Background & Aims

While chemotherapy has dramatically improved survival outcomes in cancer, many commonly used chemotherapy agents such as platinums, and taxanes can cause neuropathy (CIPN). Prevalence varies depending on chemotherapy agent, with up to 70% of people developing some symptoms during chemotherapy, and CIPN persisting in around a third of people. Symptoms of CIPN may include distal pain in limbs, numbness, weakness and impaired co-ordination. Treating symptoms has limited benefits and there is no prevention other than dose reduction/agent switching. CIPN is often detected late as the symptoms tend to be unusual and misinterpreted by patients. Therefore, many studies have focused on methods of more accurate detection. Although significant effort has been invested to determine whether Quantitative Sensory Testing (QST) can aid diagnosis of CIPN, it is not clear whether QST does have predictive utility. This review aims to identify the current state of evidence and the remaining challenges.

Methods

We performed a search for publications which included QST as part of CIPN research. The search was conducted via Google Scholar using various combinations of keywords such as: “longitudinal”, “quantitative sensory testing”, “chemotherapy-induced neuropathy”, “test-retest” etc. After initial screening, the following criteria were applied: papers had to be published after 2006 (coinciding with QST standardization guidance from the German Research Network on Neuropathic Pain), and QST measurements had to occur on multiple occasions (prior, during and after treatment). Longitudinal tracking of changes in QST parameters relative to CIPN status is crucial in order to determine predictive utility. The 10 papers selected (see reference list) for this review were then examined with a focus on inferences drawn about QST utility in diagnosing CIPN. Finally, methodological and analytical challenges were critically evaluated.

Results

Most publications focused on Oxaliplatin induced neuropathy (7/10), one focused on the effects of Bortezomib and one on Taxanes while one paper included a heterogeneous sample of chemotherapy agents. The median number of recruited participants per study was 48 (falling to 22 by study end). The total number of patients was 438 (45.6% female) with a mean age of 60.9. In order to assess the utility of QST as a predictor of CIPN the diagnosis or grouping of participants should be based on criteria independent of QST. Six papers assign CIPN and non-CIPN patients based on independent measures (the National Cancer Institute – Common Terminology Criteria for Adverse Event grading used in 4 papers). Their results show there is potential for QST parameters, particularly thermal and vibration detection thresholds, as useful indicators of the presence of well established CIPN. It is less clear whether onset and early diagnosis can be identified by examining QST profiles.

Conclusions

We found that there are too few longitudinal studies to make firm conclusions. Additionally, many of the analytical choices, combined with small sample sizes, mean that within-participant change of QST parameters is under-explored. The prevalence of Oxaliplatin research provides potential for a meta-analysis provided the data is accessible (no study has open access data). It is not currently possible to advocate for or against routine clinical use of QST as a diagnostic method for CIPN. However, this review does identify avenues for improvement. First, multi-centre studies would help reach adequate sample sizes to power statistical procedures required to determine predictive utility. Second, agreement on testing and diagnosis standards alongside adoption of data reporting and sharing standards would help with data aggregation. Finally, development of more accessible, easier to use QST equipment deployed at scale would allow for more frequent observations within longitudinal designs.

References

Attal N, Bouhassira D, Gautron M, Vaillant JN, Mitry E, Lepère C, Rougier P, Guirimand F. Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: A prospective quantified sensory assessment study. Pain 2009;144:245–252. doi:10.1016/j.pain.2009.03.024.

de Carvalho Barbosa M, Kosturakis AK, Eng C, Wendelschafer-Crabb G, Kennedy WR, Simone DA, Wang XS, Cleeland CS, Dougherty PM. A Quantitative Sensory Analysis of Peripheral Neuropathy in Colorectal Cancer and Its Exacerbation by Oxaliplatin Chemotherapy. Cancer Research 2014;74:5955–5962. doi:10.1158/0008-5472.can-14-2060.

Griffith KA, Couture DJ, Zhu S, Pandya N, Johantgen ME, Cavaletti G, Davenport JM, Tanguay LJ, Choflet A, Milliron T, Glass E, Gambill N, Renn CL, Dorsey SG. Evaluation of chemotherapy-induced peripheral neuropathy using current perception threshold and clinical evaluations. Support Care Cancer 2013;22:1161–1169. doi:10.1007/s00520-013-2068-0.

Hammond EA, Pitz M, Lambert P, Shay B. Quantitative sensory profiles of upper extremity chemotherapy induced peripheral neuropathy: Are there differences in sensory profiles for neuropathic versus nociceptive pain? Canadian Journal of Pain 2019;3:169–177. doi:10.1080/24740527.2019.1665992.

Krøigård T, Svendsen TK, Wirenfeldt M, Schrøder HD, Qvortrup C, Pfeiffer P, Gaist D, Sindrup SH. Early changes in tests of peripheral nerve function during oxaliplatin treatment and their correlation with chemotherapy?induced polyneuropathy symptoms and signs. Euro J of Neurology 2019;27:68–76. doi:10.1111/ene.14035.

Krøigård T, Svendsen TK, Wirenfeldt M, Schrøder HD, Qvortrup C, Pfeiffer P, Gaist D, Sindrup SH. Oxaliplatin Neuropathy: Predictive Values of Skin Biopsy, QST and Nerve Conduction. JND 2021;8:679–688. doi:10.3233/jnd-210630.

Reddy SM, Vergo MT, Paice JA, Kwon N, Helenowski IB, Benson AB, Mulcahy MF, Nimeiri HS, Harden RN. Quantitative Sensory Testing at Baseline and During Cycle 1 Oxaliplatin Infusion Detects Subclinical Peripheral Neuropathy and Predicts Clinically Overt Chronic Neuropathy in Gastrointestinal Malignancies. Clinical Colorectal Cancer 2016;15:37–46. doi:10.1016/j.clcc.2015.07.001.

Szpejewska JE, Yilmaz M, Falkmer UG, Arendt-Nielsen L, Mørch CD. New diagnostic measures of oxaliplatin-induced peripheral sensory neuropathy. Cancer Treatment and Research Communications 2022;31:100543. doi:10.1016/j.ctarc.2022.100543.

Velasco R, Videla S, Villoria J, Ortiz E, Navarro X, Bruna J. Reliability and accuracy of quantitative sensory testing for oxaliplatin-induced neurotoxicity. Acta Neurol Scand 2014;131:282–289. doi:10.1111/ane.12331.

Vichaya EG, Wang XS, Boyette-Davis JA, Mendoza TR, He Z, Thomas SK, Shah N, Williams LA, Cleeland CS, Dougherty PM. Subclinical pretreatment sensory deficits appear to predict the development of pain and numbness in patients with multiple myeloma undergoing chemotherapy. Cancer Chemother Pharmacol 2013;71:1531–1540. doi:10.1007/s00280-013-2152-7.

Presenting Author

Marin Dujmovic

Poster Authors

Marin Dujmovic

PhD

School of Physiology, Pharmacology, and Neuroscience, University of Bristol

Lead Author

James Dunham

University of Bristol, United Kingdom.

Lead Author

Lesley Colvin

University of Dundee

Lead Author

BHUSHAN THAKKAR

University of Dundee

Lead Author

Anthony Pickering MB ChB

PhD

University of Bristol

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral