INTRODUCTION — Neurologic complications of anticancer therapy may result from direct toxic effects on the nervous system or indirectly from drug-induced metabolic derangements or cerebrovascular disorders. A wide range of neurologic complications are associated with antineoplastic drug treatment (table 1) [1-4].
Their recognition is important because of potential confusion with metastatic disease, paraneoplastic syndromes, or comorbid neurologic disorders that do not require dose reduction or discontinuation. If the neurologic disorder is caused by the chemotherapy, discontinuation of the offending agent may prevent irreversible injury.
Among the widely used anticancer drugs, the platinum compounds cisplatin and oxaliplatin are most commonly associated with various forms of neurotoxicity. The incidence, clinical manifestations, possible mechanisms of neurotoxicity, and management of neurotoxicities other than peripheral neuropathy with cisplatin, oxaliplatin, and the less neurotoxic analog carboplatin will be reviewed here. The neurologic complications of other chemotherapy agents and biologic therapies, as well as preventive strategies and treatments for established chemotherapy-induced peripheral neuropathy, are discussed separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Neurologic complications of cancer treatment with molecularly targeted and biologic agents" and "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)
CISPLATIN — The range of cisplatin-induced neurotoxicity includes peripheral neuropathy, ototoxicity (hearing impairment and tinnitus), vestibulopathy, and encephalopathy; the most common are peripheral neuropathy and ototoxicity.
Peripheral neuropathy — Symmetrical, predominantly sensory peripheral neuropathy is a common complication of cisplatin therapy that develops in most patients typically only after a cumulative dose of 300 mg/m2 is reached. Once established, there is no effective therapy, and treatment is symptomatic only. Most patients improve over time, although recovery is often incomplete.
Cisplatin causes an axonal neuropathy that predominantly affects large myelinated sensory fibers (table 2) [5-8]. The primary site of damage is the dorsal root ganglion [9], although the peripheral nerve may also be affected.
Incidence and risk factors — Cisplatin-induced peripheral neuropathy is related to the total cumulative dose. Neuropathy usually develops only after a cumulative cisplatin dose beyond 300 mg/m2, and at a cumulative dose of 500 to 600 mg/m2 almost all patients have objective evidence of neuropathy [8,10,11]; however, there is marked interindividual variation in susceptibility [5,10,12]. Genetic polymorphisms in some enzymes responsible for cisplatin metabolism (eg, glutathione S-transferase) may contribute to some of the observed interindividual differences in the incidence and severity of neuropathy [13,14]. Other conditions predisposing to neuropathy, such as diabetes, may contribute [15]. Higher cisplatin dose intensity (ie, higher doses per unit time) does not appear to enhance the severity of the neuropathy [16].
Clinical and electrophysiologic manifestations — Clinically, cisplatin-induced peripheral neuropathy is characterized by the subacute development of numbness, paresthesias (abnormal sensations), and occasionally pain, which usually begins in the toes and fingers, spreading proximally to affect the legs and arms (table 2). The earliest observable sign is a decreased vibratory sensitivity in the toes and loss of ankle jerks [8]. Although proprioception is impaired and reflexes are lost, pinprick, temperature sensation, and motor strength are usually spared, or less severely affected. Autonomic neuropathies are rare [17].
More prolonged treatment may worsen symptoms and signs with generalized loss of deep tendon reflexes, and more proximal vibratory sensory impairment. Lhermitte's sign, a shock-like sensation of paresthesias radiating from the back to the feet during neck flexion, is occasionally observed, typically after weeks or months of treatment [18]. It has also been reported in patients receiving high cumulative doses of oxaliplatin. Lhermitte's sign is believed to result from transient demyelination of the posterior columns. (See 'Oxaliplatin' below.)
Nerve conduction studies show sensory axonal damage with decreased amplitude of sensory nerve action potentials (SNAP) and prolonged sensory latencies [19,20]. Motor nerve conduction velocities and compound muscle action potentials are typically unchanged during treatment. On sural nerve biopsy, both demyelination and axonal loss are evident.
Differential diagnosis — The differential diagnosis includes paraneoplastic neuropathies and those associated with autoimmune disorders. Paraneoplastic neuropathies usually involve all sensory fibers, and there may be an antineuronal antibody (anti-Hu) in the serum. Patients with autoimmune neuropathies often have clinical features of an underlying connective tissue disease, and autoantibodies are usually present in the serum. Tetany in the hands and feet resulting from cisplatin-related electrolyte imbalance (ie, hypomagnesemia, hypocalcemia) may also be confused with peripheral neuropathy [21]. The symptoms of peripheral neuropathy may sometimes be confused with those of hand-foot syndrome (acral erythema), which can occasionally be seen with cisplatin. (See "Cutaneous adverse effects of conventional chemotherapy agents" and "Differential diagnosis of peripheral nerve and muscle disease" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Subacute sensory neuronopathy' and "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease".)
Mechanism — The major site of pathology is the dorsal root ganglion. Cisplatin (and oxaliplatin (see 'Oxaliplatin' below)) enters into the dorsal root ganglion and binds to nuclear and/or mitochondrial DNA, causing apoptosis. There are two main mechanisms proposed to explain the pathophysiology of platinum-induced peripheral neuropathy:
●Platinum compounds form intrastrand adducts and interstrand crosslinks that alter the tertiary structure of the DNA [22,23]. This effect on DNA promotes alterations in cell-cycle kinetics, which leads to an attempt of differentiated postmitotic dorsal root ganglion neurons to re-enter the cell cycle, which leads to the induction of apoptosis [24]. Oxaliplatin forms fewer platinum-DNA adducts than does cisplatin, and thus is slightly less neurotoxic [22].
●The second mechanism proposes involvement of oxidative stress and mitochondrial dysfunction as the trigger of neuronal apoptosis [25-27].
