Vol 18, No 2 2020
Corresponding Author: Allan J. Pantuck, MD, University of California, Los Angeles, 200, Medical Plaza Driveway Suite 140, Los Angeles, CA 90095; Phone: (310) 794-7700. Email: APantuck@mednet.ucla.edu
Current Guidelines for Treating Oligometastatic RCC:
An Ever-changing Paradigm Integrates New Strategies
Alexandra Drakaki, MD, PhD
Assistant Professor of Medicine
(Hematology/Oncology) and Urology
Medical Director of the GU Oncology
Program at the Institute of Urologic
Oncology at UCLA
Los Angeles, California
Albert J. Chang, MD
Associate Professor, Vice Chair of Surgical Services
and Brachytherapy Service Chief
Department of Radiation Oncology
David Geffen School of Medicine at UCLA
and UCLA Institute for Urologic Oncology
Los Angeles, California
Allan J. Pantuck, MD, MS, FACS
Professor and Vice Chair for Academic Affairs
Department of Urology
UCLA Institute for Urologic Oncology
Los Angeles, California
Keywords: oligometastases, renal cell carcinoma, ablation, radiotherapy, metastasectomy, nephrectomy, active surveillance, SBRT, IMDC risk factors, systemic therapy.
Corresponding Author: Allan J. Pantuck, MD, University of California, Los Angeles, 200, Medical Plaza Driveway Suite 140, Los Angeles, CA 90095; Phone: (310) 794-7700. Email: APantuck@mednet.ucla.edu
This review provides an update on emerging data from current literature on the treatment of oligometastatic renal cell carcinoma. A rapidly evolving paradigm of treatment reflects multimodal approaches ranging from active surveillance to combinations of stereotactic radiotherapy and systemic therapies. Guidelines for determining optimal choices are presented.
Oligometastatic disease can be conceptualized as an intermediate state between limited, organ-confined primary cancer and diffuse, polymetastatic disease. Oligo, which means few or scanty, is derived from the Greek “oligos.” For clinicians, the term refers to a limited tumor burden potentially amenable to local treatment approaches, and a number of studies have redefined this definition over 25 years.1-3 When first used, the term referred to a state of limited metastatic burden, where some patients may be amenable to cure if all known metastatic deposits can be extirpated or ablated, and further distant progression delayed or avoided altogether.1 A more quantitative definition of the oligometastatic state suggests up to three or up to five lesions, by various accounts. Oligometastases may be present at the initial time of diagnosis of the primary tumor (called synchronous), or separated by an interval of time for recurrence since the initial diagnosis or treatment of the primary tumor (called metachronous). Metachronous oligometastases, particularly those with a long delay in the time to recurrence, are generally thought to have a better prognosis than tumors with metastatic disease at the time of presentation.
Clear cell renal cell carcinoma (ccRCC) is capable of both lymphatic and hematogenous spread, and has been noted to have the ability to spread to nearly every possible site in the body. Historically, it was noted that a small subset of patients presented with an indolent form of advanced disease in which surgical resection of small volume metastatic deposits led to serial, protracted disease free intervals, lending early support to the concept of metastasectomy. These early clinical observations have recently been supported by modern, large-scale genomic sequencing initiatives that have defined the genetic underpinnings for the diversity of metastatic phenotypes. These patterns of spread range from rapid and simultaneous metastatic dissemination to multiple tissue sites, to a highly attenuated pattern characterized by slower progression to solitary or oligometastatic disease. The most extreme such presentation being described comprises a protracted latency of up to two decades as a feature of tumors that metastasize to the pancreas.4 While the hallmark genomic drivers of ccRCC metastases appear to be loss of chromosomes 9p and 14q,4-6 cases that are multi-site rapid progressors are characterized by VHL wildtype and BAP1 driven evolutionary subtypes.4 On the other hand, tumors that display a more attenuated phenotype of spread appear to harbor clones with PBRM1 mutations.4
The treatment paradigm for oligometastatic renal cell carcinoma (RCC) has moved in multiple directions beyond just surgery, especially in the post-cytokine era, as new treatments have vastly expanded the armamentarium and debunked earlier concepts of how outcomes can be improved. One of the concepts discarded from earlier studies was that oligometastatic RCC represents a radiation-resistant malignancy, showing a high degree of resistance to conventionally fractionated radiation therapy. Stereotactic body radiotherapy (SBRT) has been increasingly utilized for treatment of metastatic sites with high local control rates and low toxicity.
