Surgical Management of Cerebral Metastases

Radiographic Assessment

Imaging is integral to determine the number, location, size, and ultimately the accessibility of intracranial metastases. Typically this is done with a magnetic resonance imaging (MRI) and is useful not only for diagnostic purposes but also for surgical preparation. These radiographic features are critical in selecting individuals for surgery as well as identifying lesions that are suspicious for another disease process warranting a biopsy instead of resection or radiation.

Number of Lesions

The number of intracranial lesions is a crucial consideration in the management of cerebral metastases and selecting patients for surgical resection, radiosurgery, or WBRT. The sensitivity of MRI outweighs that of computed tomography (CT) in detecting small lesions or those within the posterior fossa and thus is recommended for establishing the number of CNS metastases. The resolution of MRI to detect metastatic tumors is influenced by the dose and timing of contrast administration. Reference to a single metastasis is distinguished from solitary metastasis. The former describes one lesion to the brain in the face of other systemic or extracranial metastases, whereas a solitary brain metastasis indicates that the brain is the only site of metastatic disease within the body. Although approximately 30% of metastases are single, solitary metastases are rare. In the setting of breast carcinoma, a solitary metastasis or brain-only metastatic disease is associated with an improved prognosis. To determine the most appropriate management strategy, patients should be classified as those with a single/solitary metastasis or with multiple cerebral metastases.

Single and Solitary Brain Metastasis

Individuals with a single or solitary brain metastasis are the optimal candidates for surgical resection. Class I evidence supports the superiority of surgical resection over WBRT alone in the treatment of a single metastasis. The evidence emanates from two randomized controlled trials reported in 1990 and 1993 comparing surgical resection plus WBRT to WBRT alone. Both studies demonstrated improvements in survival, duration of functional independence, and local tumor control. ^,

Patchell and colleagues completed the first study comparing surgical resection followed by WBRT with WBRT alone. The authors included 47 patients with a single brain metastasis, high performance status (Karnofsky performance scale [KPS] score ≥70), and limited extent of extracranial disease. They found that the rate of local recurrence was significantly ( P < .02) lower in the surgical cohort (20%) compared with WBRT alone (52%). The length of survival was significantly longer ( P < .01) following surgical resection plus WBRT (median, 40 weeks) compared with WBRT alone (median, 15 weeks). Improvement was also seen in the duration of functional independence (38 weeks in the surgical group vs. 8 weeks in the WBRT group, P < .005). A multivariate analysis further indicated that surgical resection ( P < .0001) and the absence of disseminated disease ( P < .0004) were predictors of improved outcomes. These results provided class I evidence in support of surgical resection plus WBRT in lieu of WBRT alone as the standard treatment of single/solitary brain metastases.

In a second randomized trial, Vecht et al. also investigated the effects of surgery when added to WBRT in patients with a single brain metastasis. Similar to the prior study, the authors reported a significantly longer median survival time after surgery followed by WBRT (43 weeks) compared with WBRT alone (26 weeks, P = .04). In contrast to the Patchell study, however, the investigators stratified subjects by histology (lung vs. non-lung) and by extracranial disease status (progressive or stable). They found that the benefits of surgery were restricted to patients with limited systemic disease. Specifically, patients with stable extracranial disease had prolonged survival when treated with surgical resection and WBRT (median, 12 months) over those treated exclusively with radiation therapy (median, 7 months, P = .04). In contrast, subjects with progressive extracranial disease generally fared worse. Their survival was independent of treatment assignment (median survival time of 5 months in both combined treatment and WBRT alone groups). Histology was not a strong predictor of survival.