Regardless of the mechanism, apoptosis results in secondary damage to peripheral nerves.
Natural history, prevention, and treatment — Even if cisplatin is discontinued, the sensory neuropathy continues to worsen for several months in 30 percent of patients (described as the "coasting" phenomenon) [6,7,28]. Neuropathy may even begin after therapy is discontinued. It eventually improves in most patients, although recovery is often incomplete [28]. In a study of long-term testicular cancer survivors who had completed treatment at least five years previously, peripheral neuropathy was still present in 20 percent, and 10 percent were symptomatic [11]. Higher levels of residual serum platinum, which can persist for years after treatment, appear to correlate with the severity of long-term peripheral neuropathy in cisplatin-treated survivors of testicular cancer [29]. In another report, factors that were related to a high risk for persistent neuropathy included age at diagnosis, smoking history, excess alcohol use, hypertension, and heritable factors [30].
There are no effective preventive strategies. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Preventive approaches'.)
In general, patients with mild neuropathy can continue to receive full doses; however, if symptoms increase in severity or the neuropathy interferes with function, the risk of potentially disabling neurotoxicity must be weighed against the benefit of continued treatment. Sometimes, a patient can be switched to an alternative, less neurotoxic agent (eg, carboplatin) if this is consistent with the goals of care. (See "Systemic chemotherapy for advanced non-small cell lung cancer", section on 'Cisplatin versus carboplatin' and "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Carboplatin-based regimens'.)
For some patients with platinum-induced neuropathy, pain is a prominent symptom. Amelioration of symptoms from the chronic neuropathy, including pain, may be achieved through use of antidepressants such as duloxetine. For symptomatic patients who fail to respond to duloxetine, other adjuvant analgesics (eg, tricyclic antidepressants, anticonvulsants), opioids, physical modalities such as cutaneous electrical stimulation, and/or interventional procedures may be indicated. Symptomatic treatment for chemotherapy-induced neuropathy is discussed in detail elsewhere. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Specific interventions that are recommended' and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain' and "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Other modalities' and "Cancer pain management: Interventional therapies".)
Ototoxicity — Ototoxicity is the second most common cisplatin-related neurotoxic effect; it is characterized by a dose-dependent, high-frequency sensorineural hearing loss, which is almost always bilateral and irreversible, and often accompanied by tinnitus and vertigo [31,32]. However, the exact incidence of tinnitus is unclear [33].
Incidence and risk factors — Although ototoxicity is typically reported after intravenous cisplatin administration, it has also been seen after intraperitoneal use [34]. (See "Intraperitoneal chemotherapy for treatment of ovarian cancer", section on 'Complications'.)
The main risk factors are cumulative dose, age at treatment, and the use of concomitant ototoxic treatments. Incidence is variable and related to the specific diagnostic criteria used to define ototoxicity [35], the total dose of cisplatin, the use of concomitant ototoxic treatments, the population under study [36], and possibly inherited polymorphisms in drug metabolism genes:
●The influence of cumulative cisplatin dose was shown in an analysis of audiometric testing of 488 North American male germ cell tumor survivors [37]. Hearing loss was defined according to the American Speech-Language-Hearing Association (ASHA) criteria as a hearing threshold at any frequency (0.25 to 12 kHz) that exceeded 20 dB for either ear. At a median 51 months following chemotherapy, hearing loss was found in 80 percent of the survivors, and 18 percent had severe or profound hearing loss. Increasing cumulative cisplatin dose (median 400 mg/m2; range 200 to 800 mg/m2) was significantly related to hearing loss at 4, 6, 8, 10, and 12 kHz. Every 100 mg/m2 increase in cumulative dose resulted in a 3.2 dB impairment in age-adjusted overall hearing threshold, and cumulative cisplatin doses >300 mg/m2 were associated with greater severity of hearing loss than were lower doses (odds ratio 1.59, p = 0.0066). Tinnitus (which was reported by 40 percent of survivors) was also significantly correlated with reduced hearing at each frequency.
In another population-based study of significant hearing loss requiring hearing assistive devices (HADs) among childhood cancer survivors in Ontario, Canada, the cumulative incidence of needing a HAD at 20 and 30 years postdiagnosis was 2.1 and 6.4 percent, respectively [38]. The 30-year incidence was highest in neuroblastoma (10.7 percent, 95% CI 3.8-21.7 percent) and hepatoblastoma (16.2 percent, 95% CI 8.6-26 percent). In a multivariate analysis, children diagnosed at age zero to four had a twofold higher risk than did older children (hazard ratio 2.2, 95% CI 1.4-3.3 percent). Relative to no cisplatin exposure, those who received cumulative doses ≥200 mg/m2 but not lower cumulative doses were at greater risk.
Others report an elevated risk of cisplatin-induced hearing loss for cumulative cisplatin doses >100 mg/m2 and for higher fractionated doses in children [39].
●Although ototoxicity has a general dose dependence, there is considerable interindividual variability. Genetic polymorphisms in enzymes responsible for cisplatin metabolism (eg, glutathione S-transferase [GST], thiopurine S-methyltransferase [TPMT], catechol O-methyltransferase [COMT]) may contribute to the observed interindividual differences in the severity of hearing loss [40-46]. Other candidate genes potentially involved in ototoxicity include excision repair cross-complementation groups 1 and 2 (ERCC1 and ERCC2), acylphosphatasse-2 (ACYP2), solute carrier family 16 member 5 (SLC16A5), and the Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) [47-51].
●Higher levels of residual serum platinum, which can persist for years following treatment, may also contribute to the severity of ototoxicity [29].
