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Optimizing Therapy for Patients With Brain Metastases
Optimizing Therapy for Patients With Brain Metastases Timothy Kuoa and Lawrence Rechtb Brain metastases from systemic cancers are the most common malignant brain tumors encountered. Although prognosis remains poor, it is possible to stratify patients according to risk. Furthermore, an aggressive therapeutic approach for good-risk patients that includes a combination of either surgery or stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) can improve survival and decrease the risk of central nervous system progression. Semin Oncol 33:299-306 © 2006 Elsevier Inc. All rights reserved.
M
ultiple retrospective analyses suggest that between 5% and 20% of all cancer patients develop brain metastases.1 While this figure is highly dependent on a number of evolving parameters, including improved imaging techniques, it does establish brain metastases as the most common intracranial tumor, with an estimated incidence of 170,000 cases per year in the United States compared with approximately 18,000 new cases per year of primary brain tumors.2,3 The tumors that most commonly metastasize to the brain include those of lung, breast, and skin (malignant melanoma). A retrospective review of more than 2,700 patients with common solid tumors showed that 16% of patients with brain metastases had lung cancer.4 Others cite a cumulative frequency as high as 50% in adenocarcinoma and small cell variants.5-7 In contrast, the incidences of brain metastases in renal, breast, and colon cancers were 10%, 5%, and 1%, respectively.4 Although brain metastases generally occur late in the course of systemic cancer, their prompt recognition and treatment can preserve quality of life and often improve survival.
Pathophysiology Solid cancers invade the brain primarily via hematogenous dissemination of tumor emboli through the arterial circulation, thus tending to occur at “watershed” areas between the territories of the major cerebral vessels. This results in a
aDepartment of Medical Oncology, Stanford University Medical School, Palo
Alto, CA. University Medical School, Palo Alto, CA. Address correspondence to Lawrence Recht, MD, Stanford University Medical School, Palo Alto, CA 94305. E-mail: [email protected]
bStanford
0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.seminoncol.2006.03.005
clustering of brain metastases at the gray-white junction.8 Metastases can occur in any brain area and up to two thirds of patients with lung cancer present with more than one metastasis. In a retrospective review of patients with brain metastases from breast cancer, 70% had cortical lesions and 52% had disease in the cerebellum.9 In contrast to the infiltrating appearance of primary brain tumors, such as gliomas, there is a sharp demarcation between the border of a metastatic lesion and the surrounding brain parenchyma.
Diagnosis Brain metastases produce symptoms due to either the mass itself or increased intracranial pressure. Headache and focal weakness are the two most common presenting symptoms. The classic description of “brain tumor headache,” defined by worsened discomfort in the morning and gradual improvement through the day, is only seen in a minority of patients. Other common symptoms include nausea, vomiting, and altered mental status. Seizures, either focal or generalized, occur in approximately 10% of patients and portend a poorer prognosis.10 In patients with cancer, any new neurologic finding warrants performance of a neuroimaging study. In a randomized study, contrast-enhanced magnetic resonance imaging (MRI) has been established as the modality of choice over computed tomography (CT) and non-contrast MRI for detection and characterization of brain metastases.11 In this study, it was noted that a non-contrast MRI was roughly equivalent to contrast-enhanced CT. Therefore, if MRI is unavailable, CT scans should be performed with the administration of intravenous contrast. Other diagnostic interventions to detect and characterize intracranial disease are usually not necessary. The utility of 299
T. Kuo and L. Recht
300 fluorodeoxyglucose positron emission tomography (PET) for screening or diagnosis is limited due to the high uptake of glucose in the brain, leading to significant false negative results. However, body PET is useful in assessing the extent of primary extracranial disease, which has significant implications for prognosis and determination of appropriate treatment. Because brain metastases are parenchymal lesions with only rare involvement of the leptomeninges, lumbar puncture with cerebrospinal fluid analysis or cytology is rarely warranted, especially considering the risks of brain herniation. In patients who initially present before the established diagnosis of cancer, a search for the primary disease is warranted. The lung is the most frequent primary site identified (60%), although one third of sites remain unknown.12 Stated another way, if the source is not the lung, identification of the primary site will only be possible in 10% to 20% of patients. The recent introduction of PET scanning may improve this percentage.13 Thus, if available, body PET scanning should be included in the initial workup of a patient with brain metastases and an undiagnosed primary tumor. If a definitive diagnosis is not found with PET scan and dedicated chest imaging (plain radiography or CT), then tissue diagnosis from brain metastasis resection or biopsy should be performed.
Symptomatic Management Mass Effect If symptoms of chronic mass effect are present, treatment with corticosteroids aimed at quickly reducing vasogenic edema is often the first intervention. Dexamethasone has been the corticosteroid of choice based on its potent glucocorticoid properties and negligible mineralocorticoid effects. It is effective in the majority of patients, with recommended dosages ranging from 4 to 16 mg per day.14 However, similar to other corticosteroids, chronic usage of dexamethasone is associated with many complications that can reduce a patient’s quality of life.9
chemotherapeutic agents. Furthermore, these interactions make it difficult to maintain therapeutic levels of phenytoin itself.18 For this reason, we recommend prescribing some of the newer available anticonvulsants, especially levetiracetam, for chronic treatment of seizures. We particularly prefer this agent because of its lack of interactions and favorable side effect profile. Another unique issue for the patient with brain metastases is whether to prescribe anticonvulsants prophylactically. Here a solid body of evidence, based on retrospective, prospective, and meta-analyses, strongly suggests that this is not indicated.19
Specific Treatment of Brain Metastasis Available evidence from many phase III trials allows an evidence-based approach to addressing many issues concerning the optimal management of brain metastases.
WBRT Provides Effective Palliation for Patients With Brain Metastases The Radiation Therapy Oncology Group (RTOG) conducted two randomized studies in patients with brain metastases that demonstrated significant improvements in neurologic function and survival after WBRT.20 However, although better than in patients for whom radiation was withheld, median survivals were still poor and the majority of patients still died as a direct cause of their brain disease. For example, the median survival for patients with metastatic breast cancer receiving WBRT was in the range of 3 to 4 months, with 1-year survival rates at 10% to 20%.9 Furthermore, multiple studies have shown no difference in effect with various fractionation schemes or maximum doses.20-22 In short, therefore, WBRT provides effective temporary amelioration for patients with brain metastases. However, there is clearly room for improvement, both so as to decrease neurologic symptoms and to prevent late complications.
