Update in the Treatment of Brain Metastases from Lung Cancer

c omprehensive review Update in the Treatment of Brain Metastases from Lung Cancer Amanda L. Schwer, Laurie E. Gaspar Abstract Brain metastases from lung cancer represent a prevalent and challenging clinical dilemma. The brain is an extremely common site of failure for non−small-cell lung cancer and small-cell lung cancer, often as a solitary site of disease. Despite steady research developments during recent years, survival rates remain poor. Some research suggests that the outcomes and characteristics of brain metastases that result from lung cancer primary sites are perhaps different than those from other primary sites. Clinical treatment strategies should therefore be adjusted accordingly. This article reviews the clinical characteristics, prognostic factors, and treatment strategies of brain metastases from lung cancer with a particular emphasis on recent research developments in the field. Clinical Lung Cancer, Vol. 8, No. 3, 180-186, 2006

Key words: Chemoradiation therapy, Prognostic factors, Surgery, Whole-brain radiation therapy

Introduction

develop them later, usually within 2 years.7 Further, it is likely that, as new systemic treatment lengthens overall survival (OS), the incidence of brain metastases will continue to increase. Despite the significant advancements in the treatment options for brain metastases that have occurred in the past 2 decades, survival rates remain suboptimal. Typical survival estimates continue to be measured in terms of months, even in the most favorable of patient subsets.8 Recent improvements, however, have been made in surgical and radiation techniques as well as in the development of new systemic therapy options. This review aims to examine the clinical features, diagnostic workup, and prognostic factors of brain metastases as a result of lung cancer, as well as to summarize recent developments regarding treatment.

Approximately 150,000-170,000 patients with cancer develop brain metastasis each year in the United States, making this the most common complication of systemic cancer.1,2 Lung cancer primary tumors are the most frequent source of brain metastases, accounting for approximately 48%-60% of all those diagnosed.2-4 In a study of patients with stage III non–small-cell lung cancer (NSCLC), Stuschke et al found that the brain was the first site of disease recurrence in 23% of patients and that 50% eventually developed brain metastases.5 Gaspar et al also looked at patients with stage III NSCLC and found that, of the 64% who experienced disease relapse after chemoradiation therapy, 20% relapsed in the brain only and 6.5% relapsed in the brain and other sites.6 Further, those who experienced relapse in the brain tended to do so very early, with a full 22.5% being diagnosed during treatment for their primary tumor and an additional 24% diagnosed within 4 months of treatment. In SCLC, > 10% of patients already have brain metastases at the time of diagnosis, and it is estimated that > 50% of those not treated with prophylactic cranial irradiation will go on to University of Colorado Health Sciences Center, Aurora Submitted: Aug 23, 2006; Revised: Oct 6, 2006; Accepted: Oct 11, 2006 Address for correspondence: Laurie E. Gaspar, MD, University of Colorado Health Sciences Center, Department of Radiation Oncology, 1665 N Ursula St, Box F-706, Suite 1032, Aurora, CO 80010-0510 Fax: 720-848-0222; e-mail: [email protected]

Clinical Presentation and Imaging The deposition of tumor cells in the brain follows a pattern that is proportional to the amount of regional blood flow. Therefore, approximately 80% of metastases occur in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem.7 Symptoms develop as the tumor cells grow and become associated with surrounding edema. The specific neurologic deficits and symptoms that develop are related to the location of metastatic growth, and symptoms typically become more pronounced as the number of metastases increase. The most common presenting symptom of brain metastases is headache, found in approximately 25%-50% of patients and often attributable to increased intra-