●Radiotherapy (RT) to the normal cochlea or cranial nerve VIII can also cause sensorineural hearing loss. Concurrent administration of cisplatin and RT results in synergistic ototoxicity, especially in the high-frequency speech range [52]. The ototoxicity of combined modality therapy with cisplatin and RT is discussed in more detail separately. Care should be taken to distinguish sensorineural hearing loss versus conductive hearing loss due to serious otitis, an early complication of radiation. Conductive hearing loss can be treated. (See "Delayed complications of cranial irradiation", section on 'Ototoxicity'.)
●Ototoxicity can be particularly severe in childhood cancer survivors [36,53-56]. Cofactors contributing to neurotoxicity include younger age (particularly <5 years), the use of cranial irradiation, diagnosis of a central nervous system tumor, diminished renal function, high cumulative doses of platinum compounds, and the use of carboplatin in addition to cisplatin as part of the treatment regimen [35,57]. Whether longer infusion durations are associated with a lower incidence of platinum-induced ototoxicity is unclear [58].
Although children may have a slightly greater capacity for improvement once treatment is discontinued, profound hearing impairment is not infrequent and can interfere with subsequent speech and language development [36], and impair neurocognitive function [59,60]. Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors are available (table 3) [61,62]. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Monitoring for late or long-term effects of cancer and its treatment'.)
Mechanism — The main targets of cisplatin- and carboplatin-related ototoxicity are the outer hair cells in the organ of Corti and the vascularized epithelium in the lateral wall of the cochlea [42,63].
This difference in risk of ototoxicity with oxaliplatin has been attributed to lower cochlear uptake as compared with cisplatin [64]. (See 'Oxaliplatin' below.)
Grading and classification of hearing loss — Several ototoxicity grading systems are currently in use (table 4). There is substantial variability in the definition of the grades among the scales, and some are designed for use in children and others for adults. There is no consensus on the optimal tool nor frequency of assessment [33], although one analysis suggests superiority for the International Society for Pediatric Oncology (SIOP) scale [65]. At least in the United States, the Common Terminology Criteria for Adverse Events (CTCAE) scale is commonly used (table 5).
Prevention
Strategies — Various strategies have been considered to minimize cisplatin ototoxicity:
●Monitoring and early detection – Early detection of ototoxicity in children receiving platinum agents may minimize the risk of severe impairment in the frequencies required for speech recognition by providing an opportunity for treatment modification, if possible before auditory damage becomes severe. Pure-tone audiometry is the standard method used for hearing assessment and generally involves the presentation of sounds across a wide spectrum of frequencies (500 to 8000 hertz [Hz]) [66]. In children being treated with either cisplatin or carboplatin, extended high-frequency audiometry (ie, at frequencies above 8000 Hz [8 kHz]) is more sensitive to early hearing loss than conventional audiometry [67]. This procedure is readily carried out in children older than five years. For children less than five years of age, ototoxicity can be assessed using electrophysiologic techniques, such as brainstem auditory-evoked response [66]. Another option, distortion product otoacoustic emissions (DPOAEs) testing, is also more sensitive than conventional audiometry.
Specific, consensus-based, age-appropriate recommendations for audiologic test batteries in children receiving ototoxic cancer treatment are available from the International Society of Paediatric Oncology [68].
●Pharmacologic agents – We suggest the use of sodium thiosulfate (STS) for children receiving cisplatin monotherapy for a variety of non-metastatic malignancies, including standard-risk hepatoblastoma (cumulative dose 480 mg/m2). However, the safety and efficacy of this approach in patients with non-metastatic hepatoblastoma who receive lower cumulative doses is not established. (See "Overview of hepatoblastoma", section on 'Approaches to minimizing long-term treatment-related toxicity'.)
The available evidence is insufficient to support the routine use of STS in children receiving cisplatin for treatment of a metastatic malignancy or in adults receiving cisplatin, or for any other pharmacologic agent to prevent cisplatin ototoxicity. (See 'Prevention' above.)
•Sodium thiosulfate – Protection against platinum-induced hearing loss has been achieved in animal models and in patients (predominantly children) using STS [69-72]. The benefit of STS in children receiving cisplatin has been addressed in two randomized trials:
-In the Children's Oncology Group (COG) ACCL0431 trial, 125 children receiving cisplatin for a variety of malignancies (germ cell cancer, medulloblastoma, neuroblastoma, osteosarcoma) who were not registered in a cancer-directed COG therapeutic study were randomly assigned to a single dose of STS six hours after each cisplatin dose or to observation [71]. The use of STS was associated with a significantly smaller proportion of patients with hearing loss four weeks after the final cisplatin dose (29 versus 56 percent, odds ratio of hearing loss 0.31, 95% CI 0.13-0.73).
Therapy was well tolerated, with no serious adverse events deemed probably or definitely related to STS. However, there were also concerns about inferior disease outcomes in the STS group (three-year event-free survival 54 versus 64 percent, overall survival 70 versus 87 percent), raising concern for a possible tumor protective effect with administration of STS. In a post hoc subgroup analysis, the inferior survival appeared to be limited to those with disseminated disease (three-year overall survival 45 versus 84 percent, relative hazard ratio 4.10, 95% CI 1.30-12.97).
Although it was postulated that better than expected outcomes in the control group with short-term follow-up might have been responsible for the apparent survival detriment with STS in those with disseminated disease (ie, that the results were an artifact of short follow-up), the detrimental impact of STS on overall survival persisted with longer-term follow-up (six-year overall survival 45 versus 73 percent, HR for death 2.74, 95% CI 1.01-7.44) [73].
-Benefit was confirmed, but without jeopardizing cancer outcomes, in the randomized phase III SIOPEL-6 trial, in which 109 children with standard-risk hepatoblastoma receiving single-agent cisplatin were randomly assigned to receive or not receive STS (administered at various doses of 10 g/m2, 15 g/m2, or 20 g/m2 based on actual body weight, over 15 minutes, six hours after each cisplatin dose) [72]. The addition of STS resulted in a significant reduction in the incidence of cisplatin-induced hearing loss (39 versus 68 percent, HR 0.58, 95% CI 0.40-0.83). At a median follow-up of 52 months, cancer outcomes were not worse in the STS group, but these patients did not have disseminated disease. (See "Overview of hepatoblastoma", section on 'Approaches to minimizing long-term treatment-related toxicity'.)
