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The role of chemotherapy in the treatment of patients with brain metastases from solid tumors

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Abstract

Brain metastases are the most frequent cancer in the central nervous system, being ten times more common than primary brain tumors. Patients generally have a poor outcome with a median survival of 4 months after diagnosis of the metastases. Therapeutic options include surgery, stereotactic, radiosurgery, whole-brain radiotherapy (WBRT), and chemotherapy. Patients with a limited number of brain metastases and well-controlled systemic cancer benefit from brain metastases-specific therapies, including surgery, radiosurgery, and conventional radiation. The role of chemotherapy for brain metastases remains limited. There is concern about drug delivery because of the blood-brain barrier. However, higher response rates are noted with initial therapies, suggesting that part of the poor response rate may be related to the late onset of brain metastases and the use of second- and third-line regimens. Recent studies have demonstrated objective responses with systemic therapy in a variety of cancer types, especially when combined with WBRT. Individual therapeutic strategies for central nervous system metastases must be chosen based on performance status, the extent of intracranial disease, and the chemosensitivity of the underlying tumor, as well as the control of the systemic cancer. In this article we review important prognostic factors and challenges in using chemotherapy. We specifically review recent advances in the treatment of brain metastases from breast and lung cancer as well as melanoma. Future treatment advances will require a multidisciplinary approach integrating surgical, radiation, and chemotherapeutic options to improve neurological function and quality of life, rather than just focusing on survival endpoints.

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References

  1. Lassman AB, DeAngelis LM (2003) Brain metastases. Neurol Clin 21:1–23, vii

    Article  PubMed  Google Scholar 

  2. Delattre JY, Krol G, Thaler HT, et al. (1988) Distribution of brain metastases. Arch Neurol 45:741–744

    PubMed  CAS  Google Scholar 

  3. Nussbaum ES, Djalilian HR, Cho KH, et al. (1996) Brain metastases. Histology, multiplicity, surgery, and survival. Cancer 78: 1781–1788

    Article  PubMed  CAS  Google Scholar 

  4. Davey P (2002) Brain metastases: treatment options to improve outcomes. CNS Drugs 16:325–338

    Article  PubMed  CAS  Google Scholar 

  5. Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 22:2865–2872

    Article  PubMed  Google Scholar 

  6. Schouten LJ, Rutten J, Huveneers HA, et al. (2002) Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 94:2698–2705

    Article  PubMed  Google Scholar 

  7. Sul J, Posner JB (2007) Brain metastases: epidemiology and pathophysiology. Cancer Treat Res 136:1–21

    Article  PubMed  Google Scholar 

  8. Gilbert MR (2001) Brain metastases: still an “orphan” disease? Curr Oncol Rep 3:463–466

    Article  PubMed  CAS  Google Scholar 

  9. Gori S, Rimondini S, De Angelis V, et al. (2007) Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors. Oncologist 12:766–773

    Article  PubMed  Google Scholar 

  10. Mamon HJ, Yeap BY, Janne PA, et al. (2005) High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation. J Clin Oncol 23:1530–1537

    Article  PubMed  Google Scholar 

  11. Zimm S, Wampler GL, Stablein D, et al. (1981) Intracerebral metastases in solid-tumor patients: natural history and results of treatment. Cancer 48:384–394

    Article  PubMed  CAS  Google Scholar 

  12. Kelly K, Bunn PA Jr (1998) Is it time to reevaluate our approach to the treatment of brain metastases in patients with non-small cell lung cancer? Lung Cancer 20:85–91

    Article  PubMed  CAS  Google Scholar 

  13. Lagerwaard FJ, Levendag PC, Nowak PJ, et al. (1999) Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys 43:795–803

    PubMed  CAS  Google Scholar 

  14. Nieder C, Nestle U, Motaref B, et al. (2000) Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes? Int J Radiat Oncol Biol Phys 46:297–302