Seizures
Classification of Patients According to Prognosis
Seizures occur at some point in approximately 20% of patients with brain metastases. Seizures may be either focal or generalized. Although treatment of status epilepticus is the same as for non-cancer patients, there are a number of treatment aspects that are unique to the oncology patient. In particular, phenytoin and other conventional anticonvulsants produce hypersensitivity reactions in a higher proportion of cancer patients and there is evidence to suggest that whole brain radiation therapy (WBRT) increases the risk of erythema multiforme and Stevens-Johnson syndrome associated with anticonvulsant administration.15,16 Thus, their use should be undertaken with caution.17 Other problems exist with the use of phenytoin, carbamazepine, and phenobarbital. Since these agents share common metabolic pathways with a variety of other medications, they interact with clearance of both corticosteroids and many
Although the general overall prognosis for patients with brain metastases is poor, there is a wide variation in terms of survival. In order to optimize treatment, therefore, it would be helpful to be able to stratify patients according to risk. A retrospective analysis of 1,200 patients by the RTOG provides the most widely accepted determination of risk categorization for patients with brain metastases.23 Based on recursive partioning analysis (RPA), three prognostically homogeneous classes were identified with significant differences in overall survival for patients receiving WBRT for brain metastases (Fig 1). In a separate analysis of 916 patients receiving WBRT for brain metastases, Lutterbach et al discovered that the number of lesions also had significant prognostic implications within each RPA class (Table 1).24 Thus, if a 6-month overall survival is used as an arbitrary cut-off for a prognostically favorable
Optimizing therapy for patients with brain metastases
301 Table 2 Comparison of Surgical Resection and WBRT Versus WBRT Alone Overall Survival (mo) Study al26
Patchell et Vecht et al27,28 Mintz et al29
Figure 1 Recursive tree identifying three prognostic classes. Reprinted with permission.23
group, patients in RPA class II with solitary brain metastases would be considered to align more closely with RPA class I, while patients in RPA class II with multiple brain metastases would be considered similar to RPA class III.
Resection of Single Brain Metastasis Improves the Effects of WBRT for Good-Risk Patients Before the emergence of radiotherapy, surgical resection of brain metastases, when possible, was the mainstay of treatment. However, when radiotherapy was shown to improve outcomes for patients with brain metastases, the role of surgery in the management of these patients was questioned, even though retrospective studies suggested some benefit, especially for those patients with solitary and accessible metastases and absent or well-controlled extracranial disease.9,25 Three prospective, randomized controlled studies have subsequently confirmed a role for surgery in certain patients. Table 1 Prognostic Factors by RPA Class Prognostic Class I
II
III
Definition
Overall Survival (mo)
KPS >70; age <65 yr; controlled primary tumor, no extracranial disease Single metastasis Multiple metastases All other patients not in class I or III Single metastasis Multiple metastases KPS <70 Single metastasis Multiple metastases
Abbreviation: KPS, Karnofsky performance status.
7.1
13.5 6.0 4.2 8.1 4.1 2.3 3.3 1.6
N
Surgery ⴙ WBRT
WBRT Alone
48 63 84
10.0 10 5.6
3.8 6 6.3
In the first, Patchell et al randomized 48 patients with solitary brain metastasis, mostly from lung cancer, to receive either biopsy and WBRT versus surgical resection and WBRT.26 Those patients who underwent initial resection followed by WBRT had a lower recurrence rate (20% v 52%; P ⫽ .02) and increased overall survival (40 v 15 weeks; P ⫽ .01) compared with the group receiving WBRT alone. In addition, the surgical group also had a better quality of life, as measured by maintaining functional independence for a longer period of time (38 v 8 weeks; P ⫽ .005). A second trial randomized 63 patients to receive either surgical resection followed by WBRT versus WBRT alone.27,28 Patients treated with surgical resection and adjuvant WBRT had an improved median overall survival (10 v 6 months; P ⫽ .04). In the subset of patients with inactive or stable extracranial disease (n ⫽ 43), the effect was even more pronounced (12 v 7 months; P ⫽ .02). In contrast, there was no difference in survival (5 months) for the subset of patients with active or progressive extracranial disease (n ⫽ 20). Finally, Mintz et al conducted a similar randomized trial that showed no survival benefit for surgical resection prior to WBRT for solitary brain metastases.29 In this trial, 84 patients with solitary brain metastases similarly received surgical resection followed by WBRT versus WBRT alone. The majority of patients (74%) were noted to have either extracranial metastases or uncontrollable primary disease. No difference in overall survival was detected between the two groups (6.3 months for WBRT alone v 5.6 months for combined modality therapy). In addition, 30-day mortality, morbidity and cause of death were not statistically different. These results are summarized in Table 2. While the results seem to be in conflict, their differences reflect variations in patient eligibility and enrollment on the studies. In the study by Mintz et al, patients in general had a far inferior outcome than the surgery arms in the other two trials (5.6 months v 10 months), thus emphasizing the importance of the patient’s clinical status as a prognostic factor. Thus, while local tumordirected therapy is likely beneficial for many patients with solitary brain metastases, the lack of primary disease control (RPA II or III) may nullify this benefit. It should also be noted that each of these trials enrolled patients with solitary brain metastases, as evidence suggests that patients with multiple brain metastases do not fare as well with such an aggressive approach.30
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302 Table 3 Median Survival of Patients Receiving SRS and WBRT Based on RPA Prognostic Class I II III
Definition KPS >70; age <65 yr; controlled primary, no extracranial disease All other patients not in class I or III KPS <70
N (%)
Median Survival With SRS and WBRT (mo)
112 (22)
16.1
356 (71) 34 (7)
10.3 8.7
Abbreviations: SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; RPA, recursive partitioning analysis; KPS, Karnofsky performance status.
The Emergence of Stereotactic Radiosurgery as an Alternative to Surgical Resection In recent years, a number of technological radiotherapeutic advances have made it possible to deliver curative doses to very precise targets (termed here generically as stereotactic radiosurgery [SRS]). The emergence of this technology offers a potential substitute to surgery with the theoretic advantages of decreasing the significance of tumor location and patient performance status for treatment feasibility. Initial retrospective analyses demonstrated a high overall (⬎80%) local control rate and a median survival of approximately 1 year,31 suggesting that the clinical efficacy of SRS and WBRT was similar to that seen with surgical resection and WBRT. Although a direct comparison of surgery and SRS has not yet been done, several prospective studies suggest further that the results with SRS are at least comparable to surgery. In a prospective trial by Kondziolka et al, 27 patients with multiple brain metastases were randomized to receive either WBRT alone or SRS with WBRT.32 SRS was permitted either before, during, or after WBRT. The two groups were equally matched, particularly with respect to the extent of extracranial disease, which is an important factor in considering survival end points. The 1-year local failure rate significantly favored the SRS arm (8% v 100%) and the median time to local failure was increased (36 v 6 months). There was a trend towards increased median survival with SRS (11 v 7.5 months), but this did not reach statistical significance. In their analysis, the investigators noted that histologic type and number of metastases did not have an effect on overall survival. The only factor influencing survival was extent of extracranial disease, with a 14-month survival for patients without systemic disease versus 7.5 months for patients with systemic disease not including lung metastases versus 5.5 months for patients with lung metastases (P ⬍.02). The RTOG conducted a prospective randomized trial (RTOG 9508) of SRS with WBRT versus WBRT alone in patients with one to three newly diagnosed brain metastases to assess the effect of SRS on survival.33 This study enrolled 331 patients, with 167 patients receiving WBRT (37.5 Gy over 3 weeks) followed by SRS within 1 week of completion of WBRT. SRS doses ranged from 15 to 24 Gy, depending on the tumor size. The remaining 164 patients received an identical dose of WBRT alone. Early and late toxicities did not differ significantly between the two treatment groups. Median overall survival also did not differ between the two
groups, although there was a trend towards improvement for the WBRT alone group (6.5 v 5.7 months; P ⫽ not significant). However, for the subset of patients with a solitary metastatic lesion, the group receiving SRS had an increased survival compared with the group receiving WBRT alone (6.5 v 4.9 months; P ⫽ .039). Univariate analyses also demonstrated improved survival for inclusion of SRS for patients in RPA class I and with tumors less than 2 cm. In multivariate analyses, factors conferring a significant improvement in survival for the SRS group included RPA class I and lung histology. As suggested by RTOG 9508, it appears that the size of brain lesion may have an impact on the outcome after SRS. A separate retrospective study of 135 patients with brain metastases, with 52% receiving SRS only, demonstrated 1- and 2-year local control rates of 86% and 78%, respectively, for lesions with diameter less than 1 cm, while the rates were only 56% and 24%, respectively, for lesions with diameter greater than 1 cm (P ⫽ .0016).34 The RTOG also conducted a large retrospective analysis of 502 patients receiving WBRT and SRS using the RPA.35 Table 3 shows the overall survival times for patients receiving SRS and WBRT in this analysis. In each class, the overall survival was increased as compared to the original RTOG RPA database of patients receiving WBRT alone, suggesting a benefit (albeit from retrospective analysis) for SRS and WBRT over WBRT alone. Therefore, although a trial directly comparing surgery with SRS has not been done, the data suggest that the results almost certainly will be comparable. Because of the advantages of SRS, including the minimal hospitalization and recovery times and the ability to irradiate more than one lesion, most centers treating these patients tend to now use SRS if possible.
