Background
Adjuvant oxaliplatin-containing chemotherapy improves survival in patients with colorectal cancer (CRC).1 Chemotherapy-induced peripheral neuropathy (CIPN) from oxaliplatin can be debilitating and is a reason for early discontinuation or dose reduction of adjuvant treatment. Acute neuropathy symptoms occur in 89% of patients, who experience sensory disturbances or pain in the extremities.2 Chronic CIPN is cumulative to oxaliplatin dose and has long-term functional implications, including impaired mobility and risk of falls.3 Symptoms can worsen even after discontinuation of treatment, a phenomenon known as coasting.2
There are no effective preventive agents and few evidence-based treatment options for CIPN, and therefore the mainstay of management is to limit exposure to oxaliplatin at the risk of attenuating treatment efficacy and affecting survival outcomes.4 Multiple risk factors for CIPN have been proposed but are inconsistently defined and reported. Research into the clinical and genetic factors predisposing to CIPN has been performed to try to identify patients at risk to allow individualization of treatment and balance toxicity and efficacy.5–7 Comorbidities such as the metabolic syndrome and diabetes can also cause peripheral neuropathy and are thought to contribute to an individual’s risk.8
CIPN is an important functional concern for patients, with those affected experiencing deficits in mobility and balance with associated risk of falls and disability.9,10 Effect of CIPN on quality of life (QoL) and distress has been reported in multiple CRC populations worldwide, with long-term worsening of patient-reported QoL and function in those with ongoing sensory and motor symptoms.11,12
Recent evidence from a multicenter randomized trial suggests that 3 versus 6 months of oxaliplatin-containing adjuvant chemotherapy provides clinically equivalent benefit, with reduction in CIPN and other toxicities.13 Our recent systematic review and meta-analysis (9,853 patients from 27 studies) estimated that approximately one-half of patients treated with adjuvant oxaliplatin for CRC have CIPN at 1 year, and one-quarter of patients have CIPN at 3 years following chemotherapy. Most patients included in the meta-analysis were planned to receive 6 months of oxaliplatin.14 Analysis of patients who received 3 months of adjuvant oxaliplatin identified considerable and pervasive CIPN.15
The aim of this study was to assess patient-reported CIPN and its associations in real-world CRC survivors, and to review the impact of neurotoxicity on dose delivery of oxaliplatin at a major tertiary cancer center, allowing for comparison with clinical trial populations.
Patients and Methods
This was a cross-sectional study with an embedded prospective longitudinal subset of patient-reported PN symptoms. Eligible patients were consenting adults (age ≥18 years) attending the Sydney Cancer Survivorship Centre (SCSC) between 2013 and 2021 who had completed curative surgery and/or chemotherapy for CRC.
Procedures
Prior to their initial visit to the SCSC patients completed comprehensive symptom patient-reported outcome (PRO) measures, including symptom questionnaire, distress screening, pain score, QoL, and diet, alcohol, and exercise information. The protocol and questionnaires have been described previously.16
Data Collection
Patients completed the Patient’s Disease and Treatment Assessment Form – General, a questionnaire assessing the incidence and severity of 48 symptoms over the last month, including numbness and tingling on a score from 0 to 10 (0 indicating no trouble at all, and 10 indicating worst I can imagine).17 The 10-point scale was divided into an estimation of the NCI CTCAE grades 0 to 4: none (0), mild (1–3), moderate (4–7), and severe (8–10).18 Although the 10-point scale and estimation has not been validated, there is systematic review evidence that other CIPN PROs at least moderately correlate with CTCAE grade.19,20
QoL was assessed using the validated Functional Assessment of Cancer Therapy-General (FACT-G). This questionnaire comprises 4 subscales: physical well-being (7 items, score of 0–28), social/family well-being (7 items, score of 0–28), emotional well-being (6 items, score of 0–24), and functional well-being (7 items, score of 0–28). The total score is the sum of the 4 subscale scores, with a higher total composite score indicating better QoL.21
A subset of consecutive patients completed the FACT/Gynecologic Oncology Group - Neurotoxicity 4-item symptom questionnaire (FACT/GOG-NTX-4) at 3-monthly subsequent visits to inform a longitudinal subset analysis. The FACT/GOG-NTX-4 asks patients about numbness/tingling or discomfort in their hands or feet. The 4-item version was used because on validation studies it was found to account for most of the longitudinal changes in score seen on the full questionnaire. It has been subsequently used in patients with other tumor types, including gastrointestinal cancer. Symptoms are scored on a scale of 0 (not at all) to 4 (very much), with a higher score indicating more severe neuropathy (score range, 0–16).22
Demographic information, including age, surgery, completion of chemotherapy, tumor stage, comorbidities (hypertension, hypercholesterolemia, cardiovascular disease, diabetes, body mass index [BMI], osteoporosis, and anxiety/depression), chemotherapy dose information, and dose modifications and reasons, were obtained from the clinical record.
