The Role of Radiation in the Management of Brain Metastases

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Contemporary Oncology, February 2014, Volume 6, Issue 1

Partner | Cancer Centers | <b>Dana Farber</b>

In this review, the role of radiotherapy in the management of brain metastases is considered from a historical perspective, in the context of other treatment modalities, and with regard to different radiotherapy techniques.

Abstract

Brain metastases represent the most common intracranial malignancy. The management of brain metastases is often complex, multidisciplinary, and highly individualized. In this review, the role of radiotherapy in the management of brain metastases is considered from a historical perspective, in the context of other treatment modalities, and with regard to different radiotherapy techniques. Data regarding coordination of systemic therapy with radiotherapy is reviewed, outlining historical findings and a paucity of data in the context of novel systemic cytotoxic and biologic therapies with whole brain radiotherapy and stereotactic radiosurgery. Controversial aspects of patient management are considered, including multifactorial patient, tumor, and treatment factors that inform treatment recommendations for individual patients. Current clinical controversies and research endeavors are reviewed as they relate to maximization of therapeutic efficacy, minimization of toxicity, and optimization of quality of life. General evidence-based approaches to management of brain metastases are considered and published guidelines are addressed in this review.

Introduction

Brain metastases represent the most common intracranial malignancy in adults and are reported to develop in 10% to 40% of patients with a known extracranial primary malignancy.1 While the exact incidence is uncertain, present estimates suggest that approximately 180,000 patients in the United States are diagnosed with brain metastases annually.1—3 With advances in systemic therapies and the potential increased longevity of cancer patients, the absolute incidence of brain metastases may increase, as may survival following therapeutic intervention for brain metastases. Thus, more than ever before, therapeutic strategies are urgently needed that offer effective, durable control of brain metastases with a favorable toxicity profile.

Whole Brain Radiotherapy

The management of brain metastases has evolved over the past several decades but has continued to rely on radiotherapy and neurosurgical resection as the predominant treatment modalities. Most systemic therapies including chemotherapy have demonstrated poor penetration of the blood brain barrier and have had limited efficacy against brain metastases. As such, whole brain radiotherapy (WBRT) has been the classic treatment for brain metastases for decades, and includes irradiation of the entire cerebrum, cerebellum, and brainstem.

The techniques utilized in the delivery of WBRT are generally straightforward but beyond the scope of this review. For the purposes of this review, the treatment may be thought of as one lateral x-ray delivered from the patient’s left and one lateral x-ray delivered from the patient’s right. Throughout the 1960s to 1980s several studies evaluating different WBRT dosing and fractionation schemes were performed.4—10 In recent decades, most institutions have used WBRT regimens involving between 5 and 20 daily fractions of radiotherapy treatment, with 10 fractions being the most common. Landmark randomized controlled trials in the 1990s evaluated the role of WBRT, surgery, and various combinations of WBRT and surgery for patients with a single brain metastasis.11—13

For patients treated with WBRT, the addition of neurosurgical resection to WBRT in patients with a single brain metastasis resulted in decreased rates of local recurrence (20% recurrence with WBRT and surgery vs 52% recurrence with WBRT and no surgery) and improved overall survival (OS; 40 weeks with surgery vs 15 weeks with WBRT alone).13 Multiple studies suggest the survival benefit is most pronounced in young patients with a single brain metastasis, good performance status, and absent/controlled extracranial disease.14,15 Of note, one study evaluating the role of surgery in patients with a Karnofsky Performance Score (KPS) of 50% or greater and one cerebral metastasis undergoing WBRT failed to show a survival benefit to the addition of surgery.16

Additional factors influencing recommendation for surgical resection include the rapidity of onset of symptoms, size of a metastasis, location (eloquent vs non-eloquent location), number of metastases, and whether a histopathologic diagnosis has previously been established. In a study evaluating the role of WBRT following upfront neurosurgical intervention for patients with a single brain metastasis, the addition of WBRT resulted in no increase in OS but did demonstrate decreased rates of local failure (10% with WBRT and surgery vs 46% with surgery alone) and decreased rates of any intracranial failure (18% with WBRT and surgery vs 70% with surgery alone).12 While no OS benefit was appreciated, the addition of WBRT to surgery reduced the rate of neurologic death in patients with a single brain metastasis (14% with surgery and WBRT vs 44% with surgery alone).12