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cranial pressure.3,7,9 Other frequent complaints include cognitive changes (20%-25%), focal weakness (20%-30%), seizures (15%20%), gait disturbances (15%), visual loss (8%), speech deficits (5%-8%), and sensory loss (5%).2,7,9 A comprehensive physical examination at the time of diagnosis is said to reveal hemiparesis or cognitive changes in 55%60% of patients with brain metastases.2,9 Signs and symptoms of brain metastases might also be quite subtle, however, and it is estimated that as many as 30% might not ever be detected.5 For these reasons, clinicians need to be continuously attentive and perform the appropriate workup in any patient with lung cancer who develops neurologic complaints. Imaging of the brain is commonly accepted as an appropriate component of the initial staging of small-cell lung cancer (SCLC). In fact, a magnetic resonance imaging (MRI) scan of the brain is recommended as part of the diagnostic workup in all patients with biopsy-proven SCLC or mixed SCLC/NSCLC, according to the most recent National Comprehensive Cancer Network practice guidelines.10 Imaging the brain as part of initial staging in NSCLC, however, is more controversial. In a 2003 review of available literature on the topic, Silvestri et al concluded that stage I/II lung cancers with normal clinical examinations require no further studies to rule out extrathoracic disease.11 However, they also recommended that patients with stage III disease routinely undergo further imaging, including the brain, to rule out more widespread disease involvement. An example of the evidence cited to support these recommendations includes a prospective study by Earnest et al who performed screening brain MRIs on 27 patients with NSCLC.12 Of this group, who had primary tumors > 3 cm (stage higher than T1) and no clinical evidence of distant metastases, 6 (22.2%) were found to have brain metastases at diagnosis. Other series, however, have found significantly lesser rates of positive screening studies, especially without clinical symptoms.13,14 For example, Hooper et al examined 83 patients with NSCLC and only found brain metastases in those who had strong clinical evidence on neurologic examination.13 Whether included as part of initial staging or else later found to be clinically indicated, it has long been agreed upon that brain MRI is superior to computed tomography (CT) scan in the evaluation of brain metastases.2,9,15-17 When compared with CT, MRI is known to detect a greater number of metastases, localize lesions in the posterior fossa more accurately, and is also capable of identifying leptomeningeal spread.15,16 Suzuki et al recently performed a prospective study of asymptomatic patients with lung cancer, all of whom underwent head CT and brain MRI as part of their initial staging workup.17 Of the 134 subjects analyzed, which included patients with NSCLC and SCLC, 19 were found to have brain metastases on MRI versus only 12 on CT scan (P = 0.02). Positron emission tomography (PET) scans are now used routinely in the initial workup of lung cancer.10 Unfortunately, the high baseline level of glucose metabolism in the brain significantly limits this modality’s ability to detect metastases there. In 2003, Rohren et al compared the effectiveness of PET and MRI in detecting brain lesions and found that PET

Table 1

Recursive Partitioning Analysis Class Definitions8 Variable

Class I

Class II

Class III

Karnofsky Performance Status

r 70

r 70

< 70

Controlled

Uncontrolled

–

< 65

r 65

–

Brain only

Brain plus other sites

–

7.1

4.2

2.3

Primary Tumor Status Age, Years Sites of Metastatic Disease Survival for Each Class (Months)

was only able to visualize 61% of the metastases seen on MRI.18 Given such information, the consensus remains that PET is not valuable in the imaging of brain metastases.

Prognostic Factors Several studies have attempted to delineate the factors that have predictive value in assessing the prognoses of patients with brain metastases. In 1997, Gaspar et al compiled the data of 1200 patients (61% with primary lung cancers, including small-cell tumors) from 3 previous Radiation Therapy Oncology Group (RTOG) protocols and analyzed survival according to multiple pretreatment characteristics using a recursive partitioning analysis (RPA; Table 1).8 Interestingly, neither the site of primary tumor nor the interval from the initial primary cancer diagnosis (> 2 years vs. < 2 years) to the subsequent development of brain metastases was found to have prognostic importance. A few years later, Rodrigus et al used these same RPA class groupings to analyze outcome of 250 patients with brain metastases from NSCLC alone.19 In this study, Class 1 patients had a median survival of 4.8 months, whereas Class 2 and 3 patients survived a median of 2.8 months and 2 months, respectively. Further, this study demonstrated the importance of control of the primary tumor site, finding that patients with an absent or controlled primary tumor had a 1-year survival rate of 26% compared with just 11% for patients with an active primary tumor (P = 0.051). Several studies have also concluded that the timing of the development of brain metastases is extremely important in predicting patient outcomes.8,20-23 In a review of patients with brain metastases who had previously been treated with Gamma Knife® stereotactic radiation surgery (SRS), Flannery et al found that patients with metachronous brain metastases (defined as occurring > 3 months after the completion of initial lung cancer therapy) had a prolonged median survival of 33.3 months compared with 8.6 months for those who were diagnosed synchronously.21 Another analysis, which also focused on the timing of brain metastases, compiled data from 422 patients who had previously participated in 1 of 4 different Southwest Oncology Group studies of stage III lung cancers.6 Of the 64% who experienced relapse or progression, 13% relapsed in the brain only, 4% relapsed in the brain and other site(s), and 47% relapsed in non-brain sites only. Sixty percent of these patients experienced progression in the brain within 6 months from their original diagnosis. Interestingly, the only pretreatment characteristics that were found to significantly correlate with prognosis were histology and patient age. Young patient age (< 50 years) and nonsquamous cancers were associated with a greater frequency of, and a shorter time interval to, the development of brain metastases.