    Article  PubMed  CAS  Google Scholar 

  15. Gaspar L, Scott C, Rotman M, et al. (1997) Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745–751

    PubMed  CAS  Google Scholar 

  16. Gaspar LE, Scott C, Murray K, et al. (2000) Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 47:1001–1006

    PubMed  CAS  Google Scholar 

  17. Hall WA, Djalilian HR, Nussbaum ES, et al. (2000) Long-term survival with metastatic cancer to the brain. Med Oncol 17: 279–286

    Article  PubMed  CAS  Google Scholar 

  18. Gerstner ER, Fine RL (2007) Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 25:2306–2312

    Article  PubMed  Google Scholar 

  19. Stewart DJ (1994) A critique of the role of the blood-brain barrier in the chemotherapy of human brain tumors. J Neurooncol 20:121–139

    Article  PubMed  CAS  Google Scholar 

  20. Lin NU, Bellon JR, Winer EP (2004) CNS metastases in breast cancer. J Clin Oncol 22:3608–3617

    Article  PubMed  Google Scholar 

  21. DiStefano A, Yong Yap Y, Hortobagyi GN, et al. (1979) The natural history of breast cancer patients with brain metastases. Cancer 44:1913–1918

    Article  PubMed  CAS  Google Scholar 

  22. Gonzalez-Angulo AM, Cristofanilli M, Strom EA, et al. (2004) Central nervous system metastases in patients with high-risk breast carcinoma after multimodality treatment. Cancer 101:1760–1766

    Article  PubMed  Google Scholar 

  23. Miller KD, Weathers T, Haney LG, et al. (2003) Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol 14:1072–1077

    Article  PubMed  CAS  Google Scholar 

  24. Rosner D, Nemoto T, Lane WW (1986) Chemotherapy induces regression of brain metastases in breast carcinoma. Cancer 58:832–839

    Article  PubMed  CAS  Google Scholar 

  25. Boogerd W, Dalesio O, Bais EM, et al. (1992) Response of brain metastases from breast cancer to systemic chemotherapy. Cancer 69:972–980

    Article  PubMed  CAS  Google Scholar 

  26. Abrey LE, Olson JD, Raizer JJ, et al. (2001) A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol 53:259–265

    Article  PubMed  CAS  Google Scholar 

  27. Christodoulou C, Bafaloukos D, Kosmidis P, et al. (2001) Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol 12:249–254

    Article  PubMed  CAS  Google Scholar 

  28. Trudeau ME, Crump M, Charpentier D, et al. (2006) Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada — Clinical Trials Group (NCIC-CTG). Ann Oncol 17:952–956

    Article  PubMed  CAS  Google Scholar 

  29. Omuro AM, Raizer JJ, Demopoulos A, et al. (2006) Vinorelbine combined with a protracted course of temozolomide for recurrent brain metastases: a phase I trial. J Neurooncol 78:277–280

    Article  PubMed  CAS  Google Scholar 

  30. Christodoulou C, Bafaloukos D, Linardou H, et al. (2005) Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study. J Neurooncol 71: 61–65

    Article  PubMed  CAS  Google Scholar 

  31. Rivera E, Meyers C, Groves M, et al. (2006) Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer 107:1348–1354

    Article  PubMed  CAS  Google Scholar 

  32. Lin NU, Winer EP (2007) Brain metastases: the HER2 paradigm. Clin Cancer Res 13:1648–1655

    Article  PubMed  CAS  Google Scholar 

  33. Stemmler HJ, Schmitt M, Willems A, et al. (2007) Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs 18: 23–28

    Article  PubMed  CAS  Google Scholar 

  34. Lin NU, Dieras V, Paul D, et al. (2009) Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452–1459

    Article  PubMed  CAS  Google Scholar 

  35. Komaki R, Cox JD, Whitson W (1981) Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep 65:811–814

    PubMed  CAS  Google Scholar 

  36. Kristjansen PE, Soelberg Sorensen P, Skov Hansen M, et al. (1993) Prospective evaluation of the effect on initial brain metastases from small cell lung cancer of platinum-etoposide based induction chemotherapy followed by an alternating multidrug regimen. Ann Oncol 4:579–583

