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Metastasectomy in Advanced Renal Cell Carcinoma: A Systematic Review

Abstract

Introduction:

Metastasectomy for advanced renal cell carcinoma has been practiced for over 80 years. However, there is uncertainty regarding the clinical benefit of this procedure and the optimum selection of appropriate patients.

Materials and Methods:

A systematic literature search was conducted according to the PRISMA statement to identify studies that reported outcomes in patients who underwent metastasectomy at any time. Primary endpoints were overall and disease-free survival. Radiation therapy studies were not included. Case reports and series with less than 20 patients were not included.

Results:

Forty-four studies were identified that met the criteria for inclusion, with a total of 4195 patients. No studies that randomized patients to surgery versus no surgery were identified. Disease-free interval, number of metastatic sites and completeness of resection were prognostic for overall survival in many of the included studies. Seventeen studies included patients with lung metastases only (1465 patients in total).

Conclusions:

Case series have documented patients with prolonged disease-free interval and survival after metastasectomy. However, without randomized data, the impact of metastasectomy on outcomes in patients with metastatic renal cell carcinoma (mRCC) remains unknown, especially in the evolving landscape of systemic therapies.

INTRODUCTION

Metastasectomy in solid tumors

Traditional oncology teaching holds that metastatic solid tumors represent a broader systemic disease process in which distant micrometastatic deposits will ultimately progress after resection of detectable disease. However, reports of favorable outcomes including prolonged disease-free interval have been reported across tumor types, primarily in retrospective series and case reports. These cases tended to be highly selected and enriched for patients with oligometastatic disease, slow progression, extended disease-free interval, or excellent functional status. Unfortunately, randomized data addressing whether there is a benefit from surgery are lacking. One study conducted at MD Anderson randomized patients with non-small cell lung cancer to consolidation local therapy (surgery or stereotactic radiosurgery) [1] after initial chemotherapy, versus maintenance chemotherapy alone. Local therapy was associated with improved disease-free survival suggesting that the traditional paradigm may be incomplete. A randomized phase II study in patients with oligometastatic prostate cancer found improved androgen deprivation-free survival with metastasis-directed therapy (surgery or radiation versus observation) [2]. Aside from these recently published examples, metastasectomy for solid tumors remains based on single-armed case series and physician experience.

Metastasectomy for mRCC

Renal cell carcinoma (RCC) can metastasize to many different organs and has a variable natural history. It may be rapidly progressive or indolent, requiring no immediate systemic treatment [3]. Identifiable metastases are present at diagnosis in up to 30% of cases or become apparent years after nephrectomy for clinically localized disease in nearly 40% of cases. The most common site of metastasis is the lung (45.2%), followed by bone (29.5%), lymph nodes (21.8%), and liver (20.3%) [4]. Several clinical factors have been associated with improved response to treatment of metastatic RCC (mRCC). These are important in determining suitability for surgical intervention and include performance status, length of disease-free interval, synchronous or metachronous metastasis, burden of metastatic disease and number of location and sites involved [5]. Although there have been many advances in the treatment of mRCC, including the development and approval of immunotherapy regimens, complete responses are still rare. As such, surgical management of metastatic disease remains an important aspect of therapy for long-term disease control.

Metastasectomy for RCC was first reported by Barney and Churchill in 1939 [6]. There have been no randomized controlled trials to address the role of metastasectomy in mRCC, however, there have been many retrospective studies and a few prospective series. This systematic review will summarize and discuss the available evidence.

MATERIALS AND METHODS

A systematic literature search was conducted according to the PRISMA statement [7] to identify studies reporting outcomes in patients who underwent surgical resection for mRCC. The search was not restricted to a particular time period. The PubMed database was searched using the search the terms “metastasectomy”, “surgery”, “renal cell carcinoma”, “kidney cancer”, “pancreas”, “bone”, “thyroid”, and “brain”. General internet search engines were also queried using these terms, as was the ASCO Abstract library. All citations were reviewed and evaluated for study design, quality of execution and relevance.

