Phase II Trial of Radiosurgery for One to Three Newly Diagnosed Brain Metastases From Renal Cell Carcinoma, Melanoma, and Sarcoma: An Easter
http://www.100md.com
《临床肿瘤学》
the University of Wisconsin, Madison, WI
Dana-Farber Cancer Institute, Boston, MA
Yale University, New Haven, CT
Thomas Jefferson University Hospital, Philadelphia, PA
University Hospitals of Cleveland, Cleveland, OH
Penn State Cancer Institute, Hershey, PA
the University of Texas M.D. Anderson Cancer Center, Houston, TX.
ABSTRACT
PURPOSE: Long-term brain metastases survivors are at risk for neurologic morbidity after whole-brain radiotherapy (WBRT). Retrospective radiosurgery (RS) reports found no survival difference when compared with WBRT. Before RS alone was evaluated with delayed WBRT in a phase III trial, the feasibility of RS alone was tested prospectively.
PATIENTS AND METHODS: Patients with renal cell carcinoma, melanoma, or sarcoma; one to three brain metastases; and performance status of 0 to 2 were enrolled. Exclusion criteria were leptomeningeal disease; metastases in medulla, pons, or midbrain; or liver metastases. On the basis of tumor size, patients received 24, 18, or 15 Gy RS. At recurrence, management was discretionary. The primary end point was 3- and 6-month intracranial progression.
RESULTS: Between July 1998 and August 2003, 36 patients were accrued; 31 were eligible. Median follow-up was 32.7 months and the median survival was 8.3 months (95% CI, 7.4 to 12.2). Three- and 6-month intracranial failure with RS alone was 25.8% and 48.3%. Failure within and outside the RS volume, when in-field and distant intracranial failures were scored independently, was 19.3% and 16.2% (3 months) and 32.2% and 32.2% (6 months), respectively. Approximately 38% of patients experienced death attributable to neurologic cause. There were three grade 3 toxicities related to RS.
CONCLUSION: Intracranial failure rates without WBRT were 25.8% and 48.3% at 3 and 6 months, respectively. Delaying WBRT may be appropriate for some subgroups of patients with radioresistant tumors, but routine avoidance of WBRT should be approached judiciously.
INTRODUCTION
Intracranial metastases are the most common malignancy affecting the brain.1,2 It is estimated that each year in the United States there are more than 170,000 new cases of brain metastases.3 The incidence of brain metastases may increase in the future with the advent of improved imaging techniques (magnetic resonance imagine [MRI]) and as cancer patients continue to live longer.4 The median survival of patients treated with supportive measures (corticosteroids alone) is 1 to 2 months; this can be increased to 3 to 6 months with conventional whole-brain radiation therapy (WBRT).5 Response rates with WBRT are approximately 40% to 50%.6,7
The addition of WBRT to patients with single brain metastases who have undergone surgical resection has been shown to decrease the risk of intracranial recurrences and neurologic death.8 Radiosurgery (RS) has also demonstrated a therapeutic benefit in the treatment of brain metastases when administered in conjunction with WBRT.9,10 However, peer-reviewed, randomized studies to determine whether the addition of up-front WBRT is necessary in patients who receive RS have not been published to date. There are several retrospective reviews in the literature with mixed results.11,12 In general, these studies have demonstrated no survival detriment with the omission of up-front WBRT, except perhaps in patients with minimal systemic disease burden, who may experience increased mortality as a consequence of intracranial failure.11
The value of low-dose WBRT in the treatment of radioresistant histologies has been questioned.13 Several retrospective studies have reported acceptable local control rates with RS alone; these series have also suggested no detrimental impact on survival with the omission of WBRT.14-17The question of whether up-front WBRT is necessary in radioresistant histologies is confounded and remains controversial. Thus, there is a need to validate the role of WBRT in a large phase III study; however, before such a study is conducted, the feasibility of RS alone needs to be tested in a smaller patient population. With this intent, the Eastern Cooperative Oncology Group completed a phase II study evaluating up-front RS alone in patients with one to three brain metastases from radioresistant primary cancers.
PATIENTS AND METHODS
Patients
Patients with histologically confirmed renal cell carcinoma, melanoma, or sarcoma with one to three newly diagnosed intraparenchymal brain metastases, on the basis of contrast-enhanced MRI performed within 2 weeks before study entry, were enrolled. The intraparenchymal tumors were required to have a maximum diameter of 4.0 cm in any dimension on the contrast-enhanced MRI scan. If multiple lesions were present and one lesion was more than 3.0 cm in diameter, the other(s) could not exceed 3.0 cm in maximum diameter. Metastases could not be within 10 mm of the optic nerve or chiasm. Patients were required to be 18 years of age, have an Eastern Cooperative Oncology Group performance status of 0 to 2, and have a life expectancy of at least 3 months. Adequate bone marrow reserve was required before study entry (hemoglobin > 8 g, absolute neutrophil count > 1,000/μL, platelets > 50,000 μL). Prior chemotherapy was allowed provided that the hematologic parameters reached the levels specified within 72 hours before study entry (systemic therapy could have been continued at the investigator's discretion after RS). Participants were allowed to have extracranial sites of disease and prior or concomitant radiation to noncranial sites. All other therapies were permissible after RS except whole-brain external-beam radiation or resection of brain metastases (stereotactic biopsy for diagnostic purposes was allowed); resection of brain metastases or WBRT was allowed if there was evidence of progression or unrelenting mass effect necessitating a craniotomy. Exclusion criteria included metastases to the brainstem, midbrain, pons, or medulla; leptomeningeal disease (documented by MRI or CSF evaluation); metastases to the optic nerve or chiasm; previous cranial irradiation; or multiple liver lesions. Pregnant and lactating women were also excluded. All patients were required to provide signed and informed consent.
