Chemotherapy-Induced Peripheral Neurotoxicity

Impact of Pain on Symptom Burden in Chemotherapy-Induced Peripheral Neurotoxicity

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Background

Chemotherapy-induced peripheral neurotoxicity (CIPN) is associated with treatment with neurotoxic chemotherapies, including platinum-based agents, taxanes, vinca-alkaloids, bortezomib, and thalidomide.1 Because there are no preventive or treatment measures for CIPN, symptoms may require chemotherapy dose modification, which could reduce effectiveness.2 Furthermore, CIPN symptoms affect the quality of life (QoL) of cancer survivors, often producing long-term disability, including an impact on fine motor skills, walking, and gait.3

The core symptoms associated with CIPN are sensory disturbances, including numbness and tingling.4–6 Neuropathic pain, often described as shooting or burning pain, is less common,7 with only 33% of patients with CIPN reporting burning pain, compared with 77% reporting severe numbness and tingling.7 This discrepancy occurs for multiple neurotoxic drugs, with patients treated with taxanes,5,8,9 bortezomib,10 and platinum-based agents2,5,9,11 all reporting more severe tingling and numbness compared with neuropathic pain.

However, our understanding of the impact of painful CIPN on patients treated with chemotherapy is inadequate. In limited previous studies, participants with painful CIPN reported worse health-related QoL than those with nonpainful CIPN.8 Furthermore, painful CIPN may be associated with comorbidities, including fatigue, anxiety, and sleep impairments.12 However, the assessment of neuropathic pain in the context of CIPN remains a challenge. There is a lack of validated diagnostic tools that address pain and its impacts separately from nonpainful CIPN symptoms. Multiple studies use the clinically graded NCI-CTCAE scale for the quantification of neuropathy severity,13 which does not include neuropathic pain. Further, few patient-reported outcome measures (PROMs) for CIPN evaluation focus on identifying pain and its impact.12 The aim of this study was to understand the differences in prevalence and symptom burden of painful versus nonpainful CIPN.

Patients and Methods

Participants

Eligible participants were cancer survivors aged ≥18 years and were 3 to 12 months post treatment with neurotoxic chemotherapy (including taxanes, platinum-based agents, bortezomib, thalidomide, and vinca alkaloids). Participants were assessed cross-sectionally on a single occasion. Relevant clinical data were retrieved from medical records, including sex and age. This study was approved by Sydney Local Health District (Royal Prince Alfred Hospital [RPAH] zone) and South Eastern Sydney Local Health District Human Research Ethics Committees, and informed consent was obtained from each participant.

CIPN and Pain Assessment: PROMs

Assessment tools are briefly described in the following sections, with further details available in Appendix 1 in the supplementary materials (available online with this article).

The validated 20-item EORTC Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy (EORTC QLQ-CIPN20) was used to assess CIPN.14 The total score as well as individual item scores assessing the impact of CIPN symptoms on patient function were investigated.

The Pain Numeric Rating Scale (PNRS) was used to assess the intensity of nerve pain experienced by participants in the 24 hours prior to testing.15 A modified Douleur Neuropathique 4 (DN4) was used to report the most common descriptors of pain in participants who had neuropathic pain, including a comparison of pain descriptors reported across different chemotherapy types.16

A semistructured qualitative interview was conducted to collect information about participant symptoms and their impact, similar to previously conducted interviews.17

Clinical Neuropathy Assessment

Trained researchers undertook a comprehensive neuropathy assessment protocol to grade CIPN severity, including clinical neuropathy grading scales and functional assessments.

The NCI-CTCAE sensory neuropathy subscale version 4.018 and the Total Neuropathy Score–clinical version (TNSc; John Hopkins University) were undertaken.19,20 Nerve conduction studies (NCS) were undertaken in the lower-limb sural and tibial nerves as per previous studies.21

Functional assessments on participants’ dominant hand assessed sensory perception via Von-Frey monofilaments22 and grating orientation task (GOT),23 as well as fine motor skills via the grooved pegboard task.24

Participant Classification

Participants were classified based on CIPN symptoms reported in the PROM (EORTC QLQ-CIPN20) as in previous studies.2 Participants who did not report any painful or nonpainful CIPN symptoms were placed in the “no CIPN” group and were excluded from further analyses. From the remaining cohort, the presence of painful CIPN was characterized using either EORTC QLQ-CIPN20 items or PNRS score (detailed in Appendix 1).

