Treatment of brain metastases in poor prognosis patients

INTRODUCTION  Metastases are the most common intracranial tumor in adults, accounting for significantly more than one-half of all intracranial tumors. The primary approaches to the treatment of brain metastases include whole brain radiation therapy (WBRT), surgery, and stereotactic radiosurgery (SRS).

Analysis of large series of patients with brain metastases has identified those factors that predict a poor response to treatment and relatively short survival. The key prognostic determinants and the management of patients with a poor prognosis will be reviewed here.

FAVORABLE VERSUS POOR PROGNOSIS  The median survival of patients with brain metastases who receive supportive care and are treated only with corticosteroids is approximately one to two months. The use of WBRT in large series increases the average survival to three to six months, and larger gains have been seen in favorable prognosis subsets .

The primary role of extracranial disease and the patient's general medical condition in determining outcome was illustrated by the use of recursive partitioning analysis (RPA) to analyze prognostic factors in 1200 patients from three Radiation Therapy Oncology Group (RTOG) brain metastases trials.

Three prognostic classes were identified and the classification correlated with median survival.

  • Class 1 The best prognosis was seen in patients who had a Karnofsky performance score 70 or higher, were less than 65 years of age with a controlled primary tumor, and had no extracranial metastases. Median survival was 7.1 months. These patients are considered to have a favorable prognosis.
  • Class 3 Patients with a Karnofsky performance score less than 70 constituted the worst prognostic subset and had a median survival of 2.3 months. This group is considered to have a poor prognosis.
  • Class 2 This intermediate prognosis group included those with a Karnofsky performance score 70 or higher, but with other unfavorable characteristics. Median survival was 4.2 months. These patients may be classified either as favorable or poor prognosis, depending largely upon the likelihood of controlling systemic disease.

In the original RTOG analysis, approximately 20, 65, and 15 percent of the patients were in classes 1, 2, and 3, respectively .

These results were subsequently validated in another RTOG trial that included 445 patients with brain metastases. The median survival was 6.2 months for Class 1 patients and 3.8 months for those in Class 2.

Because patients with a poor prognosis have such a short expected survival, aggressive treatment generally is not warranted. For this group, WBRT is the preferred approach if active treatment is indicated, while SRS and surgery are generally reserved for patients with a relatively favorable prognosis.

A possible exception to this approach is when the poor performance status is due exclusively to the brain metastases. At least one study has suggested that aggressive treatment with SRS may be associated with improved survival when brain metastases are responsible for the poor performance status and are not accompanied by extracerebral disease .

WBRT  The main goal of WBRT is to improve neurologic deficits caused by the metastases and surrounding edema and to prevent any further deterioration of neurologic function. The extent of improvement after WBRT is directly related to the time from diagnosis to radiation therapy, and early treatment is generally associated with a better outcome .

Efficacy  The overall response rate to WBRT ranges from 50 to 85 percent in various studies . The outcomes after WBRT can be illustrated by two large series:

  • In an analysis of 183 patients, neurologic symptoms such as headache improved in 74 percent, two-thirds of whom maintained the improvement for the duration of their lives or for at least nine months. Cranial nerve deficits improved in approximately 40 percent of patients.
  • When response was assessed by CT scan in 108 patients with 336 metastatic lesions, 59 percent of lesions responded (24 percent complete and 35 percent partial responses) to treatment with 30 Gy in 10 fractions . Responses were common in patients with small cell lung cancer, breast cancer, and squamous cell carcinoma, and infrequent with radioresistant tumors (eg, melanoma, renal cell carcinoma).

For most patients, overall survival is likely to be determined by the activity and extent of extracranial disease, not by the success of treatment in controlling brain metastases. Survival of patients who are not treated or are treated with corticosteroids alone is approximately one to two months; median survival is increased to three to six months with WBRT.

Dose fractionation  The Radiation Therapy Oncology Group (RTOG) conducted a series of randomized trials to determine the optimal dose and fractionation schedule for WBRT in patients with brain metastases . Patients were assigned to 40 Gy in four weeks, 40 Gy in three weeks, 30 Gy in three weeks, 30 Gy in two weeks, or 20 Gy in one week. The overall response rate (75 to 80 percent for symptom palliation) and median survival (15 to 18 weeks) were equivalent in all arms of these studies. Patients treated with larger fractions over a shorter time responded more quickly, but the duration of the clinical response and the time to progression were similar in all treatment arms. Brain metastases caused death in 40 percent of patients.

Subsequent RTOG trials exploring the use of ultrarapid fractionation schedules , dose escalation in favorable prognosis subgroups , accelerated fractionation , and the use of radiosensitizers failed to show any benefit over conventional radiation therapy.

