Radiation Therapy in the Management of Brain Metastases From Renal Cell Carcinoma

Transcription

1 Radiation Therapy in the Management of Brain Metastases From Renal Cell Carcinoma Review Article [1] May 01, 2006 Oncology Journal [2], Kidney Cancer [3], Renal Cell Carcinoma [4] By Lucius S. Doh, MD [5], Robert Amato, DO [6], Arnold C. Paulino, MD [7], and Bin S. Teh, MD [8] Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed. he incidence of renal cell carcinoma (RCC) has increased for more than 2 decades. The cause of the increase is not known, but improved diagnostic techniques and early detection are suspected to be contributors.[1] According to the US census and cancer statistics, carcinoma of the kidneys affected approximately 36,160 lives in 2005,[2,3] more than 80% of whom had RCC. A third of the patients with RCC have evidence of metastases at the time of the diagnosis, and up to half of the patients treated for localized disease eventually develop a recurrence.[4] Approximately 4% to 17% of all RCC patients eventually develop brain metastases, with 50% of these suffering from multiple lesions.[5] Untreated, patients with brain metastasis from RCC have a poor prognosis and a mean survival of 3.2 months.[6] The distribution of RCC brain metastases, as with many other types of brain metastases, parallels brain weight and blood flow.[7] T Radioresistance RCC is considered to be radioresistant. Conventional radiation therapy has not been effective in controlling this type of tumor in the curative or adjuvant settings. The lack of effectiveness may well be due to the intrinsic radioresistance of the tumor. In the linear-quadratic model, a low alpha-beta ratio implies radioresistance. Recent experiments with human cell lines of RCC have revealed a low alpha-beta ratio, ranging from 2.6 to (Table 1).[8-10] The exact cellular mechanisms of radioresistance in RCC remain elusive, but various intranuclear and extranuclear molecular markers (including p53, BRCA1, BRCA2, HER2/neu, Bcl-2, PI-3k, ataxia telangiectasia kinase, IFG-I, HER1, HER2, VEGF, and ECF) have been shown to influence radiosensitivity for other tumor types. Page 1 of 18

2 On the other hand, the failure of radiation to control RCC in the curative or adjuvant setting may have more to do with the tolerance of neighboring structures to the kidney than intrinsic tumor resistance. The organs of the abdomen including the liver and small bowel have a relatively low tolerance for radiation, and thus the curative and adjuvant trials have generally been restricted to moderate radiation doses of 30 to 55 Gy. In contrast to the curative or adjuvant setting, radiation has been effective in palliating RCC, especially in the metastatic setting.[11-13] Differences in results may be attributable to differences in radiation technique. Metastatic RCC has been treated with higher doses and more hypofractioned radiation including stereotactic radiosurgery, whereas curative cases have used lower total doses and conventional fractionations. RCC may be more responsive to radiation at higher doses or in a hypofractionated form (including stereotactic radiosurgery). Systemic treatments may also have synergistic effects with radiation. Whole-Brain Radiotherapy Survival Whole-brain radiation therapy (WBRT) has been the community standard for treating brain metastases from many types of cancers. In general, the median survival time for patients with brain metastases treated with steroids alone is about 2 months. WBRT can increase median survival by 1 to 4 months for most tumor types.[14] The percentage of patients responding to WBRT varies greatly from study to study, with response rates of 50% to 70% generally reported.[15] WBRT alone results in median survivals of 7.1, 4.2, and 2.3 months for Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class I, II, and III, respectively, in patients with brain metastases from nonradioresistant tumors.[16] Page 2 of 18

3 Despite the reports of radioresistance, retrospective studies suggest that WBRT is an effective treatment modality for patients with brain metastases from RCC. Patients with untreated brain metastases from RCC have a median survival of 3 to 4 months.[6] In three retrospective series, patients with brain metastases from RCC treated with WBRT had slightly improved overall survivals of 3.0 to 7.0 months (Table 2).[17-19] Moreover, WBRT provided up to 60% local control (control at the sites of radiographically apparent disease), with only 8% of distant brain failure (incidence of new brain lesions away from initial sites of disease).[18] Reports of median survivals according to RTOG RPA classes further support the effectiveness of WBRT for metastatic RCC (Table 3). The median survival in patients with brain metastases from RCC treated with WBRT is 8.5, 3, and 0.6 months for classes I, II, and III, respectively. Page 3 of 18

