Abstract
Background. Stereotactic radiotherapy is a non-invasive, ablative technique which may be particularly effective in treating metastatic renal cell carcinoma (RCC). The study objective was to analyse outcomes and toxicity of stereotactic radiotherapy in metastatic RCC.
Material and methods. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of Medline was performed in March 2013. Exclusion criteria included mixed histology studies and case series. Local control, overall survival and toxicities were analysed.
Results. From 148 publications identified, 16 and 10 publications for cranial and extracranial metastatic RCC met inclusion criteria, respectively. There were 810 intracranial patients and 2433 targets. The weighted local control was 92%. Overall survival ranged from 6.7 to 25.6 months. Significant Grade 3–4 toxicity ranged from 0% to 6%. The weighted rate of treatment-related mortality was 0.6%, all secondary to intratumoral haemorrhage. There were 389 extracranial patients and 730 targets. The weighted local control was 89%. Median overall survival ranged from 11.7 to 22 months. Grade 3–4 toxicity ranged from 0% to 4%. Treatment-related mortality was 0.5%.
Conclusion. Stereotactic radiotherapy is associated with excellent local control and low rates of toxicity for intracranial and extracranial metastatic RCC. Future randomised studies are required to confirm the additional benefit of Stereotactic Ablative Body Radiotherapy (SABR) above standard conservative or palliative approaches.
The incidence of renal cell carcinoma (RCC) is rising, particularly in patients aged 70–90 years [Citation1]. Overall, 50% of patients will eventually develop metastatic disease [Citation2]. Common sites of metastatic disease include the brain, lung and bones. In patients with metastatic disease, the median survival time ranges from six to 12 months, and in patients with brain metastases, the mean survival time is three months [Citation3,Citation4].
Brain metastases are commonly treated with whole brain radiotherapy (WBRT), surgery, or both. Increasingly intracranial stereotactic radiosurgery (SRS) and stereotactic ablative body radiotherapy (SABR) are being used as non-invasive ablative techniques for metastatic disease. These techniques may be a particularly attractive option in an ageing patient population with multiple co-morbidities, as well as a more effective option in treating metastatic RCC, which is traditionally thought to be a ‘radioresistant’ disease.
Intracranial SRS is a highly precise ablative radiotherapy technique administered in a single treatment session commonly used to treat brain metastases. SABR is an approach to stereotactic radiotherapy, which extrapolates from the principles used in intracranial SRS. Stereotactic radiotherapy typically uses vastly different total doses and doses per fraction compared to more traditional palliative radiotherapy regimens, such as 20 Gy in 5 fractions, or 30 Gy in 10 fractions. There is heterogeneity of dosing regimens used within the stereotactic radiotherapy literature itself. A widely used method to allow comparison of the biological effect of various dosing regimens utilises the linear quadratic (LQ) model. This model employs laboratory derived α/β estimates of various cell lines in order to calculate a biological equivalent dose (BED) [Citation5].
The use of stereotactic radiotherapy for metastatic RCC has been investigated by a relatively large number of small studies. The aim of this study was to perform a systematic review to more accurately assess the use of stereotactic radiotherapy in cranial and extracranial metastatic RCC, focusing on associated outcomes including local control (LC), overall survival (OS) and toxicity. A critical analysis of radiation technique, comparative dose using BED calculations, and patient outcomes was performed.
Material and methods
A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [Citation6].
Search strategy
We searched for English language papers published from January 1946 to March 2013 using Ovid MEDLINE and the Cochrane Library. The search strategy for the MEDLINE search utilised the following Medical Subject Headings (MeSH) and text words (TW): renal cell carcinoma (TW), kidney neoplasms (MeSH), kidney cancer (TW), kidney tumor (TW), radiosurgery (MeSH), radiosurgery (TW), sabr (TW), stereotactic (TW), sbrt (TW), neoplasm metastasis (MeSH), metastasis (TW), and oligometastases (TW). From this search, 148 records were found. The same MeSH terms were used to search the Cochrane Library, with no additional studies found. A grey literature search was also performed, with no additional studies found. An abstract search was also performed of major radiotherapy and oncology journals: International Journal of Radiation Oncology, Biology and Physics, Radiotherapy and Oncology, Acta Oncologica, Strahlentherapie und Onkologie, American Journal of Clinical Oncology, Clinical Oncology and Radiation Oncology. This yielded one additional study. Titles and abstracts were subsequently screened by two authors (GK, SS) and full text copies of 130 records of potentially relevant articles were obtained and reviewed, yielding a total of 25 studies for inclusion within the systematic review. A secondary search was performed during which the reference lists of all full text articles reviewed was also screened, with no additional studies found (see Supplementary Figure 1 available online at http://informahealthcare.com/doi/abs/10.3109/0284186X.2014.939298).