The findings of this study were supported by an additional multiinstitutional randomized trial by the European Organization for Research and Treatment of Cancer (EORTC) evaluating the role of WBRT after surgical resection or stereotactic radiosurgery (SRS) for patients with 1-3 brain metastases.17 The authors found that regardless of the local treatment modality (surgery or SRS), the addition of WBRT decreased rates of recurrence at the site of index lesion(s) (27% with WBRT and surgery vs 59% with surgery alone; 19% with WBRT with SRS vs 31% with SRS alone) and reduced the likelihood of patients developing new brain metastases (23% with WBRT and surgery vs 42% with surgery alone; 33% with WBRT and SRS vs 48% with SRS alone).17

As in the prior study of neurosurgical resection with/ without WBRT, no OS advantage was appreciated, though rates of neurologic death were reduced (44% without WBRT vs 28% with WBRT). The potential advantages of adjuvant WBRT must be weighed against potential drawbacks of WBRT, including potential neurologic toxicity and a recently reported transient reduction in health-related quality of life in patients treated with WBRT in the EORTC phase III study of SRS or surgery followed by WBRT or observation.18

Stereotactic Radiosurgery

At the same time that the roles of WBRT and surgery were being evaluated regarding their relative benefits in the management of brain metastases, a more recently developed radiotherapeutic technique, SRS, was being developed and refined as a mechanism for conformal, ablative high-dose radiation treatment of individual metastatic lesions, instead of irradiation of the entire brain.19

Though SRS was developed by Lars Leksell in the early 1950s, it was not widely utilized in the United States until the mid-1990s and early 2000s, when radiographic imaging techniques caught up with treatment delivery systems, allowing for improved visualization of intracranial radiotherapy targets with CT- and MRI-based imaging. Presently, several SRS platforms exist. Treatment may be delivered with: 1) a standard linear accelerator (LINACbased SRS) with adequate stereotactic capabilities; 2) the CyberKnife® system, which is a photon-only single-energy LINAC mounted on a robotic arm; 3) TomoTherapy®, which is helical delivery LINAC-based SRS; 4) the GammaKnife® system, which delivers SRS using highly focused photons from 192- 201 60Co radionuclide sources; and 5) particle-therapy SRS, most commonly utilizing protons (see Table). The intricacies of the different SRS treatment delivery techniques are beyond the scope of this review. However, all of these systems deliver multiple small photon beams from a large number of angles. The contribution of each beam (or beamlet) is very small and delivers an exceedingly low dose of radiation, but, at the point where all of the individual beams (or beamlets) converge, a very large dose of radiation is delivered. Protons may also be used in delivery of SRS, though in the United States SRS is generally delivered with photons.

Table. Stereotactic Radiosurgery Treatment Platforms

Modality

Type of Radiation Delivered

Invasive Head Frame Required

Source of Radiation

Image Guidance

Advantages

Disadvantages

Linear Accelerator

Photons

Depends on technique

Linear accelerator

Stereoscopic x-rays and/or cone-beam CT

Able to perform stereotactic and nonstereotactic radiotherapy to other parts of the body; electron therapy

Alignment must be checked and verified before each isocentric treatment; requires intense physics assessment before each patient’s treatment

CyberKnife® (Single energy linear accelerator)

Photons

No

Small linear accelerator mounted on a robotic arm

Stereoscopic x-rays

Linear accelerator on robotic arm allows treatment delivery with nearly unlimited treatment angles

Single energy photon; no electrons; no portal imaging

TomoTherapy®

Photons

No

Linear accelerator with helical delivery of x-rays

Cone-beam CT

Capable of treating very long fields in a continuous fashion

Treatment plan does not have traditional review

GammaKnife®

Photons

Depends on technique

192-201 radioactive cobalt-60 sources

Rigid frame placement

Multiple isocenters easily treated in same session; daily quality assurance allows treatment of multiple lesions and multiple patients

Radioactive source/ regulations; if patient undergoes multiple fractions (SRT), often requires overnight stay with frame in place; treatment is limited to high cervical spine and above

