A Review of Stereotactic Radiosurgery in the Management of Brain Metastases

Transcription

1 Technology in Cancer Research & Treatment /SSN / \kllume 2. Number 2. April (2003) Adenine Press (2003) A Review of Stereotactic Radiosurgery in the Management of Brain Metastases Paul W. Sperduto, M.D. Methodist Hospital Minneapolis. Minnesota This review addresses the epidemiology, historical reports, current issues, data and controversies involved in the management of brain metastases. The literature regarding surgery, whole brain radiation therapy, stereotactic radiosurgery or some combination of those treatments is discussed as well as issues of cost-effectiveness. Ongoing prospective randomized trials will further elucidate the optimal management for patients with brain metastases. Until those data are available, clinicians are encouraged to apply the existing data reviewed here in conjunction with best clinical judgment. A brief clinical guide is as follows. Patients with a solitary metastasis in an operable location and symptomatic mass effect should undergo surgery. Patients with poor performance status (KPS < 70) or more than three brain metastases should receive WBRT alone. Patients with 1-3 brain metastases and KPS ~ 70, should receive WBRT + SRS. If the patient refuses WBRT or needs salvage after WBRT, then SRS alone is appropriate. Clinicians should not be too dogmatic and should always apply the best clinical judgment. Key words: stereotactic radiosurgery, radiation therapy, brain metastases Introduction Metastases to the brain are the most common malignancy affecting the brain (1-3). Autopsy series have shown that as many as 25% of patients who die of cancer will have intracranial metastases. involving brain parenchyma in about 15% (3. 4). The majority of patients with intraparenchymal metastases have only one or two or three metastases. 49%. 21%. and 10%. respectively. and the remaining 20% have more than three. Approximately 80% of brain metastases are located supratentorially (5). Historically. the standard treatment for patients with brain metastases has been glucocorticoids and whole brain irradiation (WBRT) which effectively relieve symptoms and restore neurological function in most patients (3). Untreated patients have a median survival time (MST) of less than 7 weeks (6). Three prospective randomized trials involving more than 1800 patients conducted by the Radiation Therapy Oncology Group (RTOG) evaluated 9 different radiation doses and schedules (7). All doses up to 50 Gray (Gy) were equivalent with respect to toxicity. neurological improvement. and survival. Higher doses resulted in greater neurologic toxicity. Median survival time (MST) of all patient subgroups were three to six months. Little difference was found between patients who received 20 Gy administered over one week and 40 Gy administered over four weeks. Furthermore. radiation boost treatment to the metastatic site did not improve these parameters when compared to WBRT (8). Detailed quality of life measurement tools were not part of these studies. * Corresponding Author: Paul W. Sperduto, M.D. psperduto@mropa.com 105

2 106 Sperduto The most common cancers to metastasize to brain are lung and breast, 34 and 30%, respectively. Of the approximately 200,000 patients with these malignancies who will die each year, 124,000 will have brain metastases (9). The cause of death in almost 30-50% is persistence oflesions or recurrence following WBRT; however, 10 to 15% of patients will survive at least one year (9, 10). These data, along with the fact that brain metastases are so frequently three or fewer, provide the rationale for the development of treatment modalities that exceed current palliative measures to actually improve patient survival, neurocognitive function and/or quality-of-life. Review ofthe Surgery Literature There is extensive literature on the surgical management of brain metastases. The