Treatment
Before enrolling patients, all participating institutions were required to have been approved for RS by the Radiation Therapy Oncology Group (RTOG) for performance of RS in prior or ongoing RTOG RS protocols. These institutions were required to have used stereotactic frame placement for imaging procedures and treatment delivery; they were also required to have a treatment planning system capable of generating dose distributions in three planes (axial, coronal, and sagittal). RS delivered with a linear accelerator or a gamma knife unit was acceptable. Tumor volume and isocenter determination was based on a contrast-enhanced MRI, computed tomography, or fused image data with the patient's head in a stereotactic frame. Stereotactic planning image thickness was not to exceed 3 mm. The target volume included the enhancing portion of the metastatic lesion; surrounding edema or margins beyond the area of enhancement were not added.
At the time of RS, a repeat MRI or computed tomography was obtained for planning. If any of the targeted metastases exceeded the acceptable upper limit, RS was not delivered. Likewise, if more than three lesions were present at the time of RS, treatment was not delivered. If any of these two scenarios occurred, WBRT was administered and the patient was considered ineligible and excluded from the study analysis. The total dose delivered during RS was dependent on the size of the metastatic lesion(s), as previously described by Shaw et al.18 Lesions measuring 2 cm in greatest diameter received 24 Gy, tumors measuring more than 2 but 3 cm in maximum diameter received 18 Gy, and lesions larger than 3 cm received 15 Gy. If the edges of any two lesions were within 1 cm of each other, then the lowest applicable prescription dose was selected for both lesions. The dose was prescribed to the isodose surface, which encompassed the edge of the metastasis. The prescription dose was delivered to the 50% to 90% (maximum, 100%) isodose surface, and was defined as the minimum dose to the target volume.
Dexamethasone was administered before RS at a starting dose of 4 to 16 mg. If a lesion disappeared at the time of diagnosis, it was not targeted for RS. At completion of RS, a corticosteroid taper and continuation of systemic therapy were allowed at the discretion of the treating physician. Anticonvulsants and pain medications were allowed at the discretion of the treating physician.
End Points and Statistical Considerations
This is a prospective observational trial to document the true incidence of brain failure by withholding WBRT in a multi-institutional context, without the added bias of retrospective single-institution selection pressures. The primary end point of this trial was to assess the 3- and 6-month intracranial progression rates inside and outside the RS volume when WBRT is omitted. At the time of study design, prospective data regarding expected brain failures by withholding WBRT for this population were not available. On the basis of a review of retrospective institutional experiences, the 3- and 6-month progression rates within the RS volume were estimated to be 10% and 20%, respectively. Progression within the brain but outside of the RS volume was estimated to be 25% and 35% at 3 and 6 months, respectively. A sample size of 30 patients was calculated to expose a minimum number of patients to this regimen and provide reasonable estimates that could be used for designing future trials with greater power. Assuming a 20% ineligibility rate or inability to proceed to RS due to increases in tumor volume or number of lesions, a total of 36 patients were to be enrolled.
Contrast-enhanced MRI scans were obtained at baseline and then at 3, 6, and 12 months after completion of RS. Progressive disease was defined as a radiographic increase of 25% or more in the size of a metastatic lesion (bidimensional product), the development of new intraparenchymal lesions, stable disease in conjunction with deterioration in neurologic examinations, or development of new intracranial metastatic foci/leptomeningeal disease.
Secondary end points included overall survival, which was measured from time of study entry to death. Patients were considered to have died as a result of a neurologic death if they had evidence of progressive intracranial disease consisting of expanding intracranial masses, CNS hemorrhage, progressive neurologic symptoms, meningeal carcinomatosis, or hydrocephalus resulting in herniation. A patient who died in the setting of a non–life-threatening event related to their cancer was also considered to have suffered a neurologic death. The Mini Mental Status Examination was used to evaluate global cognitive function and was scheduled to be administered at baseline and then at 3, 6, 9, and 12 months after entering the study, then every 3 months until progression; it was not administered after disease progression was established.19 Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria version 2.0.
