Platinum-containing cytostatic drugs

General information

Although the main platinum-containing cytotoxic drugs, cisplatin, carboplatin, and oxaliplatin, share some structural similarities, there are marked differences between them in therapeutic uses, pharmacokinetics, and adverse effects profiles [ ]. Compared with cisplatin, carboplatin has inferior efficacy in germ-cell tumors, head and neck cancers, and bladder and esophageal carcinomas, whereas the two drugs appear to have comparable efficacy in ovarian cancer, extensive small-cell lung cancers, and advanced non-small-cell lung cancers [ ].

Oxaliplatin belongs to the group of diaminocyclohexane (DACH) platinum compounds. It is the first platinum-based drug that has marked efficacy in colorectal cancer when given in combination with 5-fluorouracil and folinic acid [ , ].

Nedaplatin has been registered in Japan, whereas other derivatives, like satraplatin (JM216, which is the only orally available platinum derivative), ZD0473, BBR3464, and SPI-77 (a liposomal formulation of cisplatin), are still under investigation [ ].

Other platinum-containing compounds under investigation include dexormaplatin, enloplatin, eptaplatin, iproplatin, lobaplatin, miboplatin, miriplatin, ormaplatin, picoplatin, sebriplatin, spiroplatin, and zeniplatin.

Adverse reactions to platinum compounds have been reviewed [ ].

Mechanism of action

Although the precise mechanism of the cytotoxic action of the platinum-containing compounds has not been fully elucidated, they are thought to act by causing interstrand and intrastrand cross-links in DNA, particularly including two adjacent guanine or two adjacent guanine adenine bases [ ]. In comparison with cisplatin-induced or carboplatin-induced DNA lesions, diaminocyclohexane (DACH) platinum DNA adduct formation has been associated with greater cytotoxicity and inhibition of DNA synthesis. In addition, there appears to be a complete lack of cross-resistance between oxaliplatin and cisplatin, which may be related to the bulky DACH carrier ligand of oxaliplatin, hindering DNA repair mechanisms within tumor cells [ , ].

Pharmacokinetics

There are significant pharmacokinetic differences among cisplatin, carboplatin, and oxaliplatin. Cisplatin is the most highly protein-bound (> 90%), followed by oxaliplatin (85%) and carboplatin (24–50%).

The negligible nephrotoxicity of oxaliplatin and carboplatin compared with cisplatin may be related to their slower rates of conversion to reactive species. As a result, intensive hydration is not warranted during carboplatin or oxaliplatin infusion, in contrast to cisplatin [ , ]. In the case of macromolecular platinum–protein complex formation, decomposition proceeds rather slowly, which may explain why the urinary excretion of total platinum is increased for a long time after treatment, particularly in patients who have been given cisplatin [ , ].

In contrast to cisplatin, carboplatin is primarily eliminated (about 75%) by glomerular filtration, whereas tubular secretion appears to be of minor importance [ ]. It has therefore been recommended that the dose of carboplatin be adjusted according to the individual glomerular filtration rate, in order to avoid high plasma drug concentrations when the dose is calculated according to body surface area [ ]. Individualized carboplatin therapy helps to avoid abnormally high drug concentrations in patients with renal dysfunction and subtherapeutic concentrations in patients with an unexpectedly high glomerular filtration rate [ , ].

Pharmacokinetic–pharmacodynamic correlations between AUC, response rates, and the extent of myelosuppression have been examined retrospectively in patients with advanced ovarian carcinoma [ , ]. AUC values below 4 minutes/mg/ml and exceeding 7 minutes/mg/ml cannot be recommended; the former is associated with low response rates and the latter is associated with more pronounced neutropenia and thrombocytopenia without higher response rates. Doses of carboplatin are generally calculated by the Calvert formula [ ].

Carboplatin dose = AUC (minutes. mg / ml) \times (GFR + 25)

$Carboplatin dose = AUC (minutes. mg / ml) \times (GFR + 25)$

However, it is still debatable which method most accurately predicts individual values of glomerular filtration rate or creatinine clearance. Whereas the Cr-EDTA method is the most accurate method of estimating glomerular filtration rate, most clinicians do not use it routinely, and prefer to collect urine for estimation of creatinine clearance. Alternatively, the use of special formulae has been proposed, for example Wright’s formula and the formulae of Cockcroft & Gault or Jelliffe [ ]. However, calculation of the glomerular filtration rate or creatinine clearance using such formulae has been associated with some bias in different ranges, regardless of which formula has been used.