Statistical Analyses

Data analysis was undertaken using SPSS Statistics, version 27 (IBM Corp). Data were assessed for normality using the Shapiro-Wilk test, and nonnormally distributed data (P<.05) were presented as median (IQR). Mann-Whitney U tests were used to explore differences between CIPN outcome measure scores, clinical characteristics, neurophysiological measurements, and treatment factors of painful and nonpainful CIPN cohorts. Chi-square tests were used to explore group differences between participants treated with taxane and platinum-based chemotherapy in the painful CIPN cohort and to investigate behavioral changes associated with CIPN subgroups. Statistical significance was considered when P<.05.

Results

Demographics and Clinical History

A total of 579 participants with a median age of 59 years (IQR, 19 years) were assessed cross-sectionally 6 months post neurotoxic chemotherapy treatment. In total, 66% of the cohort were female (n=384). The most common cancer types were breast (32%; n=184), gastrointestinal (28%; n=162), and gynecologic (18%; n=102). The most common chemotherapy types were taxanes (57%; n=329) and platinum-based (33%; n=194).

Overall, 28% (n=159) reported no CIPN, 24% (n=140) reported painful CIPN, and 48% (n=280) reported nonpainful CIPN. Participants not reporting CIPN at the time of assessment were excluded from the analysis (n=159). Of those with CIPN (n=420), females were more likely to report painful CIPN than males (P=.02). However, there were no differences in cancer type, cancer stage, or chemotherapy type between patients with painful versus nonpainful CIPN (all P>.05) (Table 1).

Table 1.

Clinical and Demographic Characteristics of Participants With CIPN

Table 1.VIEW TABLE

There were no demographic differences between both groups in terms of age and body mass index (both P>.05). However, participants reporting painful CIPN were significantly farther from treatment completion (6 [IQR, 5] months) than participants with nonpainful CIPN (4 [IQR, 3] months) (P=.02) (Table 1).

Neuropathy Profiles and Subgroups

Participants with painful CIPN had a greater symptom burden than those with nonpainful CIPN across multiple measures, including the clinically graded scale (NCI-CTCAE; P<.001) (Table 2) and the PROM (EORTC QLQ-CIPN20; P<.001) (Figure 1A and Table 2, and Supplementary Table S1). Participants with painful CIPN also had worse neurologic examination scores (TNSc; P<.001) (Figure 1B), including higher report of sensory (P=.003) and motor (P=.001) symptoms in the extremities (Table 2). However, there were no significant differences in pinprick or vibration scores, functional assessments (all P>.05), or sural (P=.10) or tibial amplitudes (P=.30) between the groups (Table 2).

Table 2.

Comparison of Neuropathy Outcomes Between Participants With Painful and Nonpainful CIPN

Table 2.VIEW TABLE

Figure 1.
Figure 1.

Items assessing the impact of symptoms on function on the PROM (EORTC QLQ-CIPN20) were investigated. Participants with painful CIPN reported significantly more functional impairments across all of these items compared with participants with nonpainful CIPN (all P≤.003) (Figure 2).

Figure 2.
Figure 2.

The severity of neuropathic pain was reported by participants with painful CIPN on the PNRS, focused on the shorter recall period of 24 hours. The median PNRS score was 4 (IQR, 6) out of 10, with 31% (n=44) reporting no pain in the 24 hours prior to testing (score, 0/10). Overall, the level of neuropathic pain on PNRS was significantly correlated with CIPN severity across all measures (all P<.05), including the PROM (Figure 3A), the neurologic examination score (Figure 3B), and the clinically graded scale (r=0.3; P=.002). Similarly, those who reported more severe pain in the past week (EORTC QLQ-CIPN20) had worse CIPN severity across all measures compared with those reporting lower pain severity (all P<.05). Common descriptors of pain are reported in Appendix 2 in the supplementary materials.

Figure 3.
Figure 3.

Subgroups Within Moderate-to-Severe CIPN Cohort

To examine further subgroup differences, comparisons were made between participants with moderate-to-severe CIPN symptoms with pain (n=102) and without pain (n=121). Even within the moderate-to-severe CIPN cohort, those with painful CIPN symptoms had worse impairments across all CIPN severity measures, including the PROM, the clinically graded scale, and the neurologic examination score (all P<.05) (Table 3). However, there were no demographic, neurophysiological, or functional differences between the groups (P>.05) (Table 3).

Table 3.

Comparison Between Participants With Worse CIPN (NCI-CTCAE ≥2) and No Pain Versus With Pain

Table 3.VIEW TABLE

Comparison of CIPN Subgroups Among Different Chemotherapy Types

The 2 largest chemotherapy-type cohorts (paclitaxel and oxaliplatin) were selected for group comparisons. There were significant differences in the prevalence of pain between the paclitaxel and oxaliplatin chemotherapy cohorts (28% vs 39%, respectively; P=.03) (Supplementary Figure S1). Group comparisons between paclitaxel-treated and oxaliplatin-treated participants can be found in Appendix 2 and Supplementary Tables S2 and S3.

