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Kidney Cancer| Volume 47, P65-72, January 2023

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Local Treatment of Recurrent Renal Cell Carcinoma May Have a Significant Survival Effect Across All Risk-of-recurrence Groups

      Abstract

      Background

      Retrospective comparative studies suggest a survival benefit after complete local treatment of recurrence (LTR) in renal cell carcinoma (RCC), which may be largely due to an indication bias.

      Objective

      To determine the role of LTR in a homogeneous population characterised by limited and potentially resectable recurrence.

      Design, setting, and participants

      RECUR is a protocol-based multicentre European registry capturing patient and tumour characteristics, risk of recurrence (RoR), recurrence patterns, and survival of those curatively treated for nonmetastatic RCC from 2006 to 2011. Per-protocol resectable disease (RD) recurrence was defined as (1) solitary metastases, (2) oligometastases, or (3) renal fossa or renal recurrence after radical or partial nephrectomy, respectively.

      Intervention

      Local treatment of recurrence.

      Outcome measurements and statistical analysis

      Overall survival (OS) and cancer-specific survival was compared in the RD population that underwent LTR versus no LTR. We constructed a multivariate model to predict risk factors for overall mortality and analysed the effect of LTR across RoR groups.

      Results and limitations

      Of 3039 patients with localised RCC treated with curative intent, 505 presented with recurrence, including 176 with RD. Of these patients, 97 underwent LTR and 79 no LTR. Patients in the LTR group were younger (64.3 [40–80] vs 69.2 [45–87] yr; p = 0.001). The median OS was 70.3 mo (95% confidence interval [CI] 58–82.6) versus 27.4 mo (95% CI 23.6–31.15) in the LTR versus no-LTR group (p < 0.001). After a multivariate analysis, having LTR (hazard ratio [HR] 0.37 [95% CI 0.2–0.6]), having low- versus high-risk RoR (HR 0.42 [95% CI [0.20–0.83]), and not having extra-abdominal/thoracic metastasis (HR 1.96 [95% CI 1.02–3.77]) were prognostic factors of longer OS. The LTR effect on survival was consistent across risk groups. OS HR for high, intermediate, and low risks were 0.36 (0.2–0.64), 0.27 (0.11–0.65), and 0.26 (0.08–0.8), respectively. Limitations include retrospective design.

      Conclusions

      This is the first study assessing the effectiveness of LTR in RCC in a comparable population with RD. This study supports the role of LTR across all RoR groups.

      Patient summary

      We assessed the effectiveness of local treatment of resectable recurrent renal cell carcinoma after surgical treatment of the primary kidney tumour. Local treatment of recurrence was associated with longer survival across groups with a risk of recurrence.

      Keywords

      1. Introduction

      Renal cancer is the 15th most prevalent cancer in the world, with over 430 000 new cases diagnosed in 2020 [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • et al.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. Depending on tumour and patient characteristics at diagnosis, 35–47% of patients with locally advanced (T2–T4) renal cell carcinoma (RCC) recur after surgery and develop metastasis [
      • Dabestani S.
      • Thorstenson A.
      • Lindblad P.
      • Harmenberg U.
      • Ljungberg B.
      • Lundstam S.
      Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study.
      ]. Despite proven efficacy of immune checkpoint inhibitors in the treatment of metastatic RCC (mRCC), only a minority of patients developed complete response in the most recent trials (8–16%) [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Motzer R.
      • Alekseev B.
      • Rha S.Y.
      • et al.
      Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
      ,
      • Rini B.I.
      • Plimack E.R.
      • Stus V.
      • et al.
      Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Motzer R.J.
      • Tannir N.M.
      • McDermott D.F.
      • et al.
      Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.
      ]. Therefore, complete removal of metastatic lesions, when technically feasible and clinically appropriate, may provide a potentially “curative” treatment alternative.
      Prior studies consistently suggest a benefit of complete local treatment of recurrence (LTR) in mRCC patients in terms of overall survival (OS), cancer-specific survival (CSS), and delay of systemic treatment. The generally poor quality of the evidence base implies that there is significant uncertainty, and therefore, caution is needed in the interpretation of available retrospective comparative studies of LTR versus no intervention [
      • Dabestani S.
      • Marconi L.
      • Hofmann F.
      • et al.
      Local treatments for metastases of renal cell carcinoma: a systematic review.
      ,
      • Ouzaid I.
      • Capitanio U.
      • Staehler M.
      • et al.
      Surgical metastasectomy in renal cell carcinoma: a systematic review.
      ]. The reported benefit may largely be due to an indication bias on the basis of differences in metastatic load and tumour biology. Potentially, patients with oligometastasis and long metachronous intervals are more likely to be candidates for LTR, whereas those with high-volume metastasis, rapid progression, and reduced performance status often do not undergo resection but were used as comparators in historical retrospective studies [
      • Dabestani S.
      • Marconi L.
      • Hofmann F.
      • et al.
      Local treatments for metastases of renal cell carcinoma: a systematic review.
      ].
      Our objective was (1) to mitigate this selection bias and determine the role of LTR in a population comparable in terms of relapse volume, defined as resectable disease (RD) at time of recurrence, and (2) to determine the association between baseline risk of recurrence (RoR) by Leibovich score or Union for International Cancer Control (UICC) at the time of (partial) nephrectomy with curative intent and OS after LTR.