Is WBRT Necessary for Optimal Brain Metastases Treatment? While generally well tolerated in the short term, WBRT is associated with significant late toxicities including cortical atrophy, leukoencephalopathy, and radionecrosis, for patients who survive longer than 12 to 18 months after therapy. These complications lead to significant cognitive decline and even death.36-41 Therefore, especially with the widespread ability to administer SRS, clinicians have questioned whether WBRT is necessary for these patients. The only randomized trial that addresses whether WBRT is
Optimizing therapy for patients with brain metastases necessary after localized tumor-directed therapy was performed by Patchell et al, who assessed whether WBRT added to surgical efficacy.42 A total of 95 patients with solitary brain metastases underwent complete surgical resection and then were randomized to receive either postoperative WBRT or no adjuvant treatment. Recurrence of disease anywhere in the brain was significantly lower for the patients receiving WBRT (18% v 70%; P ⬍.001), and time to recurrence was longer for patients receiving WBRT (220 v 26 weeks; P ⬍.001). When specifically looking at recurrence at the original operative site, WBRT reduced the recurrence rate from 46% to 10% (P ⬍.001). There was no significant difference in median overall survival between the two groups (48 v 43 weeks; P ⫽ .39). However, when only considering deaths due to neurologic causes, essentially negating the effect of systemic disease activity and control, there was a survival advantage for the group receiving WBRT (115 v 81 weeks; P ⫽ .03). The investigators argued that deaths due to neurologic causes are more relevant when evaluating a therapy directed solely at the brain. All patients in this study had good performance status (RPA I and II), and subsequent analysis showed that the reduction in tumor recurrence and overall survival results were independent of RPA class.43 Only retrospective data are available to assess whether SRS is sufficient to control brain metastases and the results are conflicting. In the largest retrospective analysis comprising 569 patients stratified by RPA class, the addition of WBRT did not improve outcome.44 Thus, median survivals for patients receiving SRS alone compared with combination therapy were 14.0 versus 15.2 months for RPA class I patients, 8.2 versus 7.0 months for class II, and 5.3 versus 5.5 months for class III, leading the authors to conclude that efficacy does not appear to be hampered with the omission of upfront WBRT. Other retrospective analyses support this conclusion. For example, a review of 105 patients with single or multiple brain metastases initially treated with either SRS or SRS with WBRT revealed that although freedom from intracranial progression at 1 year from treatment was worse with SRS alone (28% v 69%), no statistical difference between the groups in terms of central nervous system control was noted (19.8 v 18.1 months) since the initial omission of WBRT allowed for salvage therapy.45 Another study of 172 patients with limited brain disease (94% with one or two tumors) revealed no differences in overall median survivals, which compared favorably with the original RTOG RPA database of patients treated with WBRT.46 Since survivals were even longer in patients with no evidence of primary tumor disease or stable disease, the investigators recommended SRS alone for patients with limited brain disease and better prognosis (young age, higher performance status, good extracranial disease control). Conversely, there are at least two other retrospective studies that draw different conclusions. In the first, the regional intracranial control rate at 1 year in 10 patients receiving SRS in conjunction with WBRT was significantly better than in six patients receiving SRS alone (80% v 0%), although no statistically significant difference in overall survival was found.47
303 In another retrospective review of 236 patients in which 158 patients receiving SRS alone were compared with 78 receiving SRS plus WBRT, there was no difference in overall survival between the two groups.48 However, in the subset of patients with no extracranial disease activity, the initial use of WBRT with SRS provided a significant improvement in overall survival over SRS alone (15.4 v 8.3 months; P ⫽ .08). Finally, in a retrospective analysis of 137 patients receiving SRS and surviving at least 1 year after treatment, improved local control from SRS was correlated with smaller tumor volume (⬍2 cm3), the use of concomitant WBRT, and the lack of extensive tumor edema. This led the authors to recommend upfront WBRT in conjunction with SRS in patients with larger tumor volumes and extensive edema.49 Patchell’s study provides good evidence that patients deemed to have solitary metastases by standard imaging techniques likely possess micrometastatic deposits at the resection bed and elsewhere in the brain. Thus, while surgery or SRS may provide adequate and immediate local tumor control, the inclusion of postoperative WBRT would seem necessary to address these micrometastases that will eventually have a major impact on patient quality of life and neurologic function. Nevertheless, from the patient’s perspective, SRS was reported to be more tolerable than WBRT based on questionnaires given to 104 patients.50 Furthermore, more patients considered SRS to be a better treatment for them than WBRT (76% v 56%) and an additional 18% believed that WBRT delayed other cancer treatments. Thus, at the present moment, a clear consensus does not exist as to the optimal timing of SRS and WBRT.
The Role of Chemotherapy and Other Agents in the Treatment of Brain Metastases Despite the theoretic difficulties with delivering chemotherapy to intracranial targets, including the presence of the blood-brain barrier,51 the poor efficacy of WBRT alone, especially in terms of controlling extracranial disease, has led to a number of investigations that have sought to evaluate a role for these agents. A meta-analysis of 12 trials including 116 patients with brain metastases from non small cell lung cancer (NSCLC) revealed that chemotherapy as a first-line treatment is capable of producing high intracranial response rates (76%) without upfront WBRT,52,53 offering reassurance for clinicians who choose to treat patients with NSCLC upfront with chemotherapy based on their active extracranial metastases. Similar support for the use of chemotherapy in patients with brain metastases from ovarian and breast cancer also has been reported.9,54-58 The results of these studies indicate similar intracranial and extracranial response rates and suggest that delivery of pharmacologic agents to brain metastases is not hampered significantly by the blood-brain barrier. This implies that chemotherapy delivery to brain metastases is not likely to be the primary issue impacting efficacy, but rather the tumor’s intrinsic susceptibility to the chemotherapy. Recently, there has been much interest in the drug temo-
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304 zolomide because it is a well-tolerated oral alklyating agent that has shown promising activity in primary brain tumors with a low incidence of myelosuppression.59-61 Temozolomide thus has been investigated without radiotherapy for the treatment of brain metastases. As a stand alone therapy, several phase II trials have demonstrated that temozolomide produces a modest effect, with objective responses generally below 10%,62-65 although this rate approaches 30% when combined with cisplatin.63 Studies have also investigated whether the addition of temozolomide increases the efficacy of WBRT; these trials also resulted in at best minimal improvements with the addition of this agent.66,67 Thus, to date, studies evaluating chemotherapy have yielded similar results in which objective response rates are increased without improvement in either survival or clinical status.32,58 Overall, therefore, the role of chemotherapy, either as a stand-alone treatment or in conjunction with WBRT, remains unclear and no specific recommendations can be generated based on current data.