Proton

SRS Protons

No

Cyclotron

Stereoscopic x-rays

No exit dose permits targeting of lesions near critical structures

Access to proton therapy is limited

Upon completion of an SRS dose-finding study,20 randomized controlled trials evaluated the role of SRS alone, WBRT alone, SRS with/without addition of WBRT (evaluating whether WBRT added any benefit to SRS), and WBRT with/without SRS (conversely evaluating whether SRS added any benefit in addition to WBRT). Patients with 1-3 brain metastases treated with SRS in addition to WBRT were noted to have better rates of local control at one year (82% for WBRT + SRS) than patients treated with WBRT alone (71% for patients treated with WBRT alone).21 The same study also noted a survival benefit in patients with favorable histology (squamous cell or nonsmall cell carcinoma of the lung) and in patients <65 years of age with KPS of ≥ 70%, controlled primary disease, and no extracranial metastases.21 Conversely, when WBRT was added to SRS in patients with 1-4 brain metastases, investigators found improved local control with the addition of WBRT (89% local control with SRS and WBRT vs 73% local control with SRS alone) as well as reduced rates of development of new brain metastases (42% developed new brain metastases with SRS and WBRT vs 64% with SRS alone).22 No difference in preservation of neurologic function was noted between patients treated with SRS alone and with SRS and WBRT.22 These studies echoed the findings of the previously discussed studies that demonstrated a survival benefit for the addition of local therapy to WBRT and a decrease of both local recurrence and in the rate of patients developing additional brain metastases when WBRT is added to surgery.

In 2010, the American Association of Neurologic Surgeons (AANS) and Congress of Neurologic Surgeons (CNS) published guidelines recommending SRS in combination with WBRT for patients with KPS ≥ 70% and 1 to 4 brain metastases all measuring ≤ 3 cm in greatest diameter.23 This recommendation was supported in 2012 by evidence-based guidelines from the American Society for Radiation Oncology (ASTRO), which advised that patients with anticipated survival of at least 3 months and a single brain metastasis ≤ 3-4 cm undergo SRS ± WBRT (or surgery + WBRT).24 In the same guidelines, patients with good prognosis and 1-3 brain metastases ≤ 3-4 cm were recommended for SRS ± WBRT or WBRT alone.24

Thus, WBRT is considered standard for most patients with > 4 brain metastases, and is also used for many patients with 1-4 metastases depending on individual patient factors. SRS is typically avoided for metastases > 4 cm in greatest diameter, and surgery and/or fractionated stereotactic radiotherapy (SRT) may be considered. While there are several reports describing the outcomes of SRS in the management of patients with > 4 brain metastases,25 SRS in this patient population remains controversial.

Patients initially managed with SRS alone have been shown to experience greater rates of local and distant intracranial failure (a new brain metastasis) than those treated with both SRS and WBRT.17,22,26 This increased intracranial failure is potentially associated with neurologic morbidity, and patients may require more salvage therapies for local and distant intracranial failure than patients who undergo initial therapeutic intervention with SRS and WBRT.27 However, the shorter overall treatment time of SRS/SRT alone compared with WBRT may allow patients to pursue additional systemic therapy without delay and may offer an opportunity to avoid potential decreases in healthrelated quality of life that patients may experience with SRS/ surgery and WBRT.18

Neurocognitive Considerations in Patients With Brain Metastases

In addition to maximizing local control and OS, optimization of neurocognitive function in patients with brain metastases becomes increasingly important. A majority of patients with brain metastases in randomized controlled trials have demonstrated impaired baseline neurocognitive function.28,29 Welzel et al noted below-normal neurocognitive function prior to WBRT, primarily noted in the verbal domain, in 62% of patients due to receive prophylactic cranial irradiation (36 Gy/18 fx), 44% of patients due to receive therapeutic cranial irradiation (40 Gy/20 fx), and 13% of controls (receiving breast radiotherapy).30 This finding may be related to the brain metastases themselves, prior systemic therapy, and/ or paraneoplastic processes. In multiple studies, intracranial failure at the site of initial metastatic involvement, or distant intracranial failure, has been associated with neurologic deterioration following SRS alone and following WBRT alone.22,29

The importance of intracranial control on neurocognition was supported by Li et al, who reported a correlation between post-treatment volumetric reduction in intracranial disease burden with survival and neurocognitive function in the domains of executive function and fine motor coordination.31 However, the same prospective study noted no statistically significant correlation between reduction in volume of intracranial metastatic burden and changes in patients’ performance on memory tasks, specifically delayed recall on Hopkins Verbal Learning Test (HVLT-R).31 As this patient cohort was noted to have earlier decline in HVLT and HVLT-R than other neurocognitive domains, the authors concluded that certain neurocognitive domains may exhibit differential radiosensitivity.31 The impact of WBRT on neurocognition had been previously reported in a retrospective review by DeAngelis et al in 1989, in which up to 5.1% of patients treated with WBRT developed severe radiation-associated dementia at a median of 14 months, though the authors estimated the risk may be as high as 19%, given their retrospective identification of only patients with severe dementia. They also note that 9 of 12 patients were treated with multiple fractions of > 300 cGy/ fx, which is a higher dose of radiotherapy per fraction than is used in many modern regimens.32 This study has limitations given that the true denominator of patients evaluated is unclear, and a proportion of these patients had a major improvement in symptoms after treatment for normal pressure hydrocephalus. An association between normal pressure hydrocephalus and radiotherapy is unclear, and patients treated with WBRT are presently not commonly diagnosed with normal pressure hydrocephalus.

