Painful Hands and Feet After Cancer Treatment: Inflammation Affecting the Mind-Body Connection
Authors: Patricia A. Ganz, Patrick M. Dougherty
Journal: Journal of Clinical Oncology (2015)

With the growing number of cancer survivors, it is critical for us to consider toxicities that arise during treatment and do not resolve after treatment ends. Some symptoms continue to burden patients for many years after the cancer has been cured, and chemotherapy-induced peripheral neuropathy (CIPN) is a conspicuous example. CIPN has taken on considerable prominence in the past decade with the more widespread use of the vinca alkaloids, taxanes, platinum analogs, and bortezomib, with an overall incidence estimated at 38%. Unfortunately, CIPN has been resistant to multiple strategies aimed at its prevention or treatment once established. A critical step in the development of new approaches to management of a cancer treatment–related symptom is to have a better understanding of the mechanism(s) associated with its development, and/or identification of those individuals who are at particularly high risk for experiencing the symptom or having persistent difficulties. We are fortunate that there is increasing research interest in symptom science, and the paper by Nudelman et al that accompanies this editorial is an example of this type of work. Although there are several classes of chemotherapeutic agents that result in CIPN, there are some common proposed causal mechanisms for CIPN that include nuclear DNA damage, mitochondrial injury, oxidative stress, calcium signaling dysregulation, and inflammation based on direct systemic toxicity to the peripheral nerves (Fig 1). Clinical assessment of neurotoxicity can include objective evaluation of sensory and motor deficits, but more often patients are asked to report on the severity of symptoms, such as numbness and tingling in the hands and feet, pain in their hands and feet, and difficulty walking or using their hands. Objectively quantifying this toxicity is labor intensive using quantitative sensory testing and other techniques, most of which are reserved for research studies. In the clinic and in clinical trials, we do not have the resources to objectively monitor toxicity resulting from the neurotoxic agents that are in widespread use. Asking the patient to report symptoms can be a double-edged sword, in that both the patient and the physician may be reluctant to reduce the dose or omit treatment with a potentially lifesaving drug. Nevertheless, patient-reported outcomes research has matured to the point where we have reliable and valid self-report questionnaires for many treatment toxicities, and when these are validated by biologic or physiologic changes in the patient that are associated with the toxicity, we can gain important insights into the potential mechanisms associated with the treatment toxicity. In the report by Nudelman et al, the investigators have taken advantage of neuroimaging data from a previous study that focused on the prospective study of cognitive function changes associated with adjuvant chemotherapy treatment in patients with early breast cancer (with and without chemotherapy) as well as healthy control participants. The parent study found a statistically significant association between changes in self-reported executive function complaints (preand postchemotherapy comparison) and structural magnetic resonance imaging findings (increased complaints associated with decreased frontal lobe gray matter density), as well as increased cerebral perfusion in association with chemotherapy that was statistically significant compared with control participants in the right precentral gyrus but was not associated with frontal gray matter density reduction. However, decreased frontal gray matter density was associated with decreased perfusion in the bilateral frontal and parietal lobes in the chemotherapytreated group. In this secondary analysis of data from the same study, the authors report on the relationship of the neuroimaging findings—cerebral perfusion and gray matter density—with respect to the symptom of sensory neuropathy (CIPN-sx). For these analyses, the sample size is somewhat smaller because not all patients were assessed with the self-report neurotoxicity questionnaire, several patients hadmissing assessments or questionnaires as part of the longitudinal study, patients with existing neuropathy symptoms before cancer treatment were excluded from the analysis, and the healthy control participants apparently were not assessed with the symptom scale. What did the authors find? Of the 24 chemotherapy-treated patients with breast cancer, only one did not receive a taxane, a platinum analog, or both. At the 1-month postchemotherapy assessment time point, in comparison with the 23 patients with breast cancer who did not receive chemotherapy, the chemotherapytreated patients had significantly increased CIPN-sx (P 5 .001), with a persistent difference 12 months later (P 5 .027). The chemotherapy-treated patients had a significant change in CIPN-sx from baseline to after treatment that persisted at the same level of severity 12 months after treatment (P , .001). In the chemotherapy-treated patients at 1 month after treatment, more severe CIPN-sx were associated with greater cerebral perfusion in several frontal region clusters; however, this relationship did not