CIs for response rates were estimated using methods for exact binomial CIs.20 Failure within the RS area and within the brain but outside of the RS area was of interest. Cumulative incidence functions for these competing events were used to estimate 3- and 6- month progression rates.21 Time to event was defined as time from random assignment to progression within the RS-treated area or to progression within the brain but outside of the RS-treated area. Deaths without documented progression in these areas of the brain were also considered a competing event. Participants alive without progression in the brain were censored at the last time known to be alive and progression free. The Kaplan-Meier method was used to estimate survival distributions.22
RESULTS
Patient Population
Eastern Cooperative Oncology Group Study E 6397 opened in July 1998 and closed in August 2003 after accruing 36 patients. Five patients were classified as ineligible; one patient was treated before registration and four patients had more than three lesions on the day of RS. Thus, there remained 31 eligible and analyzable patients. Baseline patient characteristics are listed in Table 1. The most common histologies were melanoma and renal cell carcinoma. All patients received at least the RS dose assigned by the protocol. Five patients received higher doses as a result of overlap between adjacent RS fields.
Toxicity
Table 2 lists the toxicities related to treatment (the table includes all participants, eligible or ineligible, who received RS). Among the 36 participants registered onto the study, 17 reported toxicities related to RS, eight reported adverse events not related to RS, seven reported no toxicities or adverse events, and four did not receive RS. Three participants reported grade 3 toxicities related to RS, consisting of one occurrence of fatigue, one occurrence of seizures, and one patient with neutropenia (the latter may not necessarily be related to RS). No life-threatening or lethal toxicities were reported.
Intracranial Failure
At the time that this analysis was performed (after a median follow-up time of 32.7 months), 21 patients had experienced intracranial progression, either within the RS area, within the brain but outside the RS area, or both. Seven patients have died without documented progression within the brain. Patterns of failure at 3 and 6 months are listed in Table 3. At 3 months, the actuarial total intracranial failure rate was 25.8% and this increased to 48.3% by 6 months. The 3- and 6-month actuarial incidence of any failure within the RS volume was 19.3% and 32.2%, respectively. The 3- and 6-month actuarial incidence of any failure outside the RS volume was 16.2% and 32.2%, respectively. Patients with simultaneous failures within the RS volume and within the brain but outside the RS volume contribute to both of the relapse pattern figures mentioned herein, and at 3 and 6 months, the incidence of such simultaneous failure was 9.7% and 16.1%, respectively. There were no statistically significant differences in intracranial failure rates and patterns based on histology.
Survival
The median survival time was 8.3 months (95% CI, 7.4 to 12.2 months; Fig 1). As of last evaluation, five patients remained alive. Causes of death are listed in Table 4. Nineteen percent of patients died from intracranial disease progression alone, 22.5% died as a result of their primary cancer, and 19% died of both causes.
Global Cognitive Function
Table 5 shows the results of Mini Mental Status Examination for the assessable patient cohort at baseline and 3 and 6 months after treatment. The maximum and best possible score for this examination was 30 points. Mini Mental Status Examination scores were available for 28 patients at baseline, for 20 patients at 3 months, and five patients at 6 months. The Mini Mental Status Examination scores did not vary significantly after RS, but the data collection beyond 3 months for this was poor.
DISCUSSION
The role of RS in the treatment of brain metastases has been the subject of several randomized trials. Kondziolka et al10 reported the first trial on this subject. The study was stopped at interim analysis demonstrating a significant benefit in local tumor control with RS plus WBRT over WBRT alone. This study accrued only 27 patients, so it is difficult to draw firm conclusions from these data.4 A recently published RTOG study compared WBRT versus WBRT plus RS in a cohort of 333 patients with one to three brain metastases. It demonstrated a survival benefit for patients with single brain metastases and improved Karnofsky functional score across all patients in the WBRT plus RS group9; higher response rates and better control of the treated lesions were also evident with combined therapy.9 However, there was no survival difference in patients with multiple brain metastases and no difference in the rate of neurologic death. This was the largest trial to date and has helped define the optimal setting and role of RS in patients who receive WBRT.
With the establishment of the efficacy of focal treatments, new controversies have arisen.4 One such controversy is whether WBRT is necessary after successful focal therapy (ie, RS or complete resection). WBRT is believed to be beneficial because it addresses microscopic disease at the tumor site after resection or in distant sites in the brain.4 Researchers at the University of Kentucky (Lexington, KY) addressed the question of adjuvant WBRT in a randomized controlled trial. In that study, patients with single brain metastases who underwent complete resection were randomly assigned to observation or WBRT (50.4 Gy).8 The primary end point for which the study was statistically powered was not survival, but intracranial recurrence. Survival was measured and analyzed as a secondary end point. Tumor recurrences anywhere in the brain (local recurrences plus recurrences within the brain but outside surgical bed) were 70% without and 18% with adjuvant WBRT. Adjuvant radiation therapy appeared to decrease recurrences significantly at both the surgical bed and distant sites, as well as the incidence of death as a result of neurologic causes. However, overall survival, the secondary end point, for which the study was not actually powered, was not influenced by the addition of WBRT.
The current study represents one of the initial prospective multi-institutional trials to address the feasibility of up-front RS alone in patients with one to three brain metastases. The median survival time of 8.3 months observed in this study compares favorably with that of other series.23 Our most important finding was that there was a high degree of failures within the brain (approximately 50% of patients by 6 months) with the omission of WBRT; this rate is higher than our estimates at the time of study design.