4 Dose-Response Effect The role of dose escalation and/or hyperfractionation in WBRT for non-rcc brain metastases is controversial. The RTOG has conducted two randomized studies that demonstrated comparable results for different fractionation schedules 40 Gy in 15 or 20 fractions, 30 Gy in 10 or 15 fractions, and 20 Gy in 5 fractions.[20,21] In these randomized trials, there was no difference in neurologic function, duration of improvement, time to progression, or survival. These results were recently challenged by Epstein and colleagues, who reported superior survival times and improved neurologic function in patients with solitary brain metastases using whole-brain doses of 32 Gy administered in 1.6 Gy fractions twice daily, followed by boost doses to 48, 54, 64, and 70 Gy.[22] Survivals increased with increasing doses, from 4.9 months with 48 Gy to 8.2 months with 70 Gy. Nieder et al found that patients who received WBRT with 30 Gy in 10 fractions had half the response rate of the group receiving 40 to 60 Gy in 20 to 30 fractions but no survival benefits.[23] These retrospective studies suggest that there may be a dose-response effect at higher doses, which is not evident at lower doses such as the ones used in the randomized RTOG trials. Although there is some evidence that dose-escalation or hyperfractionation may improve response rates and survival in patients with non-rcc metastases, such data are scant in RCC. A retrospective study of RCC patients by Cannady and colleagues found that patients who receive more than 30 Gy had significantly longer survival than patients who received 30 Gy or less. This result, however, was confounded by the fact that patients who received higher doses also had better prognostic factors such as Karnofsky performance status and RPA class. Thus, it remains unclear whether a change in dose or fractionation has an impact on the treatment of RCC brain metastases. WBRT continues to be the treatment of choice for patients with a single brain metastasis not amenable to surgery or radiosurgery, for patients with poorly controlled systemic disease and thus a relatively short life expectancy, and for patients with multiple brain metastases whose metastases are too numerous for stereotactic radiosurgery or surgery. The most commonly reported dose for WBRT in RCC is 30 Gy in 10 fractions. In practice, the dose and fraction size of WBRT should be individualized to take into consideration the status of systemic or extracranial disease as well as performance status. While higher fractional dose as well as total dose may increase the chance of complications, non-rcc research suggests that increased doses may improve quality of life and survival. Dose escalation in RCC should be explored especially in combination with other therapeutic modalities such as surgery, radiosurgery, and systemic therapy (eg, molecular targeted therapy). Page 4 of 18

5 Surgery Surgical resection of a metastatic brain tumor has several advantages, including: confirmation of pathology, rapid reversal of neurologic symptoms, no risk of radionecrosis, and durable local control. In non-rcc patients, randomized trials have evaluated the benefits of surgery in patients with good performance status or limited or controlled systemic disease.[24-26] Three randomized trials by American, Dutch, and Canadian investigators have tested surgery plus WBRT vs WBRT alone. The American and Dutch studies have primarily included patients with controlled or limited systemic disease, and both have reported 9- to 10-month survivals with surgery plus WBRT vs 3 to 6 months with WBRT alone.[24,25] In contrast, the Canadian study, which included a higher proportion of patients with active systemic disease and lower performance scores, failed to show any advantage of surgery plus radiotherapy over radiotherapy alone.[26] In addition, in the setting of brain metastases from non-rcc disease, complete surgical resections of up to three lesions yielded similar results to those for a single lesion among patients with accessible lesions and good performance status.[27,28] However, these lesions may require multiple resections and prolonged surgical interventions, and involve the risk of complications from anesthesia and surgery. The results of surgical resection of brain metastasis from RCC have been investigated in three retrospective studies.