Patient-reported Strategies for Prevention and Treatment of Chemotherapy- induced Peripheral Neuropathy

doi:10.21203/rs.3.rs-4888430/v1

Download PDF

Research Article

Patient-reported Strategies for Prevention and Treatment of Chemotherapy- induced Peripheral Neuropathy

https://doi.org/10.21203/rs.3.rs-4888430/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating toxicity of many drugs used in cancer treatment. There are numerous available strategies for preventing or treating CIPN, but few are guideline-recommended, due to limited evidence of their effectiveness. The primary objective of this survey was to understand what strategies patients used to prevent or treat CIPN, and to understand their perceptions around CIPN prevention and treatment.

Methods: The Multinational Association of Supportive Care in Cancer (MASCC) Neurological Complications Study Group created a cross-sectional online survey to recruit individuals who are currently or had previously received neurotoxic chemotherapy treatment and self-reported peripheral neuropathy. Descriptive statistics were reported.

Results: Most of the 447 survey participants did not use any CIPN prevention strategy (71%), though given options of any strategy the plurality preferred a prescribed medication or supplement (30%). The most common treatment strategy used was exercise (47%), with some patients trying prescription medications including non-guideline recommended gabapentin (33%) or guideline-recommended duloxetine (8%) options. Nearly half of participants (49%) used at least one non-prescribed medication for treating CIPN. Patient’s often followed suggestions of their medical oncology clinical team, but sometimes relied on the internet or other patients to recommend non-prescription strategies.

Conclusion: In the absence of many guideline-recommended strategies for CIPN prevention and treatment, some patients use options with minimal evidence of effectiveness. Additional research is needed to determine which strategies are effective for prevention and treatment so these can be implemented in practice to improve treatment outcomes in patients with cancer.

chemotherapy-induced peripheral neuropathy

prevention

treatment

survey

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose limiting toxicity of several commonly used anticancer drugs including taxanes, platinums, vinca alkaloids, proteasome inhibitors, and thalidomide¹. Clinical manifestations of CIPN typically include numbness and tingling, which may include a painful burning sensation. Some people may also experience functional impairments, such as diminished manual dexterity, or have difficulty with activities of daily living, such as clothing themselves. Impaired function in the lower limbs can alter gait stability and balance increasing risk of falls and injury^2-4.

The two general approaches for reducing CIPN are to prevent it from occurring (i.e., prevention) or to treat it after it has occurred (i.e., treatment). The American Society of Clinical Oncology⁵ (ASCO) and European Society of Medical Oncology⁶ (ESMO) have each published guidelines for the prevention and treatment of CIPN. Unfortunately, these guidelines include very few evidenced-based, guidelines-recommended strategies for CIPN prevention (none) and treatment (duloxetine for painful CIPN manifestations). This may contribute to patients using pharmacological and non-pharmacological strategies to prevent or treat CIPN that are not supported by high-quality evidence of their effectiveness. Currently, little is known about the pharmacological and non-pharmacological strategies patients are using to prevent or treat CIPN. The aim of this international patient survey was to evaluate the strategies patients used to prevent or treat CIPN.

Survey Development

The methods for development and distribution of this survey have been previously published in a publication that focused on patient’s perception of altering chemotherapy treatment due to CIPN⁷. Briefly, the Multinational Association of Supportive Care in Cancer (MASCC) Neurological Complications Study Group created a survey to collect data on demographics, neurotoxic cancer treatment, and CIPN symptoms, perceptions, communication, and prevention/treatment. The survey was developed and reviewed by all co-authors. Individuals with lived experience of CIPN were also involved in developing the survey. Two patient advocates who are based in the United States and two Patient and Public Involvement members from the United Kingdom reviewed the patient information sheet and survey questionnaire.