-A meta-analysis of these two studies and a third trial that examined intravenous STS [70] concluded that STS was effective at preventing cisplatin ototoxicity (risk ratio 0.57, 95% CI 0.45-0.73) [74]. When the analysis was limited to the two trials conducted in children, event-free survival (hazard ratio [HR] 1.13, 95% CI 0.70-1.82) and overall survival (HR 1.90, 95% CI 0.90-4.03) were not significantly worse with STS; however, the range of the confidence intervals was wide and the authors concluded that additional large scale studies were indicated to assess impact on survival outcomes.
Largely based on these two studies, STS has been approved by the US Food and Drug Association (FDA) as treatment to help decrease the risk of cisplatin-related ototoxicity in pediatric patients aged one month or older who have received a diagnosis of localized, non-metastatic solid malignancies [75]. The approved dose is based on actual body weight, as outlined in the United States Prescribing Information [76].
•Amifostine – Whether amifostine offers protection in children receiving cisplatin is unclear. Benefit has been suggested in some [77,78] but not all uncontrolled trials [79], while two small randomized trials (one in patients with osteosarcoma, the other in hepatoblastoma) failed to show benefit for prophylactic amifostine [80,81]. An updated 2016 Cochrane review concluded that the data were insufficient to make any definite conclusions as to amifostine efficacy or lack thereof [82]. 2008 guidelines from the American Society of Clinical Oncology (ASCO) also concluded that the data were insufficient to support the routine use of amifostine to prevent cisplatin ototoxicity [83].
•Vitamin E – Animal models suggest a potential protective effect of vitamin E against ototoxicity [84]. Only limited data are available in humans. One double-blind trial randomly assigned 108 patients initiating treatment for a solid tumor with cisplatin to receive vitamin E (400 mg daily) or an identical placebo, with both treatments administered daily during cisplatin and for three months thereafter [85]. Unfortunately, only 23 were included in the final analysis; 40 dropped out early on (predominantly because of disease progression), 27 were excluded because the cumulative cisplatin dose was <300 mg/m2, and of the remaining 41, 18 completed only one visit and were not included in the statistical analysis. At one-month audiography, the control group had significant hearing loss in both ears, while there were no significant changes in the active group. Interpretation of this trial is severely limited by the high number of dropouts and the lack of information on preintervention and postintervention serum vitamin E levels.
•Intratympanic treatments – A benefit for intratympanic glucocorticoid injections was suggested in a small trial in which 28 patients age <18 years, with a neoplastic disease for which the curative intent protocol included cisplatin, had local injection of dexamethasone into a randomly assigned middle ear; the other ear of the same patient served as the control [86]. Of the 15 patients who completed the study, compared with the control ears, ears with intratympanic dexamethasone had significantly attenuated hearing loss at 6000 Hz and decreased outer hair dysfunction as measured by differences in the Audiometry and Distortion Product Otoacoustic Emissions tests (DPOAEs) at baseline and at one week after the cumulative dose of cisplatin reached 400 mg. Although these results are promising, additional data in a larger number of patients and longer-term observations are needed before concluding that there is benefit from this invasive procedure.
In addition, three small trials have explored the benefit of intratympanic N-acetylcysteine, two of which were conducted entirely in adults, and two of which suggested potential benefit [87-89]. A systematic review concluded that efficacy conclusions were limited by the small sample sizes, open-label designs, and lack of direct comparison of ears using paired tests [90].
•Diethyldithiocarbamate – Three trials, all conducted in adults, failed to show any benefit from diethyldithiocarbamate and disulfiram, both thiol heavy metal chelating agents, as protectants against cisplatin ototoxicity [91-93].
A major challenge to the development of effective otoprotective agents is the lack of consensus on the best ototoxicity assessment criteria [42,94]. (See 'Grading and classification of hearing loss' above.)
Guidelines from expert groups — Evidence-based guidelines for prevention of cisplatin-induced ototoxicity in children and adolescents with cancer are available from a multidisciplinary multinational expert panel [95]. Regarding the use of sodium thiosulfate, the panel made a strong recommendation for its use in patients treated for non-metastatic hepatoblastoma, a weak recommendation for its use in other non-metastatic cancers, and a weak recommendation against its use in patients with metastatic cancer. Despite these recommendations, unfortunately, a suitable sterile formulation of sodium thiosulfate for this use is not yet commercially available in any country. The panel also made a strong recommendation against the use of amifostine, sodium diethyldithiocarbamate, and intratympanic therapy in any setting.
Encephalopathy — Encephalopathy is rare and has been observed most often after intra-arterial administration [96]. Symptoms include seizures and focal neurologic symptoms, including cortical blindness [97,98]. The encephalopathy is associated with reversible abnormalities in the white matter of the occipital, parietal, and frontal lobes (reversible posterior leukoencephalopathy). (See "Reversible posterior leukoencephalopathy syndrome".)
Cisplatin-induced encephalopathy must be distinguished from metabolic causes, including water intoxication caused by prehydration, treatment-induced renal impairment, hypomagnesemia, hypocalcemia, and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Paraneoplastic SIADH may accompany some malignancies for which cisplatin is commonly used, particularly small cell lung cancer. Rare cases of cisplatin-induced SIADH are reported [99,100]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)" and "Cisplatin nephrotoxicity" and "Clinical manifestations of lung cancer".)
Other complications — Cisplatin has been associated with a number of other neurologic complications, including:
●A vestibulopathy, resulting in ataxia and vertigo, dysgeusia, and a myasthenic syndrome [17].
