Exploring the Evolving Role of Metastasectomy in Advanced Renal Cell Carcinoma
Article information
Abstract
In the treatment of metastatic lesions in advanced renal cell carcinoma (RCC), no clear consensus exists regarding whether immunotherapy should be combined with surgical resection or metastasectomy. Systemic therapies have significantly improved outcomes for advanced RCC patients and extended both progression-free and overall survival. However, complete disease eradication with drug therapy alone remains rare, and this limitation has renewed interest in metastasectomy for metastatic RCC. Although robust evidence is still lacking, many researchers have suggested that aggressive surgical approaches involving metastasectomy may improve survival in selected patients by controlling the cancer burden through the resection of primary and metastatic lesions. Novel immunotherapies have transformed solid tumor treatment, prompting a reevaluation of the role of metastasectomy. Recent studies have shown promise in combining systemic therapies with metastasectomy for metastatic RCC, emphasizing the need for further research and individualized, multidisciplinary approaches.
INTRODUCTION
Approximately 25%–30% of patients with renal cell carcinoma (RCC) present with metastatic disease at diagnosis, and 15%–30% develop metastases after nephrectomy [1-4]. The role of surgery in treating metastatic disease has been explored since 1939, when the first metastasectomy for RCC was reported. Historically, the role of surgery in metastatic cancer was largely limited to palliative resections, as highlighted by Barney and Churchill [5], who reported a case where a patient with RCC remained disease-free for 5 years following nephrectomy and left lobectomy for lung metastasis. Over the past 2 decades, systemic therapies targeting vascular endothelial growth factor and mammalian target of rapamycin, along with the more recent introduction of immune checkpoint inhibitors, have significantly advanced the treatment of advanced RCC. These therapies have been shown to reduce tumor size by approximately 20%–30% and improve both progression-free survival (PFS) and overall survival (OS) [6-8]. However, complete eradication of the disease using only drug therapy remains rare in clinical practice. This limitation has recently reignited interest in the role of metastasectomy in the treatment of metastatic RCC (mRCC). Advancements in drug therapies have prompted a shift in the traditional role of metastasectomy, integrating it into a comprehensive treatment strategy [9]. The primary goal of surgical metastasectomy is to control the cancer burden in selected patients by resecting the primary tumor and, when feasible, the metastatic lesions to improve survival outcomes. Although randomized studies are lacking, numerous observational studies have suggested that an aggressive surgical approach involving metastasectomy may be associated with improved survival rates. Research on metastatic cancers, including RCC, has shown that better outcomes in high-volume centers have contributed to the wider adoption of metastasectomies and the dissemination of standardized surgical techniques [10-14]. This indicates that the treatment of mRCC has evolved from a singular approach to a new era that integrates various treatment modalities, including systemic targeted therapies, immunotherapy, and surgical metastasectomy [15]. A study from the Registry of Metastatic RCC (REMARCC) demonstrated that metastasectomy significantly improved both overall and cancer-specific survival in patients with mRCC. This study analyzed 1,130 patients with a median follow-up of 36.7 months. The metastasectomy group showed significantly improved survival rates. Multivariate analysis identified metastasectomy as an independent prognostic factor for both overall and cancer-specific survival (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.44–0.68; p<0.001 and HR, 0.54; 95% CI, 0.43–0.68; p<0.001) [16]. However, while the role of metastasectomy has been widely discussed, evidence from retrospective studies remains ambiguous, and the treatment sequence for metastasectomy as an adjuvant or neoadjuvant therapy is still under discussion. Despite accumulating evidence supporting the use of immunotherapy in the context of metastatic cancer, there is still no clear consensus on combining immunotherapy with surgical resection of metastatic lesions or on the optimal timing and sequencing of these treatment approaches [17-22].
In this context, we aimed to review the current literature on the role of metastasectomy in the era of novel immunotherapies and provide a comprehensive overview of current treatment strategies derived from clinical trials.
SURGICAL METASTASECTOMY IN ADVANCED RCC
The European Urology Association has incorporated a strategy for considering metastasectomy in most metastatic sites, excluding the brain and possibly bone, as outlined in their 2014 guidelines based on a systematic literature review [19]. In 2018, Ouzaid et al. [18] conducted a systematic literature review and discovered that patients who underwent metastasectomy had a longer median OS compared to those who did not undergo the procedure (36–142 vs. 8–27 months). This finding aligns with a systematic literature review and meta-analysis by Zaid et al. [17], which demonstrated a reduction in overall mortality risk associated with surgical metastasectomy. A recent retrospective analysis that explored factors influencing survival in patients with mRCC identified surgical metastasectomy as a significant predictor of survival, with a HR of 0.667 and a 95% CI of 0.468–0.951 (p=0.03). Conversely, a recent matched cohort study found no survival benefit from surgical metastasectomy in patients with tumors exhibiting sarcomatoid features compared to those who did not undergo the procedure [18,23]. Improvements in clinical benefits, including PFS and OS, have also been reported in non–clear cell RCC, particularly in patients without liver metastasis and those with metachronous metastasis [24].