The impact of WBRT on cognition, specifically verbal memory and verbal learning, has been reported in multiple studies to have a potentially deleterious effect.26,30,31 In 2009, Chang et al published results from their single institution randomized controlled trial of SRS ± WBRT in patients with 1-3 brain metastases. The study met its early stopping criteria for the primary endpoint of a >5 point reduction in HVLT-R from baseline findings, which was noted in 49% of patients with SRS + WBRT and 23 % of patients with SRS alone.26 A similar impact on a related verbal learning neurocognitive tool (the Auditory Verbal Learning Test) was noted at a similar time point of 6 to 8 weeks following WBRT in a descriptive study one year earlier by Welzel et al, who also reported the greatest decline was noted in patients with above average initial performance, while patients with initial documentation of neurocognition of average or below average levels demonstrated less pronounced decreases from baseline or improvement in neurocognitive testing.30

Taken together, these studies suggest WBRT may preferentially impact verbal learning 2 to 4 months following WBRT. Additional follow-up at subsequent time points is indicated to evaluate the long-term effects of radiotherapy. Prevention of neurocognitive deficits as a result of WBRT with memantine was recently evaluated in a randomized controlled trial (RTOG 0614), in which patients with brain metastases undergoing WBRT were randomized to receive concurrent memantine or placebo, which was continued for 6 months following WBRT administration.33

Patients receiving memantine, an inhibitor of the glutamatergic NMDA receptor, demonstrated a significantly longer time to neurocognitive decline, with reduced neurocognitive failure at 24 weeks (53.8% vs 64.9%, defined as 2 standard deviations [SD] below the patient’s baseline neurocognitive function). Also noted was superior executive functioning in the memantine group at 8 and 16 weeks, superior processing speed at 24 weeks, and superior delayed recognition at 24 weeks.33 Another potential mechanism by which neurocognitive side effects may be minimized is through hippocampal-sparing WBRT techniques, as researchers previously have noted a correlation between neurocognitive function and radiotherapy to the hippocampus.34,35

The RTOG has completed accrual of a phase II study evaluating the role of hippocampal sparing WBRT in patients with at least one brain metastasis (excluding small cell lung cancer, germ cell tumors, and hematologic malignancies), KPS ≥ 70%, with a primary objective of evaluating patients’ delayed recall (HVLT-R) at 4 months following hippocampalsparing WBRT, a time point known to be associated with a decrease in neurocognitive testing in the HVLT-R domain.

Initial results suggest a less pronounced decrease in HVLTdelayed recall at 4 months than historical controls.36 Plans for a phase III randomized control trial evaluating hippocampalsparing WBRT with conventional WBRT in patients undergoing prophylactic cranial irradiation for small cell lung cancer (RTOG 1316) are currently under way.

Systemic Therapy

The role of systemic therapy in the management of brain metastases, as previously noted, has historically been limited, as most cytotoxic agents have poor penetration of the blood brain barrier. Moreover, several studies have demonstrated conflicting efficacy in improving OS and tolerability. Limited data exists regarding administration of modern cytotoxic and non-cytotoxic systemic therapies with concurrent WBRT.

Following publication of two articles that reported a 15%-25% rate of severe neurocognitive dysfunction in patients with concurrent chemotherapy and WBRT (including 10% fatal leukoencephalopathy in one study) treated for primary central nervous system lymphoma, concurrent chemotherapy with whole brain radiotherapy was generally cautioned against.37,38

A delay between chemotherapy administration and WBRT may reduce the likelihood and potential severity of toxicity of systemic therapy combined with WBRT. Theoretically, a delay may allow for repair of a potential radiotherapy-associated disruption in the blood-brain barrier that may contribute to neurocognitive toxicity. Several conflicting studies have been published regarding the tolerability and efficacy of several systemic therapies administered concurrently with WBRT.39- 47 Concurrent systemic therapy and radiotherapy has recently been revisited,48—58 but remains controversial. The interval between systemic therapy and radiotherapy—and whether a waiting period is required with more recently developed systemic therapies—is not well understood and is likely to be an area of active research in the future.

Recurrent and Progressive Brain Metastases

Patients with progressive or persistent disease at the site of previously treated brain metastases may be considered on an individual basis.59 Management options in these scenarios include surgical resection, SRS ± WBRT, repeat WBRT, and/or supportive care. These options are considered in the context of symptomatology, time to recurrence, overall prognosis, location, size, and nature of prior therapeutic interventions. New brain metastases at previously untreated regions may be managed as per recommendations for index lesions as discussed above.

