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THE FUTURE OF KIDNEY CANCER QUO VADIS: Edited by Vitaly Margulis and Manuela Schmidinger

The role of cytoreductive surgery in the era of targeted agents

Noe, Allarda; Stewart, Grant D.b; Bex, Axela

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doi: 10.1097/MOU.0000000000000192
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Abstract

INTRODUCTION

In the cytokine era, the role of cytoreductive nephrectomy was defined by two randomized trials [1,2]. From a current viewpoint, these trials had loose eligibility criteria, that is, there was no histological subtype identification or risk stratification of patients prior to enrolment, as is done now by the validated Memorial Sloan Kettering Cancer Center (MSKCC) or the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk groups [3]. There was a statistically significant overall survival (OS) benefit in favour of cytoreductive nephrectomy in the larger Southwest Oncology Group (SWOG) trial, albeit by only 3 months [1]. In a combined analysis of both trials, the median OS improved by 5.8 months in favour of cytoreductive nephrectomy [4]. After the introduction of the targeted agents, the paradigm of performing cytoreductive nephrectomy in patients with performance status 0–1 continued, although systemic therapy had changed profoundly [5,6]. One argument often brought forward in support of cytoreductive nephrectomy in the targeted therapy era is that 80–90% of patients enrolled in pivotal trials establishing targeted therapy in first line had a nephrectomy [7–9]. However, most of these patients had nephrectomy for localized disease prior to developing metachronous metastases. The question is therefore in how far cytoreductive nephrectomy confers an independent survival benefit or must be seen as a part of a multimodality approach in which the vascular endothelial growth factor (VEGF)-targeting drugs are an unknown variable. This lack of evidence has been recognized, and the randomized trials, Clinical Trial to Assess the Importance of Nephrectomy (CARMENA) (NCT00930033) and Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME) (NCT01099423) were opened in 2009 and 2010, respectively, to define the role and sequence of cytoreductive nephrectomy in combination with VEGF-targeted therapy [10,11]. These trials will not be reported before the end of 2016.

Box 1
Box 1:
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PURPOSE OF REVIEW AND EVIDENCE AQUISITION

In the interim, it became evident that targeted agents do not cure metastatic renal cell carcinoma (mRCC); however, they do appear to temporarily control both the primary tumour and metastatic sites [12]. Primary tumours respond to VEGF-targeted therapy in more than 70% of the cases, with a mean reduction of diameter of 9–28% depending on the agents studied [12–15]. A retrospective series of patients, with low-risk disease treated with their primary tumours in situ, revealed a median OS of up to 30.3 months [16]. Taken together, these data question the need to perform a cytoreductive nephrectomy in a scenario in which cure is still elusive. It has been recognized that primary mRCC is clinically and biologically heterogeneous, and selecting patients for cytoreductive nephrectomy is paramount [17]. Whereas the decision to perform cytoreductive nephrectomy or not is not challenging at both extreme ends of the clinical presentation of primary mRCC, most metastatic patients will fall between the two extremes. There is little doubt that patients with solitary or oligometastasis can either potentially be: cured by cytoreductive nephrectomy and complete resection of metastatic sites; or may benefit from a substantial delay and reduction in associated side-effects of systemic therapy before further progression requires medication [18,19▪,20]. It should be pointed out that this group of patients with low metastatic burden will not be eligible for the CARMENA or the SURTIME trial, since there is no need for immediate targeted therapy. On the contrary, retrospective series consistently showed that patients with Eastern Cooperative Oncology Group (ECOG)/WHO performance status of at least 2 or a Karnofsky performance status of less than 80% have a short OS and poor outcome [21]. Again, this group of patients is excluded from the ongoing randomized cytoreductive nephrectomy trials based on the performance status. The majority of primary mRCC patients, however, have a good performance status, are asymptomatic, but have irresectable metastases at more than one site. Single institution studies reported on potential risk factors that may be used to help select the majority of patients for cytoreductive nephrectomy [22]. A nomogram has been developed to predict the 6-month probability of death after cytoreductive nephrectomy [23]. Whereas these surgical risk factors and nomograms discriminate long versus short-term survivors, they have been generated from single-institution databases including patients from the cytokine era and none has been externally validated.