Following these two reports, a third prospective multiinstitutional study was published. A total of 84 subjects were randomized to surgical resection of a single metastasis with WBRT or WBRT alone. In contrast to the preceding studies, there was no difference in survival observed between those randomized to surgery (24 weeks) or conventional radiation therapy (27 weeks, P = .24). In addition, the length of time patients remained functionally independent, defined as a KPS score of 70 or greater, was no different between treatment allocations. However, the results did support prior conclusions that extracranial metastases and progressive systemic disease were important predictors of mortality. An essential difference between this study and the two aforementioned trials was that the investigators included patients with a lower performance status (inclusion criterion was KPS score ≥50, compared with ≥70). Consequently, 21% of their subjects had a KPS score of less than 70, and 45% suffered from extracranial metastases. In contrast, individuals with active extracranial disease comprised only 37% of patients in the study performed by Patchell et al. and 32% of patients in the study by Vecht et al. A lower functional status and active extracranial disease are both associated with poor survival. From the differences in outcomes between these studies, it can be concluded that the benefits of surgical resection are diminished in individuals with more advanced disease. The systemic tumor burden predominates in the clinical course. Such disparities also demonstrate how patient selection and study design alter the overall outcome of clinical trials.

On the basis of these three randomized controlled trials, a Cochrane meta-analysis concluded that for individuals with an acceptable performance status (KPS score ≥70) and controlled systemic disease, surgical resection followed by adjuvant WBRT provides a superior outcome for patients with single brain metastases. This same conclusion was reached in recently published guidelines. ^, The collective data suggest that the benefits of surgery extend not only to improved overall survival but also to preservation of functional independence and local disease control by reducing death and disabilities from neurologic causes. For patients with lower performance status (KPS score <70), the evidence is less clear because the burden of extracranial disease potentially outweighs the influence of the cerebral pathology. However, when considering the implications of these data in clinical practice, it is important to note that the benefits of surgical resection are not limited to the outcome measures examined in these clinical trials. The role of surgery in reversing neurologic symptoms and deficits by immediate decompression of local mass effect and prevention of death from brain herniation cannot be overemphasized. For example, a somnolent patient harboring a large posterior fossa single metastasis may be unjustly denied a life-saving operation should the decision to operate be based solely on performance status. Therefore recommendation for surgery requires not only justification from sound literature-based evidence but also the exercise of good clinical judgment, with an ultimate goal of maximizing the clinical outcome of each individual.

Multiple Brain Metastases

The traditional treatment of multiple cerebral metastases was WBRT, and the presence of multiple metastases was considered a contraindication to surgical resection regardless of their accessability. However, an increasing number of studies have suggested that surgery may have a role in the treatment of multiple metastases for a defined population. In a retrospective analysis, Bindal et al. reported the outcomes of 56 patients who underwent resection of multiple brain metastases. Patients were divided into those who had one or more lesions left unresected (group A, n = 30) and those who had undergone resection of all lesions (group B, n = 26). These individuals were compared with a group of matched controls who had single metastases that were surgically resected (group C, n = 26). There was no difference in surgical mortality (3%, 4%, and 0% for groups A, B, and C, respectively) or morbidity (8%, 9%, and 8% for groups A, B, and C, respectively) regardless of treatment group. Most importantly, patients with multiple metastases who had all the lesions resected (group B) had a significantly longer survival (median, 14 months) than patients who had some lesions that were not resected (group A; median, 6 months; P = .003). The overall survival in patients who had all lesions resected (group B) was similar to patients with a single metastasis (group C; median, 14 months). From this it was concluded that removal of multiple metastatic lesions is as effective as resection of single metastases, with the important caveat that all lesions were removed.

In support of these findings, Iwadate and colleagues reported a median survival time of 9.2 months following resection of multiple brain metastases in 61 patients; this was similar to the survival time of 8.7 months following resection of a single brain metastasis in 77 contemporary patients. Predictors of shorter survival were age greater than 60 years, KPS score less than 70, incomplete surgical resection, and the presence of extensive systemic disease. Similarly, in a recent single-surgeon retrospective series of 208 patients, resection of one or more symptomatic tumors in 76 patients harboring multiple brain metastases achieved a median survival time of 11 months. This outcome compared favorably with the median survival time of 8 months in the 132 patients with surgically resected single metastases.