After intravenous administration of oxaliplatin, about 33% and 40% of the dose is bound to erythrocytes and plasma proteins. The half-life averages 26 days, which is in accordance with the normal life expectancy of erythrocytes (12–50 days). Oxaliplatin undergoes rapid non-enzymatic biotransformation to form a variety of reactive platinum intermediates, which bind rapidly and extensively to plasma proteins and erythrocytes. The antineoplastic and toxic properties appear to reside in the non-protein bound fraction, whereas platinum bound to plasma proteins or erythrocytes is considered to be pharmacologically inactive. Biotransformation produces DACH-platinum dichloride, 1,2-DACH-platinum dicysteinate, 1,2-DACH-platinum diglutathionate, 1,2-DACH-platinum monoglutathionate, and 1,2-DACH-platinum methionine. The erythrocyte contains only thiol derivatives, whereas all derivatives can be recovered from the plasma.

The platinum-containing metabolites of oxaliplatin are predominantly excreted in the urine (about 50% of the dose within 3 days), whereas drug excretion via the feces is of minor importance (about 5% of the dose after 11 days). The mean total platinum half-life averages 9 days after oxaliplatin administration (130 mg/m ² intravenously) [ , ]. There is a strong negative correlation between the mean plasma concentration of unbound oxaliplatin and renal function; however, moderate renal impairment does not increase the risk of acute toxicity associated with oxaliplatin [ ].

General adverse effects and adverse reactions

The comparative toxicity and mutagenic effects of platinum anticancer drugs have been reviewed [ ].

Of the clinically established platinum compounds, cisplatin has the most toxic effects on organs like the nervous system, the organ of Corti, and the kidneys. The dose per cycle has therefore usually been limited to 100–120 mg/m ² intravenously, in order to avoid drug-induced irreversible organ dysfunction [ , ]. The complete spectrum of late or long-term adverse reactions to cisplatin in survivors of testicular cancer has been reviewed [ ].

In contrast to cisplatin, myelotoxicity represents the most prominent adverse reaction to carboplatin. Based on its lower organ toxicity and its better predictable pharmacokinetic behavior, carboplatin has extensively replaced cisplatin in combination chemotherapy for the treatment of ovarian cancer and extensive small cell and non-small cell lung cancer. For other indications, one has to weigh the possibly inferior efficacy of carboplatin against the more pronounced undesirable adverse effects of cisplatin, which may limit its long-term use. Based on its marked organ toxicity, high-dose cisplatin-containing regimens are not feasible, in contrast to carboplatin, which is part of several dose-intensified combination chemotherapy regimens [ , ].

Like carboplatin, oxaliplatin does not usually cause nephrotoxicity. In addition, both drugs are only moderately emetogenic, in contrast to cisplatin. The most important dose-limiting adverse effect of oxaliplatin is a sensory peripheral neuropathy, which has two different forms:

1.
a unique acute peripheral sensory (and motor) toxicity that often occurs during or within hours after drug infusion and which is rapidly reversible and aggravated by cold;
2.
a peripheral sensory neuropathy related to the cumulative dose, which is generally moderate and slowly reversible, in contrast to the forms that have been described after cisplatin administration.

Triplatin tetranitrate (BBR3464)

Triplatin tetranitrate was the first congener of a novel group of platinum compounds, the so-called cationic trinuclear platins. It binds to DNA more rapidly than cisplatin, which results in long-range interstrand and intrastrand cross-links. It is more potent than cisplatin, and very low dosages were effective in phase I trials. With a 1-hour intravenous infusion of 1.1 mg/m ² every 28 days, diarrhea (preceded by abdominal cramps), nausea/vomiting, and neutropenia were the most prominent drug-related adverse effects. There were no signs of drug-related nephrotoxicity, neurotoxicity, or lung dysfunction [ , , ].

Heptaplatin

Heptaplatin (cis-malonate[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II), SKI-2053R, Sunpla) has high antitumor activity against various cancer cell lines, including cisplatin-resistant tumor cells. Preliminary results suggested that it is less nephrotoxic than cisplatin. However, a comparative trial showed that intravenous heptaplatin 400 mg/m ² was more nephrotoxic than intravenous cisplatin 60 mg/m ² in terms of uremia and proteinuria, which occurred despite the use of hyperosmolar mannitol and appropriate concomitant hydration (fluid intake at least 3500 ml/day) [ , ].

Nedaplatin

Nedaplatin (cis-diammineglycolatoplatinum, CDGP, 254-S) has some structural similarities to cisplatin and carboplatin. Since 1995 it has been available for therapeutic use in Japan. In phase II trials, it had promising antineoplastic activity in patients with head and neck cancers, non-small cell lung cancers, esophageal cancer, testicular tumors, and cervical cancer. A distinct number of patients with ovarian cancer have responded to nedaplatin (for example 100 mg/m ² intravenously) even after relapsing following treatment with cisplatin/carboplatin and cyclophosphamide. Its pharmacokinetic behavior is similar to that of carboplatin. It causes less nephrotoxicity than cisplatin, but hematological toxicity is dose-limiting. Other adverse effects include nausea/vomiting and mild peripheral neuropathy [ , , ]. Although nedaplatin is less nephrotoxic than cisplatin, incidental cases of severe nephrotoxicity have occurred. In addition, ototoxicity, similar to that observed after cisplatin, has been documented. Nedaplatin is excreted primarily unchanged by glomerular filtration, and there is a formula for predicting the clearance of unbound platinum after its administration [ ].