Eligibility criteria
Published studies of the use of stereotactic radiotherapy in patients with metastatic RCC were included if they reported clinical outcomes such as LC, OS and toxicity following stereotactic radiotherapy for metastatic RCC. These included studies that also included patients with non-metastatic RCC. Both prospective and retrospective studies were included in the review in order to allow as complete an overview of the available evidence as possible.
Studies were excluded however if they were case series of fewer than five patients, given the limited utility in quantifying outcomes from such a small number of patients. Studies were also excluded if they included patients with cancer types other than RCC, they were review articles or commentaries that contained no original data, and if there were multiple publications reporting overlapping patient cohorts, in which case only the most recent or most relevant publication was included.
Evaluation of studies
The evaluation of studies was performed independently by two authors (GK, SS). The studies were qualitatively assessed for their internal validity and risk of bias at the study and outcome level. There is no standardised system for assessing and including studies within a systematic review and final selection was based upon consensus [Citation6].
Data extraction and management
From the studies included, information including patient characteristics, radiotherapy details, clinical outcomes and toxicity data were obtained. There was variation in how the dose was prescribed, including whether it was prescribed to the isocentre or periphery, and in some cases this information was missing. Where available, the marginal doses were recorded. The median or mean dose for single dose regimens or the modal dose for hypofractionated regimens was used to calculate the BED of each treatment, using the α/β estimates of the two common human RCC cell lines, Caki-1 and A498 (6.9 and 2.6, respectively) [Citation7]. Clinical outcomes abstracted included one-year LC and OS. When data regarding LC were not provided, they were extrapolated from reported time points, if available, assuming a constant hazard and consistent censoring of data. Weighted crude LC and one-year LC rates were calculated using the average of each of the categories with respect to the number of targets within each study.
Intracranial SRS
A total of 16 studies were found suitable for inclusion, all of which were retrospective studies (see and Supplementary Tables I and II, available online at http://informahealthcare.com/doi/abs/10.3109/0284186X.2014.939298). One study by Ikushima et al. [Citation8] reported outcomes for both patients who received stereotactic radiotherapy (n = 10) as well as patients who did not receive stereotactic radiotherapy, but received a combination of WBRT with or without surgery (n = 22). Another study by Fokas et al. [Citation9] reported outcomes for patients who received stereotactic radiotherapy (n = 68) as well as patients who did not receive stereotactic radiotherapy, but received WBRT alone (n = 20). The remainder of the studies reported exclusively on patients who received stereotactic radiotherapy. Staehler et al. [Citation10] reported outcomes for both cranial and extracranial RCC and was included in both groups.
Table I. Intracranial characteristics.
Patient and target characteristics
Within the intracranial literature, there were 810 patients with 2433 targets. The patient population was heterogeneous in terms of baseline characteristics, burden of metastatic disease, and prior treatment. The median age of patients within the studies ranged from 55 to 64 years old. There was wide variability in the literature with respect to the number of brain metastases, with the percentage of patients with single brain metastases ranging from 18% to 90%. The median Karnofsky Performance Status (KPS) ranged from 70 to 90. The percentage of patients with extracranial metastases ranged from 32% to 100%. The recursive partitioning analysis (RPA) class was reported in six studies with the percentage of patients with RPA class I [< 65 years of age with a KPS of at least 70, and a controlled primary tumour with the brain the only site of metastases] ranging from 7% to 29%. The percentage of patients with a single brain metastasis ranged from 18% to 90%. Eleven of 16 studies reported on prior WBRT, which was received in 0–50% of patients within the studies. Only five studies reported the location of lesions within the brain, with a majority (64%) being within the supratentorial region. Ten studies reported mean tumour volume and this ranged from 1 cm3 to 6 cm3 (minimum < 1 cm3; maximum 76 cm3).
