Persistent chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine

Abstract

Purpose: Chemoneuropathy remains a painful, burdensome complication of cancer treatment for patients receiving a range of chemotherapeutics, yet the cause and persistence of this condition are not fully documented. This study was designed to quantify the longevity of and contributions to neuropathy following treatment with the plant alkaloids paclitaxel and vincristine.

Methods: Quantitative sensory testing was conducted approximately 18 months apart on 14 patients, seven of which had been treated with paclitaxel and seven with vincristine and compared to data from 18 healthy control subjects. In addition, skin biopsies were obtained to investigate changes in the density of Meissner's corpuscles and epidermal nerve fibers (ENFs), the loss of which is thought to contribute to multiple forms of neuropathy.

Results: Impairments in motor skills, as measured by a grooved peg-board, were found. Deficits in touch detection were observed using von Frey monofilaments, as were changes in sharpness detection using a weighted needle device. Using a Peltier device, warmth and heat detection were impaired. These deficits were consistent across time. Remarkably, the average length of time patients reported painful neuropathy was over four and a half years. Skin biopsies were found to be deficient in Meissner's corpuscles and ENFs.

Conclusions: The combination of widespread deficits in sensory testing and decreases in skin innervation for cancer patients receiving paclitaxel or vincristine document a persistent polyneuropathy which severely impacts these patients. Decreases in Meissner's corpuscles and ENFs indicate a possible mechanism for the neuropathy.

Fig. 1

Description of pain (a) and average pain ratings (±SEM) (b) in patients with paclitaxel and vincristine-induced neuropathy pain at an initial test (gray bars) and at a retest time point (black bars). VAS visual analog scale (range: 0–10)

Fig. 2

Touch detection thresholds and peg-board completion times in patients at the test and the retest. The left side of the graph depicts mean (±SEM) von Frey touch detection thresholds obtained from the three areas of the body tested (Fingertip, Palm, and Volar Forearm) for control subjects (open bars) and from patients with chemoneuropathy at the test (gray bars) and retest (black bars) examinations. The right side of the graph shows the mean (±SEM) slotted peg-board completion times for the dominant and non-dominant hands in control subjects (open bars) and patients at the test (gray bars) and retest (black bars) examinations. *p < .05; **p < .01

Fig. 3

Sharpness detection thresholds (±SEM) for control subjects (open bars) and from patients with chemoneuropathy at the test (gray bars) and retest examination (black bars). *p < .05

Fig. 4

Thermal detection thresholds in patients at the test and the retest examinations. The bar graph in (a) shows the mean (±SEM) temperature for detection of warming and heat pain at the three bodily test areas (Fingertip, Palm, Volar Forearm) for control subjects (open bars) and patients with chemoneuropathy at the time of the initial test (Test, gray bars) and the long-term follow-up examination (Retest, black bars). The bar graph in (b) shows the mean (±SEM) temperature for the detection of skin cooling and cold pain in the same manner depicted in (a). *p < 0.05

Fig. 5

Meissner’s corpuscle and epidermal nerve fiber densities in biopsies obtained from a healthy control subject and a patient with chemoneuropathy. This figure shows immunohistochemistry staining with the pan-neuronal marker PGP9.5 (green) in the biopsies of a patient with bortezomib-related chemoneuropathy in the area of pain (finger tip) (a), the border zone (palm) (b) and the non-painful area (forearm) (c). These biopsies can be compared to similar biopsies from a control subject (d, e, f). Epidermal Nerve fibers (ENF) can be seen in the control subject crossing the dermalepidermal junction (D/E J) into the epidermis (Epid) in all regions. Note the extensive decrease in epidermal nerve fibers in the patient biopsies. Also within the control subject biopsies from the fingertip and palm, Meissner’s corpuscles (MC) can be clearly seen within the epidermis. These structures are notably absent in the patient biopsies. (scale: 100 μm)