    PubMed  CAS  Google Scholar 

  37. Lee JS, Murphy WK, Glisson BS, et al. (1989) Primary chemotherapy of brain metastasis in small-cell lung cancer. J Clin Oncol 7:916–922

    PubMed  CAS  Google Scholar 

  38. Seute T, Leffers P, Wilmink JT, et al. (2006) Response of asymptomatic brain metastases from small-cell lung cancer to systemic first-line chemotherapy. J Clin Oncol 24:2079–2083

    Article  PubMed  CAS  Google Scholar 

  39. Twelves CJ, Souhami RL, Harper PG, et al. (1990) The response of cerebral metastases in small cell lung cancer to systemic chemotherapy. Br J Cancer 61:147–150

    PubMed  CAS  Google Scholar 

  40. Groen HJ, Smit EF, Haaxma-Reiche H, et al. (1993) Carboplatin as second line treatment for recurrent or progressive brain metastases from small cell lung cancer. Eur J Cancer 29A:1696–1699

    Article  PubMed  CAS  Google Scholar 

  41. Korfel A, Oehm C, von Pawel J, et al. (2002) Response to topotecan of symptomatic brain metastases of small-cell lung cancer also after whole-brain irradiation. a multicentre phase II study. Eur J Cancer 38:1724–1729

    Article  PubMed  CAS  Google Scholar 

  42. Postmus PE, Haaxma-Reiche H, Smit EF, et al. (2000) 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. J Clin Oncol 18: 3400–3408

    PubMed  CAS  Google Scholar 

  43. Grossi F, Scolaro T, Tixi L, et al. (2001) The role of systemic chemotherapy in the treatment of brain metastases from small-cell lung cancer. Crit Rev Oncol Hematol 37:61–67

    Article  PubMed  CAS  Google Scholar 

  44. Stupp R, Mason WP, van den Bent MJ, et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  45. Antonadou D, Paraskevaidis M, Sarris G, et al. (2002) Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 20:3644–3650

    Article  PubMed  CAS  Google Scholar 

  46. Bernardo G, Cuzzoni Q, Strada MR, et al. (2002) First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: a phase II study. Cancer Invest 20:293–302

    Article  PubMed  CAS  Google Scholar 

  47. Cortes J, Rodriguez J, Aramendia JM, et al. (2003) Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology 64:28–35

    Article  PubMed  CAS  Google Scholar 

  48. Crino L, Scagliotti GV, Ricci S, et al. (1999) Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced nonsmall-cell lung cancer: a randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 17:3522–3530

    PubMed  CAS  Google Scholar 

  49. Franciosi V, Cocconi G, Michiara M, et al. (1999) Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 85:1599–1605

    Article  PubMed  CAS  Google Scholar 

  50. Minotti V, Crino L, Meacci ML, et al. (1998) Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer. Lung Cancer 20:93–98

    Article  PubMed  CAS  Google Scholar 

  51. Fujita A, Fukuoka S, Takabatake H, et al. (2000) Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhGCSF support in patients with brain metastases from non-small cell lung cancer. Oncology 59:291–295

    Article  PubMed  CAS  Google Scholar 

  52. Wong ET, Berkenblit A (2004) The role of topotecan in the treatment of brain metastases. Oncologist 9:68–79

    Article  PubMed  CAS  Google Scholar 

  53. Dziadziuszko R, Ardizzoni A, Postmus PE, et al. (2003) Temozolomide in patients with advanced non-small cell lung cancer with and without brain metastases. A phase II study of the EORTC Lung Cancer Group (08965). Eur J Cancer 39:1271–1276