●Cognitive impairment [101]. (See "Cognitive function after cancer and cancer treatment", section on 'Neurobiologic basis'.)
●The development of hiccups in patients receiving cisplatin-based regimens. Although cisplatin may contribute to this toxicity, dexamethasone also appears to play a causative role [102]. (See "Hiccups", section on 'Medication-induced'.)
●Guillain-Barré syndrome is rarely reported [103]. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)
●Intracarotid cisplatin infusion may be associated with optic neuritis and retinopathy [17,104]. By contrast, cisplatin does not appear to interfere with olfactory function [105]. Focal lumbosacral plexopathy or mononeuropathy has been reported following infusion of the internal or external iliac arteries [106].
CARBOPLATIN
Peripheral and central nervous system toxicity — Peripheral neuropathy and central nervous system toxicity are uncommon when carboplatin is given at conventional doses (table 2). However, a severe neuropathy can develop after higher than standard-dose carboplatin, as used in the setting of high-dose therapy with hematopoietic cell transplantation [107]. (See "Preparative regimens for hematopoietic cell transplantation".)
Hearing loss — In adults, carboplatin is less ototoxic than is cisplatin [108], although ototoxicity can still occur with high-dose (myeloablative) therapy [109-111].
Ototoxicity has been more prominent in younger children (especially infants), but not in all studies:
●The administration of carboplatin to children treated for retinoblastoma usually does not lead to acute or subacute hearing loss [112-114]. In one of these studies, hearing loss affected only 5 percent of patients at a median of 3.7 years after treatment [114].
●However, much higher rates of ototoxicity were reported in another study of 60 children receiving carboplatin and etoposide for retinoblastoma [109]. Twelve (20 percent) developed ototoxicity at a median of eight months after the start of therapy, and nine required hearing aids. The only factor that predicted sustained hearing loss was younger age at start of treatment (median age at treatment initiation of the patients who developed hearing loss versus those who did not was 2.3 versus 10.3 months).
One of the reasons hypothesized to account for these findings was the dosing of carboplatin based upon body surface area (BSA) rather than body weight alone. Particularly in small children weighing <10 kg, this could result in exposure to potentially toxic serum levels of drugs [115]. The common practice of normalizing chemotherapy doses to weight rather than BSA in infants weighing <10 kg (which was done in the other three studies [112-114]) results in lower doses that offset differences in drug disposition and end organ sensitivity. (See "Retinoblastoma: Treatment and outcome", section on 'Hearing'.)
Long-term audiometric follow-up is advisable for all children who receive carboplatin for treatment of retinoblastoma. Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors are available (table 3) [61,62]. (See 'Ototoxicity' above.)
Other manifestations — Other manifestations of neurotoxicity from carboplatin include a microangiopathic hemolytic anemia resulting in progressive neurologic impairment and death [116], reversible posterior leukoencephalopathy syndrome [117], Guillain-Barré syndrome [103], and retinal toxicity following intra-arterial administration for brain tumors [118].
OXALIPLATIN — Oxaliplatin is a third-generation platinum compound used in the treatment of several gastrointestinal malignancies, most notably metastatic colorectal cancer (CRC). (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'FOLFOX versus FOLFIRI'.)
Clinical manifestations — Two distinct syndromes have been reported: an acute neurosensory complex, which can appear during or shortly after the first few infusions, and a cumulative sensory neuropathy, with distal loss of sensation and dysesthesias (table 2). Neuromotor toxicity is much less common. Ototoxicity is rare with oxaliplatin, unlike cisplatin [119].
Other rare manifestations of neurotoxicity include urinary retention and Lhermitte's sign, which have been reported in patients receiving high cumulative oxaliplatin doses [120,121]. Reversible posterior leukoencephalopathy is also reported [122-124]. (See "Reversible posterior leukoencephalopathy syndrome".)
Acute neurotoxicity — The majority of patients treated with oxaliplatin (>85 percent in two reports [125,126]) experience symptoms of acute neurotoxicity. Typical symptoms include discomfort swallowing cold items; throat discomfort; sensitivity to touching cold items; paresthesias and dysesthesias of the hands, feet, and perioral region; and muscle cramps [127,128]. Numbness and tingling are more prominent than shooting or burning pain [127] Symptoms generally evolve over 24 to 96 hours, and typically abate over the same time frame [127].
In addition to muscle cramps, other motor symptoms that may develop include jaw tightness, voice changes, ptosis, visual field abnormalities, and, rarely, priapism (table 2) [129]. One case report suggests that acute motor symptoms may be particularly responsive to treatment with oral pregabalin (Lyrica) [130].
The range and frequency of oxaliplatin-induced acute neurotoxicity from a series of 170 patients treated with an oxaliplatin-based regimen for metastatic CRC, 146 of whom (86 percent) manifested any degree of acute neuropathy, was as follows [125]:
●Cold-induced perioral paresthesias – 95 percent
●Cold-induced pharyngolaryngeal dysesthesia – 92 percent
●Dyspnea – 40 percent
●Muscle cramps – 34 percent
●Jaw stiffness – 34 percent
●Dysphagia – 30 percent
●Visible fasciculations – 30 percent
●Voice changes – 6 percent
●Ocular changes – 0.7 percent
Acute symptoms are observed more frequently at doses of ≥130 mg/m2 than at ≤85 mg/m2 and are infusion-rate dependent [131]. Increasing the duration of infusion from two to six hours during subsequent treatments has been reported to diminish the incidence, particularly of the pseudolaryngospasm [132]. While it has been classically thought that acute neuropathy completely resolves after a few days, more recent data support the view that it does not completely resolve between oxaliplatin doses, at least with repeat dosing every two weeks [126].