Satraplatin

Satraplatin (bis-acetato-ammine-dichloro-cyclohexylamine-platinum, JM 216, BMS-182751) is the first oral platinum compound among the third-generation platinum complexes with activity in platinum-sensitive and some platinum-resistant preclinical models. Adverse effects were generally modest (grades I and II), including nausea, fatigue, anorexia, diarrhea, and altered taste. In addition, myelosuppression and rare cases of grades II and III increases in serum creatinine were reported. During phase II trials satraplatin was given in a dose of 120 mg/m ² /day for 5 consecutive days every 3 weeks in untreated patients with lung cancer or 30 mg/m ² /day for 14 consecutive days every 5 weeks in patients with metastatic squamous cell carcinoma. There was no nephrotoxicity or neurotoxicity [ ]. Pharmacokinetic studies showed that very little intact parent compound reached the systemic circulation after oral administration, perhaps because of extensive metabolic biotransformation or rapid reaction of platinum(II) species with DNA or other compounds. One of the intermediate compounds released during biotransformation is JM118, which has a longer half-life than the parent compound. Its particular role in the overall activity of satraplatin is still being investigated [ ].

SPI-77

SPI-77 is a stealth liposomal dosage form of cisplatin. One of the main features of stealth liposomes is that they are pegylated on the liposomal surface. Compared with conventional liposomes (for example DaunoXome or Myocet) the half-life of the liposome and its embedded drug in plasma is significantly increased by this modification, because degradation by cells of the mononuclear phagocytic system is impaired; the cells are thereby, as it were, tricked. Liposomal encapsulation of cisplatin has been suggested to reduce systemic drug exposure and may help to increase drug delivery into tumor tissue. Pharmacokinetic studies have shown a slow rate of release of cisplatin from the liposomes, resulting in low systemic exposure to unbound drug. In contrast to conventional cisplatin, the incidence of gastrointestinal toxicity after SPI-77 was low, and so prophylactic antiemetics could be avoided. In addition, renal toxicity has not been observed, which also makes hydration before or after chemotherapy unnecessary. Extensive neurological measurements did not show any adverse effects. In conclusion, the toxicity profile of SPI-77 is encouraging compared with conventional cisplatin. However, despite its favorable pharmacokinetic behavior, enhanced platinum accumulation in tumor tissue has not yet been detected [ ].

Tetraplatin

The development of the third-generation platinum derivative tetraplatin (ormaplatin, trans- d , l -1,2-diaminocyclohexane tetrachloroplatinum) was abandoned, because drug-induced severe motor and sensory peripheral neuropathy occurred even at low cumulative doses. The high neurotoxic potential of tetraplatin may be associated with its pharmacokinetics: it is rapidly metabolized to 1,2-DACH-platinum dichloride, which was 3.8 times more neurotoxic than oxaliplatin in a neurite outgrowth assay [ ].

ZD0473

ZD0473 (formerly AMD473, JM473) was developed in order to overcome acquired or intrinsic (de novo) resistance to cisplatin. Based on the steric bulk of its methyl-substituted pyridine moiety, thiol substitution and drug inactivation is hindered compared with cisplatin. In several in vitro studies, ZD0473 was active even in cisplatin-refractory tumor cells, whose key mechanism of resistance was based on thiol substitution. In addition, ZD0473 is also active in cisplatin-resistant tumor cells, in which resistance is based on altered drug transport mechanisms or enhanced DNA repair.

Based on encouraging preclinical results, ZD0473 entered clinical phase I/II trials in several solid tumors, including non-small cell lung cancers, mesothelioma, head and neck cancers, and ovarian carcinoma. Its most prominent adverse effects included myelosuppression and nausea/vomiting. Thrombocytopenia and neutropenia were the dose-limiting adverse effects at intravenous doses of 130–150 mg/m ² . In contrast to cisplatin, neurotoxicity, ototoxicity, and renal toxicity have not yet been reported during or after treatment with ZD0473 [ , , , ].

Organs and systems

Cardiovascular

Asymptomatic sinus bradycardia (for example 30–40/minute) is observed within 30 minutes to 2 hours after the start of cisplatin infusion. When cisplatin is withdrawn normal rhythm is restored. Because patients who receive platins are not routinely monitored, drug-induced sinus bradycardia may not be detected in practice. However, several case reports have included heavily pretreated patients, making it much more difficult to assess a direct relation between cisplatin administration and the onset of cardiotoxic symptoms. In conclusion, no dosage adjustment appears to be warranted in patients with cisplatin-induced sinus bradycardia; however, attention should be paid to patients with resting bradycardia or those using medications known to slow the heart rate [ , ].