Impact of Painful CIPN on Sleep, Exercise, and Treatment-Seeking Behavior

To characterize the impact of painful CIPN on behavior and patient function, we compared the painful (n=87) and nonpainful CIPN (n=193) cohorts who completed the structured interview in terms of self-reported sleep dysfunction, exercise impairment, and treatment-seeking behavior.

Participants with painful CIPN were more likely to report that their symptoms affected their ability to exercise (odds ratio [OR], 2.1; P=.007) than those without pain, with 43% (n=37) in the painful CIPN cohort reporting their exercise ability being affected by CIPN compared with 26% (n=51) of those without pain. Similarly, participants with painful CIPN were more likely to report that they had trouble sleeping (OR, 2.8; P<.001), with 47% (n=41) in the painful CIPN cohort reporting sleep dysfunction due to CIPN compared with 24% (n=46) of those without pain (Supplementary Table S4).

In addition, participants with painful CIPN were more likely to report seeking treatment of their symptoms than those without pain (OR, 3.2; P<.001) (Supplementary Table S4), with 69% (n=60) of the painful CIPN cohort reporting trying to find treatment options compared with 41% (n=79) of those with nonpainful CIPN. Furthermore, participants with painful CIPN were 4 times as likely to report the use of medication to ameliorate neuropathy than those with nonpainful CIPN (P<.001; Supplementary Table S5). These medications included anticonvulsants (pregabalin and gabapentin) and antidepressants (duloxetine and amitriptyline). In total, 12% (n=17) of the painful CIPN cohort were receiving medication for CIPN at the time of assessment, compared with 3% (n=9) of the nonpainful CIPN cohort.

Discussion

This study investigated neuropathic pain and its impact on symptom severity, sensory function, and behavior in participants with CIPN. Overall, 33% of participants with CIPN reported painful CIPN, which was associated with higher symptom severity across all CIPN outcome measures. The participants with painful CIPN reported more functional consequences than those without pain and were more likely to take neuropathy medications and report sleep dysfunction and exercise intolerance. Pain descriptors were similar between paclitaxel-treated and oxaliplatin-treated cohorts; however, pain was more prevalent in the oxaliplatin-treated cohort.

Other cohort studies have reported a similar prevalence of neuropathic pain, ranging between 20% and 33% of patients,25–27 in line with our results. In this study, participants with painful CIPN had worse global CIPN severity across all measures compared with participants with nonpainful CIPN. The presence of painful CIPN was associated with worse impairment of activities of daily living, a particularly reduced ability to distinguish temperature, more instability when standing or walking, and difficulty writing and manipulating small objects with fingers.

However, there were no group differences in performance on functional assessments and NCS. This suggests a potential separation between the perception of overall symptom burden and objective measures of neuropathy severity. Discrepancies between patient-reported symptoms of CIPN and neurologic examination have been previously identified,28 suggesting that these assessment tools address different aspects of CIPN.29 Patient reports of CIPN symptom severity and impact often provide a broader perspective compared with focal quantification of neurologic status. In addition, most neurophysiological measures of CIPN, including NCS, measure large nerve fiber function, whereas small nerve fiber dysfunction is less accessible to measure, presenting a potential limitation in fully capturing objective deficits.30 Importantly, patient report remains a key metric of CIPN severity, particularly given the lack of efficacy of measures such as NCS to identify differences between CIPN cohorts.

Participants with painful CIPN may be higher symptom reporters due to their increased symptom severity. A previous study found that participants who reported painful CIPN also reported higher anxiety and depression,31 suggesting that there may be a modulating effect of psychological factors on pain perception in patients with CIPN. However, the direction of this association remains uncertain, given that patients with painful CIPN were more likely to have persisting anxiety and depression following treatment, in contrast to patients with nonpainful CIPN, who demonstrated greater improvements in anxiety and depression following treatment cessation.8

The presence of neuropathic symptoms, including pain, negatively impacts the QoL of cancer survivors. In this study, the presence of painful CIPN affected patient-reported sleep, exercise, treatment-seeking behavior, and functional capacity. Although one previous study also highlighted the association between painful CIPN and comorbidities, including increased sleep dysfunction, fatigue, anxiety, and depression,32 research on the comorbidities associated with painful CIPN remains limited12 and represents a gap in enabling personalized management strategies for people with CIPN.

