et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: Results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol 2012;23:200-5.
41Grothey A, Qin R, Dakhil S, Fehrenbacher L, Stella P, Atherton P, et al. O-0032 phase III randomized, placebo(PL)-Controlled, double-blind study of intravenous calcium/magnesium (CAMG) to prevent oxaliplatin-induced sensory Neurotoxicity (SNT), N08CB: An alliance for clinical trials in oncology study1. Ann Oncol 2013;24 Suppl 4:iv24.
42Argyriou AA, Bruna J, Marmiroli P, Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): An update. Crit Rev Oncol Hematol 2012;82:51-77.
43Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): What we need and what we know. J Peripher Nerv Syst 2014;19:66-76.
44Majithia N, Temkin SM, Ruddy KJ, Beutler AS, Hershman DL, Loprinzi CL, et al. National cancer institute-supported chemotherapy-induced peripheral neuropathy trials: Outcomes and lessons. Support Care Cancer 2016;24:1439-47.
45Smith EM, Knoerl R, Yang JJ, Kanzawa-Lee G, Lee D, Bridges CM, et al. In search of a gold standard patient-reported outcome measure for use in chemotherapy- induced peripheral neuropathy clinical trials. Cancer Control 2018;25:1073274818756608.
46Cavaletti G, Frigeni B, Lanzani F, Mattavelli L, Susani E, Alberti P, et al. Chemotherapy-induced peripheral neurotoxicity assessment: A critical revision of the currently available tools. Eur J Cancer 2010;46:479-94.
47Kuroi K, Shimozuma K, Ohashi Y, Hisamatsu K, Masuda N, Takeuchi A, et al. Prospective assessment of chemotherapy-induced peripheral neuropathy due to weekly paclitaxel in patients with advanced or metastatic breast cancer (CSP-HOR 02 study). Support Care Cancer 2009;17:1071-80.
48Postma TJ, Heimans JJ, Muller MJ, Ossenkoppele GJ, Vermorken JB, Aaronson NK, et al. Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann Oncol 1998;9:739-44.
49Cavaletti G, Bogliun G, Marzorati L, Zincone A, Piatti M, Colombo N, et al. Grading of chemotherapy-induced peripheral neurotoxicity using the total neuropathy scale. Neurology 2003;61:1297-300.
50Smith EM, Beck SL, Cohen J. The total neuropathy score: A tool for measuring chemotherapy-induced peripheral neuropathy. Oncol Nurs Forum 2008;35:96-102.
51Gewandter JS, Dworkin RH, Finnerup NB, Mohile NA. Painful chemotherapy-induced peripheral neuropathy: Lack of treatment efficacy or the wrong clinical trial methodology? Pain 2017;158:30-3.
52Calhoun EA, Welshman EE, Chang CH, Lurain JR, Fishman DA, Hunt TL, et al. Psychometric evaluation of the functional assessment of cancer therapy/Gynecologic oncology group-neurotoxicity (Fact/GOG-ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 2003;13:741-8.
53Atkinson TM, Mendoza TR, Sit L, Passik S, Scher HI, Cleeland C, et al. The brief pain inventory and its “pain at its worst in the last 24 hours” item: Clinical trial endpoint considerations. Pain Med 2010;11:337-46.
54Hausheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol 2006;33:15-49.
55Chou R, Carson S, Chan BK. Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: Discrepancies between direct and indirect meta-analyses of randomized controlled trials. J Gen Intern Med 2009;24:178-88.