Prognostic Tools

Several prognostic tools have been developed to aid in identifying patient populations in whom aggressive therapy may be warranted.60,61 Most recently, a nomogram has been developed that may aid in estimating survival in patients with brain metastases.62 This nomogram is based on site and histology, status of primary disease, metastatic spread, age, KPS, and number of brain lesions. These factors are included in aiding prediction of 6-month survival probability, 12-month survival probability, and predicted median survival (days).62 The nomogram may assist in further identifying patients in whom various brain metastasis therapies may provide the greatest benefit.

Overall Recommendations and Published Guidelines

For patients with newly diagnosed brain metastases, corticosteroid administration is recommended for associated neurologic symptoms.63 Corticosteroid use in patients with asymptomatic brain metastases is not well delineated. Surgical resection is advised for patients with oligometastatic disease with significant symptoms, patients requiring histopathologic diagnosis, and in patients with large metastases, recognizing there are conflicting size cut-offs at which point surgical intervention is recommended over SRS/SRT.

Anti-epileptic agents are recommended only for patients with prior seizure activity. For all patients undergoing craniotomy for resection of a parenchymal brain metastasis, the perioperative risk of seizure is approximately 3%-5% (3% rate of clinically significant seizure activity), and was not shown to be reduced with perioperative phenytoin in a recent study.64 The same study reported an overall rate of seizure activity in 13%-15% of all patients with brain metastases who had undergone prior resection for metastatic disease.64 While literature reviews and meta-analyses demonstrate no benefit or insufficient evidence to support prophylactic use of antiepileptic medications in patients undergoing neurosurgical resection for brain tumors,65,66 single-institution data suggest newer agents including levetiracetam are tolerable and may be effective in preventing perioperative seizures in this patient population when compared with phenytoin.67,68 Patients who have undergone neurosurgical intervention and have been prophylactically placed on anti-epileptic regimens should be tapered off approximately 1-2 weeks after surgery.69 Postoperative radiotherapy is considered standard, using WBRT and/or SRS to the surgical cavity,70—86 even though there has not been a survival advantage associated with postoperative radiotherapy. Similarly, patients with 1 to 3 brain metastases ≤ 4 cm may be considered for SRS ± WBRT; those undergoing WBRT may be considered for memantine during WBRT and for 6 months following WBRT. Patients with metastases ≥ 4 cm may be considered for multifraction SRT to an intact metastasis and/or to a resection cavity in the postoperative setting. Patients with > 4 metastases may be considered for SRS, though this is currently not considered standard of care.

Technologic advances over the past several decades have resulted in improved imaging techniques, allowing for improved sensitivity in detection of brain metastases and earlier treatment of smaller, asymptomatic lesions. This progress in radiologic imaging has been paralleled by improvements in neurosurgical techniques, novel systemic agents, immunomodulators, developments in radiation delivery capabilities, further understanding of tumor biology, and deeper appreciation of potential treatment toxicities. In the coming decades, anticipated increases in cancer diagnoses paired with these therapeutic advances will likely result in an increased number of cancer survivors. It stands to reason that further understanding of patient, tumor, and treatment factors will allow for greater individualization of therapeutic recommendations with goals of optimizing local control of existing brain metastases, preventing development of new brain metastases, and minimizing treatment-related toxicity.

ABOUT THE AUTHORS

Affiliations: Abigail L. Stockham, MD, is a neuro-radiation oncology fellow at the Brigham and Women’s Hospital/Dana-Farber Cancer Institute in Boston, MA. Nils D. Arvold, MD, is attending physician, Neuro-Radiation Oncology, Brigham and Women’s Hospital/Dana- Farber Cancer Institute.

Disclosures: Drs. Stockham and Arvold report no conflicts of interest to disclose.

Address correspondence to:

Abigail L. Stockham, MD, Brigham and Women’s Hospital/Dana- Farber Cancer Institute, 75 Francis Street, ASB1-L2, Boston, MA 02115. Phone: (617) 732-6313, #3; fax: (617) 975-0932; Email: astockham@partners.org.