A recent multi-institutional Japanese phase III trial (Japanese Radiation Oncology Group [JROSG] 99-1) evaluating RS alone has been reported in abstract form.23 In this study, 132 patients with one to four brain metastases were randomly assigned to RS alone versus WBRT plus RS. Although this study demonstrated no statistically significant difference in survival or death as a result of neurologic causes between the two arms, there was a significantly higher rate of intracranial failures with the omission of WBRT. This was observed with respect to local failures (30% v 14% at 12 months; P = .001) and new brain metastases (64% v 42% at 12 months) with RS alone versus WBRT plus RS, respectively. Table 6 compares the intracranial failure rates of the current study versus the recent Japanese trial and the study reported by the University of Kentucky in 1998. A high intracranial failure rate is seen in all three prospective clinical trials with the omission of WBRT.
The failure rate within the RS volume in this trial (32%) is higher than retrospective experiences with brain metastases from a range of malignancies.11,17,24 This is also contrary to what has been reported in retrospective studies of RS alone in brain metastases from radioresistant histologies such as melanoma and renal cell carcinoma.14,15,17 A likely explanation is the fact that retrospectively reported data contain patients that are selected for RS, as opposed to requiring the treatment of the majority that enroll onto a clinical trial. Consequently, included in these retrospective reports are patients who may be days, weeks, or months from completion of WBRT, and these patients may constitute a more favorable biologic subgroup. Second, the distinction between tumor progression and necrosis after RS is sometimes complex and could lead to differences in estimates among different reports.
One of the arguments against the use of WBRT is the possibility of diminished neurocognitive functioning in long-term survivors.25 However, the adverse effects of WBRT may have been overestimated in the past and may be at an acceptable range with current fractionation schedules.4 Several recent studies have demonstrated that recurrence/progressive disease may be the primary factor influencing neurocognitive decline in these patients.26-28 The current study did not demonstrate that global cognitive function, as measured by the Mini Mental Status Examination, was significantly altered. One explanation is that longer follow-up is needed to see changes in cognitive function, and only five patients were alive, were progression free, and had scores beyond 6 months. Likewise, the recent Japanese multi-institutional trial did not show a detriment in cognitive function, using performance status as a surrogate, between the two study arms, despite the fact that the RS-alone arm had greater degree of intracranial failure.23 Therefore, an additional explanation for the lack of evidence for cognitive decline may be that measures such as Mini Mental Status Examination and performance status are simply not sensitive enough. These tests may not be adequate to detect neurocognitive loss, which may be evident if more sensitive methods are used. Prospective studies have used a battery of neurocognitive tests before and after WBRT to measure neurocognitive impairment.28,29 These studies have demonstrated that a significant number of patients (> 90%) have impaired neurocognitive functioning at baseline despite a Karnofsky performance score 70.28 Moreover, patients with progressive disease have greater median changes in their overall neurocognitive decline (decline in z score), and only patients with responses demonstrate improvements in individual tests of executive function.28
In conclusion, this study demonstrated that the median survival time of patients treated with RS up front was equivalent to published surgical and concurrent RS plus WBRT series. Intracranial failures with the omission of WBRT were high. Although this may not manifest in a detriment in survival, which is largely determined by systemic disease, more sensitive neurologic assessment tools may helping identify WBRT’s impact on mental performance. How this relates to one's ability to manage finances, recognize unsafe behaviors, comply with medication regimens, and perform higher executive functions needs to be better established. On the basis of the observed intracranial failure rate in this trial, the routine practice of avoiding WBRT should be used judiciously outside a clinical trial. To better define the survival impact as well as quantify quality of life and neurocognitive functional changes, an ongoing North Central Cancer Treatment Group/American College of Surgeons Oncology Group phase III clinical trial is underway.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Presented as an oral presentation at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5–8, 2004, New Orleans, LA.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Clouston PD, DeAngelis LM, Posner JB: The spectrum of neurological disease in patients with systemic cancer. Ann Neurol 31:268-273, 1992
Johnson JD, Young B: Demographics of brain metastasis. Neurosurg Clin N Am 7:337-344, 1996
Posner JB: Management of brain metastases. Rev Neurol 148:477-487, 1992
Patchell RA: The management of brain metastases. Cancer Treat Rev 29:533-540, 2003
Wen PY, Loeffler JS: Management of brain metastases. Oncology (Huntington) 13:941-954, 1999
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
Cairncross JG, Kim JH, Posner JB: Radiation therapy for brain metastases. Ann Neurol 7:529-541, 1980
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
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. Lancet 363:1665-1672, 2004
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
Pirzkall A, Debus J, Lohr F, et al: Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. J Clin Oncol 16:3563-3569, 1998
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
Wronski M, Maor MH, Davis BJ, et al: External radiation of brain metastases from renal carcinoma: A retrospective study of 119 patients from the M. D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 37:753-759, 1997