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Update in the Treatment of Brain Metastases from Lung Cancer Table 2 Randomized Studies of Whole-Brain Radiation Therapy with or Without Surgery in Solitary Brain Metastases Study

Patchell et al41

Vecht et al42

Mintz et al43

Median Survival (Weeks)

Treatment WBRT alone

15

WBRT + surgery

40

WBRT alone

26

WBRT + surgery

43

WBRT alone

24

WBRT + surgery

22

(P < 0.01)

(P = 0.04)

(P = 0.24)

Local Control (%)

Neurologic Deaths (%)

48

50

80

29

ND

35

ND

35

ND

ND

ND

ND

Abbreviation: ND = no data reported

Recently, Videtic et al presented retrospective data that attempted to delineate whether ethnicity and sex affected survival across the 3 RPA classes.24 In this study, the median survival for women was significantly higher than for men (6.3 months vs. 5.5 months; P = 0.013). Further, the difference in median survival between ethnic groups neared significance, favoring white over black patients (6 months vs. 5.2 months, respectively; P = 0.08).

Treatment of Brain Metastases from Lung Cancer Whole-Brain Radiation Therapy Until recent years, whole-brain radiation therapy (WBRT) has been the standard of care for the majority of patients with brain metastases, with survival generally in the range of 4-7 months.25-31 Currently, most centers use a regimen consisting of 30 Gy in 10 fractions, delivered in a 2-week period.26,27 Brain metastases from SCLCs are often treated differently than those from other primary sites and are often excluded from experimental trials. These facts have been previously justified by the greater tendency of brain metastases in SCLC to be associated with other sites of progressing disease and to be multiple. However, multiple studies have failed to demonstrate a significant difference in treatment outcomes between brain metastases from NSCLC and those from SCLC.4,32-34 In general, WBRT remains the standard for the treatment of SCLC brain metastases. Multiple methods have been tested in attempts to improve on the low survival rates achieved with WBRT alone. Efaproxiral (RSR13) is an allosteric small-molecule chemical modifier that noncovalently binds to hemoglobin and reduces its affinity for oxygen.26,31,35,36 A phase III study comparing WBRT with efaproxiral versus WBRT alone for patients with brain metastases found a nearly significant improvement in median survival among NSCLC and breast cancer populations (P = 0.07).35 Further statistical analysis, however, seemed to indicate that this benefit derived mainly from patients with breast cancer. Motexafin gadolinium is a metallotexaphyrin, a porphyrinlike molecule that forms stable complexes with large metal cations and accumulates preferentially in tumor cells.26,36,37 Its radiation sensitization comes from its ability to catalyze the oxidation of several intracellular-reducing metabolites and thereby generate reactive oxygen species.26,34,38 A phase III study by Mehta et al randomly assigned 401 patients with brain

