Current Treatment Strategies for Brain Metastasis and Complications From Therapeutic Techniques: A Review of Current Literature

Each year approximately 170,000 patients are diagnosed with brain metastasis in the United States, making this the most common intracranial tumor in adults. Historically, treatment strategies focused on the use of whole brain radiation therapy (WBRT) for palliation, yielding a median survival time of only 3 to 6 months. The possible effect of WBRT on cognitive function has generated much concern and debate regarding the use of this modality. Thus, the use of WBRT alone, or in conjunction with other treatment modalities should take into account both risks and benefits, to ensure the best patient outcome with regard to disease state and functional status. The advent of technologies permitting local dose-escalation have clearly increased local control rates, and in select patients, even survival, thereby, further intensifying the debate regarding the use of WBRT. Here, we review the use of WBRT, radiosurgery, and resection for the treatment of brain metastases. Further, we will review the use of radiation sensitizers and blood–brain barrier penetrating cytotoxics such as temozolomide. Finally, we will discuss current treatment strategies for possibly maintaining and improving cognitive function for these patients.

[1]  J. Lester,et al.  Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: a Cochrane Review. , 2005, International journal of radiation oncology, biology, physics.

[2]  P. Wen,et al.  Management of brain metastases. , 1999, Oncology.

[3]  W. Hall,et al.  Brain metastases: Histology, multiplicity, surgery, and survival , 1996 .

[4]  A. Twijnstra,et al.  Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma , 2002, Cancer.

[5]  W. Curran,et al.  Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  T. Phillips,et al.  A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916). , 1991, International journal of radiation oncology, biology, physics.

[7]  M. Sharr Intracranial metastases , 2004, Journal of Neuro-Oncology.

[8]  K Takakura,et al.  [Metastatic brain tumors]. , 1980, Rinsho hoshasen. Clinical radiography.

[9]  P Chomy,et al.  Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. , 1995, Journal of the National Cancer Institute.

[10]  M. Burt,et al.  The treatment of patients with recurrent brain metastases. A retrospective analysis of 109 patients with nonsmall cell lung cancer , 1995, Cancer.

[11]  R A Patchell,et al.  Brain metastases. , 1991, Neurologic clinics.

[12]  L Souhami,et al.  Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. , 2000, International journal of radiation oncology, biology, physics.

[13]  F. Barker Craniotomy for the resection of metastatic brain tumors in the U.S., 1988–2000 , 2004, Cancer.

[14]  L. Collette,et al.  Prophylactic cranial irradiation in extensive small-cell lung cancer. , 2007, The New England journal of medicine.

[15]  E. Shaw,et al.  RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  L. Deangelis,et al.  Radiation‐induced dementia in patients cured of brain metastases , 1989, Neurology.

[17]  J. Suh Efaproxiral: a novel radiation sensitiser , 2004, Expert opinion on investigational drugs.

[18]  E. Shaw,et al.  Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  L Gaspar,et al.  Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. , 1997, International journal of radiation oncology, biology, physics.

[20]  R. Sawaya,et al.  Surgical treatment of multiple brain metastases. , 1993, Journal of neurosurgery.

[21]  R Timmerman,et al.  Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  Maria Werner-Wasik,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 , 2004, The Lancet.

[23]  T. Phillips,et al.  Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: report of RTOG trial 89-05. , 1995, International journal of radiation oncology, biology, physics.

[24]  J. Mackey,et al.  Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  W. Curran,et al.  Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  G. Duncan,et al.  A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis , 1996, Cancer.

[27]  Roy A. Patcheil Metastatic brain tumors. , 1995 .

[28]  H. Treuer,et al.  Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. , 1999, Brain research. Molecular brain research.

[29]  H. Marsiglia,et al.  Results of the Phase III ENRICH (RT-016) Study of Efaproxiral Administered Concurrent with Whole Brain Radiation Therapy (WBRT) in Women with Brain Metastases from Breast Cancer , 2008 .

[30]  A. Twijnstra,et al.  Follow-up of cognitive functioning in patients with small cell lung cancer. , 1995, International journal of radiation oncology, biology, physics.

[31]  C. Nieder,et al.  Tumor-related prognostic factors for remission of brain metastases after radiotherapy. , 1997, International journal of radiation oncology, biology, physics.

[32]  A S Garden,et al.  Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. , 1995, International journal of radiation oncology, biology, physics.

[33]  M. Mehta,et al.  Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method. , 2001, International journal of radiation oncology, biology, physics.

[34]  E. Gore RTOG 0214: a phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell lung cancer. , 2005, Clinical advances in hematology & oncology : H&O.

[35]  Deepak Khuntia,et al.  Motexafin gadolinium: a clinical review of a novel radioenhancer for brain tumors , 2004, Expert review of anticancer therapy.

[36]  G. Krol,et al.  Distribution of brain metastases. , 1988, Archives of neurology.

[37]  L. Crinò,et al.  Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors. , 2007, The oncologist.

[38]  L. Crinò,et al.  Medical treatment of brain metastases from solid tumours. , 2000, Forum.

