Neurotoxicity of antineoplastic agents

Critical Reviews in Oncology/Hematology, 1993; 14:61-15 0 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 1040-8428/93/$24.00

61

ONCHEM 00042

Neurotoxicity of antineoplastic agents

Maha Hussain, Antoinette J. Wozniak and Mark B. Edelstein Department of Medicine, Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI 48201 and the VAMC Allen

Park, MI 48101, USA

(Accepted 21 September 1992)

Contents

I. Introduction ....................................................

II. Vinca alkaloids ................................................ A. Pathophysiology and electrophysiology ......................... B. Variables affecting vincristine neurotoxicities .................... C. Treatment of neurotoxicity ...................................

III. Cisplatin and platinum analogues ................................ A. Electrophysiology and nerve biopsy ............................ B. Variables effecting cisplatin neurotoxicity .......................

IV. Other neuropathic chemotherapeutic agents .......................

V. Biologic response modifers (BRM) ............................... A. Interferon .................................................. B. Interleukin-2 ................................................

VI. Models for evaluating neurotoxicity of anti-cnacer agents ...........

VII. Conclusion ....................................................

Summary ...............................................................

References .............................................................

61

62 63 63 64

65 66 66

67

69 69 69

70

70

71

71

I. Introduction

Neurotoxicity has been associated with many anti- cancer agents. The vinca alkaloids, in particular vincristine and cisplatin have been the drugs most extensively described.

Interestingly, neurotoxicity has been a prominent side effect of several of the newest anti-cancer agents that have recently been introduced into clinical practice. Ifosfamide, hexamethylmelamine, and interferon, as well as several of the newer agents screened by the Na- tional Cancer Institute with solid tumor selectivity, have all proven to be neurotoxic and at times this toxicity is

Correspondence to: Maha Hussain, M.D., Section of Hematology and Oncology, VAMC, Allen Park, MI 48101, USA.

dose limiting. Table 1 provides a comprehensive list of anti-neoplastic agents under the headings of their more

common neurotoxicities. Since the previous reviews of this subject [l-4],

several analogues of older drugs have been investigated, biologic response modifiers have been more widely introduced into clinical practice, high-dose chemotherapy with bone marrow rescue is being more commonly utilized and grades of neurotoxicity have been better defined. This review will focus on the clinical, pathological and laboratory aspects of vinca alkaloid and cisplatin neurotoxicity in order to help in the understanding of the various etiologies of chemotherapy related neurotoxicity and to establish some important guidelines in directing the management of the neurotoxicities that complicate anti-cancer drug therapy in

62

TABLE 1 TABLE 2

Neurologic syndromes caused by systemic administration of antineoplastic agents

Neurotoxicities associated with vincristine

A. Acuie encephalopathy High dose methotrexate

(‘stroke like’) Asparaginases 5-FU (with allopurinol),

Ftorafur High dose thiotepa Procarbazine High dose Ara-C Hexamethylmelamine/

Pentamethylmelamine Spiromustine 5Azacytidine Ifosfamide Interferon

C. Peripheral neuropathies Vinca alkaloid Cis-platinum Procarbazine Hexamethylmelamine Methyl-gag

D. SIADH Vinca alkoloid Cyclophosphamide

Toxicity Incidence References

Peripheral neuropathy Loss deep tendon reflexes Paresthesia in digits Wrist drop and foot drop Slapping gait Mononeuropathy Quadriparesis

Interleukin-2 with or without LAK cells

Fludarabine

Autonomic neuropathy GI symptoms

Constipation, abdominal pain Paralytic ileus

Bladder atony Impotence Postural hypotension

B. Acute cerebellar syndromes/ataxia

5-FU Procarbazine Hexamethylmelamine High dose Ara-C Ifosfamide

Cranial nerve palsies

Ocular manifestations Ptosis, ophthalmoplegia Optic atrophy

Trigeminal nerve Jaw pain Loss of cornea1 reflex

Hoarseness Facial atrophy

general. We will also review the neurotoxic side effects and high

dose chemotherapy.

confusion, seizure, coma

SIADH secretion

II. Vinca alkaloids

The vinca alkaloids

are widely used in cancer therapy for solid tumors and hematologic malignancies. Vincristine the most frequently utilized vinca alkaloid and its primary dose-limiting toxicity many of clinical manifestations of vincristine-related neurotoxicities and their relative incidence. of deep

tendon reflexes the digits are the earliest and common side effects [ 1,5-81. Mus- cle pain, weakness, gait disturbance and sensory impairment can ensue with continued drug administration. Usually the sensory and motor neuropathies are bilateral and symmetrical, Many of the manifestations of vincristine neuropathy are slowly reversible with paresthesias being the most readily reversible followed by the motor and other sensory deficits [5,7,11]. The depressed deep tendon reflexes return slowly if at all

WI.

Gastrointestinal symptoms represent the most common autonomic neuropathy and are dose-related particularly with doses larger than 2 mg; however, they are not cumulative with repeated dosages. Cranial nerve palsies are rare, usually bilateral and generally reversible on drug discontinuation with ocular findings occurring most frequently [ 131.

Central nervous system (CNS) toxicity is not clearly established. Vincristine penetration into the CNS is not significant as shown by the very low concentrations detected in the cerebrospinal fluid [ 11. Seizures are rare so that if they occur other causes should be excluded [4,5,12,21].

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is felt to be secondary to a direct effect of vincristine on the hypothalamus, neurohypo- physial tract, or posterior pituitary [12,23,24].

