To our knowledge, this study is the first to depict the phenotype and trajectories of CIPN through symptom cluster analysis using longitudinal data. The findings illustrated the relationship and development pattern among the diverse symptoms associated with CIPN over time, which have not been determined by previous research. This exploration of the interrelationships of symptoms linked with CIPN has also allowed us to refine and redefine what CIPN is, particularly around the mixed sensorimotor experience and the less common autonomic symptoms. The deeper understanding of CIPN during the course of chemotherapy and one-year follow-up period will help us develop more targeted symptom management strategies to meet the needs of cancer patients.
Concept of CIPN symptom clusters
This study identified four symptom clusters of CIPN, namely the sensory neuropathy symptom cluster, the motor-sensory neuropathy symptom cluster, the sensorimotor neuropathy symptom cluster, and the autonomic neuropathy symptom cluster, in cancer patients treated with neurotoxic chemotherapy agents from baseline to 12-month follow-up. Sensory neuropathy symptoms were predominant in half of the CIPN symptom clusters. No pure motor but a mixed motor-sensory neuropathy symptom cluster was identified, which may indicate a significant impact of sensory neuropathy symptoms in CIPN. Before the initiation of chemotherapy, the four symptom clusters were also identified and this may be related either to the specific scale used or to pre-existing symptomatology [22].
Sensory nerves are most commonly affected in cancer patients treated with neurotoxic agents and cause various sensory symptoms [3]. These patients often experience tingling and numbness in the hands and/or feet even for a long period [5, 23, 24]. This was confirmed by this study as a stable sensory neuropathy symptom cluster was identified with tingling in the feet, tingling in the hands, and numbness in the feet presented as the core symptoms over time. As a secondary symptom, burning pain in the hands and/or feet only presented at the early two assessment time points in the sensory neuropathy symptom cluster. This may be partially explained by Wolf et al.’s [5] study, which indicated that burning pain in hands and/or feet is less common and does not necessarily exist together with numbness and tingling. However, in our study, the symptoms of burning pain in hands and/or feet were identified in the motor-sensory and the sensorimotor neuropathy symptom clusters rather than completely disappearing. Similarly, the symptoms of cramps in hands and/or feet occurred in the sensory neuropathy symptom cluster at the time points from T1 to T3 but was more prominent in the sensorimotor neuropathy symptom cluster as sensory neuropathy became more stabilized. This may indicate an association between the development of sensory and motor neuropathy symptoms. Future research examining the underlying mechanisms of neuropathy and the associations between CIPN signs and symptoms is warranted.
The motor-sensory neuropathy symptom cluster was defined based on its inclusion of two motor neuropathy symptoms as the core symptoms and several sensory neuropathy symptoms as important secondary symptoms. As was similarly indicated in a previous study, both sensory and motor dysfunctions were detected in cancer patients with established CIPN [25]. However, the relationship between sensory and motor symptoms of CIPN is not clear. As sensory symptoms were predominant and occurred earlier in patients with established CIPN [1, 26], the motor symptoms were possibly a result of prolonged or worsening sensory symptoms of CIPN.
The sensorimotor neuropathy symptom cluster was named as such because it had a sensory neuropathy symptom as its single core symptom but simultaneously contained both motor and sensory neuropathy symptoms as secondary symptoms over time. The secondary symptoms of the sensorimotor neuropathy symptom cluster were flexible and affected both hands and feet; this may reflect an association between the symptoms in hands and feet. However, such association is not high according to Wolf et al.’s [5] report, which demonstrated a difference in patients’ experience of CIPN symptoms between hand and feet.
The last symptom cluster identified by this study was the autonomic neuropathy symptom cluster, with blurred vision serving as the single core symptom. Blurred vision often happens when the retina and optic nerves are affected by neurotoxic agents [27, 28]. Having difficulty hearing was a frequently identified secondary symptom in the autonomic neuropathy symptom cluster. Such an ototoxic effect has been reported in cancer patients treated with platinum and taxanes [29, 30]. It may be caused by damage in the Corti, lateral wall of inner ear, auditory nerve fibers, or spiral ganglion neurons [29]. Other commonly found secondary symptoms included having difficulty in remembering things and having difficulty in concentration. This interesting finding may be linked with chemotherapy-related cognitive impairment or “chemo brain” [31]. Future research is needed to explore the underlying mechanisms of the cognitive symptoms presented in the cluster. However, the autonomic neuropathy symptom cluster was not stable as its internal consistency was moderately low at six out of the ten time points. Furthermore, the core symptom (i.e., blurred vision) had only moderate loadings (< 0.60) at half of the time points. The instability in symptoms, lower item loadings or lower reliability values in this cluster may indicate that autonomic dysfunction as a result of CIPN is not clear or certain, and results perhaps are linked with other treatment-related symptomatology or earlier/pre-existing conditions, not commonly manifested as a result of CIPN. This hypothesis, however, requires further verification.