References

  1. Fox BD, Cheung VJ, Patel AJ, Suki D, Rao G. Epidemiology of metastatic brain tumors. Neurosurg Clin N Am. 2011;22(1):1—6, v.
  2. Klos KJ, O’Neill BP. Brain metastases. Neurologist. 2004;10(1):31—46.
  3. Langer CJ, Mehta MP. Current management of brain metastases, with a focus on systemic options. J Clin Oncol. 2005;23(25):6207—6219.
  4. Murray KJ, Scott C, Greenberg HM, et al. A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys. 1997;39(3):571—574.
  5. Harwood AR, Simson WJ. Radiation therapy of cerebral metastases: a randomized prospective clinical trial. Int J Radiat Oncol Biol Phys. 1977;2(11-12):1091—1094.
  6. Haie-Meder C, Pellae-Cosset B, Laplanche A, et al. Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases. Radiother Oncol. 1993;26(2):111—116.
  7. Kurtz JM, Gelber R, Brady LW, Carella RJ, Cooper JS. The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1981;7(7):891—895.
  8. 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. 1980;6(1):1—9.
  9. Borgelt B, Gelber R, Larson M, Hendrickson F, Griffin T, Roth R. 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. 1981;7(12):1633—1638.
  10. Chatani M, Teshima T, Hata K, Inoue T, Suzuki T. Whole brain irradiation for metastases from lung carcinoma. A clinical investigation. Acta Radiol Oncol. 1985;24(4):311—314.
  11. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33(6):583—590.
  12. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280(17):1485—1489.
  13. 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. 1990;322(8):494—500.
  14. 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. 1994;29(4):711—717.
  15. Tendulkar RD, Liu SW, Barnett GH, et al. RPA classification has prognostic significance for surgically resected single brain metastasis. Int J Radiat Oncol Biol Phys. 2006;66(3):810—817.
  16. 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. 1996;78(7):1470—1476.
  17. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29(2):134—141.
  18. Soffietti R, Kocher M, Abacioglu UM, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant wholebrain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol. 2012;31(1):65—72.
  19. Suh JH. Stereotactic radiosurgery for the management of brain metastases. N Engl J Med. 2010;362(12):1119—1127.
  20. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47(2):291—298.
  21. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363(9422):1665—1672.
  22. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295(21):2483—2491.
  23. Linskey ME, Andrews DW, Asher AL, et al. The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2009;96(1):45—68.
  24. Tsao MN, Rades D, Wirth A, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol. 2012;2(3):210—225.
  25. Salvetti DJ, Nagaraja TG, McNeill IT, Xu Z, Sheehan J. Gamma Knife surgery for the treatment of 5 to 15 metastases to the brain: clinical article. J Neurosurg. 2013;118(6):1250—1257.
  26. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037—1044.
  27. Regine WF, Huhn JL, Patchell RA, et al. Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery alone in patients with newly diagnosed brain metastases: results and implications. Int J Radiat Oncol Biol Phys. 2002;52(2):333—338.
  28. Mehta MP. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol. 2003;21(13):2529—2536.
  29. Regine WF, Scott C, Murray K, Curran W. Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. accelerated-hyperfractionated radiotherapy: an analysis from Radiation Therapy Oncology Group Study 91-04. Int J Radiat Oncol Biol Phys. 2001;51(3):711—717.
  30. Welzel G, Fleckenstein K, Schaefer J, et al. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys. 2008;72(5):1311—1318.
  31. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol. 2007;25(10):1260—1266.
  32. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39(6):789—796.
  33. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-Oncol. 2013;15(10):1429—1437.
  34. Gondi V, Tomé WA, Mehta MP. Why avoid the hippocampus? A comprehensive review. Radiother Oncol. 2010;97(3):370—376.
  35. Gondi V, Hermann BP, Mehta MP, Tomé WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85(2):348—354.
  36. Gondi V, Mehta M, Pugh S, et al. Memory preservation with conformal avoidance of the hippocampus during whole-brain radiotherapy (WBRT) for patients with brain metastases: primary endpoint results of RTOG 0933. Presented at: 4th Quadrennial Meeting of the World Federation of Neuro- Oncology. San Francisco,CA; November 21-24, 2013. Abstract NC-012.
