Characterising vincristine-induced peripheral neuropathy in adults: symptom development and long-term persistent outcomes

Adult patients (aged > 18 years) prescribed vincristine therapy for the treatment of haematological cancers were recruited into an observational study of neuropathy outcomes from hospitals in Sydney, Australia [12]. Patients were eligible if were either about to commence vincristine treatment (prospective arm) or had completed treatment between 3 months and 5 years prior (cross-sectional arm). The study was approved by the Human Research Ethics Committees of South-Eastern Sydney and Sydney Local Health Districts and was conducted in accordance with the Declaration of Helsinki. All patients provided informed written consent prior to study participation.

Patients were eligible for inclusion in this analysis if they had received a cumulative vincristine dose of ≥ 2.8 mg/m². To phenotype persistent neuropathy, 57 patients who had completed vincristine treatment (median = 10 months, range = 3–56 months) were included for cross-sectional analysis. To examine the development and progression of VIPN, a subset of 20 patients who had been longitudinally evaluated for neuropathy outcomes were included for prospective analysis (Fig. 1). These patients were assessed at four timepoints: T1—Early treatment (N = 2 prior to vincristine treatment, N = 18 following single vincristine dose), T2—midway through prescribed treatment protocol, T3—upon completion of treatment protocol and T4—3–6 months after vincristine treatment.

At each timepoint, patients completed a comprehensive battery of neuropathy assessments as described below, undertaken by trained researchers. All researchers received uniform neurologist-led training. Procedure protocols and training manuals were devised by senior researchers specifically for this study and were followed in all study visits. Assessors regularly met and worked together to ensure competence and quality control. Patient demographic (including age, BMI, diabetic status, cancer type) and neurotoxic treatment information (including dose, treatment frequency) was collected from medical records.

Summary statistics are presented as mean and standard deviation or median and interquartile range (IQR). The presence or absence of VIPN was categorised by whether patients reported core VIPN symptoms on the CIPN20: sensory (Q1, 2, 3, 4), motor (Q7, 8, 13, 15) or painful (Q5, 6), (Supplementary table). Comparisons between outcome measures are calculated with independent sample t tests or Mann–Whitney U tests for non-parametric data. Comparison of data between timepoints was calculated using paired sample t tests or Wilcoxon matched-pairs signed-rank test. Results are presented as mean ± standard error or median (IQR). Correlations are presented as Spearman’s rho, with 0.3, 0.5 and 0.8 indicating weak, moderate and strong correlations [22]. Comparisons between two observed groups are calculated using chi-square. Clinical risk factors (age, sex, body mass index (BMI), diabetic status and cumulative vincristine dose (mg/m²)) associated with persisting VIPN was investigated with univariate logistic regressions presented and as odds ratios (OR). Statistical significance was defined at P < 0.05. All statistical analyses were performed using Stata version 14 (StataCorp, College Station, TX, USA).

At 16.3 ± 15.6 months following vincristine treatment, 80.7% (n = 46/57) of patients reported persistent VIPN (EORTC-QLQ-CIPN20). To account for the range of time since vincristine completion, patients were categorised by time since treatment (less than 1 year (n = 29), 1 to 2 years (n = 15) and greater than 2 years (n = 13)). Comparison of neuropathy severity assessed via the CIPN20 found no significant difference between the three cohorts (P > 0.05).

Twenty participants were prospectively evaluated to investigate the development and recovery of VIPN (Fig. 1).

At T2 (7.0 ± 3.3 weeks post T1), 77.8% of patients reported VIPN (14/18) (Supplementary Table 1). Overall CIPN20 scores significantly worsened compared to T1 (Table 2). In particular, patient-reported sensory, motor and lower limb symptoms demonstrated significant worsening (Table 2, Fig. 3). There were similar proportions of patients with VIPN reporting motor (78.6%, 11/14) and sensory (71.4%, 10/14; P > 0.05) symptoms although majority of patients reported both sensory and motor involvement (57.1%, 8/14). Only one patient reported painful VIPN. Prevalence of symptoms in the hands (95.6%, 13/14) and feet (85.7%, 12/14) were similar, with most patients (78.6%, 11/14) reporting both upper and lower limb involvement. Autonomic symptoms were reported in 38.9% (7/18) of patients, compared to 15.0% (3/20) at T1; however, this difference was not significant (P > 0.05).