This study also found that oxaliplatin-treated patients had overall worse CIPN symptoms, significantly lower sural amplitudes, and greater functional changes in sensory perception and fine motor skills than those treated with paclitaxel. The different CIPN profiles of taxane and platinum-based chemotherapies have been previously reported,33–35 with reports at 1-year follow-up being similar to the current study.33 On the contrary, there were no differences in subjective or objective measures of CIPN between taxane-treated or platinum-treated patients at 5-year follow-up.35 With regard to pain, in this current study it was significantly more prevalent in oxaliplatin-treated patients than paclitaxel-treated patients. Interestingly, oxaliplatin-treated patients with painful CIPN also benefitted the most from duloxetine treatment in clinical trials, suggesting that different pain phenotypes may guide treatment responsiveness between chemotherapy types.36,37 Understanding differences in the chemotherapy-specific profiles of CIPN is important to guide patients and clinicians in understanding the likelihood of symptom recovery and adaptation over time.29

To date, treatment options recommended for the management of painful CIPN remain limited.36 In this study, only 12% of participants with painful CIPN reported taking anticonvulsants or antidepressants for neuropathy treatment. This reflects similar experiences with low medication uptake in Australian3 and international settings.38,39 Although duloxetine is recommended for the treatment of painful CIPN by international guidelines,40 in real-world practice, duloxetine treatment of painful CIPN is limited, with high rates of nonresponse and side effects leading to lack of tolerability.38 Better phenotyping of patients to determine who is most responsive to duloxetine and other therapies will likely improve real-world outcomes.36,37

Although there are emerging strategies for the management of neuropathic pain, including both pharmacologic and nonpharmacologic approaches,41,42 both will require the identification of patient subgroups likely to benefit most. Novel therapies, such as targeted drug delivery and neurostimulation methods, hold promise for reducing neuropathic pain but require additional testing and validation.41 Preliminary findings suggest that nonpharmacologic approaches, such as cognitive behavioral therapy, might improve QoL in patients with neuropathic pain42 and be more acceptable to patients.

Overall, this study provides a clearer understanding of differing symptom patterns in a large cohort. We used a combination of subjective and objective measures of CIPN as well as the combination of patient-reported and clinically graded outcome measures of CIPN. An issue limiting the previous understanding of painful CIPN is the use of combined descriptors of CIPN, collapsing sensory and painful symptoms of CIPN into a singular measure.43 For this reason, we used specific PROM items that assessed numbness, tingling, and shooting or burning pain in the last 7 days to capture a broader recall period and separate patients into groups according to neuropathic pain.2,7,33 However, these measures are not specifically validated to identify neuropathic pain. Although we did use validated neuropathic pain tools to assess pain intensity and descriptors, we did not use them for the purpose of participant classification due to the recall period only pertaining to the last 24 hours prior to participant testing.

Given that prior studies have demonstrated a “coasting” effect for up to 3 months post treatment completion,44 we chose to examine a cross-sectional cohort between 3 and 12 months post treatment completion. However, the cross-sectional nature of this study may be a limitation, and future prospective analyses will provide insights into the development of painful CIPN over time. Furthermore, we included multiple cancer and chemotherapy types in the analysis and did not control for all preexisting conditions that cause peripheral neuropathy or pain. However, >70% of this cohort developed neuropathy during treatment, suggesting that the CIPN symptoms identified were related to treatment-emergent toxicity rather than other factors. Furthermore, the inclusion criteria were deliberately broad to capture a naturalistic cohort reflecting patients receiving chemotherapy in a clinical setting. Although participants were asked about functional limitations, this study did not quantify the number of falls or participant balance performance. In addition, participants did not report whether they had tried medications to treat neuropathic symptoms previously and why these were discontinued.

Overall, given the outcomes of this study, we recommend that neuropathic pain be assessed in research and clinical settings as part of a comprehensive CIPN assessment. The tools used for this purpose should use a recall period longer than 24 hours, such as the EORTC QLQ-CIPN20. Other CIPN outcome measures, including the clinically graded scale (NCI-CTCAE) and the neurologic examination score (TNSc), which are used to assess CIPN severity, do not include questions to address neuropathic pain severity, and additional tools are required to address this. Finally, we recommend assessment of the impact of neuropathic pain on patient function and behavior, because our study has highlighted the long-term and deleterious consequences of pain on cancer survivors with CIPN.

Current guidelines for CIPN discuss the assessment of CIPN and include potential treatment options.40,45 However, these guidelines lack information relevant to patient subgrouping and phenotyping, particularly patients with neuropathic pain. The use of PROMs remains important in identifying clinically relevant symptom patterns, whereas NCS may not provide useful information in the classification of CIPN subgroups. Critically, the lack of accurate assessment of painful and nonpainful CIPN symptoms in clinical trials may lead to inaccurate results regarding intervention efficacy. Accordingly, it is essential that appropriate outcome measures be used to enable differentiation of painful and nonpainful symptoms.