51%

23-36%

Rare Rare

40%

26% Rare Rare Rare

Rare

Unknown

More frequent in children

1, 5-8

1, 5-7

9 IO

5,7

5,14 1 5,15,16

5,4.17

7,12

18,19 5,20

4,5,12,21,22

12,23,24 3

63

Both vindesine and vinblastine are associated with neurotoxicity that is qualitatively similar to vincristine

induced neuropathy. Of the three drugs vinblastine is the least neurotoxic with myelosuppression as the dose- limiting toxicity, while vindesine neurotoxicity is

moderate [25-27,33-381. Vindesine sulfate (desacetyl vinblastineamide sulfate)

is a vinblastine derivative, that manifests neurotoxicity initially as mild paresthesias in 35-60% of patients [29,30] and generally begins after 3-4 courses of weekly bolus dose therapy. In addition, hyporeflexia, muscle weakness, abdominal cramps, constipation, hoarseness, fatigue, myalgias, jaw pain, paralytic ileus, diarrhea, tinnitus, tremors, SIADH and urinary retention have been

reported [28,3 l-381.

ZZ. A. Pat~o~~ysiol~gy and electruphysiology

All vinca alkaloids bind tubulin preventing its polymerization into microtubules [39,40]. In addition to their role in mitosis, microtubules are involved in ax-

oplasmic transport and a variety of secretory functions [40,41].

Despite differing degrees of neurotoxicity, the affinity for tubulin has been shown to be much the same for all three vinca compounds 142,431; therefore, mechanisms other than microtubular disruption may be responsible for the variable toxicities [42].

Chan et al. has compared the three vinca alkaloids in

a de-sheathed cat sciatic nerve preparation model. At a low drug concentration (25 pg), he demonstrated that vincristine was more potent than vinblastine which was more potent than vindesine in blocking axoplasmic transport. At higher drug concentrations, axoplasmic block occured so rapidly that the difference between the

three agents was not significant [44]. Using 3H labeled vincas, Iqbal et al. demonstrated that differences in the toxicity of the three vincas may be attributed to differences in drug uptake by the nerve fibers [45].

Nerve conduction studies in vincristine treated patients show that sensory and motor nerve conduction velocities usually are only slightly impaired even when significant clinical neuropathy is present 158,461.

Although no abnormalities in neuro-muscular trans- mission have been demonstrated [8,19]; electromyo- graphic testing of distal muscles show abnormal pat- terns compatible with denervation [8,46]. These findings as a whole suggest axonal degeneration of the ‘dying- back’ type (centripetal axonal degeneration as a result of metabolic derangement of the neuron).

There is a dose-dependent decrease of action potential amplitude with vincristine, however, there is no change of electroneurographical values noted in vindesine

treated patients who manifest clinical evidence of

neurotoxicity [47]. The electrophysiologic findings of axonal degeneration have been confirmed by nerve biopsies and tissue obtained at autopsy from vincristine treated patients [8,9,48]. This finding is in contrast with segmental demyelination noted in vincristine treated animals [48,49]. Loss of microtubules and accumulation of nemofilaments is revealed by ultra-stuctural studies of neurons from the spinal ganglia, spinal cord and brain stem [12,50].

ZZ. B. Variables affecting vincristine neurotoxicities

Several factors seem to influence the incidence and severity of vincristine neuropathy. The schedule of administration of vincristine has been noted to influence the incidence of neurotoxicity as illustrated in Table 3. Vincristine neurotoxicity is related to both the in-

dividual dose and the frequency of administration. The majority of patients will develop early symptoms of neuropathy after 5-6 mg of vincristine [51] and significant toxicity will occur after a total dose of 15-20 mg on a weekly schedule. Higher cumulative doses can be tolerated over a given period of time if the individual dose is smaller than 2 mg and/or the interval between treatments is longer than a week [ 13,52-541.

Gastrointestinal side effects appear to be related to the magnitude of a single dose. Doses greater than 2.5 mg result in significant gastrointestinal motility impairment and if the dose is larger than 3 mg, paralytic ileus may occur [7].

It is conceivable that the single dose and the cumulative dose effects may be more important than the schedule effect, since reduction in frequency of administration will result in a smaller cumulative dose over

TABLE 3

Author Schedule and dose Neurotoxicity

Whitelow [55]

Holland [7]

3 mg twice week-

ly x 4-6 week

then 3 mg Q week

vs. 2 mg Q week or

twice weekly

12.5-75 jog/

kg/week

Jackson [54]*

Thant [53]*

1.4 mgIm* (max. 2 mg)

Max 2 mg days 1 & 8

Max 2 mg Q 3 weeks

Higher toxicity

with 3 mg dose

Earlier onset of

paresthesias at

higher dose

55% grade 1-2

36% grade 3

64% grade l-2

36% grade 3

50% grade 1

*Definition of neurotoxicity grade varies.

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a given period of time and hence a lower incidence of neurotoxicity.

Although it is widely believed that there is a signiti-

cant relation between age and the dose of vincristine re- quired to cause neurotoxicity [4,13], available published data do not absolutely support this conclusion [5,55]. There are few reports [56,57] suggesting enhancement of vincristine neurotoxicity by radiation therapy. These data are suggestive but insufficient to support an inter-

action between radiation and vincristine. Vincristine is predominantly excreted via the biliary

system, therefore liver impairment increases the susceptibility to neurotoxicity. Sandler et al. [5] reported that patients who had an elevated bilirubin level developed high grade neurotoxicity at a total vincristine dose of 2-6 mg/m2 over 3-4 weeks.