Despite these findings, the role of metastasectomy in metastatic disease remains a matter of debate. It is crucial to identify individuals who are most likely to benefit from surgical intervention. Ideally, surgery is most appropriate for a select group of metastatic patients whose lesions are confined to a single organ. However, in practice, the extent of metastatic burden significantly influences the determination of suitable candidates for a complete metastasectomy [25]. The timing of metastasectomy should also be considered a critical aspect of this discussion [26]. Nevertheless, there is still a lack of research providing consistent criteria based on factors such as the completeness of resection, the presence of single versus multiple metastases, and the types of organs involved.
COMPLETENESS OF SURGICAL RESECTION FOR METASTASIS IN ADVANCED RCC
Maintaining an adequate surgical margin is crucial to prevent recurrence of RCC [27]. Numerous studies have shown that complete resection of metastatic lesions is linked to higher survival rates [28,29]. Research indicates that patients who undergo complete resection of all known lesions have better survival outcomes than those with incomplete resections, with a reported 5year survival rate of up to 88% [18,28,30]. Hofmann et al. [21] performed a retrospective analysis on the impact of pulmonary metastasectomy in 64 patients with advanced RCC. They discovered that the timing of metastasectomy was a significant prognostic factor. Patients with synchronous metastases had the poorest prognosis (HR, 7.8; 95% CI, 1.5–11.5; p=0.005), suggesting that the timing of the metastasis itself, not just the metastasectomy, is crucial. Those who underwent complete metastasectomy had a significantly longer median OS compared to those with incomplete resections (median survival: 46.6 months vs. 13.3 months). The most robust evidence regarding metastasectomy comes from a comprehensive systematic literature review by Dabestani et al. [20] in 2014, which included 16 retrospective comparative studies and a meta-analysis of 8 studies. This research showed that patients who underwent complete metastasectomy had better OS than those who had incomplete resections or no surgery at all (OS: median, 40.8 months; interquartile range, 31.6–48.0 vs. 14.8 months, 13.3–21.0). Zaid et al. [17] analyzed 8 studies involving 2,267 patients with mRCC. Complete surgical metastasectomy was associated with a lower overall mortality risk compared to incomplete surgical metastasectomy (pooled HR, 2.37; 95% CI, 2.03–2.87; p<0.001). This association remained significant even after adjusting for key prognostic factors, including performance status. Factors such as the number of metastatic lesions, disease-free interval, lymph node involvement, and the size of pulmonary nodules are known to affect prognosis. However, it has been reported that long-term survival (over 10 years) is possible following complete metastasectomy in some cases, provided that a complete resection is achieved [29,31]. In a retrospective study analyzing 205 patients diagnosed with advanced RCC between 2006 and 2020, Shimizu et al. [32] found significantly better median cancer specific survival in the complete metastasectomy group compared to those receiving only systemic therapy (6.1 years vs. 3.1 years; HR, 0.45; p<0.001). Remarkably, the group that underwent only metastasectomy (patients who underwent repeated metastasectomies without any systemic therapy) demonstrated an impressive cancer-specific survival of 11.3 years. Although these patients were highly selected with a disease burden low enough to forego systemic therapy, the results were notably favorable.
Metastasectomy can provide an opportunity for long-term survival in select patients [32]. Therefore, achieving complete resection should be the primary objective for patients undergoing surgical metastasectomy to enhance oncological outcomes in advanced RCC. However, it is important to recognize that complete surgical metastasectomy might not always be the best option, especially in situations where complete resection could result in functional complications, such as with brain or bone metastases.
