Background
Approximately 4600 individuals are diagnosed with new hematological and/or oncological malignancies each day [
1], of which many will require neurotoxic chemotherapy (e.g., platinums or taxanes) for the treatment of the cancer [
2]. Chemotherapy-induced peripheral neuropathy (CIPN) occurs in up to 68% of individuals receiving neurotoxic chemotherapy [
3] and results from chemotherapy-induced damage to peripheral nerves (e.g., “dying back” axon degeneration) [
4]. Patients with CIPN symptoms may experience numbness, tingling, pain (sensory symptoms), or reductions in strength (motor symptoms) that present in a stocking-glove distribution [
2]. CIPN may linger long after treatment completion if not adequately assessed and managed during neurotoxic chemotherapy treatment [
5].
Several recent studies have investigated the impact of CIPN symptoms on physical function during and after neurotoxic chemotherapy treatment [
6‐
9]. Overall, the data suggest that individuals with sensory and/or motor CIPN symptoms report a decrease in physical function and an increase in the number of falls in comparison to individuals without CIPN symptoms. Specifically, Kolb et al. [
6] reported that of 116 individuals receiving neurotoxic chemotherapy, individuals with sensory CIPN symptoms (
n = 32) were 2.7 times more likely to have a fall or near fall event than those without sensory CIPN symptoms. Decreased physical function due to unmanaged CIPN symptoms may result in 1) increased health care utilization (e.g., cost of care) [
10], 2) the inability to return to work immediately following treatment [
11], and 3) difficulty completing daily activities [
12]. However, despite the known negative effects of unmanaged CIPN symptoms on physical function, CIPN is not routinely assessed in clinical practice [
13,
14]. Novel interventions are needed that prioritize the early identification of CIPN symptoms to provide prompt treatment (e.g., chemotherapy dose modification or supportive care strategies such as duloxetine) [
15,
16] and referral to rehabilitation services [
17‐
19] to reduce the impact of unmanaged CIPN symptoms on physical function [
9].
Electronic care planning systems that 1) facilitate patient-clinician discussions about cancer treatment-related toxicities, 2) provide recommendations for self-care and referral to other support services, and 3) promote patients’ activation in cancer symptom management have shown promise in improving the assessment and management of cancer-related symptoms, such as CIPN, in clinical practice [
20‐
23]. The Electronic Symptom Assessment – Cancer (ESRA-C) [
23] is a web-based symptom self-report and self-care intervention that collects patient reported data through the administration of standardized questionnaires in between and prior to the patients’ clinic visits. In addition, based on the patient’s symptoms and/or quality of life issues, the platform provides patients with self-care education, instructions about how to communicate symptoms to the provider, and the ability to monitor symptom progression over time (e.g., graphs, journal). Further, the platform creates a summary of reports for clinicians about symptoms (i.e., based on severity scores associated with patient reported outcome measures). The use of these embedded tools may facilitate the early identification and management of CIPN symptoms via increased patient self-report and patient-provider communication about CIPN symptoms. Despite inclusion of physical function and CIPN assessment and self-care strategies, a formal comparison of the benefits of the ESRA-C have not been reported for patients receiving platinum or taxane-based chemotherapy.
Purpose
The purpose of this analysis is to compare self-reported physical function of participants receiving platinum and taxane-based chemotherapy regimens randomized to the ESRA-C intervention or electronic symptom assessment alone. Secondary measures include pain intensity, sensory CIPN, motor CIPN, fatigue, depression, and insomnia.
Discussion
The findings from this secondary analysis revealed that intervention group participants reported less reduction in physical function in comparison to control group participants following use of the ESRA-C. Control group participants’, but not intervention group participants’, mean physical function score at the end of treatment met the threshold for clinical importance (≤ 83/100) [
45] and mean change in physical function score from baseline to posttest approached the minimal clinically meaningful difference for deterioration ( -9) [
46]. However, our results should be interpreted with caution as there were no differences in sensory or motor CIPN severity between groups. To our knowledge, this analysis is among the first to explore the efficacy of a web-based symptom assessment and management platform to preserve physical function in a large sample of individuals receiving neurotoxic chemotherapy. Previous studies have examined the implementation of electronic assessment and management platforms in practice on outcomes such as technology usability [
20], patient activation [
21], and provider documentation of CIPN assessment and management [
47] in individuals receiving neurotoxic chemotherapy. Additionally, Tofthagen and colleagues developed an algorithm to guide nursing management of CIPN symptoms and associated functional impairment [
48] that was later incorporated into a web-based psychoeducational intervention for individuals with acute CIPN symptoms. Results of the intervention study revealed that use of the web-based psychoeducational program led to improvements in pain-related interference (
d = 0.39,
N = 14) [
49]. Finally, the authors of a secondary analysis evaluated an automated telephone symptom reporting system for chemotherapy-related neuropathic pain management in patients receiving taxane or platnium-based chemotherapy agents. During chemotherapy, intervention and control group participants (
N = 252) called the telephone system every day to self-report chemotherapy-related symptoms, but intervention group participants received automated self-management information and nurse practitioner follow up phone calls for more severe symptoms. Participants in the intervention group reported less days with moderate (
p < 0.001) and severe CIPN symptoms (
p = 0.006) and decreased activity interference due to CIPN (
p = 0.08) in comparison to control group participants [
22].