Recently, larger datasets reported on incidence, treatment, prognosis and outcome of primary mRCC, and provide real-world data which may help to better define the role of cytoreductive nephrectomy in the targeted therapy era. This review therefore focuses particularly on retrospective population-based studies from the past 18 months. Relevant databases (Medline, Cochrane Library, trial registries, conference proceedings) were searched for the period September 2013 and March 2015.

POPULATION-BASED DATA ON USE OF CYTOREDUCTIVE NEPHRECTOMY AND INCIDENCE OF PRIMARY mRCC

Publications on RCC consistently repeat that approximately 30% of patients diagnosed with a primary tumour in place harbour distant metastasis at diagnosis [24]. Recent evidence from national tumour registries and cancer statistics suggests that the incidence of primary mRCC declined profoundly in some countries. In a population-based study from the national Swedish kidney cancer registry published in 2014, the frequency of primary mRCC decreased from 22% in 2005 to 15% in 2010 (P < 0.001) [25▪▪]. In the same period, the mean tumour size decreased from 70 to 64 mm (P = 0.024). Although unproven, it is intriguing to speculate that a reduced incidence in primary mRCC could be related to more small renal masses being diagnosed and treated. In the Swedish registry, 55% of patients with primary mRCC underwent cytoreductive nephrectomy, and the percentage remained stable throughout the observation period [25▪▪]. Siegel et al.[26▪▪] reported a 17% rate of primary mRCC in the 2014 US cancer statistics.

Regarding the use of cytoreductive nephrectomy, publications from 2014 and 2013 indicate a decreased utility of this procedure linked to the introduction of targeted therapy. Using data from the Surveillance, Epidemiology, and End Results (SEER) registry, Conti et al.[27▪▪] described an increase in the proportion of patients undergoing cytoreductive nephrectomy, from 29% in 1993 to 39% in 2004. From 2005, a modest decrease in utilization of cytoreductive nephrectomy became apparent to 34% in 2010. A year previously, Tsao et al.[28] published a similar SEER analysis on stage IV RCC between 2001 and 2008. Cytoreductive nephrectomy use remained stable at 50% between 2001 and 2005, but decreased after the introduction of the targeted therapy in 2006 to 38% in 2008 [28]. Trends in a US private insurance database of 610 patients with mRCC from the period of 2004 to 2010 revealed a peak in cytoreductive nephrectomy in 2005 with 31.3%. By 2010, the cytoreductive nephrectomy rate had declined to 14.8% (P = 0.045) [29▪]. These data suggest that more patients are currently being treated with targeted therapy and their primary tumour in place.

