This study has several important findings. First, it shows that oxaliplatin administration is associated with mild, progressive, sensory > motor axon loss that can be detected using several accepted peripheral nerve measures. Second, our results suggest that axon loss can progress after cessation of oxaliplatin administration and that this may be irreversible. These results provide a rationale to include such a patient population in neuroprotection studies and have implications for the design of such studies. Finally, these results underscore the difficulty in distinguishing between neuropathy symptoms and axonal loss.
Several measures documented a significant decrease in nerve function over time including distal leg IENFD, rTNS, as well as the peroneal motor and sural nerve amplitudes. There was no change in nerve conduction velocity measurements or in the distal thigh IENFD. Of these different measures, the decrease in the peroneal nerve amplitude was the smallest and was subclinical. Sensory symptoms and signs as well as NCV abnormalities accounted for the majority of points in the rTNS. We did not observe any correlation between age, stage of tumor or other medical condition, and severity of peripheral neuropathy, though we recognize that our sample size is small.
Based on these findings, we conclude that oxaliplatin induces distal sensory and motor axon loss though the degree of loss was mild (no patient developed an abnormal sural or peroneal amplitude, or an IENFD below the fifth percentile).14
Additionally, the significant decrease in the distal leg IENFD in the setting of no change at the distal thigh IENFD suggests that chronic oxaliplatin-induced neuropathy is a length-dependent process preferentially affecting the terminals of the longest axons. Patients with sensory ganglionopathies typically have IENFD reductions at both proximal and distal sites,16
which was not observed in our study. While cisplatin is accepted to have dorsal root ganglion toxicity, these data imply that the toxicity was not detected at proximal sites.
These findings have several implications for future chemotherapy-induced neuropathy studies. First they imply that oxaliplatin-induced neuropathy is an attractive paradigm for neuroprotection studies as we were able to reliably measure axon loss by several measures. Patients receiving chemotherapy are suitable for neuroprotection studies given that the timing of the toxic exposure is known and can be quantified. This advantage is partially offset by comorbidities in a patient population that often is chronically ill, on multiple neurotoxic medications, receiving different chemotherapy regimens, and subject to study fatigue toward ancillary studies. Objective measures of axon loss performed well in this study and appear to be well-suited to such studies. The skin biopsy procedure was well-tolerated and the distal leg was the best site to monitor axon loss. Additionally, skin biopsy is attractive as it is unbiased, quantitative, and requires limited subject time commitment and no neurologic expertise by the person performing the biopsy. Furthermore, the progression of axon loss following the cessation of chemotherapy is consistent with the phenomenon of coasting and these data suggest that periods longer than 6 months may be needed before recovery can be detected. These results also imply that neuroprotection studies might increase the power to detect a drug effect by having a study duration that exceeds the period of oxaliplatin administration.
and National Cancer Institute Common Toxicity Criteria18
grading systems have both been used to detect neuropathy progression in oxaliplatin based regimens. These scoring systems are heavily weighted toward subject symptoms and are consistent with a focus on palliation in advanced colorectal cancer. Several of our subjects developed prominent symptoms that interfered with drinking, walking, or performing dexterity tasks, though these symptoms were not captured by the rTNS and were not associated with axon loss. This distinction between axon loss and neuropathy symptoms is similar to reports demonstrating that the pain associated with CTS does not correlate with the severity of electrophysiologic abnormalities.19
In general, scoring systems that rely solely on neurologic examinations have performed poorly in documenting the severity of and following subjects' neuropathy.20,21
Objective peripheral nerve measures, including IENFD, may therefore complement existing symptom and examination-based scales in ON.
Oxaliplatin is associated with mild sensory and motor axon loss that could be detected by several measures including rigorous NCV testing, rTNS, and a distal leg IENFD. These results also suggest that patients receiving oxaliplatin are an attractive population to assess potential neuroprotective agents and that such objective measures of peripheral nerve function complement existing symptom-based scales. A distal leg skin punch has potential as such a measure as it is well-tolerated, requires little subject participation, and is well-suited to multicenter trials that include sites with little neurologic expertise.