In the past 20 years, surgical resection has found an established role in the management of metastatic brain tumors. Several factors, however, make strong evidence-based medicine impossible to provide for all possible patient presentations. These important factors, such as patient variables (eg, age, medical comorbidities, preoperative performance), tumor variables (eg, number, size, location, histology), and primary disease status must be taken into account on a case-by-case basis to guide patient selection and treatment strategy. Although progress has been made to answer some of the major questions in the management of metastatic brain tumors, several important questions remain. Future studies comparing surgery with stereotactic radiosurgery, for example, are needed to delineate patient selection, complications, and outcome for both of these important modalities.
Secondary metastases to the brain are 10 times more common than primary brain tumors, making brain metastases by far the most common intracranial tumor in adults. The percentage of patients with systemic cancer and symptomatic brain metastases ranges from 20% to 40%, comprising a patient population of as large as a half million patients annually in the United States. The systemic malignancies that most commonly lead to the development of metastatic brain tumors include lung, breast, kidney, colon, and melanoma. Although 80% of the time metastatic brain tumors present after the diagnosis of systemic malignancy, this may be an underestimate given that not all patients with cancer routinely undergo neurologic imaging.
Background and overview
Surgical intervention played a role in the treatment of metastatic brain tumors since Grant first reported on the procedure in 1926. The morbidity and mortality of this procedure, however, was considered high and surgery was often superseded by whole-brain radiotherapy (WBRT) and corticosteroids. Improved surgical technique, developments in neuroanesthesia, and better patient selection, however, improved outcomes after surgical resection. In the 1990s, two randomized clinical trials showed that surgery for solitary metastatic lesions improves outcomes for a subset of patients with metastatic brain tumors.
Varying levels of evidence exist for performing surgery in different patient presentations and levels of disease burden. A recent set of evidence-based guidelines was published in the January 2010 issue of Journal of Neuro-Oncology , compiled by a panel of doctors from the Tumor Section of the American Association of Neurologic Surgeons and the Congress of Neurologic Surgeons. These guidelines used strict methodology to report levels of evidence existing for major clinical care questions related to metastatic brain tumors and formed a useful set of recommendations.
The major treatment options for metastatic brain tumors include surgery, WBRT, and stereotactic radiosurgery. This article outlines the clinical evidence supporting patient selection, prognostic factors, and expected outcomes in the surgical management of metastatic brain tumors.
Clinical evidence
Surgical Resection and WBRT
Only one randomized clinical trial compares the role of surgery and WBRT versus surgery alone for the initial management of a single metastatic brain tumor. In this trial, published in 1998 by Patchell and colleagues, 95 adult patients with good preoperative neurologic function who underwent a complete resection of a single, MRI-confirmed, biopsy-proven metastatic brain tumor were randomized to postoperative WBRT or no further treatment. Patients were stratified by primary tumor and the extent of systemic disease. The primary outcome was intracranial tumor recurrence.
The trial showed that recurrence occurred significantly more frequently in the surgery-alone group (surgery alone: 32/46 [70%] vs surgery plus WBRT 9/49 [18%]; P <.001). Recurrence in the WBRT group was less common at the original tumor site and at distant sites in the brain. In addition, if recurrence did occur, the time to recurrence was longer in the WBRT group than in the surgery group at the original tumor site and at distant sites in the brain. Most importantly, mortality was decreased in the WBRT group (surgery alone: 17/39 [44%] vs surgery plus WBRT: 6/43 [14%]; P = .003). Overall survival and the duration of functional independence did not differ between groups, however. This trial played a significant role in establishing surgery as a major component of the multimodality regimen in the treatment of solitary metastatic brain tumors.
The study by Patchell and colleagues was the major randomized controlled trial that established a role for surgery in the case of solitary brain lesions. In this study, the authors randomized a total of 48 patients to surgery and WBRT (25 patients) versus needle biopsy and WBRT alone (23 patients). The results showed that recurrence at the tumor site was more frequent in the WBRT alone group (12/23 [52%] vs 5/25 [20%]; P <.02); survival was longer in the surgical group, with a median of 40 weeks versus 15 weeks ( P <.01); and functional independence was longer in the surgical group with a median of 38 weeks versus 8 weeks in the radiation group ( P <.005). This trial clearly established a role of surgical resection in the case of solitary brain lesions.