RESULTS

A search of electronic databases was performed to identify reports of patients who had undergone metastasectomy for mRCC. The initial PubMed search using the terms “metastasectomy” AND “renal cell carcinoma” OR ”kidney cancer” identified 329 references. Additional references were identified using the organ-specific terms such as “pancreas” or “bone”, including qualifying studies that did not appear in the initial search. Original, prospective and retrospective studies of patients who underwent metastasectomy for mRCC were identified. Additional studies were identified by manual review of references contained within the reports and review articles from the initial PubMed search. Case reports and series with fewer than 20 cases were excluded. Forty-four studies were ultimately included in the analysis. Table 1 summarizes the findings reported in these studies, which included a total of 4195 patients. One study in this table, an analysis of 1976 records in the National Cancer Database, was not included in this numerical total [8]. Baseline information included in these publications generally included demographics, as well as oncologic features and treatment history, including disease-free interval (DFI) from prior nephrectomy, number of metastatic sites, presence of lymph nodes, organ site of metastases, and whether resection was complete or incomplete. Overall survival was reported as a landmark data point at 1 to 10 years and also as a median value in most of the series. A smaller subset of the studies provided outcomes on disease-free survival (DFS). The length of follow up was reported in 14 studies. No randomized studies of metastasectomy versus no surgery for RCC were identified. However, several papers compared metastasectomy patients to matched controls who did not undergo surgery. There was considerable heterogeneity in the reporting of outcomes among the studies. Most reported an analysis of risk factors for outcomes, generally overall survival. Twenty two of 44 studies included a multivariate analysis. Some of the studies were limited to metastases to individual organ sites: these data are discussed below, and denoted in Table 1.

Table 1

Studies of metastasectomy in mRCC. The 44 studies that were met criteria for inclusion in this systematic review are here. NA = not available; Multi = Multiple sites

StudyYearsN*ComparitorFollow-up months: median (range)mDFS (months)Median OS5 year OS (%)OrganRef.
Jett 19831970–197944NoneNANA3327Lung[47]
Cerfolio 19921965–198996None36 (2–280)NA3835.9Lung[48]
Pogrebniak 19921985–199123NoneNANA43NALung[49]
Kierney 19941970–199041None38NA4131Multi[50]
Althausen 19971977–199638NoneNANA7255Bone[16]
Fourquier 19971960–199450None42 (1–200)NANA44Lung[51]
Kavolius 19981980–1993211NoneNANANA44Multi[52]
Friedel 19991980–199577NonreNANANS39Lung[53]
Piltz 20021980–2000105NoneNANA4340Lung[54]
Pfannschmidt 20021985–1999191None21.4 (0.1–157.8)NANA36.9Lung[11]
Hofmann 20051975–200364NoneNANA39.233Lung[55]
Murthy 20051986–200192NoneNANANA31Lung[56]
Marulli 20061988–200459NoneNANANA53Lung[57]
Assaoud 20071984–200565NoNANANA34.4Lung[58]
Kwak 20071990–200421No surgery (n = 41)NANA36.547.6Multi[59]
Lin 20081974–2004295NoneNANANA11Bone[15]
Thelen 20071988–200731None29 (1–185)274838.9Liver[20]
Eggner 20081989–200744No surgery (n = 85)NANA4549Multi[60]
Iesalnieks 20081983–200745NoneNANA7151Thyroid[61]
Zerbi 20081998–200623No surgery (n = 13)NA44NA88%Pancreas[62]
Daliani 20091991–199938NoneNA21.656.4NAMulti[45]
Alt 20111976–2006382No surgery (505)NANANANAMulti[10]
Kanzaki 20111973–200848None39 (3–177)NANA47Lung[63]
Kawashima 20111998–200825NoneNA7.433.935.5Lung[64]
Meimarakis 20111986–2006202NoneNANA39.539Lung[65]
Naito 20111988–2009556NoneNANA8048.9Multi[66]
Ruys 20111990–200833NoneNA103343Liver[18]
Petralia 20121999–200857Nephrectomy only (n = 121)21 (1–235)NA14NAMulti[67]
Kudelin 20131999–2009116NoneNANA63.447Multi[13]
Tosco 201311998–2011109None52.7 (1.37–283)NA54.746.9Multi[68]
Renaud 20141993–2011122NoneNA22.19466Lung[12]
Santoni 20142005–201442No surgeryNA36.2103NAPancreas[24]
Untch 20141993–201223Panc. Met. Other primaryNANA96NAPancreas[23]
Baier 20151996–2012237None46 (2–198)606954%Lung[14]
Benhaim 20151997–201220None69 (1–150)NANANAPancreas[22]
Du 20152006–201533No surgery (n = 81)24.1 (16–32)NA39.1NABone[17]
Yu 20152004–201342No surgery (n = 54)45NA54/162NAMulti[69]
Jakubowski 20161990–2013172None3625NANAMulti[70]
Thomas 201631986–201167Targeted therapy only (n = 121)NANA8.4/6.2NAMulti[71]
You 20162006–201361No surgery (n = 263)NA29.5/18.8292.5/29.62NAMulti[72]
Ohtaki 20171993–201484NoneNANA79.259.7Lung[73]
Verbiest 20181995–201743NoneNA1712173Multi[38]
Procopio 20182012–201836/324None2135/294NANAMulti[44]
Sun 201852006–20131976No Surgery (n = 5018)NANA24.1NAMulti[8]