Radiotherapy characteristics
Within the intracranial literature, 10 studies used Gamma Knife, while five studies used LINAC-based therapy, with one of these studies by Staehler et al. [Citation10] utilising CyberKnife®, (Accuray, Inc., Sunnyvale, California) technology. One study by Goyal et al. [Citation11] used both LINAC based and Gamma Knife SRS. Fifteen of 16 studies used single dose regimens. The median or mean marginal dose ranged from 17 Gy to 25 Gy. One study by Ikushima et al. [Citation8] used fractionated stereotactic radiotherapy to a dose of 42 Gy in 7 fractions. The BED6.9 ranged from 58 to 116, and the BED2.6 ranged from 125 to 265.
Local control
Crude LC rates were reported in 14 of 16 cranial studies which ranged from 75% to 100%. The definition of LC varied, and within three studies it was calculated using the number of patients rather than targets that progressed locally. The weighted crude LC rate calculated from these 14 studies was 92%. Seven studies also calculated a one-year LC rate using the Kaplan-Meier method, and this ranged from 71% to 100%. For a further five studies, we were able to extrapolate the one-year LC as described previously. From these 12 studies, we calculated the weighted one-year LC to be 88%. The percentage of patients that experienced distant brain failure (DBF) was also reported in eight studies and ranged from 29% to 60%. A further two studies estimated one-year DBF to be 51% and 70%.
Factors reported to correlate with LC included dose delivered and tumour volume. Shuto et al. was the only study within the intracranial literature which reported a significant correlation between LC and delivered dose, as well as LC and intracranial tumour volume on univariate and multivariate analysis [Citation12]. Kano et al. found a statistically significant correlation between marginal dose to the tumour of greater than 17 Gy and improved OS on univariate but not multivariate analysis [Citation13].
Survival
All of the 16 intracranial studies reported median OS, which ranged from seven to 26 months. Eleven studies reported one-year OS and this ranged from 36% to 90%, while 10 studies reported two-year OS and this ranged from 15% to 54%. The largest study in the group was by Kano et al. which reported outcomes for 158 patients, with the median OS in this group being eight months [Citation13]. Upon multivariate analysis, factors associated with a longer survival time included younger age (p = 0.04), higher KPS (p < 0.01), fewer brain metastases (p = 0.01), no prior WBRT (p = 0.02), and no prior chemotherapy and/or immunotherapy (p < 0.01) [Citation13]. Ikushima et al. reported the highest median OS within the intracranial studies, and also showed that OS was improved with stereotactic radiotherapy compared with surgery and WBRT (19 months) and WBRT alone (4 months) although the total number of patients in this study was small (n = 35).
Treatment-related toxicity
Within the cranial literature, 15 of 16 studies provided information regarding treatment toxicity, however only three studies reported toxicity using a standardised toxicity grading system. From the three studies that used a toxicity grading system two of 129 (2%) of patients reported Grade 3 or 4 acute toxicity and four of 129 (3%) patients reported a Grade 3 or 4 late toxicity. From the 15 studies that reported toxicity, there were four of 731 treatment-related deaths, with a weighted treatment-related mortality of 0.6%. All four deaths were secondary to intra-tumoural haemorrhage.
Extracranial SABR
A total of 10 studies were found suitable for inclusion, of which two were prospective studies (see and Supplementary Tables III and IV, available online at http://informahealthcare.com/doi/abs/10.3109/0284186X.2014.939298). Within the extracranial literature, three studies also included patients treated with SABR for primary RCC, although the total number of patients was small (n = 14). As previously noted Staehler et al. reported outcomes for both cranial and extracranial RCC and was included in both groups.
Table II. Extracranial characteristics.
Patient and target characteristics
Within the extracranial literature, there were 389 patients with 730 targets. The patient population was heterogeneous in terms of baseline characteristics, burden of metastatic disease, and prior treatment. Median or mean age was provided in seven studies and ranged from 58 to 63. KPS was only provided in four studies, and in most of these patients was 60 or higher. Of the 10 studies, Staehler et al. [Citation10] was the only study in which patients received concurrent systemic treatment with anti-angiogenic treatment. In three studies, no patients had received prior radiotherapy to the target lesion. Five studies included patients treated with SABR to bony metastases only, predominantly to the spine, while the remaining five studies included a variety of locations, most commonly to the lung. Six studies reported the mean or median target volume, which ranged from 30 cm3 to 92 cm3 (minimum < 1 cm3; maximum 1137 cm3).
Radiotherapy characteristics
Within the extracranial studies, all but two studies used linear accelerator-based delivery systems, whilst the two others reported on the use of CyberKnife® (Accuray, Inc., Sunnyvale, CA, USA). A wide range of total doses and dose fractionation schedules were used. The BED6.9 ranged from 48 to 143 and the BED2.6 ranged from 98 to 305. Five studies incorporated the use of single fraction regimens, with the total SRS dose ranging from 8 Gy to 24 Gy.