Metastatic RCC accounts for up to 25-30% of patients at diagnosis and leads to death in most cases.7 Additional studies from that period pointed toward a poor prognosis for patients with oligometastatic RCC, with a 5-year survival rate of <10%.8 As part of their identifying the challenges in the pre-cytokine era, these reports also examined other issues, for example, whether the number of metastatic sites rather than location dictated overall survival in oligometastatic RCC. One of these reports by Han et al,9 found that oligometastatic RCC confined to only one organ site had a better prognosis than RCC in multiple organs. Survival in patients with disease limited to the lung was similar to that of patients whose disease was limited to bone.
This early pivotal retrospective study is important for other reasons, offering a benchmark for how much more information was needed at the time (2003) on the treatment of oligometastatic RCC and suggesting how future reports would explore more precisely emerging data. For example, Han et al9 urged physicians to consider enrolling patients with multiple organ involvement into clinical trials because these patients appear to have a lower response rate to immunotherapy. It would be years after this published study that immunotherapy would begin to have a much more robust influence on the treatment of oligometastatic RCC in patients with multiple organ involvement and it is intriguing to consider how much the treatment algorithm has changed in the post-cytokine environment and the advent of checkpoint inhibitors.
Since then new concepts about treatment have ushered in a dramatically different era, albeit with its own set of new challenges. But unlike the challenges of decades ago when oligometastatic RCC was perceived as largely radioresistant, new challenges have emerged. These challenges are driven by advances in targeted therapies, the use of immune checkpoint inhibitors, and perhaps most significantly, the application of stereotactic body radiation therapy (SBRT) for oligometastatic RCC, thus improving outcomes in an otherwise radioresistant malignancy.
Challenging Choices in Treatment
These new challenges, however, are more related to our ability to sort through and resolve many issues and questions related to an abundance of data affecting our choices—whether to treat the tumors as metastatic or local disease, should it be removed, radiated, or observed? In evaluating our choices, we need to determine criteria for selection of appropriate candidates for surgical metastasectomy, understand the safety of combining SBRT with TKI agents and checkpoint inhibitors, assess the extent to which patients can undergo active surveillance as opposed to upfront systemic therapy, determine what time between nephrectomy and recurrence of RCC could be an indicator for observation, and consider how unique metastatic site influences the symptoms, deterioration of general condition and activities of daily living.
In addressing these issues, this review will focus on the most recent papers in the field and how emerging data could reshape treatment rationale. One of the controversies addressed extensively has been the role of complete surgical metastasectomy of RCC in the post-cytokine era. This is important in view of the fact that data supporting complete metastasectomy (CM) were derived primarily from the era of cytokine therapy.10 Studies like those of Lyon et al addressed whether complete metastasectomy remains beneficial in patients who receive more recently approved systemic therapies. In doing so, they examined survival outcomes among patients treated with CM in the era of targeted therapy and checkpoint blockade availability.
Lyon et al identified 586 patients who underwent partial or radical nephrectomy of unilateral, sporadic renal cell carcinoma with a first occurrence of metastasis between 2006 and 2017. Of these patients 158 were treated with complete metastasectomy. The authors observed that CM was associated with improved CSS and OS compared to incomplete or no CM in the era of targeted therapy and checkpoint blockade availability. This association persisted after adjusting for the timing, location and number of metastases and it was observed in the context of 93% of patients who underwent CM but did not receive systemic treatment of the index metastasis.10
These data suggest that CM should continue to have a role in the management of oligometastatic RCC despite the improved efficacy of targeted therapies and checkpoint inhibitors relative to previously available systemic agents. Careful patient selection for this approach remains key. In this series most patients chosen for CM had a solitary metastasis and a prolonged disease-free interval between nephrectomy and metastasis development, consistent with known prognostic features of CM. Moreover, a strategy of CM followed by observation has the potential advantage of sparing patients the additional morbidity of systemic agents while preserving the efficacy of these agents for use later in the disease process.
Emphasizing that careful patient selection for SM is essential, Kato et al.11 analyzed a host of factors all of which should be considered when determining which patients are candidates for surgery. Reviewing the literature in an editorial commentary, Kata et al cited numerous articles pointing toward a general consensus on clinical and pathological factors, including: performance status, disease-free interval, abnormal laboratory data, and sites of metastases, Fuhrman grade, and risk category in prognostic models. Acknowledging reports that complications and in-hospital mortality rates are not negligible in patients treated with targeted therapy who undergo surgical resection.12,13 Kato et al identified patients with a good indication for SM of RCC. These patients should have the following features:
Surgical Metastasectomy: Site-specific Clinical Factors
Treatment strategies may be influenced by site-specific clinical factors with prognostic value for local treatment of metastases.11 The four most common metastatic sites for RCC are lung, bone, non-regional lymph nodes, and liver.
