Doh and colleagues are to be commended for summarizing the complex issues inherent in the management of patients with brain metastasis, including those from renal cell carcinoma (RCC). Given the space limitations of this commentary, we are not able to cover all aspects of the topic. However, we will address two major issues that need further examination: the role and efficacy of focal therapies (conventional surgery and stereotactic radiosurgery) in the management of multiple brain metastases and the controversy regarding the use of adjuvant whole-brain radiation therapy (WBRT) in association with surgery and stereotactic radiosurgery.\n\nEfficacy of Focal Therapies for Multiple Brain Metastases\n\nThroughout their review, Doh et al appear to accept the concept that surgery and stereotactic radiosurgery have been shown to be effective in the treatment of multiple brain metastases. Such is not the case. With regard to conventional surgery, there have been no randomized trials addressing the issue, and the retrospective data are contradictory. For stereotactic radiosurgery, the situation is clearer; there have been three randomized trials[1-3] assessing the efficacy of stereotactic radiosurgery in the treatment of multiple metastases.\n\nThe first randomized trial was reported by Kondziolka et al. In that study, 27 patients with multiple brain metastases were randomized to treatment with WBRT alone or WBRT plus a stereotactic radiosurgery boost. The study was stopped early because the authors claimed to have found a large difference in recurrence rates in favor of stereotactic radiosurgery. Unfortunately, the study used nonstandard end points to measure recurrence. The investigators used any change in measurement of the lesion rather than the more usual 25% increase in diameter. No attempt was made to control for steroid use, radiation changes, or other factors that might produce small fluctuations in lesion size on magnetic resonance imaging. Also, a study with only 27 patients lacked the statistical power to support any meaningful conclusion, regardless of P values. As a result, this study was uninterpretable.\n\nA second study reported in abstract form by Chougule et al randomized patients with one to three brain metastases to treatment with stereotactic radiosurgery alone, stereotactic radiosurgery plus WBRT, or WBRT alone. This study enrolled 109 patients. There was no statistically significant difference in survival among the three treatment arms. Median survival times for the stereotactic radiosurgery, stereotactic radiosurgery plus WBRT, and WBRT alone-treated groups were 7, 5, and 9 months, respectively. Local control rates in the brain were also not significantly different.\n\nHowever, this trial suffered from several methodologic problems. The most serious issue was that 51 of the patients had had surgery for at least one symptomatic brain metastasis prior to entry into the study. No attempt was made to stratify for previous surgery or to otherwise ensure that surgical patients were equally distributed among the treatment groups. The inclusion of the surgical patients effectively made this a six-arm trial (the original three subdivided again into surgically treated patients and nonsurgically treated patients), and therefore, the size of this trial was not large enough to support a meaningful analysis. Also, since surgery is in all probability an effective therapy for brain metastases, the nonrandom distribution of surgically treated patients among the treatment arms substantially weakened the trial. Therefore, this study, although ostensibly negative, is uninterpretable.\n\nA third study, reported by Andrews and colleagues-Radiation Therapy Oncology Group (RTOG) 9508-was summarized by Doh et al. The primary end point was survival. Overall, there was no significant difference in survival between the two treatment groups (median: 6.5 months for stereotactic radiosurgery plus WBRT and 5.7 months for WBRT alone, P = .1356). The investigators found no survival benefit from stereotactic radiosurgery in patients with multiple metastases (median: 5.8 months for stereotactic radiosurgery plus WBRT and 6.7 months for WBRT alone, P = .9776). However, stereotactic radiosurgery-treated patients with a single metastasis experienced a significant survival advantage (median: 6.5 vs 4.9 months, P = .0393). Lower posttreatment Karnofsky scores and steroid dependence were more common in the WBRT alone group.\n\nMultiple subgroup analyses were performed, and a benefit for stereotactic radiosurgery plus WBRT was found in several subgroups, including patients with single and multiple metastases. These subgroups were recursive partitioning analysis (RPA) class I patients, patients with metastases equal to or larger than 2 cm, and lung cancer patients with squamous cell histology. However, these subset analyses were not prespecified, and the P values needed for significance should have been adjusted for inflation of type I error. When this was done, none of these subgroup analyses showed a positive benefit for stereotactic radiosurgery. So, for multiple brain metastases, this was a completely negative trial with regard to the major end points-prevention of death due to neurologic causes and overall survival.