The most commonly used regimen is a total dose of 30 Gy in 10 daily fractions of 3 Gy. The decision in an individual case depends upon the severity of CNS symptoms, the extent of systemic disease, and physician preference.

The dose and fractionation schedule should take into account the overall clinical status of the patient to maximize symptom palliation and minimize the risk of long-term complications. For patients with a relatively poor prognosis, we use 30 Gy in 3 Gy daily fractions. In contrast, those with a more favorable prognosis may be treated with prolonged fractionation to decrease the likelihood of late CNS toxicity. In these patients, we use a higher total dose in smaller fractions (eg, 40 to 45 Gy in 1.8 to 2.0 Gy daily fractions).

  Acute toxicity  Acute toxicity associated with WBRT is generally mild and self limited.

Cerebral edema may be induced or worsened after the initiation of radiation. As a result, WBRT should be preceded by corticosteroid therapy for at least 48 hours if there is evidence of significant edema and mass effect, regardless of the dose and fractionation schedule. In these patients, corticosteroids should be continued throughout the course of radiation and then the dose decreased as tolerated. Patients with small metastases and no mass effect may not need corticosteroids. The recommended steroid regimen is presented separately.

  Late toxicity  Although most patients treated with WBRT for brain metastases have a limited survival, patients with longer survival may have debilitating late complications. These include the following:

  • Leukoencephalopathy and brain atrophy, leading to neurocognitive deterioration and dementia
  • Radiation necrosis, with symptoms related to the site of necrosis
  • Normal pressure hydrocephalus, causing cognitive, gait and bladder dysfunction
  • Neuroendocrine dysfunction, most commonly hypothyroidism
  • Cerebrovascular disease

The risk for late complications is related to the total radiation dose, fraction size, patient age, extent of disease, and neurologic impairment at presentation. Delayed complications of WBRT are discussed elsewhere.

Recurrent brain metastases  Most patients who recur within the CNS also have progressive extracranial disease, and only a small fraction of patients require retreatment. However, when the patient's overall condition is satisfactory, possible options include surgery, SRS, reirradiation, as well as systemic therapy.

  Reirradiation  Retreatment with WBRT or partial brain reirradiation may provide some benefit for carefully selected patients who are not candidates for surgery or SRS. Several retrospective studies have reported clinical response rates of 42 to 75 percent and median survival of 3.5 to 5 months from the time of reirradiation . There is no consensus on dose fractionation; dosing in these studies ranged from 8 Gy in two weeks to 30.6 Gy in three weeks with a median of approximately 20 Gy in two weeks.

It is not known how early after the initial course of radiation therapy reirradiation can be administered. We suggest that reirradiation should be considered for patients who experience neurologic deterioration four or more months after a satisfactory response to the initial course of WBRT

Reirradiation is likely to exceed the brain's tolerance and may result in delayed toxicity if the patient survives long enough. However, the risk of symptomatic late radiation-induced neurotoxicity must be weighed against short-term symptom palliation in patients with a limited life expectancy.

  Surgery or SRS  Surgery and SRS can have a role in the treatment of patients with recurrent brain metastases, primarily when systemic disease is well-controlled.

CHEMOTHERAPY  The main role for systemic chemotherapy in treating brain metastases in poor prognosis patients is for the management of progressive or recurrent disease, when further WBRT and radiosurgery are not feasible. This is discussed elsewhere.

SYMPTOM MANAGEMENT  Treatment of patients with brain metastases is similar to the approach used in those with primary brain tumors. Key components include the control of peritumoral edema and increased intracranial pressure with corticosteroids, the treatment of seizures, and the management of venous thromboembolic disease.

SUMMARY AND RECOMMENDATIONS  Patients with brain metastases who have a poor performance status, widespread or uncontrolled systemic disease or extensive intracranial metastases have a poor prognosis. Treatment of brain metastases in these patients focuses on control of symptoms from the brain metastases, and maintenance of neurologic function.

  • WBRT We recommend WBRT for specific treatment of brain metastases

    - Although no dose fractionation schedule has demonstrated superiority, we suggest a total dose of 30 Gy in 10 fractions for most patients, to achieve a balance between the need for quick relief of symptoms versus the risk of late toxicity. A higher dose with slower fractionation (eg, 40 to 45 Gy in 20 to 25 fractions) may be preferred in patients thought to have a longer life expectancy.

  • Symptom management We recommend medical management with corticosteroids to control peritumoral edema. Treatment for other tumor-related complications (eg, seizures, venous thromboembolic disease) may also be required.