Drs. Boyd and Mehta provide a comprehensive yet concise overview of the role of radiosurgery in the management of selected patients with brain metastases. They specifically address the fundamental rationale for employing this developing technology, as well as the clinical results and prognostic factors. Most importantly, however, the authors provide a review of current literature that highlights the controversies not only relating to radiosurgery but also with regard to surgical resection and the role of whole-brain radiotherapy.
Over the past decade, radiosurgical treatment has become widespread, and brain metastases represent the leading use of radiosurgery worldwide. In the absence of randomized clinical trials of radiosurgery, the clinician needs to understand the retrospective, comparative, and phase I/II studies outlined in the article in order to make informed choices.
What Are the Treatment Options?
Patients with solitary brain metastases represent a very heterogeneous population. The selection of patients for aggressive, costly treatment approaches, which may include whole-brain radiation, surgical resection, radiosurgery, or combination therapy, is difficult, but several key selection factors have been identified. The most important of these are stable or absent extracranial tumor and good performance status.
The goals of any treatment for brain metastases should be the prolongation of survival and preservation of the highest possible quality of life by controlling intracranial disease, as well as the minimization of treatment toxicities and patient discomfort. However, at best, current brain treatments can only change the pattern of death from cranial to extracranial, and nearly all patients with metastatic solid tumors will eventually succumb to disease progression no matter how carefully they are selected for aggressive brain treatments.
This current rationale embraced by many physicians and patientsnamely, controlling brain disease now so that death can ensue later from systemic diseasehas motivated clinical trials of surgical resection. These trials, in turn, have fostered the rationale for the application of radiosurgical treatment. Because of the difficulty in demonstrating a survival and quality-of-life advantage for treatments in this patient group, comparing surgery and radiosurgery will likely require several hundred patients to demonstrate a benefit of one treatment over the other, or the equivalence of the two modalities.
Radiosurgery is currently being used to treat inoperable lesions or as an alternative to resection for operable lesions. For patients selected for aggressive intracranial treatment, several treatment schemes are being applied in treatment centers, either within or outside of the context of formal clinical trials. Some of the treatments in current use include: (1) surgical resection followed by whole-brain radiation; (2) resection alone; (3) radiosurgery followed by whole-brain radiation; (4) radiosurgery alone; (5) whole-brain radiotherapy, with salvage treatments later, if needed.
The authors present a balanced view of many of the controversies that clinicians face when deciding on a treatment approach for patients with brain metastases. In particular, working within a vast and varied literature, they logically and concisely allow the reader to understand why the application of radiosurgery for brain metastases has been so widely embraced. An analysis of data that support the use of radiosurgery is presented. These include data from the authors own institution, which dem-onstrate a survival of 13 months for a cohort of radiosurgically treated patients with similar prognostic factors as those treated in surgical trials.
Radiosurgery Treatment Delivery
The authors comprehensive review of approximately 1,700 patients treated with radiosurgery reveals a wide range of control rates (25% to 99%; median, 67%) and overall survival durations (5 to 15 months; median, 9.4 months). These wide ranges are due, in part, to varying patient selection criteria and technical factors used by different centers.
The heterogeneity of radiosurgical results underscores the need for a unified treatment algorithm based on large prospective studies. Currently, we await the results of the Radiation Therapy Oncology Group (RTOG) study that is randomizing patients with three or fewer brain metastases to whole-brain radiotherapy with or without radiosurgery. These results will certainly help us resolve the debate over the most appropriate application of this widely employed treatment.
We must keep in mind the large variation among radiosurgery centers with regard to radiosurgical techniques, doses applied, treatment planning methods, and treatment philosophies. Such factors as the method of treatment (Gamma Knife, linear accelerator arc-based, three-dimensional fixed blocked-fields, intensity-modulated delivery, heavy particles), percentage of target covered, imaging modality used for planning (computed tomography [CT] vs magnetic resonance imaging [MRI]), and target-dose inhomogeneity, can have profound effects on radiation dose distributions. Differences in dose distributions, in turn, can alter tumor control and normal tissue complication probabilities.[2,3] The clinical impact of such factors is only beginning to be realized.
Role of Whole-Brain Radiotherapy
With the increasing application of surgical resection and radiosurgery in the management of selected patients with solitary brain metastases, the role of whole-brain radiotherapy has come into question. The randomized study of Patchell et al assessing complete surgical resection with or without whole brain radiotherapy had a primary end point of brain recurrence. The results revealed intracranial relapse rates of 18% and 70% in favor of the addition of whole-brain radiation. Postoperative radiotherapy prevented brain recurrence at the site of resection (10% vs 46%) and at other brain sites (14% vs 37%). Although mortality due to intracranial events was lower in the radiotherapy group (14% vs 44%), there was no significant difference in overall survival time (48 vs 43 weeks).
Clearly, this study demonstrated that whole-brain radiotherapy increases intracranial control well beyond that achieved by surgical resection alone. As an alternative to the use of whole-brain radiotherapy for selected patients, a local boost to the tumor bed (via conformal external-beam radiation or radiosurgery) may at least lessen the significant local recurrence rate seen in this and other studies of surgical resection. How this boost should be applied and what effects it has on survival and quality of life remain to be determined.
A favorable group of patients
treated on RTOG brain metastasis protocols employing whole-brain radiotherapy alone has been identified in a recursive partitioning analysis performed by Gaspar et al. Patients with a Karnofsky performance score > 70, absent/controlled extracranial disease, and age < 65 years had a median survival of 7.1 months. The number of brain metastases was not identified as a significant factor in the analysis. This number can be used as a comparison for radiosurgery outcomes, but favorable results must be interpreted with caution.
The field of radiosurgery has seen tremendous growth during the past decade. Technical innovations, such as noninvasive immobilization systems, dynamically controlled multileaf collimators, treatment planning based on MRI or positron emission tomography (PET), and more automated linear accelerator and Gamma Knife units will allow treatments to be more conformal, accurate, comfortable, efficient, and cost- effective.
While the controversies regarding the role of radiosurgery await the result of full-scale clinical trials, the article by Drs. Boyd and Mehta will undoubtedly help clinicians decide which patients are the most appropriate potential candidates for radiosurgery and will aid in predicting outcomes and side effects.