Symptoms tend to recur with subsequent doses. On average, symptoms are twice as severe after the second dose as compared with the first dose, but thereafter, symptom intensity remains similar for all subsequent doses; acute neurotoxicity does not appear to worsen cumulatively over time [126]. Patients with the most severe acute symptoms are at higher risk to develop more severe chronic neuropathy. (See 'Other factors' below.)
Mechanism — Acute neurotoxicity caused by oxaliplatin is thought to result from chelation of calcium by oxalate (a metabolite of oxaliplatin) with transient activation of disinhibited peripheral nerve voltage-gated calcium-dependent sodium channels causing hyperexcitability of peripheral nerves [133,134]. This has been attributed to disruption in cell membrane ion channels [135-140]. Acute changes in axonal excitability seem to become less pronounced in later treatment cycles, possibly because chronic nerve dysfunction and sensory loss mask the acute effects at higher cumulative doses [138].
Prevention — Supplemental calcium and magnesium infusions are of no benefit and should not be offered to patients receiving oxaliplatin therapy. This subject is addressed elsewhere. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Vitamins, minerals, and dietary supplements'.)
Cumulative sensory neuropathy — The dose-limiting, late-onset neuropathy seen with oxaliplatin is comparable to that observed with cisplatin. Characteristically, this is a cumulative, dose-dependent, sensory, symmetric distal axonal neuropathy without motor involvement, and with rare autonomic [141] involvement (table 2). In an analysis of 346 patients treated with oxaliplatin in the phase III Alliance trial N08CB, tingling was the most severe symptom, followed by numbness, and then pain [126].
Oxaliplatin-related neuropathy can have a profound impact on quality of life, particularly that of cancer survivors. It may also adversely affect oncologic outcomes by forcing dose modifications and/or premature treatment discontinuation.
The mechanism of neuropathy appears similar to that discussed for cisplatin, although oxaliplatin forms fewer platinum-DNA adducts then does cisplatin, and thus is a slightly less neurotoxic agent [22]. (See 'Mechanism' above.)
Incidence, severity, risk factors, and natural history — The incidence and severity are predominantly related to cumulative dose, although other factors (eg, diabetes, severity of acute neuropathy) may contribute [15]. Patients with more severe acute neurotoxicity during the first cycle of therapy may experience more chronic sensory toxicity [126].
In general, oxaliplatin neurotoxicity improves after discontinuation of therapy. However, it may continue to worsen for a few months after treatment is discontinued (a phenomenon referred to as "coasting"). Neuropathy is at least partially reversible in approximately 80 percent of patients; one-half of these patients report complete resolution within eight months after treatment discontinuation [142]. However, higher rates of persisting neuropathy are reported by others, particularly in studies utilizing patient-reported outcome measures. In general, hand symptoms are more severe during therapy while feet symptoms become more prominent during follow-up [126].
Impact of dose intensity and length of treatment — In the adjuvant setting, higher dose intensity therapy (ie, doses above 85 mg/m2 every two weeks) has not been associated with a greater incidence or severity of neurotoxicity [143].
In the setting of metastatic disease, patients are often treated for longer than six months, and neuropathy increases with a longer planned treatment duration [144-146]. As an example:
●In a prospective trial in which patients received oxaliplatin 85 mg/m2 per cycle in conjunction with short-term infusional fluorouracil and leucovorin, severe (grade 2 or 3) neuropathy occurred in 10 percent of patients after nine, in 25 percent after 12, and in 50 percent after 14 treatment cycles [145].
These findings have important implications for clinical care. Clinicians should be particularly vigilant about routinely assessing sensory neuropathy after approximately four months of therapy with an oxaliplatin-based regimen containing 85 mg/m2 oxaliplatin every two weeks. The use of oxaliplatin-free intervals in patients treated for metastatic CRC as a means of delaying or preventing neuropathy is discussed elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Patients receiving oxaliplatin'.)
Other factors — Whether other clinical factors are useful in predicting higher rates or greater severity of oxaliplatin-related peripheral neuropathy is unclear [147]:
●Patients who have a more severe or more complex combination of acute neuropathy phenomenon are at higher risk for more severe chronic cumulative neuropathy [125,127,146]. In a prospective study of 200 patients with metastatic CRC receiving 24 weeks of an oxaliplatin-based regimen who underwent electrophysiologic testing at baseline, mid-treatment, and at the end of treatment, multivariate analysis disclosed three factors that were independently associated with the risk of developing severe (grade 3 or worse) oxaliplatin sensory neuropathy: the number of acute neurotoxicity symptoms and a >30 percent decrease (from the baseline value) in sensory nerve action potentials in radial and dorsal sural nerves at midcycle [146]. Although this study suggests potential for benefit, the value of serial nerve conduction studies in patients receiving oxaliplatin is not established, and we generally don't use them. (See 'Acute neurotoxicity' above.)
●Diabetes increases the risk for neuropathy, but there is disagreement as to whether such patients have more severe neuropathy, or develop it at a lower cumulative oxaliplatin dose [148,149].
●At least some data suggest that the specific fluoropyrimidine paired with oxaliplatin may influence the risk of neurotoxicity:
•In a report of the ACHIEVE trial, which compared three versus six months of adjuvant oxaliplatin-based chemotherapy, those patients treated with oxaliplatin plus the oral drug capecitabine (CAPOX) had a lower incidence of persisting peripheral sensory neuropathy at three years than did those receiving oxaliplatin in conjunction with leucovorin and short-term infusional fluorouracil (the FOLFOX regimen), regardless of whether they received six months of treatment (21 versus 34 percent) or three months of treatment (7.9 versus 15.7 percent) [150]. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Oxaliplatin-based therapy'.)
•A similar finding was noted in an earlier analysis of 150 patients receiving either FOLFOX or CAPOX in either the adjuvant or metastatic disease setting [151]. FOLFOX was associated with a higher incidence of chronic neurotoxicity (83 versus 60 percent), despite a very similar median cumulative dose of oxaliplatin during both regimens.
