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 Table of Contents  
REVIEW ARTICLE
Year : 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


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

Date of Submission26-Mar-2019
Date of Acceptance23-Apr-2019
Date of Web Publication7-Aug-2019

Correspondence Address:
Deborah Lee
MSN, FNP.C, ACNP.BC Michigan State University, School of Nursing, East Lansing, MI
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/apjon.apjon_14_19

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  Abstract 


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.

Keywords: Cancer, chemotherapy-induced peripheral neuropathy, prevention, treatment


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;6:318-32

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 2019 Oct 16];6:318-32. Available from: http://www.apjon.org/text.asp?2019/6/4/318/259494


  Introduction Top


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: Critical appraisal criteria for the assessment of internal validity in Phase III chemotherapy-induced peripheral neuropathy intervention studies

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  Methods Top


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: Internal validity threats in Phase III chemotherapy-induced peripheral neuropathy prevention and management trials

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  Results Top


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: PRISMA 2009 Flow Diagram

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[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: Chemotherapy-induced peripheral neuropathy Phase III prevention and treatment evidence

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Table 4: Summary of findings and limitations by agent

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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: Recommendations for further testing of pharmacological agents for chemotherapy-induced peripheral neuropathy prevention or treatment: Comparison to American Society of Clinical Oncology clinical guidelines

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  Discussion Top


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.


  Limitations Top


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.



 
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Deborah Lee


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