LINDA GAY PETERSON, M.D. MICHAEL K. POPKIN, M.D.
Neuropsychiatric effects of chemotherapeutic agents for cancer ABSTRACT: A review of the literature finds a reported incidence of eNS complications from cancer chemotherapy ranging from 5% to 86% for different classes of drugs. Patients receiving cancer chemotherapy are rarely given a systematic psychiatric evaluation, however. Psychiatric sequelae are rarely noted in the absence of neurologic disturbances. Organic mental disorders and affective disturbances are most often noted; acute psychotic reactions are rarely seen. As detailed in this review, most changes appear reversible with the exception of a significant incidence of chronic eNS effects following high-dose intravenous or intrathecal methotrexate therapy. Studies relating psychosocial variables and emotional characteristics to the genesis of cancer are fairly numerous. I- 6 Even more common are reports describing patients' adjustments to the diagnosis and sequelae of malignancy.7-'9 In contrast, reports on the psychiatric aspects of cancer chemotherapy agents have appeared only rarely.20.21 Psychiatric disturbances are sometimes included under the general rubric of central nervous
system (CNS) toxicity,22-29 but more information is needed on the effects of cancer drugs on the patient's cognition and affect. Several factors have confounded assessment of the psychiatric aspects of cancer drugs. These include (I) the use of multiple agents in treatment protocols; (2) the metabolic derangements caused by the disease or its therapy30; (3) direct and indirect effects of the malignancy itself on the CNS3); and (4)
Dr. Peterson is clinical instructor ofpsychiatry and Dr. Popkin is associate prOfessor ofpsychiatry and medicine at the University of Minnesota Hospital. Reprint requests to Dr. Peterson, Department of Psychiatry, University Hospital, Box 393, Mayo Memorial Building, Minneapolis, MN 55455. FEBRUARY 1980· VOL 21· NO 2
the inclusion of a corticosteroid such as prednisone in many treatment protocols. Prednisone is well known as a producer of major mood change and, less often, psychosis. 32 A linear relationship between steroid dosage and untoward psychiatric reactions has been demonstrated. 33 Thus, depending on the dosage of prednisone, its inclusion in a multi-agent protocol can be expected to confound appreciation of the psychiatric effects of the other medications that the patient receives. This paper will review critically the existing literature describing psychiatric effects of the major groups of cancer chemotherapy agents exclusive of hormones. Allowing for differences in diagnostic criteria as well as for such variables as the dosage schedule and route of administration of the agents, this report directs attention to the alterations in cognitive and affective function that may be caused by these drugs. Data on agents associated with significant psychiatric toxicity are summarized in the Table. 141
Alkylating agents The alkylating agents interfere with protein synthesis by causing DNA miscoding. All are lipophilic and cross the blood-brain barrier, but they differ in rate of absorption and metabolism as well as in toxicity and effectiveness. They include (I) nitrogen mustards (mechlorethamine, cyclophosphamide, chlorambucil, and melphalan); (2) alkyl sulfonates (busulfan); (3) ethylenimine derivatives (TEPA, thioTEPA, and hexamethylamine); (4) nitrosoureas (carmustine, 10mustine); (5) triazines (dacarbazine). All nitrogen mustards are powerful CNS stimulants with cholin-
Reported Agent· Alkylating agents Dacarbazine Hexamethylamme Ant,metaboliles Methotrexate
percentage of behavioral sequelae
Nature of psychiatric reaction OMD or depression
10-20 50 15-25
OMD Developmental and behavioral
Vinca alkaloids Vinblastine
OMD or depreSSIon
Enzymes L-Asparagi nase Hormones Prednisone
cytic leukemia, Hodgkin's disease, and related lymphomas. Godfrey and associates 3S mentioned an instance of psychiatric illness following administration ofchlorambucil, but did not give details. The only reported CNS effects of cyclophosphamide (used to treat Hodgkin's disease,lymphosarcoma, and acute lymphoblastic leukemia) are mild nausea and vomiting. 23 .34 However, at doses of greater than 50 mg/kg, it may cause inappropriate secretion of ADH,36 and it has also been observed to cause internal hydrocephalus in chick embryos.J7 The alkyl sulfonates have not been reported to cause affective or
Table-Cancer Chemotherapeutic Agents Associated with Significant Psychiatric Toxicity
ergic properties. Mechlorethamine produces the most severe immediate reaction and cyclophosphamide the least. The primary toxic reaction occurring with the nitrogen mustards is a syndrome of nausea, vomiting, and a state akin to alcohol intoxication. 34 Mechlorethamine is used primarily for Hodgkin's disease and lymphomas. In reviewing the known data regarding the CNS toxicity of this drug, Bethlenfalvay29 reported a single case of recurrent toxic encephalopathy attributed to the development of internal hydrocephalus. Chlorambucil is used to treat chronic Iympho-
