CHAPTER 38 Management of the Tumor Patient
Primary brain cancer, those tumors that arise from the substance of brain itself, account for 1% of all cancers.1,2 Approximately 14 per 100,000 people in the United States are diagnosed with primary brain tumors each year. Of these, roughly 7 per 100,000 are diagnosed with a primary malignant brain tumor and will account for approximately 2% of all cancer-related deaths. Brain tumors most commonly occur in the fifth and sixth decades of life but are the second most common form of cancer in childhood next to leukemia. Recently, there has been conjecture that the incidence of brain tumor is increasing. Analysis of this speculation is complicated by diagnostic discrepancies and ascertainment bias in registry data. However, after extensive review, this apparent increase is most likely due to factors such as better diagnostic procedures, improved access to medical care, and enhanced care for the elderly, all leading to greater detection rather than an actual increase in incidence. Nevertheless, more standardized and unbiased diagnosis and registration methods must become established and widely used before such speculation is truly resolved.
Metastases to the brain occur at some point in 10% to 15% of persons with cancer and are more common than primary brain tumors. Tumors arising in any other part of the body (most commonly from lung, breast, kidney, and skin) may metastasize to the brain; metastatic tumors to the brain are usually multiple, although a solitary metastasis can mimic a primary brain tumor.
Primary brain tumors may develop from any of the types of cells found in the brain.3 Tumors may originate from nerve cells or neurons; however, tumors of the supporting cells known as “glial” cells (including astrocytes, oliogodendrocytes, ependymal cells) are more common. A tumor is generally named after the cell of origin. Thus, a tumor derived from glial cells is known as a glioma. To be more specific, a tumor from astrocytic cells is called an astrocytoma and a tumor from the ependymal cells is called an ependymoma. Tumors of the neurons include neuroblastoma, neurocytoma, and ganglioneuromas. Meningiomas are tumors that originate from cells in the meninges. Other tumors include those derived from specialized brain structures such as the pineal gland, pituitary gland, or choroid plexus.
Normally, brain tumors are graded pathologically on the basis of the most malignant or aggressive area identified according to the World Health Organization (WHO) II grading system. The grade of a tumor refers to how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and thus correlates to the prognosis of the patient. For example, astrocytomas are graded on a scale from 1 to 4, with grade 1 being the slowest growing and grade 4 being the most rapidly growing and malignant lesions.
Research into the causes of brain tumors is complicated by many factors, including the relative rarity of the disease and swift death of patients with aggressive subtypes. Most brain tumors have no known cause and, to date, studies have revealed little with regard to specific causes. Some inherited conditions do predispose a person to the development of brain tumors. For instance, patients with neurofibromatosis type 1 (NF1), tuberous sclerosis, and familial polyposis have a tendency to develop astrocytomas. However, these syndromes explain less than 5% of brain tumor cases.
Viruses are known to produce genetic changes in cells that in laboratory animals can induce the formation of a tumor. There is an association in people infected with the Epstein-Barr virus and primary central nervous system (CNS) lymphoma and perhaps glioma, although a definite causal relationship remains to be established. Radiation can produce genetic damage in cells and induce tumors. It was once standard medical practice to use low doses of radiation to treat ringworm of the scalp in children. Years later it was found that children treated this way had an increased chance of developing tumors of the scalp, skull, and brain, particularly meningioma. These radiation-associated tumors have a much greater likelihood of being malignant than those that occur spontaneously, although they account for only a small proportion of cases.
The field of molecular genetics is devoted to understanding the changes that transpire in cells that allow them to acquire characteristics of cancer cells and form tumors. Many of these cell alterations have been identified, although the process of how these changes lead to the development of tumors still requires further investigation. A variety of statistical and environmental associations have been made, but no chemical or environmental agent has been shown to cause brain tumors. Several genetic abnormalities in genes governing growth factor–signaling pathways or cell-cycle control are evident in glioma. Discovering how and why these genetic mutations occur may lead to an improved understanding of the disease and to better treatments.