METASTASECTOMY FOR SOLITARY/MULTIPLE METASTASIS IN ADVANCED RCC
Patients with solitary metastatic RCC lesions can achieve long-term survival benefits through nephrectomies and metastasectomies. One study reported that patients with solitary site metastases accounted for 50.6% of all mRCC cases [33]. The International Metastatic RCC Database Consortium risk classification system is a crucial prognostic factor for mRCC. This model stratifies patients into favorable, intermediate, and poor-risk groups based on 6 clinical and laboratory parameters. Additionally, there is a trend toward poorer prognosis as the number of metastatic sites increases [34]. In a meta-analysis of 8 cohort studies involving 2,267 patients (958 complete and 1,309 incomplete metastasectomies), Suzuki et al. [35] examined the impact of complete surgical metastasectomy on survival in patients with metastatic RCC. Complete surgical metastasectomy, when achievable, significantly improves OS compared to incomplete metastasectomy, particularly in cases of solitary metastasis. Median OS ranged from 36.5 to 142 months for complete metastasectomy, versus 8.4 to 27 months for incomplete metastasectomy. The pooled adjusted HR for all-cause mortality was 2.37 (95% CI, 2.03–2.87; p<0.001), favoring complete metastasectomy. These findings suggest that solitary metastasis accompanied by complete surgical metastasectomy may offer substantial survival benefits in selected patients. A recent study from the REMARCC registry reported significantly higher median OS in patients with solitary metastasis who underwent metastasectomy (97.8 months vs. 35.9 months; HR, 0.40; 95% CI, 0.29–0.56; p<0.001). In another study evaluating the role of surgical metastasectomy in solitary or oligometastatic RCC, Ferriero et al. [36] reported that metastasectomy and primary tumor AJCC stage were independent predictors of OS on multivariate analysis (p=0.019 and p=0.035, respectively). Kaplan-Meier analysis showed that metastasectomy significantly improved OS compared to systemic therapy alone (p<0.001). These results demonstrate that metastasectomy significantly improves OS when no evidence of disease status exists. Nonetheless, it is important to recognize that metastasectomy may delay but does not always eliminate the need for systemic therapy.
Recent retrospective studies have shown that factors such as the size and number of metastases, completeness of resection, and the disease-free interval following nephrectomy are more significant than the specific sites of metastases (such as the adrenal glands, lungs, pancreas, thyroid, and liver) [18]. However, patients with a solitary metastasis confined to the lungs experience the greatest survival benefits when complete resection is feasible. In clear cell RCC, the incidence of solitary lung metastasis is higher than that of multiple metastases, and patients with a single metastasis in the lung have an excellent prognosis [33,37,38]. A study by Alt et al. [28] evaluated the outcomes of complete surgical metastasectomy in 125 patients with 2 or more metastatic lesions. It revealed that patients with metastases confined to the lungs benefited the most, achieving a 5-year cancer-specific survival rate of 74% [13]. Conversely, patients with metastases at multiple sites, excluding the lungs, had lower 5year cancer-specific survival rates than those with metastases confined to the lungs. Nevertheless, complete surgical metastasectomy still provided significant survival advantages over incomplete resections, with 5-year cancer-specific survival rates of 32.5% versus 12.4%; p<0.001. This study underscores that complete surgical metastasectomy improves survival not only for lung metastases but also for multiple nonpulmonary metastases. Considering the existing evidence, it is advisable to consider surgical metastasectomy after thorough consultation with multidisciplinary teams, even in cases where risk stratification indicates unfavorable prognostic factors. This approach is recommended for patients where complete resection is feasible, despite the presence of factors such as advanced primary tumor T stage (≥3), high Fuhrman grade (≥3), presence of nonpulmonary metastases, short disease-free interval (<12 months), and multiple organ metastases.
LOCATION OF METASTASIS AND OUTCOME FOLLOWING METASTASECTOMY
RCC exhibits a strong propensity for metastasis, with the lungs being the most common site of distant dissemination, affecting 45%–60% of cases. Other frequent metastatic sites include the bone (30%–40%), lymph nodes (22%), liver (20%), and brain (8%) [31,39]. Patients with lung, liver, and pancreatic metastases experience significantly better OS rates when complete resection is achieved, compared to those with incomplete or no resection [17].