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metastases to receive WBRT with or without motexafin gadolinium.39 Overall, the addition of motexafin gadolinium caused only a small and insignificant increase in median survival (from 4.9 months to 5.2 months; P = 0.48) as well as a small decrease in time to neurologic progression (from 9.5 months to 8.3 months; P = 0.98). Interestingly though, when only the subset of 251 patients with NSCLC were analyzed, the WBRT with motexafin gadolinium arm had a significant improvement in the time to neurologic progression from 7.4 months to a median value not yet reached in those who received the experimental agent. Further analysis revealed that the addition of motexafin gadolinium to WBRT led to improved memory, executive function, and overall neurologic function in patients with NSCLC brain metastases. To confirm this improvement, Mehta et al performed another phase III study randomizing 554 patients with brain metastases from NSCLC to receive WBRT with or without motexafin gadolinium.40 When data from all participating centers were analyzed, no significant differences were found. However, when data from North American participating centers were analyzed alone, motexafin gadolinium significantly delayed the time to neurologic progression from 8.8 months to 24.2 months (P = 0.004). This geographic difference was attributed to the fact that North American centers tended to initiate radiation earlier after diagnosis, with an earlier start date being significantly correlated with the benefit from motexafin gadolinium (P = 0.017). Surgical Resection Whereas WBRT alone was once the mainstay of treatment, surgery has emerged as a very important and common treatment option for patients with small numbers of brain metastases from NSCLC. Several studies from the previous 2 decades have been critical in establishing the significance of surgery. For instance, in 1990, Patchell et al concluded that the surgical resection of a single brain metastasis preceding WBRT produced significantly better survival rates than WBRT alone.41 In these 48 patients, of whom 77% had NSCLC primary tumors, median survival was increased from 15 weeks to 40 weeks with first-line surgery. Further, patients in the surgery group also experienced significantly longer duration of functional independence versus the WBRT alone group (38 weeks vs. 8 weeks; P < 0.005). Other randomized studies have been performed on this subject, with results summarized in Table 2.41-43 Having proven the benefit of resection of brain metastases before WBRT, Patchell et al then set out to delineate the efficacy of adjuvant WBRT. In his 1998 randomized trial, 95 patients (58% of whom had NSCLC) who underwent WBRT after the surgical resection of a solitary brain metastasis had less frequent tumor recurrences in all sites of the brain as well as decreased rates of death from neurologic causes than did those who did not receive WBRT.44 No difference was found in OS, however. Traditionally, surgical resection has been reserved for patients with solitary tumors, good performance status, controlled extracranial disease, and surgical accessibility.45,46 Other criteria often examined preoperatively include adequate imaging, young age, RPA Class I, need for immediate tumor debulking, large tumor

Amanda L. Schwer, Laurie E. Gaspar size, and absence of leptomeningeal involvement.46 In recent years however, with rapidly improving surgical techniques, the spectrum of patients considered for resection is widening. Recently, a body of data has accumulated that supports aggressive surgical treatment in patients with synchronous brain metastases and otherwise early-stage lung cancers.47-50 For instance, one small review of patients with synchronous brain metastases found fairly low overall rates of survival, but also some longterm survivors who had yet to have further evidence of disease in the 3 or more years after aggressive surgeries.47 Factors that significantly improved OS included WBRT (P = 0.002) and aggressive surgical management of the primary site of disease (P = 0.005). Using these and several other similar studies as justification, current National Comprehensive Cancer Network guidelines recommend that surgical resection of the primary lung cancer and the synchronous brain metastasis occur primarily in patients who have otherwise stage I/II tumors and only solitary brain lesions.10 Surgical resection plays a much more limited role in the treatment of primary SCLC and its metastatic brain lesions. This is because of its significant predilection for extracranial metastases. Further, brain metastases from SCLC tend to be multiple, and therefore little data exist to support craniotomy. Stereotactic Radiation Surgery Stereotactic radiation surgery (SRS) has emerged in recent years as a possible alternative to surgical resection in patients with single and multiple brain metastases.51-55 Stereotactic radiation surgery involves the administration of a high dose of ionizing radiation in a single fraction to a small area, usually within the brain parenchyma. Treatments can be delivered using various machines, including a modified linear accelerator, the Gamma Knife®, CyberKnife®, or using heavy charged particles produced by a cyclotron or synchrotron machine.53 The RTOG 9508 study randomized 333 patients with 1-3 newly diagnosed brain metastases to receive WBRT alone or with an SRS boost.52 Sixty-three percent of included patients had lung cancer as their primary site of disease. The addition of the SRS boost was found to improve the median survival from 4.9 months to 6.5 months in patients with solitary metastatic lesions. Median survival benefits were also conferred in RPA Class I patients (11.6 months vs. 9.6 months; P = 0.0453) and in those whose lesions measured > 2 cm in diameter (6.5 months vs. 5.3 months; P = 0.0449). Patients in the SRS group also were more likely to have a stable or improved performance status at 6 months of follow-up (P = 0.03) as well as an improved local control rate of 82% (vs. 71% with WBRT alone; P = 0.01). Further, when the authors looked specifically at patients with squamous/NSCLC, the addition of an SRS boost came very close to producing a statistically significant benefit in median survival (5.9 months vs. 3.9 months; P = 0.0508). More recently, a relatively small randomized study compared WBRT and SRS with SRS alone in 132 patients (of whom 67% had lung cancer primary tumors) with 1-4 brain metastases.54 Overall survival was not different between groups, at 7.5 months and 8 months, respectively. However, the local

