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The role of active surveillance and cytoreductive nephrectomy in metastatic renal cell carcinoma
Cancer Treatment and Research Communications 23 (2020) 100169
Contents lists available at ScienceDirect
Cancer Treatment and Research Communications journal homepage: www.elsevier.com/locate/ctarc
The role of active surveillance and cytoreductive nephrectomy in metastatic renal cell carcinoma Amanda Nizama, Jonah A. Schindelheimb, Moshe C. Ornsteina, a b
T
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Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, United States Department of Medicine, Touro College of Osteopathic Medicine, Middletown, NY, United States
A R T I C LE I N FO
A B S T R A C T
Keywords: Metastatic renal cell carcinoma Active surveillance Cytoreductive nephrectomy Kidney cancer Surgery
Treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by an expanding armamentarium of systemic therapies, which have resulted in improved patient outcomes. Multimodal approaches that include cytoreductive nephrectomy (CN), immunotherapy, and targeted therapy are necessary to optimize clinical care. Active surveillance (AS) and CN are two cornerstones of treatment in mRCC, which require reexamination in the context of new systemic therapies. Herein, we review the data and provide a practical approach for the incorporation of AS and CN in the management of mRCC.
Introduction Renal cell carcinoma (RCC) accounts for approximately 74,000 new cancer cases and almost 15,000 deaths per year in the United States [1]. The majority of renal cell carcinomas are localized or locally advanced at the time of diagnosis and are treated surgically with curative intent. However, approximately one-third of patients present with de novo metastatic disease and close to 30% of patients who undergo surgical treatment for localized RCC will eventually develop metastatic disease. The treatment of metastatic renal cell carcinoma (mRCC) involves a complex interplay between systemic therapy and surgical management with cytoreductive nephrectomy (CN) [2,3]. Although data exist to help guide CN decision, these data are limited to time periods in which the standard treatments for mRCC included interferon and targeted therapies, and as such their applicability to the current checkpoint inhibitor (CPI) era is questionable [4,5]. Similarly, although the role of active surveillance (AS) in mRCC has been well established [6], patient selection in an era of improved systemic therapies is not well defined. We review the roles of CN and AS in the treatment of patients with mRCC and provide a practical approach based on existing data.
clinical outcomes, multiple prognostic scoring systems exist for patients with mRCC. The Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic RCC Consortium (IMDC) criteria are the most commonly used prognostic tools, which stratify patients into favorable, intermediate, and poor risk categories on the basis of laboratory and clinical features [7,8]. These prognostic criteria are based on patients receiving targeted therapy. More recent risk stratification criteria incorporate genomic information (specifically, BAP1, PBRM1, and TP53 mutations) in addition to clinical and laboratory criteria [9]. The MSKCC and IMDC prognostic model’s data highlight the diverse biology of patients with mRCC. In these models, median overall survival (OS) ranges from less than one year for poor risk patients to greater than three years for favorable risk patients. The spectrum of disease course includes those patients with an indolent RCC biology who may require minimal (or no) treatment to those with aggressive disease likely to be refractory to standard treatments. This inter-patient variability in biology and outcome underscores the role of active surveillance (AS) for a subset of patients in whom close monitoring without systemic therapy is unlikely to negatively impact clinical outcome.
Active surveillance in metastatic renal cell carcinoma
Retrospective data
Rationale for active surveillance
A host of retrospective data for active surveillance (AS) in mRCC exist. A report by Matsubara et al. described outcomes of 29 patients with mRCC who chose AS over systemic therapy between 2000 and 2011 [10]. All patients had IMDC favorable or intermediate risk mRCC.
Significant inter-patient variability exists in the disease course and underlying biology of mRCC. To account for various factors impacting
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Corresponding author. E-mail address: [email protected] (M.C. Ornstein).
https://doi.org/10.1016/j.ctarc.2020.100169
2468-2942/ © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
2
a
98% favorable or intermediate 52a Rini et al.[6]
Phase 2 trial of patients with asymptomatic mRCC placed on AS
38.1 months
9.4 months
44.5 months
Favorable group (≤ 1 IMDC criteria and ≤ 2 metastatic organ sites): median 22.2 months on surveillance Unfavorable group (> 1 IMDC criteria or > 2 metastatic organ sites): median 8.4 months on surveillance
Occurred where IFN was standard of care. In current era, many of these patients would have likely received standard systemic therapy and not AS. Above limitation likely accounts for discrepancy between this study's TTP and that of Rini et al.[6] Non-randomized No specific criteria for initiation of systemic therapy Predictors of progression hypercalcemia, hypoalbuminemia, elevated lactate dehydrogenase, anemia, KPS < 80%, and ≥ 2 organ sites of metastatic disease 25 months 8 weeks Predated IMDC risk 15 Wong et al. [13]
IMDC Risk Number of patients Trial
Table 1 Key trials of active surveillance in mRCC.