salient literature can be briefly summarized as follows. Surgical resection of solitary brain metastases is increasingly performed on patients with favorable prognostic factors, accessible lesion(s), and/or metastatic lesions from relatively radio-insensitive tumors such as renal cell carcinoma and melanoma (8, 11-16). Since metastases are usually well demarcated from surrounding brain, complete removal with a minimum of morbidity and mortality is often possible. Relief of symptoms of intracranial hypertension and focal brain dysfunction has been demonstrated. Patient survival is also dependent on the extent of extracranial disease. Resection preceding WBRT appears to improve survival compared to WBRT alone. Two prospective randomized trials in which surgical excision followed by radiation therapy compared to radiation therapy alone in patients with single metastases have been done (17, 18). Patchell and colleagues randomized patients with single metastases to either surgical excision followed by WBRT (25 pts) or biopsy followed by WBRT (23 pts). In this study, the MST (40 vs. 21 weeks), the duration of functional independence (38 vs. 8 weeks), and the rate of intracranial recurrence (20% vs. 52%) were improved with surgery and WBRT compared to WBRT alone. These results confirmed those ofearlier uncontrolled studies showing the benefits ofsurgical resection (13, 19). Vecht et a/. randomized 63 patients to the same regimens with similar results (18). Bindal et a/., in a retrospective analysis of 56 patients with multiple resected metastases, 50% of whom received WBRT, reported a MST equivalent to that of patients with a single resected metastasis but longer than that of patients who had one or more lesions remaining after surgery (9). Based on these reports, surgical removal in patients with a solitary accessible lesion followed by WBRT appears superior to WBRT alone for selected patients. The post-operative delivery of WBRT for such patients has been considered beneficial to sterilize residual disease in the tumor bed or other sites of occult disease in the brain. For patients who have undergone removal of solitary brain metastases, the addition of WBRT appears to result in a lower inci- denee of brain recurrence. The University of Kentucky randomized patients with single brain metastases to surgery alone (46 patients), or surgery followed by WBRT (49 patients) (20). Although MST and functional independence survival times of the two groups were similar, local recurrence occurred in 46 and 10%, respectively with distant recurrence 37 and 14%. Death due to neurologic disease was 44% and 14%. There are several retrospective studies involving relatively small numbers of patients in which surgery followed by WBRT has been compared to surgery alone (4, 21, 22). Smalley and colleagues demonstrated a statistically significant benefit in survival and fewer recurrences in 85 patients who received WBRT following surgery (23). In a second retrospective analysis by the same investigators, the MST among 229 patients was 15 months for those who underwent surgery followed by adjuvant WBRT as compared to 8 months for patients who underwent surgery but did not receive WBRT (24). On the other hand, Hagan et al. found no advantage to WBRT following surgery in patients with melanoma, a radioresistant tumor (22). Likewise, Dosoretz et a/. found no survival advantage to low dose WBRT among 33 patients with resected solitary lesions and no active systemic cancer (21). Review ofthe Stereotactic Radiosurgery Literature There is extensive literature suggesting stereotactic radiosurgery is as good or better than surgical resection in terms of local control and is noninvasive and more cost-effective (25, 26). Over a decade of reports have suggested a role for stereotactic radiosurgery (SRS) in the treatment of metastatic brain tumor (27-39). The development of linear accelerators modified to