The major treatment-limiting toxicity of paclitaxel is CIPN [31–33], which predominantly presents as sensory symptoms [8, 9], with motor symptoms in some patients [8–11]. There are no known effective treatments that can prevent or ameliorate CIPN , which can be due to the unclear mechanism of CIPN . Differentiation of CIPN into symptom subtypes has been recommended to improve the success of CIPN intervention and biomarker discovery trials [14, 16, 17]. This exploratory analysis used PRO CIPN data collected prospectively during weekly paclitaxel treatment to investigate whether sensory and motor CIPN are distinct subtypes. As expected, more sensory than motor CIPN was reported. Interestingly, patient groups were identified with no CIPN, mixed CIPN, and sensory-dominant CIPN, but not motor-dominant CIPN. The metabolomics and nutrient biomarker results for motor CIPN were similar to those previously reported for sensory CIPN, suggesting there may not be distinct predictive metabolic biomarkers for motor CIPN from paclitaxel treatment.
Patients with breast cancer receiving taxane treatment experience both sensory and motor CIPN , but sensory CIPN is more common, especially with paclitaxel [6, 35–37]. Our findings are consistent with previous studies that sensory symptoms are more common, and we found that when motor symptoms occur, they usually co-occur with sensory symptoms. We did not find an appreciable group of patients with motor-only or motor-dominant CIPN; the only patient who experienced motor-dominant symptoms was also the only patient with appreciable motor CIPN symptoms at baseline (Figure 2, CIPNM=25). A prior case report described a patient who developed objective evidence of motor-only CIPN based on nerve function impairment, however, the motor symptoms were not detected by a PRO questionnaire . Sensitive nerve conduction studies have found that distal motor symptoms can occur alone , but the evidence from patient-report and clinician-assessment indicates that this is rare and motor symptoms are more likely to be a progression from sensory symptoms [39, 40].
Our clustering analysis of paclitaxel-treated patients identified No CIPN, Mixed CIPN, and Sensory-dominant CIPN groups. A previous analysis in patients with any cancer receiving any neurotoxic chemotherapy identified four clusters: Sensory, Motor-dominant Mixed, Sensory-dominant Mixed, and a less clear Autonomic cluster; a subgroup analysis of patients receiving paclitaxel alone (N=33) or with the somewhat neurotoxic carboplatin (N=50) had similar clustering results . While both studies agree that there is a lack of a motor-only subgroup from paclitaxel treatment, our study did not identify evidence of a Motor-dominant group. One of the core symptoms in their Motor-dominant Mixed cluster was difficulty manipulating small objects , which can be indicative of either motor or sensory impairment [40, 41]. We explored alternative definitions of the motor subtype that removed the two potentially confounded items, manipulating small objects and using pedals [41, 42], and still did not identify any motor-only or motor-dominant clusters (data not shown). The other difference between the studies is that we did not identify an autonomic cluster. We did not analyze the autonomic subscale of the CIPN20 because this subscale has been shown to be unstable and an unreliable indicator of CIPN [41–44], and autonomic CIPN symptoms are uncommon from paclitaxel treatment [3, 45].
Our analysis found that predictive metabolic biomarkers for motor CIPN were generally similar to those we previously reported for sensory CIPN [27, 28]; we did not find any evidence of distinct motor CIPN biomarkers. The majority of paclitaxel CIPN biomarker research has not differentiated between CIPN subtypes or has focused exclusively on the sensory subtype [19–28]. We are aware of only one study, also conducted in patients with breast cancer receiving paclitaxel, that found higher baseline levels of sphingolipids were associated with higher incidence of motor, but not sensory, CIPN . These hypothesis-generating results require validation in independent patient cohorts to determine whether baseline lipid levels may be predictive biomarkers of motor CIPN in patients treated with paclitaxel and perhaps other neurotoxic chemotherapy agents.
Overall, our results cast some doubt on recent recommendations for differentiating between motor and sensory CIPN in clinical trials and biomarker research, at least for paclitaxel [14, 16, 17]. The lack of a motor-only or motor-dominant subtype, and previous evidence that motor symptoms may be a progression from sensory symptoms, instead favors focusing prevention and treatment efforts on earlier sensory symptoms to avoid onset of the clinically troubling motor effects [12, 13]. In terms of CIPN monitoring, PRO questionnaires have several advantages over clinician-assessment [30, 46–49], one of which may be the ability to more clearly differentiate sensory and motor symptoms. This would be particularly helpful if someday there were treatments that were specifically effective in one or the other subtype. Finally, although it was only a single patient, our results indicate that patients with baseline motor neuropathy symptoms may have elevated risk of treatment-induced motor CIPN. This suggests that more sensitive baseline screening may help identify patients who should be considered for non-neurotoxic alternatives or enhanced CIPN monitoring, perhaps using novel wearable or app-based monitoring strategies .
This analysis used sensitive PRO data collected weekly throughout treatment in a relatively homogeneous cohort of patients with breast cancer receiving paclitaxel and investigated metabolic and nutrient biomarkers of motor CIPN. Despite these strengths, this study has several limitations. First, the modest sample size limits our confidence in concluding there is no motor-dominant patient group or motor-specific biomarkers. Second, although PRO are more sensitive and reliable than CTCAE , there is evidence that the CIPN20 subscale structure may have suboptimal structural validity [41, 43, 44], and the subscales may not optimally characterize the symptom subtypes . Third, we only examined a subset of metabolites and nutrients including vitamin D, vitamin B12, folate, homocysteine, and metabolite data generated by nuclear magnetic resonance spectroscopy; this metabolomics approach is less sensitive and results in fewer named metabolites than liquid chromatography-mass spectroscopy. Our ongoing lipidomics and proteomics analyses will attempt to validate previously reported biomarker candidates of sensory and/or motor CIPN [26, 29]. Finally, our findings are likely confined to only paclitaxel, and further research is needed to determine whether they should be generalized to docetaxel and perhaps other classes of neurotoxic chemotherapy. We plan to investigate symptom subtype clusters and predictive biomarkers in SWOG 1714 (NCT03939481), a recently completed observational clinical trial investigating clinical and physiologic predictors of CIPN in patients receiving paclitaxel or docetaxel treatment.
In conclusion, our findings suggest that in paclitaxel-treated patients, introduce the possibility that sensory and motor are not independent CIPN subtypes. Rather, motor symptoms co-occur with sensory symptoms. Prediction, prevention, and treatment of CIPN from paclitaxel should focus primarily on the more common sensory subtype. These findings need to be validated in larger cohorts of patients treated with paclitaxel and then tested in cohorts receiving docetaxel and other neurotoxic agents to determine the optimal approach to evaluate interventions for CIPN prevention and treatment, which could improve clinical outcomes in patients with cancer.