Trial design
Prospective data of AS in mRCC are more limited (see Table 1). One of the first prospective trials of AS was conducted by Wong et al. in which patients with mRCC who underwent debulking nephrectomy were placed on a “watch and wait” protocol and did not receive systemic therapy until disease progression [13]. A total 15 patients enrolled on this trial. With a median follow-up of 18 months (range, 4–46), 12 (67%) patients developed disease progression. Median TTP was eight weeks after nephrectomy. Subsequent systemic therapy included chemotherapy (gemcitabine and capecitabine) and IFN-based therapies. Median OS for all patients was 25 months with three patients alive at the 46-month follow-up. The presence of abnormal laboratory values (specifically, hypercalcemia, hypoalbuminemia, elevated lactate dehydrogenase, anemia), KPS < 80%, and ≥ 2 organ sites of metastatic disease were predictive of tumor progression. In the largest prospective trial of AS in mRCC, Rini et al. enrolled 52 patients across three countries (US, UK, Spain) who had asymptomatic, treatment-naïve mRCC into a AS protocol [6]. The primary endpoint of the trial was time from initiation of AS to initiation of systemic therapy. Of the 48 patients included in the analysis, the median age was 67, 36 (75%) were male, 46 (96%) clear cell histology, and 47 (98%) either favorable or intermediate risk by IMDC criteria [6,7]. The median time from diagnosis to metastatic disease was 5.1 months (Interquartile ratio [IQR] 0.7–25.7). The median follow-up for all patients was 38.1 months and the median time on AS was 14.9
18 months
Prospective data
CN followed by observation until progression
Median follow-up
Median TTP
Median OS
Key findings
Limitations
With a median follow-up of 35.3 months the median PFS in these patients was 26.1 months with 14% of patients dying during the follow-up period. Despite disease progression in 21 (72%) patients only 12 (57%) of these patients actually received systemic therapy during the followup period. The remaining 9 (43%) of patients declined systemic therapy at the time of disease progression. At the time of analysis, the median OS had not been reached. The 1 and 4 year OS rates were 96.4% and 83.8%, respectively. Despite initial AS in patients with mRCC, mPFS, and OS rates were certainly no worse than prospective trials of approved agents. Similarly, a retrospective analysis mRCC patients on AS from 2000–2012 investigated factors associated with rapid disease progression [11]. Of the 58 patients included, the median follow-up was 31.4 months with a median time to progression (TTP) of 12.4 months (95% CI 8.4–16.5). At the time of data cutoff, 47 (81%) patients developed disease progression. Factors associated with shortened TTP were the presence of liver metastases, KPS < 100%, and time from diagnosis to AS of < 1 year. The majority of patients subsequently received sunitinib or pazopanib as their systemic therapy with objective response rates of 71% and 46%, respectively. Although median OS was not reached, the estimated mOS was 91.1 months (95% CI 31.7–151.6). More recently, retrospective data on AS in mRCC from the Canadian Kidney Cancer Information System (CKCis) were presented [12]. In this analysis of mRCC patients diagnosed between 2011 and 2016, outcomes of patients who received immediate systemic treatment (within 6 months of diagnosis) were compared to those who were went on AS. AS was defined as delayed systemic therapy for ≥ 6 months or patients who never received systemic therapy but were alive ≥ 1 year following diagnosis. A total of 848 patients received immediate treatment and 863 were identified who received AS. Of the AS patients, 370 received systemic therapy ≥ 6 months after diagnosis and 493 did not go on to receive systemic therapy and had an OS of ≥ 1 year. Median time on AS was 14.2 months (range, 6–71). Notable differences (p<0.001) between the AS and immediate treatment cohorts were that AS patients were older, had fewer sites of metastatic disease, and were more likely to have had a metastasectomy. Importantly, 5 year OS probability for the AS and immediate treatment patients was 70.2% and 32.1% (p<0.0001), respectively. Most patients in this analysis subsequently received sunitinib or pazopanib as a primary therapy.
48 patients included in the analysis. mRCC = Metastatic renal cell carcinoma; CN = Cytoreductive nephrectomy; IFN = Interferon; OS = Overall survival; TTP = Time to progression; IMDC = International Metastatic RCC Database Consortium; KPS = Karnofsky Performance Status.
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trial. With a median follow-up of 50.9 months the median OS for sunitinib cohort (18.4 months) was non-inferior to the CN-sunitinib cohort (18.4 months vs 13.9 months; HR 0.89; 95% CI 0.71–1.10). These were the first prospective data in the targeted-therapy era to demonstrate that CN might not be appropriate for all patients with mRCC. In the updated analysis, with a median follow-up of 61.5 months, the investigators isolated the intermediate risk patients to assess whether the number of metastatic sites (1 vs > 1) and/or number of IMDC risk criteria (1 vs 2) could help define a population better suited for sunitinib alone. When stratified by number of metastatic sites, there was no statistically meaningful difference between the CN-sunitinib and sunitinib alone groups. However, the data did suggest that patients with two IMDC risk factors were less likely to benefit from nephrectomysunitinib (median OS 17.6) vs sunitinib-alone (median OS 31.2 months; HR 0.63; 95% CI 0.44–0.97; p = 0.033) [16]. There are a number of inherent limitations with the CARMENA data. Over 40% of patients in this trial were poor-risk. A host of data already exist indicating