1Cause-specific survival reported. 2Complete/incomplete metastasectomy. 3Sarcomatoid cases only. OS: synchronous/metachronous. 4Observation/sorafenib. 5National Cancer Registry Database review. Median OS for postpropensity matched cohort (n = 3390).

Lung

The lung is the most common target organ for metastasis from RCC. Of the 44 studies reviewed here, 17 were comprised of patients who had metastasectomy for RCC lung metastases. These accounted for 1462 out of 4195 total patients included in this systematic review. Prognostic factors for survival with lung metastases have been studied in multiple series and meta-analyses. In a systematic review of 16 studies with a total of 1447 patients, Zhou et al. reported 1, 3, 5, and 10–year overall survival (OS) rates of 84%, 59%, 43%, and 20%, respectively following lung metastasectomy [9]. They identified lymph node involvement, incomplete resection, multifocality, size, synchronous metastases, and a short DFI as poor prognostic factors. Another report from the Mayo Clinic detailed 887 patients who underwent nephrectomy for RCC and subsequently developed metastatic disease. Of these 125 patients had complete resection of all metastatic disease. Patients who had lung-only disease had a 5–year cancer-specific survival (CSS) of 73.6% after complete resection compared with 19% for those without complete resection [10]. Similarly, in a Heidelberg series of 191 patients with pulmonary RCC metastases, 149 patients achieved complete resection [11] for a 5–year OS of 41.5% compared with 22.1% without complete resection. Notably, in this series, lymph node involvement decreased the 5–year OS to only 24.4%.

The negative impact of concomitant lymph node involvement was also emphasized by Renaud and colleagues. In their report of 122 patients who underwent pulmonary metastasectomy, 35% had lymph node involvement, decreasing OS from 107 months to 37 months (p = 0.003) [12]. Kudelin and colleagues completely resected all mediastinal lymphadenopathy at the time of pulmonary metastasectomy with overall survival of 49% and 21% at 5 and 10 years, respectively [13]. Mediastinal lymph nodes were positive in 46%. Notably, in this series the presence of intra-thoracic lymph node metastases did not result in inferior survival after metastasectomy, suggesting there may be clinical benefit to lymphadenectomy [13].

Finally, Baier and colleagues examined complete resection of multi-focal pulmonary RCC metastases (mean 13/patient). Using laser resection in 237 patients, they achieved complete resection in 208 for a median OS of 69 months compared with 19 months for those with an incomplete resection (p < 0.00001) [14]. Although a higher number of metastases was associated with a shorter OS, the advantage of complete resection was maintained for all levels of disease.