deliver focused irradiation has expanded the availability of SRS (40-42). Advantages of SRS are ease of administration from the patient's viewpoint (a one-day noninvasive treatment usually performed as an outpatient), the ability to treat metastases located in areas of the brain not amenable to complete surgical resection, the ability to treat multiple metastases in a single session (unlike craniotomy), the ability to treat microscopic projections beyond the visible tumor (in contrast to many surgical tools that may leave clonogens completely untreated at the margin of resection) and the potential to decrease neurosurgery and radiation related morbidity and mortality (21, 43-45). SRS allows delivery of a high dose of focal irradiation in a single fraction to the tumor from multiple angles (46). Brain metastases are ideal targets for SRS because the majority are small «3 em in diameter), most are spherical with distinct tumor margins on contrast enhanced imaging studies and most displace rather than infiltrate normal brain (40). SRS minimizes the amount of radiation received by the non-target regions of the brain, and the area targeted generally does not include functional brain (32, 42). Technology in Cancer Research & Treatment, Volume 2, Number 2, April2003

3 Radiosurgery for Brain Metastases 107 Retrospective analyses show that brain metastases from a large number of different types of malignancies including less radioresponsive malignancies such as colon cancer, renal cell carcinoma and melanoma respond to SRS (32, 35, 38, 46). Local control to complete radiographic obliteration has been achieved in 80 to 90% of cases (36, 39). Noordijk et al. treated 52 brain metastases in 33 patients with SRS (14). At 5.5 months follow up, 10 (29%) patients' metastatic lesions had completely disappeared, 15 (50%) had decreased in size and four had stable intracranial disease. Mehta et al. reported the results of a prospective trial in which patients with single brain metastasis were randomized to undergo surgical resection of the metastasis followed by SRS to the preoperative tumor margins and/or residual tumor or SRS alone (49). MST for patients who received surgery and SRS was 40 weeks compared to 15 weeks for patients who received SRS alone. There were fewer recurrences at the site of the original brain metastasis in patients who underwent surgery plus SRS compared to SRS alone, 20 vs 52%, respectively. The quality of life of patients in the former group was also markedly improved. Variables affecting response and complications include performance status, patient age and lesion size (30, 35, 44, 52). Review ofthe RTOG Radiosurgery Experience The RTOG has been at the forefront of clinical trials on the management of patients with brain metastases since the 1970s. In addition to the trials in the pre-radiosurgery era described in section 1.2, there is now a significant database in the radiosurgery era. The RTOG dose-escalation study (RTOG 9005) reported the maximum tolerated radiosurgery dose in patients with recurrent irradiated primary brain tumors and brain metastases (n=156) for lesions of <!=2.0cm, cm and cm in maximum diameter were 24Gy, 18Gy and 15Gy, respectively (51). Sanghavi et al, recently reported a retrospective multi-institutional recursive partitioning analysis (RPA) suggesting there was a significant survival benefit for patients treated with WBRT plus SRS when compared to an RTOG database of patients treated with WBRT alone and that this benefit existed in all three RPA classes (52). The RTOG RPA classes are defined as follows: Class I: patients with KPS ~ 70, age <65 with a controlled primary tumor and no extracranial metastases; Class III: KPS < 70; and Class II: all others (53). The RTOG has recently completed a prospective randomized trial (RTOG 9508) of WBRT versus WBRT plus SRS for patients with 1-3 brain metastases. WBRT plus SRS provided a survival