that poor risk patients are less likely to benefit from CN and this previously established poor prognostic population may have drastically biased the results of the trial [17–19]. Additionally, patients in this trial had approximately 60% of their tumor burden limited to their renal mass. As such despite a “debulking” nephrectomy, approximately 40% of their tumors still remained in situ. It is thus no surprise that the data from this trial do not support a CN in this population. The outcome of mRCC following CN is related to the degree of tumor debulking that occurs during the surgery with multiple reports demonstrating that optimal outcomes following CN occurs when the fractional percentage of tumor volume removed during a debulking nephrectomy is greater than 90% [20,21]. Given the high percentage of poor-risk patients as well as the high extra-renal tumor burden in the CARMENA patient population, the trial is unlikely to be generalizable to the broader mRCC patient population. Whereas CARMENA measured efficacy of sunitinib vs nephrectomysunitinib, the phase 3 SURTIME trial randomized patients to receive immediate CN followed by sunitinib vs a deferred CN cohort in which patients received three cycles of S followed a CN (deferred CN) [5]. Although 458 patients were needed for the primary endpoint of PFS, given poor accrual, the trial was closed after 99 patients enrolled. The 28 week progression-free rate in the immediate CN arm was 42% compared to 43% in the deferred CN arm (p = 0.61). The intent-to-treat OS did favor deferred CN over immediate CN (mOS 32.4 vs 15.0; HR 0.57; 95% CI 0.34–0.95; P = 0.03). Of note, 14 patients (29%) in the SCN arm had systemic progression prior to the CN and thus did not undergo CN [5]. Although the data are not definitive given the poor accrual, this trial does suggest that a subset of mRCC patients will achieve maximal benefit by receiving systemic therapy as their initial
months (95% CI 10.6–25.0). The median time to progression for all patients was 9.4 months (95% CI 7.4–13.4). Of the 43 (90%) who had RECIST-defined PD while on AS, 37 were started on systemic therapy and six continued on surveillance. Importantly, although 23 patients who experienced PD started systemic therapy immediately, the remaining 20 patients who experienced disease progression continued on surveillance for a median of 15.8 months (95% CI 3.0–24.1). The estimated median OS for all patients (calculated from initiation of AS) was 44.5 months (95% CI 37.6-NR) [6]. On multivariate analysis, the presence of 0–1 IMDC risk factors and no more than two organ sites involvement of metastatic disease were independently prognostic of time on surveillance. The authors thus established favorable (≤ 1 IMDC criteria and ≤ 2 metastatic organ sites) and unfavorable (presence of at least one of the aforementioned) cohorts with a median surveillance time of 22.2 and 8.4 months, respectively [6]. Such criteria, established in AS patients on a prospective trial can be used when trying to determine whether a patient might benefit from AS vs immediate systemic therapy.
Cytoreductive nephrectomy in metastatic renal cell carcinoma Initial support for cytoreductive nephrectomy (CN) in patients with newly diagnosed mRCC originated from two randomized controlled trials conducted in an era in which interferon-α (IFN-α) was the standard systemic therapy (see Table 2). Both the Southwest Oncology Group (SWOG) and European Organization for Research and Treatment of Cancer (EORTC) designed randomized clinical trials in which mRCC patients underwent CN followed by IFN-α vs immediate systemic therapy with IFN-α without prior CN [14,15]. In the SWOG trial of 246 patients, the patients who underwent CN followed by IFN-α 2b had an overall median survival of 11.1 months compared to 8.1 months in those receiving IFN-α 2b alone (p = 0.05) [14]. The EORTC trial contained 83 patients and also noted a survival benefit in those who underwent CN prior to systemic therapy (17 months vs 7 months; HR 0.54; 95% CI 0.31–0.94) [15]. Importantly, both studies predated the IMDC risk criteria and did not define histological subtypes. Moreover, given the relatively poor efficacy of systemic therapies at the time of these studies, the ability to extrapolate these data and apply them in patients receiving CPI is uncertain. In the targeted therapy era, the phase III CARMENA trial randomized patients with newly diagnosed intermediate and poor risk mRCC to undergo cytoreductive nephrectomy followed by sunitinib (CN-sunitinib group) vs sunitinib alone without an upfront CN (sunitinib group) [4]. The trial was designed to assess the non-inferiority of sunitinib vs CN-sunitinib with regards to OS with the upper bound limit of the 95% CI set at ≤1.20. A total of 450 patients were enrolled in the
Table 2 Prospective randomized controlled trials investigating cytoreductive nephrectomy in RCC. Trial
Experimental arms
IMDC risk groups
Primary endpoint(s)
Limitations
SWOG[14] n = 246 EORTC[15] n = 83
CN → IFN-α 2b IFN-α 2b alone CN → IFN-α 2b IFN-α 2b alone
N/A
Median OS: 11 mos. vs 8 mos. (p = 0.05)
N/A
CARMENA[4] n = 450 (ITT population)
Sunitinib alone Immediate CN → Sunitinib
Median TTP: 5 mos. vs 3 mos. (HR 0.60, 95% CI 0.36–0.97) Median OS: 17 mos. vs 7 mos. (HR 0.54, 95% CI 0.31–0.94) Median OS: 18.4 mos. vs 13.9 mos. (HR 0.89, 95% CI 0.71–1.10)
Histology subtypes not defined. Predated IMDC risk stratification. Histology subtypes not defined. Predated IMDC risk stratification.
SURTIME[5] n = 99 (ITT population)
Immediate CN → Sunitinib 3 cycles Sunitinib → CN
Intermediate & poor-risk
Intermediate &poor-risk
ITT 28-week PFR: 42% vs 43% (p = 0.61)* *Original primary endpoint of PFS required sample size of 458. Due to poor accrual, ITT 28-week PFR reported instead.