Deidentified data were collected and stored using the REDCap data management platform.23 Ethics approval was granted by the Sydney Local Health District Human Research Ethics Committee–Concord Repatriation General Hospital (HREC/14/CRGH/23). Patients consented to the use of deidentified data for quality assurance and research.
Statistical Analysis
Descriptive statistics were used to summarize the demographic and clinical details of participants, their symptoms, comorbidities, and risk factors. Data were summarized as mean, standard deviation (symmetric normal data), median, interquartile range (skewed data or ordinal data), proportions, and odds ratio (OR) with 95% confidence intervals. The significance of the difference in numbness score and overall QoL and its domains were evaluated using independent samples t test (for 2 groups) or ANOVA (for ≥3 groups). The homogeneity of variance assumption was evaluated using Levene’s test. When violated, an unequal variances version of the t test or Welch robust test for ANOVA was used. Association between numeric variables was evaluated using Pearson product-moment correlation. The association between the likelihood of any numbness and severe numbness with risk factors was assessed using logistic regression. All the statistical tests were performed at a 0.05 level of significance. All statistical analyses were performed in SPSS Statistics, version 26 (IBM Corp).
Results
Participant Characteristics
The cohort comprised 233 patients with CRC (52% male) who attended the SCSC between July 2013 and September 2021 and had data available for analysis. Mean age was 63 years. Mean time from diagnosis to evaluation at the SCSC was 11.5 months (range, 5–90 months). Patients who received chemotherapy attended their first survivorship clinic a mean of 6.3 months after completion of chemotherapy (range, 0–82 months). Table 1 summarizes the patient characteristics.
Patient Characteristics of CRC Survivors Attending the Sydney Cancer Survivorship Centre
Younger patients and those with a higher CRC stage were more likely to receive chemotherapy, and more likely to receive oxaliplatin. Patients with diabetes, hypercholesterolemia, osteoporosis, and anxiety/depression were less likely to receive chemotherapy.
Oxaliplatin Dosing
We identified 127 patients who received oxaliplatin as part of their adjuvant chemotherapy: 79 received FOLFOX (folinic acid/fluorouracil/oxaliplatin), 47 received CapOx (capecitabine/oxaliplatin), and 1 received FOLFOXIRI (folinic acid/fluorouracil/oxaliplatin/irinotecan) as part of a treatment escalation study (DYNAMIC-III; ACTRN 12617001566325). Oxaliplatin dose reduction or cessation was recorded in 101 of 127 (80%) of patients. Dose reduction was needed in 32 (25%) patients, early cessation in 43 (34%), and both were used in 25 (20%) patients. Data were unavailable in 5 (4%) patients due to treatment at a different site.
Mean [SD] number of cycles of oxaliplatin given prior to any dose changes was 4 [2.9]. Of the 101 patients whose oxaliplatin was dose reduced or ceased early, PN was the most common reason, affecting 61% of patients, followed by myelosuppression of any cell line affecting 26%. Twelve percent of patients had both myelosuppression and PN listed as the reason for dose reduction or cessation of oxaliplatin. No reason was documented in 2 cases. The reasons for oxaliplatin discontinuation are summarized in Figure 1.
Reasons for dose reduction of early discontinuation of oxaliplatin.
Abbreviation: PN, peripheral neuropathy.
aNausea (n=1), fatigue (n=1), vomiting (n=1), bleeding (n=1), thrombophlebitis (n=1), de-escalated due to clinical trial (n=2).
Citation: Journal of the National Comprehensive Cancer Network 20, 12; 10.6004/jnccn.2022.7050
Reasons for dose reduction of early discontinuation of oxaliplatin.