Radiation Sensitizers A number of potentially radiation sensitizing agents have been studied over the past several years with overall disappointing results. However, two recently assessed agents have shown beneficial results for selected patients with brain metastases and are still being investigated. RSR13 (efaproxiral) is a synthetic allosteric modifier of hemoglobin that decreases hemoglobin-oxygen binding affinity. This facilitates increased release of oxygen from hemoglobin and higher tissue oxygen concentrations necessary for optimal radiation effect. Shaw et al conducted a phase II study administering RSR13 in conjunction with WBRT to RPA class II patients with brain metastases.68 Compared with historical survival times for RPA class II patients, the 57 patients receiving RSR13 experienced a beneficial effect (6.4 v 4.1 months; P ⫽ .0174). Significant adverse effects included hypoxia, headache, and anemia. A phase III trial evaluating RSR13 with WBRT for patients with brain metastases is ongoing. Another agent, motexafin gadolinium (MGd), generates reactive oxygen species by catalyzing the oxidation of intracellular reducing metabolites, thus lowering the apoptotic threshold and rendering tissues more sensitive to the effects of radiation. Mehta et al conducted a phase III study of WBRT with or without MGd in patients with brain metastases.69 Just over 400 patients were enrolled and no differences in overall survival or time to neurologic progression were found. However, in a subgroup analysis of the 251 patients with metastases from NSCLC, treatment to neurologic progression was lengthened with the addition of MGd, just barely meeting the cutoff for statistical significance. While these agents may eventually prove efficacious, further studies are still needed before either can be recommended for patients with brain metastases.
metastases were found to be a frequent site of relapse in patients with small cell lung cancers (SCLC) with a cumulative incidence of 50% at 2 years from diagnosis.5,6 This led to a number of studies that assessed the role of prophylactic cranial irradiation (PCI) in reducing this incidence. In a meta-analysis of seven randomized trials comparing PCI versus observation in patients with SCLC in complete remission, there were statistically significant increases in overall survival, disease-free survival, and incidence of development of brain metastases for the group treated with PCI.70 In NSCLC, prospective randomized trials have shown a trend towards reduced risk of brain metastases in patients receiving PCI, but have not shown any survival advantage.7,71 However, in a nonrandomized cohort study following patients who received PCI (30 Gy over 3 weeks) for locally advanced NSCLC, several benefits of PCI were identified compared with patients who did not receive PCI.72 With a median follow-up of 50 months, these benefits included a reduced probability of brain relapse as the first failure (8% v 30% at 4 years; P ⫽ .005) and a reduced probability of overall brain relapse at any time (13% v 54% at 4 years; P ⬍.0001). Serial neuropsychological testing did not reveal any significant differences between the two groups at a follow-up duration of 43 to 81 months, suggesting that PCI produced minimal side effects.
Treatment Algorithm Based on the available data, we propose a simple treatment algorithm for patients with brain metastases shown in Fig 2. This algorithm essentially considers two management approaches dependent on patient assessment and prediction of survival time. The more aggressive approach, reserved for patients with predicted survival ⱖ6 months (RPA I with ⱕ3 metastases and RPA II with solitary metastasis), includes both local, tumor-directed therapy (surgery or SRS) and regional intracranial therapy (WBRT). While the RPA I class was an independent predictor of benefit from SRS in RTOG 9508, this trial only included patients with one to three brain metastases and the utility of treating a higher number of lesions with SRS is not known. The less aggressive approach, suggested for the group of
Prophylactic Cranial Irradiation As improvements in chemotherapy and thoracic radiation therapy led to increased rates of complete remission, brain
Figure 2 Treatment algorithm for brain metastases.
Optimizing therapy for patients with brain metastases patients with predicted survival less than 6 months (RPA I with ⱖ4 lesions, RPA II with ⱖ2 lesions or any RPA III), utilizes WBRT alone. Surgical resection is not supported for multiple metastases nor is it supported for solitary metastases in RPA III patients based on a reduced tolerance for invasive procedures in this patient population (Karnofsky performance status ⬍70). The justification to omit SRS for this group is less clear, but analysis of the SRS trials show that favorable responses are restricted to good risk patients.32,33 Since, as previously noted, the RTOG 9508 trial did not include patients with more than three lesions, it remains unclear whether there is a role for SRS in RPA I patients with ⱖ4 lesions. In this patient population, WBRT alone provides reasonable disease control while maintaining quality of life. The late effects of WBRT are generally not a factor for this group with a shortened life expectancy due to their overall disease activity.
Conclusion With the completion of several randomized clinical trials examining the effects of various therapies on brain metastases, it is possible to generate a treatment algorithm based on high-level data. We propose a simplified algorithm that attempts to use the various tools in a judicious manner while attempting to stay within the confines of supporting data. From the many clinical studies reviewed, it is clear that the most important initial step in determining a treatment course for a patient with brain metastases is to assess prognosis, since even as new technological and medical advances are made to improve the success of treatment, the application of these advances is predicated on the individual’s ability to tolerate treatment. To this end, in parallel with the drive to develop more effective therapies, continued effort is necessary to refine risk prediction models.