In summary, these studies demonstrate the relative safety and feasibility of resection of pulmonary metastasis and the potential for favorable outcomes. The impact of surgery on overall survival, however, is not definitively established by these non-randomized studies.

Bone

Bone is the second most common site of metastatic disease in RCC. Surgery (both resection and mechanical stabilization) and radiotherapy are often performed to mitigate local complications. Outcomes data in large series, however, are limited. A retrospective study of 295 patients with bone metastases who underwent orthopedic metastasectomy at MD Anderson showed an OS of 47% and 11% at 1 year and 5 years, respectively [15]. Another report of patients treated between 1977 and 1996 at Massachusetts General Hospital showed a 5 year OS of 55% [16]. These results are particularly notable, because they were obtained prior to the development of effective systemic therapies. Both identified a solitary site of bone metastasis as a strong predictor of overall survival. A more recent published series included 33 patients who underwent surgical resection with or without radiation, plus systemic targeted therapy [17]. Median OS was 39.1 months for surgical resection versus 7.6 months for 59 patients with bone metastases who did not undergo surgery. The authors acknowledge the potential for selection bias in these data. The impact of metastasectomy on survival in patients with RCC bone metastases remains unknown without randomized data. However, local disease control for palliation and preservation of function provides a strong clinical rationale for surgery in many cases and would make randomization of these patients to surgery versus no surgery clinically challenging.

Liver

A retrospective review from 14 centers in the Netherlands identified 33 patients who underwent resection or ablation of liver metastases [18]. The OS at 1, 3, and 5 years was 79%, 47%, and 43% respectively. Metachronous metastases and radical resection were statistically significant prognostic factors. Size <50 mm, solitary metastases and presence of extrahepatic metastases did not significantly impact survival. Another retrospective study by Staehler et al. identified 88 patients with liver metastases, including 68 who underwent metastasectomy [19]. The 5–year OS after metastasectomy was 62% compared to 29% in those who did not have a resection. A retrospective study by Thelen et al. of 31 patients who underwent surgery for liver metastases reported overall survival of 82%, 54% and 39% at 1, 2 and 5 years [20]. Incomplete resection or positive margins emerged as a statistically significant prognostic factor in multivariate analysis.

Pancreas

Renal cell carcinoma can metastasize to the pancreas, in many cases as the only site of recurrent disease. Published case series are generally small, but favorable survival outcomes have been reported. In a series of 19 patients who underwent surgery for pancreatic RCC metastases by Fikatas et al., 5–year OS was 71.4% [21]. A similar series of 20 patients with pancreatic metastasectomy showed a 72% OS at 4 years [22]. Consistent with these findings, a study of 27 patients undergoing pancreatic metastasectomy at Memorial Sloan-Kettering Cancer Center found a median OS of 8 years [23]. In contrast, a retrospective study of patients from 16 Italian centers with pancreatic metastases included 44 patients who underwent surgery with or without systemic therapy and 59 patients who had systemic therapy alone [24]. Median OS was 103 months in the patients who underwent surgery and 86 months in those who did not: a difference that was not statistically significant. MSKCC prognostic group was predictive of overall survival. Median overall survival was not reached in the good risk group; 86 months in the intermediate risk group and 42 months in the poor risk group. The authors conclude that outcomes are favorable in patients with pancreatic RCC metastases, and that pancreatic resection did not improve survival. Taken together, these studies suggest that patients with pancreatic metastases of RCC generally have an indolent course and favorable prognosis.

Brain

Brain metastases from RCC can cause devastating neurological complications. Therefore, these cases are generally treated promptly with stereotactic radiosurgery (SRS), whole brain radiation, or surgical resection. A series from MD Anderson of patients treated with SRS observed a median OS of 4–11 months after diagnosis with a 5–year OS of 12% [25]. Large surgical series were not identified in the literature. Local control of brain disease remains an objective of the highest priority regardless of impact on overall disease status, owing to the critical importance of preserving CNS function.