The undifferentiated character of brain tumors and recent investigation into cancer stem cells has fueled debate as to whether neural stem cells give rise to brain tumors via acquisition of oncogenic mutations. Until relatively recently, the adult brain was thought to be a static environment. It is now known that several regions of the brain contain cells capable of proliferation. Such cells are either stem cells (multipotent and self-renewing) or progenitor cells (self-renewing precursors capable of producing astrocytes or oligodendrocytes). Thus, either stem cells or progenitor cells, in addition to differentiated glia, could be the substrate for neoplastic transformation into brain tumors.4
Symptoms of brain tumors are produced by the tumor mass, the nearby brain edema, and the damage of normal tissue caused by tumor infiltration. Brain tumors can cause either generalized or focal neurologic symptoms.
Included within the generalized category are those symptoms related to increased intracranial pressure (ICP) and seizures. As a tumor grows, it occupies space and causes swelling in the surrounding brain. Because the brain is in a rigid and unyielding skull, only a limited amount of tumor mass and swelling is tolerated before symptoms are produced by increased pressure from the tumor. The symptoms produced by increased ICP include headache, nausea, vomiting, exhaustion, imbalance, and blurred or double vision.
Headache occurs in approximately 50% of patients with brain tumors. The headaches usually are not severe and are classically more noticeable in the morning, tend to improve later in the day, and worsen with coughing or straining. Of course, headache is a nonspecific symptom, occurring in most people as the result of many causes other than a brain tumor. Furthermore, the most distinguishing feature of a brain tumor headache is its association with other neurologic symptoms such as personality changes, weakness, or seizures.
Seizures in patients with brain tumors may occur at initial presentation and/or during the course of disease. The incidence of seizures at presentation of a brain tumor varies with histologic subtype, ranging from 90% in patients with low-grade gliomas to 35% of patients with glioblastoma multiforme. Whether a tumor will produce a seizure and what type of seizure likely depends on the location and growth rate of the tumor. Seizures are more frequent when the tumor is cortical and slow growing. When a seizure occurs for the first time in an adult, a thorough evaluation, which includes a neurologic examination and a diagnostic brain scan, should be done. However, not everyone with a seizure will have a brain tumor and not everyone with a brain tumor will have a seizure.
Although the incidence of seizures in patients with brain tumors is variable, the use of antiepileptic drugs in this patient population is common. However, randomized controlled studies demonstrate that prophylactic antiepileptic drugs are unlikely to be useful in patients with brain tumors who have not had a seizure. The American Academy of Neurology’s practice parameters state that antiepileptic drugs should be used in brain tumor patients who experience a seizure. They also state that prophylactic antiepileptic drugs should not be administered to patients with newly diagnosed brain tumors and should be discontinued in the first postoperative week in patients who have not experienced a seizure.
Antiepileptic drugs also are associated with adverse effects or drug interactions that require change in medication in up to 23% of patients. Such drug interactions may alter the type and severity of toxicity that patients experience while on chemotherapy. For example, patients taking paclitaxel or irinotecan while taking enzyme-inducing antiepileptic drugs may have lower than expected plasma levels and higher than expected tolerated doses. As a result of this, more recent brain tumor clinical trials exclude patients on enzyme-inducing antiepileptic drugs or stratify patients into those on and off these agents.
The second category of symptoms occurs because of focal or localized brain dysfunction. A tumor may invade or compress the surrounding brain. Depending on the extent or location of the tumor, the normal function of the brain at that location may be impaired. This loss of function may be noticed as numbness or weakness of an arm or a leg, loss of vision, difficulties with speech, and impaired memory and judgment. A brief location-specific discussion of symptoms follows:
Frontal lobes of the brain: Tumors in the frontal lobe often cause changes in decision-making ability or mood. If the left frontal lobe is involved, the patient may experience difficulty with speaking.
Temporal lobes of the brain: A tumor in the left temporal lobe may lead to difficulty understanding speech, whereas right-sided lesions may disturb the perception of musical notes or quality of speech. Temporal lobe involvement may also cause olfactory or gustatory seizures in which the patient experiences odd smells or tastes; these events may be accompanied by lip smacking or licking movements and an impaired level of alertness. More generalized involvement of the temporal lobes may lead to emotional changes, behavioral difficulties, and auditory hallucinations.
Parietal lobes of the brain: Tumors of the parietal lobe may cause loss of sensation or sensory seizures. Sensory loss may result in the feeling of numbness on one side of the body or an inability to detect where one’s limbs are without looking at them with the eyes. If the left parietal lobe is affected, the patient may experience difficulty with reading or writing.
