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Journal of Neuroscience Nursing:

High‐Dose Methotrexate and Primary Central Nervous System Lymphoma

Fahey, Jean B.; DiMaggio, Carolyn

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Questions or comments about this article may be directed to Jean B. Fahey, MSN RN CCRN CNRN APRN BC, at She is a neuroscience clinical nurse specialist at Massachusetts General Hospital, Boston, MA.

Carolyn DiMaggio, BSN RN, is a neuroscience and neuro‐oncology staff nurse at Massachusetts General Hospital, Boston, MA.

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Primary central nervous system lymphoma (PCNSL) is a rare disease that is managed differently from other primary brain tumors and other types of systemic lymphomas. The use of high‐dose methotrexate (HD‐MTX) has improved survival rates. This article describes the experience of a patient treated with HD‐MTX and outlines the essential aspects of care for the bedside practitioner. An understanding of the diagnostic workup and principles of treatment can minimize complications and maximize patient function as nurses care for the unique physical and emotional needs of this population.

Primary central nervous system lymphoma (PCNSL) is a rare type of non‐Hodgkin's lymphoma (NHL) confined to the nervous system. The disease is managed quite differently from other primary brain tumors or systemic NHL. Unlike many primary brain tumors, PCNSL is responsive to treatment, and aggressive management may lead to prolonged remission or cure (Lister, Abrey, & Sandlund, 2002). The use of high‐dose methotrexate (HD‐MTX), 8 g/m2, for PCNSL has greatly increased median survival rates (DeAngelis & Hormingo, 2004; Plotkin & Batchelor, 2001; Yamanaka & Tanaka, 2004). Although whole‐brain radiotherapy results in responses of more than 90%, radiation therapy is associated with high relapse rates and delayed neurotoxicity (Correa et al., 2003). HD‐MTX used alone is associated with significantly fewer treatment‐associated toxic side effects (DeAngelis & Hormingo; Plotkin & Batchelor; Yamanaka & Tanaka).

Methotrexate is an antimetabolite that penetrates the blood brain barrier when given in high doses intravenously. MTX exerts its chemotherapeutic effect by counteracting and competing with folic acid in cancer cells, resulting in folic acid deficiency and cell death. Normal cells are not spared; thus, significant side effects can occur.

The care of the patient treated with HD‐MTX requires nurses fluent in both the neuroscience assessment and the principles of cancer care. The timely recognition of signs of increasing intracranial pressure or specific neurological deficits can minimize and perhaps prevent neurological complications. The hazards of HD‐MTX administration involve identifying the systemic complications and managing the side effects associated with chemotherapy. This article presents a case study of a patient with PCNSL treated with HD‐MTX.

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PCNSL is defined as lymphoma limited to the craniospinal axis without systemic disease. Once considered a rare tumor, accounting for less than 1% of all systemic NHLs, the incidence of PCNSL has been increasing steadily since the 1970s. The rising incidence of PCNSL in the immunosuppressed patient population can be attributed to the spread of human immunodeficiency virus and to the more prevalent use of immunosuppressive agents (Fine, 2002). The incidence of PCNSL has been steadily increasing during the last two decades. Today, PCNSL represents 4% of all primary brain tumors in the United States (Central Brain Tumor Registry, 2000). Further analysis found a tenfold or greater increase between 1973 and 1992 (Lister et al., 2002). Of equal concern are recent data showing a threefold increase in the incidence of PCNSL in patients who are immunocompetent. The factors accounting for this increase are unknown (Olson et al., 2002). No environmental risk factors for PCNSL have been identified.

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Case Presentation

In May 1997, a 50‐year‐old left‐handed female named Maura was in her usual state of good health when she noticed difficulty focusing her vision and occasional double vision. She also noticed a right eyelid droop when she was tired. She had not thought it was a problem until she noticed that her balance was also slightly abnormal when she walked and that she had some difficulty forming her words as she spoke. Maura was admitted for a diagnostic evaluation. During her examination she realized that she had lost 15 lb over the previous 8 months because she simply did not feel like eating.

