ONCOLOGY.
No. 4
REVIEW ARTICLE
Innovation in the Management of Brain Metastases
By Ravi D. Rao, MD, Paul D. Brown, MD, Jan C. Buckner, MD |
April 1, 2007
1Assistant Professor, Department of Oncology 2Associate Professor,
Department of Radiation Oncology 3Professor, Department of Oncology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
The role of systemically delivered therapies for the treatment of brain metastases is still a matter for investigation. Due to concerns about the penetration of chemotherapeutic agents into the brain, this topic has not received much attention in the clinical research arena. However, the available literature suggests that brain metastases from melanoma, lung, and breast cancers appear to respond to chemotherapy.[37-39] Anecdotal responses of brain metastases from breast cancer to hormonal therapies have been reported.[40] Recently, investigators have reported on brain metastases from non-small-cell lung cancer responding to orally administered inhibitors of epidermal growth factor receptor (EGFR).[41,42] These observations have been confirmed by the authors' clinical experience. Likewise, preliminary data suggest that brain metastases from HER2/neu-positive breast cancers may respond to lapatinib ditosylate (Tykerb), an oral inhibitor of HER2/neu and EGFR.[43] While such data are preliminary, they raise the possibility of using such signal-transduction inhibitors in selected situations to specifically treat brain metastases in the future.
Overall, since the response rates of brain metastases to systemically delivered therapies are low, radiation and neurosurgery continue to be the mainstays of therapy for brain metastases. At the same time, systemic modalities (eg, chemotherapy, hormonal therapy) are an essential part of the overall treatment plan for a patient with systemic (ie, extracranial) metastases, as the ability to control the growth of systemic metastases is a sine qua non for optimal long-term outcomes.
The morbidity and mortality of patients with brain metastases depend to a significant degree on the response of the metastasis to therapy. Therefore, methods to increase response to radiation have the potential to improve outcomes in this patient population. Several modalities (mostly radiation sensitizers) have been tested as adjuncts to WBRT, but most of these studies have been negative.[44,45] Three agents that have been tested for this indication are efaproxiral (RSR-13), temozolomide(Drug information on temozolomide) (Temodar), and motexafin gadolinium (Xcytrin).
• Efaproxiral—Efaproxiral is a novel agent that binds to, and modifies, the structure of the hemoglobin molecule, reducing its oxygen-carrying capacity. The effect of this interaction is an increase in oxygen delivery to tissues. The use of efaproxiral as a radiation sensitizer is based on the rationale that increased tissue oxygen delivery would result in increased oxygen radical production induced by radiation, thereby enhancing the effects of this modality.
Preliminary clinical trials suggested safety and possible efficacy of efaproxiral when the agent is used concurrently with radiation to treat brain metastases. These data led to a phase III clinical trial in patients receiving WBRT, with half the patients randomized to efaproxiral therapy.[21] Patients treated with efaproxiral had a higher rate of response to radiation; however, this did not translate into a survival benefit. Subset analysis revealed that patients with breast cancer and those who were able to tolerate higher doses of the drug appeared to benefit with higher response rates and prolongation of survival.[21,46] Further studies with this agent are planned in patients with brain metastases from breast cancer.
• Temozolomide—Temozolomide is an orally available alkylating agent that is lipid soluble, and hence, penetrates the blood-brain barrier readily. Temozolomide therapy has been associated with a low rate of response in brain metastases (of different histologies) even when used as a single agent.[47] The combination of temozolomide and radiation has been shown to be synergistic, which has led to several trials using this combination. In some of these trials, a small benefit (in response rates) was noted for the combination of temozolomide with WBRT, compared to WBRT alone.[20,48,49] A problem common to all these trials has been that, primarily due to the progression of systemic metastases, improvements in response rates in the brain do not translate into better survival. Further studies using this drug in combination with radiation are ongoing.[50,51]
• Motexafin Gadolinium—Gadolinium texaphyrin or motexafin gadolinium is an agent that localizes to cells with a high rate of metabolism (as in cancer cells), and interferes with cellular respiratory pathways, resulting in the production of oxygen radicals, oxidative damage, and apoptosis. Based on data that suggested potential synergism with radiation, this drug has been evaluated as an adjuvant radiosensitizer.
