Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the central nervous system (Central Brain Tumor Registry of the United States, 2005). It tends to recur locally and to be fatal within a short period of time. Even in the most favorable situations, most patients die within 2 years, with a median survival of 14 months for treated patients (Stupp et al., 2005). The ability of supratentorial GBM to metastasize along cerebrospinal fluid (CSF) pathways to the spinal cord was first described in 1931 (Cairns & Russell). However, such metastasis is rare; when it does occur, it is usually associated with recurrence or progression of the primary tumor and with anatomic location of the tumor close to CSF pathways (Alatakis, Malham, & Thien, 2001). This case study presents the challenge of a woman with GBM who developed a spinal metastasis.
Initial Case Presentation
The patient was a 63‐year‐old female with no significant personal or family history of disease. She possessed a doctorate, worked in a laboratory, and was married with children and grandchildren. She had a remote history of smoking for approximately 10 years, and she drank alcohol socially.
The patient initially reported a 6‐week history of mild cognitive and word‐finding difficulties. She also noted headaches, which were worse in the morning. She discussed these symptoms with her primary care physician. Her Mini Mental State Examination was completely normal, as was her neurological examination. She attributed her symptoms to increased stress at work. Within 2 weeks, she was terminated from her job, partly due to work performance. Approximately 1 month after her visit with her primary care physician, she developed sudden expressive aphasia. She reported to the emergency department, where a computed tomography (CT) scan was performed. The scan demonstrated a necrotic‐appearing hyperdense mass in the left temporal lobe. Shortly thereafter, a magnetic resonance imaging (MRI) scan demonstrated a ring‐enhancing mass, 3.2 mm × 3.9 mm × 4.6 mm in size, in the left temporal lobe. There was a 7‐mm midline deviation with subfalcine and uncal herniation (Fig. 1). The patient's neurological examination revealed expressive aphasia, with difficulty repeating and naming. The rest of the neurological examination was normal.
The patient was admitted to the hospital and placed on a high dose (10 mg every 6 hours) of intravenous (IV) dexamethasone. She was also started on prophylactic IV phenytoin, 1 g, with a maintenance dose of 300 mg per day. The following day she underwent an awake left frontotemporal craniotomy with intraoperative speech mapping. Intraoperative stimulation produced dysarthria upon stimulation of one gyrus away from the proposed resection, and speech arrest two gyri away from the proposed resection. This information helped the surgeons resect as much of the tumor as safely feasible without worsening the patient's speech or cognitive function. Histopathological examination of the specimen revealed a GBM (World Health Organization [WHO] Grade IV). A postoperative MRI scan revealed a resection cavity with no residual enhancing tumor. Following the operation, the patient had minimal speech difficulty, mostly naming difficulty. She was discharged home 2 days after the resection. The patient and her husband were instructed on a tapering schedule of oral dexamethasone to a final dose of 2 mg twice a day (BID) in preparation for anticipated radiotherapy.
The current standard of care for GBM is surgical resection to the safest extent feasible, followed by adjuvant radiotherapy and temozolomide (Stupp et al., 2005). Approximately 2 weeks after the resection, the patient began fractionated focal radiation given conformally in daily fractions of 2 grays (Gy), 5 days per week for 6 weeks, for a total of 60 Gy. At the same time, she started continuous daily oral temozolomide, 75 mg per square meter of body surface area (BSA) per day, 7 days per week, throughout the course of her radiation therapy. The patient took prochlorperazine, 10 mg orally, 1 hour before the temozolomide, and she experienced no nausea or vomiting. Complete blood counts performed on the patient every 2 weeks showed no abnormalities. Approximately 2 weeks after initiation of the radiation, she experienced a minimal amount of fatigue, which persisted until several weeks after the cessation of the radiation treatments. She remained on oral dexamethasone, 2 mg BID, during the radiation therapy, due to the potential for cerebral edema during treatment.
Three weeks after the completion of the radiotherapy and daily temozolomide, the patient underwent an MRI scan, which demonstrated no evidence of tumor recurrence. At that time, she was started on oral temozolomide, 150 mg per square meter of BSA, for 5 days during each 28‐day cycle. She was prescribed oral ondansetron, 8 mg, to be taken 1 hour before taking the temozolomide and twice daily, as needed for nausea. A complete blood count was obtained at 3 weeks, to coincide with the expected nadir for bone marrow suppression (Polovich, White, & Kelleher, 2005). A complete blood count, comprehensive metabolic panel, and phenytoin level were obtained at 4 weeks, before the start of the next cycle of temozolomide. All of the patient's laboratory values were within normal limits, except for a low lymphocyte count (0.45 K/mcl). Because of the potential for patients with lymphopenia to develop pneumocystis pneumonia, a course of inhaled pentamidine, 300 mg, was started. The patient and her husband were instructed on the signs and symptoms of pneumonia and were told to call immediately if any signs developed. The patient's neurological examination remained normal, with no evidence of speech difficulties, and she was tapered off the dexamethasone.