    Article  PubMed  CAS  Google Scholar 

  54. Giorgio CG, Giuffrida D, Pappalardo A, et al. (2005) Oral temozolomide in heavily pre-treated brain metastases from nonsmall cell lung cancer: phase II study. Lung Cancer 50:247–254

    Article  PubMed  Google Scholar 

  55. Ceresoli GL, Cappuzzo F, Gregorc V, et al. (2004) Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 15:1042–1047

    Article  PubMed  CAS  Google Scholar 

  56. Abrey LE, Wen P, Govindan R, et al. (2008) Patupilone for the treatment of recurrent/progressive brain metastases in patients (pts) with non-small cell lung cancer (NSCLC): an open-label phase II study. J Clin Oncol (Meeting Abstracts) 26: 2033

    Google Scholar 

  57. Robinet G, Thomas P, Breton JL, et al. (2001) Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) Protocol 95-1. Ann Oncol 12: 59–67

    Article  PubMed  CAS  Google Scholar 

  58. Guerrieri M, Wong K, Ryan G, et al. (2004) A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lung. Lung Cancer 46:107–111

    Article  PubMed  Google Scholar 

  59. Cortot AB, Geriniere L, Robinet G, et al. (2006) Phase II trial of temozolomide and cisplatin followed by whole brain radiotherapy in non-small-cell lung cancer patients with brain metastases: a GLOT-GFPC study. Ann Oncol 17:1412–1417

    Article  PubMed  CAS  Google Scholar 

  60. Addeo R, De Rosa C, Faiola V, et al. (2008) Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases. Cancer 113:2524–2531

    Article  PubMed  CAS  Google Scholar 

  61. Jacquillat C, Khayat D, Banzet P, et al. (1990) Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases. Cancer 66:1873–1878

    Article  PubMed  CAS  Google Scholar 

  62. Mornex F, Thomas L, Mohr P, et al. (2003) A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Melanoma Res 13:97–103

    Article  PubMed  CAS  Google Scholar 

  63. Agarwala SS, Kirkwood JM, Gore M, et al. (2004) Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 22:2101–2107

    Article  PubMed  CAS  Google Scholar 

  64. Schadendorf D, Hauschild A, Ugurel S, et al. (2006) Dose-intensified bi-weekly temozolomide in patients with asymptomatic brain metastases from malignant melanoma: a phase II DeCOG/ADO study. Ann Oncol 17:1592–1597

    Article  PubMed  CAS  Google Scholar 

  65. Margolin K, Atkins B, Thompson A, et al. (2002) Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. J Cancer Res Clin Oncol 128:214–218

    Article  PubMed  CAS  Google Scholar 

  66. Danson S, Lorigan P, Arance A, et al. (2003) Randomized phase II study of temozolomide given every 8 hours or daily with either interferon alfa-2b or thalidomide in metastatic malignant melanoma. J Clin Oncol 21:2551–2557

    Article  PubMed  CAS  Google Scholar 

  67. Hwu WJ, Panageas KS, Menell JH, et al. (2006) Phase II study of temozolomide plus pegylated interferon-alpha-2b for metastatic melanoma. Cancer 106:2445–2451

    Article  PubMed  CAS  Google Scholar 

  68. Larkin JM, Hughes SA, Beirne DA, et al. (2007) A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma. Br J Cancer 96:44–48

    Article  PubMed  CAS  Google Scholar 

  69. Hwu WJ, Lis E, Menell JH, et al. (2005) Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study. Cancer 103:2590–2597

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neuro-Oncology, Unit 431, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA

    Tobias Walbert & Mark R. Gilbert

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  1. Tobias Walbert
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  2. Mark R. Gilbert
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Correspondence to Mark R. Gilbert.

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Walbert, T., Gilbert, M.R. The role of chemotherapy in the treatment of patients with brain metastases from solid tumors. Int J Clin Oncol 14, 299–306 (2009). https://doi.org/10.1007/s10147-009-0916-1

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