Pulmonary metastases. SM is most commonly performed for patients having a limited number of unilateral pulmonary metastases. Patients with disease limited to the lung are the best responders to cytokine or targeted therapy.14 Although many studies have reported clinical benefit for pulmonary lesions, a poor prognosis is more likely to be observed in patients with a higher number of lesions, concomitant mediastinal nodal metastases, and incomplete resection.
Bone metastases. As the second most common metastatic site in mRCC, lesions to the spine are the most affected bone site. Excisional surgery of bone metastases is an extraordinary and technically demanding procedure because the metastases are hypervascular and destructive, with reconstruction further complicating the likelihood for a successful outcome. In view of the negative impact of complication after SM in bone and brain metastases, SBRT may represent an alternative option to improve treatment options in these patients.
Lymph nodes, liver and pancreatic metastases. The data are sparse on these metastatic sites, particularly for isolated lymph nodes. The guideline from Kato et al is that SM for these lesions should be carefully considered in patients with good performance status and completely resectable solitary metastases.15 RCC tumors spread rarely to the pancreas, but when they do, they represent solitary metastatic involvement in up to half of these cases.16 This fact, combined with the often attenuated and delayed pattern of spread noted above, supports surgical resection as an option with durable long term survival in surgically amenable cases.
The controversy surrounding the benefit of SM is largely due to the lack of high-level evidence on its role in terms of improving survival in the era of systemic therapy. No randomized trials have evaluated the role of complete SM, although many observational studies have suggested a survival benefit of an aggressive surgical approach.17 A systematic review of the literature derived from 56 retrospective studies in Embase and Medline databases offers valuable insights, however, with regard to prognostic factors to consider in clinical decision making when patients may be candidates for SM. Median overall survival in this review by Ouzaid et al17 ranged from 36 to 1432 months for those undergoing SM vs 8 to 27 months when SM was not performed. The most important prognostic factor for OS was complete resection of metastases. Other prognostic factors included disease-free survival from nephrectomy, primary tumor features (T stage 3 or more, high grade, sarcomatoid features, and pathological status), the number of metastases, and performance status. Survival benefit was most apparent with lung metastasectomy.
Concluding that only a small subgroup of patients may benefit from SM, Ouzaid17 nevertheless suggest it is a worthwhile option to consider, reiterating the conventional wisdom that the best candidates are those with good performance status, a long time interval with no evidence of disease, a relatively limited burden of disease (ideally a solitary metastasis), and achievable metastases-free status. Confirming what almost every series in the literature has observed, the review suggests that patients with synchronous metastases have worse prognosis. Some sites—such as brain and liver—are also associated with a poor prognosis and SM in this subset may not provide potential benefit.
An intriguing question raised by the literature is to what extent outcomes may be influenced by more specific secondary analyses following cytoreductive neph-rectomy for oligometastatic RCC. A case in point: a study by Pierorazio et al18 who examined whether outcomes could be predicted based on the fractional percentage of tumor removed (FPTV). Few studies have followed up on the hypothesis raised by this report, but the authors suggest some significant results: 55 patients had their FPTV calculated; 45 had >90% FPTV. The median disease-specific survival times were 11.6 and 2.9 months for patients with >90% and <90% FPTV removed (P=0.002).
The value of this provocative study also lies in its hypothesis-generating aspects. Although FPTV may not be the primary explanation for the discrepancy in survival, this measure could be an easy-to-calculate surrogate for complex factors driving the survival benefit in patients who had higher results for FPTV. Thus, the FPTV criteria could allow surgeons to easily identify patients who will benefit from cytoreductive surgery without using complex performance scales or nomograms.
Active Surveillance: When Can Immediate Aggressive Treatment be Delayed?
With the publication of a pivotal, prospective, Phase 2 trial by Rini et al19 in 2016, the concept of active surveillance began to undergo more consideration as a viable approach. This study encouraged further investigations that also undercut the widely held perception that tumors needed to be treated immediately and aggressively. Since the publication of the Rini paper, a significant shift in thinking, including guidelines issued by the European Society for Medical Oncology, have had a sharp impact on treatment approaches.20
Figure 1. Treatment algorithm for oligometastases. Factors to be considered in managing oligometastases related to the primary tumor are indicated in this treatment algorithm. Active surveillance can be an option when immediate aggressive treatment can be delayed. In surgically resectable cases, stereotactic body radiation therapy (SBRT) is an option in selected patients. High local control rates have been observed with SBRT in RCC tumors once thought to be radioresistant, and is increasingly utilized for treatment of oligometastatic disease.
