Author: Wang, Mian
Title: Phenotyping and managing chemotherapy-induced peripheral neuropathy : using the Medical Research Council (MRC) framework to develop a repetitive transcranial magnetic stimulation intervention
Advisors: Molassiotis, Alex (SN)
Chiang, Vico (SN)
Degree: Ph.D.
Year: 2022
Award: FHSS Faculty Distinguished Thesis Award (2021/22)
Subject: Neuropathy
Cancer -- Chemotherapy -- Complications -- Treatment
Magnetic brain stimulation
Hong Kong Polytechnic University -- Dissertations
Department: School of Nursing
Pages: xxviii, 562 pages : color illustrations
Language: English
Abstract: Background
Chemotherapy-induced peripheral neuropathy (CIPN) is prevalent among cancer patients treated with a variety of chemotherapeutic agents, especially platinum compounds and taxanes. Clinical presentation of CIPN are sensory, motor, and autonomic symptoms and neurological signs such as decline of vibration sensibility, pin/tactile sensibility, tendon reflex, and motor strength. However, its phenotype has not been well explored. Severe and persistent CIPN may adversely affect patients' functions and quality of life. Due to unclear mechanisms, CIPN is not preventable at present. There is also a lack of effective treatment for established CIPN according to the most updated guidelines. Most of currently tested interventions were designed by referring to the experience of managing diabetic neuropathy, while none was developed based on understanding the phenotype of CIPN.
Aim and objectives
The overall research aim was to develop an effective intervention for managing CIPN based on its phenotype. Specific objectives of the doctoral research were: (1) to identify the currently evaluated interventions for managing CIPN; (2) to identify the theoretical basis of the most promising interventions for managing CIPN; (3) to define a theoretically relevant conceptual model for better understanding and managing CIPN; (4) to develop an intervention for managing CIPN based on the newly defined conceptual model; and (5) to design a study protocol for testing the feasibility and efficacy signals of the newly developed intervention.
This doctoral research project was conducted following the framework proposed by the Medical Research Council (MRC) aiming to guide the development and evaluation of complex interventions. The project comprises three steps for the intervention development, which include (1) identifying the evidence base, (2) identifying and developing relevant theories, and (3) modelling the process and outcomes. In the first step, a systematic review was conducted to examine recent research evidence of interventions for established CIPN. A supplemental systematic review was conducted to evaluate the safety, feasibility, and efficacy of non-invasive neuromodulation techniques, a class of non-pharmacological interventions that were found promising for the management of CIPN in the first systematic review. The theoretical basis of the non-invasive neuromodulation techniques was also sought in the systematic review.
In the second step, three exploratory studies were conducted to provide empirical evidence for the development of a theoretically relevant conceptual model to understand CIPN. The first exploratory study identified symptom clusters specific to CIPN through a secondary analysis of patient-reported outcomes from baseline before chemotherapy to 12-month follow-up in cancer patients who received neurotoxic chemotherapy. The second exploratory study analyzed multimodal assessment data from cancer patients with established CIPN who were enrolled in a randomized controlled to further examine the phenotype of CIPN and its relationship with general symptoms and quality of life. The third exploratory study examined the phenotype and value of nerve conduction studies (NCS) in CIPN assessment through a secondary analysis of pooled data from five original studies, to understand their value of it in assessing CIPN. Afterwards, a theoretical analysis was performed by linking the synthesized evidence from the systematic reviews and the empirical evidence from the exploratory studies to develop a conceptual model of CIPN.
In the third step, a hypothesis evaluation was conducted by integrating the conceptual model and the existing literature on the mechanism of intervention to develop an intervention theory. Causal modelling approach was used to represent the expected process and outcomes proposed in the intervention theory.
The first systematic review showed that duloxetine remains to be the only recommended pharmacological intervention for pain related to CIPN, while the non-invasive neuromodulation techniques may also have potential for managing CIPN and warrant future research. The supplemental systematic review indicated that non-invasive central neuromodulation techniques including neurofeedback and repetitive transcranial magnetic stimulation (rTMS) developed on the basis of neuromatrix theory could significantly reduce chronic pain and neuropathic symptoms related to CIPN. The rTMS that requires less patient effort might be more practical in clinical practice, whereas its efficacy and optimal parameters should be further verified before making clinical recommendation.
The first exploratory study identified a clear sensory neuropathy symptom cluster, a mixed motor-sensory neuropathy symptom cluster, a mixed sensorimotor neuropathy symptom cluster, and a less clear autonomic neuropathy. The symptom clusters had relatively stable core symptoms but diverse secondary symptoms. The second exploratory study confirmed the existence of sensory, sensorimotor, and autonomic neuropathy symptom clusters, and identified a neuro-psychological symptom cluster independent of but co-occurring with the CIPN-specific symptom clusters. General symptom distress and physical well-being were found deteriorating with increased CIPN severity (all adjusted p < 0.008 = 0.05/6 after Bonferroni's correction for multiple comparisons). Cancer patients with painful CIPN showed greater CIPN severity, higher general symptom distress, and worse physical well-being than those with non-painful CIPN (all adjusted p < 0.007 = 0.05/7 after Bonferroni's correction for multiple comparisons). The third exploratory study indicated that NCS results confirmed sensory-predominant feature of CIPN at different stages of neurotoxic chemotherapy. However, NCS parameters were not significantly associated with clinical examination outcomes (all unadjusted p ˃ 0.0003 = 0.05/150 after Bonferroni's correction for multiple comparisons), CIPN symptoms (adjusted p ˃ 0.001 = 0.05/45 after Bonferroni's correction for multiple comparisons), and quality of life (all adjusted p < 0.001 = 0.05/45 after Bonferroni's correction for multiple comparisons), nor did they perform well in discriminating clinically relevant CIPN (area under the Receiver Operating Characteristic curve [AUC] = 0.51-0.77, p = 0.062-˃ 0.9).
Since the systematic reviews have shown that non-invasive central neuromodulation techniques based on the neuromatrix theory can significantly relieve pain associated with CIPN, and the exploratory studies have identified that painful CIPN is more disabling, a conceptual model relevant to the neuromatrix theory was developed to understand painful CIPN and its impact on cancer patients.
Following the conceptual model of painful CIPN and the analysis of literature on rTMS, an intervention theory was developed which hypothesizes that high frequency (≥ 5 hertz [Hz]) rTMS delivered over bilateral primary motor cortex (M1) could relieve pain and related symptoms and improve overall quality of life of cancer patients with symmetrically distributed chronic painful CIPN by modulating the maladaptive plasticity of the neuromatrix. A causal model presented the expected process and outcomes of high frequency rTMS for managing painful CIPN.
Informed by the intervention theory and causal model, a study protocol was developed to test the feasibility and efficacy signals of the newly developed intervention, i.e., high frequency (10 Hz) rTMS over M1 (hand representation) of dual hemispheres. Participants were planned to receive induction sessions of rTMS in any five consecutive days. The first maintanence session will be provided at two weeks (14 days) after the final induction session, while the second maintanence session will be provided at two weeks (14 days) after the first maintanence session. However, the feasibility study was terminated prematurely due to the COVID-19 restrictions.
This doctoral research project conducted following the MRC framework has identified a novel perspective for understanding painful CIPN and developing relevant intervention. It has also contributed to understanding the phenotype of CIPN and the notorious painful subtypes. The high frequency rTMS intervention developed in the project warrants refinement and evaluation in the future studies.
Rights: All rights reserved
Access: open access

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