Leptomeningeal metastasis

Prognosis and complications
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By Jai Grewal MD and Harpreet K Grewal MD

With leptomeningeal metastasis from solid tumors, the prognosis is dismal. Without treatment, survival is generally measured in weeks rather than months. Balm and colleagues found that among patients who were not treated, approximately one fourth of their patients, survival averaged only 3 weeks (Balm and Hammack 1996). Bokstein and associates reported that 32% of their patients died during radiotherapy (Bokstein et al 1998). Several retrospective series of aggressively treated patients have reported average survival of 5 to 7 months (Wasserstrom et al 1982; Glantz et al 1995), but they may have achieved better results than others by carefully selecting patients for treatment or by reporting only patients who were stable after radiotherapy. Most other series of patients with leptomeningeal metastasis from solid tumors treated aggressively describe survival of only 8 weeks to 4 months. A clinical trial documented median survivals of 3.5 months with liposomal cytarabine and 2.6 months with methotrexate (Glantz et al 1999b).

Most patients with leptomeningeal metastasis from solid tumors do not improve clinically despite aggressive treatment. Among 252 patients from multiple series, 28% improved clinically with treatment, 32% stabilized for a period of time, and 40% progressively worsened (Wasserstrom et al 1982; Balm and Hammack 1996).

With selected malignancies, the prognosis is somewhat better. Patients with leptomeningeal leukemia or lymphoma often live at least several months, and some of these patients may be cured. Patients with medulloblastoma or CNS germ cell tumors metastatic to leptomeninges at diagnosis have a good chance of cure when treated with craniospinal radiotherapy and chemotherapy.

Prediction of the prognosis of individual patients may help in treatment decisions. The prognosis is much worse when the systemic cancer is progressing than when it is stable (Grossman et al 1993). Patients with more favorable tumors, such as breast carcinoma, lymphoma, and leukemia, can be expected to survive longer than those with unfavorable tumors, such as melanoma and non-small cell lung carcinoma (Grant et al 1994). Long duration of symptoms at presentation is predictive of better prognosis (Balm and Hammack 1996), as is a good level of function, including ability to care for one's self. Different series have indicated that supratentorial involvement or cranial neuropathies predict shorter survival (Grossman et al 1993; Balm and Hammack 1996). Bulky disease evident by MRI and blocked CSF pathways are associated with a worse prognosis, especially when the block cannot be corrected with radiotherapy (Glantz et al 1995). High CSF protein has been found to have negative predictive value, whereas intrathecal chemotherapy is associated with better survival (Balm and Hammack 1996).

Complications of the disorder include electrolyte disturbances (notably hyponatremia), infections such as pneumonia and urinary tract infections, thromboembolic complications, such as deep vein thrombosis and pulmonary embolism, and decubitus ulcers.

Side effects of radiotherapy are usually mild; serious complications are rare. Alopecia, mild fatigue, anorexia, and weight loss are common side effects of cranial radiotherapy. Pancytopenia is common with radiotherapy to the entire spine but uncommon with partial spine or cranial irradiation. The more serious late complications of radiotherapy such as radiation myelopathy are uncommon, partly because the radiation doses used for treatment of this condition are usually modest and partly because few patients survive long enough to be at risk for such complications. When combined with methotrexate, radiation undoubtedly contributes to leukoencephalopathy.

The tolerability of intra-CSF chemotherapy in conjunction with systemic chemotherapy or radiotherapy is being evaluated by several ongoing studies.

Complications of ventricular catheter and reservoir placement are common (Obbens et al 1985; Chamberlain et al 1997). Among 1076 patients, complications included infection (early or late) in 7.5%, technical complications such as catheter disconnection or nonfunctioning catheter in 6.8%, intracranial hemorrhage in 1.4%, and poor wound healing in 0.5%.

Intrathecal chemotherapy can cause a variety of complications. Lumbar or ventricular injection of chemotherapy may cause symptoms and signs of meningeal irritation including headache, nuchal rigidity, fever, and vomiting as well as symptoms of encephalopathy. Meningeal irritation and acute encephalopathy are more prominent with methotrexate than with cytarabine, and they usually resolve within 1 to 3 days. Lumbar injection of methotrexate or cytarabine rarely causes myelopathy; the etiology is unknown.

An important and serious complication is the late occurrence of leukoencephalopathy (Bleyer and Byrne 1988; Phillips 1991). Although methotrexate (especially intraventricular) and cranial radiotherapy can each independently cause this problem, the risk is greatest when the treatments are combined. Obbens described leukoencephalopathy in only 2% of 295 patients treated with intraventricular methotrexate, but the incidence may be above 50% in patients who survive 1 year or more after intensive treatment with radiation and intraventricular methotrexate (Obbens et al 1985; Liang et al 1993). The risk is thought to be much lower with cytarabine and liposomal cytarabine than with methotrexate. Patients with this syndrome typically have dementia and a gait disturbance. Seizures, quadriparesis, and disturbed control of the bowel and bladder may ensue. Leukoencephalopathy often progresses to cause the patient's death. A more limited form of this syndrome may consist only of mild cognitive deficits, a problem most commonly seen in long-term survivors of leukemia who have undergone treatment or prophylaxis with radiation and intrathecal methotrexate. Pathological findings range from myelin pallor in mild cases to frank necrosis with calcium deposits in severe cases.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
References cited
Contributors