Abbreviation: PN, peripheral neuropathy.
aNausea (n=1), fatigue (n=1), vomiting (n=1), bleeding (n=1), thrombophlebitis (n=1), de-escalated due to clinical trial (n=2).
Citation: Journal of the National Comprehensive Cancer Network 20, 12; 10.6004/jnccn.2022.7050
Reasons for dose reduction of early discontinuation of oxaliplatin.
Abbreviation: PN, peripheral neuropathy.
aNausea (n=1), fatigue (n=1), vomiting (n=1), bleeding (n=1), thrombophlebitis (n=1), de-escalated due to clinical trial (n=2).
Citation: Journal of the National Comprehensive Cancer Network 20, 12; 10.6004/jnccn.2022.7050
Burden of PN Single Item Score of Numbness and Tingling
Of the CRC survivors who completed the Patient’s Disease and Treatment Assessment questionnaire, 127 of 233 (54.5%) reported any numbness or tingling. Neuropathy symptoms were reported by a total of 126 patients: 92 of 127 (72.4%) who received oxaliplatin, 23 of 65 (35.4%) treated with fluoropyrimidines alone, and 11 of 41 (26%) who received no chemotherapy.
Patients receiving FOLFOX or CapOx had significantly higher numbness scores (mean [SD], 3.31 [2.83]) compared with patients receiving fluoropyrimidines alone (mean [SD], 1.37 [2.28]) or no chemotherapy (mean [SD], 0.66 [1.37]). There was a significant difference in patients’ numbness and tingling scores across chemotherapy regimens (Welch W [2, 129.4]=33.080; P≤.001).
Numbness score indicated a weak but statistically significant negative association with age (n=233; r = −0.212; P=.001). There was no significant difference (P=.568) in numbness score between males (mean [SD], 2.21 [2.69]) and females (mean [SD], 2.57 [2.82]).
The odds of any numbness were significantly higher following FOLFOX/CapOx compared with no chemotherapy or fluoropyrimidines alone (OR, 5.6; 95% CI, 3.2–9.8). The proportion of patients with severe numbness was significantly higher in the group that received oxaliplatin (11/127) compared with no chemotherapy or fluoropyrimidines alone (chi-square = 5.0; P=.03), with an OR of severe numbness of 4.9 (95% CI, 1.1–22.8). The distribution of participants treated with or without oxaliplatin who experienced numbness and tingling is represented in Figure 2.
Distribution of patients with numbness and tingling based on chemotherapy regimen received. Data are based on responses to a single question from the Patient’s Disease and Treatment Assessment asking patients about numbness and tingling.
Abbreviations: CapOx, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
Citation: Journal of the National Comprehensive Cancer Network 20, 12; 10.6004/jnccn.2022.7050
Distribution of patients with numbness and tingling based on chemotherapy regimen received. Data are based on responses to a single question from the Patient’s Disease and Treatment Assessment asking patients about numbness and tingling.
Abbreviations: CapOx, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
Citation: Journal of the National Comprehensive Cancer Network 20, 12; 10.6004/jnccn.2022.7050
Distribution of patients with numbness and tingling based on chemotherapy regimen received. Data are based on responses to a single question from the Patient’s Disease and Treatment Assessment asking patients about numbness and tingling.
Abbreviations: CapOx, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
Citation: Journal of the National Comprehensive Cancer Network 20, 12; 10.6004/jnccn.2022.7050
Evidence supporting shorter duration of doublet chemotherapy was reported in 2017.25,26 In our cohort, 29 (23%) patients were planned to receive 3 months of adjuvant therapy, and the remainder (n=97; 77%) were to receive 6 months. Mean “numbness and tingling” reported by patients planned for 3 and 6 months of chemotherapy was 2.7 versus 3.9, respectively (2-sample t test, P=.023), with 67% and 82% of patients, respectively, reporting any numbness.
The comparison of characteristics between participants with mild versus moderate-severe numbness is summarized in Table 2. No significant difference in numbness score was found for hypercholesterolemia, osteoporosis, hypertension, and anxiety or depression conditions (P≥.05). Patients without cardiovascular comorbidities indicated a significantly higher numbness score compared with those with cardiovascular comorbidity. Comorbid diabetes did not significantly affect the likelihood of any numbness or severe numbness.