[29-31] Wronski, O Dea, and Salvati have reported median overall survivals of 14.5 to 27.5 months (Table 4). When comparing the results of surgical series to other treatment modalities for RCC, such as WBRT or stereotactic radiosurgery, one must keep in mind that patients in the surgical series had a much lower burden of disease (80% had only a solitary brain metastasis) and higher performance status than those in the other series. A randomized trial of WBRT vs surgical resection has not been reported, and in the absence of such a report, it is difficult to assess the true impact of surgery vs WBRT. However, given the weight of data from non-rcc randomized trials as well as retrospective RCC studies, current data support the proposition that surgery increases the median survival for patients with good performance status, limited systemic disease, and a single brain metastasis. Furthermore, based on non-rcc data, the benefits of surgery may extend to patients with up to three brain metastases from RCC.[27,28] Adjuvant WBRT The benefits of postoperative WBRT, including a 52% reduction in recurrences in the brain, have been validated in phase III randomized trials.[32] Patchell showed that postoperative WBRT administered to a dose of 50.4 Gy in 28 fractions reduced brain recurrence at the local or distant brain sites to 18%, compared to 70% in the observation arm. In addition, most retrospective studies support the viewpoint that combined surgery plus WBRT improves survival in patients without evidence of extracranial disease but not in patients with uncontrolled systemic disease. In RCC, however, the effectiveness and role of adjuvant WBRT continue to be controversial. The two RCC surgical series by Wronski et al and Salvati et al have failed to show a benefit with postoperative WBRT (Table 4), both in terms of brain recurrences and overall survival.[29,31] Notably, the radiation doses used by Wronski and Salvati were lower than those in the randomized trial by Patchell. The average dose in Wronski's series was 30 Gy in 10 to 15 fractions, whereas Salvati used various doses and fractions 30 Gy in 10 fractions, 40 Gy in 20 fractions, 45 Gy in 25 fractions, or stereotactic radiosurgery. No significant differences in survival time were noted in the various radiotherapy groups. Whether patients with RCC would benefit from higher-dose WBRT as used by Patchell remains untested and would be of significant interest. Stereotactic Radiosurgery Local and Distant Control In a single session, stereotactic radiosurgery provides, a high dose of radiation to a localized brain Page 5 of 18

6 tumor volume while minimizing the dose to the surrounding normal tissues. The accuracy of the commonly available stereotactic radiosurgery devices range from 1.1 to 1.3 mm.[33-35] For patients with brain metastases from non-rcc disease, stereotactic radiosurgery can produce results equivalent to surgery. Bindal and colleagues reported improved survival and local control for patients undergoing surgical resection compared to stereotactic radiosurgery.[27] However, most studies support the notion that stereotactic radiosurgery, alone or in conjunction with WBRT, yields results that are comparable to those reported with surgery followed by WBRT for brain lesions less than 3 cm and for up to two metastases.[28,36,37] In addition, randomized trials in non-rcc patients have reported the benefits of stereotactic radiosurgery for those with favorable characteristics. A randomized trial by RTOG with 333 patients reported a 6.5- vs 4.9-month overall-survival advantage in favor of stereotactic radiosurgery plus WBRT vs WBRT alone for patients with a solitary brain metastasis, RPA class I, age less than 50 years, non-small-cell lung cancer, or any squamous cell carcinoma. In general, stereotactic radiosurgery provides a local tumor response rate of 80% to 90% with a median survival of 7 to 12 months.[38] Many retrospective studies have investigated the role of stereotactic radiosurgery in brain metastases from RCC. Table 5 summarizes 11 retrospective RCC series that included stereotactic Page 6 of 18

7 radiosurgery as one of the main treatment modalities.[5,39-48] When stereotactic radiosurgery is one of the major components of the treatment of brain metastases from RCC, the results are encouraging. The local tumor control rate is 94% (range: 85%-100%), with a distant brain failure rate of 37% (range: 17.2%-50%). The median survival is 11 months (range: months). Dose-Response Effect The effective dose for stereotactic radiosurgery in RCC-associated brain metastasis is unclear. Hemibrain irradiation of healthy beagles in a single fraction suggests that there may be a sigmoid-shaped dose-effect curve with a sharp increase in radiation-induced brain changes occurring around 14 to 15 Gy.[49] In human studies, some have argued that radiotherapy effects are dose-dependent, whereas others have not found any evidence for this. Breneman and colleagues reported a significant improvement in local control with radiation doses greater than 18 Gy (median time to failure: 52 weeks with high-dose therapy vs 25 weeks with low-dose therapy; P =.008).