      2. Patients and methods

      2.1 RECUR database and study design

      The RECUR database collected data from consecutive patients with a primary localised (N0M0) RCC from 15 centres in ten European countries who underwent surgery with curative intent from January 2006 to December 2011. The database collects demographic, surgical, and tumour characteristics, and information on risk scores as well as the type and frequency of imaging according to a protocol to establish associations for guideline recommendations for follow-up [
      • Dabestani S.
      • Beisland C.
      • Stewart G.D.
      • et al.
      Intensive imaging-based follow-up of surgically treated localised renal cell carcinoma does not improve post-recurrence survival: results from a European multicentre database (RECUR).
      ,
      • Dabestani S.
      • Beisland C.
      • Stewart G.D.
      • et al.
      Increased use of cross-sectional imaging for follow-up does not improve post-recurrence survival of surgically treated initially localized R.C.C.: results from a European multicenter database (R.E.C.U.R.).
      ,
      • Dabestani S.
      • Beisland C.
      • Stewart G.D.
      • et al.
      Long-term outcomes of follow-up for initially localised clear cell renal cell carcinoma: RECUR database analysis.
      ]. RECUR has appropriate institutional review board approval. Patients with <4 yr of follow-up and alive, or with incomplete data regarding subtype or risk scores were excluded.
      Patients who recurred after radical nephrectomy (RN) or partial nephrectomy (PN), and presented with RD at recurrence were included in the study. Two groups were compared: patients who underwent LTR (LTR group) versus patients whose recurrence was not treated locally (no-LTR group).

      2.2 Definition of RD

      In the RECUR protocol, RD was defined as follows:
      • 1.
        Solitary metastases
      • 2.
        Oligometastases of up to three metastases at one site
      • 3.
        Local renal fossa recurrence after RN or renal recurrence after PN
      To account for other factors that may have influenced the decision to treat recurrences locally, intent of treatment and factors (comorbidities and sites) that may have contributed were collected.

      2.3 Risk scores

      All patients were classified according to their risk score of progression after nephrectomy. As per the RECUR protocol, for clear cell RCC (ccRCC), the Leibovich score [
      • Leibovich B.C.
      • Blute M.L.
      • Cheville J.C.
      • et al.
      Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.
      ] was used to document the baseline RoR at the time of (partial) nephrectomy with curative intent. The Leibovich score is a scoring algorithm based on tumour stage, regional lymph node status, tumour size, nuclear grade and histologic tumour necrosis that can be used to predict disease progression after patients undergo RN for clinically localised ccRCC. For non-ccRCC, the UICC risk score was used [
      • Rosiello G.
      • Larcher A.
      • Fallara G.
      • et al.
      Head-to-head comparison of all the prognostic models recommended by the European Association of Urology guidelines to predict oncologic outcomes in patients with renal cell carcinoma.
      ,
      • Usher-Smith J.A.
      • Li L.
      • Roberts L.
      • et al.
      Risk models for recurrence and survival after kidney cancer: a systematic review.
      ].

      2.4 Outcomes

      OS and CSS were defined from the time of recurrence until death from any cause and death caused by RCC, respectively. Those still alive at the last follow-up were censored. Death from RCC was defined based on death certificate review or death following a recent medical visit for mRCC.

      2.5 Statistical analysis

      Frequencies and proportions were computed for categorical variables, whereas medians and interquartile ranges were calculated for continuous variables. Statistically significant differences between groups were estimated using the exact chi-square and Mann-Whitney tests for categorical and continuous variables, respectively.
      The 1-, 2-, 3-, and 4-yr and median survival rates were obtained using the Kaplan-Meier method. Cox proportional hazard regression analyses including age at recurrence, time to recurrence, risk score, site of recurrence (abdomen, thoracic, and other), and LTR status were conducted to determine the impact of independent risk factors on OS. All statistical comparisons were two sided, with a p value of <0.05 as a threshold of statistical significance. SPSS version 25 (IBM Corporation, Armonk, NY, USA) was used for the analyses.