Mori Y, Kondziolka D, Flickinger JC, et al: Stereotactic radiosurgery for brain metastasis from renal cell carcinoma. Cancer 83:344-353, 1998
Mori Y, Kondziolka D, Flickinger JC, et al: Stereotactic radiosurgery for cerebral metastatic melanoma: Factors affecting local disease control and survival. Int J Radiat Oncol Biol Phys 42:581-589, 1998
Alexander E, Moriarty TM, Davis RB, et al: Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 87:34-40, 1995
Flickinger JC, Kondziolka D, Lunsford LD, et al: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 28:797-802, 1994
Shaw E, Scott C, Souhami L, et al: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: Final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:291-298, 2000
Murray KJ, Scott C, Zachariah, et al: Importance of the mini mental-status examination in the treatment of patients with brain metastases: A report from the Radiation Therapy Oncology Group Protocol 9104. Int J Radiat Oncol Biol Phys 48:59-64, 2000
Cox DR, Snell EJ: Analysis of Binary Data (ed 2). London, United Kingdom, Chapman and Hall, 1989
Kalbfeisch JD, Prentice RI: The Statistical Analysis of Failure Time Data. New York, NY, Wiley, 1980
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
Aoyama H, Shirato H, Nakagawa K et al: Interim report of JROSG99–1 Multi–institutional prospective randomized trial comparing SRS alone vs. WBI+SRS for 1–4 brain metastases. J Clin Oncol 22:108, 2004 (suppl; abstr 1506)
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
DeAngelis LM, Delattre JY, Posner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 39:789-796, 1989
Regine WF, Huhn JL, Patchell RA, 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 Radiat Oncol Biol Phys 52:333-338, 2002
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
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
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(Rafael Manon, Anne O'Neil)
Dana-Farber Cancer Institute, Boston, MA
Yale University, New Haven, CT
Thomas Jefferson University Hospital, Philadelphia, PA
University Hospitals of Cleveland, Cleveland, OH
Penn State Cancer Institute, Hershey, PA
the University of Texas M.D. Anderson Cancer Center, Houston, TX.
ABSTRACT
PURPOSE: Long-term brain metastases survivors are at risk for neurologic morbidity after whole-brain radiotherapy (WBRT). Retrospective radiosurgery (RS) reports found no survival difference when compared with WBRT. Before RS alone was evaluated with delayed WBRT in a phase III trial, the feasibility of RS alone was tested prospectively.
PATIENTS AND METHODS: Patients with renal cell carcinoma, melanoma, or sarcoma; one to three brain metastases; and performance status of 0 to 2 were enrolled. Exclusion criteria were leptomeningeal disease; metastases in medulla, pons, or midbrain; or liver metastases. On the basis of tumor size, patients received 24, 18, or 15 Gy RS. At recurrence, management was discretionary. The primary end point was 3- and 6-month intracranial progression.
RESULTS: Between July 1998 and August 2003, 36 patients were accrued; 31 were eligible. Median follow-up was 32.7 months and the median survival was 8.3 months (95% CI, 7.4 to 12.2). Three- and 6-month intracranial failure with RS alone was 25.8% and 48.3%. Failure within and outside the RS volume, when in-field and distant intracranial failures were scored independently, was 19.3% and 16.2% (3 months) and 32.2% and 32.2% (6 months), respectively. Approximately 38% of patients experienced death attributable to neurologic cause. There were three grade 3 toxicities related to RS.
CONCLUSION: Intracranial failure rates without WBRT were 25.8% and 48.3% at 3 and 6 months, respectively. Delaying WBRT may be appropriate for some subgroups of patients with radioresistant tumors, but routine avoidance of WBRT should be approached judiciously.
INTRODUCTION
Intracranial metastases are the most common malignancy affecting the brain.1,2 It is estimated that each year in the United States there are more than 170,000 new cases of brain metastases.3 The incidence of brain metastases may increase in the future with the advent of improved imaging techniques (magnetic resonance imagine [MRI]) and as cancer patients continue to live longer.4 The median survival of patients treated with supportive measures (corticosteroids alone) is 1 to 2 months; this can be increased to 3 to 6 months with conventional whole-brain radiation therapy (WBRT).5 Response rates with WBRT are approximately 40% to 50%.6,7
The addition of WBRT to patients with single brain metastases who have undergone surgical resection has been shown to decrease the risk of intracranial recurrences and neurologic death.8 Radiosurgery (RS) has also demonstrated a therapeutic benefit in the treatment of brain metastases when administered in conjunction with WBRT.9,10 However, peer-reviewed, randomized studies to determine whether the addition of up-front WBRT is necessary in patients who receive RS have not been published to date. There are several retrospective reviews in the literature with mixed results.11,12 In general, these studies have demonstrated no survival detriment with the omission of up-front WBRT, except perhaps in patients with minimal systemic disease burden, who may experience increased mortality as a consequence of intracranial failure.11
The value of low-dose WBRT in the treatment of radioresistant histologies has been questioned.13 Several retrospective studies have reported acceptable local control rates with RS alone; these series have also suggested no detrimental impact on survival with the omission of WBRT.14-17The question of whether up-front WBRT is necessary in radioresistant histologies is confounded and remains controversial. Thus, there is a need to validate the role of WBRT in a large phase III study; however, before such a study is conducted, the feasibility of RS alone needs to be tested in a smaller patient population. With this intent, the Eastern Cooperative Oncology Group completed a phase II study evaluating up-front RS alone in patients with one to three brain metastases from radioresistant primary cancers.
