Current and Future Management of Brain Metastasis

D. G. Kim, L. D. Lunsford

• Publisher: S. Karger
• Year: 2012
• ISBN:
  9783805596183
• Topic: Medicine
• Subtopic: Neurosurgery

Recent strategies combining multiple modalities have opened up a whole new field of brain metastasis management focusing on disease control. The management of brain metastasis in modern times is no longer confined to palliation but seeks preservation of life quality and not only prolonged survival. Up-to-date guidelines and the main aspects of brain metastasis management as well as practical points on how to deal with difficult situations in daily clinical practice are presented. Epidemiology and biology and various effective treatment methods such as surgery, radiosurgery, radiation therapy and chemotherapy are well explained. Each chapter encompasses extensive reviews and presents broad perspectives on specific topics by the most renowned personages who have continuously shown their excellence in this rapidly progressing field.This book contains the most current information on the understanding of brain metastasis management. It is valuable reading for neurosurgeons, neuro-oncologists and radiation oncologists who are searching for the best all-round treatment for their patients.

Future Perspective of Brain Metastasis Treatment

Kim DG, Lunsford LD (eds): Current and Future Management of Brain Metastasis.
Prog Neurol Surg. Basel, Karger, 2012, vol 25, pp 287-308

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Future Perspectives on Brain Metastasis Management

Edward A. Monaco III · Phillip V.Parry · Ramesh Grandhi · Ajay Niranjan · Hideyuki Kano · L. Dade Lunsford

Center for Image-Guided Neurosurgery, Department of Neurological Surgery, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pa., USA

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Abstract

Brain metastases are the most common intracranial tumors encountered by physicians. Historically, the mainstays of therapy were limited to surgery and whole brain radiation. Surgery is typically reserved for safely accessible and symptomatic tumors in patients well enough to tolerate a procedure. Whole-brain radiation therapy has proven to have limited efficacy and concerns have arisen regarding its toxicity. Advances in the treatment of systemic cancers have yielded improved long-term survival and quality of life for patients. To parallel these efforts in systemic treatment, continual improvement of the treatment of brain metastases is a must. The last two decades have seen a paradigm shift in the thinking about metastatic brain tumor treatment as a result of the advent of stereotactic radiosurgery. Radiosurgery has proven to be an efficacious, minimally invasive, and highly selective treatment for metastatic brain tumors. In this review, we discuss the evolution of metastatic brain tumor management, the appropriately diminished role for reflexive whole brain radiation, and the growing importance of stereotactic radiosurgery as an upfront treatment modality in conjunction with surgery and subsequent salvage radiosurgery.

Copyright © 2012 S. Karger AG, Basel

Paradigm of the Past

Role of Whole-Brain Radiation Therapy

Metastatic tumors of the brain are the most common form of intracranial tumor, with an estimated nearly 200,000 new cases diagnosed each year in the United States alone [1-3]. The incidence of brain metastases far outnumbers the total number of all primary intracranial tumors combined [3]. Historically, however, the detection of distant metastases to the brain led treating physicians to switch goals from active intervention to palliation. A brain metastasis meant that a life expectancy stop watch was clicked. In the absence of treatment, a patient harboring a single metastasis to the brain could expect a median survival of approximately 1 month [4-6]. Traditionally, the default palliative management for patients with brain metastases was fractionated whole-brain radiation therapy (WBRT). This treatment paradigm was based on the potential benefit of radiation therapy in the absence of other treatment alternatives, the widespread availability of radiation therapy technologies, the ability to rapidly begin WBRT without significant planning time, the failure of chemotherapeutic agents to penetrate the blood brain barrier of the central nervous system, and the possible benefit of prophylactic treatment of presumed micrometastatic disease not resolvable by then available imaging techniques. With the widespread use of WBRT, median survival for patients with single metastases expanded to 3-6 months [7, 8].

Various studies were conducted to improve survival outcomes with WBRT. Despite the use of different fractionation and dosing schedules as well as selected radiation sensitizing agents, median survivals failed to budge [9-12]. Regardless of treatment with WBRT, 50% of patients suffered intracranial tumor progression by 6 months. Most patients died from neurological progression of their brain metastases [13]. However, as more aggressive management of the systemic malignancy has evolved, patient survivals have improved. An effective, less toxic, potentially repeatable strategy to manage brain metastatic tumors was needed. The recursive partitioning analysis (RPA) methodology identified patients for whom more aggressive therapy might improve survival: those with a good performance status, those younger than 65, and those with controlled extracranial disease. This potential paradigm shift set the stage for comparative trials that could better determine the roles of WBRT, surgery and stereotactic radiosurgery (SRS) [14].

