Surgical Management of Cerebral Metastases

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Chapter 15 Surgical Management of Cerebral Metastases

Cerebral metastases are a leading cause of morbidity and mortality for patients with systemic cancer and are among the most common tumors encountered by neurosurgeons. The contemporary neurosurgical management of brain metastases has become progressively more complex as the number of available treatment options increases. For half a century, corticosteroids and whole-brain radiation therapy (WBRT) were regarded as the standard of care for patients with brain metastases. However, due to technological advances in operative neurosurgery and radiation therapy over the last two decades, surgical resection and stereotactic radiosurgery (SRS) have become integral parts of the management armamentarium. Additionally, with modern advances in neuro-imaging, the detection of small, asymptomatic metastases has become increasingly frequent, allowing for the performance of highly controlled surgical resections with minimal morbidity, yet at the same time deepening the controversy surrounding the optimal roles of surgery versus SRS in the management of brain metastases. The increasing trend toward aggressive and novel systemic therapy for both early and late stage cancer has also led to the expectation that the treatment of brain metastases should not excessively delay or interfere with treatment of the systemic disease. Modern neurosurgeons, therefore, are faced with complex treatment decisions when encountering patients with brain metastases and must be familiar with the risks and benefits of all available management options in order to integrate the appropriate surgical interventions into the overall treatment plan of the cancer patient.

This chapter provides an overview of the currently available neurosurgical treatments for cerebral metastases, with a particular focus on defining the role of surgical resection in the cancer patient. Specific attention is given to patient selection, operative techniques, surgical outcomes, as well as treatment alternatives.

Magnitude of the Problem

Cerebral metastases are the most common brain tumors in adults.¹ Approximately 20% to 40% of patients with cancer develop brain metastases during the course of their illness.²^–⁵ It has been estimated that of more than 560,000 patients in the United States dying each year of cancer, approximately 19%, or more than 100,000 patients, will have brain metastases.⁶^–⁸ Most brain metastases arise from lung, breast, and renal cell tumors; however, melanoma, followed by lung, breast, and renal cell carcinoma, has the greatest propensity to develop brain metastases (Table 15-1). Characteristically, breast and renal cell carcinomas tend to present as a single metastasis within the brain, while melanoma and lung cancers have an increased incidence of multiplicity.^3,^9,¹⁰ In addition, the interval between the diagnosis of the primary cancer and the brain metastasis depends on the histology of the primary cancer, with breast cancer generally exhibiting the longest interval (mean, 3 years) and lung cancer the shortest (mean, 4 to 10 months).¹¹ The highest incidence of brain metastases is seen in the fifth to seventh decades of life and is equally common among males and females. However, lung carcinoma is the source of most brain metastases in males, and breast carcinomas the most common source of metastases in females. Males with melanoma are more likely to develop brain metastases than are females.¹⁰

Table 15-1 Proportion of Brain Metastases and Propensity to Metastasize to Brain According to Primary Tumor

Treatment Goals: Advantages of Surgical Resection

The goals of treating brain metastases are (1) to establish a histologic diagnosis, (2) to relieve neurologic symptoms, and (3) to provide long-term local disease control. Compared with other treatment options (i.e., corticosteroids, WBRT, and SRS), surgical resection has distinct advantages for achieving these goals.

First, surgery is the only treatment modality that can provide a histologic diagnosis. Although progress in imaging techniques such as magnetic resonance (MR) spectroscopy may allow for precise determination of tumor pathology in the future, surgery remains the only established method for achieving this goal at present. The importance of tissue diagnosis is paramount when the diagnosis of brain metastasis is in question. This occurs most commonly in patients without a diagnosis of primary cancer, or rarely in patients with two known primary tumors. Nevertheless, even for patients with a single known systemic cancer, failure to obtain histologic confirmation may still lead to erroneous diagnosis in 5% to 11% of the cases.^12,¹³ Therefore, it is important not to omit tissue sampling when clinical features raise suspicion of other disease processes such as cerebral abscess or primary lymphoma, whose imaging findings may be indistinguishable from metastatic tumors.

Second, compared with other modalities, surgery is most effective in immediately relieving symptoms caused by the mass effect of the lesion. Although corticosteroids reduce the effects of vasogenic edema, they do not alter the pressure exerted from the lesion itself, and their side effects preclude long-term use. Radiation treatment, including SRS, may reduce the tumor mass, but the effect is delayed.