A 60-year-old woman with a squamous cell lung carcinoma developed a paroxysmal supraventricular tachycardia during administration of cisplatin 20 mg/m ² and etoposide 75 mg/m ² . The dysrhythmia appeared to be related to cisplatin since normal rhythm was restored after cisplatin was withdrawn [ ].

Orthostatic hypotension was reported in “several” of 126 patients given cisplatin 50 mg/m ² on days 1, 8, 29, and 36 as part of treatment for lung cancer in combination with etoposide and chest radiotherapy [ ].

There have been 21 reports of life-threatening disease affecting large arteries in patients treated with cisplatin, bleomycin, and vinblastine in combination for germ cell tumors [ , ]. Five patients died during or after therapy, three from acute myocardial infarction, one from rectal infarction, and one from cerebral infarction. Other patients who developed major vascular disease, including coronary artery and cerebrovascular disease, have been reported. Symptoms occurred acutely in some (within 48 hours of starting therapy), and after months or years had relapsed in others.

Reduced peripheral circulation, Raynaud’s phenomenon, and polyneuropathy have been described after the combined use of cisplatin, bleomycin, and vinblastine for testicular tumors. Of eight cases with polyneuropathy that were investigated, it was not possible to confirm a causative association between Raynaud’s phenomenon and the chemotherapy [ ].

Platinum compounds have rarely been described to cause phlebitis after intravenous administration [ ].

Respiratory

Seven patients died from irreversible respiratory failure after receiving combined cisplatin plus bleomycin chemotherapy; five had raised serum creatinine and all received cisplatin before the bleomycin [ ]. The authors recommended extreme caution with this combination, and suggested that bleomycin should precede the cisplatin infusion.

Ear, nose, throat

A 67-year-old white woman with a small cell lung cancer was given six courses of cisplatin and etoposide once every 4 weeks and after the last course developed acute shortness of breath, hoarseness, and stridor, due to bilateral vocal cord paralysis [ ].

Nervous system

The neurotoxicity of platinum-containing compounds has been reviewed [ , ], as has the prevention of cisplatin-associated neurotoxicity [ ]. In experimental measurements of sensory nerve conduction velocity: oxaliplatin caused the most impairment, followed by cisplatin, carboplatin, and satraplatin [ ]. The cumulative incidence of grade 2 peripheral sensory neuropathy with oxaliplatin was 19% [ ].

Conventional dosages of carboplatin have been associated with the lowest risk of peripheral neuropathy (for example mild paresthesia) among the approved platinum compounds. It has been estimated that about 4–6% of patients who receive carboplatin develop a peripheral neuropathy. Patients over 65 years of age or patients pretreated with other neurotoxic agents may be at a slightly higher risk [ ].

A 47% incidence of peripheral neuropathy of all grades has been reported with cisplatin [ ], and a 31% off-therapy deterioration of peripheral neuropathy presenting as muscle cramps and demyelination syndromes has been described [ ]. Cisplatin causes a well-recognized reversible sensory peripheral neuropathy, starting with depressed deep tendon reflexes and loss of vibration sense, progressing to a sensory ataxia [ ]. This may be age-related, as the use of high-dose cisplatin in children with neuroblastoma has not been associated with peripheral neuropathy [ ]. Motor nerves are spared [ ]. There have also been case reports of cerebral herniation and coma, severe encephalopathy, tonic-clonic seizures with concomitant visual disturbances and changed mental state, insomnia, anxiety, and parkinsonian symptoms. The symptoms generally resolved within several weeks [ ]. In some studies, the nervous system effects were the consequence of cisplatin-induced electrolyte disturbances (for example hyponatremia, hypocalcemia, or hypomagnesemia), rather than a direct action of the platinum derivative in the nervous system [ ]. For example, mental status improved in one patient who was given 3% sodium chloride in order to increase the serum sodium from 118 to 128 mmol/l, whereas diazepam, phenytoin, phenobarbital, and dexamethasone were ineffective [ ].