Conclusions

Although the pathophysiological mechanisms underlying the differences in symptom expression within CIPN remains unclear, improved screening for pain and associated functional changes will allow a better appreciation of symptom burden and encourage more tailored intervention strategies to improve the QoL of cancer survivors.

Patient-Reported Outcome Measures in Chemotherapy-Induced Peripheral Neurotoxicity: Defining Minimal and Clinically Important Changes

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Background

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a debilitating adverse event of neurotoxic cancer treatments and is particularly prominent with taxanes, platinum-based agents, vinca-alkaloids, proteasome inhibitors, and immunomodulatory drugs. CIPN produces numbness, tingling, and pain in a length-dependent manner, affecting the hands and feet, and may result in functional impairments, such as difficulty with fine motor tasks, problems with balance, and increased falls risk,1 that can persist long term and negatively impact on health-related quality of life.2 There are currently no interventions established to prevent CIPN development, and the only treatment moderately recommended is duloxetine.3,4 Consequently, evaluating CIPN with a valid, reliable, and responsive outcome measure is critical in identifying early signs of nerve damage and effects of intervention aimed at preventing long-lasting or severe neurotoxicity.

There are numerous approaches to assessing CIPN, with patient-reported outcome measures (PROMs) recognized as valuable tools that provide a patient-based perspective essential to accurate assessment.5 Previously demonstrated discordance between patient- and clinician-reported CIPN6 suggests that PROMs may depict a broader spectrum of CIPN severity than clinician-based assessments,7 enabling better understanding of symptom manifestation and effects on function.8

A number of PROMs have been developed to assess CIPN9; the 2 most commonly used and extensively validated are the EORTC Quality of Life – Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20)10 and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity questionnaire (FACT/GOG-NTX).11 Previous studies have demonstrated that both PROMs are responsive in identifying change in CIPN symptoms over time.7,11–15 However, the utility of these PROMs remains limited due to the lack of guidelines regarding thresholds for identifying the development of clinically relevant and functionally significant CIPN.

Estimates of the smallest meaningful change in an outcome measure (termed the minimally important difference [MID]) enable clinicians and researchers to assess the clinical significance of changes in outcomes over time. CIPN PROMs are currently used in multiple research settings, including observational studies and clinical trials, without clear guidelines on how to interpret change in scores. MID estimates will aid and increase interpretability for CIPN PROMs by helping guide clinical judgement about whether and when change in CIPN symptoms has reached clinical relevance, facilitating routine use of CIPN PROMs as clinical trial outcome measures and in clinical practice. Although previous studies have attempted to estimate MIDs for the QLQ-CIPN20 and FACT/GOG-NTX,16,17 methodological constraints remain that may affect the reliability, clinical interpretability, and utility of these estimates.18 Consequently, this study aimed to estimate MIDs for the QLQ-CIPN20 and FACT/GOG-NTX to provide guidance for clinical threshold of CIPN development. Furthermore, thresholds for clinically significant CIPN were also estimated.

Methods

Patients and Study Design

Patients were recruited into a prospective longitudinal study at 2 hospitals in Sydney, Australia, from August 2015 to March 2021. Patients were eligible if they were scheduled to commence treatment with neurotoxic agents, including taxanes, platinums, vinca-alkaloids, proteasome inhibitors, or immunomodulatory drugs, and were recruited at treatment commencement. Patients were assessed at baseline (prior to the second administration of neurotoxic agent), midtreatment (halfway through treatment protocol), and end-of-treatment (upon completion of neurotoxic treatment). Demographic and treatment dosing information were obtained from medical records.

The study was approved by the Sydney Local Health District (SLHD) and South-Eastern Sydney Local Health District (SESLHD) Human Research Ethics Committees, and all patients provided informed signed consent in accordance with the Declaration of Helsinki. This study followed the STROBE reporting guidelines.19

CIPN Assessments

At each timepoint, patients completed a comprehensive battery of CIPN assessments as reported in prior studies,20,21 including key assessment tools described later that were used for the threshold estimation analysis. CIPN assessments were undertaken by trained researchers following a standardized testing protocol to ensure reproducibility. Full details of outcome measures and scoring are provided in eAppendix 1 (available with this article at JNCCN.org).

PROMs included the QLQ-CIPN20, a validated CIPN PROM consisting of 20 items addressing symptoms and functional impacts of CIPN (https://qol.eortc.org/).10 A reduced variant of the QLQ-CIPN20, consisting of 8 items (termed CIPN8) from the original scale,22 was also examined due to its recent use in translational studies.22–24 Another validated PROM assessing CIPN, the FACT/GOG-NTX consisting of 13 items (https://www.facit.org/),11 and its reduced version with 4 items (NTX4),25 were also examined.

