Biomarkers in Chemotherapy-Induced Peripheral Neurotoxicity

Therapy with chemotherapeutic drugs can make a huge impact on survival and quality of life in patients with cancer. Advances in medical monitoring and the effectiveness of these therapies have significantly improved outcomes so that a definitive cure or long-term survival is more likely. Cancer survivors are used to dealing with serious side effects of their therapy; however, some of the side effects from the chemotherapy drugs persist even after the medication course is completed. The impact of these sequelae on quality of survival is increasingly being appreciated and forming an important new direction of cancer care. One of the more severe side effects of chemotherapy is peripheral neurotoxicity resulting in neuropathy or neuronopathy.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the least predictable and most prolonged sequelae with effects ranging from pain, numbness and tingling to diffuse weakness sometimes to the extent of paralysis. It results from damage or alteration in function of peripheral nerves usually, but not always, in a length-dependent manner. An indirect impact of CIPN includes difficulties with balance and susceptibility to falls. There are currently no therapies that have been proven to prevent CIPN. Similarly, there are few medications that are known to be effective in the reversing CIPN once it develops or effectively treating symptoms of CIPN. Currently, diagnosis is based mainly on clinical examination and electrophysiological testing to monitor CIPN; identification of candidate biomarkers through which disease onset can be identified at an earlier stage and which reflect presumed pathophysiologic mechanisms is of paramount importance.

There are different theories of CIPN pathogenesis. One of the leading hypotheses relates to mitochondrial dysfunction and oxidative stress affecting both the dorsal root ganglia neurons and supportive endothelial cells of the vasa nervorum. Here at Dartmouth, a specialized technique has been developed that allows the non-invasive assessment of tissue oxygen in and around peripheral nerve. This technique, called "electron paramagnetic resonance" (EPR) oximetry, allows for repeated measurements over time that can be correlated with other metrics of peripheral nerve function. Given its relevance to an important pathophysiologic mechanism of disease, EPR oximetry may provide an early marker of disease onset.

Neurofilament light chain (NF-L) is also emerging as a sensitive blood-based biomarker of axonal degeneration. NF-L is a component of the axonal cytoskeleton that leaks out of degenerating axons. NF-L has been reported to be elevated in plasma or serum in a wide range of neurodegenerative disorders, including CNS disorders such as multiple sclerosis and ALS as well as PNS disorders such as Charcot Marie Tooth and Guillain-Barre syndrome. To date, there are no published reports of elevated blood NF-L levels in patients with CIPN, although it has been reported to increase in rat model of vincristine-induced neuropathy.

In this proposal, the investigators will be testing the hypothesis that these could both be biomarkers of CIPN. It is hoped that the oximetry measurement and blood NF-L levels will (i) reflect the changes that occur on a cellular level and the damaged nerves, (ii) reflect the damage occurring to nerves more sensitively than existing techniques, and (iii) help to better understand the reason the nerves are being damaged. It is also hoped that these will be something that can be used in future clinical trials.