Presentation

In about 90% of patients, oxaliplatin is associated with acute neurosensory toxicity, including dysesthesia and paresthesia. Neurosensory toxicity affects the fingers, toes, perioral and oral regions, and the pharyngolaryngeal tract (in about 1–2% of cases), which is generally induced or aggravated by coldness. As a result, patients should be instructed to avoid exposure to cold. Such symptoms can occur during or shortly after the first course of oxaliplatin. The symptoms are commonly mild and disappear within a few hours or days. Some patients also develop muscle cramps or spasms. The risk of acute neuropathy appears to be lower if oxaliplatin is given in a dosage of 85 mg/m ² every 2 weeks rather than 130 mg/m ² every 3 weeks. A further strategy to reduce the risk of acute recurrent pseudolaryngospasm is to increase the infusion duration from 2 to 6 hours during subsequent cycles [ , ]. The prophylactic use of infusions containing calcium and magnesium sulfate before and after oxaliplatin can prevent acute neurotoxic symptoms [ ].

A woman developed bilateral blindness and lumbosacral myelopathy within 1 month of having received an autologous bone marrow transplant, cisplatin 55 mg/m ² , carmustine 600 mg/m ² , and cyclophosphamide 1875 mg/m ² [ ].

In addition to the acute neurotoxic symptoms caused by oxaliplatin, about 10–15% of patients develop a moderate neuropathy, particularly after cumulative intravenous doses of 700–800 mg/m ² . The symptoms of cumulative neuropathy include non-cold-related dysesthesia, paresthesia, superficial and deep sensory loss, and eventually sensory ataxia and functional impairment, which persists between treatment cycles. Most of these symptoms usually resolve a few weeks or months after oxaliplatin withdrawal. Lower cumulative doses (for example 510–765 mg/m ² ) and higher cumulative doses exceeding 1020 mg/m ² have been associated with incidences of cumulative grade 3 neurotoxicity of 3.2% and 50% respectively [ , , , ]. In addition, higher cumulative doses, exceeding 1000 mg/m ² , have been associated with severe, atypical neurotoxic symptoms, such as micturition disturbances and Lhermitte’s sign, mimicking cord disease. However, these signs have been observed in only a few patients so far (3.3% in phase 3 trials). Both symptoms appear to be reversible after oxaliplatin withdrawal [ ]. In some patients oxaliplatin treatment is feasible for as long as 18 months (for example cumulative oxaliplatin dose over 3000 mg/m ² ) with no signs of dysesthesia or paresthesia causing functional impairment, indicating high interindividual variability with respect to sensitivity to oxaliplatin-induced cumulative neuropathy [ , ]. Whether cumulative sensory neuropathy can occur as a result of accumulation of dichloro-DACH-platinum, a biotransformation product of DACH-platinum, in the axonal and dorsal root ganglia neurons, needs further investigation [ ].

Persistent Lhermitte’s sign (an electric-like sensation induced by flexion of the neck) suggestive of irreversible spinal cord toxicity has been reported in a patient taking cisplatin and etoposide [ ]. Of four patients with oxaliplatin neurotoxicity, two presented with Lhermitte’s sign, one had urinary retention, and one had both [ ]. All had received cumulative doses of 1248–2040 mg/m ² , which is more than the generally accepted neurotoxic threshold for oxaliplatin (1000 mg/m ² ).

Peripheral paresthesia has been reported 5 years after adjuvant cisplatin-based treatment for stages I and II testicular cancer [ ].

Four of eight children developed acute neurological toxicity. Three had seizures and one had transient blindness after high-dose cisplatin (200 mg/m ² ) given by continuous infusion over 5 days, followed 10 days later by a further 2 days with 40 mg/m ² /day. These children had the greatest deterioration in renal function, and they may have had impaired clearance of and increased exposure to cisplatin [ ].

Peripheral neuropathy with clinical signs and/or symptoms was found in 80% of patients who had received a cumulative dose of 576 mg/m ² of cisplatin. There was a dose-related reduction in sensory action potential amplitudes [ ]. The clinical and neurophysiological time progression of the severity of cisplatin polyneuropathy during and after treatment with cisplatin up to a cumulative dose of 600 mg/m ² has been described [ ].

The paraneoplastic neuropathy experienced by women with epithelial ovarian cancer receiving cisplatin has been attributed in certain cases to the drug [ ].

A woman with cancer of the ovary and a man with oat cell carcinoma both developed paresthesia of all four limbs, reduced control of fine movements, and unstable gait after receiving a cumulative dose of 500 mg/m ² of cisplatin [ ]. There was distal hypesthesia, with conservation of temperature and pain sensation, areflexia, and sensory ataxia. The woman also had continuous pseudoathetosis. Neurophysiological studies showed absence of peripheral and central sensory potentials and of H-reflexes, normal electromyography, normal motor conduction, and normal mixed silent period.

The target organ in cisplatin neurotoxicity is the dorsal root ganglion. This patient had a syndrome that clinically and neurophysiologically suggested diffuse neuropathic involvement of the dorsal ganglion, in which absence of sensory and H-reflex potentials showed that the small myelinic cells were not altered, consistent with the preservation of pain and temperature sensation.