The clinical symptoms of PCNSL are similar to any intracranial space‐occupying lesion. Maura's intermittent diplopia, ptosis, ataxia, and anorexia with weight loss are typical findings with lesions in the deep brain structures near the optic chiasm, thalamus, and third cranial nerve. Other symptoms might include mental status changes—behavioral changes, seizures, and signs and symptoms suggestive of increased intracranial pressure (headache, nausea, vomiting, and papilledema).

Surgery for primary central nervous system lymphoma should be limited to the least invasive procedure that can yield a diagnostic surgical specimen.

On bedside examination, Maura was distractible, displayed some inattentive behavior, and had decreased muscle bulk and postural instability. A gadolinium‐enhanced brain magnetic resonance imaging (MRI) scan showed an enhancing right subthalamic mass. Computed tomography (CT) scans of the chest, pelvis, and abdomen were normal. The thalamus and subthalamus innervation areas of the frontal lobe, optic tract, and cranial nerves III, IV, and VI, which control extraocular muscles and eyelid muscles, were responsible for Maura's symptoms. Clinical presentation of lesions within the deeper structures varies widely as clinico‐pathological manifestations are not always anatomically precise.

Gadolinium‐enhanced MRI is the neuroimaging technique of choice to identify specific lesions in the brain. Brain lesions from PCNSL tend to show less edema on MRI than gliomas or metastases of the same size. More than 90% of PCNSL lesions enhance with contrast. Three‐quarters of all cases of PCNSL are located adjacent to cortical convexities or ventricular surfaces, probably representing the propensity of this tumor to spread along cerebrospinal fluid (CSF) pathways. The lesions from PCNSL are commonly multifocal (Plotkin & Batchelor, 2001).

A tissue diagnosis should be made as soon as possible. PCNSL lesions are very responsive to steroids, and the tumors can shrink dramatically after steroid use, thus making a biopsy very difficult to perform and rendering the pathological diagnosis inconclusive (Weller, 1999). Surgery for PCNSL should be limited to the least invasive procedure that can yield a diagnostic surgical specimen because although aggressive surgery has clear benefits in many malignant brain tumors, including malignant gliomas and medulloblastomas, it is not advantageous in PCNSL. The PCNSL tumors tend to be located in deep, surgically risky areas and are often in multifocal regions of the brain which makes surgical intervention limited. When PCNSL is suspected, the neurosurgeon typically will perform a stereotactic biopsy to establish diagnosis (DeAngelis & Hormingo, 2004). In some instances, a craniotomy is performed to establish diagnosis, especially if the etiology of the lesion is unclear.

A stereotactic brain biopsy demonstrated large B‐cell lymphoma. An ophthalmic slit‐lamp exam revealed bilateral intraocular lymphoma. Ocular lymphoma is present in 20%‐25% of patients with PCNSL (Plotkin & Batchelor, 2001). Treatment with intravenous HD‐MTX and calcium leucovorin rescue was begun.

After diagnosis of PCNSL is obtained, treatment may be started. During this induction phase, intravenous HD‐MTX is given once, in a 4‐hour infusion. The hospital course for each treatment is usually 3‐5 days or until the serum MTX level is less than 0.1 micromoles (mcmol) per liter. This regimen is repeated every 2 weeks, and MRI scans are taken after each 2‐week cycle. The induction phase ends when the scans show a complete tumor response, demonstrated by absence of abnormal enhancement on MRI. The induction phase may require several months of therapy. Progression of tumor growth on MRI may determine that further treatment with HD‐MTX is not warranted, and alternative treatment may be sought with or without the use of radiation therapy. When complete tumor response is achieved, two consolidation cycles are given 2 weeks apart, and treatment is then administered on a monthly maintenance schedule at the same dose.

The preadmission preparation for every patient receiving HD‐MTX therapy is an important aspect of care. A nurse‐designed patient information pamphlet on HD‐MTX therapy is provided to every patient upon initial admission (Kelly, 2004). Because severe bone marrow suppression and gastrointestinal toxicity can occur with methotrexate, patients are instructed to avoid aspirin or any nonsteroidal antiinflammatory drugs for 3 days prior to admission. Patients are reminded to have a 24‐hour urine and blood test before each admission. The dose of methotrexate given is based on these results. Emphasis is placed on the importance of drinking a minimum of 8 ounces of water each waking hour on the day of admission and taking the prescribed sodium bicarbonate pills before coming into the hospital. The pamphlet also explains the rationale for urine testing every 2 hours, even through the night. Information in the pamphlet is reviewed with the patient and family members. Frequent reinforcement of the information is necessary.