Survey Distribution

A cross-sectional online survey (Supplemental File 1) was distributed between January to June 2022 through Qualtrics^TM. Recruitment targeted adult individuals who self-identified as having CIPN symptoms, through online social media sites such as Facebook^TM and X™ (formerly Twitter^TM). Cancer organisations and patient charities (Supplementary File 2) were also asked to distribute the link to the survey questionnaire within their organization membership and via their social media accounts. Respondents affirmed their consent to participate at the beginning of the survey, prior to collection of any data. There was no financial compensation for participation.

Data Analysis

Data analysis was reported using medians and interquartile range for continuous variables and frequencies and percentage for categorical variables. The sources of information that led to using each prevention (i.e., cryotherapy) or treatment (i.e., duloxetine, vitamin B complex, exercise) strategy and the clinical expectations of using each treatment strategy were collected by individual strategy but were analysed in categories (i.e., prevention strategies, prescription medication treatments, non-prescription medication treatments, non-pharmacological treatments) due to small numbers for most individual strategies. This was done by summing the data for all members of that category and reporting as percentages. The data are available upon reasonable request to the corresponding author.

Survey Participants

Detailed demographic information about the 447 survey participants included in this analysis was previously reported⁷. Briefly, their Results are reported on 447 valid survey responses. The median age of respondents was 57 years, 93% were white, most were from the United Kingdom (53%) or United States of America (38%), the most common cancer type was breast cancer (36%) and more than half (56%) reported that they had metastatic cancer.

CIPN Prevention Strategies

Most patients (71%, 291/411) did not use a non-pharmacological strategy to prevent CIPN. In patients who did, the most common options included keeping the hands and/or feet cold via cryotherapy (13%, 54/411) or keeping them compressed (6%, 24/411, Figure 1). Many patients selected “Other” (16%, 67/411) and reported the use of a variety of approaches including acupuncture, exercise, heat application, and a variety of different topical or systemic nutraceuticals. Patients were then asked what information led them to use each of these CIPN prevention strategies. The most common response was advice from the patient’s medical oncology team (33%, 27/83, Figure 2), followed by a fellow patient (24%, 20/83) or the internet (24%, 20/83).

Additionally, patients were asked about their preferred strategy for preventing CIPN, assuming that all were proven to be effective. The most commonly selected preferred option by respondents (n=397) was taking a prescribed medication or supplement (30%, n=121), followed by exercise (24%, n=96), cryo-compression (17%, n=67), acupuncture or massage (14%, n=56), non-prescribed medication or supplement (10%, n=41), and cannabis (4%, n=16), which was the least preferred option selected.

Prescription Medication for CIPN Treatment

Among 397 respondents, most did not use any prescribed drugs to treat CIPN (60%, n=239, Figure 3). The most commonly used prescription medications were gabapentin (33%, n=97), pregabalin (12%, n=47), duloxetine (8%, n=30) or amitriptyline (8%, n=30). Prescription medication treatment for CIPN was mostly recommended by the medical oncology team (56%, 138/245, Figure 2) or the primary care physician (20%, 49/245). There was minimal evidence that prescription medications were recommended by other patients or the internet (each <5%).

Non-Prescription Medication for CIPN Treatment

Slightly less than half of participants (n=396) used at least one non-prescribed medication for treating CIPN (49%, n=195, Figure 4). The most commonly used non-prescription medication for CIPN treatment was vitamin-B complex (29%, n=113) followed by magnesium (22%, n=88) and calcium (15%, n=61). Those who tried any non-prescription medications (n=373) did so mainly because it was either recommended by their medical oncology clinical team (23%, n=84, Figure 2) or they heard about it on the internet (23%, n=87).

Non-pharmacological CIPN Treatment

Of the 397 respondents, less than one third did not try any non-pharmacological strategy to treat CIPN (30%, n=118, Figure 5). Nearly half of patients tried exercise (47%, n=187) and more than one third tried massage (36%, n=141). Other strategies including cannabis (12%) and scrambler therapy (5%) were used by fewer patients. Most often these non-pharmacological strategies were self-initiated (38%, n=209, Figure 2), though sometimes they were recommended by the medical oncology clinical team (16%, n=86), a fellow patient (14%, n=80), or the internet (14%, n=78).

