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The role of the neurologist in the management of cancer
The Role of the Neurologist in the Management of Cancer
JEROME B. POSNER, M.D. New York, New York
Do neurologists need to be more involved in the management of patients with cancer? There is growing support for such a contention-it is even becoming a subspecialty. Neuro-oncology is the relatively new subspecialty of neurology which deals with the diagnosis and treatment of patients suffering from neurologic complications of systemic cancer as well as from involvement of the nervous system by primary neoplasms and from pain caused directly or indirectly by systemic neoplasia. Oncologists and internists do not usually consult neurologists when managing patients with systemic cancer. There are several reasons for this. Most neurologic complications of cancer occur late in the course of metastatic disease and are often viewed as terminal manifestations for which treatment is neither required nor desirable. Furthermore, when neurologists are consulted, they are frequently not helpful. Common neurologic syndromes may have uncommon causes when they occur in patients with systemic cancer (e.g., strokes are more likely due to nonbacterial thrombotic endocarditis than to hypertensive or arteriosclerotic cerebrovascular disease); consequently, neurologists without specific training or experience in neuro-oncology are less likely to arrive at the correct diagnosis. However, the situation is now changing. New developments in cancer therapy have led many physicians to treat patients with systemic cancer more aggressively and often more effectively. As a result, neurologic complications often become limiting; of necessity internists are assuming a more activist attitude toward the diagnosis and treatment of patients with these complications. This situation, I believe, requires neurologists to become more interested in neuro-oncology and requires oncologists and internists caring for patients with cancer to seek neurologic assistance more frequently. The rationale for my belief is as follows: (1) NERVOUS SYSTEM COMPLICATIONS COMMON.
From the Department of Neurology Memorial Sloan-Kettering Cancer Center, and Cornell University Medical College, New York, New York. Requests for reprints sholuld be addressed to Dr. Jerome 8. Posner. 1275 j ‘ark Avenue, New York, New York 10021. Manusczipt accepted April 13, 1978.
4
July 1978
The American Journal of Medicine
OF CANCER ARE
Cancer is the nation’s second leading cause of death. In 1977 there were 690,000 new cases of cancer and 365,000 cancer deaths. Approximately 85,000 of these patients died with intracranial metastases [l], at least half of whom had neurologic symptoms during life. Moreover, intracranial metastases are only one of several neurologic complications of systemic cancer, and-if one considers all such complications, the prevalence of neurologic disease increases correspondingly. At Memorial Sloan-Kettering Cancer Center (MSKCC) in 1977 the neuro-oncology service evaluated for significant neurologic
Volume 85
ROLE OF THE NEUROLOGIST IN MANAGEMENT OF CANCER-POSNER
disability over 1,800 of the 13,000 adults admitted (14 per cent). One-third of the brains examined at autopsy at MSKCC have significant pathologic lesions which include not only cerebral metastases but also cancerrelated vascular lesions, such as hemorrhages and infarction, and central nervous system infections. (2) THE INCIDENCE OF NEUROLOGIC COMPLICATIONS OF CANCER IS INCREASING. Our autopsy data show a steady increase in the postmortem incidence of cerebral metastases and feptomeningeal carcinomatosis from 1970 through 1976 [ 11. Others have remarked on the increasing incidence of cerebral metastases from childhood sarcomas and testicular tumors as well as the increased incidence of leptomeningeal carcinomatosis in patients with carcinoma of the breast and oat cell carcinoma. The reason for this increase is not clear and trivial explanations may be offered (e.g., (a) the greater clinical recognition of leptomeningeal carcinomatosis and cerebral metastases may have led to more accurate diagnosis during life, and (b) some patients may be living longer, allowing wider dissemination of metastases to all organs.) However, it is also possible that the central nervous system represents a sanctuary for neoplastic cells elsewhere controlled by parenteral chemotherapy. According to this view, the increased incidence of central nervous system complications merely recapitulates the experience with acute lymphoblastic leukemia: Meningeal leukemia was an uncommon disorder before effective chemotherapy for the systemic illness was developed. Once effective systemic therapy became available, the incidence of meningeal leukemia increased rapidly until, in the late 1960’s, it reached approximately 50 per cent. Following the introduction of central nervous system prophylaxis, meningeal leukemia once again became an uncommon complication of acute lymphoblastic leukemia. (3) NEUROLOGIC COMPLICATIONS ARE SERIOUS.