Local control and pain relief
Nine of 10 studies had crude LC data available. The weighted crude LC was 89%. One-year LC was reported using the Kaplan-Meier method for only one study, and was able to be extrapolated from the available data for a further eight studies, giving a weighted one-year LC of 86%. Three studies reported local progression-free survival (PFS) which ranged from 71.2% to 82%.
Several of the studies also suggested that higher biological doses resulted in better LC. Zelefsky et al. [Citation14] reported the three-year local PFS (88%) with a high single-dose (24 Gy; n = 45) was greater than both a low single-dose (< 24 Gy; n = 14), or hypofractionation regimens (n = 46) at 21%, and 17%, respectively. Multivariate analysis revealed that both a higher single dose compared with a lower dose, and single dose regimens compared with hypofractionation were both significant predictors of improved local PFS (p < 0.01). Gerszten et al. [Citation15] reported that in two cases of tumour progression, a relatively low dose of 18 Gy (BED6.9 62) was administered. Svedman et al. [Citation16] reported only one local progression. In this case, a relatively low dose of 40 Gy in 5 fractions was administered (BED6.9 86). In another study by Ranck et al. [Citation17] there were only two of 39 incidents of local progressions seen, both in patients who received relatively low doses of 24 Gy in 3 fractions (BED6.9 52) and 30 Gy in 3 fraction regimens (BED6.9 73).
One study also suggested that a higher mean tumour volume was associated with lower LC with a 40% higher mean tumour volume of 102.6cc in the six cases of local progression, which was 40.7cc greater than the overall mean volume of 61.9cc for all targets [Citation15].
Five studies reported on the number of patients that experienced improvement in pain following SBRT with a total of 113 of 164 patients (69%) experiencing improvement in pain, and up to 67% of patients in a study by Balagamwala et al. [Citation18] reporting complete pain relief at nine months.
Survival
Median OS for all patients with metastatic RCC only was reported in three studies and ranged from 12 to 22 months. In one of these studies, Staehler et al. reported KPS as the only significant factor associated with OS on multivariate analysis (p < 0.01) [Citation10]. Two studies reported estimated one-year OS of 49% [Citation18] and 72% [Citation19], while another study by Ranck et al. [Citation17] reported two-year OS of 85%. In the latter study, 67% (12/18) of patients had oligometastatic disease (five or less metastatic lesions) and underwent SABR to all known sites of disease [Citation17]. Wersall et al. provided median survival outcomes for patients with limited disease (one to three lesions), and found this to be higher compared to those with greater than three lesions (37 months and 19 months, respectively) [Citation20]. The two prospective trials in this group were Gerszten et al. [Citation15] and Svedman et al. [Citation16]. No OS outcomes were reported in the former study, while Svedman et al. [Citation16] reported a median survival of 32 months, however, this included four patients of 30 with primary RCC.
Treatment-related toxicity
Toxicity data were available for all 10 studies, however only seven identified an established grading system that was used. Within these studies, Grade 3–4 toxicities ranged from 0% to 4%. Within the 10 publications there were a total of two treatment- related deaths. One patient who died was treated for a large metastatic lesion (516 cm3) in the lung close to the pleura, and died 10 weeks after SABR to 48 Gy in 4 fractions, following being admitted to hospital with electromechanical dissociation (EMD). The second mortality was due to a fatal gastric haemorrhage four months after treatment for a metastasis in the pancreas adjacent to the stomach and duodenum. No details regarding radiotherapy dose was available in this patient.
Discussion
This review, which synthesises data from 25 studies, 1199 patients, and 3163 targets, suggests that the use of stereotactic radiotherapy for metastatic RCC is associated with excellent LC rates and low toxicity. In this study, we found that the one-year weighted LC rates for metastatic RCC using stereotactic radiotherapy were extremely high being 88% and 86% for intracranial and extracranial RCC, respectively. This is comparable to studies which have included patients with non-RCC histology [Citation21–24], challenging the long-held view that RCC is a radioresistant disease. Certainly, the high rates of LC seen in the metastatic setting are also evident in the context of primary RCC [Citation25]. The high-dose per fraction employed with stereotactic radiotherapy techniques may be particularly advantageous due to the radiobiological behaviour of RCC, and the relatively low α/β values of RCC cell lines compared to other malignancies.