While intervention group participants reported less reduction in physical function in comparison to control group participants, little is known about the possible mechanisms by which physical function was preserved. The principles of causal mediation state that the intervention must significantly affect the hypothesized mediator in comparison to the control for mediation to occur [
50]. Depression was the only symptom where significant differences were observed between treatment groups. While it is possible that depression was a significant mediator of physical function preservation, it is unlikely that improvements in depression alone mediated physical function preservation as the change in mean depression severity score between groups was not clinically significant [
51]. Further, our original hypothesis was that interventions like the ESRA-C may work to prevent reductions in physical function in individuals receiving neurotoxic chemotherapy by increasing the early identification and management of CIPN (e.g., referral to specialty services such as neurology or physical therapy, chemotherapy dose modification). As there were no formal clinical practice guidelines for CIPN management when the original trial was conducted (2009–2011), chemotherapy-dose reduction would have been one of the primary treatments for patients with CIPN [
19]. Thus, our results provide evidence against our initial hypothesis as there were no differences in sensory or motor CIPN severity between treatment groups and there were no differences in the frequency of neurotoxic chemotherapy dose reduction due to CIPN. We may not have observed differences in many of the secondary outcomes because symptom severity scores were low, and few participants scored high enough on the associated measures to prompt the receipt of symptom specific self-care messages. As such, it is puzzling that in individuals receiving cumulative neurotoxic chemotherapy dosages that were associated with more severe CIPN, intervention group participants reported less severe sensory and motor CIPN than control group participants. A replication study in the future may be warranted as more is currently known about evidence-based treatments for CIPN (i.e., duloxetine 60 mg/day) [
15,
16].
It is possible that intervention group participants reported better physical function at posttest in comparison to control group participants because they experienced small improvements in all symptoms. This hypothesis may be partially explained using the Theory of Unpleasant Symptoms (TOUS) as a guiding framework [
52]. Per the TOUS, it is hypothesized that physical and psychological influencing factors (i.e., depression, insomnia, fatigue), symptoms (i.e., sensory/motor CIPN, pain intensity), and performance outcomes (i.e., physical function) all influence one another. Intervention group participants may have been able to experience small improvements in multiple symptoms because while few scored high enough on the study specific scales associated with each outcome measure to prompt the receipt of self-care messages, previous research suggests that a majority (233/374, 62.3%) of intervention group participants in the original trial were exposed to the ESRA-C intervention (e.g., clicked on self-care messages or symptom reports at least twice) [
53]. Many intervention group participants may still have been able to use the strategies (e.g., patient-provider communication strategies) and self-care information to increase patient activation in cancer treatment-related symptom management [
21]. In sum, our findings highlight the need for further research to determine variables that mediate physical function preservation following the implementation of web-based symptom assessment and management interventions to tailor such interventions in the future to variables known to positively influence physical function.
Due to the lack of differences in sensory or motor CIPN between groups, the ESRA-C intervention may be modified in the future to further bolster strategies for the self-management of CIPN and associated symptoms to ultimately preserve physical function. Recent evidence has revealed that increased BMI and low participation in moderate-vigorous physical activity are associated with the development of CIPN [
54]. Thus, self-management programs that encourage daily physical activity may be a promising treatment approach. Two recent prospective trials provide evidence supporting the efficacy of exercise interventions in reducing CIPN symptoms and/or improving function in patients receiving chemotherapy [
55,
56]. Further, cognitive behavioral pain management strategies (e.g., sleep hygiene, relaxation, activity pacing) [
57] have been shown to have a positive effect on common cancer treatment-related symptoms (e.g., pain, anxiety, fatigue, insomnia) [
58‐
60]. Specifically, the authors of a recent randomized controlled trial demonstrated that the delivery of cognitive behavioral pain management strategies via the internet may significantly improve worst CIPN pain severity in individuals with chronic painful CIPN [
60]. Taken together, incorporating exercise and cognitive behavioral strategies into web-based symptom assessment and management platforms like the ESRA-C, may provide patients with additional efficacious self-management strategies to improve CIPN symptoms and preserve physical function during neurotoxic chemotherapy treatment.
The results of this study have several implications for practice. Nurses may consider implementing common components of web-based technology such as the ESRA-C to facilitate patient-nurse communication about cancer treatment-related symptoms during neurotoxic chemotherapy administration. Components of the ESRA-C that nurses may translate to their practice include: 1) using standardized patient-reported outcome measures to help patients identify cancer treatment-related symptoms and 2) providing self-care instruction for cancer treatment-related symptoms. Increased patient-nurse communication about cancer treatment-related symptoms may lead to earlier identification and management of symptoms, thereby preventing reductions in physical function in individuals receiving neurotoxic chemotherapy.
Limitations
This study has several limitations. First, symptom severity scores for all secondary outcomes were fairly low, and therefore, we may not have observed any statistically significant differences between groups in some outcomes due to a floor effect. Similarly, there were many cases in which individuals in the intervention arm did not score high enough on the associated symptom measures to trigger the receipt of the additional ESRA-C self-care messages. This limitation is a potential threat to internal validity because in these cases, the content of the intervention and control arms were not significantly different. Second, the effect of the ESRA-C intervention on physical function was evaluated soon after the completion of chemotherapy treatment or late within the treatment course. It is important to evaluate long term outcomes in individuals with CIPN because CIPN symptoms may persist or worsen after the completion of treatment, especially following platinum-based chemotherapy [
35]. Third, this study was conducted in a homogenous patient population (Caucasian, middle aged, receiving care at comprehensive cancer centers) and subsequently, our results may not be widely generalizable. Fourth, this analysis used a subset of the full sample from the primary study and may be underpowered for all outcome comparisons. Finally, patients and clinicians were not blinded to treatment assignment in the original randomized-controlled trial.
Acknowledgements
The authors would like to acknowledge Fangxin Hong, PhD and Traci Blonquist, MS for statistical consultation. This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health.