      3. Results

      During the study period, a total of 3039 patients with localised RCC were treated with curative intent with either RN or PN. Of these patients, 505 (16.6%) presented with RCC recurrence after curative treatment, of whom 245 had RD. Of the latter, 97 underwent LTR (89, five, and three patients received metastasectomy, radiotherapy, and ablation, respectively), 79 patients did not receive any intervention, and data were missing for 69 patients (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Flowchart of the patients included in the study. PN = partial nephrectomy.
      Table 1 shows baseline characteristics of the two groups. Patients in the LTR group were younger at nephrectomy and had a better risk score profile, longer time to recurrence, and lower pT stages (Table 1). The no-LTR group presented with a higher number of patients with liver (7% vs 0%, p = 0.006) or bone (20.3% vs 4.1%, p = 0.001) metastasis (Table 2).
      Table 1Baseline characteristics
      LTR group (n = 97)No LTR group (n = 79)p value
      Age at recurrence, yr (range)64 (40–80)69 (45–87)0.001
      Age at nephrectomy, yr (range)61 (37–77)67 (43–85)<0.001
      Primary tumour size (cm)7.067.980.1
      Risk score (%)
      Leibovich or UICC.
      Low risk29.913.90.009
      Intermediate risk33.027.8
      High risk37.158.2
      Time to recurrence (mo)31240.023
      Chest recurrence (%)25.838.00.082
      Abdomen recurrence (%)27.846.40.012
      Other site of recurrence (%)21.627.80.034
      Male (%)67.065.80.97
      NSS (%)21.616.50.39
      Histologic subtype (%)
       ccRCC85.687.30.804
       Papillary RCC10.38.9
       Chromophobe RCC3.13.8
       Other10
      Tumour grade (%)
       12.13.90.741
       237.238.2
       344.738.2
       41619.7
      pT (%)
       pT1a23.710.10.048
       pT1b15.57.6
       pT2a10.312.7
       pT2b11.37.6
       pT3a30.952.4
       pT3b7.216.5
       pT3c01.3
       pT412.5
      pN
       pN021.627.80.059
       pN1 or N22.18.9
       pNx76.363.3
      ccRCC = clear cell RCC; LTR = local treatment of recurrence; NSS = nephron-sparing surgery; RCC = renal cell carcinoma; UICC = Union for International Cancer Control.
      a Leibovich or UICC.
      Table 2Location of recurrence per study group
      LTR (n = 97), %No LTR (n = 79), %p value
      Lung27.832.90.47
      Pleura11.30.88
      Retroperitoneal LN2.12.50.84
      Liver070.006
      Pancreas3.13.80.8
      Adrenal9.32.50.067
      Contralateral kidney19.62.50.001
      Bone4.120.30.001
      Brain3.15.10.5
      Other9.36.30.472
      Local recurrence (after RN)11.311.40.99
      Local recurrence (after PN)10.36.30.35
      LN = lymph node; LTR = local treatment of recurrence; PN = partial nephrectomy; RN = radical nephrectomy.
      Systemic treatment after recurrence was administered to 21.8% (n = 17) and 39% (n = 30) in the LTR and no-LTR group, respectively (p = 0.02).

      3.1 Survival analysis

      The mean study follow-up was 34 mo. The median OS was 70.3 mo (95% confidence interval [CI] 58–82.6) versus 27.4 mo (95% CI 23.6–31.15) in the LTR and no-LTR group, respectively (log rank p < 0.001; Fig. 2). OS periods at 12, 24, 36, and 48 mo after recurrence were, respectively, 97%, 86%, 72%, and 65% for the LTR Group versus 72%, 57%, 38%, and 27% for the no-LTR group. Both OS analysis excluding contralateral kidney recurrences and CSS findings mirrored those from OS (Supplementary Fig. 1 and 2)
      Figure thumbnail gr2
      Fig. 2Kaplan-Meyer curves for overall survival after recurrence (log rank p < 0.0001). LTR = local treatment of recurrence.

      3.2 Survival analysis stratified by baseline risk score

      The survival analysis stratified by RoR shows median OS of 66.39 (95% CI 33.67–99.11) versus 25.1 (95% CI 12.2–37.9) mo for high-risk patients in the LTR versus no-LTR group (log rank p < 0.001). In intermediate-risk patients, the median OS was not estimable versus 27.6 (95% CI 22.2–32.9) mo for the LTR versus no-LTR group (log rank p = 0.02). For low-risk patients, the median OS was not estimable versus 28.19 (95% CI 0–64.8) mo for the LTR versus no-LTR group (log rank p = 0.013; Fig. 3).
      Figure thumbnail gr3
      Fig. 3Kaplan-Meyer curves for overall survival per risk-of-recurrence group. LTR = local treatment of recurrence.
      Within the group of patients submitted to LTR, despite the superior numerical survival in those patients with favourable and intermediate RoR, no statistically significant differences were found (log rank p = 0.107; Supplementary Fig. 3)
      The effect of LTR on survival was consistent across risk groups: high-risk patients had an OS HR of 0.36 (0.2–0.64), intermediate-risk groups had an OS HR of 0.27 (0.11–0.65), and low-risk groups had an OS HR of 0.2 (0.08–0.8).