advantage compared to WBRT alone in each of the following patient categories: i) solitary brain metastases (for which the study was stratified) and the following sub- sets; ii) 1-3 metastases and RPA class I; iii) 1-3 metastases and age < 50 years and; iv) 1-3 metastases and non-small cell lung cancer or any squamous carcinomas. Furthermore, all subsets of patients in the WBRT + SRS group were more likely to have a stable or improved performance status, improved local control and reduced steroid dependence compared to the WBRT alone group. Systemic disease remained the primary cause of death (> 2/3) in both groups. Toxicities and the rate of re-operation were comparable in the two groups. Re-operation pathology showed necrosis in all patients in the WBRT + SRS arm and viable tumor in all patients in the WBRT alone arm (44). Reviewofthe Debate about Whole Brain Radiation Therapy: Pro and Con Despite the wealth of literature referenced above, there remain conflicting data and opposing practice patterns are emerging regarding whether WBRT is beneficial or not when added to SRS. Several prominent institutions are treating selected patients with SRS alone. Pro: As previously discussed, in the Patchell trial in which patients with a single brain metastasis were randomized to surgery alone vs. surgery followed by WBRT. the patients in the WBRT group were less likely to die of neurologic causes than patients in the observation group (14% vs. 44%, P = 0.003). This is despite the fact that among the 70% of patients in the observation group who experienced a brain tumor recurrence, 88% received salvage WBRT either alone or in combination with surgery or SRS. A more recent report from the University of Kentucky shows that despite the use of high resolution treatment planning and every 3 month follow-up MRI in patients with newly diagnosed brain metastases, usc of SRS alone is associated with an increasing risk of brain recurrence with increasing survival time. In addition, the majority of such recurrences are symptomatic and associated with a neurologic deficit (54). Debate is burgeoning regarding whether the quality of life and neurocognitive function of these patients is optimized by the use of WBRT to better control the brain metastases or by avoiding the side effects of WBRT. The Kentucky data clearly would favor the use ofwbrt. Con: A recent report from UCSF by Sneed and associates (55) suggested that radiosurgery alone results in equivalent survival and intracranial control when compared to radiosurgery and WBRT for one to four metastases to brain. In this retrospective report 62 patients treated with radiosurgery alone were compared to 43 treated with both modalities. Survival was 11.3 and 11.1 months, respectively. Remote failure was higher in the radiosurgery group (72 vs. 31%), but high successful salvage resulted in intracranial control 62 and 73% (not significantly different), respectively. It should be noted that selection bias was acknowledged and evident Technoloav in Cancer Research & Treatment, Volume 2, Number2, April 2003

4 108 Sperduto as there was a statistically significant greater number of patients with solitary metastases in the SRS alone arm. The UCSF data, in fact, support the opposite conclusion, that WBRT + SRS is better because it brings a worse prognostic group (multiple metastases) up to the outcomes associated with the good prognostic group (solitary metastases). In other words, if SRS alone cannot achieve outcomes for good prognostic patients better than WBRT + SRS does for poor prognostic patients, then SRS alone is not better, but worse treatment. Furthermore, the WBRT + SRS is more costeffective because patients treated with SRS alone in the UCSF series received salvage SRS more than twice as commonlyas those treated with WBRT + SRS (40% vs 19%) and some patients received SRS more than twice. Clearly WBRT + SRS is more cost-effective than SRS