Third, surgical resection is well documented to result in long-term local control of metastatic lesions with minimal morbidity. Although WBRT and SRS may provide local control, eradication of the lesion, as objectively demonstrated on imaging studies, is less predictable for these modalities when compared with surgery. In contrast, with modern techniques, complete resection can be achieved in nearly all cases. The certainty in predicting such an immediate outcome is a major advantage over radiation-based modalities.

Patient Selection

Patient selection is the cornerstone of surgical management. Not all patients with brain metastases are candidates for resection, and decisions to operate should be based on a firm understanding of the variables influencing surgical outcomes. Determining whether surgical resection is the best option for a particular patient requires a careful consideration of a number of parameters, including the multiplicity, the location, and the size of the lesion(s), in the context of the clinical status of the patient as well as the histology of the primary tumor. The decision for surgical resection must be weighed against and integrated with other treatment options, namely WBRT and SRS.

Radiographic Assessment

Preoperative studies, particularly MR imaging, are used to determine the number, location, size, and resectability of intracranial metastases. These tumor features are critical in selecting patients for surgery.

Number of Lesions

A primary consideration in deciding to operate is the number of lesions. MR imaging is more sensitive than computed tomography (CT) for the detection of small metastases or those within the posterior fossa ¹⁴^–¹⁶ and is thus recommended for definitively establishing the number of intracranial metastases. The term “single” cerebral metastasis is used to describe one metastasis to the brain in the face of other systemic metastases, whereas “solitary” cerebral metastasis indicates that the brain is the only site of metastatic disease within the body.¹⁷ Although single cerebral metastases constitute approximately 30% of all cases of patients with brain metastases, solitary metastases are rare.¹⁸ To determine management options, patients should be divided into two broad categories: patients with single/solitary metastases or with multiple brain metastases.

Single and Solitary Brain Metastasis

Patients with single/solitary brain metastases are the best candidates for surgery. It has been demonstrated by class I evidence that surgical resection of single or solitary brain metastases is superior to treatment with WBRT alone. The evidence is derived from three randomized controlled trials reported in the 1990s comparing surgical resection plus WBRT with WBRT alone, of which two showed a significant reduction of recurrence and extension of survival with surgical treatment.^12,^19,²⁰

Patchell and colleagues reported the first study comparing surgical resection plus WBRT with WBRT alone.¹² The authors included patients (n = 47) with single brain metastases, good performance status (Karnofsky Performance Scale [KPS] score ≥ 70), and limited extent of disease. They found that the rate of local recurrence was significantly (p < 0.02) lower in the surgical group (20%) compared with the WBRT group (52%). Likewise, the overall length of survival was significantly longer (p < 0.01) following surgical resection plus WBRT (median, 40 weeks) compared with WBRT alone (median, 15 weeks). Importantly, the improved survival was accompanied by maintenance of functional independence (38 weeks in the surgical group vs. 8 weeks in the WBRT group, p < 0.005). A multivariate analysis further indicated that surgical resection (p < 0.0001) and the absence of disseminated disease (p < 0.0004) were predictors of better outcome. These results provided, for the first time, class I evidence in support of surgical resection plus WBRT in lieu of WBRT alone as the gold standard for treatment of single/solitary brain metastases.

In a second prospective randomized study, Vecht and colleagues also compared surgery plus WBRT with WBRT alone in patients with single brain metastases. Like Patchell et al., they included only patients with good performance status and reported a significantly longer median survival time after surgery plus WBRT (43 weeks) compared with WBRT alone (26 weeks, p = 0.04).²⁰ A major difference from the trial of Patchell and colleagues, however, was that the investigators stratified the patients by site (lung cancer vs. non-lung cancer) and by status of extracranial disease (progressive vs. stable). Importantly, they found that the benefits of surgery were most evident in patients with limited systemic disease. Specifically, patients with stable extracranial disease had a more prolonged survival when treated with surgical resection and WBRT (median, 12 months) than when treated with WBRT alone (median, 7 months, p = 0.04).In contrast, patients with progressive extracranial disease generally fared worse and the survival was independent of whether or not surgical resection was performed (median survival time of 5 months in both combined treatment and WBRT alone groups). The tumor type, lung versus non-lung histology, was not a strong predictor of survival.