Expectations of CIPN Treatment Strategies

Finally, patients were asked what they expected as clinical outcomes from the CIPN treatment they used (Figure 6). Overall, the expected clinical outcomes were similar across all three categories (prescription medication vs. non-prescription or non-pharmacological treatments), with slightly more expected improvement in pain from prescription medication compared to non-prescription and non-pharmacological treatments (32% vs. 20% vs. 25%).

CIPN is a common, dose-limiting toxicity of cancer treatment that can cause long-term reductions in manual dexterity and balance, leading to reduced quality of life and increased falls risk^2-4. ASCO⁵ and ESMO⁶ guidelines have few recommended strategies for CIPN prevention and treatment. The primary objective of this survey was to understand what strategies patients used to prevent or treat CIPN, and then to also understand some of their other perceptions around CIPN prevention and treatment.

Our findings reveal that most patients do not use any strategies for CIPN prevention or treatment. For CIPN prevention, this is not surprising as there has been no clear evidence for an effective strategy to delay the onset or reduce the severity of CIPN. Several studies have explored the role of compression therapy^{8, 9} and/or cryotherapy^10-12 for reducing CIPN, though results are still conflicting. Ongoing (NCT05642611) and future trials may provide further data. Other strategies that patients reported using, such as acupuncture, exercise, and topical or systemic nutraceuticals, also have minimal evidence of effectiveness for CIPN prevention^{5, 6}.

Similarly, there is little evidence that any of the currently available strategies are effective in treating existing CIPN. The most used strategy, according to our survey, is exercise (47%). There is a growing interest for exercise in CIPN prevention¹³ or treatment¹⁴, including an ongoing treatment trial (NCT04888988), but a recent systematic review did not find conclusive evidence that exercise is effective for treating CIPN¹⁵. Nevertheless, exercise has a multitude of other health benefits and can be recommended for patients with CIPN who can safely participate, given the multitude of benefits of exercise in both healthy people and patients with cancer^16-18 and the absence of meaningful direct costs or toxicities.

Despite a paucity of evidence demonstrating their effectiveness, a substantial number of patients used supplements to treat CIPN symptoms (49%). Of these supplements, vitamin B (29%), magnesium (22%), and calcium (15%) were most used, despite prospective clinical trials demonstrating no benefit to using these supplements to prevent or treat CIPN^{19, 20}. The potential dangers of taking unproven supplements may include worsening of CIPN, as was demonstrated to be the case for acetyl-L-carnitine²¹, or perhaps even an impairment of survival²², which may be due to interactions with active cancer treatment²³. Patients should be cautioned against using supplements that have not been demonstrated to be safe and effective.

The most commonly used prescription medication was gabapentin (33%), which is beneficial for neuropathic pain but has not been demonstrated to be effective specifically in CIPN²⁴ and is not recommended by guidelines, partially due to causing dizziness that can exacerbate balance concerns in patients with CIPN^{5, 6}. However, recent evidence demonstrates that oncology clinicians often do recommend gabapentin for painful CIPN²⁵. In contrast, in our study, relatively few patients with CIPN reported using duloxetine (8%), despite prospective clinical trial evidence of its effectiveness in treating painful CIPN²⁶ and moderate evidence to support recommendations for its use in this clinical context^{5, 6}. One interesting survey finding is that respondents were most interested in effective prescription pharmacological intervention, contrary to prior research suggesting a preference for non-pharmacological treatments^{27, 28}.

Our survey also explored data sources that led to treatment patterns. Our finding that clinicians are an important resource for selecting prescription medications for CIPN treatment strategies is consistent with previous evidence of the importance of the patient’s trust in their oncologist when reporting CIPN^{29, 30}. On the other hand, patients often took recommendations from the internet, patient support groups, or other patients when selecting non-prescription strategies. Social networks can be critical sources of support and information, though it is challenging to ensure that the information available through these sources is accurate and/or high-quality³¹. Finally, most patients self-initiated healthy lifestyle activities including exercise and massage. These common lifestyle interventions were not recommended more often by the patient’s general practitioner, as previously shown by others in the context of ongoing survivorship care³².

