Personalized Management of Chemotherapy‐Induced Peripheral Neuropathy Based on a Patient Reported Outcome: CALGB 40502 (Alliance)

Abstract

Chemotherapy‐induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient‐reported outcome and (2) propose a dose‐adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose‐neuropathy model was developed using dosing and patient‐reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin–bound paclitaxel or ixabepilone as first‐line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose‐adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin–bound paclitaxel, and ixabepilone, simulations with the proposed dose‐adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient‐reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.

CYP3A genetic variation and taxane-induced peripheral neuropathy: a systematic review, meta-analysis, and candidate gene study

“…Alpha-lipoic acid has also been studied as an effective intervention for the treatment of diabetic neuropathy ( Abubaker et al, 2022 ). Other studies are evaluating dose modifications ( Sharma et al, 2020 ), and exercise programme ( Kleckner et al, 2018 ; Müller et al, 2021 ; Chung et al, 2022 ) to prevent or manage PN. Despite some encouraging results, given that we do not fully understand the mechanisms of CIPN/TIPN, whether these intervention strategies will be successful is unclear, and continuing further research is needed.…”

Neuropathy severity at the time of oxaliplatin treatment alteration in patients with colon cancer (Alliance A151912).

“…27 A modeling and simulation study using patient-reported CIPN during taxane treatment suggested that treatment alterations based on CIPN severity after 3 cycles could substantially reduce CIPN severity at the end of 6 cycles of treatment. 28 However, prospective clinical trials are needed to demonstrate the bene t and understand the risks of decreasing oxaliplatin dosing based on early indicators of CIPN. Prospective testing of a similar strategy of oxaliplatin treatment alteration informed by early changes in quantitative sensory testing did not reduce CIPN.…”

Ganglioside Monosialic Acid Alleviates Peripheral Neuropathy Induced by Utidelone Plus Capecitabine in Metastatic Breast Cancer From a Phase III Clinical Trial

“…Likewise, ixabepilone, a semisynthetic epothilone analog, has been approved by the FDA as a monotherapy or combination therapy with capecitabine for patients with metastatic or locally advanced breast cancer, especially those who have anthracycline, taxane, or capecitabine resistance ( 6 ). However, ixabepilone-related toxicities always resulted in permanent discontinuation, due to myelosuppression, peripheral neuropathy, and fatigue ( 9 ). In our center population, the incidence of peripheral neuropathy after utidelone treatment decreased upon cessation of capecitabine.…”