[50] In an analysis of data from the University of California, San Francisco, Shiau and colleagues found that a minimum prescribed dose of greater than or equal to 18 Gy yields a greater failure-free survival rate at 1 year (90%), compared with those receiving less than 18 Gy (77%).[51] On the other hand, Alexander and colleagues have reviewed the impact of dose and found that it did not influence local control.[52] Reports by Shirato and Flickinger and colleagues also failed to show a correlation between dose and survival.[53,54] In general, larger tumors are treated with lower doses, confounding the presently available retrospective data. Future studies are needed to determine the effect of dose on tumor control for RCC as well as other tumor types. Currently, the radiation regimen is generally guided by toxicity and not the minimum effective dose. Maximum tolerable doses of 24, 18, and 15 Gy for lesions < 2 cm, 2-3 cm, and 3-4 cm, respectively, have been recommended by the investigators who conducted RTOG 90-05, a prospective dose-escalation trial of stereotactic radiosurgery in patients with recurrent or previously irradiated primary brain tumors and brain metastases.[55] Tumors less than 3 cm may be treated with 18 Gy, either with or without WBRT. This dose is considered to be effective with an acceptably low risk of toxicity. As for tumors 3 to 4 cm in size, the highest dose that should be given in one fraction is 15 Gy, again with or without WBRT. This dose may still be effective, but little evidence exists to suggest that doses < 15 Gy are effective in tumor control. Number of Lesions Although radiosurgery is a local procedure, it can be used multiple times to treat different lesions. Approximately half of the patients treated with stereotactic radiosurgery in RCC series have had multiple brain metastases. However, the maximum number of lesions that can be safely and efficaciously treated with stereotactic radiosurgery has not been identified for either RCC or other types of metastases. Some have suggested that patients with 10 or more metastases can be safely treated with a good quality-of-life outcome.[56,57] That said, repeated use of stereotactic radiosurgery for multiple lesions may not be more effective than simple WBRT. Studies suggest that the WBRT is equivalent to stereotactic radiosurgery alone for patients with three or more brain metastases.[52,58] Stereotactic Radiosurgery and WBRT A retrospective study by Sanghavi and colleagues demonstrated an improved median survival (P <.05) for non-rcc patients treated with stereotactic radiosurgery boost in addition to WBRT, compared to RPA-stratified patients from earlier RTOG studies of WBRT alone.[59] Three randomized trials have shown a local control benefit with the addition of stereotactic radiosurgery to WBRT.[60-62] The largest of the three studies by RTOG showed a median survival benefit of 1.5 months when stereotactic radiosurgery was added to WBRT. A randomized study by Brown University investigators compared stereotactic radiosurgery vs stereotactic radiosurgery plus WBRT, reporting local control rates of 87% vs 91% and distant brain failure rates of 43% vs 19%.[61] A fundamental problem with the Brown trial was that 53% of the patients had undergone surgery prior to randomization. Furthermore, these patients were not evenly distributed among the three treatment arms. To investigate the role of stereotactic radiosurgery and WBRT together in patients with brain metastases from RCC, we performed a subgroup analysis of published local and distant failure rates in patients who were treated initially with stereotactic radiosurgery plus WBRT or stereotactic radiosurgery alone. The analysis included 11 retrospective RCC series that used stereotactic radiosurgery as one of the main treatment modalities. A total of 39 patients were eligible for analysis in the stereotactic radiosurgery-plus-wbrt arm, and 50 patients were eligible in the radiosurgery-alone arm. The combination resulted in a local failure rate of 0% and a distant brain failure rate of 21% in this selected group.[45-48] In comparison, stereotactic radiosurgery alone Page 7 of 18