      3.3 Multivariate analysis

      After a multivariate analysis, LTR (HR 0.37 [95% CI 0.23–0.59], p < 0.001), low versus high RoR (HR 0.42 [95% CI 0.21–0.83], p = 0.016), and longer time to recurrence (HR 0.98 [95% CI 0.97–0.996], p = 0.01) were prognostic factors of longer OS. Having a nonthoracic/nonabdominal recurrence (HR 1.96 [95% CI 1.02–3.77], p = 0.042) was a risk factor for shorter OS (Table 3).
      Table 3Multivariate Cox regression—predictors of overall mortality
      HR95% CIp value
      LTR (vs no LTR)0.370.23–0.59<0.001
      Age (at recurrence)1.031.0–1.050.012
      Time from nephrectomy to recurrence0.980.97– 0.990.004
      Risk of recurrence score
       Poor vs favourable2.41.2–4.80.016
       Intermediate vs favourable1.20.58–2.60.608
      Thoracic recurrence0.790.41–1.540.49
      Abdominal recurrence1.070.56–2.060.833
      Other site of recurrence1.961.02–3.770.042
      CI = confidence interval; HR = hazard ratio; LTR = local treatment of recurrence.

      4. Discussion

      In this series of RCC patients with comparable, potentially resectable, low-volume cancer recurrence after nephrectomy, we report superior OS and CSS in those submitted to any form of local treatment of the lesions. This finding was confirmed after a multivariate analysis where local treatment conferred a 63% reduction in the risk of death. In this population, longer time to recurrence and a low baseline RoR at the time of (partial) nephrectomy were also found to be prognostic factors for longer OS after recurrence. We demonstrate that LTR of well-selected mRCC patients is associated with long-term OS across all RoR groups at the time of nephrectomy with curative intent.
      Current guidelines recommend LTR for metachronous RCC in patients with metastatic disease and favourable disease factors, and in whom complete resection is achievable [
      • Ljungberg B.
      • Albiges L.
      • Abu-Ghanem Y.
      • et al.
      European Association of Urology guidelines on renal cell carcinoma: the 2019 update.
      ,
      • Bedke J.
      • Albiges L.
      • Capitanio U.
      • et al.
      2021 Updated European Association of Urology guidelines on the use of adjuvant pembrolizumab for renal cell carcinoma.
      ]; in patients who develop oligometastases after a prolonged disease-free interval from nephrectomy [
      • Motzer R.J.
      • Jonasch E.
      • Boyle S.
      • et al.
      NCCN guidelines insights: kidney cancer, version 1.2021.
      ]; and in patients with good performance status, solitary metastases or oligometastases, metachronous disease with disease-free interval of >2 yr, absence of progression on systemic therapy, low or intermediate Fuhrman grade, and possibility of complete resection [
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • et al.
      Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]
      A survival benefit with complete metastasectomy versus either incomplete or no metastasectomy for RCC metastases to parenchymal organs was found in previous studies [
      • Dabestani S.
      • Marconi L.
      • Hofmann F.
      • et al.
      Local treatments for metastases of renal cell carcinoma: a systematic review.
      ,
      • Hsieh P.Y.
      • Hung S.C.
      • Li J.R.
      • et al.
      The effect of metastasectomy on overall survival in metastatic renal cell carcinoma: a systematic review and meta-analysis.
      ]. The current body of evidence is composed of retrospective, often noncomparative, studies and is hampered by a high risk of confounding regarding previous treatments, tumour histology, grade, and especially size, number, and volume of metastases [
      • Zelefsky M.J.
      • Greco C.
      • Motzer R.
      • et al.
      Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma.
      ,
      • Zerbi A.
      • Ortolano E.
      • Balzano G.
      • Borri A.
      • Beneduce A.A.
      • Di Carlo V.
      Pancreatic metastasis from renal cell carcinoma: which patients benefit from surgical resection?.
      ,
      • Dragomir A.
      • Nazha S.
      • Wood L.A.
      • et al.
      Outcomes of complete metastasectomy in metastatic renal cell carcinoma patients: the Canadian Kidney Cancer information system experience.
      ,
      • Eggener S.E.
      • Yossepowitch O.
      • Kundu S.
      • Motzer R.J.
      • Russo P.
      Risk score and metastasectomy independently impact prognosis of patients with recurrent renal cell carcinoma.
      ,
      • Fuchs B.
      • Trousdale R.T.
      • Rock M.G.
      Solitary bony metastasis from renal cell carcinoma: significance of surgical treatment.
      ]. Several recent studies from the tyrosine kinase inhibitor era found favourable survival outcome with metastasectomy compared with nonmetastasectomy in patients treated with targeted therapy [