Miscellaneous agents Procarbazine Mitotane
OMD Organic mental dIsorder • As used In s anderd treatment protocol
cognitive sequelae, and there are no reports of psychiatric symptoms from TEPA or thioTEPA. Hexamethylamine, administered alone or in combination with dacarbazine, has been noted to cause confusion, depression, hallucinations, and even suicide in 20% of those receiving it. Whether these behavioral symptoms represent manifestations of an underlying organic mental syndrome or an affective disturbance remains unclear. Symptoms begin several days to several weeks after the onset of chemotherapy, and recovery occurs within days to weeks after withdrawal of hexamethylamine. 38 Bergevin and associates 39 observed that the psychiatric effects of hexamethylamine show no dose or time relationship. CNS toxicity has been reported for the nitrosoureas,40 but no recent studies mention behavioral effects. Despite the extensive use of intrathecal nitrosoureas to treat brain tumors experimentally, no psychiatric disturbances have been noted. 41 -45 Confusion or depression develops in approximately 5% of patients receiving dacarbazine, which is used to treat malignant melanoma, Hodgkin's disease, and soft-tissue sarcomas. 22,46-50 As noted above, the incidence of psychiatric disturbances when dacarbazine is given in combination with hexamethylamine reaches 20%. Accounts of these psychiatric aberrations have been inadequate with respect to diagnostic criteria, timing, and reversibility. Antimetabolites The antimetabolites interact with specific enzymes to inhibit them or to cause the synthesis of an aberrant molecule that cannot function normally. This group of agents FEBRUARY 1980 • VOL 21 • NO 2
consists of folic acid antagonists such as methotrexate, purine analogs such as 6-mercaptopurine, and pyrimidine analogs such as 5fluorouracil. Methotrexate (MTX), the primary folic acid antagonist, is used to treat acute lymphocytic leukemia and choriocarcinoma. It crosses the blood-brain barrier poorly and therefore is used intrathecally for CNS treatment or prophylaxis. Acute and delayed CNS effects may occur. Features of the acute syndrome include nausea, vomiting, headache, lethargy, and fever in about 40% of children given intrathecal methotrexate. Symptoms begin two to four hours
Prednisone is weN known to evoke major mood clumge and, less often, psychosis. after the drug is given and last for 12 to 72 hours. The frequency of the syndrome is greater with a high dose of methotrexate or if a CNS tumor is already present. To evaluate the chronic CNS effects of intravenous MTX, Meadows and Evans 24 studied 23 children five years after they were given this drug for malignancy. Seizures, paraplegia, and dementia were present in four of the patients; ten of the other patients were found to have mild clinical or EEG abnormalities. McIntosh and Aspnes 25 evaluated 23 leukemic children who were receiving intrathecal methotrexate prophylaxis along with intravenous cytosine arabinoside, cyclophosphamide, and cranial irradiation. By the tenth to eighteenth month of therapy, 50% of these patients had neurologic symptoms. Five had sei-
zures and four had abnormal motor, perceptual, and behavioral development. CNS folate and methotrexate levels did not correlate with the presence or absence of symptoms or with their severity. These symptoms are not reported to be reversible and no treatment for them is known. Methotrexate may cause a fulminant dementing process called multifocal leukoencephalopathy, which resembles multiple sclerosis. The features include irritability, insomnia, confusion, tremor, and ataxiaY All of a group of patients studied by Kay and associates 28 had EEG abnormalities from the leukoencephalopathy, and those treated with intravenous folic acid improved. Several authors have felt that the combination of intrathecal methotrexate and cranial irradiation is responsible for this dementing process,52-54 but in a study of the effects ofCNS irradiation alone, no neurologic or psychologic differences were noted 18 months after the treatment in children receiving irradiation as compared with a control group of children. 26 Pathologic studies have shown patchy white-matter destruction,55.56 and computerized axial tomography has been used to follow the course of leukoencephalopathy.57 Among the theories as to the cause of leukoencephalopathy, the most promising is a lowering of CSF folate. Intravenous folic acid may reverse the syndrome, and organic mental disorders and affective disturbances have been described in folic acid deficiency.58.59 Triazinate, another folic acid antagonist, has been limited in its usefulness because of dose-related toxicity. When given intravenously, the drug may cause such symptoms as light-headedness, somnolence, 143