By T3 (8.1 ± 1.7 weeks post T2), CIPN severity remained stable, with no significant worsening in CIPN20 scores compared to T2 (Table 2) and a similar proportion of symptomatic patients (75%, 12/16; P > 0.05) reporting VIPN. However, severity for all patient-reported symptom categories except for pain were significantly greater than T1 (Fig. 3). Sensory and motor symptoms were equally prevalent (both 75.0%, 9/12) with 50.0% (6/12) of patients with VIPN reporting both sensory and motor symptoms. The majority of patients (75.0%, 9/12) reported both upper and lower limb involvement.

At T4, half of patients (50%, 10/20) reported persistent VIPN. Overall CIPN20 as well as subscale scores had improved compared to T3 and were no longer different to T1, except for lower limb symptoms (Table 2). In the patients with persisting symptoms (n = 10), 90% (9/10) reported sensory and 60% (6/10) reported motor symptoms; however, this difference was not significant (P > 0.05). Rates of autonomic symptoms also dropped to baseline levels, at 10.0% (2/20).

While the present study determined that 78% of patients developed VIPN, previous studies have suggested a large range of reported prevalence, from 44 to 92%, across studies [24, 28]. This most likely reflects the range of methods utilised for assessing neuropathy, with the most commonly used measure in large-scale clinical trials, NCI-CTCAE, known to have low inter-rater reliability [10]. Accordingly in the present study, VIPN assessment included patient symptom report as patient reported measures are becoming increasingly recognised as a valuable tool to capture neuropathy information [29]. Another important consideration that may affect reported VIPN prevalence is that the NCI-CTCAE sensory neuropathy subscale is most commonly used in clinical trials, which does not incorporate motor neuropathy symptoms, which is also a critically important characteristic of VIPN.

At mid-treatment, VIPN symptoms had reached the threshold of clinical significance (score increase of > 4.26 on the CIPN20) [30]. VIPN presented as motor and sensory neuropathy, affecting upper and lower limbs. Although prior studies investigating VIPN phenotypes are limited, early studies suggested VIPN to be predominantly sensory [23, 31], while others have demonstrated motor involvement is also significant on clinical [11, 32] and electrophysiological [33, 34] examination. This significant motor neuropathy development is characteristic of vincristine neurotoxicity. Other neurotoxic agents including taxanes, platinums, bortezomib and thalidomide are typically associated with only minor motor neuropathic symptoms [35]. Autonomic symptoms were more common in this current cohort compared to prior studies (30–39% versus 19%, [25]), and this is likely due to the varying methods of assessing autonomic neuropathy. While the present study utilised the autonomic items of the EORTC-QLQ-CIPN20, prior studies have highlighted limitations to this autonomic subscale [15]. Future studies should assess autonomic symptoms in vincristine-treated patients more directly to investigate the burden of autonomic nerve damage following vincristine.

The ‘coasting’ phenomenon, whereby symptoms worsen after end of treatment, was also previously associated with VIPN [24]. However, the present study incorporating multiple assessment techniques found that symptoms had reached their peak by the end of treatment. As observed in a prior study [36], symptom improvement occurred soon after treatment completion with significant improvements in 3 months post vincristine. This discrepancy may be due to dosing differences, as current practice is to cap each vincristine infusion at 2 mg, and the dosing limit was not applied in the earlier study where 90% of patients had a first dose > 2 mg [24]. In patients that experience improvement, the timecourse of VIPN recovery is similar to that seen in paclitaxel- and bortezomib-induced peripheral neuropathy, where symptom improvement occurs by 3 months after treatment completion [37, 38]. However, this pattern of recoverability is different to platinum agents, where symptoms may worsen for up to 6 months post treatment [39].