Some reports incriminate several agents such as INH [4], asparaginase [4], VM-26 [58] and vinblastine [59] in potentiating the neurotoxic effect of vincristine. More recent reports suggest an interaction between etoposide (VP16-213) and vincristine resulting in more severe neurotoxicity. Thant et al. [53] described increased neurotoxicity when VP-16 was added to a vincristine containing regimen. In this study, patients with small

cell lung cancer were treated with a schedule that included giving vincristine on day 1 and day 8 every 3 weeks. The increased toxicity was probably related to the schedule of vincristine administration, in that moditica- tion of dose schedule to once every 3 weeks resulted in marked reduction of neurotoxic side effects. Both

Jackson et al. [54] and Comis [60] reported that there was no difference in neurotoxicity when etoposide was added to a vincristine containing drug regimen.

A pre-existing neurologic dysfunction may make patients more susceptible to vincristine neurotoxicity. Ex- acerbation of the neurologic deficit in patients with

Charcot-Marie-Tooth syndrome has been reported [61]; however, peripheral neuropathy secondary to diabetes mellitus or Parkinson’s disease did not appear to be worsened by vincristine [46,62].

II. C. Treatment of neurotoxicity

Currently there are no effective methods of routinely preventing or decreasing vincristine neurotoxicity other than dose and schedule modification or discontinuation of the drug. Trials of thiamine, Bi2 [2] and folinic acid generally have been unsuccessful.

In murine models pyridoxine has shown some protec-

tion by prolonging survival when lethal doses of vincristine were administered, but it did not prevent the gait changes which may represent neurotoxicity in this

species [63]. When tested in humans at doses of 1.5

g/day for 6 weeks orally, Jackson et al. reported no protective effect for pyridoxine [64].

Glutamic acid was also tested by Jackson et al. in a randomized, placebo controlled trial in stage II breast cancer patients receiving vincristine 1 mg/m2/week for 6 weeks. Glutamic acid in a dose of 1.5 g/day in the study

patients resulted in a statistically significant reduction

TABLE 4

Clinical manifestations of cisplatin neurotoxicity

Toxicity Clinical manifestations Incidence References

Ototoxicity

Peripheral neuropathy

Lhermitte’s sign

Other

Tinnitus

Clinical hearing loss

Audiogram abnormality

[4000-8000 Hz)

Paresthesia

Dysesthesia

Vibratory and position

sensation changes

Diminution or loss of

deep tendon reflexes

Gait difficulties

Distal weakness -

Papilledema,

Retrobulbar neuritis,

loss of taste, memory loss,

intention tremors, postural

hypotension, tetany

9% (O-33%)

6%

25% (O-90%)

14/300 patients

Rare

[67-771

[67-781

[68-70,72.

[76,78-801

[78,81-831

(841 14,781

65

only in the development of paresthesia and a decreased

achilles reflex [65]. Mechanism of action of glutamic

acid in this setting remains unclear.

III. Cisplatin and platinum analogues

Cisplatin (CDDP) . CDDP is one of the most potent

cytotoxic agents in the present anticancer armamen- tarium with a unique spectrum of anti-tumor activity. Its major dose-limiting toxicity in phase I studies was

renal [66]. Neurotoxicity has been noticed with some frequency, especially with changes in drug administration and hydration methods and more effective an-

tiemetics resulting in a reduction of nephrotoxicity, nausea and vomiting [72-741. The more common neurotoxicities reported with CDDP and their clinical manifestations are listed in Table 4.

Both tinnitus and hearing loss are associated with CDDP therapy. Tinnitus is reversible but not clearly dose-related [73,74]. Less common is clinical hearing loss which is dose-related but not clearly reversible [67-781. The audiogram abnormality with high frequency pure tone hearing loss can occur as early as 4 days after drug administration and is not reversible [68-70,72,76,78-801.

CDDP usually causes sensory and occasionally sensory plus motor neuropathy (usually characterized by gait difficulties). Most patients have bilateral symmetrical neuropathy with vibratory and position sensation being most often affected. EMG studies in these patients showed serious neurogenic involvement with a

reduction of the interference pattern of the motor unit potential and abundant fibrillation at rest, however, clinical motor neuropathy is usually absent or subtle and difficulty with gait or handwriting is presumably

related to a proprioceptive abnormality [4]. Lhermitte’s sign is described as a sensation of electric

shock and tingling of abrupt onset in the legs and/or arms on neck flexion. This sign is a well recognized self- limiting complication of radiation therapy of the spinal cord. Eeles et al. [84] reported that 14/300 patients treated with CDDP containing chemotherapy for metastatic testicular cancer demonstrated this sign. Symptoms appeared during the treatment in 6 patients, within 1 month after starting treatment in 5 patients and in 1 patient at 2 months. The duration of symptoms ranged from 2-8 months. None of the patients had received radiation therapy to the cervical or dorsal spine and the authors did not observe a platinum dose effect. Concomittant peripheral neuropathy was noted in 12 patients.