A third randomized controlled trial examined the question of surgery and WBRT versus WBRT alone in a study involving 63 patients. The outcome measures used in this trial were survival and functionally independent survival (FIS), defined as the World Health Organization performance status of less than or equal to one and neurologic function less than or equal to one. The results showed that the combined treatment or surgery with WBRT compared with WBRT alone led to longer survival ( P = .04) and a longer FIS ( P = .06). This study, in addition the 1990 study from Patchell and colleagues, established a role for surgery in the case of solitary lesions.
In addition to these randomized controlled trials, three retrospective studies have been published addressing the same question in particular primary disease subsets. Two of three of these studies found no significant difference among treatment groups. Skibber and colleagues, however, found that median survival was longer in the surgery plus WBRT group (surgery alone: 6 months vs surgery plus WBRT: 18 months; P = .002). The level one evidence from Patchell and colleagues, supported by level three evidence from Skibber and colleagues, provides sufficient evidence for solid evidence-based medicine recommendations to surgically resect solitary brain metastases in good functioning patients and to follow that intervention with WBRT.
Surgical Resection and Stereotactic Radiosurgery
One randomized controlled trial compared surgery plus WBRT versus stereotactic radiosurgery alone for the treatment of metastatic brain tumors. This trial randomized 64 adult patients presenting with a single, resectable metastatic brain tumor smaller than 3 cm, good Karnofsky score, and stable systemic disease to undergo either surgical resection plus WBRT or stereotactic radiosurgery alone. The study was prematurely concluded because of poor patient accrual. No difference was seen between groups in terms of survival, death caused by neurologic disease, or freedom from local recurrence. Freedom from distant recurrence, however, was more likely in the surgery plus WBRT group ( P = .04). However, this effect was lost when adjustment for the effects of salvage radiosurgery was performed. Other positive secondary outcomes included improved functional and quality of life scores at 6 weeks in the stereotactic radiosurgery group ( P <.05), but this effect was lost at 6 months.
Several retrospective studies have examined the respective roles of surgery versus stereotactic radiosurgery in combination with WBRT. The two major designs for these studies have been surgery versus stereotactic radiosurgery plus WBRT, and surgery versus stereotactic radiosurgery plus WBRT versus WBRT. Nine studies have used various combinations of these two designs, and conclude in general that surgical resection may be of benefit in treating larger lesions (>3 cm) or those causing significant mass effect (>1 cm midline shift). Other retrospective studies suggest that surgical resection may have a role in treating recurrence after stereotactic radiosurgery.
Other studies have attempted to address the combined use of surgical resection followed by stereotactic radiosurgery to the resection bed in an attempt to decrease the incidence of local recurrence. Further high-quality studies are needed to more clearly define the combined role of surgery and stereotactic radiosurgery in the treatment of metastatic brain tumors.
When addressing the question of whether surgery should be used for treating multiple metastatic brain lesions, no randomized controlled trials have been conducted and little evidence exists to inform clinicians in this scenario. Sawaya and colleagues retrospectively matched 31 consecutive patients with new brain metastases who were treated with either radiosurgery or surgical resection at the MD Anderson Cancer Center from 1991 to 1994. Patients were matched based on Karnofsky score, time to brain metastasis, number of brain metastases, and patient age and sex. The median survivals were 16.4 and 7.5 months for the surgical and radiosurgical groups, respectively.
Clinical evidence
Surgical Resection and WBRT
Only one randomized clinical trial compares the role of surgery and WBRT versus surgery alone for the initial management of a single metastatic brain tumor. In this trial, published in 1998 by Patchell and colleagues, 95 adult patients with good preoperative neurologic function who underwent a complete resection of a single, MRI-confirmed, biopsy-proven metastatic brain tumor were randomized to postoperative WBRT or no further treatment. Patients were stratified by primary tumor and the extent of systemic disease. The primary outcome was intracranial tumor recurrence.
The trial showed that recurrence occurred significantly more frequently in the surgery-alone group (surgery alone: 32/46 [70%] vs surgery plus WBRT 9/49 [18%]; P <.001). Recurrence in the WBRT group was less common at the original tumor site and at distant sites in the brain. In addition, if recurrence did occur, the time to recurrence was longer in the WBRT group than in the surgery group at the original tumor site and at distant sites in the brain. Most importantly, mortality was decreased in the WBRT group (surgery alone: 17/39 [44%] vs surgery plus WBRT: 6/43 [14%]; P = .003). Overall survival and the duration of functional independence did not differ between groups, however. This trial played a significant role in establishing surgery as a major component of the multimodality regimen in the treatment of solitary metastatic brain tumors.