After two cycles of temozolomide at 150 mg per square meter of BSA, the patient had an MRI scan, which demonstrated no new tumor enhancement. As the patient tolerated the dose of temozolomide without nausea, vomiting, or evidence of bone marrow suppression, her dose was increased to 200 mg per square meter of BSA for 5 days during each 28‐day cycle. She was prescribed ondansetron, 8 mg, to be taken 1 hour before taking the temozolomide and twice daily as needed for nausea. A complete blood count was obtained at 3 weeks, followed by another complete blood count and a comprehensive metabolic panel at 4 weeks. The patient had serial MRI scans after every two cycles to evaluate for tumor progression. The patient completed six cycles of this dose of temozolomide. She had occasional mild neutropenia (lowest white blood cell [WBC] count 3.0 K/mcl) and thrombocytopenia (lowest platelet count 135 K/mcl) at week 3, which resolved by week 4. She never had to delay a cycle due to low blood counts.
A Change in the Clinical Course
The MRI after the sixth cycle of temozolomide at 200 mg per square meter of BSA, 11 months after the diagnosis of GBM, was the first scan to demonstrate new enhancement in the surgical bed of the left temporal lobe. Although this observation was worrisome, it was not thought to indicate obvious tumor progression. A change in MRI scanning technique was a possible cause of the changes. The patient also had a vague subjective complaint of decreased sensation in her chest on the left side in the T6 distribution. Her neurological examination was normal, including muscle strength and pinprick, light touch, position, vibration, and temperature sensations. Reflexes were normal throughout; no pathological reflexes were elicted. The plan was to continue with another cycle of temozolomide at 200 mg per square meter of BSA and to obtain a brain MRI with spectroscopy before the next cycle.
The patient traveled during the following week, and, upon returning, she went to the emergency department with complaints of difficulty walking, a band‐like sensation over the left aspect of her chest, and abdominal discomfort. The treating physician found the patient to have a benign abdominal examination and normal neurological examination, and she was instructed to have a spinal MRI with her next scheduled brain MRI. The patient contacted her treating neurologist, and the following day she went to the outpatient clinic. She complained of a bandlike sensation in the chest at the level of T7‐T8 on the left side and decreased sensation along the anterior and posterior aspect of her left chest, abdomen, and left leg. She also complained of constipation and frequent urination. Her abdominal examination revealed suprapubic fullness and distention and mild to moderate tenderness on percussion of her lower abdomen, leading to suspicion of bladder distention. Her neurological examination showed subtle changes, including hip flexor weakness (4/5) on the left side and reflex asymmetry in her lower extremity, with a 3+ patellar reflex on the left side and a 2+ on the right side. Her Babinski reflex was negative on the right side and unequivocal on the left side. There was no clonus, and Hoffman's sign was negative. She had a normal sensory examination, including intact light touch, pinprick, position, vibration, and temperature sensations. She had a moderately unsteady gait, because she avoided bearing weight on her left side. Given the worrisome changes in her neurological examination, the patient was admitted to the hospital.
On admission, the patient was catheterized post void for 800 cc of urine, and an indwelling urinary catheter was placed. She had thoracic and lumbar MRIs, which demonstrated marked signal abnormality in the thoracic cord. An abnormal increased signal was seen from T3 to T9 both on T2‐weighted images and postgadolinium‐enhanced T1‐weighted images. Within this area, a small region at T4‐T7 had an even brighter signal. The abnormal signal extended through the entire thickness of the cord (Fig. 2). There was no evidence of leptomeningeal metastasis coating the surface of the cord. The differential considerations were transverse myelitis, demyelinating disease, metastatic disease, or primary cord neoplasm. A lumbar puncture was performed to investigate the possibility of leptomeningeal spread of the GBM. There were no malignant cells in the CSF. The patient was started on high‐dose methylprednisolone (1 g intravenous per day for 3 days) for presumed transverse myelitis.
The patient's neurological function continued to decline during the next 12 hours, leading to paraplegia with a complete sensory loss below T6, absent lower extremity reflexes, and loss of bowel control. A second lumbar puncture showed no malignant cells. The patient was then started on intravenous immunoglobulin G at 400 mg/kg for 5 days to treat presumed progressive tranverse myelitis. Her physicians were reluctant to biopsy the area due to the risk of spinal cord injury and the clinical indicators of transverse myelitis. Her symptoms did not change. A spinal MRI performed 1 week after the initial scan showed no interval change in the area of signal abnormality.