8 resulted in a mean local failure rate of 8% and a distant brain failure rate of 36% (Figure 1). Compared to stereotactic radiosurgery plus WBRT, radiosurgery alone may result in higher rates of distant brain failure as well as a high risk of local failures. Some authors suggest that salvage therapy is effective for both recurrences and new metastasis after stereotactic radiosurgery, and this approach would spare the majority of patients the toxicities of WBRT.[53,54,63] To date, retrospective series of RCC patients and prospective studies from non-rcc patients suggest that the addition of stereotactic radiosurgery to WBRT improves control of brain metastases without undue toxicities. The benefits of reserving WBRT for salvage therapy over upfront stereotactic radiosurgery and WBRT remain to be proven. Hypofractionated Stereotactic Radiotherapy Ikushima and colleagues reported on a series of patients with brain metastases from RCC who were treated with hypofractionated stereotactic radiotherapy vs surgery/conventional radiation vs conventional radiation only.[64] Median survival rates were 25.6 months for the hypofractionated radiotherapy group, 18.7 months for the surgery-plus-conventional radiation group and 4.3 months for the conventional radiation group. Hypo-fractionated stereotactic radiotherapy produced local control rates of 88% and 55.2% at 1 and 2 years, respectively. None of the 10 patients who were treated with hypofractionated radiotherapy suffered from acute or late complications during or following treatment, with a median follow up of 17.5 months from the beginning of treatment. The hypofractionated treatment group was treated to 42 Gy in 7 fractions over 2.3 weeks, dosed to the tumor isocenter using a 6-MV linac. Local control rates for the hypofractionated stereotactic radiotherapy group were not significantly better than historically reported values for stereotactic radiosurgery in RCC patients. Although the idea that such treatment could lessen toxicity is interesting and has been reported in several retrospective studies, it remains to be established in future investigations. WBRT Toxicity Acute side effects occurring during or soon after radiotherapy include hair loss, otitis media, skin irritations, and brain edema. With the possible exception of hair loss, these symptoms are generally transient and can be managed conservatively. The long-term side effects of radiotherapy are usually not a significant issue in the treatment of brain metastases from RCC because of the relatively short survival of these patients. Long-term survivors (> 12 months) frequently develop radiographic changes on computed tomography (CT) or magnetic resonance imaging (MRI), including hypodense areas in the white matter, cerebral atrophy, an increase in the sulcal width, and/or enlargement of the ventricles. However, only some long-term survivors (up to 11%) develop clinical symptoms such as dementia, ataxia, and urinary Page 8 of 18

9 incontinence.[65,66] Although the pathogenesis of these alterations is unknown, leukoencephalopathy is implicated. Leukoencephalopathy or white matter necrosis is generally associated with the combination of brain radiotherapy and intravenous or intrathecal methotrexate; the greatest injury occurs when all three modalities are used.[67] High-fractional dose (> 2 Gy per fraction) and high-dose schedules may also be a factor.[65] Consequently, patients with favorable prognostic factors are optimally treated with conventional fractions of 1.8 to 2 Gy to a total dose of 40 to 50 Gy, instead of 3-Gy fractions to a total dose of 30 Gy, as commonly employed. Radiation Necrosis Radiation necrosis is a loosely defined term referring to any changes noted on MRI (or other imaging) that are felt to represent a radiation treatment effect rather than recurrent tumor.[68] This potential complication is associated with stereotactic radiosurgery as well as whole-brain radiotherapy. Radiation necrosis can produce symptoms that are as disabling as tumor recurrence; the condition can be progressive and fatal. Surgical debulking should be performed if corticosteroids do not provide relief. Biopsy is the ultimate diagnostic test for radiation necrosis. Although biopsy-proven rates as high as 24% have been reported,[69] the true incidence of radiation necrosis is difficult to assess, as chemotherapy, fraction size, total dose, and diagnostic modalities all complicate findings. According to Sheline and colleagues, the brain can tolerate a total dose of 50 to 54 Gy if given in 2-Gy administrations once a day, with the estimated cerebral necrosis rate at 0.04% to 0.4%.[70] Cognitive Function Decline in intellectual function (IQ) is best studied in children. Radcliffe et al published a prospective study of 19 children treated for brain tumors with whole-brain radiotherapy; 14 of 19 also received adjuvant chemotherapy.