IMDC favorable risk and those with single or oligometastatic disease excluded. High percentage of poor risk patients. Extensive extra-renal tumor burden IMDC favorable risk and those with single or oligometastatic disease excluded. Terminated early due to poor accrual.
mRCC = Metastatic renal cell carcinoma; n = number; CN = Cytoreductive nephrectomy; IFN-α 2b = Interferon-α 2b; OS = Overall survival; TTP = Time to progression; HR = Hazard ratio; CI = Confidence interval; ITT = intention to treat; PFR = Progression-free rate; PFS = Progression-free survival. 3
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Fig. 1. Cytoreductive nephrectomy and surveillance considerations in newly diagnosed mRCC 1 Fevers, chills, night sweats, etc. 2Greater than 20%. 31–2 IMDC risk factor or ~15% extra-renal tumor burden. 4<10%. 5Significant pain or hematuria. AS = Active surveillance; CN = cytoreductive nephrectomy; IMDC = International Metastatic RCC Database Consortium; mRCC = metastatic renal cell carcinoma.
by deferred CN vs continued systemic therapy and no CN in IMDC intermediate and poor-risk mRCC [27]. Similar CN trials are being proposed through cooperative groups such as SWOG [29]. Most ongoing surveillance trials include treatment-free observation of patients who received CPI therapy and have a significant response to therapy [30–32]. These patients subsequently enter active surveillance until they develop pre-defined tumor regrowth. To our knowledge, no AS trials in treatment-naïve mRCC are currently ongoing. Until prospective data from such trials materialize, practical approaches incorporating CPI-based combinations, CN, and AS should be developed to drive decision making for patients with newly diagnosed mRCC.
treatment modality. Discussion Given the expanding treatment repertoire of mRCC treatment and the improved outcomes from CPI-based combination treatments as a standard frontline option for mRCC, it is critical to analyze whether the clinical benefit of cytoreductive nephrectomy (CN) remains applicable and whether active surveillance (AS) is appropriate [22,23]. Importantly, should patients who would have received a CN in the targeted-therapy ear still undergo surgery in the CPI era or are they more likely to benefit from systemic therapy upfront [14,15]? Similarly, given the improved outcomes in mRCC, the role of AS is less clear. The rationale for AS in an era of targeted therapies in which the PFS ranges from 8 to 11 months is understandable given the marginal benefit of systemic therapy [24,25]. However, the role of AS in the CPI era in which over 70%% of patients are alive at 24 months and in which the median OS has not been reached with 30 month follow-up is less certain [26]. Perhaps patients who historically would have proceeded with AS over sequential single agent targeted therapies, should instead receive CPI-based combination therapies. As outlined in the sections above, there are clear features to portend good prognosis in patients who undergo CN and AS. Ultimately, management of mRCC in the CPI era requires a more nuanced approaches that incorporates historical CN and AS data into individualized management plans. A practical approach to the management of newly-diagnosed mRCC is to take into consideration the potential for AS when considering a CN (see Fig. 1). Patients who present with systemic symptoms including fevers, chills, and night sweats are likely to benefit from systemic therapy first and forgo an immediate cytoreductive nephrectomy. Similarly, patients with high volume extrarenal disease should undergo systemic therapy as the benefit of CN in this setting is less certain. Conversely, patients who have minimal extra-renal tumor burden and limited IMDC risk criteria, and as such would be good AS candidate following CN, should be considered for an immediate CN. In this manner, the role of AS is taken into consideration in a newly diagnosed patient with mRCC, and the potential for AS actually serves to guide decision making regarding a CN (see Fig. 1). Despite this practical algorithm, additional data is needed to prospectively investigate the role of CN and AS in the CPI era. A number of such trials are planned and accruing to better define these issues in the patients treatment with CPI therapies [27,28]. For example the NORDIC-SUN trial will investigate ipilimumab and nivolumab followed
Conclusion The treatment of mRCC has progressed at a rapid pace with a variety of trials demonstrating improved clinical outcomes with checkpoint inhibitor (CPI)––based combination therapies as frontline treatment. Incorporating surgical approaches and active surveillance into the current era demands extrapolation of historical data and its application and incorporation to current systemic treatment paradigms. Individualized decisions with multidisciplinary teams are critical in determining best approach per patient. Ultimately, biomarker-based prospective trials of CN and AS in the CPI era are sorely needed to optimize patient outcomes. References [1] R.L. Siegel, K.D. Miller, A Jemal, Cancer statistics, 2019, CA Cancer J. Clin. 69 (2019) 7–34. [2] A. Kokorovic, R. Rendon, Cytoreductive nephrectomy in metastatic kidney cancer: what do we do now? Curr. Opin. Support. Palliat. Care 13 (2019) 255–261. [3] T. Kuusk, B. Szabados, W.K. Liu, T. Powles, A Bex, Cytoreductive nephrectomy in the current treatment algorithm, Ther. Adv. Med. Oncol. 11 (2019) 1758835919879026. [4] A. Méjean, A. Ravaud, S. Thezenas, S. Colas, J.-.B. Beauval, K. Bensalah, L. Geoffrois, A. Thiery-Vuillemin, L. Cormier, H. Lang, et al., Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma, New Engl. J. Med. 379 (2018) 417–427. [5] A. Bex, P. Mulders, M. Jewett, J. Wagstaff, J.V. van Thienen, C.U. Blank, R. van Velthoven, M del P Laguna, L. Wood, H.H.E. van Melick, et al., Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the surtime randomized clinical trial, JAMA Oncol. 5 (2019) 164–170. [6] B.I. Rini, T.B. Dorff, P. Elson, C.S. Rodriguez, D. Shepard, L. Wood, J. Humbert, L. Pyle, Y.-.N. Wong, J.H. Finke, et al., Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial, Lancet Oncol. 17 (2016) 1317–1324. [7] D.Y.C. Heng, W. Xie, M.M. Regan, M.A. Warren, A.R. Golshayan, C. Sahi, B.J. Eigl, J.D. Ruether, T. Cheng, S. North, et al., Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial
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Cancer Treatment and Research Communications journal homepage: www.elsevier.com/locate/ctarc
The role of active surveillance and cytoreductive nephrectomy in metastatic renal cell carcinoma Amanda Nizama, Jonah A. Schindelheimb, Moshe C. Ornsteina, a b
T
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Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, United States Department of Medicine, Touro College of Osteopathic Medicine, Middletown, NY, United States
A R T I C LE I N FO
A B S T R A C T
Keywords: Metastatic renal cell carcinoma Active surveillance Cytoreductive nephrectomy Kidney cancer Surgery
Treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by an expanding armamentarium of systemic therapies, which have resulted in improved patient outcomes. Multimodal approaches that include cytoreductive nephrectomy (CN), immunotherapy, and targeted therapy are necessary to optimize clinical care. Active surveillance (AS) and CN are two cornerstones of treatment in mRCC, which require reexamination in the context of new systemic therapies. Herein, we review the data and provide a practical approach for the incorporation of AS and CN in the management of mRCC.