PATIENTS AND METHODS
Patients
Patients with histologically confirmed renal cell carcinoma, melanoma, or sarcoma with one to three newly diagnosed intraparenchymal brain metastases, on the basis of contrast-enhanced MRI performed within 2 weeks before study entry, were enrolled. The intraparenchymal tumors were required to have a maximum diameter of 4.0 cm in any dimension on the contrast-enhanced MRI scan. If multiple lesions were present and one lesion was more than 3.0 cm in diameter, the other(s) could not exceed 3.0 cm in maximum diameter. Metastases could not be within 10 mm of the optic nerve or chiasm. Patients were required to be 18 years of age, have an Eastern Cooperative Oncology Group performance status of 0 to 2, and have a life expectancy of at least 3 months. Adequate bone marrow reserve was required before study entry (hemoglobin > 8 g, absolute neutrophil count > 1,000/μL, platelets > 50,000 μL). Prior chemotherapy was allowed provided that the hematologic parameters reached the levels specified within 72 hours before study entry (systemic therapy could have been continued at the investigator's discretion after RS). Participants were allowed to have extracranial sites of disease and prior or concomitant radiation to noncranial sites. All other therapies were permissible after RS except whole-brain external-beam radiation or resection of brain metastases (stereotactic biopsy for diagnostic purposes was allowed); resection of brain metastases or WBRT was allowed if there was evidence of progression or unrelenting mass effect necessitating a craniotomy. Exclusion criteria included metastases to the brainstem, midbrain, pons, or medulla; leptomeningeal disease (documented by MRI or CSF evaluation); metastases to the optic nerve or chiasm; previous cranial irradiation; or multiple liver lesions. Pregnant and lactating women were also excluded. All patients were required to provide signed and informed consent.
Treatment
Before enrolling patients, all participating institutions were required to have been approved for RS by the Radiation Therapy Oncology Group (RTOG) for performance of RS in prior or ongoing RTOG RS protocols. These institutions were required to have used stereotactic frame placement for imaging procedures and treatment delivery; they were also required to have a treatment planning system capable of generating dose distributions in three planes (axial, coronal, and sagittal). RS delivered with a linear accelerator or a gamma knife unit was acceptable. Tumor volume and isocenter determination was based on a contrast-enhanced MRI, computed tomography, or fused image data with the patient's head in a stereotactic frame. Stereotactic planning image thickness was not to exceed 3 mm. The target volume included the enhancing portion of the metastatic lesion; surrounding edema or margins beyond the area of enhancement were not added.
At the time of RS, a repeat MRI or computed tomography was obtained for planning. If any of the targeted metastases exceeded the acceptable upper limit, RS was not delivered. Likewise, if more than three lesions were present at the time of RS, treatment was not delivered. If any of these two scenarios occurred, WBRT was administered and the patient was considered ineligible and excluded from the study analysis. The total dose delivered during RS was dependent on the size of the metastatic lesion(s), as previously described by Shaw et al.18 Lesions measuring 2 cm in greatest diameter received 24 Gy, tumors measuring more than 2 but 3 cm in maximum diameter received 18 Gy, and lesions larger than 3 cm received 15 Gy. If the edges of any two lesions were within 1 cm of each other, then the lowest applicable prescription dose was selected for both lesions. The dose was prescribed to the isodose surface, which encompassed the edge of the metastasis. The prescription dose was delivered to the 50% to 90% (maximum, 100%) isodose surface, and was defined as the minimum dose to the target volume.
Dexamethasone was administered before RS at a starting dose of 4 to 16 mg. If a lesion disappeared at the time of diagnosis, it was not targeted for RS. At completion of RS, a corticosteroid taper and continuation of systemic therapy were allowed at the discretion of the treating physician. Anticonvulsants and pain medications were allowed at the discretion of the treating physician.
End Points and Statistical Considerations
This is a prospective observational trial to document the true incidence of brain failure by withholding WBRT in a multi-institutional context, without the added bias of retrospective single-institution selection pressures. The primary end point of this trial was to assess the 3- and 6-month intracranial progression rates inside and outside the RS volume when WBRT is omitted. At the time of study design, prospective data regarding expected brain failures by withholding WBRT for this population were not available. On the basis of a review of retrospective institutional experiences, the 3- and 6-month progression rates within the RS volume were estimated to be 10% and 20%, respectively. Progression within the brain but outside of the RS volume was estimated to be 25% and 35% at 3 and 6 months, respectively. A sample size of 30 patients was calculated to expose a minimum number of patients to this regimen and provide reasonable estimates that could be used for designing future trials with greater power. Assuming a 20% ineligibility rate or inability to proceed to RS due to increases in tumor volume or number of lesions, a total of 36 patients were to be enrolled.