Neurologic syndromes can be caused by regional administration of antineoplastic agents (Table 5). Frustaci

TABLE 5

Neurologic syndromes caused by regional administration of antineoplastic agents

A. Acute encephalopathy Intrathecal methotrexate

- radiotherapy Intracarotid BCNU Intracarotid cisplatin

B. Arachnoiditislmyelopathy Intrathecal methotrexate Intrathecal Ara-C lntrathecal thiotepa

C. Chronic reactions 1. Necrotizing leukoencephalopathy

Radiotherapy - intrathecal methotrexate Intrathecal methotrexate or IV methotrexate Intrathecal Ara-C

2. Mineralizing microangiopathy Radiotherapy + intrathecal methotrexate

3. Cerebra1 atrophy Intrathecal methotrexate f radiotherapy Intrathecal Ara-C f radiotherapy

4. Pontine myelinolysis/somnolence syndrome Radiotherapy f intrathecal methotrexate

D. Peripheral neuropathykranial nerve palsy Cis-platinum

et al. [85] reported on 63 previously untreated patients with head and neck cancer who were treated with intra-

arterial cisplatin (IA-CDDP). Cranial nerve palsies were noted in 4 patients a few days after the infusion on the ipsilateral side. The 12th cranial nerve was involved in I patient, 7th cranial nerve in another and 9th, lOth, 1 lth and 12th cranial nerves in 2 patients and complete recovery occured only in 1 patient. Stewart et al. [86] reported 3 cases of retinal blindness and 5 cases of severe encephalopathy in 11 patients treated with IA-CDDP for brain tumors. Castellanos et al. [87] reported that 9/l 1 patients treated by internal or external iliac artery infusion of CDDP had parasthesias and/or weakness oc- curing within 48 h. Neurologic examination revealed

decreased pain and/or touch sensation in the Ls-SI or the sciatic nerve distribution in 6 patients and decreased joint position and vibratory sensation in the toes in 4 patients; all 9 patients had weakness. EMG/NCV studies in 6 patients were compatible with lower lumbo-sacral plexopathy (axonal in nature) and 2 patients developed mononeuropathy. Only 1 patient had partial recovery. The authors felt that the mechanism of this form of neurotoxicity was chemotherapy-related small vessel damage resulting in infarction of the neural tissues supplied by the perfused vessels. A direct neurotoxic effect of CDDP, however, could not be excluded.

66

III. A. Electrophysiology and nerve biopsy

Peripheral neuropathy. Nerve conduction studies have suggested greater sensory nerve involvement than motor nerve involvement. Of 107 patients treated with CDDP, Von Hoff reported that 3 patients developed peripheral

neuropathy after 210-560 mg/m’ of the drug, and 2 patients showed absent sensory nerve action potentials in the upper and lower extremities. Sural nerve biopsies

revealed scattered myelin damage with intact axons [83]. Thompson et al. [81] noted that the primary damage

was axonal with secondary myelin damage. He did elec- tron microscopic studies of peripheral nerves in 4 patients. Nerve conduction velocity in the right median

nerve, and peroneal nerves remained normal while sural nerve responses abruptly disappeared without previous slowing of conduction velocities in 6 patients at a mean

CDDP dose of (383 mg f 103 mgm’). Cowan et al. 1881 prospectively studied 7 patients treated with CDDP by performing pretreatment and serial electrophysiol-

ogic testing. Two of 7 patients had pretreatment decreased vibratory sensation and 317 had abnormal nerve conduction compatible with peripheral neuro-

pathy. Following CDDP therapy no new clinical peripheral neuropathies were noted but reduced nerve conduction was noted in 3 patients. This suggests that

not all nerve conduction abnormalities in these cancer patients resulted from chemotherapy.

In a report by Carenza et al. [82], 23 of 86 patients with gynecologic neoplasia treated with CDDP based combination chemotherapy were studied serially. None had clinical or neurophysiologic abnormalities prior to therapy. EMG studies post therapy showed reduction of the interference pattern of the motor unit potentials and abundant fibrillation at rest. In 7 symptomatic patients sensory conduction velocity was decreased with slight decrease of the sensory action potential. In 5 patients

maximal motor conduction velocity (MMCV), distal latency and amplitude of the motor potential did not change which is compatible with sensory dysfunction alone. In the other 2 patients no decrease in sensory action potential was noted, but MMCV and motor action potential were reduced and distal latency increased suggesting motor and sensory dysfunction. The authors conclude that this picture is compatible with a degenerative axonal lesion with a secondary myelinic damage similar to the picture of the so called ‘dying- back neuropathies’, the most common morphologic reaction of peripheral nerves to metals like arsenic and thallium [82]. A similar conclusion was drawn by Mabin et al. [89]. In their series patients without any electrophysiologic abnormalities had slowing of the motor nerve conduction velocities at 100 mg/m2 of CDDP

with no further worsening at 300 mg/m2 and prolonga- tion of the distal latency of the sensory median nerve after 300 mg/m2. No changes were noted in the electrophysiologic studies of patients without clinical abnormality but with delayed latency of the Hoffmann reflex.

As in humans, rats treated with CDDP showed evidence of neuropathy in both the CNS and peripheral nervous system, the mechanism of which was shown to be secondary to axonal degeneration [go].

Ototoxicity, demonstrated by loss of hair cells in the organ of corti, has been seen in several animal models

including guinea pigs, rats and monkeys [91]. In monkeys hearing loss was transient with doses as high as the LD,o. The pathology of hearing loss has not been

studied well in man. Clinical studies have suggested a high incidence of cochlear toxicity with a predilection for involvement of the higher frequency range [SO]. In-

itial auditory function testing is recommended as a base line. Recommendations vary for follow up, with some suggesting regular testing in patients committed to long term CDDP therapy to assess the magnitude of potential change [80], while others recommend and we concur, that auditory testing be done when patients develop clinical hearing loss, since changes in therapy may be

warranted [78].