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305 11. Sze G, Milano E, Johnson C, et al: Detection of brain metastases: Comparison of contrast-enhanced MR with unenhanced MR and enhanced CT. AJNR 11:785-791, 1990 12. Agazzi S, Pampallona S, Pica A, et al: The origin of brain metastases in patients with an undiagnosed primary tumour. Acta Neurochir (Wien) 146:153-157, 2004 13. Klee B, Law I, Hojgaard L, et al: Detection of unknown primary tumours in patients with cerebral metastases using whole-body 18Fflouorodeoxyglucose positron emission tomography. Eur J Neurol 9:657-662, 2002 14. Vecht CJ, Hovestadt A, Verbiest HBC, et al: Dose-effect relation of dexamethasone on brain tumor edema: A randomized study with 16 mg, 8 mg and 4 mg per day. Neurology 44:675-680, 1994 15. Delattre JY, Safai B, Posner JB: Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin. Neurology 38:194-198, 1988 16. Hoang-Xuan K, Delattre JY, Poisson M: Stevens-Johnson syndrome in a patient receiving cranial irradiation and carbamazepine. Neurology 40: 1144-1145, 1990 17. Roujeau JC, Kelly JP, Naldi L, et al: Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333:1600-1607, 1995 18. Grossman SA, Sheidler VR, Gilbert MR: Decreasing phenytoin levels in patients receiving chemotherapy. Am J Med 87:505-510, 1989 19. Glantz MJ, Cole BF, Forsyth PA, et al: Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Neurology 54:1886-1893, 2000 20. Borgelt B, Gelber R, Kramer S, et al: The palliation of brain metastases: Final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 6:1-9, 1980 21. Borgelt B, Gelbert R, Larson M, et al: Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: Final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 7:1633-1638, 1981 22. Franchin G, Minatel E, Roncadin M, et al: Accelerated split course regimen in the treatment of brain metastasis. Radiother Oncol 12:3944, 1988 23. Gaspar L, Scott C, Rotman M, et al: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745-751, 1997 24. Lutterbach J, Bartelt S, Ostertag C: Long-term survival in patients with brain metastases. J Cancer Res Clin Oncol 128:417-425, 2002 25. DiStefano A, Yap HY, Hortobagyi GN, et al: The natural history of breast cancer patients with brain metastases. Cancer 44:1913-1918, 1979 26. Patchell RA, Tibbs PA, Walsh JW, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494500, 1990 27. Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 29:711-717, 1994 28. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al: Treatment of single brain metastasis: Radiotherapy alone or combine with neurosurgery. Ann Neurol 33:583-590, 1993 29. Mintz AH, Kestle J, Rathbone MP, et al: A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 78:1470-1476, 1978 30. Hazuka MB, Burleson WD, Stroud DN, et al: Multiple brain metastases are associated with poor survival in patients treatede with surgery and radiotherapy. J Clin Oncol 11:369-373, 1993 31. Auchter RM, Lamond JP, Alexander E, et al: A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 35:27-35, 1996 32. Kondziolka D, Patel A, Lunsford LD, et al: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45:427434, 1999 33. Andrews DW, Scott CB, Sperduto PW, et al: Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients
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M
ultiple retrospective analyses suggest that between 5% and 20% of all cancer patients develop brain metastases.1 While this figure is highly dependent on a number of evolving parameters, including improved imaging techniques, it does establish brain metastases as the most common intracranial tumor, with an estimated incidence of 170,000 cases per year in the United States compared with approximately 18,000 new cases per year of primary brain tumors.2,3 The tumors that most commonly metastasize to the brain include those of lung, breast, and skin (malignant melanoma). A retrospective review of more than 2,700 patients with common solid tumors showed that 16% of patients with brain metastases had lung cancer.4 Others cite a cumulative frequency as high as 50% in adenocarcinoma and small cell variants.5-7 In contrast, the incidences of brain metastases in renal, breast, and colon cancers were 10%, 5%, and 1%, respectively.4 Although brain metastases generally occur late in the course of systemic cancer, their prompt recognition and treatment can preserve quality of life and often improve survival.
Pathophysiology Solid cancers invade the brain primarily via hematogenous dissemination of tumor emboli through the arterial circulation, thus tending to occur at “watershed” areas between the territories of the major cerebral vessels. This results in a
aDepartment of Medical Oncology, Stanford University Medical School, Palo
Alto, CA. University Medical School, Palo Alto, CA. Address correspondence to Lawrence Recht, MD, Stanford University Medical School, Palo Alto, CA 94305. E-mail: [email protected]
bStanford
0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.seminoncol.2006.03.005
clustering of brain metastases at the gray-white junction.8 Metastases can occur in any brain area and up to two thirds of patients with lung cancer present with more than one metastasis. In a retrospective review of patients with brain metastases from breast cancer, 70% had cortical lesions and 52% had disease in the cerebellum.9 In contrast to the infiltrating appearance of primary brain tumors, such as gliomas, there is a sharp demarcation between the border of a metastatic lesion and the surrounding brain parenchyma.
Diagnosis Brain metastases produce symptoms due to either the mass itself or increased intracranial pressure. Headache and focal weakness are the two most common presenting symptoms. The classic description of “brain tumor headache,” defined by worsened discomfort in the morning and gradual improvement through the day, is only seen in a minority of patients. Other common symptoms include nausea, vomiting, and altered mental status. Seizures, either focal or generalized, occur in approximately 10% of patients and portend a poorer prognosis.10 In patients with cancer, any new neurologic finding warrants performance of a neuroimaging study. In a randomized study, contrast-enhanced magnetic resonance imaging (MRI) has been established as the modality of choice over computed tomography (CT) and non-contrast MRI for detection and characterization of brain metastases.11 In this study, it was noted that a non-contrast MRI was roughly equivalent to contrast-enhanced CT. Therefore, if MRI is unavailable, CT scans should be performed with the administration of intravenous contrast. Other diagnostic interventions to detect and characterize intracranial disease are usually not necessary. The utility of 299
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300 fluorodeoxyglucose positron emission tomography (PET) for screening or diagnosis is limited due to the high uptake of glucose in the brain, leading to significant false negative results. However, body PET is useful in assessing the extent of primary extracranial disease, which has significant implications for prognosis and determination of appropriate treatment. Because brain metastases are parenchymal lesions with only rare involvement of the leptomeninges, lumbar puncture with cerebrospinal fluid analysis or cytology is rarely warranted, especially considering the risks of brain herniation. In patients who initially present before the established diagnosis of cancer, a search for the primary disease is warranted. The lung is the most frequent primary site identified (60%), although one third of sites remain unknown.12 Stated another way, if the source is not the lung, identification of the primary site will only be possible in 10% to 20% of patients. The recent introduction of PET scanning may improve this percentage.13 Thus, if available, body PET scanning should be included in the initial workup of a patient with brain metastases and an undiagnosed primary tumor. If a definitive diagnosis is not found with PET scan and dedicated chest imaging (plain radiography or CT), then tissue diagnosis from brain metastasis resection or biopsy should be performed.
Symptomatic Management Mass Effect If symptoms of chronic mass effect are present, treatment with corticosteroids aimed at quickly reducing vasogenic edema is often the first intervention. Dexamethasone has been the corticosteroid of choice based on its potent glucocorticoid properties and negligible mineralocorticoid effects. It is effective in the majority of patients, with recommended dosages ranging from 4 to 16 mg per day.14 However, similar to other corticosteroids, chronic usage of dexamethasone is associated with many complications that can reduce a patient’s quality of life.9
chemotherapeutic agents. Furthermore, these interactions make it difficult to maintain therapeutic levels of phenytoin itself.18 For this reason, we recommend prescribing some of the newer available anticonvulsants, especially levetiracetam, for chronic treatment of seizures. We particularly prefer this agent because of its lack of interactions and favorable side effect profile. Another unique issue for the patient with brain metastases is whether to prescribe anticonvulsants prophylactically. Here a solid body of evidence, based on retrospective, prospective, and meta-analyses, strongly suggests that this is not indicated.19
Specific Treatment of Brain Metastasis Available evidence from many phase III trials allows an evidence-based approach to addressing many issues concerning the optimal management of brain metastases.