visual disturbance, weakness, and respiratory distress. 60 The purine analogs 6-mercaptopurine and 6-thioguanine are used to treat acute leukemia. Necrosis of fetal forebrain and spinal cord has been reported following the injection of 6-mercaptopurine into 12day-old chick embryos,61 but neurologic or psychiatric toxicity has not been reported following treatment with these agents. Azathioprine is a purine analog that is used as an immunosuppressive agent. Meningitis has occurred after azathioprine administration to SLE patients,62.63 but determining whether these cases represent sequelae of azathioprine or meningitis due to CNS lupus is exceedingly difficult. The main pyrimidine analogs are 5-ftuorouracil (5-FU), ftoxuridine, and cytosine arabinoside. Prenatal and postnatal exposure to pyrimidine analogs may cause cerebellar damage. 64 - 66 5-FU, which readily crosses the blood-brain barrier, is used in treating carcinoma of the breast or gastrointestinal tract. It may produce variable CNS toxicity ranging from a reversible cerebellar ataxia that is not dose-related, to a parkinsonian syndrome including mood lability and impaired concentration when the drug is given at a dose of 15 mg/kg intravenously. Remission occurs several weeks after treatment is discontinued. 67.68 A related agent, ftorafur, may cause ataxia, dizziness, anxiety, confusion, retrograde amnesia, and headache lasting two to four hours after administration. 69 Cytosine arabinoside crosses the bloodbrain barrier and is used in the treatment of adult-onset acute myelogenous leukemia and intrathecally in the treatment ofCNS leukemia. A few instances of irrita146
tive meningitis have been noted, but no long-term behavioral sequelae have been reported. 70.71 Vinca alkaloids Vincristine and vinblastine, the principal vinca alkaloids, act by binding to cell microtubules to block mitosis and thus prevent cellular replication. The two agents differ in their antitumor spectra, potency, and toxic effects. Vincristine is used to treat hematologic malignancies, and vinblastine to treat choriocarcinoma and other solid tumors. Vincristine is unique in that its neurologic toxicity is often doselimiting. 40 The peripheral and autonomic effects are dose-related
Depression or tlllXiety Iuu been "oted ill up to 80% of patimts given villbkutille therapy. and cumulative, but they usually reverse with discontinuation of therapy.72 Central nervous system effects appear later and range from irritability and depression to seizure and coma when a high dose is given. 73 Hallucinations may appear in patients receiving 75 ILg/kg of the drug, and coma may occur with a higher dosage, but the incidence of these effects is less than 5%.73 Rare cases of inappropriate ADH secretion lasting one or two weeks have also been describedY Temporary mental depression, occurring on the second or third day of vinblastine treatment, has also been noted. 40 In fact, depression or anxiety has been noted in up to 80% of patients given vinblastine therapy. This is of particular interest since other indole derivatives, such
as LSD, reserpine, and 5-hydroxytryptophan, are known to produce a variety of mood and behavioral alterations. Antibiotics Antibiotics used in cancer therapy include actinomycin D, mithramy00, bleomycin, doxorubicin, and daunorubicin. Based on animal data, it is probable that, at certain dosage levels, all these agents have central nervous system effects. However, because of their extreme bone marrow toxicity they are generally not used at these levels in humans. Actinomycin D is used in some tumors of childhood, testicular tumors, and choriocarcinoma. It crosses the blood-brain barrier in small amounts, and is used in very low doses because of systemic toxicity. Anorexia, nausea, and vomiting are seen clinically.40 Actinomycin D has been given intracerebrally in animals in an effort to reproduce effects on learning and memory demonstrated by puromycin. Injection of actinomycin D into the cerebrospinal ftuid of animals was found to cause a progressive neurologic dysfunction that is manifested by tremors, nausea, loss of appetite, apathy, and peripheral nerve damage. 74.75 Mithramycin is used in the treatment of embryonal cell carcinoma and for palliation in some forms of hypercalcemia. It is a potent inhibitor of RNA synthesis, and causes a high incidence of anxiety and irritability at clinical doses. Kennedy76 has reported an 86% incidence of CNS reactions including headache, irritability, akathisia, lethargy, and increasing agitation during the course of therapy. These features are dose-related and reversible. Bleomycin is used to treat squaPSYCHOSOMATICS