III. B. Variables effecting cisplatin neurotoxicity

Dose and schedule: presently the most effective way to ameliorate CDDP neurotoxicity is to limit the single and/or cumulative dose used. A high incidence of

deafness was reported with single doses of 160-200 mg/m2 [92], suggesting that perhaps a single dose should not exceed 150 mg/m2. Similarly, peripheral neuropathy has been reported with cumulative doses as low as 210 mg/m2, however, clinical tindings usually may not become apparent before a cumulative dose of

at least 350-640 mg/m2 [81,83,93,94]. Pharmacologic modulators of neurotoxicities includ-

ing thiosulfate, WR-2721 (S-2-[3-amino propylamino]

ethylphosphorothioic acid) and ACTH analogues have been used to ameliorate the neurotoxicity of CDDP. The use of these agents has been prompted by preclinical efficacy in animal models. Table 6 summarizes the clinical trials that have been performed. The use of these agents remains investigational.

Hypertonic saline hydration: Legha and Dimery [93] observed significant peripheral neuropathy manifesting as ataxia and difficulty with ambulation in 6/8 patients treated with high dose CDDP [30-40 mg/m2 x 5 days) based chemotherapy. Hydration without hypertonic saline was utilized. The median cumulative dose in patients who developed neurotoxicity was 775 mg/m’.

TABLE 6

Pharmacologic modulators of cisplatin neurotoxicity

Agent Mechanism Clincial trials

Thiosulfate Neutralizes toxic effects [95-971

WR-2721 Protects normal tissue from radiation and alkyl- ating agent chemotherapy in animal models

t1001

ACTH Animal studies analogues protection from (Org 2766) neurotoxicity

[105,106]

Recombin- Animal studies ant nerve Protection from growth neurotoxicity factor UO81

(I) Low clinical neurotoxicity with high dose intracavitory CDDP (2) No worsening of pre-existing CDDP-induced neurotoxicity

198,991 (I) Glover [loll -7152 mild to moderate peripheral neuropathy at 870 mgim* (cumulative dose) -No ototoxicity (2) Mollman [IO21 - Lower incidence of

neuropathy (25% as compared to 47-100%) -Median dose (635 mgim2) at onset of neuropathy was higher (3) Glover [IO31 -8136 grade 1-2 peripheral neuropathy at median dose of 670 mg/m* -20/36 mild to severe high frequency hearing loss -3136 clinical hearing loss (4) Kish [104] CDDP 120 mg/m’ with or without WR-2721 No protection Randomized, double blind placebo-controlled study

If071 -Fewer neurologic symptoms with high-dose Org 2766 -Increased threshold for vibration perception -No change in cytotoxic effect

When CDDP was administered in hypertonic saline to 47 patients, neurologic toxicity was mild, with significant peripheral neuropathy seen in only 1 patient. A reduction in auditory acuity was seen in 30% of patients treated at 30 mg/m2/day x 5 or more, but it was dose- limiting in only 2 patients. The authors note that this incidence is comparable to trials using CDDP at 120 mg/m2 and the discrepancy in the degree and preval- ence of peripheral neuropathy compared with other studies may be explained by the small cumulative dose in this study and the relatively few patients with prior

CDDP therapy [94]. Haines and colleagues reported a 25% incidence of

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ototoxicity and 39% incidence of neuropathy in their series of patients treated with 187.5 mg!m2 CDDP administered over 5 days in hypertonic saline [109]. In animal models salt loading with 3% saline did not result in significant difference in CDDP localization in the

inner ear when compared to non-saline loaded animals.

This is in contrast to the low CDDP localization in the kidneys of the saline loaded animals, explaining the

kidney protective effect of saline hydration [ 1101. Radiation: CDDP administered to 8 children with

recurrent brain tumors and prior cranial radiation was

associated with significant hearing loss in 5 of 6 evaluable patients. Hearing loss progressed on re- challenge with CDDP. In addition, 2 patients developed

profound deterioration of neurologic status within 72 h after CDDP infusion [ 11 I]. A similar observation was

reported by Schell et al. [112]. This effect may be of im-

portance in certain patients such as those with head and neck cancer or others who receive CDDP and radiation therapy to the head and may warrant prospective

evaluation of this phenomenon. Platinum analogues. The potential for dose limiting

and/or permanent gastrointestinal toxicity, renal toxicity and/or neuropathy remains despite the present methods of CDDP administration and supportive care, hence the importance of the development of analogues that might demonstrate greater or equivalent clinical ac-

tivity with decreased toxicity.

Recently two platinum analogues have been introduced into clinical trials, carboplatin (CBDCA), which is currently approved for clinical use and iproplatin

(CHIP). In a preclinical trial no significant functional or morphologic cochlear toxicity was reported with CHIP

or CBDCA [ 1 lo]. In phase I and II studies no high frequency sensorineural hearing loss was detected [113-1161. Recently Bishop et al. [117] noted that only 2194 patients treated with CBDCA + VP-16 developed

clinical ototoxicity. Audiograms were not routinely performed in these patients. No peripheral neuropathy has been reported.

IV. Other neuropathic chemotherapeutic agents

It is clear that dose, schedule and route of administra-

tion are operational variables influencing the incidence and outcome of neurotoxicity for vinca alkaloids and CDDP. In fact this does not only apply to these drugs but also to some established and newer anti-cancer agents. Table 7 summarizes these agents and their reported neurotoxicities.