Despite the resolution of VIPN in a proportion of patients, this analysis of chronic VIPN identified significant symptoms which lasted more than 1 year post treatment. Persistent VIPN was associated with reduced spatial acuity in both the upper and lower limbs, reduced fine motor function, reduced sensory and motor nerve amplitudes and increased overall disability. This profile of long-term neuropathy symptoms is similar to deficits resulting from peripheral neuropathy due to other chemotherapies including taxanes and platinums [12, 40].

In the paediatric cohort, VIPN typically presents as motor predominant [4, 41, 42]. However, sensory neuropathy is difficulty to evaluate in young children, as they may have difficulty in communicating their experiences of sensory symptoms such as ‘numbness and tingling’. On the other hand, motor neuropathy is easier to clinically detect, with patients often being visibly weaker, and less active. Conversely in adults, ‘numbness and tingling’ is a unique abnormal sensation that patients can often easily recognise and report, whereas motor neuropathy symptoms including weakness and cramping are often difficult to attribute solely to treatment side-effects as opposed to cancer or age-related deconditioning.

Electrophysiological examinations in paediatric VIPN have also demonstrated greater motor compared to sensory nerve involvement [4, 43, 44] suggesting the motor-predominant neuropathy may not purely be due to symptom communication difficulties, or due to myopathy. While specific reasons behind this difference remains unknown, the difference in phenotypes may be related to age-dependent molecular changes in axonal function which may affect repair or regeneration pathways [45, 46]. Experimental models of traumatic injury or inherited neuropathy have also demonstrated differences in phenotypic expression of symptoms based on age [47, 48], highlighting that age-dependent changes in axonal function may influence VIPN presentation between adults and children. In the present adult study, there were reductions in both motor and sensory amplitudes by end of treatment; however, patients reporting persisting symptoms did not have lower amplitudes than patients without neuropathy. This may be related to inter-individual variability in baseline amplitudes. Further, electrophysiological, clinical and patient reported approaches to neuropathy assessment have been demonstrated to not directly conform [49, 50], suggesting each outcome measure alone is not sufficient to entirely capture the severity, impact and experience of neuropathy. Discrepancies between clinical examination and neurophysiological studies are common [50] and potentially reflect the different sensitivity of techniques to identify dysfunction.

This study was an observational natural history investigation of VIPN, with a limited sample size. Due to the nature of longitudinal research, not all prospective patients were able to attend all testing timepoints, and the authors acknowledge this as a limitation to the study. Future studies should conduct a priori power analyses to determine the sample sizes needed to detect change in neuropathy signs and symptoms. This will also reduce chances Type 1 errors, which may have occurred in this present study. Furthermore, longer-term follow-ups may provide greater insight in VIPN recovery as well as patterns of adaptation in chronic VIPN. NCS were only performed on the lower limbs in the present study, and future studies should also investigate neurophysiological changes in the upper limbs. Assessment of autonomic neuropathy was brief in this study, and future studies should incorporate more rigorous outcome measures, including objective markers of autonomic neuropathy to detail the severity and impact of autonomic neuropathy. As some patients were recruited cross-sectionally, the prevalence of VIPN in this cohort needs to be considered in this context as it may be higher than a purely prospective study. Cross-sectional participants were also recruited from a range of time since vincristine treatment, and vincristine regimens. While this was intentional in order to examine a representative sample of chronic VIPN presentation, this has resulted in a heterogenous participant sample. Other chemotherapies taken concurrently with vincristine were not controlled for; however, it is unlikely that this would have affected the profile of VIPN. In order to more fully identify risk factors for VIPN development such as cumulative dose, larger prospective studies are necessary. A number of genetic polymorphisms have been associated with VIPN, particularly in children [51]. These should be interrogated in prospective series utilising comprehensive neuropathy assessment protocols in order to better guide identification of patients at risk of long-term sequelae.