Based on the conclusions from these studies, individuals with multiple metastases should not be excluded a priori from undergoing surgical resection. However, it should be noted that the definition of multiple metastases in most reports was three to four. In clinical practice, patients with more than four lesions are typically not considered optimal surgical candidates and are treated with conventional WBRT or SRS. Nevertheless, with the advent of SRS, multimodal treatment that includes surgical resection for larger (>3 cm in diameter) lesions and SRS for smaller lesions has made it more feasible to offer local treatment for even more than four lesions. For example, resection of one or two larger symptomatic lesions and SRS for two or three smaller (1 to 2 mm in maximal diameter) metastases are accepted as standard practice.

Location

Resectability (i.e., whether a tumor can be removed with minimal morbidity) is dictated primarily by tumor location. With modern microneurosurgical techniques there are few, if any, regions within the brain that are inaccessible to the neurosurgeon. However, accessibility of a lesion does not necessarily equate to its resectability. The most important features that determine resectability are whether the tumor is deep or superficial and whether the tumor is within or near eloquent tissue. Stereotactic image-guided surgical techniques and skull base exposures have made previously unreachable tumors resectable. A variety of techniques such as awake motor and speech mapping help to preserve functionally important brain regions during resection. Nevertheless, lesions that are deeply located or within eloquent areas are inevitably associated with higher surgical morbidity than those within noneloquent and superficial areas. In this context, Sawaya and colleagues studied 400 consecutive patients undergoing craniotomies for brain tumor resection. They found that major neurologic complications occurred in 13% of patients undergoing resection of tumors from eloquent locations, whereas the incidence was 5% and 3%, respectively, for patients undergoing resection of tumors located within near-eloquent and noneloquent tissue. The potential morbidity (hence, recovery time) associated with surgical removal must therefore be weighed against the limited survival expectancy of this patient population. Patients with metastases to the brain stem, thalamus, and basal ganglia are generally not considered candidates for surgical resection, except in rare circumstances. Treatment of lesions in these locations with noninvasive or minimally invasive modalities such as SRS or laser interstitial thermal therapy (LITT) may be warranted. However, it must be noted that both SRS and LITT are not exempt from associated morbidity or mortality. ^,

Lesion Size

Tumor size and the associated mass effect are additional factors considered when selecting the most appropriate treatment. For metastases exceeding 3 cm in diameter, surgical resection is the preferred option. Resection offers immediate and effective improvement in the degree of mass effect from what are frequently symptomatic lesions. In contrast, radiosurgery is generally not applicable for tumors greater than 3 cm in diameter or 10-cc in volume. Treatment of large lesions with radiosurgery is limited by the unacceptably high radiation dose that would be delivered to surrounding normal brain due to the limited degree of conformity that can be achieved for large volume tumors. Thus larger-volume lesions typically require a reduced radiation dose and are associated with an increased rate of failure following SRS. For lesions less than 1 cm in maximum diameter, radiosurgery is often the ideal treatment because most of these tumors are asymptomatic, and localizing small lesions at surgery, even with MRI guidance, may be difficult, especially when they are located deep with in the brain.

The most difficult lesions for which to decide an optimal treatment are those between 1 and 3 cm in maximum diameter. For these lesions, either surgery or radiosurgery can be applied. Currently, there is limited evidence available demonstrating the superiority of one treatment over the other (see the following). For these patients, other factors such as the resectability, extent of the systemic disease, and the presence of comorbidities may influence the final decision.

Clinical Assessment

The extent of systemic or extracranial disease is a critical consideration when deciding to proceed with surgical resection. Advanced systemic disease is associated with shortened survival, whereas limited or stable extracranial disease correlates with increased survival times in patients undergoing surgery for cerebral metastases (see previous). ^{, , ,} Indeed, after resection of a single brain metastasis, up to 70% of patients will succumb to their systemic disease and not their CNS disease. In general, most individuals with absent or stable systemic disease are surgical candidates, whereas those with widely disseminated cancer are not. Patients harboring significant systemic disease burden that is responding to therapy are particularly challenging to manage. One practical approach is to determine the expected duration of survival, excluding the presence of cerebral metastases. At many centers, individuals with expected survival of more than 3 to 4 months are usually deemed appropriate surgical candidates.