Among the salient factors accounting for this change in rationale is the paradigm of risk stratification from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Rini et al19 relied on tis classification scheme to propose that AS may be an acceptable option. Patients can be classified into good, intermediate, or poor prognosis according to:
The absence of all previous parameters identifies patients in a favorable risk group; the presence of one or two, and at least 3 prognostic factors classifies patients into intermediate and poor-risk categories, respectively. The ESMO guidelines introduced the possibility of managing selected patients with favorable disease using AS. The Rini study has been touted as the study with the best available evidence; 48 patients with treatment-naïve, asymptomatic RCC were followed with AS for a median of 14.9 months. The key findings from the Rini report:
Although hypothesis-generating at this point, Rini et al postulated an immunogenic basis for the good outcome in patients who had a better prognosis with AS. The report raises a tantalizing biologic basis for the outcomes by observing that patients on AS had significantly fewer immunosuppressive cells and a higher number of interferon-gamma-producing T cells than the cohort of patients who began systemic therapy immediately. If this were true, then such a phenotype could be associated with an anti-tumor response, perhaps accounting for the relatively indolent nature of tumor growth reported in patients on AS.
Following the Rini report, additional studies have further delineated factors possibly accounting for the variation in benefit related to AS. Two retrospective analyses picked up on the direction from Rini et al. One of these by Woldu et al,21 derived from 4 years of the National Cancer Data Base, looked at the timing of targeted therapy after cytoreductive nephrectomy—early within 2 months), moderately delayed (2- months), and delayed (6- months). The analysis, based on data from 2716 patients, found that delay in initiation of therapy was not independently associated with overall survival. The conclusion: in carefully selected patients, outcomes might not be compromised with initial observation.
A retrospective analysis by Bimbatti et al,22 studying 52 patients with RCC over 9 years, examined whether IMDC risk class, number of metastatic sites, and tumor burden (TB) changed over time, whether these factors affected survival and how using such data could influence the decision about when it is appropriate to initiate systemic therapy. TB was defined as the sum in millimeters of the longest tumor diameter of each lesion.
Seen through the lens of IMDC prognostic classes, the median time on AS was 20.4 months in the favorable risk group, 17.8 months in the intermediate-risk group, and 5 months in the poor-risk group. Baseline IMDC class was the only factor to independently predict time on AS. An increased number of metastatic sites during AS and an increase in TB adversely affected overall survival. The “take-home” messages from Bimbatti et al are:
Do the results from Rini et al, Bimbatti et al and similar findings suggest that AS is underutilized and should be integrated more widely in the treatment algorithm? An Editorial Commentary by Ficarra et al23 suggests not necessarily. For these authors, AS is a cautionary tale, of value in a well-selected subset of patients with indolent, asymptomatic, and good-risk. They conclude that delaying systemic treatment does not seem to have negative consequences on overall survival but questions persist. They suggest that there is a dilemma as to whether cancer control in patients managed with an initial AS protocol vs immediate systemic therapy is compromised, and to what extent initial debulking is also critical. They leave open the question whether AS in oligometastatic RCC should be considered an option or an exception until further studies clarify the risks and benefits.
SBRT: Widening the Net for Local Control of Oligometastatic RCC
Advances in imaging and precision of modern radiation delivery has enabled the development and adoption of SBRT for the treatment of both primary tumors and metastatic sites.24 High local control rates have been observed with SBRT in RCC tumors once thought to be radioresistant, and is increasingly utilized for treatment of oligometastatic disease. In select de novo oligometastatic and oligorecurrent patients, SBRT offers the potential to delay the onset of a new line of systemic therapy that may be associated with adverse side effects.24 Recent studies have demonstrated the advancement of SBRT in comparison to earlier studies of conventional fractionated radiotherapy (CF-EBRT). Reports have suggested that SBRT leads to greater and more durable radiographic responses and improved local control compared to CF-EBRT with minimal toxicity.
In addition to the editorial commentary by Beckham et al, recent reports have illustrated the integration of SBRT into the treatment algorithm25-29 and have addressed a broad spectrum of issues related to its use to improve outcomes for enlarging or anatomically problematic masses.28 In 2019, the National Comprehensive Cancer Network (NCCN) included the use of SBRT for recurrent and metastatic RCC into its guidelines.25 In their meta-analysis of 28 studies, Zaorsky et al. found that SBRT is safe and effective for RCC oligometastases, with local control at 90% and any significant toxicity at 1%. One of the caveats to emerge from this meta-analysis—and confirmed by other studies—concerns the worse survival rates observed among patients with intracranial RCC oligometastases vs those with extracranial disease.
