The role of radiation therapy in the treatment of brain metastases.

Coia LR

Fox Chase Cancer Center/University of Pennsylvania, Department of Radiation Oncology, Philadelphia 19111.

Whole brain irradiation is the most effective means for treating the patient with brain metastases with symptom relief occurring in 70 to 90% of patients. However, 25-50% of patients with brain metastases will die due to eventual failure in the brain and therefore entry of patients into investigative trials is essential for continued progress in the management of this problem. For the patient who is not part of an investigative trial, short courses of radiation of 20 Gy in 1 week or 30 Gy in 2 weeks are generally as effective as more prolonged courses and even shorter courses of treatment could be considered, particularly for the patient with an estimated survival of only 5-6 weeks. The importance of the treatment of brain metastases on the practice of radiation oncology is significant and comparable to other major cancers treated with radiation. It is critical that radiation oncologists can apply this treatment modality in a cost effective manner with careful consideration for the patients' quality of life.

Neurosurg Clin N Am 1996 Jul;7(3):505-15

Radiotherapy for cerebral metastases.

Sneed PK, Larson DA, Wara WM

Department of Radiation Oncology, University of California, San Francisco, USA.

Whole brain radiotherapy (WBRT) for patients with unresected brain metastases results in symptomatic response in about 50% of patients and improvement in median survival to 3 to 6 months. Most patients with brain metastases are appropriately treated with a conventional palliative course of 30 Gy in 10 fractions over 2 weeks, although accelerated hyperfractionation with 32 Gy to the whole brain plus a boost to at least 54.4 Gy at 1.6 Gy twice daily yields better results for patients with solitary metastases. Patients with a life-expectancy of greater than 6 months should receive at most that or equal to 2.0 Gy per fraction to minimize the risk of radiation-induced leukoencephalopathy and dementia. Patients with good performance status, absent or controlled primary tumor, and no extracranial metastases might benefit from surgical resection or radiosurgery (with or without adjunctive WBRT) to improve local control.

Int J Radiat Oncol Biol Phys 2000 Jan 15;46(2):297-302

Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes?

Nieder C,

The Department of Radiotherapy, The Saarland University Hospital, Homburg/Saar, Germany. c

We performed a retrospective analysis of prognostic factors for survival and time to non-CNS death in 528 patients treated at a single institution with radiotherapy or surgery plus radiotherapy for brain metastases. For this purpose, patients were divided into groups with Karnofsky performance status (KPS) <70% and KPS > or =70%, as proposed by the RTOG. RESULTS: Median overall survival was 2.9 months (2.0 months for patients with KPS <70% and 3.6 months for patients with KPS > or =70%, p < 0.001). We did not find other variables splitting patients with KPS <70% in different prognostic groups. However, advanced age, multiple brain metastases, presence of extracranial metastases, and uncontrolled primary tumor each predicted shorter survival in patients with KPS > or =70%. When grouped into the original RTOG RPA classes, our data set split into three subgroups with different prognosis and median survival times of 10.5, 3.5, and 2 months, respectively (p < 0.05). Only 3% of patients fell into the most favorable group. Median time to non-CNS death was 4.1 months (12.9 months in RPA class I, 4.9 months in RPA class II, and 3.8 months in RPA class III, respectively, p > 0.05 for RPA class II versus III). However, it was 8.5 months in RPA class II patients with controlled primary tumor, which was found to be the only prognostic factor for time to non-CNS death in patients with KPS > or =70%. In patients with KPS <70%, no statistically significant prognostic factors were identified for this endpoint. RPA class I patients seem to be most likely to profit from aggressive treatment strategies and should be included in appropriate clinical trials. However, their number appears to be very limited. Considering time to non-CNS death, our results suggest that certain patients in RPA class II also might benefit from increased local control of brain metastases.

Int J Radiat Oncol Biol Phys 1990 Jul;19(1):111-5

The influence of extent and local management on the outcome of radiotherapy for brain metastases.

Hoskin PJ, Crow J, Ford HT

Department of Radiotherapy and Oncology, Royal Marsden Hospital, Sutton, Surrey, U.K.

The results of cranial irradiation for brain metastases in 164 consecutive patients have been reviewed to evaluate a policy of localized high dose irradiation for solitary metastases. Fifty of the 164 patients receiving whole brain irradiation (35 Gy in 15 daily fractions) were selected for boosts delivering 15 Gy in 8 daily fractions to the site of solitary deposits. No difference in overall survival or the incidence of death from progressive brain metastases was seen between the patients receiving a boost and those who did not. Overall median survival was 112 days with 62% of patients dying from metastatic disease outside the brain. Factors associated with increased survival were early response to radiotherapy and, in breast cancer patients, a disease-free interval of 2 years. Palliation of presenting symptoms was achieved in 86% of patients at 3 weeks from starting radiotherapy. It is concluded that whereas whole brain irradiation results in useful symptom control, there is no advantage for high dose treatment in the majority of patients with solitary metastases even in the absence of metastatic disease elsewhere.

Cancer 1993 Feb 15;71(4):1362-7

Improved survival duration in patients with unresected solitary brain metastasis using accelerated hyperfractionated radiation therapy at total doses of 54.4 gray and greater. Results of Radiation Therapy Oncology Group 85-28.

Epstein BE,

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia.