“Atypical” Metastases

In a study which defined “atypical” sites of metastasis as those that did not occur in the thorax, bone, liver, brain or adrenal, 37 patients who had “atypical” metastasectomy were compared to 57 patients who had lung metastasectomy. The authors reported that those who underwent atypical metastasectomy had a median overall survival of 40.8 months, whereas those who underwent lung metastasectomy had a median overall survival of 50.7 months (p = 0.372) [26].

Prognostic factors

Most of the studies included in this review attempted to identify prognostic factors associated with favorable outcomes after metastasectomy. Univariate and multivariate analysis of prognostic factors for overall survival are summarized in Table 2. Variables that were only evaluated in a minority of the studies were not included in the table. Some of these excluded variables, such as tumor size and MSKCC or IMDC risk score, were associated with survival in individual studies. In general, solitary or oligometastatic disease, metachronous metastasis with a disease-free interval of >2 years, complete resection, and absence of lymph node involvement are associated with favorable outcome after metastasectomy [27, 28].

Table 2

Clinical variables that were most likely to be associated with overall survival. Studies that examined the relationship between clinical variable and overall survival were included. The most common variables associated with overall survival are shown. Additional variables are examined in the individual publications. NA = not available. NS = not significant

NOrganMulti/Univariate analysisExtent of resectionSynchronous/MetachronousDisease-Free IntervalNumber of sitesNodal involvement
Jett 198344LungUnivariateNSNAp = <0.05NSNA
Cerfolio 199296LungUnivariateNANAp = <0.01p = <0.05NA
Pogrebniak 199223LungUnivariatep = 0.02NSNSNSNA
Kierney 199441MultiUnivariateNANANSNSNA
Althausen 199738BoneUnivariateNANAp = 0.0007p = 0.05NA
Fourquier 199750LungUnivariatep = 0.2NSNSNSNS
Kavolius 1998211MultiMultivariatep = <0.09NAp = <0.0001p = <0.001NA
Piltz 2002105LungUnivariatep = <0.0001NANSp = 0.029p = <0.001
Pfannschmidt 2002191LungMultivariatep = 0.049p = 0.028p = 0.012p = 0.002p = 0.0038
Hofmann 200564LungMultivariatep = 0.001p = 0.033p = 0.005p = 0.02NA
Murthy 200592LungMultivariatep < 0.0001NAp = 0.03NAp = 0.02
Marulli 200659LungMultivariateNSNANSNSNA
Assaoud 200765LungMultivariateNSNAp = 0.14NAp = 0.0018
Kwak 200721MultiMultivariateNANAp = 0.159p = 0.166NA
Lin 2007295BoneUniveriatep = .52NANAp < 0.0001NA
Thelen 200731LiverMultivariatep = 0.005NAp = 0.012
Daliani 200938MultiMultivariatep < 0.0001NSNSNSNS
Alt 2011392MultiMultivariatep = 0.001NAp = 0.0010.86NA
Kanzaki 201148LungMultivariatep = 0.034NSp = 0.009NSNS
Kawashima 201125LungMultivariatep = 0.004NANANSNA
Meimarakis 2011202LungMultivariatep < 0.001p = 0.009p = 0.010p = 0.011p = 0.002
Naito 2011556MultiMultivariatep = 0.001NSNSNSNS
Ruys 201133LiverUnivariatep = <0.001p = 0.03p = 0.051p = 0.93NA
Petralia 201257MultiMultivariatep = 0.02NANAp < 0.001NA
Kudelin 2013116MultiMultivariateNSNANSNSNS
Tosco 2013109MultiMultivariatep = 0.0002p = 0.63p = 0.058NANA
Renaud 2014122LungMultivariateNANAp = 0.02p = 0.34p = 0.01
Baier 2015237LungMultivariatep = <0.0001p = 0.14p = 0.71p = 0.0029p = 0.34
Yu 201542MultiMultivariatep = 0.033NAp = 0.003NANA
Jakubowski 20161172MultiUnivariatep = 0.003p = 0.02p = 0.023NANA
Thomas 201667MultiMultivariateNSNSNSNSp = 0.03
You 201661MultiMultivariateNANANAp < 0.001NA
Ohtaki 201784LungMultivariatep = 0.015NANANSNS

1Recurrence-free survival.