mous cell carcinoma of the head and neck, testicular neoplasms, and other carcinomas. It inhibits DNA synthesis. Behavioral sequelae were not noted in 274 patients who received the drug,77 though confusion thought to be due to hypertensive encephalopathy was observed in one patient who was receiving bleomycin therapy.78 Doxorubicin and daunorubicin are anthracyclic antibiotics. They bind DNA, causing disordered DNA synthesis. Doxorubicin has a wide spectrum of antitumor activity, whereas daunorubicin is used primarily to treat acute leukemia. Doxorubicin crosses the bloodbrain barrier only at doses above those used clinically. Central nervous system effects are not significant.",80 L-Aspuaginase An enzyme that does not cross the blood-brain barrier, L-asparaginase has been used in the treatment of acute lymphoblastic leukemia, particularly in children. It is also used to treat some malignant lymphomas. Required for the growth of certain tumor cells, it acts by rapidly inhibiting protein synthesis and more slowly inhibiting DNA and RNA syntheses in these tumor cells. The incidence of central nervous system dysfunction following administration of L-asparaginase has been reported to range from 21 % to 60%.81,82 The toxicity appears to occur predominantly in adults and has rarely been reported in children. 83 Psychiatric alterations consist· primarily of affective disturbances of varying degrees or organic mental disorders. 84- 90 Though confusional states, delirium, and stupor have been described, no schizophreniform or manic states FEBRUARY 1980· VOL 21 • NO 2
have been reported. Careful assessment of mental status is not documented in these reports, so it is not clear whether the affective changes occur independently or in the context of a more generalized cerebral dysfunction. Psychiatric presentations have been observed from 2 to 19 days after administration of Lasparaginase,2o but with cessation of treatment the manifestations have promptly remitted. 84 •91 .92 These temporal patterns parallel the liver enzyme changes, such. as increased SGOT and bilirubin, that are noted in three fourths of patients during the first two weeks of treatment with L-asparaginase.
mentlll syndromes OCCUl' slwrtly after administration ofthe ctllWltive agents.
similarity of these EEG changes to the usual findings in hepatic encephalopathy has led some to suggest that the hepatic toxicity of Lasparaginase underlies its CNS sequelae. However, high ammonia concentrations created by Lasparaginase have not been found to impair CNS function,93 and ammonia levels were not seen to coincide with CNS symptoms." Blood asparagine levels do correlate temporally with CNS dysfunction. 89 Dosage of L-asparaginase has not been shown to be clearly related to either the occurrence of psychiatric disturbances or their severity,2o.87 though a more rapid onset of changes has been noted with larger doses. 94 L-asparagine infusion may ameliorate the CNS dysfunction provoked by Lasparaginase,2O,89 but the etiology of this organic mental disorder is as yet unresolved. 95
Ohnuma and associates89 have postulated that the psychiatric effects of L-asparaginase may be biphasic. An acute organic mental disorder may be linked to increments in ammonia and aspartic acid, and a delayed organic mental disorder may be related to decreased protein synthesis and hypoalbuminuria. Mild, reversible cognitive changes may routinely accompany the administration of L-asparaginase. EEG changes occurred in more than 70% of a series of patients treated with the enzyme, though only 21% were behaviorally symptomatic. 81 These changes reversed at the end of therapy. In other studies, electroencephalograms of patients manifesting psychiatric dysfunction from Lasparaginase have been shown to be diffusely abnormal.82.85.88 The
Three miscellaneous agents that deserve mention because of CNS toxicity are procarbazine, mitotane, and cis-platinum. Procarbazine, a hydrazine, is a weak MAO inhibitor that crosses the blood-brain barrier. It is used to treat lymphomas and Hodgkin's disease. A third of patients treated with procarbazine develop depression of the CNS ranging from mild drowsiness to profound stupor; 80% develop nausea and vomiting, sensory changes, and neuritis. 96 These symptoms are accompanied by a pattern of diffuse slow waves on EEG.97 Symptoms start shortly after the initiation of therapy and are apparently reversible. Procarbazine also potentiates the effects of alcohol, barbiturates, and phenothiazines. 98 In one reported instance, a manic episode occurred
The 1lUlj0rity oforganic