twice. Summary Ongoing prospective randomized trials by the RTOG and ACOSOG will further elucidate the optimal management for patients with brain metastases. Until those data are available, clinicians are encouraged to apply the existing data reviewedhere in conjunction with best clinical judgment. In brief, patients with a solitary metastasis in an operable location and symptomatic mass effect should undergo surgery. Patients with poor performance status (KPS < 70) or more than three brain metastases should receive WBRT alone. For patients with 1-3 brain metastases and KPS ~ 70, should receive WBRT + SRS. Ifthe patient refuses WBRT or needs salvage after WBRT, then SRS alone is appropriate. Clinicians should not be too dogmatic and should always apply the best clinical judgment. References I. Cairncross, J. G. Posner. J. B. Neurological Complications of Systemic Cancer in Oncologic Emergencies. eds., Yarboro. J. W. Bomstein. R. S. Grune and Stratton. New York (1981). 2. Clouston, P. D. DeAngelis. L. M., Posner. J. B. The Spectrum of Neurological Disease in Patients with Systemic Cancer.Ann. Neurol. 3I (1992). 3. Posner. J. B. Chernik, N. L. Intracranial Metastases from Systemic Cancer. In: Advances in Neurology.ed. Bruce S. Schoenberg. Raven Press. New York. pp (1978). 4. Posner. J. B. Management of Brain Metastases. Rev. Neurol (1992). 5. Delattre, J. Y., Krol, G., Thaler. H. T. Posner. J. P. Distribution of Brain Metastases. Arch. Neurol (1988). 6. Cairncross, J. G. Kim. J. H. Posner. J. R. Radiation Therapy for Brain Metastases. Ann. Neurol (1980). 7. Borgelt, B. Gelber. R. Kramer. S., et al. The Palliation of Brain Metastases: Final Results of the First Two Studiesof by the Radiation Therapy Oncology Group. Int. J. Rad. Oncol. BioI. Phys. 6. I (1980). 8. Hoskins. P. J., Crow. J. Ford. H. T. The Influence of Extent and Local Management-on the Outcome of Radiotherapy for Brain Metastases. Int. J. Rad. Oneol. BioI. Phys (1990). 9. Bindal, A. K.. Bindal, R. K.. Hess. K. R. Shiu, A.. Hassenbusch, S. J. Shi, W. M. Sawaya. R. Surgery Versus Radiosurgery in the Treatment of Brain Metastasis. J. Neurosurg (1996). 10. DeAngelis, L. M.. Mandell. L. R. Thaler. T.. Kimmel. D. w.. Galicich, Fuks, Z.. Posner. J. P. The Role of Postoperative Radiotherapy After Resection of Single Brain Metastases. Neurosurgery (1989). II. Auchter. R. M. Lamond. J. P. Alexander.E. Buattti, J. M. Chappell. R. Friedman. W.A. Kinsella.T. J. Levin. A.. Noyes. W. R.. Schultz. e. J.. Loeffler. J. S.. Mehta. M. P. A Multiinstitutional Outcome and Prognostic Factor Analysis of Radiosurgery for Resectable Single Brain Metastasis.lnt1 Radiat Oncol Bioi Phys (1996). 12. Bindal,R. K.. Bindal,A. K.. Sawaya. R. Outcomeof SurgicalTherapy for Metastatic Cancer to the Brain. Adl~ Surg (1997). 13. Ferrara. M., Bizzozero, L.. Talamonti, G., D'Angelo. V.A. Surgical Treatment of 100 Single Brain Metastases: Analysis of the Results. J NeurosurgSci (1990). 14. Noordijk, E. M.. Vecht, C. J. Haaxrne-Reicbe, H.. et al. The Choice of Treatment of Single Brain Metastasis Should be Based on ExtracranialTumor Activity and Age. Int 1 Rad Oncol Bioi Pliys (1994). 15. Patchell. R. A. Posner. J. B. Neurologic Complications of Systemic Cancer. Neurologic Clinics (1985). 16. Sawaya. R. Ligon, B. L.. Bindal, A. K.. Bindal, R. K.. Hess. K. R. Surgical Treatment of Metastatic Brain Tumors. 1 Neurooncol 27, (1996). 17. Patchell, R. A. Tibbs, P. A. Walsh, J. W. Dempsey. R. J.. Maruyama. Y. Kryscio, R. J.. Markesbury,W. R. MacDonald. J. S.. Young.B. A RandomizedTrial of Surgery in the Treatment of Single Brain Metastases to the Brain. N. Eng. J. Med (1993). 18. Vecht, C. J. Haaxma-Reiche, H. Noordjik, E. M. Treatment of Single Brain Metastasis: Radiotherapy Alone or Combined with Neurosurgery?Ann. Neurol. 33, (1993). 19. Patchell. R. A.. Ciprincione, C. Thaler. H. T. et al. Single Brain Metastasis: Surgery Plus Radiation or Radiation Alone. Neurology (1986). 