      • Sun M.
      • Meyer C.P.
      • Karam J.A.
      • et al.
      Predictors, utilization patterns, and overall survival of patients undergoing metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy.
      ,
      • Li J.R.
      • Ou Y.C.
      • Yang C.K.
      • et al.
      The impact of local intervention combined with targeted therapy on metastatic renal cell carcinoma.
      ,
      • Tornberg S.V.
      • Visapaa H.
      • Kilpelainen T.P.
      • et al.
      Surgery for metastases of renal cell carcinoma: outcome of treatments and preliminary assessment of Leuven-Udine prognostic groups in the targeted therapy era.
      ].
      In the current study, we analysed a contemporary population from a multicentre European registry that started to include patients after widespread availability of targeted therapy [
      • Dabestani S.
      • Beisland C.
      • Stewart G.D.
      • et al.
      Intensive imaging-based follow-up of surgically treated localised renal cell carcinoma does not improve post-recurrence survival: results from a European multicentre database (RECUR).
      ]. We attempted to control heterogeneity in number, size, and volume of recurrence by including only patients with RD, as defined according to the RECUR protocol. Reported general and site-specific factors associated with a favourable outcome after local treatment of metastases from RCC are good performance status, Memorial Sloan Kettering Cancer Center (MSKCC) favourable and intermediate risk, solitary or oligometastatic disease, long disease-free interval, absence of sarcomatoid component, clear cell subtype, and complete surgical resection [
      • Dabestani S.
      • Marconi L.
      • Hofmann F.
      • et al.
      Local treatments for metastases of renal cell carcinoma: a systematic review.
      ]. Especially the number of lesions and their sites seem to have an important prognostic impact [
      • Psutka S.P.
      • Master V.A.
      Role of metastasis-directed treatment in kidney cancer.
      ]. In our study, RD was defined as three or fewer recurrences at a single site. Interestingly, this cut-off was used for eligibility to enter the phase 2 randomised open-label RESORT trial, which investigated the potential benefit of postoperative treatment with sorafenib compared with observation alone after complete metastasectomy in mRCC patients [
      • Procopio G.
      • Apollonio G.
      • Cognetti F.
      • et al.
      Sorafenib versus observation following radical metastasectomy for clear-cell renal cell carcinoma: results from the phase 2 randomized open-label RESORT study.
      ].
      A recent study on 51 patients with metastasectomy concluded that the number of metastatic sites and sarcomatoid features but not MSKCC score were associated with recurrence after complete metastasectomy [
      • Takagi T.
      • Fukuda H.
      • Ishihara H.
      • et al.
      Predictive factors for recurrence after complete metastasectomy in patients with metastatic renal cell carcinoma in the targeted therapy era.
      ]. It is very important to accurately estimate a patient's prognosis related to both the tumour and the patient's competing comorbidities, and to weigh the risks and benefits of LTR and its associated toxicity. We have shown that the baseline RoR at the time of (partial) nephrectomy with curative intent has a prognostic value even after recurrence and that LTR is associated with a significant survival benefit across all risk groups compared with no LTR. Nevertheless, despite OS benefits following LTR, the downward trend of the survival curves especially in high-risk disease suggests that patients experience further disease progression after local treatment and that cure is unlikely with this approach. We hypothesised that the RoR at the time of nephrectomy might also maintain a role as a prognostic factor after LTR. In the survival analysis by risk score in those patients who underwent LTR, we found that the baseline RoR lost its prognostic discrimination. This could be explained by the low number of events in the low- and intermediate-risk groups. To our knowledge, this is the first study that controls for baseline RoR by either Leibovich score or UICC in the comparison of LTR versus no LTR, and explores its prognostic value after LTR. We believe that there is currently only the Leuven-Udine metastasectomy prognostic score available for contemporary risk assessment; however, its validation could not be repeated externally [
      • Tornberg S.V.
      • Visapaa H.
      • Kilpelainen T.P.
      • et al.
      Surgery for metastases of renal cell carcinoma: outcome of treatments and preliminary assessment of Leuven-Udine prognostic groups in the targeted therapy era.