Introduction Renal cell carcinoma (RCC) accounts for approximately 74,000 new cancer cases and almost 15,000 deaths per year in the United States [1]. The majority of renal cell carcinomas are localized or locally advanced at the time of diagnosis and are treated surgically with curative intent. However, approximately one-third of patients present with de novo metastatic disease and close to 30% of patients who undergo surgical treatment for localized RCC will eventually develop metastatic disease. The treatment of metastatic renal cell carcinoma (mRCC) involves a complex interplay between systemic therapy and surgical management with cytoreductive nephrectomy (CN) [2,3]. Although data exist to help guide CN decision, these data are limited to time periods in which the standard treatments for mRCC included interferon and targeted therapies, and as such their applicability to the current checkpoint inhibitor (CPI) era is questionable [4,5]. Similarly, although the role of active surveillance (AS) in mRCC has been well established [6], patient selection in an era of improved systemic therapies is not well defined. We review the roles of CN and AS in the treatment of patients with mRCC and provide a practical approach based on existing data.
clinical outcomes, multiple prognostic scoring systems exist for patients with mRCC. The Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic RCC Consortium (IMDC) criteria are the most commonly used prognostic tools, which stratify patients into favorable, intermediate, and poor risk categories on the basis of laboratory and clinical features [7,8]. These prognostic criteria are based on patients receiving targeted therapy. More recent risk stratification criteria incorporate genomic information (specifically, BAP1, PBRM1, and TP53 mutations) in addition to clinical and laboratory criteria [9]. The MSKCC and IMDC prognostic model’s data highlight the diverse biology of patients with mRCC. In these models, median overall survival (OS) ranges from less than one year for poor risk patients to greater than three years for favorable risk patients. The spectrum of disease course includes those patients with an indolent RCC biology who may require minimal (or no) treatment to those with aggressive disease likely to be refractory to standard treatments. This inter-patient variability in biology and outcome underscores the role of active surveillance (AS) for a subset of patients in whom close monitoring without systemic therapy is unlikely to negatively impact clinical outcome.
Active surveillance in metastatic renal cell carcinoma
Retrospective data
Rationale for active surveillance
A host of retrospective data for active surveillance (AS) in mRCC exist. A report by Matsubara et al. described outcomes of 29 patients with mRCC who chose AS over systemic therapy between 2000 and 2011 [10]. All patients had IMDC favorable or intermediate risk mRCC.
Significant inter-patient variability exists in the disease course and underlying biology of mRCC. To account for various factors impacting
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Corresponding author. E-mail address: [email protected] (M.C. Ornstein).
https://doi.org/10.1016/j.ctarc.2020.100169
2468-2942/ © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
2
a
98% favorable or intermediate 52a Rini et al.[6]
Phase 2 trial of patients with asymptomatic mRCC placed on AS
38.1 months
9.4 months
44.5 months
Favorable group (≤ 1 IMDC criteria and ≤ 2 metastatic organ sites): median 22.2 months on surveillance Unfavorable group (> 1 IMDC criteria or > 2 metastatic organ sites): median 8.4 months on surveillance
Occurred where IFN was standard of care. In current era, many of these patients would have likely received standard systemic therapy and not AS. Above limitation likely accounts for discrepancy between this study's TTP and that of Rini et al.[6] Non-randomized No specific criteria for initiation of systemic therapy Predictors of progression hypercalcemia, hypoalbuminemia, elevated lactate dehydrogenase, anemia, KPS < 80%, and ≥ 2 organ sites of metastatic disease 25 months 8 weeks Predated IMDC risk 15 Wong et al. [13]
IMDC Risk Number of patients Trial
Table 1 Key trials of active surveillance in mRCC.