DISCUSSION

Although metastasectomy was first reported for advanced renal cell carcinoma almost 80 years ago [6], there have still been no randomized studies addressing the potential benefit of this procedure. Many retrospective series have been reported, some of which have incorporated case-control comparisons to matched patients who did not undergo surgery. These case series are small to moderate in size, but a number of systematic reviews and meta-analyses have pooled the data from selected series into larger data sets. Zaid et al. analyzed 8 cohort studies with a total of 2,267 patients who underwent metastasectomy [29]. Median OS ranged from 36.5 to 142 months in those who underwent complete metastasectomy compared to 8.4 to 27 months for incomplete metastasectomy. Complete metastasectomy was independently associated with a reduction in mortality. Similar conclusions were reached in a systematic review of patients who underwent local therapies for mRCC including metastasectomy and radiation therapy: examination of 16 studies in detail suggested that complete metastasectomy was associated with greater survival versus incomplete or no surgery [2]. A large retrospective study using the National Cancer Database identified 6994 mRCC patients, 1976 of whom underwent metastasectomy [8]. Patients who underwent metastasectomy had an improved OS compared to those who did not (HR 0.83; p < 0.001). This improvement was seen in the patients who received targeted therapy (HR 0.77; p = 0.008). Although multivariate analysis was performed to account for confounding factors in the systematic reviews and some of the primary series, the possibility of unseen confounders limits the strength of the conclusions that can be drawn regarding the benefit of surgery. The association between metastasectomy and longer OS could be explained by unmeasured enrichment for favorable disease biology or host characteristics in patients selected by their physicians for surgery [27].

In spite of the shortcomings in the available data, expert panels have recommended that metastasectomy be considered in selected cases of mRCC. The National Comprehensive Cancer Network (NCCN) guidelines recommend metastasectomy as an option for patient with oligometastatic clear cell or non-clear cell disease [30]. The ESMO clinical practice guidelines recommend consideration of metastatectomy or radiation therapy patients with mRCC after multidisciplinary review: particularly patients with oligometastatic disease, disease-free interval greater than 2 years, complete surgical resection, low pathologic grade and disease control through systemic therapy [31].

Cytoreductive nephrectomy: A paradigm for the study of metastasectomy

While there have been no randomized trials evaluating metastasectomy for RCC, studies of cytoreductive nephrectomy demonstrate the feasibility randomizing patients to surgery in a similar population: two studies published independently in 2001 by the SWOG and EORTC cooperative groups demonstrated an overall survival benefit to cytoreductive nephrectomy followed by interferon α-2b versus interferon alone [32, 33]. A combined analysis of the studies found a 31% reduction in the risk of death associated with surgery [34] and cytoreductive nephrectomy has been incorportated into the standard of care. Since that time, however, systemic therepy for mRCC has shifted away from interferon to targeted therapies such as sunitinib, introducing uncertainty regarding the role of cytoreductive nephrectomy. To address this question, the CARMENA study randomized patients to standard of care cytoredutive nephrectomy followed by sunitinib vs sunitinib alone. The study found that sunitinib alone was non-inferior to cytoreductive nephrectomy followed by sunitinib [35]. The SWOG, EORTC and CARMENA studies of cytoreductive nephrectomy serve as a paradigm for potential randomized studies of metastasectomy in the appropriate setting.

