Are we mis-estimating chemotherapy-induced peripheral neuropathy? Analysis of assessment methodologies from a prospective, multinational, longitudinal cohort study of patients receiving neurotoxic chemotherapy

Chemotherapy- induced peripheral neuropathy (CIPN) is one of the major dose-limiting side effects of many chemotherapeutic agents including platinum analogues, vinca alkaloids, and taxanes [1]. The structure and function of peripheral motor, sensory and autonomic neurons are affected, causing peripheral neuropathic signs and symptoms [2]. In a systematic review of 31 studies (N = 4179), CIPN prevalence was 68.1% at the first month of chemotherapy to 30% six-months after chemotherapy, with wide variance in prevalence from 12.1–96.2%, depending on different timings of assessment and type of chemotherapy, and many assessing CIPN as part of a drug trial or with studies being cross-sectional [3].

What is already known is that neuropathic symptoms tend to progress during chemotherapy and generally regress once treatment stops; symptoms can consist of a mixture of motor, sensory, and autonomic signs; and the pain associated with CIPN can be prolonged and severe, and its treatment is usually difficult [3‐5]. Furthermore, neuropathy can have a negative impact on patient’s quality of life [4]. Studies showed that CIPN is associated with fatigue, psychological distress and decline in physical independence [6‐10]. CIPN may have an impact on the patients’ ability to work [11] and is associated with significantly higher medical costs ($17,344 more/patient) and higher healthcare utilization than non-CIPN patients [12].

It is clear in the literature that the assessment of CIPN is suboptimal [6]. A recent study using a Delphi technique in a small number of clinicians and consumers showed that there is no consensus as to the best assessment method for CIPN [13]. The NCI Common Toxicity Criteria (CTC) assessment for neuropathy may overestimate the presence of motor neuropathy and misdiagnose CIPN [14], although a consensus meeting suggested that the NCI CTC has good intra/interrater scores and validity [15]. Haryani et al. [16] reviewed available scales and suggested that the FACT-COG-Ntx scale and the Total Neuropathy Scale (TNS) as psychometrically optimal scales out of 20 tools examined. In another study, the Patient Neurotoxicity Questionnaire (PNQ) and the TNS were recommended [13]. The PNQ in particular seems to have received extensive evaluation in response to identified assessment problems with high variance and lack of reliability and concordance of past scales [1, 17‐20], and was recommended as a patient-reported outcome preferred tool by another study [13]. It is also clear that there is a significant discrepancy between clinician-rated CIPN through available tools and patient-reported outcome scales, with clinicians under-estimating the severity of CIPN [19]. Another study showed that EORTC-CIPN20 scores may not be reliably converted to CTCAE scores [21]. While the NCI CTC score is generally considered unreliable [6], it has shown significant correlations with the more accepted and reliable TNS [22]. There are multiple studies on this topic, all providing different and often contradictory views on the most appropriate CIPN assessment method, with no ‘gold standard’ consensus being reached yet.

Longitudinal studies to systematically determine the incidence, severity and natural history of CIPN with different neurotoxic chemotherapy drugs are vital in order to quantify the extent of the problem and inform future design of interventional studies; such studies are uncommon in the literature [23]. Also, prevalence may be linked with the particular assessment scale used in each study, and the sensitivity of scales to detect CIPN is variable in the literature. While some assessment tools have received significant attention in the literature (most with variable reliability/validity issues as mentioned above), there may be other tools that can be utilised in the assessment of CIPN and have received minimal attention that are however used in other areas of medicine effectively (ie. in assessing diabetic neuropathy, etc). Hence, the present study aims to identify the natural history and progression of CIPN within different chemotherapy drugs for up to 12 months after the patient’s first infusion of chemotherapy and to analyse consistency of different assessment methods, including the introduction of some more novel approaches in CIPN assessment in detecting prevalence.

The current study is the largest and one of a few longitudinal assessments of CIPN (2399 observations) using a heterogeneous population that increases the generalizability of the results. It showed that prevalence was significantly different from measure to measure used, patient reported outcome measures (through quality of life scales) consistently showed much higher CIPN rates than clinician-based or objective measures, and with highest rates in patients receiving taxanes (primarily paclitaxel). Cumulative dose was not linked with higher CIPN prevalence, but time since starting chemotherapy was. Correlations among scales were generally low, although these increased in the later assessments primarily among sensory neuropathy assessments. NCS data confirmed the sensory and motor impairment of participants.