RETROSPECTIVE POPULATION-BASED STUDIES AND SURVIVAL

The SEER and other registries have been used extensively in 2014 to study an association of cytoreductive nephrectomy with improved survival (Table 1) [27▪▪,30▪▪,31▪–33▪]. OS was found to improve to 19 months after cytoreductive nephrectomy in the targeted therapy era, compared to 13 in the cytokine era, but remained only 4 months for patients not receiving cytoreductive nephrectomy [27▪▪]. Abern et al.[32▪] restricted the SEER analysis specifically to the survival of patients in the period from 2005 to 2009. Of the 7143 primary mRCC patients, only 2629 (37%) underwent cytoreductive nephrectomy, confirming the aforementioned decrease in use. In a multivariate analysis, cytoreductive nephrectomy remained associated with improved OS [hazard ratio 0.40, 95% confidence interval (CI) 0.37–0.43]. Aizer et al.[33▪] specifically analysed a subset of 591 of 4914 patients in the SEER registry, with primary nonclear cell mRCC during the period 2000–2009. They reported that a survival benefit remained significantly associated with the cytoreductive nephrectomy status regardless of the subtype, including patients treated in the era of targeted therapy. Despite having access to large populations, the SEER registry is limited by missing information on potentially confounding factors, especially prognostic factors and performance status. Consequently, the results need to be interpreted with caution. Culp et al.[34▪▪] therefore limited their analysis of the SEER registry to patients who specifically underwent cytoreductive nephrectomy during the period 2005–2010 and the availability of potential factors associated with survival. Overall, median disease-specific survival was 21 months. However, the study did not include patients without cytoreductive nephrectomy and consequently has no comparator. Bamias et al.[31▪] performed a multicentre retrospective analysis in 186 patients with primary mRCC treated with sunitinib, and found that patients after cytoreductive nephrectomy had a significantly longer OS than patients without cytoreductive nephrectomy (median OS 23.9 versus 9 months; P < 0.001). In the univariate analysis, cytoreductive nephrectomy status was significantly associated with better performance status (P < 0.001), normal lactate dehydrogenase (LDH) (P = 0.006), age below 65 years (P = 0.005), absence of brain and liver metastases (P = 0.001), and absence of poor IMDC or modified MSKCC risk (P < 0.001). In the final multivariate analysis, IMDC and MSKCC risk models were associated with prognostic significance. However, cytoreductive nephrectomy status remained as an independent prognostic factor, which is in line with a previously published retrospective series on 314 patients in the era of targeted therapy [21]. In 2014, the IMDC released the currently largest real-world dataset on 1658 patients with primary mRCC in whom cytoreductive nephrectomy status was adjusted to number of IMDC prognostic factors in the targeted therapy era [30▪▪]. Similar to the smaller study published by Bamias et al., median OS of patients who underwent cytoreductive nephrectomy was 20.6 versus 9.5 months for those who did not (P < 0.0001) [30▪▪,31▪]. Patients who had cytoreductive nephrectomy had a better IMDC prognostic risk. After adjusting for IMDC risk groups, the hazard ratio of death remained 0.60 (95% CI 0.52–0.69, P < 0.0001) in favour of cytoreductive nephrectomy. Nevertheless, despite being a large series linked to the prognostic subgroups, the study is retrospective and may be confounded by other factors and lack of randomization. Perhaps, the most important conclusion of the IMDC study is therefore related to patient selection based on IMDC prognostic factors.

Table 1
Table 1:
Retrospective studies published in 2014 on survival after cytoreductive nephrectomy versus no nephrectomy in the targeted therapy era

PROGNOSTIC FACTORS TO PREDICT SURVIVAL AFTER CYTOREDUCTIVE NEPHRECTOMY

Several studies have been published in the past 18 months (Table 2) [23,30▪▪,34▪▪,35▪,36▪], but the most robust data stem from the IMDC analysis in which 982 mRCC patients who underwent a cytoreductive nephrectomy were compared with 676 mRCC patients who did not [30▪▪]. The authors compared the gain in median OS in subgroups of increasing number of risk factors. In addition, they analysed increments of estimated survival times and the cut-off separating a statistical significant survival gain after cytoreductive nephrectomy. They found that patients with an estimated survival of less than 12 months or at least four IMDC prognostic factors may not benefit from cytoreductive nephrectomy. You et al.[37▪] reviewed the records of 171 patients from Korea, of whom 96 were treated with cytoreductive nephrectomy followed by targeted therapy and 75 with targeted therapy alone. They identified four preoperative risk factors (Karnofsky PS, haemoglobin, neutrophils and clinical N stage) to aid selection of patients who would not benefit from cytoreductive nephrectomy, three of which are in fact independent factors of the IMDC risk model. Culp et al.[22] previously published a retrospective analysis of a single-institution database of factors associated with poor outcome after cytoreductive nephrectomy. On the basis of the factors – at least T3 stage, symptoms caused by metastases, retroperitoneal and/or mediastinal lymph node involvement, liver metastases, LDH and serum albumin – the risk categories were established. Patients with at least four factors had no benefit from cytoreductive nephrectomy. Taking multifactor analysis further, Culp et al. found in 2014 in a SEER registry analysis of 2478 patients who underwent cytoreductive nephrectomy that a higher number of the factors – age at least 60 years, African-American race, at least T3 stage, high Fuhrman nuclear grade (3 or 4), primary tumor size at least 7 cm, regional lymphadenopathy, both distant lymph node and visceral metastases, and sarcomatoid histology – correlated with an increased risk of disease-specific death (P < 0.001). Although the authors conclude that these factors can be used to better select suitable patients for cytoreductive nephrectomy, intra-tumour heterogeneity may require a full pathological work-up of the nephrectomy specimen to accurately identify Fuhrman grade and sarcomatoid histology [38]. In addition, the number of independent factors is high, which may limit clinical practicability. In 2014, single factors were suggested. Sakai et al.[36▪] found C-reactive protein associated with OS, but the study was small. Corcoran et al.[35▪] suggested that hypoalbuminaemia may identify patients at risk of short OS. In a multi-institutional retrospective study on 246 patients who underwent cytoreductive nephrectomy, nutritional markers such as BMI, serum albumin and preoperative weight loss were evaluated from a period of almost 20 years. Hypoalbuminaemia less than 3.5 g/dl was the single independent nutritional predictor of OS (8 versus 23 months; P < 0.001) and remained in multivariate analysis a significant predictor of death for OS (hazard ratio 2.0, 95% CI 1.4–2.8, P < 0.001). Hypoalbuminaemia as a risk factor has been reported before. In 2013, Margulis et al. published pre and postoperative nomograms developed from the predictors identified by Culp et al.[22,23]. With albumin and LDH as the only variables, the preoperative nomogram predicted the 6-month probability of death after cytoreductive nephrectomy, with an area under the curve of 0.76. However, the population used to establish the nomogram had exclusively undergone cytoreductive nephrectomy and included patients from the cytokine era. Without an external validation, it is unknown how the preoperative nomogram performs in patients with the primary tumour in place who have yet to take the decision for or against cytoreductive nephrectomy. In contrast, the IMDC risk model has been externally validated and is currently the most accepted risk model in the targeted therapy era to assess prognosis based on six readily available clinical factors. The IMDC analysis on the cytoreductive nephrectomy status therefore provides the most robust retrospective dataset to council patients with primary mRCC in a practical manner, until data from the ongoing randomized cytoreductive nephrectomy trials become available.