Patient selection

Although disease-free interval, number of metastases and other factors have been associated with favorable outcomes after metastasectomy, there are no clear guidelines for selecting which patients will benefit from surgery. The MSKCC and IMDC instruments provide prognostic information for patients with mRCC based on readily available clinical data [36, 37]. In some of the studies covered by this retrospective review, MSKCC or IMDC risk group was prognostic for outcome following metastasectomy. However, these data are prognostic, and are not predictive for benefit from surgery. In recent years, the molecular characteristics of cancers have been added to these clinical features for both prognosis and prediction of benefit from particular therapies. In order to identify a molecular signature predictive of favorable outcome after metastasectomy in mRCC, Verbiest et al. performed a retrospective study of molecular tumor subtypes 43 mRCC patients who underwent complete metastasectomy, [38]. Four molecular subtypes in the metastatic setting were identified that differed in terms of mRNA expression, methylation status, mutation profile, cytogenetic abnormalities, and immune infiltration [39, 40]. The subtypes (ccrcc1–4) differed in their OS and also response rate and PFS on the angiogenesis inhibitors sunitinib and pazopanib. Patients with ccrcc1 or ccrcc4 tumors were at a higher risk of relapse after complete metastasectomy, whereas patients with a ccrcc2 or ccrcc3 tumor usually experienced a long DFS [38]. As our understanding of the molecular features of RCC improves, there is the potential for additional predictive models for metastasectomy in addition to particular systemic therapies.

Perioperative systemic therapy and metastasectomy

Adjuvant systemic therapy after nephrectomy for non-metastatic RCC has been studied in a number of randomized trials over the past 3 decades, and sunitinib was FDA approved for high risk, non-metastatic RCC based on the results of the S-TRAC study [41]. The optimal adjuvant therapy following nephrectomy remains under evaluation [42], and randomized studies of several anti-PD–1 checkpoint inhibitors are underway. An analogous question regarding the benefit of systemic therapy arises after complete metastasectomy with no evidence of disease (NED) post-operatively. A number of completed and ongoing studies have examined this question. The Cytokine Working Group conducted a randomized study of a single cycle of high dose interleukin–2 vs. observation for high risk patients after nephrectomy for RCC [43]. The study also included a separate cohort of 25 patients who were status post metastasectomy with NED. The study did not meet its endpoint of improvement in disease-free survival. The randomized phase II RESORT trial assigned patients who were NED after metastasectomy to 52 weeks of sorafenib treatment versus placebo [44]. The study was closed before planned accrual was complete, and the primary endpoint of improvement in recurrence-free survival with sorafenib was not reached. More than half the patients were free of recurrent disease at 24 months; while not randomized to no surgery, these prospectively enrolled and monitored subjects provide a unique high-quality data set regarding outcomes after metastasectomy. The integration of systemic therapy and metastasectomy was also addressed by Daliani, Jonasch et al., who published a prospective study of patients who underwent metastasectomy after systemic therapy (generally a cytokine based treatment with or with 5–fluorouracil) and were followed by post-operative systemic therapy of a similar nature [45]. Median PFS was 21.6 months, and median OS was 56.4 months.

There are additional randomized trials currently underway, one of which is studying adjuvant pazopanib versus placebo (NCT01575548) and another is a phase II trial of adjuvant sunitinib following resection of pulmonary metastases (NCT01216371). Ongoing adjuvant studies of PD–1 and PD–L1 antibody checkpoint inhibitors are including patients with completely resected small volume synchronous metastatic disease (pembrolizumab–NCT03142334, atezolizumab-NCT03024996). Pre-clinical data support the hypothesis that a minimum volume of disease is required for maximum anti–PD–1 checkpoint inhibitor activity [46]. This paradigm is being evaluated in the PROSPER-RCC randomized study of nivolumab prior to and following surgery for high risk disease (NCT03055013).

CONCLUSION

Metastasectomy has been employed in the care of patients with mRCC for many decades, although the clinical benefit is based primarily on retrospective, non-randomized series. Selection of appropriate patients must currently rely on the physician’s experience, as well as retrospective analyses suggesting that factors such as disease-free interval and number of metastases are associated with favorable survival. The utility of metastasectomy must be evaluated in the setting of available systemic therapy, which has been evolving at an accelerating pace. Historical data must be considered in light of this shifting landscape. Randomized studies would be highly informative, but are subject to the same concerns.

CONFLICT OF INTEREST

Leonard J. Appleman: Research funding to Institution: BMS, Calithera, Merck, Peleton, Seattle Genetics.

Jodi Maranchie: None

Tala Achkar: None.

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