Trial design
Prospective data of AS in mRCC are more limited (see Table 1). One of the first prospective trials of AS was conducted by Wong et al. in which patients with mRCC who underwent debulking nephrectomy were placed on a “watch and wait” protocol and did not receive systemic therapy until disease progression [13]. A total 15 patients enrolled on this trial. With a median follow-up of 18 months (range, 4–46), 12 (67%) patients developed disease progression. Median TTP was eight weeks after nephrectomy. Subsequent systemic therapy included chemotherapy (gemcitabine and capecitabine) and IFN-based therapies. Median OS for all patients was 25 months with three patients alive at the 46-month follow-up. The presence of abnormal laboratory values (specifically, hypercalcemia, hypoalbuminemia, elevated lactate dehydrogenase, anemia), KPS < 80%, and ≥ 2 organ sites of metastatic disease were predictive of tumor progression. In the largest prospective trial of AS in mRCC, Rini et al. enrolled 52 patients across three countries (US, UK, Spain) who had asymptomatic, treatment-naïve mRCC into a AS protocol [6]. The primary endpoint of the trial was time from initiation of AS to initiation of systemic therapy. Of the 48 patients included in the analysis, the median age was 67, 36 (75%) were male, 46 (96%) clear cell histology, and 47 (98%) either favorable or intermediate risk by IMDC criteria [6,7]. The median time from diagnosis to metastatic disease was 5.1 months (Interquartile ratio [IQR] 0.7–25.7). The median follow-up for all patients was 38.1 months and the median time on AS was 14.9
18 months
Prospective data
CN followed by observation until progression
Median follow-up
Median TTP
Median OS
Key findings
Limitations
With a median follow-up of 35.3 months the median PFS in these patients was 26.1 months with 14% of patients dying during the follow-up period. Despite disease progression in 21 (72%) patients only 12 (57%) of these patients actually received systemic therapy during the followup period. The remaining 9 (43%) of patients declined systemic therapy at the time of disease progression. At the time of analysis, the median OS had not been reached. The 1 and 4 year OS rates were 96.4% and 83.8%, respectively. Despite initial AS in patients with mRCC, mPFS, and OS rates were certainly no worse than prospective trials of approved agents. Similarly, a retrospective analysis mRCC patients on AS from 2000–2012 investigated factors associated with rapid disease progression [11]. Of the 58 patients included, the median follow-up was 31.4 months with a median time to progression (TTP) of 12.4 months (95% CI 8.4–16.5). At the time of data cutoff, 47 (81%) patients developed disease progression. Factors associated with shortened TTP were the presence of liver metastases, KPS < 100%, and time from diagnosis to AS of < 1 year. The majority of patients subsequently received sunitinib or pazopanib as their systemic therapy with objective response rates of 71% and 46%, respectively. Although median OS was not reached, the estimated mOS was 91.1 months (95% CI 31.7–151.6). More recently, retrospective data on AS in mRCC from the Canadian Kidney Cancer Information System (CKCis) were presented [12]. In this analysis of mRCC patients diagnosed between 2011 and 2016, outcomes of patients who received immediate systemic treatment (within 6 months of diagnosis) were compared to those who were went on AS. AS was defined as delayed systemic therapy for ≥ 6 months or patients who never received systemic therapy but were alive ≥ 1 year following diagnosis. A total of 848 patients received immediate treatment and 863 were identified who received AS. Of the AS patients, 370 received systemic therapy ≥ 6 months after diagnosis and 493 did not go on to receive systemic therapy and had an OS of ≥ 1 year. Median time on AS was 14.2 months (range, 6–71). Notable differences (p<0.001) between the AS and immediate treatment cohorts were that AS patients were older, had fewer sites of metastatic disease, and were more likely to have had a metastasectomy. Importantly, 5 year OS probability for the AS and immediate treatment patients was 70.2% and 32.1% (p<0.0001), respectively. Most patients in this analysis subsequently received sunitinib or pazopanib as a primary therapy.
48 patients included in the analysis. mRCC = Metastatic renal cell carcinoma; CN = Cytoreductive nephrectomy; IFN = Interferon; OS = Overall survival; TTP = Time to progression; IMDC = International Metastatic RCC Database Consortium; KPS = Karnofsky Performance Status.
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trial. With a median follow-up of 50.9 months the median OS for sunitinib cohort (18.4 months) was non-inferior to the CN-sunitinib cohort (18.4 months vs 13.9 months; HR 0.89; 95% CI 0.71–1.10). These were the first prospective data in the targeted-therapy era to demonstrate that CN might not be appropriate for all patients with mRCC. In the updated analysis, with a median follow-up of 61.5 months, the investigators isolated the intermediate risk patients to assess whether the number of metastatic sites (1 vs > 1) and/or number of IMDC risk criteria (1 vs 2) could help define a population better suited for sunitinib alone. When stratified by number of metastatic sites, there was no statistically meaningful difference between the CN-sunitinib and sunitinib alone groups. However, the data did suggest that patients with two IMDC risk factors were less likely to benefit from nephrectomysunitinib (median OS 17.6) vs sunitinib-alone (median OS 31.2 months; HR 0.63; 95% CI 0.44–0.97; p = 0.033) [16]. There are a number of inherent limitations with the CARMENA data. Over 40% of patients in this trial were poor-risk. A host of data already exist indicating