The neurotoxicity of high dose methotrexate has been associated with an elevation of myelin basic protein

68

TABLE 7

Neuropathic chemotherapeutic agents

Dw Clinical manifestation References

Methotrexate (3-16 g/m2)

Thiotepa (1125-1575

mg/m2)

Reversible stroke-like syndrome Transient encephalopathy Mild cognitive dysfunction Mild to severe behavioral changes Grade 2-4 neurotoxicity Toxicity usually reversible

[118-120)

11211

BCNU Intracarotid High dose (2250-2850

mp/m2) High dose (2 1050 mg/m2) cranial irradiati 5-Fluorouracil (Bolus dosing)

Cytosine Arabinoside (High dose i.e. 3

p/m2 twice daily x 6

days) Ifosfamide (600-4000 mg/m2/day) Hexamethyl- melamine

Acute encephalopathy Encephalomyelopathy leading to coma and death Neuroretinitis

+ on

Taxol

Fludarabine (High dose) Etoposide (VP-16) Cyclophosphamide Suramin (association with peak steady-state, plasma levels of 350 &ml)

Spiromustine

Cerebellar syndrome Gait and limb ataxia Dysarthria Nystagmus Hypotonia Usually reversible Cerebellar symptoms

CNS toxicity approaches

50% at 54 g’m* cumulative dose Acute encephalopathy Acute cerebellar syndrome Incidence < l-30% Depression, hallucination, insomnia, dysphasia, Parkinson’s like tremor, ataxia, peripheral neuropathy Schedule dependent Sensory neuropathy, rapid onset and cumulative, resolves within months after drug discontinuation, motor dysfunction has been reported Altered mental status, Blindness, coma and death peripheral neuropathy SIADH Peripheral neuropathy; generalized flaccid paralysis, variable recovery, distal extremity and peri-oral paresthesias Alteration in cortical integrative function, decreased level of con- sciousness, association with high peak plasma levels, ? cumulative effect

[122-124)

[1251

11251

[I,41 [131-1331

[136,138,139]

[140,141,143]

[4,1441

[147-1501

[151-1531

[154-1561 [157-1591 [160-1621

11631

(MBP) in the CSF suggesting toxic demyelination as a mechnism since MBP is a major component of the protein fraction found in the myelin sheaths [ 1181.

There is an association of neuroretinitis with other intensive BCNU series, other than those mentioned in Table 7 and with intra-carotid BCNU suggesting that this complication is indeed related to the high dose

BCNU. Burger et al. (1261 described the histopathologic features of encephalomyelopathy. It is noteworthy that Takvorian et al. [ 1271 noted no unique pattern of CNS

toxicity in his group of patients treated with 600-1400 mg/m* BCNU and bone marrow rescue. Autopsies per-

formed on 15 patients who died subsequent to their

treatment revealed no specific CNS pathology. The incidence of the cerebellar syndrome associated

with 5-FU appears to increase with higher dose. It is almost negligible with doses of 7.5- 15 mg/kg but increases in incidence to 3-7% in patients receiving bolus high dose weekly therapy with 15 mg/kg/week or more [l]. However, this toxicity is rare with an infusional 5- FU schedule [128,129]. Attempts to modulate 5-FU metabolism with allopurinol or thymidine has resulted in a higher incidence of the cerebellar syndrome

[ 130,131]. Cerebellar ataxia secondary to this agent has been closely examined. 5-FU readily crosses the blood- brain barrier and achieves significant CNS levels [ 134,135]. Early data suggested that the cerebellar toxicity may be related to the production of flurocitrate or fluroacetate. This concept has been questioned because thymidine which blocks 5-FU catabolism and presumably would reduce flurocitrate and acetate production, may actually enhance the neurotoxicity of 5-FU [ 1311. These compounds may be catabolites of 5-FU and can produce cerebellar lesions in animal models that are similar to those identified in humans [ 136,137].

The mechanism of ifosfamide neurotoxicity is

unclear. Goren et al. suggest that prior therapy with cisplatin resulting in renal tubular damage could lead to alterations in ifosfamide metabolite clearance enhancing the susceptibility of the patient to not only neurotoxicity but also hematologic and renal toxicity [ 1421. Pratt et al. [143] pointed to the development of toxic levels of chloracetaldehyde (an oxidation product of ifosfamide) as a possible cause of the acute neurotoxicity. Chlor- acetaldehyde was felt to be similar to acetaldehyde (ethanol product) in its toxic effect on the brain and the neuro-symptoms of patients treated with ifosfamide resemble many of those seen in patients with alcohol intoxication. All signs, symptoms and EEG abnormalities were transient.

Some of the new agents introduced by the NC1 have been associated with acute CNS side effects [145,146]. These agents include fludarabine, spiromustine, taxol and suramin. It is interesting to note that new drugs with

69

solid tumor selectivity have shown significant neurotoxicity, however, it remains to be seen whether there is a

scientific explanation for such an observation. Taxol, a plant alkaloid, has shown promise in the

treatment of breast and ovarian cancers. Neurotoxicity was not observed in phase I trials using single-dose, multiple-dose or 3-h infusional schedules [ 1471. Neurotoxic effects has been reported with 6 and 24 h

infusions with doses greater than 170-200 mg/m2 [147-1491.