In a third study, Mintz et al. reported a multicenter prospective trial that randomized 84 patients to either surgery plus WBRT or WBRT alone.¹⁹ In contrast to the previous two trials, there was no difference in the median survival time of the surgery plus WBRT group (24 weeks) compared with the WBRT alone group (27 weeks, p = 0.24). Likewise, the duration of time that patients maintained a KPS score ≥ 70 was not different between the two groups. However, the data did support previous findings that extracranial metastases were an important predictor of mortality. One key difference between the study of Mintz et al. and the other two randomized trials was that Mintz et al. included patients with lower performance status (inclusion criterion was KPS score ≥ 50, compared with > 70 in the other studies). Consequently, 21% of their study population had a KPS score < 70, and 45% of patients suffered from extracranial metastases. In contrast, patients with active extracranial disease comprised only 37% of patients in the study of Patchell et al. and 32% of patients in the study of Vecht et al. Because low KPS scores and active extracranial disease are associated with poor survival, the differences between these trials suggest that the benefits of surgery may diminish in patients with more advanced disease as the systemic tumor burden predominates in the clinical course. Such differences also highlight the influence of study populations in altering the overall outcome of clinical trials.

On the basis of these three randomized controlled trials, a Cochrane meta-analysis concluded that for patients with good performance status (KPS score ≥ 70) and controlled systemic disease, surgical resection plus WBRT provides the best outcome for patients with single brain metastases.²¹ This same conclusion was also reached in recently published guidelines.²² The collective data suggest that the benefits of surgery extend not only to prolongation of overall survival but also to maintenance of functional independence and local disease control, by reducing deaths and disabilities from neurologic causes. For patients with lower performance status (KPS score < 70), the evidence is less clear, as the burden of the extracranial disease is likely to outweigh 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, and the role of surgery in reversing neurologic symptoms and deficits by immediate decompression of local mass effects and prevention of death from brain herniation cannot be overemphasized. For example, a drowsy 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 patient.

Multiple Brain Metastases

The traditional treatment of multiple brain metastases is with WBRT, and the presence of multiple metastases has been considered in the past a contraindication to surgery, even when the tumors are surgically accessible.²³^–²⁶ However, an increasing volume of literature in recent years has suggested that surgery may have a role in the treatment of multiple metastases for a defined patient population. In a retrospective analysis, Bindal et al. reported the outcome of 56 patients who underwent resection for 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).²⁷ These patients 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 left unresected (group A; median, 6 months; p = 0.003). The survival time of patients who had all lesions removed (group B) was similar to that of patients with resected single metastases (group C; median, 14 months). It was concluded that removal of multiple metastatic lesions is as effective as resection of single metastases, with the important caveat that all lesions had to be removed.²⁷

In support of the above 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.²⁸ Predictors of shorter survival were age greater than 60 years, KPS score < 70, incomplete surgical resection, and the presence of extensive systemic cancer. 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.²⁹ This outcome compared favorably with the median survival time of 8 months in the 132 patients with surgically resected single metastases.²⁹

Based on these studies, patients with multiple metastases should not be excluded a priori from surgery. However, it should be noted that the definition of “multiple” in most reported studies was three to four tumors, and in practice, patients with more than four lesions are generally not considered good surgical candidates and are conventionally treated with WBRT alone. Nevertheless, with the advent of SRS, a multimodal treatment model that includes surgical resection for larger (>3 cm in maximal 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 providing SRS for two or three smaller (1–2 mm in maximal diameter) metastases is becoming an increasingly accepted approach.

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 very few, if any, regions within the brain that are inaccessible to the neurosurgeon. However, accessibility and resectability are not the same. The most important features that determine resectability are whether the tumor is deep or superficial and whether the tumor is within or near “eloquent” brain. Stereotactic image-guided surgical techniques and skull base exposures have made previously unreachable tumors resectable. A variety of techniques help to preserve functionally important brain regions during resection. Nevertheless, lesions that are deeply located and within “eloquent areas” are inevitably associated with slightly 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.³⁰ They found that major neurologic complications occurred in 13% of patients undergoing resection of tumors from “eloquent” brain regions, whereas the incidence was 5% and 3%, respectively, for patients undergoing resection of tumors located within “near-eloquent” and “noneloquent” brain regions. 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 surgical candidates, except in rare circumstances. Treatment of lesions in these locations with noninvasive modality such as SRS may be warranted. However, it must be noted that significant morbidity could also develop with SRS when treating lesions near the eloquent brain or cranial nerves, and no study to date has convincingly showed that the morbidity of surgery is more than that of SRS in these circumstances.