Cerebellum: In the case of cerebellar tumors, if the middle of the cerebellum is affected, the patient will experience difficulty with balance while standing. If one of the hemispheres of the cerebellum is affected, the patient will experience incoordination of the ipsilateral arm and leg.
Spinal cord: Patients with primary spinal tumors generally present with pain in a portion of the body or of an arm or leg. The onset of symptoms may be gradual or fast, and generally one side of the body is more affected than the other. The exact set of symptoms depends on which spinal cord level is affected. In general, cervical spinal cord tumors affect the arms, shoulders, and neck regions. Thoracic or truncal tumors affect the abdominal muscles and region. Lumbosacral tumors may affect the legs, pelvic region, and bladder.
When a brain tumor is suspected, the initial step in evaluation is brain imaging with CT or MRI. These images will assist the neurosurgeon in determining the location and size of the tumor and whether a biopsy or surgical resection should be performed. The images also will likely be used by the radiation oncologist to develop a precise treatment plan of radiation to the specific area of the tumor. These scans are repeated during the course of treatment to determine how the tumor is responding. The exact type of imaging study chosen will depend on the preferences of the treating physicians and may be influenced by the results of an initial scan. MRI is generally the preferred study because it provides a more accurate three-dimensional reconstruction of the tumor, which can better guide surgical resection or biopsy. MR images also provide the best definition between normal brain and tumors and can best depict the swelling associated with these tumors.
Routine blood tests are performed as a baseline and followed as treatment is given. Some tumors secrete substances that can be measured in the blood and cerebrospinal fluid (CSF). CSF may also be examined for tumor cells from tumors that have a tendency to spread from the brain into the spinal cord or its covering. A lumbar puncture may be risky when there is increased intracranial pressure.
It is rare for most primary brain tumors to spread outside the CNS so staging procedures of organs in the rest of the body are not routinely performed. Certain brain tumors do have a tendency to spread not only in the brain but also into the spinal cord. These tumors include primary CNS lymphoma, medulloblastoma, pineoblastoma, germ cell tumors, and ependymoma. When these kinds of tumor are suspected or diagnosed, staging of the spinal cord is also required. This staging process typically includes preoperative MRI of both the brain and spine and a lumbar puncture to obtain CSF for microscopic evaluation.
When a metastatic tumor of the brain is discovered, a thorough staging of the rest of the body should be performed, typically with CT of the chest and abdomen. Treatment of a patient with a metastatic brain tumor will depend on the extent of spread of the primary tumor.
• Even tumors regarded as slow growing or benign can produce symptoms as severe and life threatening as malignant tumors. This is because they may occur in a vital area of the brain or because when they reach a critical size there is no room for them to expand within the surrounding skull, which puts significant pressure on key structures.
• Treatment of a tumor can result in a new neurologic deficit. For example, a temporary or permanent loss of function can occur after surgery and problems of brain swelling can occur during radiation treatments.
• Unless a dramatic, early and sustained improvement occurs after therapy, it may be difficult to determine the response to treatment. Treatments may produce temporary neurologic deterioration that might take weeks or months to improve.
Surgery is the initial treatment for primary brain tumors. The principal goal of surgery is to determine the pathology and grade of tumor and to remove as much of the tumor as possible without causing a loss of neurologic function. A few types of brain tumors may be completely removed and the patient cured, but surgery alone is not sufficient to cure a patient with a higher-grade or malignant tumor, and other forms of treatment are required. Surgically reducing the size of the tumor may improve the effectiveness of these other therapies.
Another goal of surgical resection is to improve a patient’s neurologic condition. Surgical removal of a tumor will reduce ICP, and a focal neurologic deficit may improve or resolve. The frequency of seizures may also be reduced by surgery. Tumors can block the CSF pathways in the brain, leading to hydrocephalus, which can be associated with symptoms of increased ICP. To relieve these symptoms, it is sometimes necessary to place a ventriculoperitoneal shunt into the ventricles.