tumor recurrence rate at 1 year was 76.4% in the SRS alone arm and only 46.8% in the arm that received SRS and WBRT (P < 0.001). Further, the overall rate of distant brain recurrence was reduced from 52% to 18% with the addition of WBRT (P < 0.001). In its recent evidence-based review on this topic, the American Society for Therapeutic Radiology and Oncology concluded that all levels of evidence exist (ie, I-III) to support the claim that an SRS boost plus WBRT significantly improves local control rates when compared with WBRT alone.55 Likely for the same reasons that SCLC brain metastases are rarely surgically resected, little data exist regarding the use of SRS in SCLC. In 2002, Serizawa et al compared outcomes from Gamma Knife® radiation surgery in a group of 245 patients with brain metastases from lung cancer.56 Thirty-four of these patients had SCLC primary tumors, and the remainder had NSCLC. Eligible patients had no history of treatment for their brain metastases, ) 25 lesions, ) 3 tumors that were > 2 cm, no unresectable lesion > 3 cm, and a life expectancy > 3 months. New lesions that arose were treated with repeated SRS and WBRT in some select cases. The 1-year tumor control rate was 94.5% in the patients with SCLC and 98% in the patients with NSCLC. Survival was equal between groups as well, but SCLC lesions tended to recur in the brain earlier than did those of NSCLC. Sheehan et al reviewed treatment records of 27 patients with SCLC brain metastases treated with SRS for recurrent brain metastases who had already been treated initially with WBRT with or without chemotherapy.57 Sixty-two percent of the metastatic lesions treated with SRS decreased in size, 19% remained stable, and only the remaining 19% eventually increased in size. Based on these studies, it can be concluded that the use of SRS in SCLC is warranted in selected patients. Chemotherapy for Non–Small-Cell Lung Cancer Brain Metastases Traditionally, the usefulness of chemotherapy in treating metastatic brain lesions has been considered minimal. This is because of the concern about the limited ability of most agents to cross the blood-brain barrier.2,24 However, new information seems to suggest that patients who have developed brain metastases inherently have a compromised blood-brain barrier.2 These data, together with several case studies of good intracranial responses to chemotherapy, have recently led to increased interest in the use of systemic agents in the treatment of brain metastases.1,2,58 Table 3 summarizes the efficacy of various chemotherapeutic agents in crossing the blood-brain barrier.59 Most data supporting the efficacy of chemotherapy in brain metastases stem from retrospective analyses, case reviews, and nonrandomized trials. To date, level I evidence remains limited. One agent that has gotten particular attention in recent years, largely because of its proven activity in malignant gliomas and metastatic melanoma, is temozolomide.2,58,59 Several recent phase II studies have documented temozolomide’s activity in some patients with brain metastases.60-63 Some of these studies have shown only a modestly improved response, whereas others have found significant improvements with the addition of this oral alkylating agent. For instance, Verger et al randomly

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Update in the Treatment of Brain Metastases from Lung Cancer Table 3 Blood-Brain Barrier Permeability by Chemotherapeutic Agent59 Permeability High Permeability