This study confirms that there is wide variation of CIPN prevalence between scales. This is supported by a meta-analysis of CIPN prevalence studies, where confidence intervals were high (i.e. at 3 months CIs = 37–84%) [3]. CIPN prevalence is reported in the literature to be high, from 54 to 73% in some studies [31‐33] but often studies are using patient-reported outcome measures to assess prevalence, where CIPN prevalence is not the primary objective. Even in our study, when patient-reported outcome measures were used, prevalence doubled or tripled from that identified by other measures. It remains to be seen if such measures are appropriate diagnostic tools, as they also include items related to autonomic changes; such changes may have pre-existed the chemotherapy and it is unclear if they represent true CIPN-related changes or they are unrelated symptoms, particularly as many of the reporting studies are cross-sectional in nature. In our data, about one-quarter of the patients reported symptoms in the EORTC quality of life CIPN subscales at baseline, before they received any chemotherapy (Table 3). Nevertheless, other studies show similar results with our study including a one-year cumulative prevalence of 28.7% [34], 23% in a sample of patients receiving docetaxel [7] and 14.1% at 1 year [35]. Thus, it is clear that if we focus on prevalence rates that do not derive from patient-reported outcome measures, then prevalence is generally lower to about 15–25% of patients, the severity is generally not high, and that patient-reported outcome measures may overestimate CIPN prevalence as they include symptoms that may have pre-existed the chemotherapy. If patient-reported outcome measures, which are generally used to assess the ‘impact’ of a symptom on patients’ lives rather than diagnose a condition, are used to show CIPN prevalence, it has to focus more clearly on symptomatology that has developed after the use of chemotherapy, and exclude those that had similar symptoms before the chemotherapy. The latter number we have seen in our study was as high as 21.2%. Hence, cross-sectional assessments of CIPN using such patient-reported outcome measures can overestimate its prevalence. Irrespective of prevalence rates, however, the impact of the presence of such symptoms is significant [4, 6‐10, 36] and every effort should be made to improve the patient symptom experience.

The issue of reliable and valid measurement of CIPN is fundamental, and based on the (relatively low) correlations between scales shown in this study, it may be that each scale measures a different phenomenon or the scales used in this study were not all sensitive enough to detect CIPN. Which scale from the available ones is best for clinical assessment remains to be identified, and perhaps there is a need for a combination of scales to be used [37]. In our study, the cotton wool assessment led to the lowest ‘pick up’ rates and at a later time from all other scales suggesting this may not be an appropriate and sensitive enough test. The WHO criterion and the monofilament were highly correlated, suggesting that the former measures more sensory changes. However, the WHO criterion is minimally used in current practice. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes [38] and hence monofilament may be a useful method in identifying CIPN. The CTCAE is the only scale that assesses separately motor and sensory problems (alongside quality of life scales/ patient-reported outcome measures); while this is an important dimension, in our study the CTCAE identified less patients with CIPN than other scales, suggesting that it may not have high sensitivity. Generally speaking, CIPN is not assessed properly and we should focus more on improving its assessment [6].

A recent review [39] suggests that CIPN is a predominantly sensory symptom with pain; however, in our study we obsered a considerable prevalence of motor neuropathy, particularly in the docetaxel subgroup, across assessments as well as paclitaxel and paclitaxel/carboplatin in the later assessments. This finding should be interpreted with caution as the only motor neuropathy-specific scale we used was the CTCAE item, and the literature suggests that the CTACE motor item overestimates its occurrence, possibly as a result of confounding factors [40] although NCS data confirms motor impairment in this sample (suggested by the decreased motor nerve amplitude in our sample). Also, it is unclear whether the motor dysfunction observed is true motor neuropathy or fine motor impairments secondary to sensory loss, which is difficult to distinguish when ‘blunt’ instruments such as the CTC are used. Motor dysfunction has been shown in a small-scale study, where decreased superexcitability of motor axons was reported [41]. Furthermore, a neurophysiological study in children receiving vincristine showed impaired myotatic reflexes and motor neural impairment [42] and a larger study in oxaliplatin-treated patients found no nerve dysfunction before the initiation of chemotherapy [43] while others studies (ie. ref. [38]) have focused on sensory subclinical changes only. NCS focusing on motor nerves, in addition to sensory nerves, could highlight if the above comment is correct, and Kandula et al. [44] review the diagnostic role of NCS in CIPN. It may be that there is a general impression that CIPN is mainly sensory impairment as most of the studies in the past assessed sensory problems, with little assessment of motor problems. Motor symptoms may also be hidden under ‘fatigue’ too, and ‘feeling weak’ may be interpreted as tired rather than myopathy. Also, it is common in clinical practice to only ask patients if they have any numbness or tingling in the hands/feet, again focusing only on sensory symptoms. There is a need to focus more concretely on the assessment of motor symptoms in the future, as they are also linked with significant impact in daily activities, and define CIPN more broadly as a motor and sensory impairment accompanied by autonomic system manifestations.