Radiation Therapy Oncology Group (RTOG) 85-28, a Phase I/II randomized trial of accelerated hyperfractionated XRT for patients with unresected supratentorial brain metastases, enrolled 153 patients with solitary brain metastasis. Whole brain dose was 32 Gray (Gy) administered in 1.6 Gy fractions twice a day with an interfraction interval of 4-8 hours. Boost dose was escalated to total doses of 48.0, 54.4, 64.0, and 70.4 Gy. RESULTS. Acute and late toxicities were acceptable. The median survival time and 1-year survival rates were 4.9 months and 20% at 48 Gy; 5.4 months and 33% at 54.4 Gy; 7.2 months and 28% at 64 Gy; and 8.2 months and 37% at 70.4 Gy, respectively. Comparison of the upper three dose treatment arms to the 48 Gy treatment arm revealed a superior survival time with doses of 54.4 Gy and greater (P = 0.05). Improvement in neurologic function appeared to increase with dose escalation, with 25% of patients experiencing improvement at doses of 48 Gy, 38% at 54.4 Gy, 50% at 64 Gy, and 63% at 70.4 Gy (P = not significant). CONCLUSION. A radiation dose response for survival time appears to exist with the use of accelerated hyperfractionated XRT for patients with unresected solitary brain metastasis.

Oncology (Huntingt) 1995 Nov;9(11):1205-12; discussion 1212-6, 1219

An overview of radiotherapy trials for the treatment of brain metastases.

Berk L

Department of Radiation Oncology, University of Pennsylvania, USA.

A review of the English literature was undertaken to (1) determine the efficacy of radiation therapy for the treatment of brain metastases, (2) identify prognostic factors, and (3) ascertain whether there is an effect of treatment technique on outcome. Critical analysis of relevant randomized trials indicated that radiation therapy can effectively palliate the symptoms of brain metastases. Prognostic factors for improved survival are good performance status and the absence of a non-central nervous system tumor. The most efficient treatment protocol is controversial, but the literature supports the use of 20 Gy in five fractions for the treatment of patients with a poor prognosis. Patients with a solitary brain metastasis and no systemic disease benefit from resection of the brain metastasis followed by postoperative radiation.

Int J Radiat Oncol Biol Phys 1993 Jul 15;26(4):653-7

Phase I/II trial of accelerated fractionation in brain metastases RTOG 85-28.

Sause WT, Scott C, Krisch R, Rotman M, Sneed PK, Janjan N, Davis L, Curran W, Choi KN, Selim H, et al

LDS Hospital, Salt Lake City, UT.

PPatients entered had controlled or absent primary with metastases other than brain which were stable or only brain metastases with the primary uncontrolled. Karnosfky status was required to be greater than 60. Patients received 1.6 Gy twice daily separated by 4-8 hr delivered 5 days a week. The entire brain was treated to 32.0 Gy and the boost dose escalated from 16.0 Gy to 22.40 Gy and subsequently 32.00 Gy and 42.40 Gy. RESULTS: We observed no undue toxicity with escalating dose of irradiation. An incremental, although not statistically significant improvement in survival was noted with escalating doses. Median survival ranged from 4.2 months to 6.4 months with escalating dose of irradiation. Median survival also increased in patients with controlled primary tumors, non-lung primaries and solitary metastasis. CONCLUSION: The incremental improvement in survival in patients with good prognostic factors appeared encouraging. The Radiation Therapy Oncology Group will test the 54.4 Gy study against 30 Gy in 2 weeks in a Phase III trial based on the results of this trial.

Int J Radiat Oncol Biol Phys 1996 Feb 1;34(3):585-90

Analysis of outcome in patients reirradiated for brain metastases.

Wong WW, S

Department of Radiation Oncology, Mayo Clinic Scottsdale,

From 1975-1993, 2658 patients received WBRT for brain metastases at our institution. Eighty-six patients were subsequently reirradiated for progressive brain metastases. The median age of these patients was 58 (range: 31-81). The most common primary sites were breast and lung. Fifty patients had metastatic disease at other sites. Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (40 patients) or 3 (38 patients). The median dose of the first course of irradiation was 30 Gy (range: 1.5-50.6 Gy). The median dose of the second course of irradiation was 20 Gy (range: 8.0-30.6 Gy). RESULTS: Twenty-three patients (27%) had resolution of neurologic symptoms, 37 patients (43%) had partial improvement of neurologic symptoms, and 25 patients (29%) had either no change or worsened after reirradiation. The median survival following reirradiation was 4 months (range: 0.25-72 months). The majority of patients had no significant toxicity secondary to reirradiation. Five patients had radiographic abnormalities of their brain consistent with radiation-related changes. One patient had symptoms of dementia that was thought to be caused by radiotherapy. Various potential prognostic factors were evaluated for possible associations with survival, including age, sex, primary site, ECOG performance status, RTOG neurologic functional class, absence of extracranial metastases, and dose of irradiation. Absence of extracranial metastasis, solitary brain metastasis, and retreatment dose > 20 Gy were associated with improved survival in univariate analysis (p=0.025, 0.033, and 0.061, respectively). The absence of extracranial disease was the only significant factor in multivariate analysis (p=0.05). CONCLUSION: The majority of patients in our series had favorable symptomatic responses. Clinically significant complications were minimal. Reirradiation should be offered to patients who develop progressive brain metastases.