The existence of a dose response relationship using stereotactic radiotherapy has been suggested in previous studies, with improved LC rates with delivery of a higher BED, although these are non- comparative studies [Citation21,Citation22]. Although a few studies suggested improved LC with higher biological doses, there was a wide variation within studies of dosing regimens and prescribing methods used, and further well-designed prospective trials are required before a consensus view regarding the optimal dose and fractionation regimen for intracranial and extracranial RCC metastases can be recommended. Apart from dose escalation, another factor investigated with respect to its effect upon LC was tumour volume. Although a few studies suggested possible decreased LC with increased tumour volume, overall in this review there was no clear correlation between increasing mean tumour volume and decreased tumour control, with the three studies reporting the highest mean tumour volumes reporting crude LC rates of 98–100%. This is also an area that requires further evaluation.
OS varied considerably between studies, likely reflecting the heterogeneity of the patient population. Various factors were suggested to correlate with OS, including age, interval between primary diagnosis and brain metastasis, RPA class, KPS, number of brain metastases and prior WBRT. Ikushima et al. was the only study within the intracranial group to show that OS was improved with stereotactic radiotherapy compared with surgery and WBRT or WBRT alone, although the total number of patients in this study was small (n = 35) [Citation8]. Within the extracranial literature, only a few studies addressed in particular the issue of oligometastatic disease and showed improved OS in these patients, particularly when all sites of disease were treated with stereotactic radiotherapy [Citation16,Citation17,Citation20]. This suggests that there may be a subgroup of patients in which excellent LC may provide durable systemic control, and is an area in which the role of stereotactic radiotherapy requires further investigation. The use of stereotactic radiotherapy in the oligometastatic setting in RCC is particularly relevant, given RCC is considered an immunogenic tumour in which the abscopal effect has been documented, and the immunomodulatory potential of stereotactic radiotherapy, which may allow local ablative therapy to also eradicate distant micrometastatic disease [Citation26,Citation27].
The current scope of literature suggests that both intracranial SRS and extracranial SABR are very well-tolerated techniques. Overall within both the intracranial and extracranial literature, the treatment-related toxicity and mortality was very low and favourable compared to rates reported for patients undergoing neurosurgery or on anti-angiogenic therapies [Citation28,Citation29]. There were significant limitations, however, in the toxicity data, reflecting in part the retrospective nature of most studies, with only 10 studies reporting the specific toxicity grading system and version used, which differed between studies, raising the possibility of under-reporting of toxicity.
Further limitations of this analysis must also be recognised. A majority of the studies were retrospective. Median follow-up was generally limited, ranging from 5.2 to 16 months in the intracranial setting, and 5 to 52 months in the extracranial setting, although the latter value included patients with both primary and metastatic RCC. This length of follow-up, however, may be sufficient in the metastatic setting. There was significant heterogeneity with respect to the patient population, as well as the planning, prescribing and delivery of radiotherapy, which may have impacted upon clinical outcomes and toxicity. In addition there was heterogeneity in the definition of LC and OS, with time to event being defined from date of stereotactic radiotherapy in 15 studies, from date of diagnosis of metastatic disease in three studies, and not defined in seven studies. Radiological LC is also difficult to establish in the face of confounding factors, such as surrounding tissue fibrosis, and may be over-estimated due to competing risks from death secondary to co-morbidity or systemic metastases. As previously reported, when data regarding one-year LC were not available, they were extrapolated from reported time points, if available, assuming a constant hazard and consistent censoring of data. In this review, BED calculations were utilised in order to compare different doses and fractionation regimes. It is important to recognise, however, that at the ablative dose range, BED calculations may not be as reliable and should be interpreted with caution [Citation30]. The relationship between BED and LC may also have been confounded by tumour size, with smaller tumours receiving higher BED, whereas larger tumour may have tended to receive lower BED, with dose limited due to surrounding critical structures.
In summary, this systemic review suggests that intracranial SRS and SABR offer a safe and effective treatment modality for patients with metastatic RCC. Further prospective, randomised data are required to compare stereotactic radiotherapy to other options, such as conformal palliative radiotherapy, chemotherapy and observation, to establish the optimal dose and fractionation regimen, and to identify the patient group that may benefit the most from this intervention.
Supplementary material available online
Supplementary Figure 1 and Tables I–IV available online at http://informahealthcare.com/doi/abs/10.3109/0284186X.2014.939298.
ionc_a_939298_sm8572.pdf
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Staff at the Central Cancer Library, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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