Maura's in‐patient nursing care involved assessment for changes from her baseline neurological examination. The frequent patient contact with the bedside nurse places the nurse in the optimal position to identify early and subtle signs of worsening neurological insult. Maura had neurological checks at least every 2‐4 hours.

Maura had potential for damage to the liver, lungs, and particularly her kidneys from the chemotherapy. One of the serious side effects of methotrexate is acute tubular necrosis. Prevention of this complication is paramount. Intravenous hydration with sodium bicarbonate and measurement of urine output and alkalinity were priorities of her care. Organ damage can be minimized by the use of intravenous calcium leucovorin, a compound that is similar to folic acid and that reduces the effects of MTX. Calcium leucovorin rescue is administered 24 hours after the start of the MTX administration.

A bedside guide on high‐dose methotrexate care was created specifically to assist the nurse with focused interventions (Fig 1; Chisholm, 2003). This guide streamlines care for nurses who have limited exposure to this population.

Most routine admissions for HD‐MTX follow a predictable pathway initially, and Maura was no exception. Height and weight are measured upon admission, and the nurse then calculates the body surface area (BSA) for the chemotherapy dose. The nurse obtains peripheral venous access or accesses the central percutaneous venous port. If the laboratory specimens were not taken before admission, the labs must be drawn as soon as possible, and the results are then used in the chemotherapy calculations. The hydration fluid with sodium bicarbonate is started as soon as venous access is obtained.

Fig 1
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The ability to treat with HD‐MTX is reviewed. Criteria include an absolute neutrophil count >1.5 th/cmm, platelet count >100 th/cmm, and serum creatinine <1.5 mg/dl. If the baseline laboratory values determine that it is unsafe to administer the methotrexate, treatment is delayed until the abnormal laboratory values normalize. The HD‐MTX dose is based on the glomerular filtration rate (GFR) and BSA. The hydration fluid with potassium chloride and sodium bicarbonate prepares the patient for the HD‐MTX. The potassium provides the necessary electrolytes needed with such large doses of hydration. Chemotherapy calculations are done by two chemotherapy certified nurses or a chemotherapy certified nurse and registered pharmacist.

The nurse administers the MTX infusion when the urine output is greater than or equal to 100 cc/hr and urine pH is greater than or equal to 7.5 for a minimum of 4 consecutive hours. Strict urine intake and output with pH testing must be completed every 2 hours to identify renal compromise. The patient is encouraged to void every 2 hours in a collection device, or if a urinary catheter is in place, it is emptied and the pH is tested every 2 hours. MTX is administered by intravenous (IV) infusion over the course of 4 hours. Serum MTX levels are obtained at the end of the infusion and repeated daily until the level is less than 0.1 mcmol/L. Other daily labs include complete blood count with differential, serum electrolytes, blood urea nitrogen, and creatinine levels to check ongoing renal function. Typical medications ordered are

* ondansetron hydrochloride 24 mg po once, 30 minutes prior to chemotherapy, then 8 mg every 8 hours as needed for nausea and vomiting

* IV calcium leucovorin 25 mg, every 6 hours, for 4 doses to begin 24 hours after the start of MTX. After 24 hours of IV calcium leucovorin, it is then given orally until MTX level is less than 0.1‐0.2 mcmol/L

* sodium bicarbonate 3.25 grams po, given every 2 hours for urine pH <7.5

* diphenoxylate with atropine (Lomotil) 1‐2 tabs po, every 6 hours as needed for loose stool

* senna tablets 2 tabs po, BID as needed for constipation

* lorazepam 1 mg po or IV, every 6 hours for nausea or vomiting

On May 25, 1997, Maura received her second cycle of MTX and was discharged. She felt anxious, so amitriptyline (Elavil) 25 mg was ordered in the evening. Dexamethasone (Decadron) 4 mg was ordered 3 times daily to reduce cerebral edema, sucrafate (Carafate) 1 gram was ordered 4 times daily to minimize the gastric irritation from the steroid use, and phenytoin (Dilantin) 300 mg was ordered daily.