The last major area of focus was the expectations of benefits from CIPN treatment strategies. Overall, patients expected similar clinical outcomes across the three intervention categories (i.e., prescription medications, non-prescription medications, and non-pharmacological strategies). Given the lack of compelling evidence of effectiveness for any of these interventions for sensory or motor CIPN symptoms, these patient expectations seem appropriate. Additionally, patients properly expected more improvement in pain from prescription medications as compared to non-prescription or non-pharmacological treatments (32% vs. 20% or 25%), which is consistent with the known effectiveness of certain prescription medications specifically for painful neuropathy²⁶.

It is important to consider limitations of this online survey. First, this was a cross-sectional survey that relied on patient’s self-reporting, in some cases of decisions made many years prior, which may lead to biases, particularly regarding who responds to the survey and what they recall or report. However, the lack of financial compensation for participants reduces the risk of duplicate or fraudulent responses³³. Additionally, our survey instrument included certain prevention and treatment strategies but may have missed some others that the patients were using. Finally, it is important to note that survey enrolment was distributed through cancer organizations and specifically enrolled patients reporting CIPN, so these data are not representative of all patients with cancer or treated with neurotoxic treatment.

In summary, there are few guideline-recommended options for CIPN prevention and treatment, leading patients to use approaches with minimal evidence of effectiveness, and in some cases, potential for harm. Additional research is needed to develop new strategies and determine which are effective for prevention and treatment in order to improve treatment outcomes in patients with cancer.

Funding: This study was conducted without any relevant funding.

Funding

The authors did not receive financial support from any organization for the submitted work.

Competing Interests

The authors declare no conflicts of interest relevant to this manuscript. MBL: Consulting for Eli Lilly, Gliead, Pfizer, AstraZeneca, Novartis.

Author Contributions

Maryam Lustberg, Mary Tanay, and Dan Hertz were involved in study conception. All co-authors contributed to study design and survey preparation. Data collection and analysis were performed by Maryam Lustberg, Mary Tanay, Dan Hertz, Cindy Tofthagen, Paola Alberti, Davide Paolo Bernasconi and Emanuela Rossi. The first draft of the manuscript was written by Mary Tanay and Dan Hertz. All authors reviewed and approved the final manuscript.

Ethics approval

The study was approved by King's College London ethics committee (Reference: HR-20/21-25358).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Acknowledgements: We would like to thank all survey respondents and organizations who helped with survey distribution, including Bowel Cancer UK and Myeloma UK.