The study by Patchell and colleagues was the major randomized controlled trial that established a role for surgery in the case of solitary brain lesions. In this study, the authors randomized a total of 48 patients to surgery and WBRT (25 patients) versus needle biopsy and WBRT alone (23 patients). The results showed that recurrence at the tumor site was more frequent in the WBRT alone group (12/23 [52%] vs 5/25 [20%]; P <.02); survival was longer in the surgical group, with a median of 40 weeks versus 15 weeks ( P <.01); and functional independence was longer in the surgical group with a median of 38 weeks versus 8 weeks in the radiation group ( P <.005). This trial clearly established a role of surgical resection in the case of solitary brain lesions.
A third randomized controlled trial examined the question of surgery and WBRT versus WBRT alone in a study involving 63 patients. The outcome measures used in this trial were survival and functionally independent survival (FIS), defined as the World Health Organization performance status of less than or equal to one and neurologic function less than or equal to one. The results showed that the combined treatment or surgery with WBRT compared with WBRT alone led to longer survival ( P = .04) and a longer FIS ( P = .06). This study, in addition the 1990 study from Patchell and colleagues, established a role for surgery in the case of solitary lesions.
In addition to these randomized controlled trials, three retrospective studies have been published addressing the same question in particular primary disease subsets. Two of three of these studies found no significant difference among treatment groups. Skibber and colleagues, however, found that median survival was longer in the surgery plus WBRT group (surgery alone: 6 months vs surgery plus WBRT: 18 months; P = .002). The level one evidence from Patchell and colleagues, supported by level three evidence from Skibber and colleagues, provides sufficient evidence for solid evidence-based medicine recommendations to surgically resect solitary brain metastases in good functioning patients and to follow that intervention with WBRT.
Surgical Resection and Stereotactic Radiosurgery
One randomized controlled trial compared surgery plus WBRT versus stereotactic radiosurgery alone for the treatment of metastatic brain tumors. This trial randomized 64 adult patients presenting with a single, resectable metastatic brain tumor smaller than 3 cm, good Karnofsky score, and stable systemic disease to undergo either surgical resection plus WBRT or stereotactic radiosurgery alone. The study was prematurely concluded because of poor patient accrual. No difference was seen between groups in terms of survival, death caused by neurologic disease, or freedom from local recurrence. Freedom from distant recurrence, however, was more likely in the surgery plus WBRT group ( P = .04). However, this effect was lost when adjustment for the effects of salvage radiosurgery was performed. Other positive secondary outcomes included improved functional and quality of life scores at 6 weeks in the stereotactic radiosurgery group ( P <.05), but this effect was lost at 6 months.
Several retrospective studies have examined the respective roles of surgery versus stereotactic radiosurgery in combination with WBRT. The two major designs for these studies have been surgery versus stereotactic radiosurgery plus WBRT, and surgery versus stereotactic radiosurgery plus WBRT versus WBRT. Nine studies have used various combinations of these two designs, and conclude in general that surgical resection may be of benefit in treating larger lesions (>3 cm) or those causing significant mass effect (>1 cm midline shift). Other retrospective studies suggest that surgical resection may have a role in treating recurrence after stereotactic radiosurgery.
Other studies have attempted to address the combined use of surgical resection followed by stereotactic radiosurgery to the resection bed in an attempt to decrease the incidence of local recurrence. Further high-quality studies are needed to more clearly define the combined role of surgery and stereotactic radiosurgery in the treatment of metastatic brain tumors.
When addressing the question of whether surgery should be used for treating multiple metastatic brain lesions, no randomized controlled trials have been conducted and little evidence exists to inform clinicians in this scenario. Sawaya and colleagues retrospectively matched 31 consecutive patients with new brain metastases who were treated with either radiosurgery or surgical resection at the MD Anderson Cancer Center from 1991 to 1994. Patients were matched based on Karnofsky score, time to brain metastasis, number of brain metastases, and patient age and sex. The median survivals were 16.4 and 7.5 months for the surgical and radiosurgical groups, respectively.
Related posts:
Review of Imaging Techniques in the Diagnosis and Management of Brain Metastases
Radiotherapy for Brain Metastases
Management of Skull Base Metastases
Radiosurgical Management of Brain Metastases
Investigational Therapies for Brain Metastases
Evidence-Based Guidelines for the Management of Brain Metastases
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