Role of Surgery

The usual role of the neurosurgeon in the management of brain metastases was confined to reasonably healthy patients with a single, symptomatic tumor in a surgically resectable location [15, 16]. Prior to the widespread availability of magnetic resonance (MR) imaging to effectively stage brain disease, studies indicated that 30-40% of patients had only a single tumor. The majority of patients undergoing surveillance MR imaging actually prove to have multiple metastases [17]. In the United States with an estimated population of 300 million people, it is likely that less than 5,000 patients each year in the United States undergo craniotomies for the initial management of metastatic cancer. With as many as 200,000-400,000 patients each year having brain metastases detected, up to 97% of patients had very limited treatment alternatives [18].

Prior to 1990, the role for surgery remained controversial. Patchell et al. [19] conducted the first randomized trial comparing WBRT alone to surgery followed by WBRT for patients with good performance statuses and single, surgically accessible tumors. The combination of surgery followed by WBRT yielded a significantly longer survival (40 vs. 15 weeks) when compared with WBRT alone. Moreover, time to recurrence, freedom from neurological death, and the duration of functional independence were all longer with the combination of surgery and WBRT. A second randomized trial by Vecht et al. [20] comparing WBRT versus surgery followed by WBRT also yielded a significantly improved survival with the combination therapy. In neither study did surgery result in increased morbidity and mortality. Although a third randomized trial failed to reproduce these results [21], momentum had been established and the movement toward surgery for initial management of a single brain metastases was ignited. A subsequent randomized trial by Patchell et al. [22] further defined the role of surgery. In this trial patients were randomized to surgery alone versus surgery followed by WBRT; fewer patients in the surgery with WBRT group had progression at the surgical site or developed distant brain metastases. The time to recurrence with combination therapy was longer and fewer patients died neurological deaths. Interestingly they could detect no significant difference in survival or the duration of functional independence between the two treatment arms. This study provided additional confirmation that eligible patients benefit from initial surgery but WBRT was required to reduce local and distant recurrences.

Outcome Variables

Survival. Survival is a fundamental measure of the efficacy of cancer treatment as well as brain metastasis management. Without brain directed therapy, median survival is approximately 1 month. WBRT improves this to 4-6 months [7, 8], while adding surgery to WBRT for a single metastasis in properly selected patients extends median survival to 10 months [19]. Median survival figures alone must be interpreted cautiously as selection bias may confound the affect of a single treatment on survival.

Prior studies indicated that most patients who receive either no treatment or only palliative treatment (i.e. corticosteroids, antiepileptics, or WBRT) died due to neurological progression. Patchell et al. [19] studied patients with a single brain metastasis treated with WBRT alone; 50% had neurological deaths, compared to 29% if they received surgery followed by WBRT. The Radiation Therapy Oncology Group (RTOG) RPA data found that the presence of extracranial metastases and uncontrolled systemic disease had a profound prognostic effect [14]. Continually emerging data from centers using aggressive multimodality cancer treatment technologies, including Gamma Knife SRS for brain metastases, has found that even patients with 10 or more metastases only die from neurological disease progression in approximately 50% of cases [23]. Any accurate projections about survival in individual patients require a firm understanding of both the status of intracranial and systemic disease.

Quality of Life. The American Society of Clinical Oncology's Outcomes Working Group was established to define the outcomes of cancer treatment. Quality of life (QOL) was identified as an endpoint of importance secondary only to survival, a measure that should surpass other outcome measures such as response to treatment [24]. Although quality of life is a subjective and multidimensional entity, a reasonable working definition was established by the World Health Organization: a ‘state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity’. In other words, optimizing QOL requires balancing treatment risk and benefit in the context of both physical and psychological effects [25].

Unfortunately, as identified by an extensive review by Wong et al. [26], very few trials to date have incorporated QOL as a primary endpoint. While the Karnofsky Performance Status (KPS) is often used as a surrogate for QOL, it only represents a single facet of this complex evaluation strategy and does not reflect the patient's own self perception [27]. While useful, KPS outcome measurements alone fail to sufficiently capture the overall concept of QOL [28-30].

As of 2008, only 14 published trials on brain metastases included an evaluation of QOL [26]. In these 14 trials, a total of seven different QOL instruments were used, evidence that there is no standard or validated QOL measurement that has gained general acceptance. Moreover, the use of multiple different questionnaires does not allow for comparisons to be made between trials. One reason for the dearth of QOL assessments is the difficulty of capturing QOL data on patients with limited life expectancies and deteriorating health during treatment. Published data have identified a high attrition rate in brain metastases QOL studies [31, 32]. More recently, improved QOL has been reported to significantly correlate with survival [33, 34].

Neurocognitive Effects. Until recently, there has been little emphasis on evaluating the neurocognitive effects of treatment for brain metastases. One of the early reports on the neurocognitive effects of brain metastasis treatment was conducted by Regine et al. [35] in a secondary analysis of RTOG 91-04. This study evaluated various WBRT fractionation schedules. In this study, brain tumor recurrence, and not differences in radiation fractionation schedules, had a detrimental effect on neurocognitive status as evidenced by lower mini-mental status examination scores. Although the most frequent measure of neurocognitive function, the mini-mental st...