A woman developed bilateral blindness and lumbosacral myelopathy within 1 month of having received an autologous bone marrow transplant, cisplatin 55 mg/m ² ,carmustine 600 mg/m ² , and cyclophosphamide1875 mg/m ² [ ].

Encephalopathy has also been reported.

A 50-year-old woman with carcinoma of the cervix was treated with radiotherapy and six courses of cisplatin (75 mg/m ² every 3 weeks; total dose 810 mg) [ ]. The therapy was completed with no obvious acute complications, but 12 weeks after the last course, she developed sudden blindness associated with occipital headache. She had mild global cognitive deficits and intermittent myoclonic jerking of both arms. Her visual acuity was limited to light perception in both eyes; her pupils were symmetrical with no afferent pupillary deficit. Anterior segment examination and dilated fundoscopy were normal; no ocular movements were elicited when a large plain mirror was held in front of her. The rest of the neurological examination was normal. Serum magnesium was reduced to 0.1 mmol/l (reference range 0.7–1.2 mmol/l). Electroencephalography showed diffuse slowing confirming an encephalopathy.
An 84-year-old woman with adenocarcinoma of the ovary had two fully reversible episodes of non-convulsive encephalopathy, each following a course of cisplatin-based chemotherapy, confirming a causal relation [ ]. She developed acute confusion, a partial left homonymous hemianopia and a left extinction hemiparesthesia 7 and 10 days after treatment. Brain MRI showed long-standing cerebral microvascular changes and an electroencephalogram showed right-sided parieto-occipital periodic lateralized epileptiform discharges over a generalized background slowing of activity.

In view of the similarity to posterior leukoencephalopathy, the second case suggests regional endovascular injury rather than direct cerebral toxicity as the initial event in the evolution of encephalopathy.

Strokes have been reported in patients receiving cisplatin.

A 21-year-old woman with a mixed germ cell tumor of the left ovary was given intravenous chemotherapy including etoposide 100 mg/m ² on days 1–5, cisplatin 20 mg/m ² on days 1–5, and bleomycin 30 units on days 2, 8, and 15, all of which she tolerated very well [ ].Three weeks later she received a second cycle, which was complicated by an episode of dizziness on day 8. The following day she had an episode of transient dysphasia for 10 minutes. Her third course was uneventful until day 7, when she collapsed with a severe right-sided hemiparesis and dysphasia. Left-sided total anterior circulation infarction was confirmed on MRI scan.
A 31-year-old man with a seminoma had an orchidectomy, followed by chemotherapy with cisplatin, etoposide, and bleomycin [ ]. A day after the end of the second course of chemotherapy he became comatose with a heart rate of 150/minute and a systolic blood pressure of 80 mmHg. Cranial angiography showed a thrombosis of the basilar artery and a cranial CT scan showed cerebellar infarction but no brain metastases.

However, the use of other drugs in these patients makes it difficult to assign causality to cisplatin.

Infusions of cisplatin into the axillary artery have led to a bronchial plexopathy rather than the more commonly described lumbosacral nerve plexus lesion [ ].

In five patients cerebral herniation followed cisplatin therapy [ ]. However, all had evidence of an intra-cerebral tumor with mass effect and the herniation of the brain was thought to be multifactorial rather than directly attributable to cisplatin.

Auditory brainstem responses have been used to detect ototoxicity from cisplatin and carboplatin when used in combination therapy [ ].

Mechanism and susceptibility factors

The mechanism of cisplatin-induced neurotoxicity has not been fully explained. Cisplatin appears to affect neurons in the dorsal root ganglia. It has also been suggested that it can act as a calcium channel blocker, altering intra-cellular calcium homeostasis and leading to apoptosis of exposed neurons, such as those of the dorsal root ganglia. Cisplatin-induced sensory neuropathy is predominantly characterized by symptoms such as numbness and tingling, paresthesia of the upper and lower extremities, reduced deep-tendon reflexes, and leg weakness with gait disturbance. The first symptoms are often observed after a cumulative dose of 300–600 mg/m ² . Risk factors include diabetes mellitus, alcohol consumption, or inherited neuropathies. Advanced age has not been identified as an independent susceptibility factor when there is no co-morbidity [ ].

The acute neurotoxic effects of oxaliplatin may result from drug-related inhibition of voltage-gated sodium currents [ ]. It has been suggested that oxalate ions, which are released during oxaliplatin metabolism, might be responsible for the inhibitory effects on the voltage-gated sodium channels, because of their calcium-chelating activity. Whether there are calcium-sensitive, voltage-gated sodium channels that can be affected by oxalate-induced calcium depletion or whether an indirect effect through changes in intracellular calcium-dependent regulatory mechanisms contributes to oxaliplatin-induced sensory neuropathy needs further investigation [ ].