OF CANCER
Many patients with systemic cancer, even those with widespread metastases, can be helped by therapy to function normally for prolonged periods. However, once neurologic complications supervene with their attendant behavioral alterations and impairment of cognition, motor and autonomic function, the patient’s clinical status changes dramatically. A patient who was able to work suddenly becomes bedridden or requires long-term hospitalization. To the degree that a cancer-related neurologic disability can be reversed, a patient may again be returned to his previous level of functioning.
(4) NEUROLOGIC DIAGNOSIS DIFFICULT.
IS OFTEN
A large number of both metastatic and nonmetastatic complications affect the nervous system, often with similar clinical presentations. Meticulous and sophisticated clinical and laboratory evaluation is frequently required in order to reach a definitive diagnosis [2]. The metastatic complications include intracranial, spinal, leptomeningeal and peripheral nerve lesions. Among the nonmetastatic complications are the following: Metabolic encepI)e/opathy in patients with cancer has a variety of causes, including failure of vital organs (liver, kidney, lung, thyroid, adrenal), electrolyte imbalances, depletion of substrates and essential nutrients (e.g., hypercalcemia, hyponatremia, hypoglycemia, vitamin deficiency), drug overdose (e.g., narcotics given to relieve pain) and sepsis. Central nervous system infections occur commonly in patients with cancer whose immune responses are also suppressed. The most common causes of meningitis are Listeria monocytogenes and Cryptococcus neoformans. Abscess formation in the brain is usually caused by fungi, such as Mucor or Aspergillus, by parasites (e.g., toxoplasmosis), or by viruses (e.g., progressive multifocal leukoencephalopathy). Central nervous system vascular disease frequently complicates systemic cancer. Intracranial hemorrhage occurs when patients become thrombocytopenic or when clotting disorders develop. Cerebral infarction in cancer patients is usually embolic, not arteriosclerotic, and is associated with nonbacterial thrombotic endocarditis. Disseminated intravascular coagulation and tumor emboli from the lungs may also cause cerebral infarction. Complications of therapy appear to be increasing in number as radiation therapists and chemotherapists become more aggressive and more effective in the treatment of primary neoplasms. Finally, there are a rare but interesting group of disorders referred to as “remote effects” of cancer on the nervous system. The cause of these disorders is unknown. Their clinical importance derives from the fact that they often precede the appearance of symptomatic neoplasia, and the physician may, if he searches for an occult neoplasm, discover a tumor which is small and potentially curable. Pain in patients with cancer has a variety of causes, often nonmetastatic, and it, like other neurologic disorders, requires meticulous neurologic evaluation. (5) THERAPY IS USEFUL. If an appropriate diagnosis can be made, aggressive therapy directed at the nervous system complication frequently relieves symptoms and prolongs life. Consider, for example, those patients in whom signs and
July 1978
The American
Journal of Medlclne
Volume
85
5
ROLE OF THE NEUROLOGIST IN MANAGEMENT OF CANCER-POSNER
symptoms of epidural spinal cord compression develop. If the diagnosis is made early, at a time when the patient is still ambulatory, and therapy is instituted without delay (whether it be radiation therapy alone or decompressive laminectomy followed by radiation therapy), two-thirds of the patients remain ambulatory for six months to a year [3]. If, however, the diagnosis is made when the patient is paraplegic, there is virtually no chance that he will ever walk again, no matter what therapy is undertaken. Paraplegia certainly diminishes the quality of the patient’s remaining life and probably, because of its attendant complications, shortens his life span as well. (6) SOME PROBLEMS IN NEURO-ONCOLOGY ARE UNIQUE. Remote effects of cancer on the nervous system and leptomeningeal carcinomatosis, and its treatment with intrathecal drugs, represent unusual clinical problems best understood in neurophysiologic rather than in oncologic terms. There are side effects of radiation and chemotherapy which are unique to nervous tissue. The relationship of the blood-brain barrier to metastatic disease, and its treatment, is an area of increasing controversy [ 41. The discovery of opiate receptors and beta endorphins suggest that pain relief is rapidly becoming a problem in applied neuropharmacology. (7) RELATIONSHIPS BETWEEN THE BRAIN AND SYSTEMIC CANCER ARE IMPORTANT. There are tantalizing hints that the central nervous system and systemic cancer bear some special rela-