Park SB, Goldstein D, Krishnan AV et al. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin 2013; 63 (6): 419-437.
Chan CW, Cheng H, Au SK et al. Living with chemotherapy-induced peripheral neuropathy: Uncovering the symptom experience and self-management of neuropathic symptoms among cancer survivors. Eur J Oncol Nurs 2018; 36: 135-141.
Staff NP, Grisold A, Grisold W et al. Chemotherapy-induced peripheral neuropathy: A current review. Ann Neurol 2017; 81 (6): 772-781.
Monfort SM, Pan X, Patrick R et al. Gait, balance, and patient-reported outcomes during taxane-based chemotherapy in early-stage breast cancer patients. Breast Cancer Res Treat 2017; 164 (1): 69-77.
Loprinzi CL, Lacchetti C, Bleeker J et al. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J Clin Oncol 2020; 38 (28): 3325-3348.
Jordan B, Margulies A, Cardoso F et al. Systemic anticancer therapy-induced peripheral and central neurotoxicity: ESMO–EONS–EANO Clinical Practice Guidelines for diagnosis, prevention, treatment and follow-up. Annals of Oncology 2020; 31 (10): 1306-1319.
Hertz DL, Tofthagen C, Rossi E et al. Patient perceptions of altering chemotherapy treatment due to peripheral neuropathy. Support Care Cancer 2023; 32 (1): 48. doi: 10.1007/s00520-00023-08209-00520.
Tsuyuki S, Senda N, Kanng Y et al. Evaluation of the effect of compression therapy using surgical gloves on nanoparticle albumin-bound paclitaxel-induced peripheral neuropathy: a phase II multicenter study by the Kamigata Breast Cancer Study Group. Breast Cancer Res Treat 2016; 160 (1): 61-67. doi: 10.1007/s10549-10016-13977-10547. Epub 12016 Sep 10512.
Kanbayashi Y, Sakaguchi K, Ishikawa T et al. Comparison of the efficacy of cryotherapy and compression therapy for preventing nanoparticle albumin-bound paclitaxel-induced peripheral neuropathy: A prospective self-controlled trial. Breast 2020; 49:219-224. (doi): 10.1016/j.breast.2019.1012.1011. Epub 2019 Dec 1020.
Sundar R, Bandla A, Tan SS et al. Limb Hypothermia for Preventing Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients: A Pilot Study. Front Oncol 2016; 6:274. (doi): 10.3389/fonc.2016.00274. eCollection 02016.
Ruddy KJ, Le-Rademacher J, Lacouture ME et al. Randomized controlled trial of cryotherapy to prevent paclitaxel-induced peripheral neuropathy (RU221511I); an ACCRU trial. Breast 2019; 48:89-97. (doi): 10.1016/j.breast.2019.1009.1011. Epub 2019 Sep 1019.
Beijers AJM, Bonhof CS, Mols F et al. Multicenter randomized controlled trial to evaluate the efficacy and tolerability of frozen gloves for the prevention of chemotherapy-induced peripheral neuropathy. Ann Oncol 2020; 31 (1): 131-136. doi: 110.1016/j.annonc.2019.1009.1006.
Streckmann F, Elter T, Lehmann HC et al. Preventive Effect of Neuromuscular Training on Chemotherapy-Induced Neuropathy: A Randomized Clinical Trial. JAMA Intern Med 2024; 1 (10).
Park SB, Tamburin S, Schenone A et al. Optimal outcome measures for assessing exercise and rehabilitation approaches in chemotherapy-induced peripheral-neurotoxicity: Systematic review and consensus expert opinion. Expert Rev Neurother 2022; 22 (1): 65-76. doi: 10.1080/14737175.14732022.12018300. Epub 14732022 Jan 14737111.
Sturgeon KM, Kok DE, Kleckner IR et al. Updated systematic review of the effects of exercise on understudied health outcomes in cancer survivors. Cancer Med 2023; 12 (24): 22278-22292. doi: 22210.21002/cam22274.26753. Epub 22023 Nov 22229.
de Boer AG, Tamminga SJ, Boschman JS et al. Non-medical interventions to enhance return to work for people with cancer. Cochrane Database Syst Rev 2024; 3 (3): CD007569. doi: 007510.001002/14651858.CD14007569.pub14651854.
Turner RR, Steed L, Quirk H et al. Interventions for promoting habitual exercise in people living with and beyond cancer. Cochrane Database Syst Rev 2018; 9 (9): CD010192. doi: 010110.011002/14651858.CD14010192.pub14651853.
Coletta AM, Basen-Engquist KM, Schmitz KH. Exercise Across the Cancer Care Continuum: Why It Matters, How to Implement It, and Motivating Patients to Move. Am Soc Clin Oncol Educ Book 2022; 42:1-7. (doi): 10.1200/EDBK_349635.