  37. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000;18(17):3144—3150.
  38. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ, Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002;20(24):4643—4648.
  39. Sperduto PW, Wang M, Robins HI, et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys. 2013;85(5):1312—1318.
  40. Meng FL, Zhou QH, Zhang LL, Ma Q, Shao Y, Ren YY. Antineoplastic therapy combined with whole brain radiation compared with whole brain radiation alone for brain metastases: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2013;17(6):777—787.
  41. Dinglin X-X, Huang Y, Liu H, Zeng Y-D, Hou X, Chen L-K. Pemetrexed and cisplatin combination with concurrent whole brain radiotherapy in patients with brain metastases of lung adenocarcinoma: a single-arm phase II clinical trial. J Neurooncol. 2013;112(3):461—466.
  42. Ge X-H, Lin Q, Ren X-C, et al. Phase II clinical trial of whole-brain irradiation plus three-dimensional conformal boost with concurrent topotecan for brain metastases from lung cancer. Radiat Oncol Lond Engl. 2013;8(1):238.
  43. Zhuang H, Yuan Z, Wang J, Zhao L, Pang Q, Wang P. Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma. Drug Des Devel Ther. 2013;7:1179—1186.
  44. Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from nonsmall- cell lung cancer. J Clin Oncol. 2013;31(7):895—902.
  45. Addeo R, Sperlongano P, Montella L, et al. Protracted low dose of oral vinorelbine and temozolomide with whole-brain radiotherapy in the treatment for breast cancer patients with brain metastases. Cancer Chemother Pharmacol. 2012;70(4):603—609.
  46. Liu W-J, Zeng X-T, Qin H-F, Gao H-J, Bi W-J, Liu X-Q. Whole brain radiotherapy plus chemotherapy in the treatment of brain metastases from lung cancer: a meta-analysis of 19 randomized controlled trails. Asian Pac J Cancer. 2012;13(7):3253—3258.
  47. Gamboa-Vignolle C, Ferrari-Carballo T, Arrieta Ó, Mohar A. Whole-brain irradiation with concomitant daily fixed-dose temozolomide for brain metastases treatment: a randomised phase II trial. Radiother Oncol. 2012;102(2):187—191.
  48. Sperduto PW, Wang M, Robins HI, et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys. 2013;85(5):1312—1318.
  49. Yuan Y, Tan C, Li M, et al. Activity of pemetrexed and high-dose gefitinib in an EGFR-mutated lung adenocarcinoma with brain and leptomeningeal metastasis after response to gefitinib. World J Surg Oncol. 2012;10:235.
  50. Hirata H, Nakamura K, Kunitake N, et al. Association between EGFR-TKI resistance and efficacy of radiotherapy for brain metastases from EGFRmutant lung adenocarcinoma. Anticancer Res. 2013;33(4):1649—1655.
  51. Fokas E, Steinbach JP, Rödel C. Biology of brain metastases and novel targeted therapies: time to translate the research. Biochim Biophys Acta. 2013;1835(1):61—75.
  52. Addeo R, Zappavigna S, Luce A, Facchini S, Caraglia M. Chemotherapy in the management of brain metastases: the emerging role of fotemustine for patients with melanoma and NSCLC. Expert Opin Drug Saf. 2013;12(5):729—740.
  53. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14(1):64—71.
  54. Dinglin X-X, Huang Y, Liu H, Zeng Y-D, Hou X, Chen L-K. Pemetrexed and cisplatin combination with concurrent whole brain radiotherapy in patients with brain metastases of lung adenocarcinoma: a single-arm phase II clinical trial. J Neurooncol. 2013;112(3):461—466.
  55. Karam I, Hamilton S, Nichol A, et al. Population-based outcomes after brain radiotherapy in patients with brain metastases from breast cancer in the pre-trastuzumab and trastuzumab eras. Radiat Oncol Lond Engl. 2013;8:12.
  56. Chua D, Krzakowski M, Chouaid C, et al. Whole-brain radiation therapy plus concomitant temozolomide for the treatment of brain metastases from non-small-cell lung cancer: a randomized, open-label phase II study. Clin Lung Cancer. 2010;11(3):176—181.
  57. Antonadou D, Paraskevaidis M, Sarris G, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol. 2002;20(17):3644—3650.
  58. Mehta MP, Paleologos NA, Mikkelsen T, et al. The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2009;96(1):71—83.
  59. Ammirati M, Cobbs CS, Linskey ME, et al. The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2010;96(1):85—96.
  60. 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. 1997;37(4):745—751.
  61. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2011;30(4):419—425.
  62. Barnholtz-Sloan JS, Yu C, Sloan AE, et al. A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro-Oncol. 2012;14(7):910—918.