Characteristics of Patients With CIPN Symptoms Based on Severity (N=126)
Patients reporting pain on their symptom questionnaire indicated significantly higher (mean [SD], 3.0 [2.8]) numbness score (mean difference, 1.0; 95% CI, 0.1–1.9) than those reporting no pain (mean [SD], 2.0 [3.0]). The BMI did not significantly impact numbness score.
Quality of Life
Overall QoL was higher (mean difference, 4.1; 95% CI, 1.3–6.8) for patients with no neuropathy (mean [SD], 51.3 [9.3]), compared with any reported neuropathy (mean [SD], 47.2 [9.4]). Physical, emotional, and functional well-being domains of the FACT-G QoL scale indicated a clinically small but significantly higher mean score for patients with no numbness compared with those reporting any numbness. There was no association between numbness and the social well-being domain (Table 3).
Comparison of QoL Scores in Patients With or Without CIPN Symptoms
Longitudinal Substudy
Longitudinal data were available for 104 of the CRC survivors who completed a total of 197 FACT/GOG-NTX-4 questionnaires. Of these, 21 had no chemotherapy, 29 received fluoropyrimidines alone, and 54 received an oxaliplatin-containing chemotherapy regimen. Table 4 presents the contingency table of numbness severity and months since chemotherapy for the patients who received chemotherapy. In each time category, persistent neuropathy of any severity was more prevalent in the oxaliplatin-treated patients.
Contingency Table of Numbness Severity and Months Since Chemotherapy Based on the FACT/GOG-NXT-4 Symptom Questionnairea
Discussion
This study describes CIPN symptoms in a real-world cohort of CRC survivors and examines the precipitating factors and outcomes of CIPN. Prevalence of CIPN symptoms was 57% in our population of CRC survivors. CIPN was strongly associated with the use of adjuvant oxaliplatin, with 74% of patients reporting neuropathy following adjuvant therapy containing oxaliplatin. A higher proportion of patients required dose modifications than reported in clinical trials, with neuropathy as the most common recorded reason in 61%. Survivors with any numbness or tingling had lower QoL scores in the physical, emotional, and functional domains. Numbness was associated with cardiovascular comorbidities, and severe numbness was associated with the presence of pain.
Delivery of oxaliplatin in this real-world cohort was substantially less than reported in clinical trials, with a mean of 4 cycles of oxaliplatin, and 80% of patients needing dose reduction or early cessation of therapy. A treatment completion rate exceeding 80% was reported in the phase III MOSAIC trial that showed a survival benefit for oxaliplatin containing adjuvant chemotherapy.24 The ACHIEVE trial reported treatment completion of 72%.25 The SCOT trial reported 83% treatment completion in patients assigned to 3 months of chemotherapy and 59% in patients assigned to receive 6 months. Of the patients who discontinued treatment early, neuropathy was the cited reason for 27%.26 In comparison, early cessation occurred in 54% of our cohort, with neuropathy recorded as the reason in 61% of patients. This discrepancy may be explained by the difference in populations, with real-world patients typically a less selected sample with more comorbidities than clinical trial participants.
Our results highlight the persistence of CIPN symptoms long after completion of therapy, with 40% of our real-world respondents reporting symptoms >36 months after completing chemotherapy. This was higher than the long-term follow-up of the initial MOSAIC trial cohort, which identified a CIPN rate of 18% with any CIPN at 3 years and 15% at 4 years.1 Our recent systematic review of clinical trials and cohort studies showed the rate of any grade CIPN after adjuvant oxaliplatin was 58% at 6 months after completion of chemotherapy, decreasing by 26% per year.14 In comparison, our real-world data cohort indicates a higher burden of CIPN in the oxaliplatin-treated population, with 72.6% of patients reporting neuropathy symptoms at a mean follow-up of 6 months.