[71] Children younger than 7 years at diagnosis had a mean IQ loss of 27 points, whereas children over 7 years at diagnosis showed no significant decrease in IQ. Decline in IQ occurred between baseline and year 2 of follow-up; no such decline was documented between years 2 and 4. In adults, many studies have shown decreases in mental function after brain irradiation but most of these fail to include pretreatment assessment of mental function. Some decline in mental function has been associated with radiologic changes, cerebral atrophy, and white matter hypodensities.[72,73] In a prospective study of patients with small-cell lung cancer, prophylactic cranial irradiation was not associated with a decline in mental function for the duration of the follow-up (6 to 20 months).[74] North Central Cancer Treatment Group (NCCTG) protocol was a two-arm prospective trial, in which 203 eligible/analyzable adult patients with supratentorial low-grade gliomas were randomized to localized radiation therapy using 50.4 Gy (arm A) vs 64.8 Gy (arm B).[75] Patients were evaluated with an extensive battery of psychometric tests at baseline (before radiation therapy) and at approximately 18-month intervals up to 5 years after completing radiation therapy. Formal cognitive testing completed before and after focal radiation therapy for low-grade glioma did not document significant detrimental effects in this group of patients evaluated prospectively over 3 years of follow-up. With a median follow-up of 7.4 years, these patients showed minimal deterioration from baseline on mini-mental examination. Deterioration from baseline occurred at years 1, 2, and 5 in 8.2%, 4.6%, and 5.3% of patients, respectively.[76] Thus, in contrast to data in children, prospective studies of adults have shown little or no decline in mental function due to WBRT with more than 5 years of follow-up. Stereotactic Radiosurgery Toxicity Specific data reporting acute toxicity for stereotactic radiosurgery is scarce and limited to small numbers of retrospective studies.[77,78] Acute toxicities are similar to that of WBRT and for the most part can be medically managed. They include edema, headaches, nausea and vomiting, worsening of preexisting neurologic deficits, and seizures. Chronic complications consist mainly of radionecrosis, cranial nerve palsies, and chronic steroid dependence. Treatment volume is the most consistent risk factor for long-term toxicity from stereotactic radiosurgery.[55,79] RTOG prospectively determined that the risk of complications from stereotactic radiosurgery increases with tumor size.[55] Varlotto and colleagues published long-term toxicity data for 137 patients treated with Gamma Knife radiosurgery at the University of Pittsburgh Medical Center.[79] The mean peripheral dose was 16 Gy (range: Gy). They reported the 1- and 5-year incidence of late complication as 2.8% and 11.4%, respectively. Treatment volume was the only significant factor associated with complications. Page 9 of 18

10 For tumors less than or equal to 2 cm3, the 1- and 5-year incidence of complications was 2.3% and 3.7%, respectively. For tumors greater than 2 cm3, complication rates at 1 and 5 years were 3.4% and 16%. Long-term toxicity will be more prominent and important in the future, as the systemic control of RCC improves. Radiation Sensitizers Hypoxic cell sensitizers make hypoxic cells susceptible to radiation effects. Although some of these agents appeared promising, none has shown benefit in the brain. The use of metronidazole was found to be beneficial 20 years ago for supratentorial glioblastomas, but the study has not held up, as the test group had a survival rate equivalent to historical controls.[80] Misonidazole has no documented benefit in gliomas.[81,82] Etanidazole (SR-2508) is being studied for metastatic brain tumors in RTOG 9502, but this agent had previously failed to show an advantage for head and neck cancers in RTOG Nimorazole, an analog of metronidazole has been shown to provide a higher local and regional control rate than placebo (49% vs 33%, P =.002) in a phase III study in head and neck cancer, producing an overall survival rate of 26% vs 16% (P =.32).[83] Tirapazamine, a hypoxic-cytotoxic agent, is also under study.[84,85] No hypoxic cell sensitizers have been found to be effective in RCC. The pyrimidines sensitize cells by being incorporated into a dividing cell. In RTOG 86-12, iododeoxyuridine showed a modest survival advantage over historical controls in anaplastic gliomas, but bromodeoxyuridine was considered to be a more promising agent.[86] Nevertheless, bromodeoxyurindine did not prove effective in a phase III setting for anaplastic glioma (RTOG 9404).[87] To date, these compounds have shown associated toxicity and do not adequately sensitize the entire tumor cell population.[88,89] Motexafin Motexafin gadolinium (Xcytrin) is a paramagnetic compound that has been shown to be taken up by tumor in MRI studies.