WBRT Provides Effective Palliation for Patients With Brain Metastases The Radiation Therapy Oncology Group (RTOG) conducted two randomized studies in patients with brain metastases that demonstrated significant improvements in neurologic function and survival after WBRT.20 However, although better than in patients for whom radiation was withheld, median survivals were still poor and the majority of patients still died as a direct cause of their brain disease. For example, the median survival for patients with metastatic breast cancer receiving WBRT was in the range of 3 to 4 months, with 1-year survival rates at 10% to 20%.9 Furthermore, multiple studies have shown no difference in effect with various fractionation schemes or maximum doses.20-22 In short, therefore, WBRT provides effective temporary amelioration for patients with brain metastases. However, there is clearly room for improvement, both so as to decrease neurologic symptoms and to prevent late complications.
Seizures
Classification of Patients According to Prognosis
Seizures occur at some point in approximately 20% of patients with brain metastases. Seizures may be either focal or generalized. Although treatment of status epilepticus is the same as for non-cancer patients, there are a number of treatment aspects that are unique to the oncology patient. In particular, phenytoin and other conventional anticonvulsants produce hypersensitivity reactions in a higher proportion of cancer patients and there is evidence to suggest that whole brain radiation therapy (WBRT) increases the risk of erythema multiforme and Stevens-Johnson syndrome associated with anticonvulsant administration.15,16 Thus, their use should be undertaken with caution.17 Other problems exist with the use of phenytoin, carbamazepine, and phenobarbital. Since these agents share common metabolic pathways with a variety of other medications, they interact with clearance of both corticosteroids and many
Although the general overall prognosis for patients with brain metastases is poor, there is a wide variation in terms of survival. In order to optimize treatment, therefore, it would be helpful to be able to stratify patients according to risk. A retrospective analysis of 1,200 patients by the RTOG provides the most widely accepted determination of risk categorization for patients with brain metastases.23 Based on recursive partioning analysis (RPA), three prognostically homogeneous classes were identified with significant differences in overall survival for patients receiving WBRT for brain metastases (Fig 1). In a separate analysis of 916 patients receiving WBRT for brain metastases, Lutterbach et al discovered that the number of lesions also had significant prognostic implications within each RPA class (Table 1).24 Thus, if a 6-month overall survival is used as an arbitrary cut-off for a prognostically favorable
Optimizing therapy for patients with brain metastases
301 Table 2 Comparison of Surgical Resection and WBRT Versus WBRT Alone Overall Survival (mo) Study al26
Patchell et Vecht et al27,28 Mintz et al29
Figure 1 Recursive tree identifying three prognostic classes. Reprinted with permission.23
group, patients in RPA class II with solitary brain metastases would be considered to align more closely with RPA class I, while patients in RPA class II with multiple brain metastases would be considered similar to RPA class III.
Resection of Single Brain Metastasis Improves the Effects of WBRT for Good-Risk Patients Before the emergence of radiotherapy, surgical resection of brain metastases, when possible, was the mainstay of treatment. However, when radiotherapy was shown to improve outcomes for patients with brain metastases, the role of surgery in the management of these patients was questioned, even though retrospective studies suggested some benefit, especially for those patients with solitary and accessible metastases and absent or well-controlled extracranial disease.9,25 Three prospective, randomized controlled studies have subsequently confirmed a role for surgery in certain patients. Table 1 Prognostic Factors by RPA Class Prognostic Class I
II
III
Definition
Overall Survival (mo)
KPS >70; age <65 yr; controlled primary tumor, no extracranial disease Single metastasis Multiple metastases All other patients not in class I or III Single metastasis Multiple metastases KPS <70 Single metastasis Multiple metastases
Abbreviation: KPS, Karnofsky performance status.
7.1
13.5 6.0 4.2 8.1 4.1 2.3 3.3 1.6
N
Surgery ⴙ WBRT
WBRT Alone
48 63 84
10.0 10 5.6
3.8 6 6.3
In the first, Patchell et al randomized 48 patients with solitary brain metastasis, mostly from lung cancer, to receive either biopsy and WBRT versus surgical resection and WBRT.26 Those patients who underwent initial resection followed by WBRT had a lower recurrence rate (20% v 52%; P ⫽ .02) and increased overall survival (40 v 15 weeks; P ⫽ .01) compared with the group receiving WBRT alone. In addition, the surgical group also had a better quality of life, as measured by maintaining functional independence for a longer period of time (38 v 8 weeks; P ⫽ .005). A second trial randomized 63 patients to receive either surgical resection followed by WBRT versus WBRT alone.27,28 Patients treated with surgical resection and adjuvant WBRT had an improved median overall survival (10 v 6 months; P ⫽ .04). In the subset of patients with inactive or stable extracranial disease (n ⫽ 43), the effect was even more pronounced (12 v 7 months; P ⫽ .02). In contrast, there was no difference in survival (5 months) for the subset of patients with active or progressive extracranial disease (n ⫽ 20). Finally, Mintz et al conducted a similar randomized trial that showed no survival benefit for surgical resection prior to WBRT for solitary brain metastases.29 In this trial, 84 patients with solitary brain metastases similarly received surgical resection followed by WBRT versus WBRT alone. The majority of patients (74%) were noted to have either extracranial metastases or uncontrollable primary disease. No difference in overall survival was detected between the two groups (6.3 months for WBRT alone v 5.6 months for combined modality therapy). In addition, 30-day mortality, morbidity and cause of death were not statistically different. These results are summarized in Table 2. While the results seem to be in conflict, their differences reflect variations in patient eligibility and enrollment on the studies. In the study by Mintz et al, patients in general had a far inferior outcome than the surgery arms in the other two trials (5.6 months v 10 months), thus emphasizing the importance of the patient’s clinical status as a prognostic factor. Thus, while local tumordirected therapy is likely beneficial for many patients with solitary brain metastases, the lack of primary disease control (RPA II or III) may nullify this benefit. It should also be noted that each of these trials enrolled patients with solitary brain metastases, as evidence suggests that patients with multiple brain metastases do not fare as well with such an aggressive approach.30
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302 Table 3 Median Survival of Patients Receiving SRS and WBRT Based on RPA Prognostic Class I II III
Definition KPS >70; age <65 yr; controlled primary, no extracranial disease All other patients not in class I or III KPS <70
N (%)
Median Survival With SRS and WBRT (mo)
112 (22)
16.1
356 (71) 34 (7)
10.3 8.7
Abbreviations: SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; RPA, recursive partitioning analysis; KPS, Karnofsky performance status.