Lesion Size

The size of the lesion is another factor that must be considered when choosing therapy. For lesions that are greater than 3 cm in maximum diameter, surgical resection is the primary option because surgery rapidly relieves the mass effect that commonly occurs with these larger, often symptomatic lesions. In contrast, SRS is generally not applicable for tumors >3 cm in diameter because SRS typically results in an unacceptably high radiation dose to the surrounding normal brain due to the limited degree of conformity that can be achieved for large volume tumors.^31,³² However, for lesions <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 MR imaging guidance, may be difficult, especially when deep 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 status of the patient’s systemic disease (i.e., the extent of the primary tumor and of noncerebral metastases) is a critical consideration in the decision to resect a brain metastasis because advanced systemic disease is a major predictor of short-term survival, whereas limited systemic disease is associated with long survival in patients undergoing surgery for cerebral metastases (see previous).^12,^20,^27,³³^–³⁵ Indeed, after resection of a single brain metastasis, up to 70% of patients will succumb to their systemic disease and not to their brain disease.¹² In this context, most patients with absent systemic disease are surgical candidates, whereas most patients with widely disseminated cancer are not. Decision making in patients with significant systemic cancer burden that is responding to therapy poses a challenge. One practical approach is to determine the expected survival time for the patient, excluding the presence of cerebral metastases. At many centers, patients who are expected to survive for more than 3-4 months are usually candidates for surgical resection.

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.^35,³⁶ However, as alluded to previously, it is important not to exclude patients from surgery on this basis alone, because 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 ≥ 70 (Table 15-2). Patients who have major cardiac, pulmonary, renal, or hematologic diseases may be better suited for nonsurgical treatment.

Table 15-2 Considerations in Patient Selection for Surgical Removal of Brain Metastases

Factor	Requirement for Surgery
Status of Systemic Disease
Control of primary cancer	Expected survival >3 months
General medical condition	Able to withstand surgery/anesthesia
Neurologic status	KPS score ≥ 70
Resectability
Accessibility	Not brain stem, basal gangila, thalamus
Size	>1 cm in maximal diameter

KPS, Karnofsky Performance Scale.

To assist in treatment decision, several investigators have advocated dividing patients into prognostic categories based on clinical features as 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 fractionization paradigms and radiation sensitizers.³⁷ The analysis identified three prognostic categories: class I included patients with a KPS score > 70, age <65 years, controlled primary cancer, and no extracranial metastases; class III was defined by patients with a KPS score < 70; and class II included all other patients. These RPA groups correlated with survival as the median survival time of class I, II, and III patients were 7.1 months, 4.2 months, and 2.3 months, respectively. Based on this analysis, it has been suggested that class I patients are good candidate for aggressive treatment including surgery whereas class III patients are not. Although in practice, these RPA classes have not been adopted into clinical use, they are commonly used as a research tool in designing, stratifying, and assessing treatment results of clinical trials. An understanding of this classification is, therefore, important in critically evaluating the current neuro-oncology literature.

Histologic Assessment

The type of primary cancer, particularly its relative radiosensitivity, is an important consideration in treatment decision making (Table 15-3). In this context, primary treatment with WBRT is strongly considered for patients with highly radiosensitive tumors, such as lymphoma, germ cell tumors, and small cell lung cancer. The most common types of tumors to metastasize to the brain, namely breast and non–small cell lung cancer, are intermediately sensitive to conventional fractionated radiotherapy, and surgery will have a role in many cases. For radioresistant tumors (e.g., melanoma, renal cell carcinoma, and sarcomas), surgical resection is often the treatment of choice. Although this categorization is useful for conventional fractionated radiotherapy, the same does not necessarily hold true for SRS, as melanoma, renal cell carcinoma, and sarcomas may respond well to radiosurgery. The reason behind this difference in response to WBRT and SRS is not entirely clear, but it has been postulated that SRS is tumoricidal because it affects tumor vasculature differently from WBRT.³⁸