20. Patchell.R. A. TIbbs.P.A. Regine,W.E, Dempsey. R. J.. Mohiuddin, M. Kryscio, R. J. Markesbery. W. R., Foon, K. A. Young, B. Postoperative Radiotherapy in the Treatment of Single Metastases to the Brain:A Randomized Trial. lama (1998). 21. Dosoretz, D. E. Blizer, P. H. Russell. Wang. C. e. Management of Solitary Metastasis to the Brain: The Role of Elective Brain Irradiation Following Complete Surgical Resection. lilt 1 Rad Oncol BioI Phys (1980). 22. Hagan. N. Cirrincione, C. DeAngelis, L. M. The Role of Radiotherapy After Resection of Single Brain Metastases from Melanoma. Neurology (Supplement I) (1989). 23. Smalley. S. R. Laws. E. R.. O'Fallon, J. R. et al. Resection for Solitary BrainMetastasis: Role of Adjuvant Radiationand Prognostic Variables in 229 Patients. J Neurosurg (1992). 24. Smalley. S. R. Schray, M. E, Laws. E. R., O'Fallon, J. R. Adjuvant Radiation Therapy After Surgical Resection of Single Brain Metastasis: Association with Patterns of Failure and Survival. lnt 1 Rad Oncol BioI Phys (1991). 25. Sperduto. P. W. Hall. W. A. The Cost-effectiveness for Alternative Treatments for Single Brain Metastases. In: Radiosurgery. ed. Kondziolka, D. Basel. Karger. I (1996). 26. Rutigliano, M. J. Lundsford, L. D., Kondziolka, D. Strauss. M. J. Khanna. V., Green. M. The Cost Effectiveness of Stereotactic Radiosurgery VersusSurgical Resection in the Treatment of Solitary Metastic Brain Tumors. Neurosurgery (1995). 27. Adler. J. R., Cox. R. S. Kaplan, I.. Martin, D. P. Stereotactic Radiosurgical Treatment of Brain Metastases. J Neurosurg 76, (1992). Technology in CancerResearch & Treatment, Volume 2, Number2, April2003

5 Radiosurgery for Brain Metastases Alexander. E. Siddon, R. L.. Loeffler. 1. S. The Acute Onset of Nausea and Vomiting Following Stereotactic Radiosurgery: Correlation with Total Dose to Area Postrema. Surg. Neurol (1989). 29. Chidel, M. A., Suh. J. H., Greskovich, 1. E. Kupelian, P. A.. Barnett. G. H. Treatment Outcome for Patients with Primary Nonsmall-cell Lung Cancer and Synchronous Brain Metastasis. Radial Oncol lnvcstig 7, (1999). 30. Engenhart, R., Kimmig, B. N.. Hover, K. H.. Wora, 8.. Romahn, J., Lorenz, W., van Kaick, G., Wannenmacher, M. Long-term Followup for Brain Metastases Treated by Percutaneous Sterotactic Single High-dose Irradiation. Cancer 71, (1993). 31. Fuller, B. G., Kaplan, I. D. Adler. J., Cox, R. S.. Bagshaw. M. A. Stereotactic Radiosurgery for Brain Metastases: The Importance of Adjuvant Whole Brain Irradiation. Int J Rad Oneol BioI Phys (1992). 32. Kim. Y. S.. Kondziolka, D., Flickinger. J. C., Lunsford, L. D. Stereotactic Radiosurgery for Patients with Nonsmall Cell Lung Carcinoma Metastatic to the Brain. Cancer 80, (1997). 33. Kjellberg. R. N., Abe, M. Stereotactic Bragg Peak Proton Beam Therapy. In: Modern Stereotactic Neurosurgery. ed., Lundsford, L. D. Martinus Niihoff Publishers, Boston. MA. pp (1988). 34. Lavine. S. Do, Petrovich. Z., Cohen-Gadol, A. A. Masri. L. S. Morton, D. L.. O'Day, S. J. Essner. R., Zelman. V.. Yu, C., Luxton, G., Apuzzo. M. L. Gamma Knife Radiosurgery for Metastatic Melanoma: An Analysis of Survival, Outcome and Complications. Neurosurgery 44, (1999). 35. Loeffler, J. S., Alexander. E., III. Radiosurgery for the Treatment of Intracranial Metasases. In: Stereotactic Radiosurgery. eds.. E. Alexander, III. J. S. Loeffler. L. D. Lunsford. New York, McGraw Hill, (1993). 36. Loeffler, J. S., Kooy, H. Mo, Fine. H. A. Cheng, C. w.. Mannarino, E. G., Tsai, J. S. Alexander. E. III. The Treatment of Recurrent Brain Metastases with Stereotactic Radiosurgery. J. Clin. Oncol (1990). 37. Mehta. M., Noyes, W., Graig, B., Lamond, 1., Auchter, R., French, M., Johnson, M., Levin, A., Badie, B., Robbins, I., Kinsella, T. A Cost-effectiveness and Cost-utility Analysis of Radiosurgery vs. Resection for Single-brain Matastases. lnt, J. Radial. Oncol. BioI. Phys. 39, (\ 997). 