Contrast-enhanced MRI scans were obtained at baseline and then at 3, 6, and 12 months after completion of RS. Progressive disease was defined as a radiographic increase of 25% or more in the size of a metastatic lesion (bidimensional product), the development of new intraparenchymal lesions, stable disease in conjunction with deterioration in neurologic examinations, or development of new intracranial metastatic foci/leptomeningeal disease.
Secondary end points included overall survival, which was measured from time of study entry to death. Patients were considered to have died as a result of a neurologic death if they had evidence of progressive intracranial disease consisting of expanding intracranial masses, CNS hemorrhage, progressive neurologic symptoms, meningeal carcinomatosis, or hydrocephalus resulting in herniation. A patient who died in the setting of a non–life-threatening event related to their cancer was also considered to have suffered a neurologic death. The Mini Mental Status Examination was used to evaluate global cognitive function and was scheduled to be administered at baseline and then at 3, 6, 9, and 12 months after entering the study, then every 3 months until progression; it was not administered after disease progression was established.19 Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria version 2.0.
CIs for response rates were estimated using methods for exact binomial CIs.20 Failure within the RS area and within the brain but outside of the RS area was of interest. Cumulative incidence functions for these competing events were used to estimate 3- and 6- month progression rates.21 Time to event was defined as time from random assignment to progression within the RS-treated area or to progression within the brain but outside of the RS-treated area. Deaths without documented progression in these areas of the brain were also considered a competing event. Participants alive without progression in the brain were censored at the last time known to be alive and progression free. The Kaplan-Meier method was used to estimate survival distributions.22
RESULTS
Patient Population
Eastern Cooperative Oncology Group Study E 6397 opened in July 1998 and closed in August 2003 after accruing 36 patients. Five patients were classified as ineligible; one patient was treated before registration and four patients had more than three lesions on the day of RS. Thus, there remained 31 eligible and analyzable patients. Baseline patient characteristics are listed in Table 1. The most common histologies were melanoma and renal cell carcinoma. All patients received at least the RS dose assigned by the protocol. Five patients received higher doses as a result of overlap between adjacent RS fields.
Toxicity
Table 2 lists the toxicities related to treatment (the table includes all participants, eligible or ineligible, who received RS). Among the 36 participants registered onto the study, 17 reported toxicities related to RS, eight reported adverse events not related to RS, seven reported no toxicities or adverse events, and four did not receive RS. Three participants reported grade 3 toxicities related to RS, consisting of one occurrence of fatigue, one occurrence of seizures, and one patient with neutropenia (the latter may not necessarily be related to RS). No life-threatening or lethal toxicities were reported.
Intracranial Failure
At the time that this analysis was performed (after a median follow-up time of 32.7 months), 21 patients had experienced intracranial progression, either within the RS area, within the brain but outside the RS area, or both. Seven patients have died without documented progression within the brain. Patterns of failure at 3 and 6 months are listed in Table 3. At 3 months, the actuarial total intracranial failure rate was 25.8% and this increased to 48.3% by 6 months. The 3- and 6-month actuarial incidence of any failure within the RS volume was 19.3% and 32.2%, respectively. The 3- and 6-month actuarial incidence of any failure outside the RS volume was 16.2% and 32.2%, respectively. Patients with simultaneous failures within the RS volume and within the brain but outside the RS volume contribute to both of the relapse pattern figures mentioned herein, and at 3 and 6 months, the incidence of such simultaneous failure was 9.7% and 16.1%, respectively. There were no statistically significant differences in intracranial failure rates and patterns based on histology.
Survival
The median survival time was 8.3 months (95% CI, 7.4 to 12.2 months; Fig 1). As of last evaluation, five patients remained alive. Causes of death are listed in Table 4. Nineteen percent of patients died from intracranial disease progression alone, 22.5% died as a result of their primary cancer, and 19% died of both causes.
Global Cognitive Function
Table 5 shows the results of Mini Mental Status Examination for the assessable patient cohort at baseline and 3 and 6 months after treatment. The maximum and best possible score for this examination was 30 points. Mini Mental Status Examination scores were available for 28 patients at baseline, for 20 patients at 3 months, and five patients at 6 months. The Mini Mental Status Examination scores did not vary significantly after RS, but the data collection beyond 3 months for this was poor.
DISCUSSION
The role of RS in the treatment of brain metastases has been the subject of several randomized trials. Kondziolka et al10 reported the first trial on this subject. The study was stopped at interim analysis demonstrating a significant benefit in local tumor control with RS plus WBRT over WBRT alone. This study accrued only 27 patients, so it is difficult to draw firm conclusions from these data.4 A recently published RTOG study compared WBRT versus WBRT plus RS in a cohort of 333 patients with one to three brain metastases. It demonstrated a survival benefit for patients with single brain metastases and improved Karnofsky functional score across all patients in the WBRT plus RS group9; higher response rates and better control of the treated lesions were also evident with combined therapy.9 However, there was no survival difference in patients with multiple brain metastases and no difference in the rate of neurologic death. This was the largest trial to date and has helped define the optimal setting and role of RS in patients who receive WBRT.