SBRT has the potential to promote an anti-tumor immune response through multiple mechanisms, including the promotion of neoantigen expression and activation of cytotoxic CD8+ T cells. This effect has been explained as dependent on type 1 interferon induction in the irradiated tumor.25 Although hypothesis generating, the concept that SBRT appears to be immunostimulatory for historically radioresistant tumors argues for a plausible biological rationale to combine stereotactic ablative radiotherapy with immunotherapy. This point was enlarged upon in the report by Dengina et al26 who also explored the immunogenic aspects of RCC. In their report on the use of extracranial SBRT with TKI or checkpoint inhibitors, they offered further insights on the mechanisms of action of stereotactic radiotherapy. The clinical response in lesions outside of the radiation field—known as abscopal effect—is worthy of further study and has been previously noted. Overall, Dengina et al suggest that SBRT can safely be administered to patients concomitantly receiving TKI or checkpoint inhibitors. The addition of SBRT to systemic therapy led to a rapid regression of the target lesions in 13 of 177 subjects, thus offering further proof of the benefit of such localized therapy.
As SBRT continues to evolve and its use better delineated, one of the underlying questions concerns its relationship to cytoreductive nephrectomy. Singhet al30 pursued this issue in a single-arm feasibility study in patients who underwent CN 4 weeks after SBRT. They found that SBRT followed by nephrectomy was safe and patients benefited from significant changes to their immune status. Patient tumors had increased expression of the immunomodulatory molecule calreticulin, tumor, tumor-associated antigen, and a higher percentage of proliferating T cells compared with archived RCC tumors.
Two phase II trials have been presented evaluating the combination of SBRT and checkpoint inhibition. The Nivolumab Plus SBRT in 2nd and 3rd Line Patients with Metastatic Renal Cell Carcinoma (NIVES) Study suggested the safety and tolerability of SBRT with the nivolumab, an anti-PD-1 checkpoint inhibitor, with an objective response rate (ORR) of 17.4%, a complete response rate (CRR) of 1.4%, and disease control rate (DCR) of 58%. Of note, the ORR and DCR were 26.9% and 82% in irradiated sites of disease. However, the primary endpoint, improvement in ORR from 25% to 40%, was not met, and the median PFS was 4.1 months, which was not improved from a prior study, CheckMate 025, in which patients receiving nivolumab alone (without SBRT) experienced a median PFS of 4.6 months.31 Given that approximately half of the patients harbored 3 or more sites of metastatic disease and that the dose of radiation (30 Gy in 3 fractions) was on the conservative side of that in the aforementioned studies, improved clinical outcomes may be observed in a study population with a more limited volume of disease (≤3 sites) with a more aggressive radiation regimen was utilized. The RADVAX trial evaluated the combination nivolumab and ipilimumab with SBRT at a higher dose (50 Gy in 5 fractions) than that used in NIVES. The ORR of 56%, median PFS of 8.21 months, and the acceptable safety profile of the treatment combination are promising.32 Further studies are necessary to understand how to optimize immunotherapy with SBRT to improve clinical outcomes.
In addition irradiation of metastatic sites, the utilization of SBRT to the primary site of disease is growing. Multiple studies have suggested high local control rates (90-100%) with acceptable toxicity (grade 3 toxicity <5%).33-36 The largest study published from the International Radiosurgery Oncology Consortium for Kidney (IROCK) included 223 patients who underwent SBRT to the primary site only. 2- and 4y local control rates were 97.8%. A small decrease in kidney function was observed with a mean decrease in GFR of 5.5 +/- 13.3 ml/min.36 A major limitation of these studies is the limited follow-up time.
Treatment of oligometastatic RCC has evolved rapidly and new treatment paradigms have emerged. In appropriately selected patients, the use of SBRT has gained support and has been integrated into widely accepted guidelines for the treatment of oligometastases, such as those by the National Comprehensive Cancer Network. Nevertheless decisions need to be individualized to achieve optimal local control based on consideration of IMDC risk factors and an approach reflecting multimodal treatments. Careful patient selection for surgical metastasectomy is essential. Patients with a good indication for surgical metastasectomy include those with solitary or oligometastatic lesions, symptomatic metastases deteriorating quality of life, resistance to radiotherapy and/or systemic therapies, and easy surgical accessibility and resectability with a lower rate of complications. There is growing evidence supporting the use of active surveillance in a well-selected subset of patients with indolent, asymptomatic, and good-risk mRCC, thus mitigating the need in some cases for immediate aggressive treatment.
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