●Other factors, including body mass index and lower level of physical activity may also contribute [149].
Molecular predictors — Inheritance of certain polymorphisms may influence the risk of oxaliplatin neurotoxicity [152-157], although the data are conflicting [158]. Whether pharmacogenetic profiling may hold some promise for identifying patients at a greater risk for severe neurotoxicity is unclear, and the data are insufficient to justify routine testing for any specific genotype prior to initiating oxaliplatin.
Natural history — Data on natural history are available from several sources:
●NSABP C-07 – The phase III The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial randomly assigned 2492 patients to six months of adjuvant fluorouracil plus leucovorin with or without oxaliplatin (85 mg/m2 on weeks 1, 3, and 5 of each of three eight-week cycles) after surgery for colon cancer, including 400 who participated in a patient-reported substudy [159]. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'FLOX and NSABP C-07'.)
The following findings were noted with respect to neurotoxicity:
•Patient-reported neurotoxicity was significantly more common in patients receiving oxaliplatin, including sensory symptoms (hand-foot pain, 26 versus 3 percent without oxaliplatin) and moderate motor weakness (27 versus 16 percent). Although hand symptoms generally resolved by 18 months, foot numbness and tingling persisted in many (prevalence 22 versus 5 percent in those not receiving oxaliplatin).
•In a later analysis of 353 of these patients who had longitudinal data on neurotoxicity and were reassessed at a median of six years after random assessment, the group receiving oxaliplatin had statistically significantly higher total neurotoxicity scores compared with those not receiving oxaliplatin (a difference of 1.8 points on a point scale ranging from 0 to 48) [160]. However, this difference was not clinically meaningful. These authors had previously proposed that a difference of four on this patient-reported scale should be considered a minimal clinically significant difference [159], although this has not been validated by others. When separate categories of neurotoxicity were assessed, the odds of persistent numbness and tingling in the hands or feet was 2 to 2.78-fold higher in those who received oxaliplatin versus those who did not receive oxaliplatin.
●MOSAIC trial – Information on the reversibility of neurotoxicity is also available from the MOSAIC trial, a randomized comparison of short-term infusional leucovorin-modulated fluorouracil with and without oxaliplatin (85 mg/m2 every other week for 24 weeks) as adjuvant chemotherapy after colon cancer resection [161]. Although some form of peripheral neuropathy developed in 92 percent of patients receiving oxaliplatin, it was severe (grade 3, as graded by clinician assessment) in only 13 percent and generally reversible. By 48 months, grade 1, 2, or 3 neuropathy was observed in only 12, 3, and 0.7 percent of patients, respectively. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'FOLFOX and the MOSAIC trial'.)
●Other studies – Other studies utilizing patient-reported outcome measures have suggested that the prevalence of persisting neuropathy is higher in long-term survivors [142,160,162-164]. As an example, in one systematic review of 27 studies, the pooled prevalence of persistent CIPN of any grade at 6, 12, 24, and 36 months after oxaliplatin-containing chemotherapy was 58, 45, 32, and 24 percent, respectively [164]. (See "Approach to the long-term survivor of colorectal cancer", section on 'Oxaliplatin-induced peripheral neuropathy'.)
Prevention and treatment — Multiple approaches have been used to prevent or minimize the cumulative neurotoxicity associated with oxaliplatin therapy. These include dose reduction, interrupting and reintroducing oxaliplatin therapy, lengthening the duration of infusion, supplemental intravenous calcium and magnesium infusions, and various pharmacologic agents.
●Prevention
•When appropriate in the clinical setting, interspersing a non-oxaliplatin-containing "maintenance" chemotherapy regimen with the oxaliplatin regimen in patients undergoing palliative chemotherapy for metastatic CRC can forestall the development of neuropathy and is reasonable. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Stopping and reintroducing oxaliplatin'.)
•There are insufficient data to support a neuroprotective benefit from lengthening the duration of oxaliplatin infusion, and it cannot be recommended. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Lengthened infusion duration'.)
•There are no established pharmacologic agents that can be recommended for the prevention of oxaliplatin-induced peripheral neuropathy. Guidelines for prevention and management of chemotherapy-induced peripheral neuropathy from the American Society of Clinical Oncology (ASCO) [165] recommend against the use of IV calcium/magnesium supplementation or any other neuroprotective agent for patients receiving oxaliplatin-based therapy.
These issues are all addressed separately. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Oxaliplatin' and "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Vitamins, minerals, and dietary supplements'.)
●Treatment – In general:
•Dose reduction guidelines for patients who develop ≥grade 2 (table 6) neuropathy during treatment are provided in the US Food and Drug Association (FDA)-approved manufacturer's labeling information. If symptoms increase in severity or the neuropathy interferes with function, the risk of potentially disabling neurotoxicity must be weighed against the benefit of continued treatment.
•Amelioration of symptoms from the chronic neuropathy, including pain, may be achieved through use of antidepressants such as duloxetine. For symptomatic patients who fail to respond to duloxetine, other adjuvant analgesics (eg, tricyclic antidepressants, anticonvulsants such as gabapentin), opioids, physical modalities such as cutaneous electrical stimulation, and/or interventional procedures may be indicated.
Symptomatic treatment for chemotherapy-induced peripheral neuropathy is discussed in detail separately. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Symptomatic treatment' and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain' and "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Other modalities' and "Cancer pain management: Interventional therapies".)
Reversible posterior leukoencephalopathy syndrome — Reversible posterior leukoencephalopathy syndrome (RPLS) has been observed rarely in clinical trials (<0.1 percent) and in postmarketing experience. Signs and symptoms include headache, altered mental function, seizures, and visual changes, with or without hypertension. The diagnosis is confirmed by brain imaging.