In addition, the preoperative neurologic status should be considered, because patients with marked neurologic deficits have been shown to have a shorter median survival time than patients who are neurologically intact. ^, However, as alluded to previously, it is important not to exclude patients from surgery on this basis alone; there are many patients whose neurologic deficits improve following resection of the offending tumor. One way to determine the potential for recovery is to assess the response of the deficit to corticosteroid administration. Patients whose neurologic deficits are likely to improve after resection usually demonstrate an improvement after treatment with corticosteroids, whereas patients who will not improve postoperatively do not have such a response to corticosteroids. In general, a surgical patient should have an expected survival of at least 3 months, be able to withstand anesthesia, and have a KPS score of 70 or greater ( Table 11.2 ). Patients who have major cardiac, pulmonary, renal, or hematologic diseases may be better suited for nonsurgical treatment.

To assist in the treatment decision-making, several investigators have advocated dividing patients into prognostic categories based on clinical features determined from prospective clinical trials. One of the most widely recognized predictive models was developed by Gaspar and colleagues, who identified three prognostic groups of patients with brain metastases based on a recursive partitioning analysis (RPA) of 1200 patients enrolled in three consecutive Radiation Therapy Oncology Group (RTOG) trials conducted between 1979 and 1993 that were originally designed to evaluate radiation fractionation paradigms and radiation sensitizers. The analysis identified three prognostic categories: class I included patients with a KPS score greater than 70, age younger than 65 years, controlled primary cancer, and no extracranial metastases; class III was defined by patients with a KPS score less than 70; and class II included all other patients. These RPA groups correlated with outcome as the median survival times of class I, II, and III patients were 7.1, 4.2, and 2.3 months, respectively. Tendulkar et al. validated the RPA classification in a retrospective study of 271 patients undergoing surgical resection of a single metastasis. The median survival correlated with RPA classification; it was approximately 21 and 9 months for class I and class III participants, respectively. Based on this analysis, it has been suggested that class I patients are appropriate candidates for aggressive treatment including surgical resection, whereas class III patients are not. Stratification of individuals by RPA classification has not been adopted in routine clinical use. Regardless, it is frequently used in clinical investigations to design, stratify, and assess treatment results of a clinical trial. An understanding of this classification is important in critically evaluating the current neuro-oncology literature. Another frequently used prognostic index is the Graded Prognostic Assessment (GPA) score. The GPA score was developed from analysis of nearly 2000 patients with cerebral metastases enrolled across four RTOG protocols and is a composite score determined by age, KPS score, number of intracranial lesions, and systemic disease status.

Histologic Assessment

The type of malignancy and its relative sensitivity to radiation are essential considerations in selecting the most appropriate treatment ( Table 11.3 ). In this context, treatment with WBRT or SRS is strongly preferred for individuals with highly radiosensitive tumors, such as lymphoma, multiple myeloma, germ cell tumors, and small cell lung cancer. The most frequently occurring brain metastases, breast and non–small cell lung cancer, exhibit intermediate sensitivity to conventional fractionated radiotherapy, whereas melanoma, renal cell carcinoma, and sarcoma are resistant. For these malignancies, surgical resection or SRS have a central role in management. Although this categorization is useful for conventional fractionated radiotherapy, the same does not necessarily hold true for SRS. Radioresistant histologies frequently respond well to radiosurgery. The reason behind this difference in response to WBRT and SRS is not completely understood. Relative to conventional radiation therapy, radiosurgery has been proposed to have enhanced tumoricidal effect through increased DNA damage and injury to the tumor microvasculature and endothelium, as well as enhancing the antitumor immune response. ^,