tionship to one another which, if unraveled, may help us to understand the biology of both. The fact that an occult neoplasm can produce degeneration of a specific part of the nervous system, such as, for example, subacute cerebellar degeneration or subacute sensory neuropathy, and that such degeneration may be associated with circulating antibody against nervous tissue, suggests a relationship between the nervous system and systemic neoplasms, perhaps via shared surface antigens. Even less well understood, but equally tantalizing, is the observation made by the late George Cotzias [5] that in several genetic strains of mice an inverse relationship exists between the incidence of spontaneous mammary cancer and the activity of dopamine-stimulated adenyl cyclase in the caudate nucleous. The brain may play a major role in the control of the immune system and of our resistance against cancer, and systemic cancer when it develops may play a major role in altering central nervous system function, including behavior. Such hints demand the attention of serious neuroscientists. For all these reasons, the time has come for central nervous system complications of systemic cancer to be taken seriously and to be attacked aggressively and collaboratively by physicians and scientists interested in both oncology (internal medicine) and neurology. It is the obligation of those who deal with cancer to call upon their neurologic colleagues for help, both in the management of patients and in the investigation of relationships between cancer and the central nervous system.
REFERENCES 1. Posner JB, Chernik NL: intracranial metastases from systemic cancer. Adv Neurol 19: 575, 1978. 2. Posner JB: Neurological complications of systemic cancer. Med Clin North Am 55: 625, 1971. 3. Posner JB, Gilbert RW: Epidural spinal cord compression from metastatic tumor. Ann Neurol 3: 40, 1978.
6
Juiy 1978
The American Journal of Medicine
Volume 85
4. Vick NA, Khandekar JD, Bigner DD: Chemotherapy of brain tumors. Arch Neurol 34: 523, 1977. 5. Cotzias GC, Tang LC: An adenylate cyclase of brain reflects propensity for breast cancer in mice. Science 197: 1094. 1977.
JEROME B. POSNER, M.D. New York, New York
Do neurologists need to be more involved in the management of patients with cancer? There is growing support for such a contention-it is even becoming a subspecialty. Neuro-oncology is the relatively new subspecialty of neurology which deals with the diagnosis and treatment of patients suffering from neurologic complications of systemic cancer as well as from involvement of the nervous system by primary neoplasms and from pain caused directly or indirectly by systemic neoplasia. Oncologists and internists do not usually consult neurologists when managing patients with systemic cancer. There are several reasons for this. Most neurologic complications of cancer occur late in the course of metastatic disease and are often viewed as terminal manifestations for which treatment is neither required nor desirable. Furthermore, when neurologists are consulted, they are frequently not helpful. Common neurologic syndromes may have uncommon causes when they occur in patients with systemic cancer (e.g., strokes are more likely due to nonbacterial thrombotic endocarditis than to hypertensive or arteriosclerotic cerebrovascular disease); consequently, neurologists without specific training or experience in neuro-oncology are less likely to arrive at the correct diagnosis. However, the situation is now changing. New developments in cancer therapy have led many physicians to treat patients with systemic cancer more aggressively and often more effectively. As a result, neurologic complications often become limiting; of necessity internists are assuming a more activist attitude toward the diagnosis and treatment of patients with these complications. This situation, I believe, requires neurologists to become more interested in neuro-oncology and requires oncologists and internists caring for patients with cancer to seek neurologic assistance more frequently. The rationale for my belief is as follows: (1) NERVOUS SYSTEM COMPLICATIONS COMMON.
From the Department of Neurology Memorial Sloan-Kettering Cancer Center, and Cornell University Medical College, New York, New York. Requests for reprints sholuld be addressed to Dr. Jerome 8. Posner. 1275 j ‘ark Avenue, New York, New York 10021. Manusczipt accepted April 13, 1978.