[39]  E. Thiel,et al.  Response to topotecan of symptomatic brain metastases of small-cell lung cancer also after whole-brain irradiation. a multicentre phase II study. , 2002, European journal of cancer.

[40]  Michael I. Seider,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. , 1997, International journal of radiation oncology, biology, physics.

[41]  T E Schultheiss,et al.  Radiation response of the central nervous system. , 1995, International journal of radiation oncology, biology, physics.

[42]  A. Hauschild,et al.  A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma , 2003, Melanoma research.

[43]  E. Boldrey,et al.  Delayed transitory clinical manifestations after radiation treatment of intracranial tumors. , 2009, Acta radiologica: therapy, physics, biology.

[44]  M. Mehta,et al.  A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. , 2002, International journal of radiation oncology, biology, physics.

[45]  Hiroki Shirato,et al.  Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases: A Randomized Controlled Trial , 2007 .

[46]  R. Gelber,et al.  The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group. , 1981, International journal of radiation oncology, biology, physics.

[47]  M. Mehta,et al.  Distribution of brain metastases in relation to the hippocampus: implications for neurocognitive functional preservation. , 2007, International journal of radiation oncology, biology, physics.

[48]  J. Kornhuber,et al.  Memantine in moderate-to-severe Alzheimer's disease. , 2003, The New England journal of medicine.

[49]  G. Krol,et al.  The combined use of radiation therapy and lonidamine in the treatment of brain metastases , 1989, Journal of Neuro-Oncology.

[50]  M. Mehta,et al.  Current Strategies in Whole-brain Radiation Therapy for Brain Metastases , 2005, Neurosurgery.

[51]  D. Kondziolka,et al.  Stereotactic radiosurgery for four or more intracranial metastases. , 2005, International journal of radiation oncology, biology, physics.

[52]  B. Yawn,et al.  Temporal and gender-related trends in brain metastases from lung and breast cancer. , 2003, Minnesota medicine.

[53]  A. Harwood,et al.  Radiation therapy of cerebral metastases: a randomized prospective clinical trial. , 1977, International journal of radiation oncology, biology, physics.

[54]  W. Curran,et al.  A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). , 2008, International journal of radiation oncology, biology, physics.

[55]  T Sahmoud,et al.  Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  R. Gelber,et al.  The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. , 1980, International journal of radiation oncology, biology, physics.

[57]  E D Bigler,et al.  Quantitative assessment of covariation between neuropsychological function and location of naturally occurring lesions in humans. , 1990, Journal of clinical and experimental neuropsychology.

[58]  Y. Nakasu,et al.  [Multidisciplinary management of brain metastases]. , 2010, Gan to kagaku ryoho. Cancer & chemotherapy.

[59]  V. Budach,et al.  Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  Armin Thron,et al.  Diagnostic Accuracy of MRI Compared to CCT in Patients with Brain Metastases , 2004, Journal of Neuro-Oncology.

[61]  W. Curran,et al.  Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  R. Sawaya,et al.  Neurologic Complications of Cancer. , 1996 .

[63]  V. Budach,et al.  Temozolomide With or Without Radiotherapy in Melanoma With Unresectable Brain Metastases , 2005, Journal of Neuro-Oncology.

[64]  P. Wen,et al.  Neurologic Complications of Cancer , 2003 .

[65]  D. Abraham,et al.  RSR-13, an allosteric effector of hemoglobin, increases systemic and iliac vascular resistance in rats. , 1996, The American journal of physiology.

[66]  Y Maruyama,et al.  A randomized trial of surgery in the treatment of single metastases to the brain. , 1990, The New England journal of medicine.

[67]  L. Recht,et al.  Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial. , 2009, International journal of radiation oncology, biology, physics.

[68]  B. Kimler,et al.  A phase I/II study of the use of Fluosol as an adjuvant to radiation therapy in the treatment of primary high-grade brain tumors. , 1990, International journal of radiation oncology, biology, physics.

[69]  van der Kogel Aj Radiation-induced damage in the central nervous system: an interpretation of target cell responses. , 1986 .

[70]  R. Demicheli,et al.  Menopausal status dependence of early mortality reduction due to diagnosis of smaller breast cancers (T1 v T2-T3): relevance to screening. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  N. Viñolas,et al.  Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. , 2005, International journal of radiation oncology, biology, physics.

[72]  D. Antonadou,et al.  Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  W. Curran,et al.  Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. accelerated-hyperfractionated radiotherapy: an analysis from Radiation Therapy Oncology Group Study 91-04. , 2001, International journal of radiation oncology, biology, physics.

[74]  J P Pignon,et al.  Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. , 1999, The New England journal of medicine.

[75]  R. Scheibel,et al.  Cognitive dysfunction following surgery for intracerebral glioma: influence of histopathology, lesion location, and treatment , 1996, Journal of Neuro-Oncology.

[76]  L D Lunsford,et al.  Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. , 1999, International journal of radiation oncology, biology, physics.

[77]  J. Nickson,et al.  Roentgen‐ray therapy of cerebral metastases , 1954, Cancer.

[78]  C. Boake,et al.  Neurobehavioral disorders in brain tumor patients: Rehabilitation strategies , 1993 .