Agent

Doxorubicin, Vincristine, Gemcitabine

assigned 82 patients (51% of whom had primary lung cancer) with brain metastases to receive treatment with WBRT alone or with the addition of 75 mg/m2 per day of concurrent temozolomide.62 The patients in the experimental arm also went on to receive 2 additional cycles of temozolomide 200 mg/m2 per day. Although the objective response rate was similar between treatment arms, the patients in the temozolomide arm were found to have an increased rate of progression-free survival at 90 days (54% for WBRT alone vs. 72% for WBRT plus temozolomide; P = 0.03) and a decreased rate of death from brain metastases (69% for WBRT alone vs. 41% for WBRT plus temozolomide; P = 0.03). Further, Antonadou et al analyzed 52 patients with brain metastases (of whom 21 had lung cancer) who had similarly been randomized to receive WBRT alone or WBRT and temozolomide.63 In this study, patients in the temozolomide arm received an additional 6 cycles of temozolomide upon the completion of WBRT. Ninety-six percent of patients in the experimental arm experienced an objective response (38% complete response and 58% partial response), a figure that was significantly better than the rate of 67% found in the WBRT-alone arm (P = 0.017). Neurologic symptoms were also reported to have significantly improved with the addition of temozolomide. Several other chemotherapy regimens have been evaluated for the initial treatment of brain metastases, including numerous agents that also have activity in treating the primary site of disease. Table 4 summarizes 4 studies, each of which found a significant benefit to first-line chemotherapy.64-67 In general, most studies have concluded that multiple-agent regimens are superior to single-agent regimens in controlling intracranial metastases.59 In a 2001 phase III study, Robinet et al attempted to settle the debate of whether chemotherapy could be used as initial therapy for brain metastases from NSCLC.68 One hundred seventy-six patients with NSCLC metastatic to the brain and no history of previous treatment were randomized to receive immediate WBRT combined with 2 cycles of vinorelbine/cisplatin alone or the same chemotherapy with WBRT delayed until there was intracranial progression. Patients in the chemotherapyalone arm who responded to their first 2 cycles received more cycles of chemotherapy, up to 6 cycles in total. Those who did not demonstrate any disease improvement initially were taken off chemotherapy and given WBRT. Further, those who demonstrated improvement of their primary disease but not of their intracranial disease received chemotherapy and WBRT. Neither the overall response rate nor the overall median survival rates

184

Study

Chemotherapy

Intracranial Response

Median Survival (Months)

Malacarne et al64

Carboplatin Etoposide

17% PR 22% SD

7.5

Franciosi et al65

Cisplatin Etoposide

7% CR 23% PR 16% SD

8

Minotti et al66

Carboplatin Teniposide

13% CR 22% PR 22% SD

5

Quadvlieg et al67

Cisplatin Gemcitabine

24% CR 38% PR

6

Carmustine, Lomustine, Procarbazine, Thiotepa

Temozolomide, Cytarabine, Topotecan, Intermediate Permeability Hydroxyurea, Etoposide, Cisplatin/Carboplatin, Irinotecan, Bleomycin, Methotrexate Low Permeability

Table 4 Results of 4 Studies of First-Line Chemotherapy in the Treatment of Brain Metastases64-67