Infection is always a concern with oncology patients.

On June 6, 1997, 2 days before her third scheduled cycle, Maura presented with nausea, vomiting, and worsening headache indicative of increased intracranial pressure. A brain MRI identified cerebral venous thrombosis. This was treated with intravenous heparin, analgesics, volume repletion, and antiemetics. She then received her third cycle of chemotherapy and was discharged to a rehabilitation facility because of increased gait unsteadiness (ataxia) and left‐sided weakness. Maura was discharged with a warfarin (Coumadin) and fentanyl (Duragesic) patch until the next admission 10 days later. Maura felt discouraged by this medical setback.

Venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), are common in neuro‐oncology patients because of the hypercoagulability associated with malignancy, as well as risk factors such as paresis and extended immobility. Nursing goals are aimed at prevention and early detection of DVT and attention to the potential complications of anticoagulation therapy. Hydration is carefully assessed, with particular attention to avoid nausea and dehydration. The ongoing neurological assessment is continued throughout the hospitalization.

On June 20, 1997, after cycle 4, Maura's MRI showed a greater than 50% tumor response, consistent with a partial response to the MTX treatment. Maura had no further diplopia and an occasional headache.

From July through August 1997, during cycles 5, 6, 7, and 8, Maura was off her fentanyl patch, was discouraged, and required a cane to ambulate. Maura's ophthalmologic exam was now normal after cycle 8. Scans taken after this cycle showed a complete tumor response demonstrated by the absence of abnormal enhancement on MRI with no evidence of recurrence.

In September 1997, the placement of an indwelling central venous catheter was done during cycle 9, Maura's first consolidation cycle. Cycle 10, the second consolidation cycle, was administered without incident. Maura's gait improved steadily. Maura's husband died unexpectedly from a heart attack between these two cycles. Maura was supported through this difficult time by the entire staff. She started to drive again and began attending the brain tumor support group.

From October 1997 to March 1998, during monthly maintenance cycles 11‐16, Maura demonstrated continual improvement. Maura's warfarin was switched to aspirin for ongoing treatment of her cerebral venous sinus thrombosis.

Maura's open and friendly manner touched everyone on the floor during these many long months. Maura connected with other patients on the floor going through similar therapy, and she became very close to a young woman her own age who was going through the same therapy regime. The staff structured the timing and location of Maura's treatments so that the two friends could be roommates on each admission. They supported each other through the many weeks and months of hospitalizations.

From April to May 1998, cycles 17 and 18, approximately 1 year after diagnosis, Maura developed symptoms of a cold, and the site around the central venous catheter became inflamed. Cellulitis developed and was treated with intravenous antibiotics. She remained stable radiographically and clinically in the stage of complete response.

Infection is always a concern with oncology patients. The central catheter started draining purulent material. Intravenous vancomycin was started, but Maura developed an allergy to this, and cefazolin was then instituted. Despite antibiotics, the central venous catheter had to be removed. Maura developed a right brachial axillary and subclavian thrombosis and partial right internal jugular thrombosis. Maura was switched from aspirin back to warfarin. The wound began to heal, and hydration, bicarbonate, and calcium leucovorin were given orally. Maura experienced no nausea or vomiting.

From June through August 1998, during cycles 19‐22, Maura was given MTX and discharged home with instructions regarding follow‐up care for urinary output and daily labs. Calcium leucovorin, sodium bicarbonate, and hydration were given to her as an outpatient. The day after discharge following cycle 22, Maura was readmitted with dehydration secondary to nausea and vomiting. She was admitted overnight for hydration of dextrose 5% and 0.45% normal saline IV with 2 ampules of bicarbonate at 100 cc/hr, ondansetron 8 mg IV, calcium leucovorin, and warfarin.

In September 1998, Maura's follow‐up slit‐lamp examination with neuro‐ophthalmology revealed recurrent bilateral ocular lymphoma. Maura underwent an ocular biopsy that was positive for lymphoma, and she subsequently received 18 sessions of radiation therapy to the eyes. The last slit‐lamp examination revealed some cells in the left eye only. Chemotherapy combined with ocular irradiation results in better control of ocular disease, which seems to be associated with survival (Ferreri, 2002). Maura's brain MRI continued to show no enhancing lesions, consistent with a complete response from her PCNSL. In November 1998, during cycle 23, the last cycle of HD‐MTX was given, approximately 21 months after diagnosis.