[79]  M. Mehta,et al.  Radiosurgery for Single and Multiple Brain Metastases , 2008 .

[80]  Ronald Brand,et al.  Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery , 1993, Annals of neurology.

[81]  V. Smith,et al.  Therapeutic irradiation and brain injury. , 1980, International journal of radiation oncology, biology, physics.

[82]  H. Mogami,et al.  Chemotherapy of brain metastases from lung carcinoma: a controlled randomized study. , 1991, Neurosurgery.

[83]  M. Gilbert,et al.  Phase II trial of radiosurgery for one to three newly diagnosed brain metastases from renal cell carcinoma, melanoma, and sarcoma: an Eastern Cooperative Oncology Group study (E 6397). , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[84]  M. Mehta,et al.  Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain metastases (RTOG 0119). , 2007, International journal of radiation oncology, biology, physics.

[85]  C. Haie-meder,et al.  Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases. , 1993, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[86]  S. Hassenbusch,et al.  A PILOT STUDY OF NEUROCOGNITIVE FUNCTION IN PATIENTS WITH ONE TO THREE NEW BRAIN METASTASES INITIALLY TREATED WITH STEREOTACTIC RADIOSURGERY ALONE , 2007, Neurosurgery.

[87]  L. Salford,et al.  Microprocesses in Perception and Personality , 1992, The Journal of nervous and mental disease.

[88]  J. Verdebout,et al.  Prophylactic cranial irradiation in small cell lung cancer: a systematic review of the literature with meta-analysis , 2001, BMC Cancer.

[89]  M. Mehta,et al.  Neurocognitive and Functional Assessment of Patients With Brain Metastases: A Pilot Study , 2003, American journal of clinical oncology.

[90]  A. D. Van den Abbeele,et al.  Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[91]  C. Meyers Neurocognitive dysfunction in cancer patients. , 2000, Oncology.

[92]  Walter Curran,et al.  A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. , 2008, International journal of radiation oncology, biology, physics.

[93]  J. Cox,et al.  Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. , 1981, Cancer treatment reports.

[94]  Suzanne F. Jones,et al.  Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[95]  P. Wen,et al.  Medical management of patients with brain tumors , 2006, Journal of Neuro-Oncology.

[96]  D. Kondziolka,et al.  Radiosurgery in patients with renal cell carcinoma metastasis to the brain: long-term outcomes and prognostic factors influencing survival and local tumor control. , 2003, Journal of neurosurgery.

[97]  S. Kramer The hazards of therapeutic iradiation of the central nervous system. , 1968, Clinical neurosurgery.

[98]  G. Barnett,et al.  Survival by radiation therapy oncology group recursive partitioning analysis class and treatment modality in patients with brain metastases from malignant melanoma , 2002, Cancer.

[99]  T. Inoue,et al.  [Prognostic factors in patients with brain metastases from lung carcinoma]. , 1986, Gan no rinsho. Japan journal of cancer clinics.

[100]  W R Markesbery,et al.  Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. , 1998, JAMA.

[101]  V. Vaitkevicius,et al.  Malignant melanoma and central nervous system metastases. Incidence, diagnosis, treatment and survival , 1978, Cancer.

[102]  H. Minn,et al.  Prognosis of patients treated for intracranial metastases with whole-brain irradiation. , 1998, Annals of medicine.

[103]  M. Gore,et al.  Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[104]  M. Mehta,et al.  Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: a planning study. , 2007, International journal of radiation oncology, biology, physics.

[105]  E. Lang,et al.  METASTATIC BRAIN TUMORS. RESULTS OF SURGICAL AND NONSURGICAL TREATMENT. , 1964, The Surgical clinics of North America.

[106]  E. Shaw,et al.  Gamma Knife surgery targeting the resection cavity of brain metastasis that has progressed after whole-brain radiotherapy. , 2006, Journal of neurosurgery.

[107]  D. Girling,et al.  Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: Results of a multicentre randomised trial , 1997 .

[108]  A. J. van der Kogel Radiation-induced damage in the central nervous system: an interpretation of target cell responses. , 1986, The British journal of cancer. Supplement.

[109]  J. Reid,et al.  Pharmacokinetics of 3-methyl-(triazen-1-yl)imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[110]  T. Inoue,et al.  Radiation therapy for brain metastases from lung carcinoma. Prospective randomized trial according to the level of lactate dehydrogenase. , 1994, Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al].

[111]  J. Dalmau,et al.  [Paraneoplastic disorders of the nervous system]. , 2007, Rinsho shinkeigaku = Clinical neurology.

[112]  K. Hess,et al.  Multifaceted end points in brain tumor clinical trials: cognitive deterioration precedes MRI progression. , 2003, Neuro-oncology.

[113]  F. Lohr,et al.  Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[114]  R. Gelber,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. , 1981, International journal of radiation oncology, biology, physics.

[115]  C. Mansfield,et al.  Randomized trial of radiotherapy versus radiotherapy plus metronidazole for the treatment metastatic cancer to brain , 2004, Journal of Neuro-Oncology.

[116]  E. Shaw,et al.  Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.