Table 15-3 Radiosensitivity of Brain Metastases to Conventional Fractionated Radiotherapy

Highly Sensitive	Intermediately Sensitive	Poorly Sensitive
Lymphoma	Breast cancer	Melanoma
Germinoma	Lung (non–small cell) cancer	Renal cancer
Lung (small cell) cancer	Colon cancer	Sarcoma

Data from JG Cairncross, JH Kim, JB Posner. Radiation therapy for brain metastases. Ann Neurol. 1980;7:529-541; and FF Lang, R Sawaya. Surgical management of cerebral metastases. Neurosurg Clin North Am. 1996;7:459-484.

Surgical Technique

Successful extirpation of cerebral metastases is based on good basic neurosurgical techniques in conjunction with technologies for tumor localization and functional brain mapping. A clear understanding of the surgical anatomy of these lesions results in safe and effective tumor removal.

Surgical Anatomy

Cerebral metastases consist of solid tumor without intervening brain tissue. Although there may be some infiltration of tumor cells into the surrounding brain, this is usually less than 5 mm deep.⁸ Typically, the mass of tumor cells is surrounded by a gliotic rim that separates the tumor from the surrounding edematous brain. The lesions commonly arise at the gray-white matter junction, where a reduction in blood vessel diameter causes the embolic tumor to become trapped.³⁹

In the supratentorial space, metastases may be classified based on their relationship to adjacent sulci and gyri.^39,⁴⁰ Metastases may occur just under the cortex and fill a gyrus (subcortical), deep within a gyrus adjacent to a sulcus (subgyral), below a sulcus (subsulcal), deep within the hemispheric white matter (lobar), or within the ventricle (intraventricular).⁴¹ In the posterior fossa, cerebellar metastases can be categorized as occurring in either deep or hemispheric locations; hemispheric lesions can be considered as lateral or medial. A subset arises directly within the vermis. Knowledge of the relationship to the sulcus is particularly important because this may determine the appropriate surgical path to the tumor (see the following).

Another important aspect of the surgical anatomy is the location of blood vessels. “Arterialized” veins that drain the lesion are often evident on the brain surface, and surgeons must carefully consider the venous drainage when resecting the lesion. More importantly, the arterial supply to most metastases comes from vessels parasitized from branches of larger vessels that arise within the sulci.

Resection Methods

Careful planning and meticulous attention to detail are necessary to minimize surgical complications. The surgeon must devote appropriate attention to each stage of the operative procedure, including positioning, opening, tumor resection, and closure. The technique must result in complete removal of the lesion, with preservation of neurologic function and minimal disruption of the surrounding brain.

Positioning

After careful review of the preoperative imaging and correlation with known anatomic landmarks, it should be possible to identify and mark the location of the tumor as it projects onto the scalp and to tentatively define the incision prior to immobilization of the head and final positioning of the patient. This is a useful exercise not only as a check of the neuronavigation system (see the following) and to decrease total reliance on such devices but also to aid in proper placement of the head immobilizer and to determine the most appropriate position for the patient. Typically, patients are positioned with the guiding principle that the lesion should be at the top of the operative field. After selection of the most appropriate position for the patient, the head is rigidly fixed in a neurosurgical head-holder (e.g., the Mayfield 3-pin clamp) and then secured to the operating table. The tumor can then be marked out on the scalp using the neuronavigation system, if available. After the location of the tumor has been determined, a final appropriate skin incision is planned. The authors generally prefer linear skin incisions, where possible, because the risk of compromising the vascular supply to the scalp is decreased as compared with utilization of flaps.

Exposure and Operative Approach

Standard neurosurgical principles of preservation of blood supply and minimal injury to tissues guide the operation. Frameless stereotaxy is preferred because it allows for smaller cranial and dural openings with minimal exposure of normal brain and because it assists in determining the optimal trajectory to the tumor. However, unless intraoperative imaging with CT or MR (and, in some cases, ultrasound) is available, the system cannot be updated during the operative procedure.

Surgical approaches to a brain metastasis are based on its anatomic location.³⁹ Supratentorial subcortical lesions are best resected by an incision in the apex of the sulcus and circumferential dissection of the tumor (transcortical approach) (Fig. 15-1

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