In February 1999, 3 months later and almost 2 years after diagnosis, Maura presented again with a 15‐lb weight loss, gait imbalance, bradykinesia, hypophonia, and a depressed affect. A brain MRI showed new enhancing lesions in the right medial anterior temporal lobe and in multiple deep structures within the fornix, internal capsule, corpus callosum, frontal white matter, and corona radiata. These findings were consistent with a lymphoma relapse. Maura was then reinducted for a second time with HD‐MTX cycle 24 (reinduction cycle 1). Maura was again provided much emotional support during these difficult times. Treatment regimes continued as in the multiple preceding admissions. Lack of adequate and consistent peripheral intravenous access continued to pose challenges to hydration and drawing daily MTX levels and laboratory specimens. Round‐the‐clock intake and output every 2 hours with pH checks continued to be a priority.

Up to 30% of patients with PCNSL are refractory to HD‐MTX therapy, demonstrating no tumor response. Approximately 20% demonstrate a partial tumor response, and 50% will demonstrate a complete tumor response (Batchelor et al., 2000; Plotkin & Batchelor, 2001). Most patients experience a relapse at some point, with new neurological symptoms occurring.

In March 1999, Maura developed leucopenia with cycle 25. A CT scan of the brain showed no improvement, disease progression, and multifocal enhancement. HD‐MTX was stopped because of the disease progression.

During the time period of April 14‐18, 1999, intravenous topotecan was administered to Maura daily for a total of 5 doses, which she received as an outpatient. The mechanism of action of topotecan as a topoisomerase I inhibitor differs from that of the antimetabolite MTX often used for PCNSL. Topotecan penetrates the CNS, reaching greater than 30% of the plasma concentration in CSF. Topotecan has been used to manage brain metastases of solid tumors and systemic non‐Hodgkin lymphomas (Fischer et al., 2004). Rituximab (Rituxan), temozolomide (Temodar), cytarabine, carmustine (BCNU), and cisplatin have also been used in various centers.

In April 1999, Maura developed a low‐grade temperature and neutropenia. Maura had increased left‐sided weakness, resulting in a fall at home. A brain CT scan revealed an increase in the PCNSL tumor burden. Whole‐brain radiation therapy was given for 16 fractions, which improved Maura's ambulation. The brain MRI showed progressive tumor enhancement. Mannitol and dexamethasone were given to manage increasing intracranial pressure. The nursing goals at this time were palliative: emotional support, prevention of infection, and safety measures to prevent Maura from injuring herself while maintaining autonomy. Maura was discharged to a palliative center.

In June 1999, Maura was admitted with complaints of right leg pain and difficulty walking, and the evaluation revealed probable steroid myopathy. Steroids were tapered. Two weeks later, Maura had a seizure. A brain CT scan showed further tumor progression with edema. Electroencephalographic abnormalities were consistent with partial‐status epilepticus. Ocular exam revealed bilateral ocular lesions. Mannitol and dexamethasone were started again. Maura had developed a nonfluent aphasia. The consensus was that her prognosis was poor and that further therapy would not likely change her course. Home hospice care was set up for her discharge.

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Several fundamental nursing interventions can augment the care of the immunocompetent patient diagnosed with PCNSL and treated with IV HD‐MTX. Accurate and comprehensive neurological bedside examinations can prevent or minimize the adverse effects of the disease and its therapies. Care specific to methotrexate administration includes the use of IV fluids with sodium bicarbonate, attention to prehydration and ongoing fluid status, routine urine pH testing, careful intake and output monitoring, and administration of IV calcium leucovorin rescue. Knowledge of the relationship of BSA and glomerular filtration is necessary to ensure correct and therapeutic chemotherapy dosing. The control of nausea and vomiting, assessment of daily laboratory values, prevention of venous thrombosis, and provision of educational and emotional support are interventions common to the care of oncology patients. A blending of neuroscience, oncology, and palliative care nursing principles guides the practitioner at the bedside to minimize toxicities and maximize function within this population.

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© 2007 American Association of Neuroscience Nurses