4
July 1978
The American Journal of Medicine
OF CANCER ARE
Cancer is the nation’s second leading cause of death. In 1977 there were 690,000 new cases of cancer and 365,000 cancer deaths. Approximately 85,000 of these patients died with intracranial metastases [l], at least half of whom had neurologic symptoms during life. Moreover, intracranial metastases are only one of several neurologic complications of systemic cancer, and-if one considers all such complications, the prevalence of neurologic disease increases correspondingly. At Memorial Sloan-Kettering Cancer Center (MSKCC) in 1977 the neuro-oncology service evaluated for significant neurologic
Volume 85
ROLE OF THE NEUROLOGIST IN MANAGEMENT OF CANCER-POSNER
disability over 1,800 of the 13,000 adults admitted (14 per cent). One-third of the brains examined at autopsy at MSKCC have significant pathologic lesions which include not only cerebral metastases but also cancerrelated vascular lesions, such as hemorrhages and infarction, and central nervous system infections. (2) THE INCIDENCE OF NEUROLOGIC COMPLICATIONS OF CANCER IS INCREASING. Our autopsy data show a steady increase in the postmortem incidence of cerebral metastases and feptomeningeal carcinomatosis from 1970 through 1976 [ 11. Others have remarked on the increasing incidence of cerebral metastases from childhood sarcomas and testicular tumors as well as the increased incidence of leptomeningeal carcinomatosis in patients with carcinoma of the breast and oat cell carcinoma. The reason for this increase is not clear and trivial explanations may be offered (e.g., (a) the greater clinical recognition of leptomeningeal carcinomatosis and cerebral metastases may have led to more accurate diagnosis during life, and (b) some patients may be living longer, allowing wider dissemination of metastases to all organs.) However, it is also possible that the central nervous system represents a sanctuary for neoplastic cells elsewhere controlled by parenteral chemotherapy. According to this view, the increased incidence of central nervous system complications merely recapitulates the experience with acute lymphoblastic leukemia: Meningeal leukemia was an uncommon disorder before effective chemotherapy for the systemic illness was developed. Once effective systemic therapy became available, the incidence of meningeal leukemia increased rapidly until, in the late 1960’s, it reached approximately 50 per cent. Following the introduction of central nervous system prophylaxis, meningeal leukemia once again became an uncommon complication of acute lymphoblastic leukemia. (3) NEUROLOGIC COMPLICATIONS ARE SERIOUS.
OF CANCER
Many patients with systemic cancer, even those with widespread metastases, can be helped by therapy to function normally for prolonged periods. However, once neurologic complications supervene with their attendant behavioral alterations and impairment of cognition, motor and autonomic function, the patient’s clinical status changes dramatically. A patient who was able to work suddenly becomes bedridden or requires long-term hospitalization. To the degree that a cancer-related neurologic disability can be reversed, a patient may again be returned to his previous level of functioning.
(4) NEUROLOGIC DIAGNOSIS DIFFICULT.
IS OFTEN
A large number of both metastatic and nonmetastatic complications affect the nervous system, often with similar clinical presentations. Meticulous and sophisticated clinical and laboratory evaluation is frequently required in order to reach a definitive diagnosis [2]. The metastatic complications include intracranial, spinal, leptomeningeal and peripheral nerve lesions. Among the nonmetastatic complications are the following: Metabolic encepI)e/opathy in patients with cancer has a variety of causes, including failure of vital organs (liver, kidney, lung, thyroid, adrenal), electrolyte imbalances, depletion of substrates and essential nutrients (e.g., hypercalcemia, hyponatremia, hypoglycemia, vitamin deficiency), drug overdose (e.g., narcotics given to relieve pain) and sepsis. Central nervous system infections occur commonly in patients with cancer whose immune responses are also suppressed. The most common causes of meningitis are Listeria monocytogenes and Cryptococcus neoformans. Abscess formation in the brain is usually caused by fungi, such as Mucor or Aspergillus, by parasites (e.g., toxoplasmosis), or by viruses (e.g., progressive multifocal leukoencephalopathy). Central nervous system vascular disease frequently complicates systemic cancer. Intracranial hemorrhage occurs when patients become thrombocytopenic or when clotting disorders develop. Cerebral infarction in cancer patients is usually embolic, not arteriosclerotic, and is associated with nonbacterial thrombotic endocarditis. Disseminated