Cisplatin is a foundational platinum-based chemotherapy drug used for several cancer types, including testicular, ovarian, and lung cancers. Although highly effective, its use is often limited by Cisplatin-Induced Peripheral Neuropathy (CIPN). CIPN involves damage to the peripheral nerves and is one of the most dose-limiting toxicities. This frequently necessitates chemotherapy dose reductions or discontinuation, significantly impairing a patient’s quality of life long after treatment ends.
How Cisplatin Damages Nerves
Cisplatin interferes with DNA replication, which is its primary function as a chemotherapy agent. Unlike cancer cells, mature sensory neurons do not divide, but cisplatin preferentially accumulates in their cell bodies. This occurs specifically in the dorsal root ganglia (DRG) near the spinal cord. The DRG lacks the protective blood-brain barrier, making it vulnerable to high concentrations of the drug.
Once inside the DRG neurons, the platinum compound forms toxic crosslinks (adducts) with nuclear and mitochondrial DNA. This DNA damage triggers neuronal dysfunction and cell death, resulting in a sensory neuronopathy. The damage causes the long sensory nerve projections (axons) to degenerate, starting at the furthest points from the cell body. Because the longest axons are affected first, symptoms begin in the toes and fingertips, leading to the classic “stocking-and-glove” distribution.
Common Signs and Sensory Changes
Cisplatin neuropathy is overwhelmingly sensory, affecting the nerves responsible for feeling rather than movement. The earliest signs involve abnormal sensations in the hands and feet. Patients often report tingling, prickling, or “pins and needles” (paresthesia), along with numbness (hypoesthesia). These sensations develop symmetrically, starting distally and moving up the limbs as the cumulative drug dose increases.
A disruptive sensory change is the loss of proprioception (the body’s sense of position) and a decreased ability to detect vibration. This loss of deep sensation can lead to balance issues and an unsteady gait. Some patients may also experience burning or sharp pain (dysesthesia), or a heightened sensitivity to cold temperatures. Motor symptoms, such as muscle weakness or difficulty with fine motor tasks, are less frequent but can occur in advanced stages of nerve damage.
Strategies for Managing Neuropathy
Management focuses on preventing further nerve damage and alleviating existing symptoms, as no agent is approved to prevent or cure CIPN. The primary clinical tool is dose modification. Oncologists may reduce the cisplatin dose or implement a temporary pause (a drug holiday) to allow nerve recovery. This strategy limits the total cumulative dose, which strongly predicts neuropathy severity.
For symptomatic relief of painful neuropathy, the SNRI duloxetine is the only pharmacological agent with strong supporting evidence. The American Society of Clinical Oncology recommends duloxetine as the first-line treatment for painful CIPN. Other medications, such as the anticonvulsants gabapentin or pregabalin, may be prescribed, though their efficacy specifically for CIPN is less established. Non-pharmacological interventions include physical therapy for balance and gait instability, and occupational therapy to maintain fine motor skills.
Prognosis and Recovery Expectations
Recovery from cisplatin neuropathy is variable and depends heavily on the total lifetime dose received. Since cisplatin causes a sensory neuronopathy involving the death of the nerve cell body, the damage is often long-lasting or permanent. A unique feature is the “coasting” phenomenon, where symptoms continue to worsen for several weeks or months after chemotherapy stops.
This post-treatment worsening occurs because the platinum compound remains in the DRG, continuing its toxic effects. After the coasting period, symptoms typically stabilize and may begin a slow recovery process that can take months or years. While some patients experience near-complete resolution, many survivors are left with persistent, chronic symptoms, such as residual numbness and decreased vibratory sense. The long-term persistence of neuropathy can severely impact physical function and quality of life years after cancer treatment.