Clinical Review

Role of Radiosurgery in the Treatment of Brain Metastasis

Craniotomy and stereotactic radiosurgery seem to be similarly effective and appropriate choices for the treatment of patients with favorable prognostic factors and limited brain metastases.

Fed Pract. 2015 October;32(10):32-37

Author(s):

Hong W. Chin, MD, PhD

Gregory Rasp, MD

Jyung Kim, MD

E. Ronald Hale

PDF Download

References

1. Limbrick DD Jr, Lusis EA, Chicoine MR, et al. Combined surgical resection and stereotactic radiosurgery for treatment of cerebral metastases. Surg Neurol. 2009;71(3):280-288.

2. 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.

3. Schöggl A, Kitz K, Reddy M, et al. Defining the role of stereotactic radiosurgery versus microsurgery in the treatment of single brain metastases. Acta Neurochir (Wien). 2000;142(6):621-626.

4. O’Neill BP, Iturria NJ, Link MJ, Pollock BE, Ballman KV, O’Fallon JR. A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys. 2003;55(5):1169-1176.

5. Stafinski T, Jhangri GS, Yan E, Manon D. Effectiveness of stereotactic radiosurgery alone or in combination with whole brain radiotherapy compared to conventional surgery and/or whole brain radiotherapy for the treatment of one or more brain metastases: a systematic review and meta-analysis. Cancer Treat Rev. 2006;32(3):203-213.

6. Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys. 1999;45(2):427-434.

7. 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.

8. Jawahar A, Shaya M, Campbell P, et al. Role of stereotactic radiosurgery as a primary treatment option in the management of newly diagnosed multiple (3-6) intracranial metastases. Surg Neurol. 2005;64(3):207-212.

9. Hasegawa T, Kondziolka D, Flickinger JC, Germanwala A, Lunsford LD. Brain metastases treated with radiosurgery alone: an alternative to whole brain radiotherapy? Neurosurgery. 2003;52(6):1318-1326.

10. Rades D, Kueter JD, Hornung D, et al. Comparison of stereotactic radiosurgery (SRS) alone and whole brain radiotherapy (WBRT) plus a stereotactic boost (WBRT+SRS) for one to three brain metastases. Strahlenther Onkol. 2008;184(12):655-662.

11. 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.

12. Chidel MA, Suh JH, Reddy CA, Chao ST, Lundbeck MF, Barnett GH. Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases. Int J Radiat Oncol Biol Phys. 2000;47(4):993-999.

13. Sneed PK, Lamborn KR, Forstner JM, et al. Radiosurgery for brain metastases: is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys. 1999;43(3):549-558.

14. Noel G, Medioni J, Valery CA, et al. Three irradiation treatment options including radiosurgery for brain metastases from primary lung cancer. Lung Cancer. 2003;41(3):333-343.

15. Hoffman R, Sneed PK, McDermott MW, et al. Radiosurgery for brain metastases from primary lung carcinoma. Cancer J. 2001;7(2):121-131.

16. Rades D, Bohlen G, Pluemer A, et al. Stereotactic radiosurgery alone versus resection plus whole brain radiotherapy for 1 or 2 brain metastases in recursive partitioning analysis class 1 and 2 patients. Cancer. 2007;109(12):2515-2521.

17. Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):655-661.

18. Twelves CJ, Souhami RL, Harper PG, et al. The response of cerebral metastases in small cell lung cancer to systemic chemotherapy. Br J Cancer. 1990;61(1):147-150.

19. Tanaka H, Takifuj N, Masuda N, et al. [Systemic chemotherapy for brain metastases from small-cell lung cancer]. Nihon Kyobu Shikkan Gakkai Zasshi. 1993;31(4):492-497. Japanese.

20. Lee JS, Murphy WK, Glisson BS, Dhingra HM, Holoye PY, Hong WK. Primary chemotherapy of brain metastasis in small-cell lung cancer. J Clin Oncol. 1989;7(7):216-222.

21. 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 Organisation for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol. 2000;18(19):3400-3408.

22. Cortes J, Rodriguez J, Aramendia JM, et al. Frontline paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology. 2003;64(1):28-35.

23. Minotti V, Crinò L, Meacci ML, et al. Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer. Lung Cancer. 1998;20(2):23-28.

24. Fujita A, Fukuoka S, Takabatake H, Tagaki S, Sekine K. Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patient with brain metastases from non-small cell lung cancer. Oncology. 2000;59(4):291-295.

25. Robinet G, Thomas R, Breton JL, et al. 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 Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol. 2001;12(1):29-67.

26. Kiricuta IC, Kölbl O, Willner J, Bohndorf W. Central nervous system metastases in breast cancer. J Cancer Res Clin Oncol. 1992;118(7):542-546.