Subgroup analysis confirmed the presence of these symptom clusters. Each chemotherapy group also manifested its unique feature in symptom clusters. For instance, motor-sensory neuropathy symptom cluster explained higher percentage of variance in the docetaxel subgroup. However, patterns of symptom clusters regarding individual chemotherapy agents were not clearly identified due to insufficient sample size. Future studies focusing on specific chemotherapy agents should be carried out to understand the morphology of CIPN symptom clusters when different chemotherapy protocols are used. Moreover, CIPN symptom clusters may vary between different races. Our data demonstrated that, compared with non-Chinese Asians and Caucasian, Chinese patients experienced less severe CIPN symptom clusters. Nevertheless, the result may be biased due to the high proportion of Chinese patients in the study sample. Prospective study using more balanced sample would help address this question.
Methodological concerns in the symptom cluster analysis
In terms of methodology, we only used principal component analysis to detect potential symptom clusters of CIPN in cancer patients treated with neurotoxic chemotherapy agents based on the observed variables in our dataset. As this study aimed to provide preliminary information for further research, a confirmatory analysis has not been conducted at present. Some of the symptom clusters identified in this study are not stable, and the structure of symptom clusters at several assessment time points varied largely. These are, to some extent, related to the approach of principal component analysis with varimax rotation used in the study, because it is a dimension reduction technique without assuming any relationship among the symptoms as well as symptom clusters [32, 33]. Currently, the mechanisms of CIPN are not fully discovered [1]. Although certain relationships between CIPN symptoms like numbness, tingling, and shooting/burning pain have been demonstrated in previous studies, information on broader relationships among all the CIPN symptoms are still unclear [5]. Hence, it is unsuitable to presuppose a theoretical model for guiding the present symptom cluster analysis. Future biological research to identify the mechanisms and relationships underlying symptoms and symptom clusters of CIPN is needed.
This study adopted a one-way symptom cluster analysis, and the results were generated from a sequence of cross-sectional analyses. This may not fully reflect longitudinal development of trajectories and the potential mechanisms of each symptom cluster experienced by patients [33]. However, it provides a clearer and broader picture of changes in the component and structure within symptom clusters at each time point than modeling techniques [11]. Better mathematical algorithms and analytical techniques are needed for future symptom cluster research.
Another methodological limitation is that the measurements used in the study were patient-reported outcomes that assess CIPN symptoms. It is worth noting that objective measured outcomes are also important in CIPN. For example, patients with CIPN are likely to have abnormal Achilles tendon reflex, which may be a cause of motor impairment [25]. In addition, objectively measured balance, gait speed, and gait pattern are closely related to physical function and risk of falls in patients with CIPN and therefore should be included in symptom cluster analysis [34]. Results of nerve conduction studies like amplitude and conduction velocity are also significant indicators of axonal damage in CIPN [3]. Therefore, more considerations are needed to determine the use of these objective outcomes in symptom cluster research in CIPN.
Clinical implications
The existence of relevant symptom clusters indicates the importance of comprehensive and real-time assessment for cancer patients with CIPN, which may enable clinicians to identify major symptoms while fully understanding the dynamic changes of other correlated symptoms over time [10]. In terms of symptom assessment, the use of validated tools with adequate symptom items like the EORTC QLQ-C30 and CIPN20 should be considered in future clinical practice. Given the predominance of sensory neuropathy in CIPN symptom clusters, more emphasis should be placed on evaluating the impact of sensory symptoms on cancer patients with CIPN.
As a total of four symptom clusters of CIPN were identified in this study, it is necessary to organize holistic interventions that targets each symptom cluster simultaneously. An evidence-based care bundle may be promising to manage the multidimensional symptom clusters of CIPN [35]. It is also necessary to adjust intervention plans timely according to the change of symptoms associated with CIPN. Although sensory symptoms are predominant and were widely identified in all of the four CIPN symptom clusters, it is unclear whether managing the sensory neuropathy symptom cluster can simultaneously relieve the motor and autonomic changes. Future research to test this hypothesis is warranted. There are some questions that remain to be answered:
What are the relationships between sensory and motor neuropathy symptoms?
What are the relationships between the CIPN symptom clusters?
What are the relationships between core symptoms and secondary symptoms within a CIPN symptom cluster?
What are the mechanisms underlying the change of CIPN symptom clusters over time?
Will change of measurement instruments alter the results of CIPN symptom clusters?
Which CIPN symptom or symptom cluster should be priority in symptom management?
Limitations
Certain limitations of this study should be mentioned. First, this study is a secondary analysis, and the sample size for subgroup analysis was not planned in the prior design. Therefore, the findings of symptom clusters in subgroup analysis with individual chemotherapy agents were not reliable at time. These should be addressed in subsequent research. Second, the study included patients with mixed cancer diagnosis, thus leading to a heterogeneous sample, although this may provide a broader picture of CIPN symptom clusters in a wider cancer population. Lastly, patients in the study were treated with different chemotherapy agents and regimen (e.g., weekly versus three weekly) and had completed different number of cycles of chemotherapy, which may influence the patterns of CIPN symptom clusters.