Etoposide (VP-16-213) has been reported to cause

peripheral nerve damage in experimental animals and in humans [154-1561, however; the incriminating data are weak. Littlewood et al. described 9 patients who were treated with VP-16-213 at a cumulative dose of x 2400 mg!m2, 319 were treated with 1400 mg/m2 of VP- 16 + cyclophosphamide. Nerve conduction studies were

either normal or showed no deterioration from pretreatment values in 8 patients who were studied [ 1561.

Cyclophosphamide-associated SIADH secretion oc-

curs 4-12 h after the drug infusion and lasts up to 20 h. The mechanism is probably related to direct ADH

release from the posterior pituitary rather than ectopic release or ADH-like action of the metabolite on the kidney.

V. Biologic response modifiers (BRM)

Adoptive immunotherapy has emerged as a promising modality in the treatment of cancer. Several types of this therapy have been introduced into clinical trials; the neurotoxicity associated with interferons and interleukin-LAK cells will be reviewed.

V. A. Interferon

Interferon was first characterized in 1957 in England [ 1641. Clinically sufficient quantities of alpha-interferon

were produced in the early 1970s from buffy coat cells and tested in several malignancies. Since 1979, alpha, gamma- and beta-interferons were successfully cloned

and large scale testing begun. Neurotoxicity has been reported with interferon therapy, usually with higher doses of both natural and cloned interferons, irrespec- tive of route of administration [ 165- 17 11.

Interferon related neurotoxicity manifests as overall mental and motor slowing; symptoms include behavioral, cognitive, affective and personality changes, marked somnolence, lethargy, confusion, loss of taste and smell and expressive dysphasia in extreme instances [ 166,168,169,172]. Death and seizures have also been reported [173,174].

Electroencephalographic studies of patients treated with interferon who experienced neurotoxicity have con- sistently revealed changes of diffuse encephalopathy

with slowing of the alpha-rhythm and the appearance of delta and theta waves predominantly in the frontal lobes [166-169,172]. Rohatiner et al. found no correlation between EEG changes and spinal fluid interferon levels

[168]. Adams et al. [169] reported on 10 patients with metastatic renal cell carcinoma who were serially

evaluated by neuropsychiatric examination to determine the nature of the fatigue-asthenia symptoms associated with alpha-interferon, Prior to therapy all the patients were found to be free of any psychiatric illnesses or cognitive impairment that might indicate cerebral

disease. Interferon produced moderately severe changes in behavior manifesting as psychomotor retardation with loss of incentive, verbal and motor spontaneity and slight to moderate changes in cognition, affect and per-

sonality in some of the patients. These symptoms disappeared when interferon was discontinued. This toxicity

was suggested to be secondary to frontal lobe dysfunction. Overt depression and episodes of psychotic

behavior have been rare [ 1711. Psychotic reaction and hallucination have been reported by several in-

vestigators when more than 20 munits/m2 of interferon has been used [ 174- 1761. CAT scan of the brain prior to interferon administration has been recommended since preexisting brain metastasis may predispose patients to worse interferon related neurotoxicity [171].

The mechanisms underlying interferon neurotoxicity are unclear, and possibilities include direct effect on frontal lobes, or deeper brain structures, impedance of neurotransmitters, alteration of cholinergic balance or release of other substances. Calvert and Gresser [177] demonstrated enhanced spontaneous neuronal activity and evoked responses when cat or rat cerebral cortex was incubated with interferon. Intracerebral injection of interferon into mice has produced endorphin-like opioid effects including decreased motor activity and catalepsy which could be reversed by naloxone [ 1781.

Adams et al. [169] found both metoclopramide hydrochloride (dopamine antagonist) and methylphen- idate (a dopamine agonist) could reverse some of the neuropsychiatric effects of leukocyte interferon. The hypersomnia with interferon may be a reflection of interferon activity in the reticular activating system of the brain stem and/or interference with the frontal lobes extensive reticular activating system connections.

Peripheral nervous system effects, particularly distal paresthesias, have been reported rarely with interferon therapy. At high doses interferon may result in denervation and neurogenic muscle atrophy [ 166,179- 18 11.

V.B. Interleukin-2 (IL-2) with or without lymphokine

activated killer (LAK) cells

Denicoff et al. [182] reported that 15/44 (30%)

70

patients with metastatic cancer treated with systemic recombinant IL-2 combined with autologous LAK cells

developed severe behavioral changes that included agitation and combative behavior of variable severity which necessitated acute intervention. Twenty two patients (50%) had severe cognitive changes and 7 developed delusions and hallucinations. These neuropsychiatric side effects appear to be dose and time

related, more frequent at a higher dose and almost uniform at the end of each treatment.

When only IL-2 was administered 17/24 (70%) patients who received 100 000 units/kg showed severe to

moderate neuropsychiatric changes compared with 6119

(30%) patients who received 30 000 units/kg (P c 0.05). All changes were reversible. Fisher et al. [ 1831 in treating metastatic renal carcinoma with IL-2 and LAK cells noted somnolence or disorientation (grade 3 toxicity) in 31% of patients. Somnolence, coma and disorientation were reported by Rosenberg et al. in patients treated with IL-2 with or without LAK cells. Most patients had appreciable improvement after 2 to 3 days and all returned to baseline behavior and cognitive scores [ 1841.