Early clinical trials suggested a very high rate of response to WBRT (> 70%) when motexafin gadolinium was concurrently administered.[52] This prompted a phase III randomized controlled trial of WBRT with or without motexafin gadolinium in patients with multiple brain metastases.[5] In this trial, motexafin gadolinium did not improve response rates or overall survival. However, the subset of patients with lung cancer had a longer duration of response[5] and better neurocognitive outcome with motexafin gadolinium therapy.[23]
In a subsequent phase III study, half of the patients receiving WBRT for therapy of brain metastases from non-small-cell lung cancer were randomly assigned to treatment with motexafin gadolinium. The primary endpoint (time to neurologic progression) was similar in both groups.[53] On post hoc analysis, patients in whom WBRT was initiated within 3 weeks of initial diagnosis appeared to benefit, but no benefit was noted in patients starting therapy later.[53] Additional studies are planned to test the benefit of this agent in selected situations.[54]
The modalities used to diagnose, treat, and monitor the effects of therapy (eg MRI scans, neurosurgery, radiation) are expensive. In addition, patients with brain metastases are usually ill with a multitude of physical complaints and require a significant amount of medical care. Thus, optimal care of these patients can cause a significant financial burden on health-care systems.
An understanding of the cost-benefit ratio of different modalities is necessary for optimal utilization of scarce medical resources. Surprisingly little research has been done to analyze the cost-effectiveness or cost-utility of various therapies. One such analysis that analyzed the costs for patients undergoing therapy for a single brain metastasis (published in 1997) concluded that the cost for each additional year of survival was $27,000 when radiation and surgery were used together and only $16,000 if radiation was used as the sole therapy.[55]
Subsequent to the publication of this study, stereotactic radiation therapy—an expensive technology—has become an increasingly available (and used) modality for these patients. In addition, as noted above, several novel agents have been used as adjuncts to increase tumor response rates. These modalities and drugs (eg, temozolomide, which costs around $2/mg), while adding significantly to the cost (and possibly to the toxicity) of therapy, appear to result in only minor improvements in outcomes. Whether such expenditure is justified for what is essentially palliative therapy in a usually ill patient population needs to be evaluated on a case-by-case -basis. Widespread adoption of these expensive drugs and technologies should await the conclusion of properly conducted randomized trials, where their exact benefits can be evaluated.
The diagnosis of brain metastases is a serious, often preterminal, complication of cancer. Properly selected patients with brain metastases (ie, younger patients with a good performance status and well controlled/minimal extracranial metastases) have good outcomes with appropriate therapy. Patients often present with significant neurologic sequelae and require supportive care measures to manage these problems. Definitive therapy of brain metastases requires an assessment of each patient's prognostic factors, and decision-making after a thorough informed discussion.
Patients with multiple brain metastases need to be treated with WBRT. The concurrent use of adjuvant drugs for radiation sensitization should be considered experimental. Patients with solitary or limited number of metastases benefit from local therapy (surgery or SRS) to be followed by WBRT in most cases. Data from recent studies suggest that surgery and SRS result in equivalent rates of local control. Moreover, in those with a limited number of brain metastases (usually four or less) who may be candidates for SRS therapy, WBRT may be omitted with the proviso that patients need to be rigorously monitored for recurrent disease. Enrollment into ongoing clinical trials that evaluate the role of SRS and WBRT in specific patient subsets should be encouraged. Systemic therapy for metastatic cancer needs to be offered, if available, as the status of systemic metastases is one of the most important determinants of long-term outcomes.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Markesbery WR, Brooks WH, Gupta GD, et al: Treatment for patients with cerebral metastases. Arch Neurol 35:754-756, 1978.
2. Johnson JD, Young B: Demographics of brain metastasis. Neurosurg Clin N Am 7:337-344, 1996.
3. Posner JB, Chernik NL: Intracranial metastases from systemic cancer. Adv Neurol 19:579-592, 1978.
4. Barnholtz-Sloan JS, Sloan AE, Davis FG, et al: Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 22:2865-2872, 2004.