The risk of oxaliplatin-induced neurosensory toxicity may be increased after surgery. Of 12 patients with meta-static colorectal cancer, seven reported immediate postoperative aggravation of pre-existing neurotoxicity. Before surgery, they had only acral paresthesia without any functional impairment, whereas after surgery they complained of major worsening of symptoms, including loss of hand grip strength, leading to dependence in dressing, eating, and use of the toilet, or loss of sensitivity, interfering with walking, which could persist for several months [ ]. The authors speculated that perioperative hemolysis had caused an increase in unconjugated bilirubin and the release of ultrafilterable oxaliplatin, which had previously been confined to the intraerythrocytic compartment. In addition, diffusion of ultrafilterable oxaliplatin out of erythrocytes into the plasma during hemodilution can contribute to the undesirable perioperative increase in unbound oxaliplatin in the plasma.

There is a correlation between the total dose of cisplatin and the vibratory perception threshold of the hand [ ].

Dose-relatedness

When three different schedules of cisplatin were evaluated with regard to the drug’s neurotoxicity, using the same dose of 450 mg/m ² for each of the schedules, it was found that cisplatin-induced peripheral neuropathy depended on both total-dose and single-dose intensity [ ].

Neurotoxicity in 22 adolescents was related to the prior cumulative dose of cisplatin that had been received; the relative risk increased 3.2-fold up to a dose of 600 mg/m ² , and 4.1-fold up to a dose of 1340 mg/m ² [ ].

By comparing 50 mg/m ² weekly with 75 mg/m ² three times weekly, using detailed neurological and neurophysiological examination, it has been concluded that cisplatin neuropathy is either of sensory or axonal type, and that both are related to total and single doses [ ]. However, others have suggested that cisplatin-induced peripheral neurotoxicity is related to dose intensity rather than to the total dose received [ ].

A 4-year follow-up of comparison of a combination of cyclophosphamide with cisplatin either 50 or 100 mg/m ² in ovarian cancer has been reported [ ]. Peripheral neuropathy was dose-limiting and persistent. Ten of 31 patients had significant toxicity in the high-dose group compared with one of 24 in the low-dose group.

High-dose cisplatin therapy . The use of aggressive hydration using hypertonic saline and sodium thiosulfate, with dose-scheduling, reduces the risks of dose-limiting nephrotoxicity of cisplatin, and this has made possible the use of high-dose cisplatin (over 200 mg/m ² per course). However, such doses can cause severe chronic peripheral neuropathy, ototoxicity, and myelosuppression, although these effects can be reduced by lengthening the infusion time of cisplatin [ ]. Peripheral neuropathy is the commonest manifestation of cisplatin neurotoxicity; with high-dose administration the incidence and severity increase with the total dose, and it appears to be age-related. It was not seen in 47 children treated with high-dose cisplatin (40 mg/m ² /day for 5 days) for neuroblastoma [ ]. Autonomic neuropathy, motor neuropathy, and denervation changes in muscles occur occasionally.

In a clinical and electrophysiological study of eight patients treated with high-dose cisplatin (800–1400 mg) plus etoposide and bleomycin, all developed a peripheral sensory neuropathy [ ]. A reduction in vibratory sensation was the earliest manifestation of the neuropathy and the findings were compatible with primary damage to the dorsal root ganglia with a central-distal axonopathy. No motor nerve abnormalities were detected, apart from one patient with carpal tunnel syndrome, but two patients had prolonged brain-stem auditory-evoked potentials, indicating a central transmission defect. In another clinical and electrophysiological study of seven patients treated with cisplatin, the sensory neuropathy was also axonal, with considerable involvement of proprioception [ ]. Postmortem study in one case showed degeneration of the posterior columns of the spinal cord and evidence of neuronal loss in the lumbar spinal ganglion.

Eleven patients referred for neurological evaluation after cisplatin infusion into the internal or external iliac arteries for pelvic or lower limb tumors all developed symptoms within 48 hours of nerve or plexus dysfunction within the territory supplied by the cannulated artery [ ]. The lumbosacral plexus was affected in nine patients, the femoral nerve in one, and the peroneal nerve in one. The doses of cisplatin ranged from 50 to 160 mg/m ² and they did not correlate with the severity or course of the neuropathy. Small-vessel injury and infarction or a direct toxic effect are likely explanations.

Time-course

In a study of the time-course and prognosis of cisplatin-induced neurotoxicity (for example sural nerve sensory action, conduction velocity, and vibration threshold in the left big toe) in 29 patients with metastatic germ cell tumors, the onset of paresthesia was delayed [ ]. After completion of chemotherapy (3–4 cycles) only 11% of the patients had neurotoxic symptoms, whereas 3 months later the proportion was 65%. Cisplatin-induced neurological disorders should therefore be evaluated at 1–4 months after the end of weekly cisplatin administration, because during this time the most severe form of cisplatin neurotoxicity is to be expected. There was resolution of symptoms in most of the patients over the next 12 months, suggesting that in some individuals a long period of regeneration is required to restore axonal sensory function. In patients with mild signs of cisplatin-related neuropathy, retreatment is generally feasible after several months [ , ].