Schloss JM, Colosimo M, Airey C et al. A randomised, placebo-controlled trial assessing the efficacy of an oral B group vitamin in preventing the development of chemotherapy-induced peripheral neuropathy (CIPN). Support Care Cancer 2017; 25 (1): 195-204.
Loprinzi CL, Qin R, Dakhil SR et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance). J Clin Oncol 2014; 32 (10): 997-1005.
Hershman DL, Unger JM, Crew KD et al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol 2013; 31 (20): 2627-2633.
Ambrosone CB, Zirpoli GR, Hutson AD et al. Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221). J Clin Oncol 2020; 38 (8): 804-814. doi: 810.1200/JCO.1219.01203. Epub 02019 Dec 01219.
Shakeel F, Fang F, Kidwell KM et al. Comparison of eight screening tools to detect interactions between herbal supplements and oncology agents. J Oncol Pharm Pract 2020; 26 (8): 1843-1849. doi: 1810.1177/1078155220905009. Epub 1078155220902020 Feb 1078155220905019.
Chang TW, Yang FY, Liu YC et al. Gabapentinoids for chemotherapy-induced peripheral neuropathy: systematic review and meta-analysis. BMJ Support Palliat Care 2024; 27 (004362): 2023-004362.
Kanzawa-Lee G, Krauss JC, Knoerl R. Exploring Chemotherapy-Induced Peripheral Neuropathy Management Practice Patterns Among Oncology Clinicians. Semin Oncol Nurs 2024; 26 (151685): 151685.
Smith EM, Pang H, Cirrincione C et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. Jama 2013; 309 (13): 1359-1367.
Dorsey SG, Kleckner IR, Barton D et al. The National Cancer Institute Clinical Trials Planning Meeting for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy. J Natl Cancer Inst 2019; 111 (6): 531-537. doi: 510.1093/jnci/djz1011.
Knoerl R, Berry D, Meyerhardt JA et al. Identifying participants' preferences for modifiable chemotherapy-induced peripheral neuropathy prevention clinical trial factors: an adaptive choice-based conjoint analysis. Support Care Cancer 2022; 30 (12): 9963-9973. doi: 9910.1007/s00520-00022-07447-y. Epub 02022 Nov 00510.
Salgado TM, Quinn CS, Krumbach EK et al. Reporting of paclitaxel-induced peripheral neuropathy symptoms to clinicians among women with breast cancer: a qualitative study. Support Care Cancer 2020; 28 (9): 4163-4172. doi: 4110.1007/s00520-00019-05254-00526. Epub 02020 Jan 00522.
Salgado TM, Liu J, Reed HL et al. Patient factors associated with discrepancies between patient-reported and clinician-documented peripheral neuropathy in women with breast cancer receiving paclitaxel: A pilot study. Breast 2020; 51:21-28. (doi): 10.1016/j.breast.2020.1002.1011. Epub 2020 Mar 1013.
Suarez-Lledo V, Alvarez-Galvez J. Prevalence of Health Misinformation on Social Media: Systematic Review. J Med Internet Res 2021; 23 (1): e17187. doi: 17110.12196/17187.
Arem H, Duan X, Ehlers DK et al. Provider Discussion about Lifestyle by Cancer History: A Nationally Representative Survey. Cancer Epidemiol Biomarkers Prev 2021; 30 (2): 278-285. doi: 210.1158/1055-9965.EPI-1120-1268. Epub 2020 Dec 1152.
Panesar P, Mayo SJ. "Taking out the trash": Strategies for preventing and managing fraudulent data in web-surveys. Can Oncol Nurs J 2023; 33 (2): 283-284. eCollection 2023 Spring.

No competing interests reported.

Download PDF

Editorial decision: Revision requested
02 Oct, 2024
Reviews received at journal
01 Oct, 2024
Reviews received at journal
30 Sep, 2024
Reviewers agreed at journal
29 Sep, 2024
Reviewers agreed at journal
23 Sep, 2024
Reviewers invited by journal
23 Sep, 2024
Editor assigned by journal
22 Sep, 2024
Submission checks completed at journal
12 Aug, 2024
First submitted to journal
09 Aug, 2024

You are reading this latest preprint version

Patient-reported Strategies for Prevention and Treatment of Chemotherapy- induced Peripheral Neuropathy

Status:

Version 1

Abstract

Figures

Background

Methods

Survey Development

Survey Distribution

Data Analysis

Results

Survey Participants

CIPN Prevention Strategies

Prescription Medication for CIPN Treatment

Non-Prescription Medication for CIPN Treatment

Discussion

Declarations

References

Additional Declarations

Status:

Version 1