The Emergence of Stereotactic Radiosurgery as an Alternative to Surgical Resection In recent years, a number of technological radiotherapeutic advances have made it possible to deliver curative doses to very precise targets (termed here generically as stereotactic radiosurgery [SRS]). The emergence of this technology offers a potential substitute to surgery with the theoretic advantages of decreasing the significance of tumor location and patient performance status for treatment feasibility. Initial retrospective analyses demonstrated a high overall (⬎80%) local control rate and a median survival of approximately 1 year,31 suggesting that the clinical efficacy of SRS and WBRT was similar to that seen with surgical resection and WBRT. Although a direct comparison of surgery and SRS has not yet been done, several prospective studies suggest further that the results with SRS are at least comparable to surgery. In a prospective trial by Kondziolka et al, 27 patients with multiple brain metastases were randomized to receive either WBRT alone or SRS with WBRT.32 SRS was permitted either before, during, or after WBRT. The two groups were equally matched, particularly with respect to the extent of extracranial disease, which is an important factor in considering survival end points. The 1-year local failure rate significantly favored the SRS arm (8% v 100%) and the median time to local failure was increased (36 v 6 months). There was a trend towards increased median survival with SRS (11 v 7.5 months), but this did not reach statistical significance. In their analysis, the investigators noted that histologic type and number of metastases did not have an effect on overall survival. The only factor influencing survival was extent of extracranial disease, with a 14-month survival for patients without systemic disease versus 7.5 months for patients with systemic disease not including lung metastases versus 5.5 months for patients with lung metastases (P ⬍.02). The RTOG conducted a prospective randomized trial (RTOG 9508) of SRS with WBRT versus WBRT alone in patients with one to three newly diagnosed brain metastases to assess the effect of SRS on survival.33 This study enrolled 331 patients, with 167 patients receiving WBRT (37.5 Gy over 3 weeks) followed by SRS within 1 week of completion of WBRT. SRS doses ranged from 15 to 24 Gy, depending on the tumor size. The remaining 164 patients received an identical dose of WBRT alone. Early and late toxicities did not differ significantly between the two treatment groups. Median overall survival also did not differ between the two
groups, although there was a trend towards improvement for the WBRT alone group (6.5 v 5.7 months; P ⫽ not significant). However, for the subset of patients with a solitary metastatic lesion, the group receiving SRS had an increased survival compared with the group receiving WBRT alone (6.5 v 4.9 months; P ⫽ .039). Univariate analyses also demonstrated improved survival for inclusion of SRS for patients in RPA class I and with tumors less than 2 cm. In multivariate analyses, factors conferring a significant improvement in survival for the SRS group included RPA class I and lung histology. As suggested by RTOG 9508, it appears that the size of brain lesion may have an impact on the outcome after SRS. A separate retrospective study of 135 patients with brain metastases, with 52% receiving SRS only, demonstrated 1- and 2-year local control rates of 86% and 78%, respectively, for lesions with diameter less than 1 cm, while the rates were only 56% and 24%, respectively, for lesions with diameter greater than 1 cm (P ⫽ .0016).34 The RTOG also conducted a large retrospective analysis of 502 patients receiving WBRT and SRS using the RPA.35 Table 3 shows the overall survival times for patients receiving SRS and WBRT in this analysis. In each class, the overall survival was increased as compared to the original RTOG RPA database of patients receiving WBRT alone, suggesting a benefit (albeit from retrospective analysis) for SRS and WBRT over WBRT alone. Therefore, although a trial directly comparing surgery with SRS has not been done, the data suggest that the results almost certainly will be comparable. Because of the advantages of SRS, including the minimal hospitalization and recovery times and the ability to irradiate more than one lesion, most centers treating these patients tend to now use SRS if possible.
Is WBRT Necessary for Optimal Brain Metastases Treatment? While generally well tolerated in the short term, WBRT is associated with significant late toxicities including cortical atrophy, leukoencephalopathy, and radionecrosis, for patients who survive longer than 12 to 18 months after therapy. These complications lead to significant cognitive decline and even death.36-41 Therefore, especially with the widespread ability to administer SRS, clinicians have questioned whether WBRT is necessary for these patients. The only randomized trial that addresses whether WBRT is
Optimizing therapy for patients with brain metastases necessary after localized tumor-directed therapy was performed by Patchell et al, who assessed whether WBRT added to surgical efficacy.42 A total of 95 patients with solitary brain metastases underwent complete surgical resection and then were randomized to receive either postoperative WBRT or no adjuvant treatment. Recurrence of disease anywhere in the brain was significantly lower for the patients receiving WBRT (18% v 70%; P ⬍.001), and time to recurrence was longer for patients receiving WBRT (220 v 26 weeks; P ⬍.001). When specifically looking at recurrence at the original operative site, WBRT reduced the recurrence rate from 46% to 10% (P ⬍.001). There was no significant difference in median overall survival between the two groups (48 v 43 weeks; P ⫽ .39). However, when only considering deaths due to neurologic causes, essentially negating the effect of systemic disease activity and control, there was a survival advantage for the group receiving WBRT (115 v 81 weeks; P ⫽ .03). The investigators argued that deaths due to neurologic causes are more relevant when evaluating a therapy directed solely at the brain. All patients in this study had good performance status (RPA I and II), and subsequent analysis showed that the reduction in tumor recurrence and overall survival results were independent of RPA class.43 Only retrospective data are available to assess whether SRS is sufficient to control brain metastases and the results are conflicting. In the largest retrospective analysis comprising 569 patients stratified by RPA class, the addition of WBRT did not improve outcome.44 Thus, median survivals for patients receiving SRS alone compared with combination therapy were 14.0 versus 15.2 months for RPA class I patients, 8.2 versus 7.0 months for class II, and 5.3 versus 5.5 months for class III, leading the authors to conclude that efficacy does not appear to be hampered with the omission of upfront WBRT. Other retrospective analyses support this conclusion. For example, a review of 105 patients with single or multiple brain metastases initially treated with either SRS or SRS with WBRT revealed that although freedom from intracranial progression at 1 year from treatment was worse with SRS alone (28% v 69%), no statistical difference between the groups in terms of central nervous system control was noted (19.8 v 18.1 months) since the initial omission of WBRT allowed for salvage therapy.45 Another study of 172 patients with limited brain disease (94% with one or two tumors) revealed no differences in overall median survivals, which compared favorably with the original RTOG RPA database of patients treated with WBRT.46 Since survivals were even longer in patients with no evidence of primary tumor disease or stable disease, the investigators recommended SRS alone for patients with limited brain disease and better prognosis (young age, higher performance status, good extracranial disease control). Conversely, there are at least two other retrospective studies that draw different conclusions. In the first, the regional intracranial control rate at 1 year in 10 patients receiving SRS in conjunction with WBRT was significantly better than in six patients receiving SRS alone (80% v 0%), although no statistically significant difference in overall survival was found.47
303 In another retrospective review of 236 patients in which 158 patients receiving SRS alone were compared with 78 receiving SRS plus WBRT, there was no difference in overall survival between the two groups.48 However, in the subset of patients with no extracranial disease activity, the initial use of WBRT with SRS provided a significant improvement in overall survival over SRS alone (15.4 v 8.3 months; P ⫽ .08). Finally, in a retrospective analysis of 137 patients receiving SRS and surviving at least 1 year after treatment, improved local control from SRS was correlated with smaller tumor volume (⬍2 cm3), the use of concomitant WBRT, and the lack of extensive tumor edema. This led the authors to recommend upfront WBRT in conjunction with SRS in patients with larger tumor volumes and extensive edema.49 Patchell’s study provides good evidence that patients deemed to have solitary metastases by standard imaging techniques likely possess micrometastatic deposits at the resection bed and elsewhere in the brain. Thus, while surgery or SRS may provide adequate and immediate local tumor control, the inclusion of postoperative WBRT would seem necessary to address these micrometastases that will eventually have a major impact on patient quality of life and neurologic function. Nevertheless, from the patient’s perspective, SRS was reported to be more tolerable than WBRT based on questionnaires given to 104 patients.50 Furthermore, more patients considered SRS to be a better treatment for them than WBRT (76% v 56%) and an additional 18% believed that WBRT delayed other cancer treatments. Thus, at the present moment, a clear consensus does not exist as to the optimal timing of SRS and WBRT.