intravascular coagulation and tumor emboli from the lungs may also cause cerebral infarction. Complications of therapy appear to be increasing in number as radiation therapists and chemotherapists become more aggressive and more effective in the treatment of primary neoplasms. Finally, there are a rare but interesting group of disorders referred to as “remote effects” of cancer on the nervous system. The cause of these disorders is unknown. Their clinical importance derives from the fact that they often precede the appearance of symptomatic neoplasia, and the physician may, if he searches for an occult neoplasm, discover a tumor which is small and potentially curable. Pain in patients with cancer has a variety of causes, often nonmetastatic, and it, like other neurologic disorders, requires meticulous neurologic evaluation. (5) THERAPY IS USEFUL. If an appropriate diagnosis can be made, aggressive therapy directed at the nervous system complication frequently relieves symptoms and prolongs life. Consider, for example, those patients in whom signs and
July 1978
The American
Journal of Medlclne
Volume
85
5
ROLE OF THE NEUROLOGIST IN MANAGEMENT OF CANCER-POSNER
symptoms of epidural spinal cord compression develop. If the diagnosis is made early, at a time when the patient is still ambulatory, and therapy is instituted without delay (whether it be radiation therapy alone or decompressive laminectomy followed by radiation therapy), two-thirds of the patients remain ambulatory for six months to a year [3]. If, however, the diagnosis is made when the patient is paraplegic, there is virtually no chance that he will ever walk again, no matter what therapy is undertaken. Paraplegia certainly diminishes the quality of the patient’s remaining life and probably, because of its attendant complications, shortens his life span as well. (6) SOME PROBLEMS IN NEURO-ONCOLOGY ARE UNIQUE. Remote effects of cancer on the nervous system and leptomeningeal carcinomatosis, and its treatment with intrathecal drugs, represent unusual clinical problems best understood in neurophysiologic rather than in oncologic terms. There are side effects of radiation and chemotherapy which are unique to nervous tissue. The relationship of the blood-brain barrier to metastatic disease, and its treatment, is an area of increasing controversy [ 41. The discovery of opiate receptors and beta endorphins suggest that pain relief is rapidly becoming a problem in applied neuropharmacology. (7) RELATIONSHIPS BETWEEN THE BRAIN AND SYSTEMIC CANCER ARE IMPORTANT. There are tantalizing hints that the central nervous system and systemic cancer bear some special rela-
tionship to one another which, if unraveled, may help us to understand the biology of both. The fact that an occult neoplasm can produce degeneration of a specific part of the nervous system, such as, for example, subacute cerebellar degeneration or subacute sensory neuropathy, and that such degeneration may be associated with circulating antibody against nervous tissue, suggests a relationship between the nervous system and systemic neoplasms, perhaps via shared surface antigens. Even less well understood, but equally tantalizing, is the observation made by the late George Cotzias [5] that in several genetic strains of mice an inverse relationship exists between the incidence of spontaneous mammary cancer and the activity of dopamine-stimulated adenyl cyclase in the caudate nucleous. The brain may play a major role in the control of the immune system and of our resistance against cancer, and systemic cancer when it develops may play a major role in altering central nervous system function, including behavior. Such hints demand the attention of serious neuroscientists. For all these reasons, the time has come for central nervous system complications of systemic cancer to be taken seriously and to be attacked aggressively and collaboratively by physicians and scientists interested in both oncology (internal medicine) and neurology. It is the obligation of those who deal with cancer to call upon their neurologic colleagues for help, both in the management of patients and in the investigation of relationships between cancer and the central nervous system.
REFERENCES 1. Posner JB, Chernik NL: intracranial metastases from systemic cancer. Adv Neurol 19: 575, 1978. 2. Posner JB: Neurological complications of systemic cancer. Med Clin North Am 55: 625, 1971. 3. Posner JB, Gilbert RW: Epidural spinal cord compression from metastatic tumor. Ann Neurol 3: 40, 1978.
6
Juiy 1978
The American Journal of Medicine
Volume 85
4. Vick NA, Khandekar JD, Bigner DD: Chemotherapy of brain tumors. Arch Neurol 34: 523, 1977. 5. Cotzias GC, Tang LC: An adenylate cyclase of brain reflects propensity for breast cancer in mice. Science 197: 1094. 1977.