[90,91] One proposed mechanism of action suggests that motexafin sensitizes cells to ionizing radiation by increasing oxidative stress as a consequence of futile redox cycling. Optimization of the concentration of ascorbate (or other reducing species) may be required when evaluating motexafin activity in vitro.[92] A phase III study of brain metastases comparing WBRT alone (30 Gy in 10 fractions) to WBRT with motexafin given before each fraction has demonstrated improved time to neurologic progression in all patients, with greatest benefit in lung cancer (the disease in ~60% of the study patients).[93] No overall survival benefit was seen in this group of patients, who mostly had uncontrolled primaries. Currently, we are investigating this agent in patients with metastatic RCC in a phase I trial. Motexafin may have a role in combination with WBRT for brain metastases from RCC, which remains to be defined. While compounds such as gadolinium offer hope, no radiation sensitizer has yet been found to be effective in renal cell carcinoma. Chemotherapy Traditionally, chemotherapy has played a limited role in the management of brain metastases. It is our current understanding that the blood-brain barrier is disrupted near tumor vasculature.[94] In support of this mechanism, a prospective study that assessed that activity of a cisplatin/etoposide without radiation in patients with brain metastases reported overall response rates of 38%, 30%, and 0% for breast cancer, non-small-cell lung cancer, and melanoma patients, respectively. These results were similar to those in patients with systemic disease who did not have brain metastases.[95] Although both the development of brain metastases and the use of whole-brain irradiation can lead to some impairment of the blood-brain barrier, it remains unclear as to what degree the disruption would allow chemotherapeutic agents to penetrate the central nervous system. The use of chemotherapy for brain metastasis should be explored further, especially in combination with whole-brain irradiation. Temozolomide Temozolomide (Temodar), the 3-methyl derivative of mitozolomide, has shown promise in gliomas because of its comparable antitumor activity in preclinical studies, favorable toxicologic profile, and excellent oral bioavailability and tissue distribution, including central nervous system penetration.[96-99] Temozolomide alone has been studied for brain metastases in recurrent/progressive disease as well as for newly diagnosed brain metastases. Used alone, the agent produces 4% to 6% complete or partial response rates for recurrent/progressive tumors[ ] and 24% to 38% complete or partial response rates for primary tumors. The best response was seen in primary melanoma, with a 40% response rate.[103,104] In combination with whole-brain irradiation, temozolomide has been studied in both Page 10 of 18

11 phase II and phase III trials, with tumor response rates favoring the combination arm by 20% to 22%.[ ] The response rate in the combined-therapy arm ranged from 35 to 96%. Unfortunately, temozolomide as a single agent or in combination with interferon-alfa has not been effective in renal cell carcinoma.[109,110] Although promising, especially in combination with radiation therapy, temozolomide currently has no defined role in RCC. Conclusions Radiotherapy has played an important role in the management of brain metastases from renal cell carcinoma despite the radioresistance of the disease. Whole-brain radiotherapy appears to be as beneficial for patients with brain metastasis from RCC as it is for other tumor types. Retrospective studies suggest that a boost of radiation to tumor sites in addition to WBRT may improve local control rates. More recently, stereotactic radiosurgery has resulted in encouraging short-term local control rates (> 90%). Surgical series of patients with good performance status and limited systemic and brain disease have reported higher median survival rates compared to stereotactic radiosurgery series in retrospective studies. Whether this is simply a function of selection bias or a true improvement in survival is unknown and should be studied prospectively. Distant brain failure continues to be a challenge for both stereotactic radiosurgery and surgery. Advances in neuroimaging (eg, MRI), radiation physics (eg, stereotactic radiosurgery technology), and radiation biology (eg, radiosensitization) have led to improvements in the targeting and effectiveness of radiotherapy, especially stereotactic radiosurgery. This progress has led some to advocate the use of stereotactic radiosurgery alone for appropriate candidates. Evidence suggests that WBRT improves distant brain failure and local control rates. However, how to most effectively address distant brain failure ie, with WBRT, or with stereotactic radiosurgery, close follow-up, and salvage therapy (stereotactic radiosurgery or surgery) remains unanswered and should be investigated in a prospective fashion. Opportunities in the management of brain metastases from renal cell carcinoma are expanding rapidly. While no systemic therapies have been shown to be effective either alone or with radiation in the treatment of metastatic brain cancer from RCC, this is an exciting area of investigation. The biotechnology of gene-expression profiling may help us identify the "radioresistance gene" in renal cell carcinoma and make this cancer more radiosensitive via the RNA interference (RNAi) approach.