that poor risk patients are less likely to benefit from CN and this previously established poor prognostic population may have drastically biased the results of the trial [17–19]. Additionally, patients in this trial had approximately 60% of their tumor burden limited to their renal mass. As such despite a “debulking” nephrectomy, approximately 40% of their tumors still remained in situ. It is thus no surprise that the data from this trial do not support a CN in this population. The outcome of mRCC following CN is related to the degree of tumor debulking that occurs during the surgery with multiple reports demonstrating that optimal outcomes following CN occurs when the fractional percentage of tumor volume removed during a debulking nephrectomy is greater than 90% [20,21]. Given the high percentage of poor-risk patients as well as the high extra-renal tumor burden in the CARMENA patient population, the trial is unlikely to be generalizable to the broader mRCC patient population. Whereas CARMENA measured efficacy of sunitinib vs nephrectomysunitinib, the phase 3 SURTIME trial randomized patients to receive immediate CN followed by sunitinib vs a deferred CN cohort in which patients received three cycles of S followed a CN (deferred CN) [5]. Although 458 patients were needed for the primary endpoint of PFS, given poor accrual, the trial was closed after 99 patients enrolled. The 28 week progression-free rate in the immediate CN arm was 42% compared to 43% in the deferred CN arm (p = 0.61). The intent-to-treat OS did favor deferred CN over immediate CN (mOS 32.4 vs 15.0; HR 0.57; 95% CI 0.34–0.95; P = 0.03). Of note, 14 patients (29%) in the SCN arm had systemic progression prior to the CN and thus did not undergo CN [5]. Although the data are not definitive given the poor accrual, this trial does suggest that a subset of mRCC patients will achieve maximal benefit by receiving systemic therapy as their initial
months (95% CI 10.6–25.0). The median time to progression for all patients was 9.4 months (95% CI 7.4–13.4). Of the 43 (90%) who had RECIST-defined PD while on AS, 37 were started on systemic therapy and six continued on surveillance. Importantly, although 23 patients who experienced PD started systemic therapy immediately, the remaining 20 patients who experienced disease progression continued on surveillance for a median of 15.8 months (95% CI 3.0–24.1). The estimated median OS for all patients (calculated from initiation of AS) was 44.5 months (95% CI 37.6-NR) [6]. On multivariate analysis, the presence of 0–1 IMDC risk factors and no more than two organ sites involvement of metastatic disease were independently prognostic of time on surveillance. The authors thus established favorable (≤ 1 IMDC criteria and ≤ 2 metastatic organ sites) and unfavorable (presence of at least one of the aforementioned) cohorts with a median surveillance time of 22.2 and 8.4 months, respectively [6]. Such criteria, established in AS patients on a prospective trial can be used when trying to determine whether a patient might benefit from AS vs immediate systemic therapy.
Cytoreductive nephrectomy in metastatic renal cell carcinoma Initial support for cytoreductive nephrectomy (CN) in patients with newly diagnosed mRCC originated from two randomized controlled trials conducted in an era in which interferon-α (IFN-α) was the standard systemic therapy (see Table 2). Both the Southwest Oncology Group (SWOG) and European Organization for Research and Treatment of Cancer (EORTC) designed randomized clinical trials in which mRCC patients underwent CN followed by IFN-α vs immediate systemic therapy with IFN-α without prior CN [14,15]. In the SWOG trial of 246 patients, the patients who underwent CN followed by IFN-α 2b had an overall median survival of 11.1 months compared to 8.1 months in those receiving IFN-α 2b alone (p = 0.05) [14]. The EORTC trial contained 83 patients and also noted a survival benefit in those who underwent CN prior to systemic therapy (17 months vs 7 months; HR 0.54; 95% CI 0.31–0.94) [15]. Importantly, both studies predated the IMDC risk criteria and did not define histological subtypes. Moreover, given the relatively poor efficacy of systemic therapies at the time of these studies, the ability to extrapolate these data and apply them in patients receiving CPI is uncertain. In the targeted therapy era, the phase III CARMENA trial randomized patients with newly diagnosed intermediate and poor risk mRCC to undergo cytoreductive nephrectomy followed by sunitinib (CN-sunitinib group) vs sunitinib alone without an upfront CN (sunitinib group) [4]. The trial was designed to assess the non-inferiority of sunitinib vs CN-sunitinib with regards to OS with the upper bound limit of the 95% CI set at ≤1.20. A total of 450 patients were enrolled in the
Table 2 Prospective randomized controlled trials investigating cytoreductive nephrectomy in RCC. Trial
Experimental arms
IMDC risk groups
Primary endpoint(s)
Limitations
SWOG[14] n = 246 EORTC[15] n = 83
CN → IFN-α 2b IFN-α 2b alone CN → IFN-α 2b IFN-α 2b alone
N/A
Median OS: 11 mos. vs 8 mos. (p = 0.05)
N/A
CARMENA[4] n = 450 (ITT population)
Sunitinib alone Immediate CN → Sunitinib
Median TTP: 5 mos. vs 3 mos. (HR 0.60, 95% CI 0.36–0.97) Median OS: 17 mos. vs 7 mos. (HR 0.54, 95% CI 0.31–0.94) Median OS: 18.4 mos. vs 13.9 mos. (HR 0.89, 95% CI 0.71–1.10)
Histology subtypes not defined. Predated IMDC risk stratification. Histology subtypes not defined. Predated IMDC risk stratification.
SURTIME[5] n = 99 (ITT population)
Immediate CN → Sunitinib 3 cycles Sunitinib → CN
Intermediate & poor-risk
Intermediate &poor-risk
ITT 28-week PFR: 42% vs 43% (p = 0.61)* *Original primary endpoint of PFS required sample size of 458. Due to poor accrual, ITT 28-week PFR reported instead.