The patient was transferred to a spinal cord injury rehabilitation unit. Two weeks later she had a brain MRI scan, which demonstrated a slight increase in the area of enhancement. A brain positron emission tomography (PET) scan showed no fluorodeoxyglucose (FDG) activity in or around the tumor bed to suggest tumor progression. The patient's neurological examination was unchanged. A thoracic MRI scan demonstrated further increased signal abnormality. The high T2 signal extended caudally to T11, with intramedullary enhancement from T3 to T9. Again, no evidence of leptomeningeal metastasis was present.
Discovery and Treatment of Spinal Metastasis
Given the presence of unresolved paraplegia and the increase in signal abnormality despite aggressive treatment, a decision was made to biopsy the lesion. The patient underwent a T5‐T6 laminectomy with biopsy. The neuropathologist identified the tissue as an anaplastic astrocytoma. However, the morphology of this spinal cord tumor was sufficiently similar to the original temporal lobe lesion to suggest that it was the same as her primary brain tumor.
Physicians met with the patient and her spouse to discuss the impact of the diagnosis and quality‐of‐life issues. The patient had intact cognitive functioning and was able to make her own decisions, and wanted her spouse included in all discussions. The patient felt strongly that, despite the paraplegia, her quality of life was acceptable, and she was interested in pursuing aggressive treatment of both the brain and the spinal cord tumors. She had a new grandchild and was interested in spending as much quality time with her family as possible. Her spouse concurred. They also discussed future care and treatment in the event that the patient should become unable to make her own decisions. The patient completed paperwork for durable medical power of attorney and a living will, naming her husband as her decision maker.
Given the patient's and spouse's desires to continue aggressive treatment, she was referred to the radiation oncologist. Spinal cord irradiation was initiated, with a treatment plan to give radiation therapy from C3 to L1 to a total dose of 36 Gy, with a subsequent boost from T2 to T10 to a total dose of 50.4 Gy. Because the tumor had progressed on temozolomide, the patient began a chemotherapy regime of oral lomustine at a dose of 110 mg per square meter of BSA every 6 weeks and oral isotretinoin at a dose of 100 mg per square meter of BSA for 21 days of a 28‐day cycle. The patient was prescribed ondansetron, 8 mg, to be taken 1 hour before the lomustine, and experienced no nausea. Because the combination of a nitrosourea and spinal cord irradiation made this patient more susceptible to bone marrow suppression, physicans planned to perform a complete blood count every 2 weeks. The expected nadir for bone marrow suppression with lomustine is 4 weeks, with resolution at 6 weeks (Polovich et al., 2005). A fasting lipid panel was monitored, due to the potential for hyperlipidemia with the use of isotretinoin. The patient and husband were also counseled about the potential for depression with the use of isotretinoin. Because the patient had documented menopause several years before her brain tumor diagnosis, the customary discussion of the teratogenic effects of isotretinoin was not indicated. The patient was discharged home, with home nursing and physical therapy. She continued to require intermittent bladder catheterization and a bowel program, procedures at which her husband became proficient after instruction. She was able to transfer herself to a wheelchair and perform the majority of her daily activities independently.
Two weeks after the initiation of radiation therapy, the patient developed right calf pain and edema. A lower extremity venous duplex examination demonstrated extensive deep vein thrombosis in the right lower extremity. The patient was admitted to the hospital and started on IV heparin. She was then anticoagulated with warfarin to a desired international normalized ratio (INR) of 2.0‐2.5. She was discharged home when her INR became therapeutic. The patient's blood counts were within normal limits. Her antiepileptic drug was changed from phenytoin to levetiracetam because of the high potential for interaction between phenytoin and warfarin. The patient had never had a seizure, but she was felt to be at risk for seizure due to the tumor location.
Four weeks after receiving lomustine, the patient's WBC count was 2.7 K/mcl, her red blood cell (RBC) count was 3.36 M/mcl, hemoglobin (Hb) was 12.4 g/dl, hematocrit (Hct) was 35.2%, and the platelet count was 80 K/mcl. This was expected because of the known nadir of lomustine; thus no treatment was initiated. Six weeks after receiving lomustine, the patient's WBC count was 3.2 K/mcl, the RBC count was 2.65 M/mcl, Hb was 9.8 g/dl, Hct was 27.9%, and the platelet count was 125 K/mcl. The patient was started on darbepoetin, 200 mcg subcutaneously every 2 weeks. The patient's second round of lomustine was postponed for 2 weeks until her blood cell counts recovered. Her spinal MRI demonstrated no new areas of enhancement, and a brain MRI also demonstrated no change. She tolerated the isotretinoin well.