[ ] Learning from other disease sites, the combination of systemic agents with radiotherapy is another area requiring further investigation. The integration of higher-dose whole-brain radiotherapy, with or without systemic agents, also warrants future testing to improve distant brain control and, hopefully, survival, and not at the expense of toxicity. The emergence of novel molecularly targeted therapy such as bevacizumab (Avastin), sorafenib (Nexavar), and sunitinib (Sutent) is likely to prolong survival in patients with metastatic renal cell carcinoma. A higher incidence of brain metastases may result from improved systemic control, as the central nervous system is believed to be a sanctuary site for disease during treatment with the majority of systemic agents. It is important to integrate radiotherapy (stereotactic radiosurgery, WBRT) properly with surgery and systemic treatment, to maximize control and prolong the survival of patients with RCC. Disclosures: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. Dr. Teh's work was supported by The Methodist Hospital Research Institute research grant. References: 1. Marshall FF, Stewart AK, Menck HR: The National Cancer Data Base: Report on kidney cancers. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 80: , Jemal A, Murray T, Ward E, et al: Cancer statistics, CA Cancer J Clin 55:10-30, Devesa SS, Silverman DT, McLaughlin JK, et al: Comparison of the descriptive epidemiology of urinary tract cancers. Cancer Causes Control 1: , Flanigan RC, Campbell SC, Clark JI, et al: Metastatic renal cell carcinoma. Curr Treat Options Oncol 4: , Page 11 of 18

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17 Phys 51: , 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: , Greig N: Implications of the blood brain barrier and its manipulation, in Neuwelt E (ed): Brain Tumor and the Blood Tumor Barrier, vol 2. New York, Plenum, Franciosi V, Cocconi G, Michiara M, et al: Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: A prospective study. Cancer 85: , Newlands ES, Blackledge GR, Slack JA, et al: Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC ). Br J Cancer 65: , Stevens MF, Hickman JA, Langdon SP, et al: Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47: , Stupp R, Dietrich PY, Ostermann Kraljevic S, et al: Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20: , Gilbert MR, Friedman HS, Kuttesch JF, et al: A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy. Neuro-oncol 4: , Christodoulou C, Bafaloukos D, Kosmidis P, et al: Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol 12: , Abrey LE, Olson JD, Raizer JJ, et al: A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol 53: , Friedman H, Evans B, Reardon D: Phase II trial of temozolomide for patients with progressive brain metastases (abstract 408). Proc Am Soc Clin Oncol 22:102, Siena S, Landonio G, Baietta E: Multicenter phase II study of temozolomide therapy for brain metastasis in patients with malignant melanoma, breast cancer, and non-small cell lung cancer (abstract 407). Proc Am Soc Clin Oncol 22:102, Bafaloukos D, Gogas H, Georgoulias V, et al: Temozolomide in combination with docetaxel in patients with advanced melanoma: A phase II study of the Hellenic Cooperative Oncology Group. J Clin Oncol 20: , Antonadou D, Paraskevaidis M, Sarris G, et al: Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 20: , Antonadou D, Coliarakis N, Paraskevaidis M: Whole brain radiotherapy alone or in combination with temozolomide for brain metastasis. A phase III study. Int J Radiat Oncol Biol Phys 54:93-94, Verger E, Gil M, Yay R: Concomitant temozolomide (TMZ) and radiotherapy (RT) in patients with brain metastasis: Randomized multicentric phase II study, a preliminary report (abstract 309). Proc Am Soc Clin Oncol 21:78a, Verger E, Gil M, Yaya R: Concomitant temozolomide (TMZ) and whole brain radiotherapy (WBRT) in patients with brain metastasis (BM): Randomized multicentric phase II study (abstract 404). Proc Am Soc Clin Oncol 22:101, Page 17 of 18

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