\n\nStereotactic radiosurgery has been put to the test in the treatment of multiple metastases and has not been established as effective. Therefore, based on the best available evidence, WBRT alone is the treatment of choice for patients with multiple brain metastases.\n\n \n\nAdjuvant WBRT and Dementia Risk\n\nThere continues to be a controversy regarding the use of WBRT adjunctively with local therapy. We think that the best available evidence establishes WBRT as the standard of care, both alone in patients with diffuse brain metastases or as an adjunct to local therapy such as stereotactic radiosurgery or surgical resection.\n\nOne of the most commonly cited and misinterpreted studies on this subject is the Memorial Sloan-Kettering experience reported by DeAngelis et al. In this study, she reported an 11% risk of radiation-induced dementia in patients undergoing craniotomy followed by radiation for brain metastasis. However, a thorough analysis reveals that the 11% risk is misleading. Although 232 patients were treated with craniotomy for brain metastasis, 134 patients (57.8%) were excluded from the analysis for a variety of reasons, including incomplete records and presence of multiple lesions. The denominator further shrank to 47 patients when only those surviving 1-year from WBRT were examined. Of these 47 patients, 5 patients developed severe dementia (thus, the 11% risk figure).\n\nIt is clear that all five of these patients were treated in a fashion that would significantly increase the risk of late radiation toxicity (ie, large daily fractions and concurrent radiosensitizer). Three patients received 5-Gy and 6-Gy daily fractions, and a fourth patient received 6-Gy fractions with concurrent doxorubicin. Only one patient received what is considered an accepted modern radiation fractionation scheme (ie, 30 Gy in 10 fractions), but this patient received a concurrent radiosensitizer (lonidamine). No patient who received the standard WBRT regimen of 30 Gy in 10 fractions experienced dementia.\n\nThe accuracy of the 11% dementia rate is further compromised by the phenomenon of the "disappearing denominator." Even though the study included 232 in the initial analysis, it only examined 47 patients who survived at least 1 year. And yet, the 11% figure is commonly quoted as the risk of dementia from WBRT. The conditional probability of event B in relationship to an event A is the probability that event B occurs given that event A has already occurred; that is, a patient has an 11% risk of dementia only if the patient survives 1 year, which is beyond most reported median survivals of patients with brain metastasis. Thus, in this study a dementia risk of 2% (5/232) would have been more accurate, since this would reflect the true risk probability ab initio for patients presenting with brain metastasis. Indeed, in a separate study of a larger cohort, DeAngelis and colleagues estimate the true risk of radiation-induced dementia for all patients presenting with brain metastasis to be only 1.9% to 5.2%, clearly demonstrating how the denominator used affects the final result.\n\nA 5% risk of dementia is not high enough to warrant withholding potentially life-saving WBRT. Advocates of withholding WBRT fail to acknowledge that WBRT may actually improve neurocognitive function in a significant number of patients with brain metastasis.\n\n \n\nProspective Trials Omitting WBRT\n\nIn a multi-institutional retrospective stereotactic radiosurgery study, Sneed and colleagues in argue that omitting upfront WBRT does not compromise overall survival. Unfortunately, in this commonly quoted study, only an overall survival analysis was performed, and no data on local control were given. In an earlier study by Sneed on the UCSF stereotactic radiosurgery experience, patients who were initially treated with stereotactic radiosurgery alone without WBRT experienced lower rates of freedom from new brain metastasis and overall freedom from progression in the brain, even though the overall survival was not different.\n\nThe omission of WBRT may have even more serious consequences for patients with more radioresistant tumors such as RCC. The stereotactic radiosurgery dose is limited by tumor size and volume, and not by whether the patient received an additional dose with WBRT. Therefore, a patient treated with WBRT plus stereotactic radiosurgery receives a much higher tumor dose than with stereotactic radiosurgery alone, a fact that is sometimes overlooked by even those who perform the procedure. Is it any surprise that ECOG E6397 demonstrated such disappointing results? In this phase II trial evaluating stereotactic radiosurgery alone in radioresistent tumors (RCC, melanoma, sarcoma), Manon reported a 6-month total brain failure rate of 48.3%. The authors correctly concluded that routine avoidance of WBRT should be approached judiciously.\n\nThere have been two other phase III studies that attempted to omit WBRT. Patchell et al demonstrated that surgical resection without WBRT led to failure rates at the original site and the entire brain of 46% and 70%, respectively. More importantly, 44% of the patients in the surgery-alone arm died as a result of neurologic sequalae from the brain failure. Preliminary results of the Japanese Radiation Oncology Study Group (JROSG) 99-1 trial have now been reported. In this phase III trial, the stereotactic radiosurgery-only arm experienced failure rates at the original site and distant sites of 30% and 64%, respectively, which decreased to 14% and 42% with the addition of WBRT. And yet, these level I data continue to be discounted.