Clinical Lung Cancer November 2006

were different between the arms. There were, however, more patients with complete responses on the initial WBRT plus chemotherapy arm. The authors concluded that initial chemotherapy alone was efficacious in the treatment of brain metastases and that the timing of WBRT did not affect the ultimate outcome. However, it should be noted that there were only a small number of patients in this study and that it was powered to show a 25% improvement in the 6-month survival for the immediate recipients of WBRT, probably an unrealistic endpoint. Chemotherapy for Small-Cell Lung Cancer Brain Metastases Small-cell lung cancers are known to be some of the most chemotherapy-responsive tumors. Chemotherapy for the treatment of brain metastases from SCLC has therefore been the subject of multiple studies.69-71 For instance, Korfel et al performed a phase II analysis of patients who had received pretreatment with WBRT, chemotherapy, or both and subsequently experienced relapse in the brain.70 Thirty-three percent of the 30 patients analyzed had a demonstrable response to single-agent topotecan, with a similar extracranial disease response rate. The authors therefore concluded that chemotherapy was warranted in the case of pretreated, recurrent brain metastases. The value of chemotherapy given concurrently with WBRT in newly diagnosed brain metastases from SCLC has also been confirmed. In 2000, Postmus et al performed a phase III study that randomized 120 patients with SCLC and resulting brain metastases to receive tenoposide chemotherapy alone or with WBRT.71 Fiftyseven percent of patients in the combined therapy arm were found to have radiographic response of their metastatic lesions, compared with only 22% in the tenoposide-alone arm. Overall survival was not different between the 2 groups, but the time to progression was also significantly improved with the addition of WBRT. These results led the authors to conclude that WBRT plus tenopisode was a superior regimen when compared with tenoposide alone. The question of whether chemotherapy alone is adequate in the initial treatment of SCLC brain metastases continues to be controversial. Multiple studies have concluded that chemotherapy is effective as a first-line treatment, with response rates ranging

Amanda L. Schwer, Laurie E. Gaspar from 53% to 100%.72-74 However, Seute et al recently performed a retrospective analysis of 24 patients with asymptomatic brain metastases from SCLC, all of whom were initially treated with cyclophosphamide/etoposide/doxorubicin.75 Whole-brain radiation therapy was administered only after patients became neurologically symptomatic. Twenty-seven percent of patients exhibited radiographic response of their intracranial disease. This figure was found to be significantly less than the 73% who responded systemically (P = 0.006). Further, all patients became symptomatic from their brain metastases and therefore required WBRT, 14% during chemotherapy and the remainder within a median time of 2.3 months. The authors concluded that chemotherapy was ineffective overall in the treatment of brain metastases because of the low rate of intracranial tumor response and the lack of delay to the development of symptoms. Molecularly Targeted Agents A relatively new and exciting area of research in oncology is the development and testing of molecularly targeted agents. To date, the agent that has received the most attention in the treatment of brain metastases is gefitinib, an orally administered epidermal growth factor receptor tyrosine kinase inhibitor. Data so far exist primarily in the form of case reviews, nonrandomized studies, and retrospective reports, nearly all of which have concluded that gefitinib shows significant activity in the treatment of brain metastases from NSCLC.76-80 Ceresoli et al performed a prospective nonrandomized study of 41 patients with brain metastases from NSCLC who had experienced progression after WBRT and/or chemotherapy or had not yet been treated for their intracranial disease.79 Patients all received gefitinib at a dose of 250 mg daily and were followed closely with radiographic imaging. A partial response was demonstrated in 10%, and an additional 17% exhibited stable disease for an average of 4 months, leading the authors to claim an overall disease control rate of 27%. The true benefit of gefitinib in brain metastases has yet to be fully delineated with randomized data. However, the RTOG has set out to provide this level I evidence with a recently opened study that will randomize patients with NSCLC brain metastases to undergo WBRT plus SRS boost with erlotinib (another epidermal growth factor receptor inhibitor) or temozolomide.

Conclusion Brain metastases from lung cancer remain a very challenging and important area of study. Despite recent advances, mortality remains high, and the incidence of intracranial disease continues to increase. Appropriate treatment regimens remain somewhat controversial. Controversies exist regarding the role of WBRT, SRS, surgery, and initial chemotherapy. A recent phase III study supports the use of SRS in addition to WBRT for patients with NSCLC with ) 3 brain metastases. The role of SRS boost in patients with SCLC with ) 3 brain metastases is reasonable in selected patients with controlled extracranial disease. For patients with NSCLC with > 3 metastases and most patients with SCLC, however, WBRT remains the standard of care in North America. In contrast, in Europe there has been emerging interest in the use of chemotherapy alone, therefore delaying WBRT until progression. Overall though, chemotherapy

continues to have a limited yet increasing role in the management of brain metastases, particularly in those who have already undergone WBRT. Further study is required to explore new agents alone or in combination with radiation therapy. Targeted agents might prove to be appropriate for some groups of patients. In order to settle these debates and all of the questions raised in this review, participation in randomized studies remains imperative.

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