IMDC favorable risk and those with single or oligometastatic disease excluded. High percentage of poor risk patients. Extensive extra-renal tumor burden IMDC favorable risk and those with single or oligometastatic disease excluded. Terminated early due to poor accrual.
mRCC = Metastatic renal cell carcinoma; n = number; CN = Cytoreductive nephrectomy; IFN-α 2b = Interferon-α 2b; OS = Overall survival; TTP = Time to progression; HR = Hazard ratio; CI = Confidence interval; ITT = intention to treat; PFR = Progression-free rate; PFS = Progression-free survival. 3
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Fig. 1. Cytoreductive nephrectomy and surveillance considerations in newly diagnosed mRCC 1 Fevers, chills, night sweats, etc. 2Greater than 20%. 31–2 IMDC risk factor or ~15% extra-renal tumor burden. 4<10%. 5Significant pain or hematuria. AS = Active surveillance; CN = cytoreductive nephrectomy; IMDC = International Metastatic RCC Database Consortium; mRCC = metastatic renal cell carcinoma.
by deferred CN vs continued systemic therapy and no CN in IMDC intermediate and poor-risk mRCC [27]. Similar CN trials are being proposed through cooperative groups such as SWOG [29]. Most ongoing surveillance trials include treatment-free observation of patients who received CPI therapy and have a significant response to therapy [30–32]. These patients subsequently enter active surveillance until they develop pre-defined tumor regrowth. To our knowledge, no AS trials in treatment-naïve mRCC are currently ongoing. Until prospective data from such trials materialize, practical approaches incorporating CPI-based combinations, CN, and AS should be developed to drive decision making for patients with newly diagnosed mRCC.
treatment modality. Discussion Given the expanding treatment repertoire of mRCC treatment and the improved outcomes from CPI-based combination treatments as a standard frontline option for mRCC, it is critical to analyze whether the clinical benefit of cytoreductive nephrectomy (CN) remains applicable and whether active surveillance (AS) is appropriate [22,23]. Importantly, should patients who would have received a CN in the targeted-therapy ear still undergo surgery in the CPI era or are they more likely to benefit from systemic therapy upfront [14,15]? Similarly, given the improved outcomes in mRCC, the role of AS is less clear. The rationale for AS in an era of targeted therapies in which the PFS ranges from 8 to 11 months is understandable given the marginal benefit of systemic therapy [24,25]. However, the role of AS in the CPI era in which over 70%% of patients are alive at 24 months and in which the median OS has not been reached with 30 month follow-up is less certain [26]. Perhaps patients who historically would have proceeded with AS over sequential single agent targeted therapies, should instead receive CPI-based combination therapies. As outlined in the sections above, there are clear features to portend good prognosis in patients who undergo CN and AS. Ultimately, management of mRCC in the CPI era requires a more nuanced approaches that incorporates historical CN and AS data into individualized management plans. A practical approach to the management of newly-diagnosed mRCC is to take into consideration the potential for AS when considering a CN (see Fig. 1). Patients who present with systemic symptoms including fevers, chills, and night sweats are likely to benefit from systemic therapy first and forgo an immediate cytoreductive nephrectomy. Similarly, patients with high volume extrarenal disease should undergo systemic therapy as the benefit of CN in this setting is less certain. Conversely, patients who have minimal extra-renal tumor burden and limited IMDC risk criteria, and as such would be good AS candidate following CN, should be considered for an immediate CN. In this manner, the role of AS is taken into consideration in a newly diagnosed patient with mRCC, and the potential for AS actually serves to guide decision making regarding a CN (see Fig. 1). Despite this practical algorithm, additional data is needed to prospectively investigate the role of CN and AS in the CPI era. A number of such trials are planned and accruing to better define these issues in the patients treatment with CPI therapies [27,28]. For example the NORDIC-SUN trial will investigate ipilimumab and nivolumab followed
Conclusion The treatment of mRCC has progressed at a rapid pace with a variety of trials demonstrating improved clinical outcomes with checkpoint inhibitor (CPI)––based combination therapies as frontline treatment. Incorporating surgical approaches and active surveillance into the current era demands extrapolation of historical data and its application and incorporation to current systemic treatment paradigms. Individualized decisions with multidisciplinary teams are critical in determining best approach per patient. Ultimately, biomarker-based prospective trials of CN and AS in the CPI era are sorely needed to optimize patient outcomes. References [1] R.L. Siegel, K.D. Miller, A Jemal, Cancer statistics, 2019, CA Cancer J. Clin. 69 (2019) 7–34. [2] A. Kokorovic, R. Rendon, Cytoreductive nephrectomy in metastatic kidney cancer: what do we do now? Curr. Opin. Support. Palliat. Care 13 (2019) 255–261. [3] T. Kuusk, B. Szabados, W.K. Liu, T. Powles, A Bex, Cytoreductive nephrectomy in the current treatment algorithm, Ther. Adv. Med. Oncol. 11 (2019) 1758835919879026. [4] A. Méjean, A. Ravaud, S. Thezenas, S. Colas, J.-.B. Beauval, K. Bensalah, L. Geoffrois, A. Thiery-Vuillemin, L. Cormier, H. Lang, et al., Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma, New Engl. J. Med. 379 (2018) 417–427. [5] A. Bex, P. Mulders, M. Jewett, J. Wagstaff, J.V. van Thienen, C.U. Blank, R. van Velthoven, M del P Laguna, L. Wood, H.H.E. van Melick, et al., Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the surtime randomized clinical trial, JAMA Oncol. 5 (2019) 164–170. [6] B.I. Rini, T.B. Dorff, P. Elson, C.S. Rodriguez, D. Shepard, L. Wood, J. Humbert, L. Pyle, Y.-.N. Wong, J.H. Finke, et al., Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial, Lancet Oncol. 17 (2016) 1317–1324. [7] D.Y.C. Heng, W. Xie, M.M. Regan, M.A. Warren, A.R. Golshayan, C. Sahi, B.J. Eigl, J.D. Ruether, T. Cheng, S. North, et al., Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial
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