Furthermore, pain was not a major issue and occurred in less than one-quarter of the participants, whereas tingling and numbness were most prevalent in more than half the sample. Pain may be more prevalent in oxaliplatin [45, 46] or paclitaxel-based chemotherapy but it seems to be less common in other taxane- or platinum-based chemotherapies [47]. Whether autonomic symptoms are the result of CIPN or symptoms reflecting other pre-existing conditions before chemotherapy treatment is not clear as yet, and more prospective work needs to be done in this area too. Also, many other symptoms were reported by patients at different degrees in each type of chemotherapy suggesting that CIPN is not the same symptom across taxanes and platins. This is an important finding to consider particularly when we assess patients or when therapeutic trials for CIPN (in terms of primary outcome) are planned.

At the 12-month assessment, a significant number (around 8% through objective and physician-based scales or 25–30% based on the patient-reported outcome measure) remained with CIPN symptoms, similar or somewhat lower to other studies in the past [7, 34, 35, 48]. As CIPN has been seen in patients even 11–12 years after chemotherapy [10, 49], it seems that this group of patients may experience chronic and long-lasting CIPN.

Cumulative dose of the chemotherapy was not a predictive factor for CIPN, against the currently held belief, in any of the chemotherapy regimens we assessed. An increasing body of literature shows similar results [31, 50]. This brings into question the current practice [51, 52] of dose reductions or chemotherapy discontinuation in patients experiencing CIPN. This finding, alongside with the key factor of time since chemotherapy, suggests that from the moment CIPN is experienced, it will continue to increase for the next few months and carry its course before we see any noticeable decreases after 6 months, irrespective of dose of chemotherapy [53], and patients may continue developing CIPN over time even if doses are reduced [54]. Whether treatment discontinuation or dose reductions have a real impact on decreasing CIPN should be assessed in future research.

Limitations of the study include the decrease in the sample over cycles (many patients did not complete more than 3–4 cycles or were ill/dead, giving significant missing data particularly in the 5th–6th cycle data. Some chemotherapy protocols also had a relatively small sample size. Where numbers were small, results should be interpreted with caution. Interrater reliability of the assessments may be an issue, although specific training and a protocol guide was provided to all assessors. The sample from Caucasians was also small compared to the Chinese and other Asian sample included. Some of the assessments used (i.e. WHO criterion; cotton wool) have not been rigorously evaluated as assessment methods in the CIPN context) and hence interpretation of results from these scales should be cautious. Cotton wool test and 10 g monofilament can detect sensory impairment, but they are unable to capture deep sensory impairment. This is typical of platinum drugs neuropathy and might partly explain why they are performing less efficiently than tuning fork examination in comparison with literature data.

This study maps the development and progression of CIPN in patients receiving taxane- and platinum-based chemotherapy, showing distinct CIPN profiles. It shows a lower level of CIPN than previously reported with significant differences among different chemotherapy protocols and scales used to measure CIPN. It brings into question the sensitivity and/or appropriateness of scales currently used to measure CIPN. Nevertheless, CIPN is a clinical problem present even 1 year after treatments and needs careful clinical attention. Practice-important findings include that early CIPN predicts CIPN in subsequent cycles, and this is the case irrespective of cumulative dose of chemotherapy. More work is needed in ascertaining best assessment methods for clinical practice and the findings call for a re-think of current clinical practices.