ORG 2766 in the Prevention of Cisplatin Neuropathy

Abstract

Peripheral neuropathy is a serious and dose-dependent side-effect of treatment with cisplatin (1–9). Symptoms usually start with paraesthesias and numbness in toes and fingers. Disturbances in fine touch and joint position sense lead to early problems with manipulation of small objects and later to sensory ataxia with gait difficulties. Rarely there is associated pain. The patient sometimes experiences a sudden electric shock from the neck to the spine, arms, or legs on bending the head: Lhermitte’s sign. On examination one finds early absence of deep tendon reflexes, disturbances of vibration, joint position sense in distal extremities and often also of small fiber sensory function. Sensory ataxia is indicated by a positive Romberg’s sign, abnormal heel-to-toe walking or an unstable broad-based gait. Muscle strength is intact unless an unusually severe neuropathy develops. Neurophysiological studies can reveal absence of sural nerve action potentials, delayed sensory nerve conduction velocities, with prolonged distal sensory nerve latencies and H-reflexes. Motor nerve conductions and distal motor latencies are mostly normal and denervation potentials of muscles are rarely observed. Sural nerve biopsies show a decrease or degeneration of large myelinated axons with signs of segmental demyelination and remyelination, indicating axonal degeneration with secondary demyelinisation (1,2,4). A few cases of spinal ganglia have been examined usually showing no abnormalities, although experimental studies show that dorsal root ganglia are highly susceptible to cisplatin (10). Most probably this is due to the absence of a blood-brain or blood-nerve barrier around ganglion cells. Large prospective studies indicate that cisplatin neuropathy occurs in at least 50% of cases after a cumulative dose of 300 mg/m² and virtually in every patient after 500–600 mg/m² cisplatin (1,2). Also with lower doses a neuropathy can occur. Recently other dose-regimens have been used to diminish side-effects of cisplatin, including renal toxicity and neuropathy. Apart from using mannitol, regimens have been developed in which the same cumulative dose was administered over 4 of 5 days at the beginning of every cycle. Administering 20 mg/m²/day on days 1–5 every 4 weeks led to no neurotoxicity, 25 mg/m²/day on days 1–4 for 3 courses to an increase of the Hoffmann-reflex in only 14% with a small incidence of reduced sensory conduction velocities of the median nerves but not to clinical neuropathy (11–13). Infusion of 30 mg/m²/day cisplatin over 5 days induced a neuropathy in 2 out of 9 patients (13). However, a dose of 40 mg/m² on 5 consecutive days every month caused a severe neuropathy in 100% of patients at a cumulative dose of 300 mg/m² (6). A dose schedule of 50 mg/m² cisplatin given each week, resulted in a significant less incidence of neuropathy than a 75 mg/m² given every 3 weeks with an identical cumulative dose of 450 mg/m² (14). These data suggest that lower doses given with one week intervals lead to less toxicity than higher bolus doses with longer intervals.