The NCI’s CTCAE (version 4) peripheral sensory neuropathy subscale26 was used to clinically grade CIPN and was adopted as the clinical anchor for MID estimations. Trained researchers graded each patient using the CTCAE scale immediately following each patient’s clinical review and comprehensive CIPN assessment to maximize the scale’s accuracy and reproducibility.27 The Total Neuropathy Score, clinical version (TNSc), which is a validated composite neurologic grading scale designed to evaluate peripheral neuropathy, was also used to evaluate CIPN severity.28,29

Statistical Analysis and Threshold Estimation Methods

Summary statistics are presented as mean and standard deviation. Mean change in PROM scores were calculated from baseline to midtreatment and to end-of-treatment timepoints, and their statistical significance from zero was assessed with unpaired t tests, with statistical significance defined at P<.05. Both anchor-based and distribution-based methods were used to estimate thresholds30 for the 4 PROMs as described later. All statistical analyses were performed using Stata, version 14 (StataCorp LP).

Anchor-Based Methods

Anchor-based methods express change in PROM scores for subgroups of patients defined by clinically relevant variables (clinical anchors). For this study, the CTCAE was chosen as the clinical anchor because it is the most commonly used method of CIPN assessment and also has clinical relevance, with dose-modifying decisions in clinical practice often made based on CTCAE neuropathy grade. To assess suitability of the clinical anchor, correlations between the CTCAE scores and PROMs were calculated at each timepoint using Spearman’s rank correlation and a correlation coefficient of r > 0.30 was required to determine plausibility of the anchor.30 PROMs and CTCAE score changes were computed between baseline to midtreatment and baseline to end-of-treatment, and correlations between PROM change scores and CTCAE grade changes were calculated using Spearman’s rank correlation to further assess anchor suitability and MID credibility.18

Three clinical change groups (CCGs) were defined: (1) CCG 0: no CIPN development (CTCAE grade 0 at all timepoints); (2) CCG 1: development of minimal CIPN (CTCAE grade 0 at baseline, developing to grade 1 at midtreatment/end-of-treatment)—this was deemed the MID, and mean changes from this group provided MID estimates for the PROMs31; and (3) CCG 2: development of clinically significant CIPN (CTCAE grade 0 at baseline, developing to grade 2 at midtreatment/end-of-treatment), sufficient to influence/inform important clinical management decisions such as dose reduction, because this was deemed the clinically important difference (CID).32 Patients who developed grade >2 neuropathy were excluded from analysis because this study aimed to estimate score changes that reflect the development of minimally important neuropathy (CCG 1) and the threshold for clinically significant neuropathy (CCG 2). TNSc scores were used as a validated neurologic score of CIPN to further examine quantitative CIPN severity between CCGs. The mean change method was used to calculate PROM score changes over time for each CCG, and statistical significance of change was assessed with paired sample t tests, expressed with a 95% confidence interval.

Distribution-Based Methods

Distribution-based methods of threshold estimation using the statistical distribution of PROM scores (such as SD or standard error of the mean [SEM]) are considered as supportive evidence to the anchor-based MID estimations.30 In this study, the distribution-based method was calculated using 0.5 SD of PROM scores at midtreatment and end-of-treatment as in previous studies.33,34 Data from patients who had completed a midtreatment or end-of-treatment timepoint were included in this analysis.

Results

A total of 478 patients were recruited to the study, with 406 patients completing a baseline and midtreatment or end-of-treatment assessment and suitable for inclusion in this analysis (Figure 1). For these 406 patients, mean [SD] age was 55.6 [12.6] years, 64.0% were female (n=260), and most were treated with taxane (38.9%; n=158), platinum (26.6%; n=108), or combination taxane/platinum-based (19.2%; n=78) neurotoxic regimens for breast (32.3%; n=131), gynecologic (19.2%; n=78), or colorectal/gastrointestinal cancers (17.7%; n=72) (Table 1).

Figure 1.

Figure 1.

Flowchart and clinical change groups across each timepoint.

Abbreviations: CCG, clinical change group; CTCAE, Common Terminology Criteria for Adverse Events.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7074

Table 1.

Patient Demographic and Clinical Characteristics (N=406)

Table 1.

At baseline assessment, most patients (79.3%; n=322/406) did not have neuropathy symptoms (CTCAE grade 0; Table 1). By midtreatment (8.9 ± 4.8 weeks from baseline), 62.2% (n=199/320) had CIPN symptoms (CTCAE grade ≥1), and by end-of-treatment (17.6 ± 10.1 weeks from baseline), 79.9% (n=274/343) had CIPN symptoms (Figure 2). Mean scores for all 4 PROMs similarly reflected statistically significant increased self-reported CIPN (P<.001) at each subsequent timepoint (supplemental eFigure 1).

