Commentary (Cumberlin): An Overview of Radiotherapy Trials for the Treatment of Brain Metastases

The author gives a comprehensive review of the literature on the treatment of brain metastasis by radiation therapy. His emphasis is on randomized trials, the most extensive and comprehensive of which are those conducted by the Radiation Therapy Oncology Group (RTOG). This commentary will provide some amplification of the data presented in the review.

The RTOG Trials

The RTOG trials, as referenced by Dr. Berk, used several fractionation regimens, ranging from 1,000 cGy in a single fraction to 5,000 cGy in 20 fractions. In the general patient population, there was no significant difference between the fractionation schemes in response or survival, although a more rapid response was seen for larger fractions, as might be expected. Favorable prognostic factors were described, which include Karnofsky status of 70 or greater, age less than 60 years, less than four lesions, absent or controlled primary, absent or controlled systemic disease, and no mid-line shift on CT scan. The author also reviews the RTOG pilot hyperfractionation study, in which 160-cGy fractions were given twice daily. The optimal dose in this study was 5,440 cGy. It was found that patients with a single lesion had better survival.

The author concludes from these data that (1) hyperfractionation appears to be advantageous in patients with unresected solitary metastasis, and (2) for the majority of patients, the most appropriate treatment is 2,000 cGy given in 400-cGy fractions. The RTOG is conducting a randomized clinical trial designed to answer the question about hyperfractionation. RTOG 91-04 is comparing standard fractionation (3,000 cGy in 10 fractions) to hyperfractionated radiotherapy (5,440 cGy given as 160 cGy bid). This study will close in September 1995, having met patient accrual requirements, and results should be forthcoming soon.

The current standard treatment in the United States is probably 3,000 cGy in 10 fractions. More rapid fractionation schemes should be used with thought not only to the issue of central nervous system (CNS) control but also to potential side effects, such as acute headache, nausea, and vomiting, and long-term complications, such as cognitive deficits, all of which are more frequent with large fraction size. Use of rapid fractionation schemes should be limited to patients who are on an adequate dose of steroids and who have poor prognostic factors that would tend to preclude extended survival.

Surgical Studies

Dr. Berk also reviews surgical studies. The classic study by Patchell et al [1] demonstrated that surgical resection resulted in significantly improved survival in patients with solitary metastasis. One other study is of interest since it concerns multiple metastases. Sawaya et al [2] compared two groups of patients who underwent surgical resection of multiple lesions with his series of patients with completely resected solitary metastasis. One group of patients with multiple lesions had complete removal of all metastases and the other had incomplete removal. There was no mention of whether or not postoperative radiotherapy was given.

Median survival in patients with completely resected multiple metastases was 15 months, with 31% of patients suffering brain relapses. This compared to a 14-month median survival and 36% CNS relapse rate among patients undergoing resection of single lesions. These numbers are similar to those of Patchell et al. Patients without complete removal of all lesions, however, had only a 6-month median survival.

These findings would suggest that the prognosis of patients with multiple metastases that are all resectable is no worse than that of patients with resectable solitary lesions. Subtotal resection as a palliative procedure should not be considered unless the specific lesion to be debulked is causing life-threatening symptoms. The need for radiotherapy in addition to surgery is unclear but may improve survival for selected patients. This question can be answered only by prospective randomized trials.

Other Radiation Modalities

Stereotactic radiosurgery is a recent development in the use of radiation for the treatment of brain metastasis. A multi-institutional study conducted by Flickinger et al [3] showed a median survival of 11 months and a local control rate of 85%, comparable to results in the surgical series cited above. Mehta et al [4] have shown, with similar local control, that lesions greater than 2.5 cc (1.6-cm diameter sphere) have a less than 50% probability of complete response. This would suggest that complete removal of the tumors is unnecessary if radiosurgery is to be performed, and therefore, that radiosurgery may replace craniotomy in the treatment of brain metastasis for lesions of appropriate size.

Brachytherapy also has played a role in the radiation therapy of brain metastasis. Several studies are of interest. Prados et al [5] and Bernstein et al [6] used high-activity iodine-125 seeds. The series of Prados et al, which included 14 patients with a single metastasis, had a median survival of 18 months. The series of Bernstein et al consisted of 9 patients with a solitary metastasis recurrent in the initial site after craniotomy and external-beam radiotherapy. Median time to progression was 8 months and median survival was 12 months. Kreth et al [7] used low-activity iodine-125 seeds in 38 patients. Median survival was 17 months. This treatment requires careful patient selection but may be appropriate for patients whose lesions are technically amenable to implant but are too large for stereotactic radiosurgery.

Conclusions

Radiation, given by several techniques, is the single most widely used treatment for brain metastasis. Despite this, however, at least one-third of patients treated by external-beam radiation alone die from brain metastasis [8]. Consequently, the search for more effective treatments continues.

A search of the PDQ database yields 10 active protocols involving CNS metastasis, most of which involve chemotherapy. Several protocols are relevant to radiation oncologists. One is a randomized study designed to determine the effectiveness of external-beam radiotherapy in patients receiving radiosurgery. If tumor control remains comparable to resection, this protocol also may provide some guidelines for the use of external-beam treatments after craniotomy. Other studies of interest include the use of hyperthermia combined with brachytherapy, and the use of interstitial photodynamic therapy. One can hope that further study will improve the results of therapy, as well as the process for choosing the most appropriate treatment.

References:

1. Patchell R, Tibbs P, Walsh J, et al: A randomized trial of surgery in the treatment of single metastasis to the brain. N Engl J Med 322:494-500, 1990.

2. Sawaya R, Bindal R, Leavens M: Surgical treatment of multiple brain metastasis (abstract). Forty-Sixth Annual Cancer Symposium in Conjunction with Society of Head and Neck Surgeons, p 88. Society of Surgical Oncology, Los Angeles, CA, March 18-21, 1993.

3. Flickinger J, Kondziolka D, Lunsford L, et al: A Multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 28:797-802, 1994.

4. Mehta M, Rozental J, Levin A, et al: Defining the role of radiosurgery in the management of brain metastasis. Int J Radiat Oncol Biol Phys 24:619-625, 1992.

5. Prados M, Leibel S, Barnett C, et al: Interstitial brachytherapy for metastatic brain tumors. Cancer 63:657-660, 1989.

6. Bernstein M, Cabantog A, Lapierriere N, et al: Brachytherapy for recurrent single brain metastasis. Can J Neurol Sci 22:13-16, 1995.

7. Kreth F, Warnke P, Ostertag C: Interstitial implant radiosurgery for cerebral metastasis. Acta Neurochir Suppl (Wein) 58:112-114, 1993.

8. Borgelt B, Gelber R, Kramer S, et al: The palliation of brain metastasis: Final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 6:1-9, 1980.