Specialized equipment used during surgery includes a microscope to magnify the area of interest, an ultrasonic aspirator that helps break up the tumor, lasers that vaporize tumor tissue, ultrasound localizing equipment, and computer-based navigational equipment to help the surgeon define the tumor’s boundaries. Specialized techniques also are used to remove a tumor located near speech or motor brain regions. The surface of the brain can be stimulated with an electrical current to “map” the function of a particular part of the brain. This is referred to as speech or motor “mapping.” A decision can then be made as to whether it is safe to remove that part of the tumor. Speech mapping is done with the patient under sedation and local anesthesia and requires cooperation by the patient. Motor mapping requires the use of general anesthesia.
Radiation therapy is commonly used in the treatment of both primary and metastatic brain tumors.5 The treatments are designed to maximize the lethal effects of radiation on the tumor and minimize the harmful effects to the surrounding brain. Whole-brain irradiation is rarely indicated for most brain tumors. Instead, computer-generated models are used to plan the dose and area of irradiation in a pattern that is “conformal” to any residual tumor not removed during surgery and to a margin surrounding the tumor and surgical cavity. Radiation treatments are generally given once a day, 5 days a week, for up to 6 weeks. A patient then generally receives a 2- to 3-week break from any type of therapy before subsequent imaging studies (e.g., MRI) are performed to assess whether the tumor responded to radiation. Some patients may experience fatigue during radiation therapy; others may develop neurologic problems such as headaches or weakness related to irradiation-induced brain swelling. If such swelling occurs, the problem is usually brief and may be treated with corticosteroid medication to alleviate the swelling.
A full course of conventional or conformal radiation is usually administered only once. Exposing the brain to further radiation may produce brain injury and create a disabling or a life-threatening problem. However, new methods of delivering additional focal radiation to brain tumors are used in special scenarios. For example, stereotactic radiosurgery (“gamma knife or cyber knife”) may be used to deliver precisely focused radiation beams at a small area of residual or recurrent tumor while the surrounding brain is spared the adverse effects. These approaches require that the tumor be small and in an area of the brain that could tolerate a radiation injury without causing the loss of an important function.
Chemotherapy may be effective and is frequently used before, during, or after surgery and irradiation.6 It can also be used at the time of diagnosis and for a recurrence. Some tumors in the brain can be exquisitely sensitive to chemotherapy, including germ cell tumors, lymphomas, and some oligodendrogliomas. One difficulty in treating brain tumors with chemotherapy is that the drugs do not easily pass through the blood vessels in the brain into the brain parenchyma where the tumor is located. Some experimental approaches have investigated ways to open this blood-brain barrier with drugs, whereas others have attempted to directly inject drugs into the major arteries feeding a tumor. Additional research is ongoing on developing strategies for injecting antitumor agents directly into the brain.
There are many novel biologic drugs in development that are not necessarily cytotoxic like traditional chemotherapy drugs. Instead they are designed to prevent further tumor growth and are commonly referred to as molecularly targeted agents. The hope of these approaches is that the treatment will affect only the tumor cells, sparing the rest of the body or brain of toxic effects.
Astrocytomas are categorized by their grade of malignancy.7 The WHO II classification of astrocytoma includes low-grade astrocytoma (grade I or II), anaplastic astrocytoma (grade III), and glioblastoma multiforme (grade IV).
• Treatment: This tumor is often treated only with complete surgical removal. However, even these patients must obtain serial MR images to make sure that the tumor does not recur. When surgery is not possible or it is unable to completely remove a juvenile pilocytic astrocytoma then irradiation or chemotherapy may be considered.
• Pathology: Well-differentiated astrocytes are seen with nuclear atypia. Mitotic figures, microvascular proliferation, and necrosis are absent. Gemistocytic astrocytoma is a variant with the tendency to rapidly progress to higher grade astrocytoma.
• Treatment: Surgical resection is followed by irradiation or chemotherapy. Those patients who have a gross total resection may be followed with serial MR images until they have evidence of recurrence. When surgery is not possible or it is not possible to completely remove a low-grade astrocytoma, irradiation is generally performed, although some patients elect chemotherapy instead despite limited data on the efficacy of this approach.8
• Treatment: Surgical resection is followed by irradiation and concurrent temozolomide chemotherapy, followed by adjuvant temozolomide. The extent of resection does not influence the choice of subsequent treatment.