Other complications — Guillain-Barré syndrome has been rarely reported [103]. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathic pain" and "Society guideline links: Cancer pain" and "Society guideline links: Hearing loss and hearing disorders in adults".)
SUMMARY AND RECOMMENDATIONS — Among the widely used anticancer drugs, the platinum compounds cisplatin and oxaliplatin are most commonly associated with neurotoxicity. (See 'Cisplatin' above and 'Oxaliplatin' above.)
●Cisplatin – The range of cisplatin-induced neurotoxicity includes peripheral neuropathy, ototoxicity (hearing impairment and tinnitus), the Raynaud phenomenon, myelotoxicity, and encephalopathy; the most common are peripheral neuropathy and ototoxicity. (See 'Cisplatin' above.)
•The peripheral neuropathy is typically symmetrical, predominantly sensory and usually begins in the toes and fingers, spreading proximally to affect the legs and arms. It is cumulative and typically develops only after a cumulative dose of 300 mg/m2 is reached. (See 'Clinical and electrophysiologic manifestations' above and 'Incidence and risk factors' above.)
-The differential diagnosis includes paraneoplastic neuropathies and those associated with autoimmune disorders, hand-foot syndrome, and symptomatic electrolyte disorders caused by cisplatin. (See 'Differential diagnosis' above.)
-There is no effective preventive strategy. If neuropathy interferes with function, the risk of potentially disabling neurotoxicity must be weighed against the benefit of continued treatment. Some patients may benefit from a switch to carboplatin. Most patients improve over time, although recovery is often incomplete. Symptoms associated with chronic neuropathy, including pain, may respond to antidepressants such as duloxetine. (See 'Natural history, prevention, and treatment' above.)
•Ototoxicity is the second most common cisplatin-related neurotoxic effect; it is characterized by a dose-dependent, typically bilateral, irreversible, high-frequency sensorineural hearing loss, often accompanied by tinnitus. Ototoxicity can be particularly severe in children. (See 'Ototoxicity' above.)
-Particularly in children receiving platinum agents, monitoring and early detection of hearing loss with the opportunity for treatment modification may minimize the risk of severe impairment in the frequencies required for speech recognition.
-We suggest the use of sodium thiosulfate (STS) for children receiving cisplatin monotherapy for a variety of non-metastatic malignancies, including standard-risk hepatoblastoma (cumulative dose 480 mg/m2) (Grade 2C). However, the safety and efficacy of this approach in patients with non-metastatic hepatoblastoma who receive lower cumulative doses is not established. (See "Overview of hepatoblastoma", section on 'Approaches to minimizing long-term treatment-related toxicity'.)
The available evidence is insufficient to support the routine use of STS in children receiving cisplatin for treatment of a metastatic malignancy or in adults receiving cisplatin, or for any other pharmacologic agent to prevent cisplatin ototoxicity. (See 'Prevention' above.)
•More rarely, cisplatin is associated with a number of other neurologic complications, including arterial thromboembolic events, encephalopathy (rare), vestibulopathy, and hiccups. (See 'Encephalopathy' above.)
●Carboplatin
•Peripheral neuropathy and central nervous system toxicity are uncommon when carboplatin is given at conventional doses (table 2). However, a severe neuropathy can develop after a higher than standard dose of carboplatin, as is used in the setting of high-dose therapy with hematopoietic cell transplantation. (See 'Carboplatin' above.)
•The administration of carboplatin to children treated for retinoblastoma usually does not lead to acute or subacute hearing loss; however, higher rates have been seen in very young patients, particularly when dosing of carboplatin was based upon body surface area rather than body weight alone. (See 'Hearing loss' above.)
●Oxaliplatin – Two distinct neuropathies are reported in patients receiving oxaliplatin (see 'Oxaliplatin' above):
•The majority of treated patients develop an acute neurosensory complex within 24 to 72 hours after each dose consisting of sensitivity to touching cold objects; paresthesias and dysesthesias of the hands, feet, and perioral region; unusual cold-induced pharyngolaryngeal dysesthesias; and muscle cramps. Symptoms generally recur with each dose. (See 'Acute neurotoxicity' above.)
Supplemental calcium and magnesium infusions are of no preventive benefit and should not be offered to patients receiving oxaliplatin therapy. This subject is addressed elsewhere. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Vitamins, minerals, and dietary supplements'.)
•A dose-limiting late-onset neuropathy that is cumulative, dose-dependent, and typically consists of a sensory, symmetric distal axonal neuropathy without motor involvement (table 2). (See 'Cumulative sensory neuropathy' above.)
Both the incidence and severity are predominantly related to cumulative dose, although other factors (eg, diabetes, severity of acute neuropathy) may contribute. (See 'Impact of dose intensity and length of treatment' above and 'Other factors' above.)
Dose reduction guidelines for patients who develop ≥grade 2 (table 6) axonal neuropathy during treatment are provided in the US Food and Drug Association (FDA)-approved manufacturer's labeling information. If symptoms increase in severity or the neuropathy interferes with function, the risk of potentially disabling neurotoxicity must be weighed against the benefit of continued treatment.
In general, oxaliplatin neurotoxicity improves after discontinuation of therapy. However, it may continue to worsen for a few months after treatment is discontinued, and recovery is often incomplete. (See 'Natural history' above.)
There are no pharmacologic agents that can be recommended to prevent the development of neuropathy. When appropriate in the clinical setting, interspersing a non-oxaliplatin-containing "maintenance" chemotherapy regimen with the oxaliplatin regimen in patients undergoing palliative chemotherapy for metastatic colorectal cancer can forestall the development of neuropathy and is reasonable. (See 'Prevention and treatment' above and "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Stopping and reintroducing oxaliplatin'.)
Symptoms associated with chronic neuropathy, including pain, may respond to antidepressants such as duloxetine.