38. Mehta, M. P. Radiosurgery for Brain Metastases In: Stereotactic Surgery and Radiosurgery. eds., Desallese, A. A. E. Goetsch. S. J. Medical Physics Publishing. Madison WI (1993). 39. Alexander, E. III, Loeffler, J. S. Radiosurgery using a Modified Linear Accelerator. Stereotactic Radiosurgery (1992). 40. Loeffler, 1. S., Siddon, R. L., Wen, P. Y., Nedzi, L. A.. Alexander, E. III. Stereotactic Radiosurgery of the Brain Using Standard Linear Accelerator: A Study of Early and Late Effects. Radiotherapy Oncol 17, (1990). 41. Philips. M. H., Stelzer, K. J. Griffin, T. W., Mayberg, M. R., Winn. R. Stereotactic Radiosurgery: A Review and Comparison of Methods. J Clin Oncol (1994). 42. DeAngclis, L. Mo, Delattre, J. Y., Posner. J. B. Radiation Induced Dementia in Patients Cured of Brain Metastases. Neurology 39, (1989). 43. Marks, L. B.. Spencer. D. P. The Influence of Volume on the Tolerance of the Brain to Radiosurgery. J Neurosurg (1991). 44. Sperduto. P. Wo, Scott, c.. Andrews, D.. Schell. M.. Werner-Wasik, M., Demas, W.. Ryu, J. K., Gaspar. L.. Curran. W. A Phase III Trial Comparing Whole Brain Irradiation Alone Versus Whole Brain Irradiation Plus Stereotactic Radiosurgery for Patients with One or Three Brain Metastases. Proceedings of the American Society of the American Society for Therapeutic Radiology and Oncology. Plenary Abstract # 5. lnt J Radiat Oncol Phys 51, 2S:3. Presented New Orleans, LA (2002). 45. Lekscll, L. Stereotactic Radiosurgery. J. Neurol. Neurosurg, Psychiatry (\983). 46. Li, Bo,Yu, J., Suntharalingam, M.. Kennedy. A. S., Arnin, P. P.. Chen. Z., Yin, R. Guo, S., Han, T.. Wang, T.. Yu, N.. Song. G.. Wang. L. Comparison ofthree Treatment Options for Single Brain Metastasis from Lung Cancer. IIlI J Cancer (2000). 47. Mori, Y., Kondziolka, D., Flickinger. J. Co, Kirkwood, J. M.. Agarwala, S., Lunsford. L. D. Stereotactic Radiosurgery for Cerebral Metastatic Melanoma: Factors Affecting Local Disease Control and Survival.lnt J Radiat Oncol Bioi Phys (1998). 48. Mori, Y.. Kondziolka, D.. Flickinger. J. c.. Logan. T.. Lunsford, L. D. Stereotactic Radiosurgery for Brain Metasstasis from Renal Cell Carcinoma. Cancer 83, (\998). 49. Mehta. M. P., Rozental, 1. M., Levin. A. B., et al. Defining the Role of Radiosurgery in the Management of Brain Metastases. Int J Rud Oneol Bioi Phys (\992). 50. Fernandez-Viciosos, E., Suh, J. H. Kupelian, P. A.. Sohn, 1. W., Barnett. G. H. Analysis of Prognostic Factors for Patients with Single Brain Metastasis Treated with Stereotactic Radiosurgery. Radiat Oncol lnvestig 5, (1997). 51. Shaw, E., Scott. C., Souhami, L.. Dinapoli, R.. Kline. R., Loeffler, J., Farnan. B. S. Single Dose Radiosurgical Treatment of Recurrent Previously Irradiated Primary Brain Tumors and Brain Metastases: Final Report of RTOG Protocol lnt J Radiation Oncology Bioi Phys (2000). 52. Sanghavi, S. N.. Miranpuri. S. S., Chappell. R., Buati, J. M.. Sneed. P. K.. Suh, J. n., Regine, W. E, Weltman, Eo, King, V. r., Goetsch. S. J., Breneman. J. C.. Sperduto. P. Wo, Scott. Co, Mabanta, So, Mehta, M. Radiosurgery for Patients with Brain Metastases: A Multi-institutional Analysis, Stratified by the RTOG Recursive Partitioning Analysis Methodology. Int. J. Rad. Oncol. BioI. Phys. 51, (2001). 53. Gaspar, L., Scott. C.. Rotman, et al. Recursive Partitioning Analysis (RPA) of Prognostic Factors in Three Radiation Therapy Oncology Group (RTOG) Brain Metastases Trials. Int. J. Rad. Oncol. Bioi. Phys. 37, (1997). 54. Regine, W. E, Huhn, Patchell, 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. Rad. Oneol. Bioi. Phys (2002). 55. Sneed, P. K., Lamborn. K. R, Forstner. 1. M.. Mcfsermort. M. W.. Chang, So,Park, E., Gutin, P. H.. Phillips. T. L.. Wara, W. M.. Larson. D. A. Radiosurgery for Brain Metastases: Is Whole Brain Radiotherapy Necessary? lnt. J. Rod. Oncol. Bioi. Phys (1999). Date Received: February 10, 2003 Technology in Cancer Research & Treatment. Volume 2, Number 2, April 2003