Figure 2.

Figure 2.

Distribution of CTCAE grades for CIPN at each timepoint.

Abbreviations: CIPN, chemotherapy-induced peripheral neurotoxicity; CTCAE, Common Terminology Criteria for Adverse Events.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7074

Patients who received taxane- or platinum-only treatments did not have significantly different CTCAE grade at midtreatment or end-of-treatment (both P>.05). Similarly, patients with stage IV disease did not have significantly different CTCAE grade than those with stage 0–III disease at either midtreatment and end-of-treatment (both P>.05).

CTCAE grades were correlated with PROM scores at each timepoint and between timepoints (r = 0.42–0.82; supplemental eTable 1). All correlations were >0.3, indicating the CTCAE grade was an appropriate clinical anchor.28 Furthermore, all but 1 of the 20 correlations were >0.50, meeting the higher threshold set by Devji et al18 for MID credibility.

Figure 1 shows the number of patients with PROM and CTCAE data that allowed them to be categorized as CCG 0, CCG 1, or CCG 2 at midtreatment and end-of-treatment. TNSc scores significantly worsened with increasing CCG both at midtreatment and end-of-treatment timepoints (P<.001; supplemental eTable 2), further supporting the CTCAE as an appropriate clinical anchor of CIPN severity.

PROM change scores for each CCG and timepoint are shown in Table 2. As expected, the CCG 0 group had the smallest mean score changes and the CCG 2 group had the largest mean score changes at midtreatment and end-of-treatment. The end-of-treatment means were larger than the midtreatment means for all PROMs and CCGs.

Table 2.

Mean Score Changes for Each CCGa

Table 2.

Distribution-based MID estimates were based on PROM data provided by 320 patients at midtreatment and 343 patients at end-of-treatment. These supportive MID estimates were smaller than the definitive MID estimates based on anchor-based methods at both time points for all PROMs (Table 3).

Table 3.

Comparison of Definitive Anchor-Based MID Estimate (CCG 1) With Supportive Distribution-Based MID Estimatea

Table 3.

Discussion

This study established score changes associated with minimal (grade 1) and clinically significant (grade 2) neuropathy development for 2 commonly used CIPN PROMs and their abbreviated versions. CIPN PROMs are widely used in clinical research and these data will enable better understanding of the PROM score differences that reflect development of minimally emergent neuropathy as well as development of significant neuropathy that would warrant consideration of dose modification. These corresponding sets of mean score changes serve as thresholds to guide clinical interpretation of score changes on these commonly used CIPN PROMs.

The reported prevalence of CIPN in this study is within the range reported by previous studies.35 However, some studies have reported lower prevalence of CIPN, which may be due to the methodology of CIPN assessment. In the present study, neuropathy grades were evaluated by trained researchers after completing a battery of CIPN assessments. This comprehensive investigation provided researchers with in-depth CIPN information and may have resulted in increased sensitivity in capturing CIPN compared with other studies.

This study used anchor-based methods, which are preferred over distribution-based estimations because they are underpinned by clinical relevance that enriches the interpretation and utility of the MIDs.30 The CTCAE peripheral sensory neuropathy subscale was used as the clinical anchor, and accordingly these MID estimations reflect development of grade 1 sensory CIPN. MIDs were estimated for both midtreatment and end-of-treatment timepoints, providing estimations of thresholds for CIPN development during treatment and quantifying overall treatment toxicity.

Choice of Clinical Anchor: Limitations and Future Directions

Choosing an appropriate clinical anchor is essential in MID estimation. The MIDs we estimated have high credibility according to the criteria developed by Devji et al18 (supplemental eTable 3), supporting the CTCAE peripheral sensory neuropathy subscale as an appropriate and robust anchor. An appropriate anchor needs to identify the threshold of a small but meaningful change in a patient’s symptoms: grade 1 of the CTCAE meets this requirement because it represents emergence of perceptible CIPN. In addition, we used the clinical significance of the higher grades to provide PROM thresholds for treatment modification indications, given that grade ≥2 CIPN often results in treatment modification. Finally, it is familiar to clinicians and researchers, further emphasizing its utility as a clinical anchor to aid interpretation of CIPN PROM scores.

Prior MIDs estimation studies for non-CIPN PROMs used more than one clinical anchor,34,36 whereas this study used only the CTCAE sensory subscale—arguably a limitation of this study. We considered other measures as additional anchors, including the TNSc.28 However, despite being a validated CIPN outcome measure, the TNSc lacks defined clinically significant cutoff values, resulting in ambiguity when benchmarking clinical significance. Although a recent study estimated MIDs for TNSc,37 the TNSc is not commonly used in routine oncology clinical practice, and accordingly there is a lack of treatment modification indications attributed to TNSc grades.