The second cycle of lomustine was given to the patient when her WBC count and platelet count recovered, 8 weeks after her first dose. Complete blood counts, obtained weekly, showed that her blood cell counts declined significantly after this second dose of lomustine. Her platelet count dropped as low as 22 K/mcl, and she received platelet transfusions on three separate occasions. The warfarin was temporarily discontinued when the platelet count was low, due to the increased risk for hemorrhage, and the patient and her family were advised of the risk. Although the patient continued to receive darbepoetin at 200 mcg every 2 weeks, her RBC count dropped to 2.69 M/mcl, Hb was 8.5 g/dl, and Hct was 25.2%. She experienced fatigue and dizziness as a result of her anemia, and she received two units of packed red blood cells. The symptoms resolved, and the patient's RBC count increased to 3.35 M/mcl, Hb to 10.2 g/dl, and Hct to 30.4%. The patient's WBC count was as low as 1.8 K/mcl, and she received two cycles of subcutaneous filgrastim, 300 mcg for 3 days.
The patient began to experience neurological worsening during the second cycle of lomustine. She had more difficulty with word finding and occasional coughing when swallowing. She also had more pain, especially in the thoracic area and in both shoulders. Her pain was controlled by a fentanyl patch, which was titrated up to 75 mcg/hr, oral gabapentin (300 mg, three times daily), and ibuprofen (200 mg orally, three times daily). She also took oral oxycodone and acetaminophen as needed for breakthrough pain. The patient underwent a brain and spinal MRI. The brain MRI demonstrated increased enhancement adjacent to the surgical bed in the temporal lobe. The spinal MRI demonstrated new foci of enhancement in the cord at the C2 and the L1 vertebral levels. Her neurological examination was unchanged, with the exception of mild word‐finding difficulties.
The MRI results were reviewed with the patient and her husband. Options for palliative end‐of‐life care versus additional treatment with other chemotherapeutic agents were discussed in an honest, forthright manner. The patient and her husband felt that her quality of life had been altered by her significant pain, transfusion dependence, and neurological worsening. They discussed the situation with their adult children and made the decision to engage in supportive care only. The patient was referred to a hospice program. Her husband wanted to provide the necessary care in their home rather than place her in an inpatient hospice facility, and she agreed. Hospice personnel provided the patient and her husband with nursing, social work, and counseling services at home, and her husband hired a caretaker to assist during the day.
The patient continued to experience increasing pain in the arms and shoulders. The fentanyl patch was adjusted as needed, and the patient eventually achieved good pain control at a dose of 200 mcg/hr. Her neurological function gradually declined. Over the course of 2 months, her speech worsened until she was unable to communicate. She began to have weakness in her right upper extremity. Supportive care decisions were made in conjunction with hospice personnel. Throughout the course of his wife's illness, the husband was given emotional support, key aspects of which were frequent contact, education, and reassurance. The patient eventually progressed to an unresponsive state, and she passed away at home 10 weeks after the initiation of supportive care, 18 months after the diagnosis of GBM, and 4 months after the metastasis was discovered.
The patient with a GBM provides a series of challenges to the neuroscience nurse. The plan of care has to be flexible as the needs of the patient change during the course of the disease. When the condition is initially diagnosed, the emphasis is on education and support. As the patient progresses through treatment, the nurse needs to be aware of possible adverse effects related to the tumor and the treatment itself. These can include fatigue, headache, seizures, chemotherapy‐induced nausea, vomiting, and bone marrow suppression. Interventions focused on minimizing these effects are important for positive patient outcomes. Consideration of the patient's wishes, neurological deficits, and quality of life direct nursing interventions. Eventually, palliative care directs the interventions, when the patient or the family makes this decision.
In this case study, the patient's neurological deficits became significant, necessitating a plan of care similar to that for a patient with a spinal cord injury. However, issues related to the GBM continued to direct the plan of care. The ongoing nursing issues for this patient included bladder management with a high risk for urinary tract infection, bowel management, and potential complications from immobility. The patient developed pressure ulcers on her heels toward the end of her life. Promoting independence for as long as possible was also an important focus in this patient's plan of care. Pain management was an issue throughout the end of the patient's life, and adequate pain control was obtained by the use of a fentanyl patch when she was no longer able to take oral medication. Emotional support for both the patient and her husband was crucial during all aspects of the disease and especially during tumor progression and metastasis.
Consideration of the patient's wishes, neurological deficits, and quality of life direct nursing interventions.
The diagnosis of GBM can be devastating to both patients and their families. The patient with a GBM often presents a challenge to the neuroscience nurse. Metastasis to the spinal cord is rare. However, as advances in primary tumor treatment are introduced and overall survival improves, metastasis may become a more common occurrence. The neuroscience nurse who develops a plan of care based on a patient's needs and outcomes should be able to meet the challenges more effectively.