      ]. Until biomarkers are available to select patients for local or systemic therapy, decision-making supporting metastasectomy can be guided by the previously mentioned factors [
      • Verbiest A.
      • Couchy G.
      • Job S.
      • et al.
      Molecular subtypes of clear-cell renal cell carcinoma are prognostic for outcome after complete metastasectomy.
      ]. In addition to surgical LTR, stereotactic body radiotherapy is an attractive approach gaining further evidence [
      • Liu Y.
      • Long W.
      • Zhang Z.
      • et al.
      Metastasis-directed stereotactic body radiotherapy for oligometastatic renal cell carcinoma: extent of tumor burden eradicated by radiotherapy.
      ,
      • Stenman M.
      • Sinclair G.
      • Paavola P.
      • Wersall P.
      • Harmenberg U.
      • Lindskog M.
      Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005–2014.
      ,
      • Siva S.
      • Bressel M.
      • Wood S.T.
      • et al.
      Stereotactic radiotherapy and short-course pembrolizumab for oligometastatic renal cell carcinoma—the RAPPORT trial.
      ].
      The current study has several limitations due to its retrospective nature. Both groups were well balanced in terms of primary tumour size, histologic subtype, and tumour grade; however, we could observe evidence of a selection bias in baseline features that predict disease aggressivity such as stage, Leibovich risk score, and time to recurrence. While we controlled for RoR in our comparison, we acknowledge that other inherent patient confounders, such as differences in comorbidities, age, and performance status, may have influenced the decision to undergo LTR in the current series. We have also found a higher proportion of patients with bone metastasis in the no-LTR group, which has been identified as an independent prognostic variable associated with poor survival [
      • Kalra S.
      • Verma J.
      • Atkinson B.J.
      • et al.
      Outcomes of patients with metastatic renal cell carcinoma and bone metastases in the targeted therapy era.
      ,
      • Ruatta F.
      • Derosa L.
      • Escudier B.
      • et al.
      Prognosis of renal cell carcinoma with bone metastases: Experience from a large cancer centre.
      ]. Further, it needs to be acknowledged that local recurrence is not distant metastatic disease. However, there were no major imbalances between both groups, and local recurrence in the renal bed portends a similarly poor prognosis to distant oligometastatic disease [
      • Itano N.B.
      • Blute M.L.
      • Spotts B.
      • Zincke H.
      Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy.
      ]. Notably, the LTR groups had more contralateral kidney recurrences. Metachronous occurrence of RCC in the contralateral kidney is associated with an unfavourable prognosis, suggesting that metachronous contralateral tumours might be metastases from the original tumours [
      • Amano H.
      • Kondo T.
      • Hashimoto Y.
      • et al.
      Contralateral metachronous tumor occurrence is more frequently associated with distant metastases or postoperative intrarenal recurrence in renal cell carcinoma patients.
      ]. To exclude confounding by de novo contralateral tumours that carry a better prognosis, we repeated the analysis without patients with contralateral recurrences and continued to observe a survival advantage in the LTR group. In RCC, survival is influenced by systemic therapy, and although we know the percentage of patients treated upon progression, data on the type and duration of treatment were not recorded. Finally, data regarding complications after LTR were not available.
      We have witnessed a major paradigm change in first-line therapy for mRCC with the introduction of immune checkpoint inhibitor–based combination as standard of care [
      • Bedke J.
      • Albiges L.
      • Capitanio U.
      • et al.
      The 2021 updated European Association of Urology guidelines on renal cell carcinoma: immune checkpoint inhibitor-based combination therapies for treatment-naive metastatic clear-cell renal cell carcinoma are standard of care.
      ]. In unselected patients, durable overall responses with these combinations are achieved in 60% and complete responses in up to 16% [
      • Bedke J.
      • Albiges L.
      • Capitanio U.
      • et al.
      The 2021 updated European Association of Urology guidelines on renal cell carcinoma: immune checkpoint inhibitor-based combination therapies for treatment-naive metastatic clear-cell renal cell carcinoma are standard of care.
      ]. Therefore, the role of LTR in the era of immune checkpoint inhibition needs to be investigated, in prospective trials, with a focus on surgical options and radiotherapy, observation, perioperative or adjuvant systemic therapy, and sequencing of immunotherapy in oligoprogressive disease.