\n\n \n\nNegative Consequences of Brain Tumor Progression\n\nWe now have overwhelming evidence that local control is improved with the combined modalities of WBRT plus stereotactic radiosurgery or surgery. Nevertheless, many argue that the increased local control does not translate into a survival benefit, and that performing repeat stereotactic radiosurgery or deferring WBRT for recurrences are reasonable approaches. To decide the issue, it is necessary to examine the negative effects of brain recurrence or progression. In a neurocognitive analysis (RTOG 91-04), Regine et al demonstrated that approximately one-third of patients had improvement in Mini-Mental State Examination (MMSE) with WBRT. More importantly, those who had uncontrolled brain metastases had an average decrement of 6 points on the MMSE. In a study of high-grade gliomas, Taylor found similar results for those who experienced tumor progression.\n\nEmerging data suggest that other factors, such as anticonvulsants, opioids, chemotherapy, craniotomy, and, most importantly, the brain tumor itself contribute significantly to the mental decline of cancer patients.[14-17] The DeAngelis paper did not include sophisticated neurocognitive testing, and it is likely that subtle neurocognitive dysfunction may indeed be present in patients undergoing WBRT. Recent studies that have used sophisticated neurocognitive testing are showing that the presence of tumor, its recurrence, and its progression have the greatest effect on mental decline. In the phase III motexafin gadolinium (Xcytrin) study, a sophisticated neurocognitive battery was employed to test memory recall, memory recognition, delayed recall, verbal fluency, pegboard hand coordination, and executive function. This study demonstrated that 21% to 65.1% of patients had impaired functioning at baseline before WBRT. Furthermore, patients with disease progression in the brain experienced significantly worse scores on all of these tests.\n\n \n\nConclusions\n\nThere is extremely strong evidence that WBRT should continue to be an integral part of the treatment of patients with brain metastasis. As systemic therapy improves and extends survival of patients with metastatic disease, it will become even more imperative that we achieve local control of brain metastases. At a time when more attention is being paid to quality of life in cancer patients, it is worth considering that the omission of WBRT results in an unacceptable detriment to the patient's quality of life.\n\n \n\n-Young Kwok, MD\n-Roy A. Patchell, MD\n\nDisclosures:\n\nThe author has no significant financial interest or other relationship with the manufacturers of any products.\n\nReferences:\n\n1. 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.\n\n2. Chougule PB, Burton-Williams M, Saris S, et al: Randomized treatment of brain metastases with gamma knife radiosurgery, whole brain radiotherapy or both. Int J Radiat Oncol Biol Phys 48:114, 2000.\n\n3. Andrews DW, Scott CB, Sperduto PW, et al: Whole brain radiation therapy with and without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomized trial. Lancet 363:1665-1672, 2004.\n\n4. Elveen T, Andrews DW: Summary of RTOG 95-01 phase III randomized trial of whole brain radiation with and without stereotactic radiosurgery boost, including presentation of a clinical case study. Am J Oncol Rev 3:592-600, 2004.\n\n5. DeAngelis LM, Mandell LR, Thaler T, et al: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 24:798-805, 1989.\n\n6. DeAngelis LM, Delattre JV, Posner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 39:789-796, 1989.\n\n7. 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.\n\n8. Sneed PK, Lamborn KR, Forstner JM, et al: Radiosurgery for brain metastases: Is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 43:549-558, 1999.\n\n9. Manon R, O’Neill A, Knisely J, 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). J Clin Oncol 23:8870-8876, 2005.\n\n10. 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.\n\n11. Aoyama H, Shirato H, Nakagawa K, et al: Interim report of JROSG99-1 multi-institutional prospective randomized trial compar-\ning SRS alone vs WBI_SRS for 1-4 brain metastases (abstract 1506). J Clin Oncol 22(suppl):108, 2004.\n\n12. Regine WF, Scott C, Murray K, 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. Int J Radiat Oncol Biol Phys 51:711-717, 2001.\n\n13. Taylor BV, Buckner JC, Cascino TL, et al: Effects of radiation and chemotherapy on cognitive function in patients with high-grade glioma. J Clin Oncol 16:2195-2201, 1998.\n\n14. Sonderkaer S, Schmiegelow M, Carstensen H, et al: Long-term neurological outcome of childhood brain tumors treated by surgery only. J Clin Oncol 21:1347-1351, 2003.\n\n15. Klein M, Engelberts NH, van der Ploeg HM, et al: Epilepsy in low-grade gliomas: The impact on cognitive function and quality of life. Ann Neurol 54:514-520, 2003.\n\n16. Brezden CB, Phillips KA, Abdolell M, et al: Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 18:2695-2701, 2000.\n\n17. Klein M, Heimans JJ, Aaronson NK, et al: Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: A comparative study. Lancet 360:1361-1368, 2002.\n\n18. 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.