Management

Among several thiol compounds, glutathione may provide neuroprotection in patients treated with cisplatin without altering its antineoplastic activity. This protective role may be based on blockade of the accumulation of p53 protein in response to platinum in dorsal root ganglia, thereby hindering platinum-based apoptosis [ , ].

The melanocortin Org2766, an ACTH analogue, which is not yet available for clinical use, alleviates neurotoxicity due to vinca alkaloids and cisplatin, perhaps by enhancing neural repair. However, whereas preliminary results suggested some neuroprotection in women with ovarian cancer treated with cisplatin, these results were not confirmed in a randomized, multicenter, double-blind, placebo-controlled dose-finding study, even with higher doses of Org 2766 [ ].

There is evidence that amifostine can reduce the frequency of cisplatin-induced peripheral neuropathy, allowing higher mean cumulative doses to be used. However, some of the results should be interpreted with caution, because the studies included patients who differed in respect to treatment regimen, disease states, and pretreatment status. The underlying protective effect of amifostine may be based on its capacity to scavenge free radicals and prevent cisplatin DNA adduct formation in several organs, including the dorsal root ganglia [ ]. In a pilot study in 15 patients, subcutaneous amifostine was given 20 minutes before oxaliplatin, in order to counteract oxaliplatin-induced peripheral neurosensory toxicity. In 10 patients, this regimen reduced the severity of cumulative neuropathy without compromising antitumor efficacy; the amifostine was well tolerated [ ].

There is increasing evidence that acute oxaliplatin-induced neurotoxicity can be improved by intravenous infusion of calcium gluconate 1000 mg and magnesium sulfate heptahydrate 1000 mg before and after oxaliplatin. It has recently been shown that this strategy could reduce the incidence of acute neurotoxic symptoms, including laryngopharyngeal dysesthesia. Of 101 patients with advanced colorectal cancers who received folinic acid (leucovorin), 5-fluorouracil, and oxaliplatin (85 mg/m ² every 2 weeks, 20 patients; 100 mg/m ² every 2 weeks, 22 patients; 130 mg/m ² every 3 weeks, 59 patients), 63 received infusions of calcium and magnesium (1 g each) before and after oxaliplatin administration (treatment group); 38 patients (control group) did not receive infusions of calcium + magnesium. The median cumulative dose of oxaliplatin was 910 (range 255–2340) mg/m ² in the calcium/magnesium group and 650 (range 255–1450) mg/m ² in the control group. At the end of treatment, 27% had neuropathy (any grade) compared with 75% in the control group; 1.6% and 26% had pharyngolaryngeal dysesthesia; and 5% and 24% had grade 3 neuropathy. However, further studies are warranted before this regimen can be generally recommended for reducing the risk of acute neurosensory symptoms associated with oxaliplatin infusion [ , ].

Carbamazepine is a potent sodium channel blocker and has therefore been studied in the prevention of oxaliplatin-induced neuropathy [ ]. The doses of carbamazepine were adjusted to produce serum concentrations in the range 30–60 mg/ml. None of the patients who took carbamazepine reported symptoms of peripheral neurotoxicity; however, two patients (one who forgot to take carbamazepine and one who stopped taking it because he felt tired) developed grade 1 peripheral sensory neurotoxicity. These symptoms were abolished when carbamazepine was restarted. One can therefore speculate that the concomitant use of carbamazepine may allow the use of a higher cumulative dose of oxaliplatin without the occurrence of grade-4 neuropathy. However, a multicenter trial is warranted to confirm these encouraging preliminary results [ ].

In 15 patients with metastatic colorectal cancer who were given gabapentin (100 mg bd or tds) if neuropathic symptoms developed with oxaliplatin, the symptoms disappeared in all patients, even in those who received up to 14 courses of oxaliplatin. Withdrawal of gabapentin resulted in recurrence. However, a controlled trial is required to verify these encouraging preliminary results.

It has been suggested that chronomodulated delivery of oxaliplatin might reduce the incidence of platinum-induced neurotoxicity [ , ]. In a randomized, multicenter trial in patients with previously untreated metastases from colorectal cancer, 93 patients were assigned chronotherapy and 93 were assigned constant-rate infusion [ ]. Chronotherapy reduced the rate of severe mucositis five-fold and halved the rate of functional impairment from peripheral sensitive neuropathy. Median and 3-year survival times were similar in the two groups.

Preliminary results have suggested that glutathione may be neuroprotective in patients receiving oxaliplatin [ ].

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here