Table 2
Table 2:
Retrospective studies from the last 18 months on risk factors associated with survival in patients undergoing cytoreductive nephrectomy in the targeted therapy era

PERIOPERATIVE OUTCOMES OF CYTOREDUCTIVE NEPHRECTOMY

Nationwide surgical audits such as the nephrectomy registry of the British Association of Urological Surgeons (BAUS) provide contemporary datasets [39▪]. From all nephrectomies registered in the UK in 2012, only 4.6% were cytoreductive (n = 279 of 6042; registry 80% complete), performed by 141 surgeons in 90 centres. On an average, each surgeon performed 1.97 cytoreductive nephrectomy or 3.1 cytoreductive nephrectomy per centre, which may reflect the general reduction in cytoreductive nephrectomy being performed and a stage shift in the disease at presentation. Perioperative complication rate was 22.6% of which only 8% was Clavien III or above. The 30-day mortality rate was 1.8% and was mainly related to cT3-4 stage as previously reported in a large dataset [40].

CONCLUSION

Recent retrospective population-based data suggest a more refined use of cytoreductive nephrectomy in the targeted therapy era, further restricting the role of cytoreductive nephrectomy. This comes at a time in which epidemiological data suggest a decrease in incidence of primary mRCC in some countries. With the exception of patients in whom cytoreductive nephrectomy and resection of oligometastatic disease may result in cure or delay of systemic therapy, performance status, prognostic models and life expectancy estimates help to define the role of cytoreductive nephrectomy in the individual patient with irresectable multiple metastases. The fact that a decrease in the use of cytoreductive nephrectomy has been noted in population-based studies from North America since the introduction of targeted therapy suggests that practitioners treating primary mRCC assess the role of cytoreductive nephrectomy more critically and treat more patients with their primary tumour in place. Current retrospective data do not allow us to conclude if this approach is inferior. The randomized controlled trials CARMENA and SURTIME are expected to provide definite answers on the role and sequence of cytoreductive nephrectomy in the targeted therapy era.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

A.B. has been a speaker during a Pfizer organized symposium and took part in an advisory board of Pfizer. G.S. and A.N. declare to have no conflict of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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Keywords:

cytoreductive nephrectomy; renal cell carcinoma; targeted therapy

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