With the establishment of the efficacy of focal treatments, new controversies have arisen.4 One such controversy is whether WBRT is necessary after successful focal therapy (ie, RS or complete resection). WBRT is believed to be beneficial because it addresses microscopic disease at the tumor site after resection or in distant sites in the brain.4 Researchers at the University of Kentucky (Lexington, KY) addressed the question of adjuvant WBRT in a randomized controlled trial. In that study, patients with single brain metastases who underwent complete resection were randomly assigned to observation or WBRT (50.4 Gy).8 The primary end point for which the study was statistically powered was not survival, but intracranial recurrence. Survival was measured and analyzed as a secondary end point. Tumor recurrences anywhere in the brain (local recurrences plus recurrences within the brain but outside surgical bed) were 70% without and 18% with adjuvant WBRT. Adjuvant radiation therapy appeared to decrease recurrences significantly at both the surgical bed and distant sites, as well as the incidence of death as a result of neurologic causes. However, overall survival, the secondary end point, for which the study was not actually powered, was not influenced by the addition of WBRT.
The current study represents one of the initial prospective multi-institutional trials to address the feasibility of up-front RS alone in patients with one to three brain metastases. The median survival time of 8.3 months observed in this study compares favorably with that of other series.23 Our most important finding was that there was a high degree of failures within the brain (approximately 50% of patients by 6 months) with the omission of WBRT; this rate is higher than our estimates at the time of study design.
A recent multi-institutional Japanese phase III trial (Japanese Radiation Oncology Group [JROSG] 99-1) evaluating RS alone has been reported in abstract form.23 In this study, 132 patients with one to four brain metastases were randomly assigned to RS alone versus WBRT plus RS. Although this study demonstrated no statistically significant difference in survival or death as a result of neurologic causes between the two arms, there was a significantly higher rate of intracranial failures with the omission of WBRT. This was observed with respect to local failures (30% v 14% at 12 months; P = .001) and new brain metastases (64% v 42% at 12 months) with RS alone versus WBRT plus RS, respectively. Table 6 compares the intracranial failure rates of the current study versus the recent Japanese trial and the study reported by the University of Kentucky in 1998. A high intracranial failure rate is seen in all three prospective clinical trials with the omission of WBRT.
The failure rate within the RS volume in this trial (32%) is higher than retrospective experiences with brain metastases from a range of malignancies.11,17,24 This is also contrary to what has been reported in retrospective studies of RS alone in brain metastases from radioresistant histologies such as melanoma and renal cell carcinoma.14,15,17 A likely explanation is the fact that retrospectively reported data contain patients that are selected for RS, as opposed to requiring the treatment of the majority that enroll onto a clinical trial. Consequently, included in these retrospective reports are patients who may be days, weeks, or months from completion of WBRT, and these patients may constitute a more favorable biologic subgroup. Second, the distinction between tumor progression and necrosis after RS is sometimes complex and could lead to differences in estimates among different reports.
One of the arguments against the use of WBRT is the possibility of diminished neurocognitive functioning in long-term survivors.25 However, the adverse effects of WBRT may have been overestimated in the past and may be at an acceptable range with current fractionation schedules.4 Several recent studies have demonstrated that recurrence/progressive disease may be the primary factor influencing neurocognitive decline in these patients.26-28 The current study did not demonstrate that global cognitive function, as measured by the Mini Mental Status Examination, was significantly altered. One explanation is that longer follow-up is needed to see changes in cognitive function, and only five patients were alive, were progression free, and had scores beyond 6 months. Likewise, the recent Japanese multi-institutional trial did not show a detriment in cognitive function, using performance status as a surrogate, between the two study arms, despite the fact that the RS-alone arm had greater degree of intracranial failure.23 Therefore, an additional explanation for the lack of evidence for cognitive decline may be that measures such as Mini Mental Status Examination and performance status are simply not sensitive enough. These tests may not be adequate to detect neurocognitive loss, which may be evident if more sensitive methods are used. Prospective studies have used a battery of neurocognitive tests before and after WBRT to measure neurocognitive impairment.28,29 These studies have demonstrated that a significant number of patients (> 90%) have impaired neurocognitive functioning at baseline despite a Karnofsky performance score 70.28 Moreover, patients with progressive disease have greater median changes in their overall neurocognitive decline (decline in z score), and only patients with responses demonstrate improvements in individual tests of executive function.28
In conclusion, this study demonstrated that the median survival time of patients treated with RS up front was equivalent to published surgical and concurrent RS plus WBRT series. Intracranial failures with the omission of WBRT were high. Although this may not manifest in a detriment in survival, which is largely determined by systemic disease, more sensitive neurologic assessment tools may helping identify WBRT’s impact on mental performance. How this relates to one's ability to manage finances, recognize unsafe behaviors, comply with medication regimens, and perform higher executive functions needs to be better established. On the basis of the observed intracranial failure rate in this trial, the routine practice of avoiding WBRT should be used judiciously outside a clinical trial. To better define the survival impact as well as quantify quality of life and neurocognitive functional changes, an ongoing North Central Cancer Treatment Group/American College of Surgeons Oncology Group phase III clinical trial is underway.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Presented as an oral presentation at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5–8, 2004, New Orleans, LA.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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