The Role of Chemotherapy and Other Agents in the Treatment of Brain Metastases Despite the theoretic difficulties with delivering chemotherapy to intracranial targets, including the presence of the blood-brain barrier,51 the poor efficacy of WBRT alone, especially in terms of controlling extracranial disease, has led to a number of investigations that have sought to evaluate a role for these agents. A meta-analysis of 12 trials including 116 patients with brain metastases from non small cell lung cancer (NSCLC) revealed that chemotherapy as a first-line treatment is capable of producing high intracranial response rates (76%) without upfront WBRT,52,53 offering reassurance for clinicians who choose to treat patients with NSCLC upfront with chemotherapy based on their active extracranial metastases. Similar support for the use of chemotherapy in patients with brain metastases from ovarian and breast cancer also has been reported.9,54-58 The results of these studies indicate similar intracranial and extracranial response rates and suggest that delivery of pharmacologic agents to brain metastases is not hampered significantly by the blood-brain barrier. This implies that chemotherapy delivery to brain metastases is not likely to be the primary issue impacting efficacy, but rather the tumor’s intrinsic susceptibility to the chemotherapy. Recently, there has been much interest in the drug temo-
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304 zolomide because it is a well-tolerated oral alklyating agent that has shown promising activity in primary brain tumors with a low incidence of myelosuppression.59-61 Temozolomide thus has been investigated without radiotherapy for the treatment of brain metastases. As a stand alone therapy, several phase II trials have demonstrated that temozolomide produces a modest effect, with objective responses generally below 10%,62-65 although this rate approaches 30% when combined with cisplatin.63 Studies have also investigated whether the addition of temozolomide increases the efficacy of WBRT; these trials also resulted in at best minimal improvements with the addition of this agent.66,67 Thus, to date, studies evaluating chemotherapy have yielded similar results in which objective response rates are increased without improvement in either survival or clinical status.32,58 Overall, therefore, the role of chemotherapy, either as a stand-alone treatment or in conjunction with WBRT, remains unclear and no specific recommendations can be generated based on current data.
Radiation Sensitizers A number of potentially radiation sensitizing agents have been studied over the past several years with overall disappointing results. However, two recently assessed agents have shown beneficial results for selected patients with brain metastases and are still being investigated. RSR13 (efaproxiral) is a synthetic allosteric modifier of hemoglobin that decreases hemoglobin-oxygen binding affinity. This facilitates increased release of oxygen from hemoglobin and higher tissue oxygen concentrations necessary for optimal radiation effect. Shaw et al conducted a phase II study administering RSR13 in conjunction with WBRT to RPA class II patients with brain metastases.68 Compared with historical survival times for RPA class II patients, the 57 patients receiving RSR13 experienced a beneficial effect (6.4 v 4.1 months; P ⫽ .0174). Significant adverse effects included hypoxia, headache, and anemia. A phase III trial evaluating RSR13 with WBRT for patients with brain metastases is ongoing. Another agent, motexafin gadolinium (MGd), generates reactive oxygen species by catalyzing the oxidation of intracellular reducing metabolites, thus lowering the apoptotic threshold and rendering tissues more sensitive to the effects of radiation. Mehta et al conducted a phase III study of WBRT with or without MGd in patients with brain metastases.69 Just over 400 patients were enrolled and no differences in overall survival or time to neurologic progression were found. However, in a subgroup analysis of the 251 patients with metastases from NSCLC, treatment to neurologic progression was lengthened with the addition of MGd, just barely meeting the cutoff for statistical significance. While these agents may eventually prove efficacious, further studies are still needed before either can be recommended for patients with brain metastases.
metastases were found to be a frequent site of relapse in patients with small cell lung cancers (SCLC) with a cumulative incidence of 50% at 2 years from diagnosis.5,6 This led to a number of studies that assessed the role of prophylactic cranial irradiation (PCI) in reducing this incidence. In a meta-analysis of seven randomized trials comparing PCI versus observation in patients with SCLC in complete remission, there were statistically significant increases in overall survival, disease-free survival, and incidence of development of brain metastases for the group treated with PCI.70 In NSCLC, prospective randomized trials have shown a trend towards reduced risk of brain metastases in patients receiving PCI, but have not shown any survival advantage.7,71 However, in a nonrandomized cohort study following patients who received PCI (30 Gy over 3 weeks) for locally advanced NSCLC, several benefits of PCI were identified compared with patients who did not receive PCI.72 With a median follow-up of 50 months, these benefits included a reduced probability of brain relapse as the first failure (8% v 30% at 4 years; P ⫽ .005) and a reduced probability of overall brain relapse at any time (13% v 54% at 4 years; P ⬍.0001). Serial neuropsychological testing did not reveal any significant differences between the two groups at a follow-up duration of 43 to 81 months, suggesting that PCI produced minimal side effects.
Treatment Algorithm Based on the available data, we propose a simple treatment algorithm for patients with brain metastases shown in Fig 2. This algorithm essentially considers two management approaches dependent on patient assessment and prediction of survival time. The more aggressive approach, reserved for patients with predicted survival ⱖ6 months (RPA I with ⱕ3 metastases and RPA II with solitary metastasis), includes both local, tumor-directed therapy (surgery or SRS) and regional intracranial therapy (WBRT). While the RPA I class was an independent predictor of benefit from SRS in RTOG 9508, this trial only included patients with one to three brain metastases and the utility of treating a higher number of lesions with SRS is not known. The less aggressive approach, suggested for the group of
Prophylactic Cranial Irradiation As improvements in chemotherapy and thoracic radiation therapy led to increased rates of complete remission, brain
Figure 2 Treatment algorithm for brain metastases.
Optimizing therapy for patients with brain metastases patients with predicted survival less than 6 months (RPA I with ⱖ4 lesions, RPA II with ⱖ2 lesions or any RPA III), utilizes WBRT alone. Surgical resection is not supported for multiple metastases nor is it supported for solitary metastases in RPA III patients based on a reduced tolerance for invasive procedures in this patient population (Karnofsky performance status ⬍70). The justification to omit SRS for this group is less clear, but analysis of the SRS trials show that favorable responses are restricted to good risk patients.32,33 Since, as previously noted, the RTOG 9508 trial did not include patients with more than three lesions, it remains unclear whether there is a role for SRS in RPA I patients with ⱖ4 lesions. In this patient population, WBRT alone provides reasonable disease control while maintaining quality of life. The late effects of WBRT are generally not a factor for this group with a shortened life expectancy due to their overall disease activity.
Conclusion With the completion of several randomized clinical trials examining the effects of various therapies on brain metastases, it is possible to generate a treatment algorithm based on high-level data. We propose a simplified algorithm that attempts to use the various tools in a judicious manner while attempting to stay within the confines of supporting data. From the many clinical studies reviewed, it is clear that the most important initial step in determining a treatment course for a patient with brain metastases is to assess prognosis, since even as new technological and medical advances are made to improve the success of treatment, the application of these advances is predicated on the individual’s ability to tolerate treatment. To this end, in parallel with the drive to develop more effective therapies, continued effort is necessary to refine risk prediction models.
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