subsequent to the administration of procarbazine. 2 \ Mitotane is a derivative of the insecticide DDT and is used to treat carcinoma of the adrenal cortex. Lethargy, somnolence, dizziness, and vertigo develop in 40% of patients so treated, and 3% develop acute confusional states.99 These effects are reversible and doserelated. Cis-platinum is used to treat testicular carcinoma. It produces otoioJtici~y in 30% to 50% of those who receive it,IOO and in experimental doses above 60 mg/kg, it is reported to cause confusion, coma, and death. 30 Summary The effect of cancer chemotherapy agents on the eNS most often results in neurologic presentations, both acute and chronic. Psychiatric sequelae in the absence of neurologic disturbances are rare. The psychiatric presentations are generally either organic mental disorders or affective disorders. The principle agents that have been associated with significant psychiatric toxicity are listed in the Table. Most of the effects appear to be reversible, and a significant number are dose-related. The majority of organic mental disorders occur shortly after administration of the causative agents, but the affective disturbance seen with Lasparaginase, some psychoses produced by steroids, and the behavioral effects of methotrexate may each appear months after treatment. Other psychiatric toxicity may not be identified or appreciated because of the time lag between introduction of a chemotherapeutic agent and development of psychiatric sequelae. The apparent low incidence of
psychiatric sequelae of cancer chemotherapy is encouraging. However, there is an absence of systematic attention to psychiatric evaluation in patients receiving chemotherapy. Few studies address behavioral features, unless they are life-threatening or dose-limiting. Reactive phenomena are not differentiated from physiologic treatment sequelae. Psychiatric diagnostic criteria are seldom uniformly applied, and multiple factors in treatment protocols together with the nature of the underlying illness confound psychiatric assessment of drug effects. Given the interest noted earlier in the psychological adjustment of the patient with cancer, it seems imperative to understand more thoroughly the effects of treatment on psychological and psychiatric function. More careful observation is obviously 0 needed. REFERENCES 1. Holland J: Psychological aspects of oncology. Med Clin North Am 61:737-748,1977. 2. Grinker RR: Psychosomatic aspects of the cancer problem. Ann NY Acad SCi 125:876882,1966. 3. Furman CE: Preliminary studies in animals concerning the relationship between the nervous system and cancer. Ann NY Acad SCi 125:952-958, 1966. 4. Leshan LL, Worthington RE: Personality as a factor in the pathogenesis of cancer: A review of the literature. Br J Med Psychol 21:4-56, 1956. 5. Rogers M, Reich P, Strom T, et al: Behaviorally conditioned immunosuppression: Replication of a recent study. Psychosom Med 31:447-451,1976. 6. Bahnson C: Psychophysiologic complementarity in malignancies: Past work and future vistas. Ann NY Acad SCi 16(3):319334,1969. 7. Shands HC: The informational impact of cancer. Ann NY Acad SCi 125:883-889, 1966. 8. Bard M: Clues to the psychological management of patients w~h cancer. Ann NY Acad SCi 125:995-999, 1966. 9. Mastrov~o RC: Acute psychiatric problems and the use of psychotropic medication in the treatment of the cancer patient. Ann NY Acad SCi 125:1006-1010, 1966. 10. Feder SL: Psychological considerations in the care of patients with cancer. Ann NY Acad Sci 125:1020-1027,1966.
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The Academy of Psychosomatic Medicine Announces
A Continuing Medical Education Workshop in Psychosomatic Medicine Don CeSar Beach Resort Hotel Friday and Saturday
St. Petersburg Beach, Fla. April 11-12, 1980
Intensive Care Unit.: Process and Rehabilitation A Dale Gulledge. M.D., F.A.P.M. Cleveland Clinic
Psychosomatic Patients: Dynamics In Evaluation and Treatment H. Keith Fischer, M.D., F.A.P.M. Temple University
Organic Brain Syndrome. Gerald C. Peterson, M.D. Mayo Clinic
Emotional Aspects of Phy.lcan Retirement: Anticipation and Adaptation Joseph V. Fisher, MD., F.A.P M. Medical University of South Carolina
Workshop co-chalrmen: M.J. Martin, M.D., F.A.P.M., Mayo CliniC Barney M. Olin. M.D., F.A.P.M , Temple UniverSity Each partiCipant will attend a Single workshop-study group In order to obtain an In·depth review of an Important area, utiliZing a distinguished faculty member as a resource person. A limited number of participants Will be accepted for each group so that each person attending may become Involved In the open-ended group discussions. A plenary session at
the end of the meeting will review the highlights of each group's discussions. Adequate open time Will be prOVided to rela and to continue diSCUSSions related 0 the workshop tOPiCS. TUition IS $40, which includes continental breakfasts and coffee breaks. ThiS program IS accredited for 8 hours of AMA Category I CME credit.
To register or obtain further Information, contact: Academy of Psychosomatic Medicine. 70 West Hubbard, SUite 202 • Chicago. IL 60610 Telephone 312-644-2623
FEBRUARY 1980· VOL 21 • NO 2