Postoperative Radiation Therapy For Solitary Brain Metastases

abstract & commentary

Synopsis: It has been shown that resection of single brain metastases followed by whole brain radiation therapy provides survival advantage when compared to whole brain radiation therapy alone. In this report, the role of adjunctive radiation therapy was examined. Ninety-five patients with single brain metastases were treated with complete resection and subsequently randomly assigned to either whole brain radiation therapy or no further therapy. Recurrence in the brain was significantly reduced by whole brain radiation therapy. Overall survival was unchanged by the addition of radiation therapy.

Source: Patchell RA, et al. JAMA 1998;280:1485-1489.

There have been two randomized trials that demonstrate surgical resection combined with postoperative radiation therapy is more effective than treatment with radiation therapy alone for single brain metastases.1,2 A third study did not demonstrate an advantage for resection,3 although the difference in that study might have been the due to the inclusion of patients with more advanced disease.4 In the trial presented in the current paper by Patchell and colleagues, adjunctive treatment with whole brain radiation therapy was compared to observation alone for individuals who had undergone resection of solitary metastases to the brain. This was a multi-center, randomized, prospective trial.

Patients were eligible if they had complete resection of single brain metastatic lesions (as assessed by postoperative gadolinium enhanced MRI scans). Patients were excluded if they had brain metastases that had not been completely removed by surgery, evidence of leptomeningeal metastases, a history of previous cranial radiation therapy, or a Karnovsky score of less than 70%. Others were excluded if they had tumors considered "radiosensitive" including small cell lung cancer, lymphoma, or multiple myeloma. Patients were recruited over an eight-year span (1989-1997). Approximately one-third of those eligible did not enroll for reasons including patient refusal and physician preference for a specific treatment. Of the 95 enrolled patients, 49 were randomly assigned to receive radiation therapy and 46 to the control (observation) group. All patients received postoperative glucocorticoids and this intervention continued slightly longer in the radiation group. For patients in the radiation group, radiation therapy was started within 28 days after surgery. They received 50.4 Gy whole brain radiation therapy over five-and-a-half weeks (1.8 Gy X 28 fractions) prescribed to the cranial midline.

In both groups, MRI scans were repeated at three-month intervals for the first year following treatment and every six months thereafter. The primary end point was recurrence of tumor in the brain (either at the surgical site or elsewhere in the brain). Secondary end points were length of survival, cause of death, and maintenance of function. For patients who died, an attempt was made to determine the cause of death and attribute it to "neurologic" causes (i.e., recurrence in the brain) or systemic progression of disease.

Recurrence of tumor in the brain was less frequent in the radiation therapy group than in the observation group (9 of 49 [18%] vs 32 of 46 [70%]; P < 0.001). Postoperative radiation therapy prevented brain recurrence at both the site of the original metastasis (10% vs 46%) and at other sites in the brain (14% vs 37%). Patients in the radiation therapy group were less likely to die of neurological causes than patients in the observation group (6 [14%] of 43 who died vs 17 [44%] of 39; P = 0.03). There was no significant difference between the two groups in overall length of survival or the length of time that patients remained functionally independent.

Overall survival was further examined. Patients in the radiation therapy group were more likely to die of systemic than neurologic causes. Thus, it appeared that whole brain radiation therapy was effective in achieving local control but that systemic disease progression was the major determinant of overall survival. Patchell et al suggested that the reduction in neurological disease, particularly as it relates to end-of-life morbidity, is rationale enough to recommend routine use of whole brain radiation therapy in the postoperative setting after resection of single brain metastases.

COMMENTARY

Studies employing computed tomographic scans suggest that in approximately 50% of cases, brain metastases were single.5 Contrast enhanced MRI scans, however, have reduced this number to closer to 25%.6 Indeed, in this series, approximately one-third of patients in the control group who were thought to have single brain lesions by MRI, developed other metastases within the brain after resection. Thus, the number of patients with true single metastases may be 20% or less. However, for those with apparent (by MRI) solitary metastasis, this study provides useful information. Radiation therapy as an adjunct to surgical resection is effective at reducing recurrence and, it appears, growth of not-previously-detected or preclinical lesions and this effect results in less neurological morbidity.

The lack of demonstrable survival advantage may relate to the relatively small number of patients evaluated and the heterogeneity of the sample. Although the two treatment groups were well balanced, there were a large number of tumor types included (lung, breast, gastrointestinal, unknown primary, melanoma, etc.) and factors such as disease-free interval were not analyzed. It is hoped that further studies will be undertaken in selected clinical settings to provide additional guidelines for treatment of resectable brain metastases. In these additional studies, attention to quality-of-life issues would be important, inasmuch as whole brain radiation is likely to add at least some morbidity. Quality of life would be particularly important to assess if no survival advantage is demonstrated and the only difference observed is the final cause of death.

In the meantime, surgical resection of brain metastases might best be reserved for those instances in which there has been a long disease-free interval or in which systemic disease is controlled and the patient’s performance status is good. The data in this report support the use of adjunctive radiation therapy in this situation. Prior reports have found that outcome is improved when surgical resection is used together with radiation therapy instead of relying on radiation therapy alone. This study points out that radiation therapy following surgical resection is also more effective than surgical resection alone.

References

1. Patchell RA, et al. N Engl J Med 1990;322:494-500.

2. Vecht CJ, et al. Ann Neurol 1993;33:583-590.

3. Mintz AP, et al. Cancer 1996;78:1470-1476.

4. Mintz AP, et al. JAMA 1998;280:1527-1529.

5. DeAngelis LM. Cancer Invest 1994;12:156-165.

6. Davis PC, et al. AJNR Am J Neuroradiol 1991;12: 293-300.