5. Mehta MP, Rodrigus P, Terhaard CH, et al: Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 21:2529-2536, 2003.
6. 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 322:494-500, 1990.
7. Hollender A, Kvaloy S, Nome O, et al: Central nervous system involvement following diagnosis of non-Hodgkin's lymphoma: A risk model. Ann Oncol 13:1099-1107, 2002.
8. Andre F, Cabioglu N, Assi H, et al: Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer. Ann Oncol 17:945-951, 2006.
9. Gaspar LE, Scott C, Murray K, et al: Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 47:1001-1006, 2000.
10. Lagerwaard FJ, Levendag PC, Nowak PJ, et al: Identification of prognostic factors in patients with brain metastases: A review of 1292 patients. Int J Radiat Oncol Biol Phys 43:795-803, 1999.
11. Patchell RA, Tibbs PA, Regine WF, et al: Postoperative radiotherapy in the treatment of single metastases to the brain: A randomized trial. JAMA 280:1485-1489, 1998.
12. Lutterbach J, Bartelt S, Ostertag C: Long-term survival in patients with brain metastases. J Cancer Res Clin Oncol 128:417-425, 2002.
13. Kondziolka D, Martin JJ, Flickinger JC, et al: Long-term survivors after gamma knife radiosurgery for brain metastases. Cancer 104:2784-2791, 2005.
14. Hall WA, Djalilian HR, Nussbaum ES, et al: Long-term survival with metastatic cancer to the brain. Med Oncol 17:279-286, 2000.
15. Pollock BE, Brown PD, Foote RL, et al: Properly selected patients with multiple brain metastases may benefit from aggressive treatment of their intracranial disease. J Neurooncol 61:73-80, 2003.
16. Andersen C, Astrup J, Gyldensted C: Quantitative MR analysis of glucocorticoid effects on peritumoral edema associated with intracranial meningiomas and metastases. J Comput Assist Tomogr 18:509-518, 1994.
17. Horton J, Baxter DH, Olson KB: The management of metastases to the brain by irradiation and corticosteroids. Am J Roentgenol Radium Ther Nucl Med 111:334-336, 1971.
18. 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 54:1886-1893, 2000.
19. Tsao M, Lloyd N, Wong R, et al: Whole brain radiotherapy for the treatment of multiple brain metastases. Cochrane Database Syst Rev 3:CD003869, 2006/
20. 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 20:3644-3650, 2002.
21. Suh JH, Stea B, Nabid A, et al: Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol 24:106-114, 2006.
22. Laack NN, Brown PD: Cognitive sequelae of brain radiation in adults. Semin Oncol 31:702-713, 2004.
23. Meyers CA, Smith JA, Bezjak A, 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. J Clin Oncol 22:157-165, 2004.
24. Li J, Bentzen SM, Renschler M, et al: Improvement in neurocognitive function (NCF) correlates with tumor regression after whole brain radiation therapy (WBRT) for brain metastases (abstract 1504). J Clin Oncol 24(18S):59s, 2006.
25. DeAngelis LM, Delattre JY, Posner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 39:789-796, 1989.
26. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al: Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery? Ann Neurol 33:583-590, 1993.
27. 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 78:1470-1476, 1996.
28. Mehta MP, Tsao MN, Whelan TJ, et al: The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 63:37-46, 2005.
29. Muacevic A, Wowra B, Kreth F, et al: A randomized trial of surgery and radiotherapy versus radiosurgery alone in the treatment of single metastasis to the brain. Doc OP256, Deutscher Krebskongress. Berlin, Deutscher Krebskongress, 2006.
30. Bindal AK, Bindal RK, Hess KR, et al: Surgery versus radiosurgery in the treatment of brain metastasis. J Neurosurg 84:748-754, 1996.
31. O'Neill BP, Iturria NJ, Link MJ, et al: A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys 55:1169-1176, 2003.
32. Kondziolka D, Patel A, Lunsford LD, et al: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45:427-434, 1999.
33. 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 363:1665-1672, 2004.
34. Phase III randomized study of stereotactic radiosurgery with versus without whole-brain radiotherapy in patients with cerebral metastases. Available at www.cancer.gov/clinicaltrials/NCCTG-N0574. Accessed February 27, 2007.