Our findings showed that development of neuropathy was relatively agnostic to age, gender, and other comorbidities. Lifestyle factors and medical comorbidities have been examined as potential risk factors for CIPN. In a cross-sectional online survey of 986 cancer survivors with predominantly breast cancer (58.9%), severe CIPN was associated with older age, higher BMI, and comorbidities, in contrast to our findings in the CRC population.27 Lifestyle factors have been examined as a risk factor for peripheral neuropathy in a systematic review of cross-sectional and cohort studies, which supported an increased severity or incidence of oxaliplatin-induced neuropathy in patients with markers of obesity, although some studies used BMI and others used body surface area.8
Consistent with our results, other studies have found poorer health-related QoL in CRC survivors with higher CIPN scores compared with those with minimal symptoms.12,28
The strengths of this study are the high completion rates of PRO measures as well as clinical information, allowing a comprehensive dataset encompassing a large number of CRC survivors in routine (nonclinical trial) practice. The longitudinal subset of patients provides additional data on the persistence of symptoms over time. The use of PROs to evaluate neuropathy symptoms is another strength of our study. Differences in clinician-assessed and patient-reported CIPN have been examined in several cohort studies. The findings have suggested that patient-reported measures may be more sensitive at intermediate levels of neuropathy and at identifying functional impairment.19,29 The score used in our cohort was a single question asking about “numbness and tingling.” It is intended as a screening tool to prompt clinicians to focus on relevant patient concerns. The authors appreciate that there are several validated patient-reported questionnaires that comprehensively assess neuropathy, including impact on driving, walking, and erectile function,30,31 but these were not feasible to use during an initial visit to SCSC where patients are already completing several PRO measures. Although consensus is lacking on the best way to measure CIPN, research into an optimal screening method suggested that a brief PRO measure without the use of an objective test provided adequate screening.32
A limitation of this analysis is that prechemotherapy symptom data were not available, and therefore neuropathy symptoms were not necessarily attributable to chemotherapy. Neuropathy reported by those who did not receive oxaliplatin could have been related to concurrent medical conditions, such as diabetic neuropathy or degenerative spinal and joint conditions, which are more prevalent in older age groups.33,34 The single-item question has not been validated against other measures of neuropathy. Although hand-foot syndrome (HFS) from fluoropyrimidines may manifest as sensory changes, the natural history of HFS is rapid resolution following cessation of treatment.35 Given that our assessment occurred at a median of 6 months following chemotherapy, it is unlikely that HFS is implicated in the “numbness and tingling” reported. We observed that patients receiving fluoropyrimidines alone were older and had more documented comorbidities, which may discourage clinicians from using oxaliplatin-containing chemotherapy in this group and may explain this observation, given that preexisting neuropathy is a relative contraindication to oxaliplatin.
Another limitation is that longitudinal data were only available for a subset of patients (45% of the total cohort), which broadens the precision of the estimates. Selection bias is another potential limitation in our dataset, because individuals with more symptoms, better health literacy, or greater motivation to improve their health may be more likely to attend the SCSC and comply with symptom reporting, omitting those who are either too unwell or lack the language proficiency to complete the questionnaires. However, we estimate that approximately 90% of eligible patients with CRC treated at our center attend the SCSC.
The clinical implications of this study are that the true burden of real-world CIPN is greater than reported in clinical trials. The persistence of symptoms and the impact on QoL domains is also demonstrated, highlighting the need for more effective prevention and treatment strategies. This study raises the potential utility of screening for patient-reported neuropathy symptoms using a single question. Pending further validation, this simple measure may be adequate to identify patients who may benefit from interventions for CIPN or prompt a more comprehensive assessment. A clinical pathway for management of such patients has been described.36 SCSC patients with CIPN can access multidisciplinary care, including allied health, pharmacologic therapy, or specialist referral as needed; outcomes have been reported separately.37
The results indicate the challenges in delivering treatment proven to be beneficial in trials into the everyday clinical context. Combined with recent phase III results indicating that 3 months of adjuvant chemotherapy provides comparable benefit to 6 months, with substantially less neurotoxicity,13 and data indicating that early discontinuation of oxaliplatin does not affect disease-free or overall survival,38 clinicians and patients can be reassured that survival outcomes are not compromised if oxaliplatin needs to be discontinued due to toxicity.
Conclusions
CIPN is a common and often persistent problem for survivors of CRC, strongly associated with use of oxaliplatin. In our cohort of CRC survivors, patient-reported neuropathy was associated with the presence of pain and reduction in QoL. As the true impact of CIPN is underreported in clinical trials, data from this and other real-world cohorts have an essential role in quantifying the prevalence and impact of CIPN, to allow more comprehensive research into its evaluation, prevention, and treatment.
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