27. Berghoff AS, Bago-Horvath Z, Dubsky P, et al. Impact of HER-2-targeted therapy on overall survival in patients with HER-2 positive metastatic breast cancer. Breast J. 2013;19(2):149-155.

28. Park IH, Ro J, Lee KS, Nam BH, Kwon Y, Shin KH. Truastzumab treatment beyond brain progression in HER2-positive metastatic breast cancer. Ann Oncol. 2009;20(1):56-62.

Since the 1980s, patients with a single intracranial metastatic lesion traditionally have been treated with surgery followed by whole brain radiation therapy (WBRT). However, there is growing concern about the debilitating cognitive effects associated with WBRT in long-term survivors.

Limbrick and colleagues studied the outcomes of surgery followed by stereotactic radiosurgery (SRS) instead of WBRT and found that the less invasive surgical resection (SR) followed by SRS was an equally effective therapeutic option for the treatment of patients with limited metastatic disease to the brain.¹ Median overall survival (OS) was 20 months and was  22 and 13 months for Classes 1 and 2 recursive partitioning analysis (RPA) patients, respectively. Recursive partitioning analysis refers to 3 prognostic classes based on a database of  3 trial studies and 1,200 patients (Table 1).² According to RPA, the best survival was observed in Class 1 patients, and the worst survival was seen in Class 3 patients. Limbrick and colleagues found that survival outcome was equivalent to or greater than that reported by other studies using surgery plus WBRT or SRS plus WBRT.¹ The WBRT was not used and was reserved as salvage therapy in cases of initial failure such as disease progression of brain metastasis.

Radiation Therapies

Stereotactic radiosurgery is not a surgical procedure but a newly developed radiotherapy technique. It is a highly precise, intensive form of radiation therapy, focused on the tumor, with the goal of protecting the surrounding normal brain tissue as much as possible. Radiosurgery was initially introduced with the Gamma Knife by Lars Leksell several decades ago in order to deliver an intense radiation dose to a small, well-defined, single focal point using extreme precision. Stereotactic radiosurgery delivers efficient and focused radiation treatment to the tumor lesion.

There are 2 practical and commercially available radiation delivery systems for SRS: linear accelerator (LINAC)-based radiosurgery and Gamma Knife systems. Use of the Gamma Knife is limited largely to treatment of central nervous system (CNS) malignancies and certain head and neck cancers. Linear  accelerator-based SRS is applicable to neoplasms in any organ system of the body (Table 2).

Proton therapy is yet another evolving and completely different mode of radiation therapy. There are currently 14 proton therapy centers in operation in the U.S., and 11 more centers are now under construction. Proton therapy uses charged heavy-particle therapy using proton beams, whereas conventional LINAC-based radiotherapy is X-ray radiotherapy, which uses high energy photon beams. Because of their relatively large mass, protons have little scatter of radiation to surrounding normal structures and can remain sharply focused on the tumor lesion. Accordingly, proton therapy delivers negligible radiation doses beyond tumor lesions, and much of the surrounding normal tissues can be saved from excessive and unnecessary radiation doses.

A single proton beam produces a narrow Bragg peak dose distribution at depth, and multiple consecutive stepwise series of different energies of proton beams are needed to administer complete coverage of the target tumor volume. The accumulation of these beam energies produces a uniform radiation dose distribution covering the entire tumor volume (Figure 1). In spite of the theoretical beneficial effects of proton beam therapy, more clinical experience is needed for it to be validated. Even then, the significantly higher costs of proton therapy represent another barrier to its wider implementation. Proton beam radiosurgery is still, in large part, an evolving technology, not widely and uniformly available.

Role of Radiosurgery

Photon (X-ray)-based radiosurgery can be an alternative to craniotomy. Patients can return to their activities immediately after treatment. The ideal candidate for radiosurgery should have a small tumor (1-3 cm is best) with a well-defined margin. Retrospective studies reported no significant difference in therapy outcomes between the 2 therapies.^3,4 Additional benefits of radiosurgery include low morbidity and mortality. Furthermore, radiosurgery can be applied to tumors near critical structures, such as the thalamus, basal ganglia, and brainstem, that are otherwise surgically inaccessible.

Most brain metastases are well defined and spherical, so they are ideally treated using SRS (Figure 1). Additionally, the brain is encased in the bony skull, which prevents significant intrafraction motion and provides a reproducible fidulial for accurate setup. Radiosurgery can tailor the radiation dose in order to precisely concentrate radiation distribution to the tumor lesion with a rapid dose falloff beyond the margin of the tumor bed, so surrounding normal brain tissues are spared from high-dose radiation. In sharp contrast, WBRT indiscriminately irradiates the entire brain without sparing the adjacent normal brain tissue (Figure 2). However, because of its limited dose distribution, radiosurgery offers no protection elsewhere in the brain from future metastasis, which is a benefit of whole brain radiation.