35. Sneed PK, Suh JH, Goetsch SJ, et al: A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 53:519-526, 2002.
36. 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 295:2483-2491, 2006.
37. Postmus PE, Haaxma-Reiche H, Smit EF, 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. J Clin Oncol 18:3400-3408, 2000.
38. Dvorak J, Melichar B, Zizka J, et al: Complete response of multiple melanoma brain metastases after treatment with temozolomide. Onkologie 27:171-174, 2004.
39. Seute T, Leffers P, Wilmink JT, et al: Response of asymptomatic brain metastases from small-cell lung cancer to systemic first-line chemotherapy. J Clin Oncol 24:2079-2083, 2006.
40. van der Gaast A, Alexieva-Figusch J, Vecht C, et al: Complete remission of a brain metastasis to third-line hormonal treatment with megestrol acetate. Am J Clin Oncol 13:507-509, 1990.
41. Lee DH, Han JY, Lee HG, et al: Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers. Clin Cancer Res 11:3032-3037, 2005.
42. Lai CS, Boshoff C, Falzon M, et al: Complete response to erlotinib treatment in brain metastases from recurrent NSCLC. Thorax 61:91, 2006.
43. Lin NU, Carey LA, Liu MC, et al: Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer (abstract 503). J Clin Oncol 24(18S):3s, 2006.
44. Komarnicky LT, Phillips TL, Martz K, 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). Int J Radiat Oncol Biol Phys 20:53-58, 1991.
45. Stewart DJ, Eapen L, Girard A, et al: Phase II study of lonidamine plus radiotherapy in the treatment of brain metastases. J Neurooncol 15:19-22, 1993.
46. Stea B, Suh JH, Boyd AP, et al: Whole-brain radiotherapy with or without efaproxiral for the treatment of brain metastases: Determinants of response and its prognostic value for subsequent survival. Int J Radiat Oncol Biol Phys 64:1023-1030, 2006.
47. Agarwala SS, Kirkwood JM, Gore M, et al: Temozolomide for the treatment of brain metastases associated with metastatic melanoma: A phase II study. J Clin Oncol 22:2101-2107, 2004.
48. Hofmann M, Kiecker F, Wurm R, et al: Temozolomide with or without radiotherapy in melanoma with unresectable brain metastases. J Neurooncol 76:59-64, 2006.
49. Verger E, Gil M, Yaya R, et al: Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: A phase II randomized trial. Int J Radiat Oncol Biol Phys 61:185-191, 2005.
50. Phase III randomized study of whole brain radiotherapy and stereotactic radiosurgery with versus without temozolomide or erlotinib in patients with non-small cell lung cancer and brain metastases. Available at www.cancer.gov/searchViewClinicalTrials.aspx?cdrid=389490 &version=HealthProfessional&protocolsearchid= 2651396. Accessed February 27, 2007.
51. Comparison study of WBRT and SRS alone versus with temozolomide or erlotinib in patients with brain metastases of NSCLC. Available at www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=463553&version= HealthProfessional&protocolsearchid=2651396. Accessed February 27, 2007.
52. Mehta MP, Shapiro WR, Glantz MJ, 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. J Clin Oncol 20:3445-3453, 2002.
53. Mehta MP, Gervais R, Chabot P, et al: Motexafin gadolinium (MGd) combined with prompt whole brain radiation therapy (RT) prolongs time to neurologic progression in non-small cell lung cancer (NSCLC) patients with brain metastases: Results of a phase III trial (abstract 7014). J Clin Oncol 24(18S):367s, 2006.
54. Study of motexafin gadolinium with whole brain radiation therapy followed by stereotactic radiosurgery boost in the treatment of patients with brain metastases. Available at www.cancer.gov/search/ViewClinicalTrials. aspx?cdrid=441282&version=HealthProfessional &protocolsearchid=2651398. Accessed February 27, 2007.
55. Mehta M, Noyes W, Craig B, et al: A cost-effectiveness and cost-utility analysis of radiosurgery vs resection for single-brain metastases. Int J Radiat Oncol Biol Phys 39:445-454, 1997.