  63. Ryken TC, McDermott M, Robinson PD, et al. The role of steroids in the management of brain metastases: a systematic review and evidencebased clinical practice guideline. J Neurooncol. 2010;96(1):103—114.
  64. Wu AS, Trinh VT, Suki D, et al. A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors. J Neurosurg. 2013;118(4):873—883.
  65. Sirven JI, Wingerchuk DM, Drazkowski JF, Lyons MK, Zimmerman RS. Seizure prophylaxis in patients with brain tumors: a meta-analysis. Mayo Clin Proc. 2004;79(12):1489—1494.
  66. Klimek M, Dammers R. Antiepileptic drug therapy in the perioperative course of neurosurgical patients. Curr Opin Anaesthesiol. 2010;23(5):564—567.
  67. Kern K, Schebesch KM, Schlaier J, et al. Levetiracetam compared to phenytoin for the prevention of postoperative seizures after craniotomy for intracranial tumours in patients without epilepsy. J Clin Neurosci. 2012;19(1):99—100.
  68. Fuller KL, Wang YY, Cook MJ, Murphy MA, D’Souza WJ. Tolerability, safety, and side effects of levetiracetam versus phenytoin in intravenous and total prophylactic regimen among craniotomy patients: a prospective randomized study. Epilepsia. 2013;54(1):45—57.
  69. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54(10):1886—1893.
  70. Hwang SW, Abozed MM, Hale A, et al. Adjuvant Gamma Knife radiosurgery following surgical resection of brain metastases: a 9-year retrospective cohort study. J Neurooncol. 2010;98(1):77—82.
  71. Jensen CA, Chan MD, McCoy TP, et al. Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis. J Neurosurg. 2011;114(6):1585—1591.
  72. Wang C-C, Floyd SR, Chang C-H, et al. Cyberknife hypofractionated stereotactic radiosurgery (HSRS) of resection cavity after excision of large cerebral metastasis: efficacy and safety of an 800 cGy × 3 daily fractions regimen. J Neurooncol. 2012;106(3):601—610.
  73. Jagannathan J, Yen C-P, Ray DK, et al. Gamma Knife radiosurgery to the surgical cavity following resection of brain metastases. J Neurosurg. 2009;111(3):431—438.
  74. Kalani MYS, Filippidis AS, Kalani MA, et al. Gamma Knife surgery combined with resection for treatment of a single brain metastasis: preliminary results. J Neurosurg. 2010;113 Suppl:90—96.
  75. Kim PK, Ellis TL, Stieber VW, et al. Gamma Knife surgery targeting the resection cavity of brain metastasis that has progressed after whole-brain radiotherapy. J Neurosurg. 2006;105 Suppl:75—78.
  76. Steinmann D, Maertens B, Janssen S, et al. Hypofractionated stereotactic radiotherapy (hfSRT) after tumour resection of a single brain metastasis: report of a single-centre individualized treatment approach. J Cancer Res Clin Oncol. 2012;138(9):1523—1529.
  77. Ogiwara H, Kalakota K, Rakhra SS, et al. Intracranial relapse rates and patterns, and survival trends following post-resection cavity radiosurgery for patients with single intracranial metastases. J Neurooncol. 2012;108(1):141—146.
  78. Connolly EP, Mathew M, Tam M, et al. Involved field radiation therapy after surgical resection of solitary brain metastases—mature results. Neuro- Oncol. 2013;15(5):589—594.
  79. Minniti G, Esposito V, Clarke E, et al. Multidose stereotactic radiosurgery (9 Gy × 3) of the postoperative resection cavity for treatment of large brain metastases. Int J Radiat Oncol Biol Phys. 2013;86(4):623—629.
  80. Hartford AC, Paravati AJ, Spire WJ, et al. Postoperative stereotactic radiosurgery without whole-brain radiation therapy for brain metastases: potential role of preoperative tumor size. Int J Radiat Oncol Biol Phys. 2013;85(3):650—655.
  81. Robbins JR, Ryu S, Kalkanis S, et al. Radiosurgery to the surgical cavity as adjuvant therapy for resected brain metastasis. Neurosurgery. 2012;71(5):937—943.
  82. Do L, Pezner R, Radany E, Liu A, Staud C, Badie B. Resection followed by stereotactic radiosurgery to resection cavity for intracranial metastases. Int J Radiat Oncol Biol Phys. 2009;73(2):486—491.
  83. Kelly PJ, Lin YB, Yu AY, et al. Stereotactic irradiation of the postoperative resection cavity for brain metastasis: a frameless linear accelerator-based case series and review of the technique. Int J Radiat Oncol Biol Phys. 2012;82(1):95—101.
  84. Soltys SG, Adler JR, Lipani JD, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys. 2008;70(1):187—193.
  85. Choi CYH, Chang SD, Gibbs IC, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases: prospective evaluation of target margin on tumor control. Int J Radiat Oncol Biol Phys. 2012;84(2):336—342.
  86. Mathieu D, Kondziolka D, Flickinger JC, et al. Tumor bed radiosurgery after resection of cerebral metastases. Neurosurgery. 2008;62(4):817—823; discussion 823–824.