      5. Conclusions

      In comparison with previous retrospective studies comparing metastasectomy with no metastasectomy, our study assessed the effectiveness of LTR in RCC in a comparable population with RD. This study supports the role of LTR across all RoR groups in a selected population.
      Author contributions: Lorenzo Marconi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
      Study concept and design: Marconi, Bex.
      Acquisition of data: Marconi, Capitanio, Beisland, Lam, Pello, Stewart, Volpe, Ljungberg, Dabestani, Bex.
      Analysis and interpretation of data: Marconi, Bex.
      Drafting of the manuscript: Marconi, Bex.
      Critical revision of the manuscript for important intellectual content: Marconi, Kuusk, Klatte, Capitanio, Beisland, Lam, Pello, Stewart, Volpe, Ljungberg, Dabestani, Bex.
      Statistical analysis: Marconi.
      Obtaining funding: None.
      Administrative, technical, or material support: None.
      Supervision: Bex.
      Other: None.
      Financial disclosures: Lorenzo Marconi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
      Funding/Support and role of the sponsor: None.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      References

        • Sung H.
        • Ferlay J.
        • Siegel R.L.
        • et al.
        Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2021; 71: 209-249
        • Dabestani S.
        • Thorstenson A.
        • Lindblad P.
        • Harmenberg U.
        • Ljungberg B.
        • Lundstam S.
        Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study.
        World J Urol. 2016; 34: 1081-1086
        • Choueiri T.K.
        • Powles T.
        • Burotto M.
        • et al.
        Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
        N Engl J Med. 2021; 384: 829-841
        • Motzer R.
        • Alekseev B.
        • Rha S.Y.
        • et al.
        Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
        N Engl J Med. 2021; 384: 1289-1300
        • Rini B.I.
        • Plimack E.R.
        • Stus V.
        • et al.
        Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
        N Engl J Med. 2019; 380: 1116-1127
        • Motzer R.J.
        • Tannir N.M.
        • McDermott D.F.
        • et al.
        Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.
        N Engl J Med. 2018; 378: 1277-1290
        • Dabestani S.
        • Marconi L.
        • Hofmann F.
        • et al.
        Local treatments for metastases of renal cell carcinoma: a systematic review.
        Lancet Oncol. 2014; 15: e549-e561
        • Ouzaid I.
        • Capitanio U.
        • Staehler M.
        • et al.
        Surgical metastasectomy in renal cell carcinoma: a systematic review.
        Eur Urol Oncol. 2019; 2: 141-149
        • Dabestani S.
        • Beisland C.
        • Stewart G.D.
        • et al.
        Intensive imaging-based follow-up of surgically treated localised renal cell carcinoma does not improve post-recurrence survival: results from a European multicentre database (RECUR).
        Eur Urol. 2019; 75: 261-264
        • Dabestani S.
        • Beisland C.
        • Stewart G.D.
        • et al.
        Increased use of cross-sectional imaging for follow-up does not improve post-recurrence survival of surgically treated initially localized R.C.C.: results from a European multicenter database (R.E.C.U.R.).
        Scand J Urol. 2019; 53: 14-20
        • Dabestani S.
        • Beisland C.
        • Stewart G.D.
        • et al.
        Long-term outcomes of follow-up for initially localised clear cell renal cell carcinoma: RECUR database analysis.
        Eur Urol Focus. 2019; 5: 857-866
        • Leibovich B.C.
        • Blute M.L.
        • Cheville J.C.
        • et al.
        Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.
        Cancer. 2003; 97: 1663-1671
        • Rosiello G.
        • Larcher A.
        • Fallara G.
        • et al.
        Head-to-head comparison of all the prognostic models recommended by the European Association of Urology guidelines to predict oncologic outcomes in patients with renal cell carcinoma.
        Urol Oncol. 2022; 40: 271.e19-271.e27
        • Usher-Smith J.A.
        • Li L.
        • Roberts L.
        • et al.
        Risk models for recurrence and survival after kidney cancer: a systematic review.
        BJU Int. 2022; 130: 562-579
        • Ljungberg B.
        • Albiges L.
        • Abu-Ghanem Y.
        • et al.
        European Association of Urology guidelines on renal cell carcinoma: the 2019 update.
        Eur Urol. 2019; 75: 799-810
        • Bedke J.
        • Albiges L.
        • Capitanio U.
        • et al.
        2021 Updated European Association of Urology guidelines on the use of adjuvant pembrolizumab for renal cell carcinoma.
        Eur Urol. 2022; 81: 134-137
        • Motzer R.J.
        • Jonasch E.
        • Boyle S.
        • et al.
        NCCN guidelines insights: kidney cancer, version 1.2021.
        J Natl Compr Canc Netw. 2020; 18: 1160-1170
        • Escudier B.
        • Porta C.
        • Schmidinger M.
        • et al.
        Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2019; 30: 706-720
        • Hsieh P.Y.
        • Hung S.C.
        • Li J.R.
        • et al.
        The effect of metastasectomy on overall survival in metastatic renal cell carcinoma: a systematic review and meta-analysis.
        Urol Oncol. 2021; 39: 422-430
        • Zelefsky M.J.
        • Greco C.
        • Motzer R.
        • et al.
        Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma.
        Int J Radiat Oncol Biol Phys. 2012; 82: 1744-1748
        • Zerbi A.
        • Ortolano E.
        • Balzano G.
        • Borri A.
        • Beneduce A.A.