Thompson et al. [185] in evaluating the influence of dose and duration of infusion of IL-2 on toxicity and immunomodulation noted transient confusion in 315 patients receiving 3 x 10% of IL-2 infused over 24 h. This persisted during IL-2 administration, did not re-

quire medication or psychiatric intervention and resolv- ed after discontinuing IL-2. Confusion was not seen in any of the other treatment groups.

VI. Models for evaluating neurotoxicity of anti-cancer

agents

It is important to be able to evaluate the potential of anti-cancer agents for producing neurotoxicity prior to their introduction into clinical trials. For example, a system that is suitable for studying factors contributing to the differences in the neurotoxic potential between certain drugs and their analogues might result in the discovery of a novel agent that exhibits low neurotoxic potential.

Animal models, used for this evaluation, have not been useful. In the case of the vinca alkaloids, only certain species manifested the neurotoxic side effects. Chicken, monkeys and cats developed neurotoxicity when treated with vincristine but not with the other two vincas. The mouse, rat, dog and guinea pig were not useful models for evaluating vinca alkaloid neurotoxicity [50]. Another barrier is that the neurotoxicity that is exhibited by animals is not necessarily pathologically similar to the toxicity noted in humans. The peripheral

neuropathy seen with vincristine is primarily secondary to axonal degeneration, while variable degrees of toxic

myopathy are noted in animals [50]. As a result, some investigators have introduced alternative systems utilizing cultures of new-born rat mid-brain [ 1861 or fetal rat hypothalamic neurons [ 1871. Such systems eliminate

pharmacokinetics as a factor in the pathogenesis of neurotoxicity, they are rapid and potentially easier to

quantitate. Some of the initial available studies indicate that the order of neurotoxicity induced by different agents appears to correlate well with their known

relative clinical toxicities [ 186,187]. Earlier models of experimental toxic neuropathy

evaluated morphologic and physiologic parameters, more recent models tend to evaluate biochemical and behavioral parameters. These may prove to be better predictors of early neurotoxicity [ 1881.

VII. Conclusion

In recent years more attention has been paid to the quality of life of cancer patients, not only when their disease is in remission but more importantly while on therapy, hence the importance of preventing and/or

modifying the neurotoxic side effects of the anti-cancer agents.

From the previous review it is clear that the dose, schedule and route of administration determine significantly the incidence and outcome of some of the anti-cancer agents’ neurotoxicity. Nevertheless, attempts at utilizing modifiers of neurototoxicity and ac- quiring a better understanding of the underlying mechanisms of this toxicity need to be made in an effort to develop an efficient and representative model that may help exclude unacceptable neurotoxic agents.

Because of the progress that has been made in ameliorating some of the distressing side effects of anti- cancer therapy, more attention has been focused on neurotoxicity. This necessitates a more detailed grading

system so that the extent of the neurotoxicity can be ap- propriately evaluated. Clinical trials should prospectively evaluate the potential for neurotoxicity of anti-cancer agents.

The WHO neurotoxicity grading system [189] is presently used. Castellanos and Field [190] introduced 14 criteria to evaluate neurotoxicity. By using a similar evaluation system, Pazdur et al. [ 1631 were able to better define and quantitate the neurotoxicity of spiromustine.

In addition to a uniform grading system it is clearly important that a reliable and predictive model is established for screening new drugs prior to the introduction of such agents into clinical trials.

71

Summary

Purpose: to review the neurotoxicity associated with antineoplastic agents.

Methods: four hundred articles, abstracts and book

chapters were selected for review. One hundred and ninety (articles, book chapters and abstracts) were identified as representative of the important aspects of neurotoxicity to be presented in this review.

Results: in general the dose, schedule and route of administration significantly determine the incidence and outcome of antineoplastic agents neurotoxicity. An up- dated and detailed review of neurotoxicity is provided with special attention to vinca alkaloids, cisplatin and

biologic response modifiers. The neurotoxic side effects

of some of the new approaches in cancer therapy and some of the investigational agents are discussed. Guidelines for the prevention and management of this toxicity are presented. In addition, suggestions are made in regard to the preclinical and clinical screening of new agents for neurotoxicity.

Conclusion: quality of life issues have become a focal point in many clinical trials. Neurotoxicity associated with antineoplastic therapy clearly has an impact on the short and long term quality of the life of cancer patients.

A better understanding of this toxicity requires develop- ing reliable and predictive models to screen new agents prior to their introduction into clinical trials; a more detailed and uniform grading system; and the prospective evaluation of neurotoxicity in clinical trials of new antineoplastic agents.

Acknowledgment

The authors thank Ms. Donna Bennett for secret- arial assistance.

Biographies

Dr. Muha Hussain is a staff Oncologist at the VA Medical Center, Allen Park, MI and an Assistant Pro- fessor of Medicine, Dept. of Internal Medicine, Division Hematology/Oncology, Wayne State University,

Detroit, MI. Dr. Wozniak is a staff Oncologist at Harper Hospital, Detroit, MI and an Assistant Professor of Medicine, Dept. of Internal Medicine, Division of Hematology/Oncology, Wayne State University, Detroit, MI. Dr. Edelstein is Chief of the Medical Ser- vice at the VA Medical Center, Allen Park, MI and an

Associate Professor of Medicine, Dept. of Internal Med- icine, Division of Hematology/Oncology, Wayne State University, Detroit, MI.

Reviewer

This paper was reviewed by Monica Spaulding, M.D.,

Buffalo VA Medical Center, 3495 Bailey Avenue, Buf- falo, New York 14215, USA.

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Neurotoxicity of antineoplastic agents