The CTCAE also has limitations as a clinical anchor, because it can have low interobserver reliability38 and low sensitivity to change,39 with the scale’s 4 grades not being able to accurately capture the spectrum of CIPN severity. Despite these shortcomings, Cavaletti et al27 demonstrated that standardized training in CTCAE grading and interpretation increases accuracy and reproducibility of results, and this has been adopted in the present study. Furthermore, in our study, the CTCAE grading was completed by trained researchers following the comprehensive CIPN assessment and discussion with the patient, which may explain the high correlations between the change scores compared with previous literature on MIDs.33,34,36 In addition, our study found significant worsening of TNSc scores between clinical change groups, further verifying the CTCAE as an appropriate proxy of CIPN severity.

This study estimated MIDs for the development of CIPN, but was not designed to estimate MIDs for CIPN improvement posttreatment, which we acknowledge may differ. Future studies estimating improvement MIDs for the QLQ-CIPN20, FACT/GOG-NTX, and their abbreviated versions will provide important thresholds, because these PROMs are also increasingly used in CIPN treatment intervention studies to ameliorate chronic CIPN symptoms. Furthermore, use of an anchor based on patient-reported perceived change in future work would provide an MID estimate better linked to patient perceptions of importance.18

Comparison With Previous MIDs Studies

Two prior studies have investigated MIDs for both the QLQ-CIPN2016 and FACT/GOG-NTX.17 However, there were some methodological differences that may limit the comparability of findings. First, the 3 timepoints used by Yeo et al16 (baseline, at second cycle of chemotherapy, and at 12-month follow-up) may not allow accurate capturing of CIPN symptom development. Because CIPN develops cumulatively with neurotoxic treatment, these timepoints may have missed the apex of CIPN symptoms, as suggested by the low proportion of their patient cohort (6.2%–6.6%) that developed CIPN. Consequently, although Yeo et al16 aimed to estimate MIDs for QLQ-CIPN20 using anchor-based methods, final estimates were based solely on distribution-based methods because their anchor-based estimates were found to be inconsistent due to the low rate of CIPN development. Cheng et al17 also used solely distribution-based methods to estimate MIDs for FACT/GOG-NTX. As discussed earlier, distribution-based methods are limited in clinical utility, lacking a direct link to a clinically relevant anchor. Furthermore, MIDs were estimated separately for the sensory and motor subscales of the QLQ-CIPN20.16 However, due to a lack of demonstrated structural validity for these QLQ-CIPN20 subscales,9 it has been recommended that the PROM be used in its entirety, rather than individual subscales.40

Utility in Different Clinical and Research Settings

Clinically relevant thresholds for PROMs have utility in both research settings and routine clinical care.41 The QLQ-CIPN20 and FACT/GOG-NTX are currently used in a wide range of research settings, including CIPN observational and natural history studies, CIPN treatment and intervention studies, and cancer treatment clinical trials. Although not as extensively validated as the original versions, the abbreviated CIPN8 and NTX4 have been used as outcome measures in observational studies22,23 and clinical trials.42,43 However, without guidelines on clinical thresholds, interpretation of observed changes in PROM scores is limited. The application of estimated MID scores in the research setting will amplify the utility of PROMs, guiding researchers to determine whether the PROM score changes are clinically meaningful and helping to define appropriate endpoints for clinical trials when assessing CIPN.

CIPN PROMs also have an important role in routine clinical care during treatment, particularly because clinician-rated CIPN grades are known to consistently underreport severity compared with patient self-report.44 Given that development of CIPN is a major reason for dose modification, it is critical that clinicians have the most accurate representation of CIPN severity when making these decisions. CIPN PROMs provide a promising data source, but to date, the use of CIPN PROMs in clinical practice has received little attention. We have estimated thresholds for clinically significant (grade 2) CIPN, because this level of CIPN often impacts on management, including dose modification. Careful considerations need to be made when adapting PROMs developed and validated for use in research to individual patient care,45 but the clinically significant thresholds we have provided are an important first step to introducing these PROMs to routine clinical practice. Furthermore, other interventions, such as increasing patient involvement in their symptom management46 and use of decision support algorithms to promote adherence to evidence-based CIPN management,47,48 may also provide clinicians with additional information and aid in treatment modification decisions. However, further studies are needed to determine how to best implement these methods into clinical practice.

Conclusions

MIDs and other clinical thresholds estimated in this study provide guidance on the meaningful interpretation of score changes for CIPN PROMs. These results will assist clinicians and researchers in identifying minimal and clinically significant CIPN development when these PROMs are used in research settings, and potentially in clinic.