        • Di Carlo V.
        Pancreatic metastasis from renal cell carcinoma: which patients benefit from surgical resection?.
        Ann Surg Oncol. 2008; 15: 1161-1168
        • Dragomir A.
        • Nazha S.
        • Wood L.A.
        • et al.
        Outcomes of complete metastasectomy in metastatic renal cell carcinoma patients: the Canadian Kidney Cancer information system experience.
        Urol Oncol. 2020; 38: 799.e1-799.e10
        • Eggener S.E.
        • Yossepowitch O.
        • Kundu S.
        • Motzer R.J.
        • Russo P.
        Risk score and metastasectomy independently impact prognosis of patients with recurrent renal cell carcinoma.
        J Urol. 2008; 180 (discussion 878): 873-878
        • Fuchs B.
        • Trousdale R.T.
        • Rock M.G.
        Solitary bony metastasis from renal cell carcinoma: significance of surgical treatment.
        Clin Orthop Relat Res. 2005; 431: 187-192
        • Sun M.
        • Meyer C.P.
        • Karam J.A.
        • et al.
        Predictors, utilization patterns, and overall survival of patients undergoing metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy.
        Eur J Surg Oncol. 2018; 44: 1439-1445
        • Li J.R.
        • Ou Y.C.
        • Yang C.K.
        • et al.
        The impact of local intervention combined with targeted therapy on metastatic renal cell carcinoma.
        Anticancer Res. 2018; 38: 5339-5345
        • Tornberg S.V.
        • Visapaa H.
        • Kilpelainen T.P.
        • et al.
        Surgery for metastases of renal cell carcinoma: outcome of treatments and preliminary assessment of Leuven-Udine prognostic groups in the targeted therapy era.
        Scand J Urol. 2018; 52: 419-426
        • Psutka S.P.
        • Master V.A.
        Role of metastasis-directed treatment in kidney cancer.
        Cancer. 2018; 124: 3641-3655
        • Procopio G.
        • Apollonio G.
        • Cognetti F.
        • et al.
        Sorafenib versus observation following radical metastasectomy for clear-cell renal cell carcinoma: results from the phase 2 randomized open-label RESORT study.
        Eur Urol Oncol. 2019; 2: 699-707
        • Takagi T.
        • Fukuda H.
        • Ishihara H.
        • et al.
        Predictive factors for recurrence after complete metastasectomy in patients with metastatic renal cell carcinoma in the targeted therapy era.
        Urol Oncol. 2020; 38: 515-520
        • Verbiest A.
        • Couchy G.
        • Job S.
        • et al.
        Molecular subtypes of clear-cell renal cell carcinoma are prognostic for outcome after complete metastasectomy.
        Eur Urol. 2018; 74: 474-480
        • Liu Y.
        • Long W.
        • Zhang Z.
        • et al.
        Metastasis-directed stereotactic body radiotherapy for oligometastatic renal cell carcinoma: extent of tumor burden eradicated by radiotherapy.
        World J Urol. 2021; 39: 4183-4190
        • Stenman M.
        • Sinclair G.
        • Paavola P.
        • Wersall P.
        • Harmenberg U.
        • Lindskog M.
        Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005–2014.
        Radiother Oncol. 2018; 127: 501-506
        • Siva S.
        • Bressel M.
        • Wood S.T.
        • et al.
        Stereotactic radiotherapy and short-course pembrolizumab for oligometastatic renal cell carcinoma—the RAPPORT trial.
        Eur Urol. 2022; 81: 364-372
        • Kalra S.
        • Verma J.
        • Atkinson B.J.
        • et al.
        Outcomes of patients with metastatic renal cell carcinoma and bone metastases in the targeted therapy era.
        Clin Genitourin Cancer. 2017; 15: 363-370
        • Ruatta F.
        • Derosa L.
        • Escudier B.
        • et al.
        Prognosis of renal cell carcinoma with bone metastases: Experience from a large cancer centre.
        Eur J Cancer. 2019; 107: 79-85
        • Itano N.B.
        • Blute M.L.
        • Spotts B.
        • Zincke H.
        Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy.
        J Urol. 2000; 164: 322-325
        • Amano H.
        • Kondo T.
        • Hashimoto Y.
        • et al.
        Contralateral metachronous tumor occurrence is more frequently associated with distant metastases or postoperative intrarenal recurrence in renal cell carcinoma patients.
        Int J Urol. 2010; 17: 615-622
        • Bedke J.
        • Albiges L.
        • Capitanio U.
        • et al.
        The 2021 updated European Association of Urology guidelines on renal cell carcinoma: immune checkpoint inhibitor-based combination therapies for treatment-naive metastatic clear-cell renal cell carcinoma are standard of care.
        Eur Urol. 2021; 80: 393-397

      Linked Article

      • The Decision to Surgically Resect Recurrent Renal Cell Carcinoma: More Evidence that Careful Case Selection by Surgeons Is Associated with Better Survival
        European Urology Open ScienceVol. 49
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          In the 80 yr since surgeons began resecting kidney cancer, our understanding of this disease has dramatically expanded. Once thought to be a single cancer, dubbed the “internist’s disease” because of its capricious clinical behavior, usually advanced at presentation, kidney cancer is now understood to be a complex family of more than 30 different tumors with unique pathological and genomic features. The oncological threat ranges from benign (20%) to indolent (25%) to highly malignant (54%) [1]. Today’s modern imaging led to tumor size and stage migration, the era of incidentaloma, the acceptance of kidney-sparing operations, and, in parallel, the development of minimally invasive surgery (MIS) and ablative techniques [2].
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