Surgical metastasectomy may be considered for patients with limited metastatic disease, especially in cases of lung metastasis. Retrospective studies have shown 5-year survival rates ranging from 21%–60% for metastasectomy overall [30], with rates reaching up to 73.6% following complete resection of lung metastases [28,39,40]. The REMARCC study reported a significantly higher OS in the metastasectomy group compared to the nonresection group for patients with lung metastases, with survival times of 89.9 months versus 28.1 months, and an HR of 0.41 (95% CI, 0.31–0.55; p<0.001) [16]. The 5-year OS rate for patients who underwent hepatic metastasectomy was 62.2%, which was significantly higher than the 29.3% observed in the nonsurgical control group. However, hepatic metastasectomy was associated with the highest risk of complications compared to metastasectomies at other sites [41]. Patients with a single resectable pancreatic metastasis showed improved outcomes after surgery, comparable to those after pulmonary metastasectomy. Surgical mortality and morbidity were reported at 3% and 50%, respectively, similar to outcomes following primary pancreatic carcinoma surgery. The best candidates for pancreatic metastasectomy are those with solitary, completely resectable metastases and a long disease-free interval, suggesting a slower tumor growth pattern [42]. However, due to high recurrence rates, continued follow-up is essential after metastasectomy. Multiple pancreatic metastases should be managed conservatively, as they offer no survival benefits and may increase morbidity. Additionally, limited resection techniques, such as enucleation, should be considered to prevent secondary diabetes, depending on the specific clinical situations [18].
As previously mentioned, complete metastasectomy can enhance survival rates, irrespective of the metastatic site, when feasible. However, further research is necessary to compare outcomes across various sites. Additionally, a thorough assessment of the risks associated with metastasectomy for each organ should be conducted beforehand.
PERIOPERATIVE NEOADJUVANT/ADJUVANT THERAPY IN METASTATIC RCC
Similar to the ongoing debate regarding the role of cytoreductive nephrectomy in mRCC, the sequencing of treatments as adjuvant or neoadjuvant therapies for metastasectomy continues to be rigorously discussed [33,34]. The rationale for administering systemic treatment prior to metastasectomy is its potential to shrink metastatic lesions, thereby facilitating surgery, enabling complete cytoreduction, and allowing for a more conservative surgical approach. Current literature on neoadjuvant immunotherapy offers limited evidence, with additional findings emerging from retrospective studies on targeted therapies. De Lichtenberg et al. [43] conducted a retrospective study involving 143 consecutive mRCC patients to evaluate outcomes following neoadjuvant therapy, which included immunotherapy in 59 patients, tyrosine kinase inhibitors (TKIs) in 49 patients, and a combination of immunotherapy followed by TKI in 35 patients. Among those with resectable metastatic lesions, patients who received first-line immunotherapy had a median survival of 16.3 months, compared to 10.9 months for those treated first with TKIs (p=0.003). However, a multivariable analysis revealed no significant difference in OS between the 2 groups (HR, 1.35; 95% CI, 0.79–2.32; p=0.27). This absence of a significant difference may be attributed to selection bias, as lower-risk patients were more likely to receive immunotherapy, while higher-risk patients were treated with TKIs. This indicates that the apparent superiority of immunotherapy could be due to patient selection bias, suggesting that the actual difference in treatment efficacy might be minimal when considering risk factors. The effectiveness of neoadjuvant therapy for mRCC needs further investigation through well-designed, prospective clinical trials.
There is a notable lack of reliable results regarding adjuvant immunotherapy following metastasectomy. Kwak et al. [44] conducted a retrospective analysis of 93 patients with mRCC to examine the role of adjuvant immunotherapy after metastasectomy. The study revealed that neither subcutaneous interferon (IFN)-α monotherapy nor the combination of IFN-α and interleukin-2 significantly affected survival. The OS rates for the immunotherapy group were 67.1% at 1 year, 30.0% at 3 years, and 7.1% at 5 years, compared to 56.5%, 34.8%, and 19.0% for the control group, respectively, with no statistically significant differences observed. In a recent systematic review evaluating the impact of post-metastasectomy adjuvant therapy on survival in patients with mRCC, while other adjuvant therapies, including sorafenib, did not show significant improvement, the pembrolizumab group demonstrated a disease-free survival of 75% at 3 years compared with 55% in the placebo group. The OS of the pembrolizumab group was 85% at 3 years compared to 70% in the placebo group [45]. Studies on TKI therapy after metastasectomy have yet to demonstrate reliable outcomes [46].
Additionally, stratifying patients by whether their metastases were metachronous or synchronous further diminished the differences between groups. These findings suggest that adjuvant immunotherapy may not significantly enhance survival following metastasectomy, nor does the timing of metastasis affect its effectiveness [44]. The efficacy of immunotherapy after metastasectomy will need to be evaluated in light of future clinical trial outcomes [47].
FORTHCOMING DIRECTIONS AND ONGOING STUDIES IN RENAL CARCINOMA METASTASIS
KEYNOTE-564 is a phase 3 clinical trial that evaluated the efficacy of pembrolizumab in patients at high risk of recurrence following nephrectomy for mRCC. The results indicated that pembrolizumab is an effective adjuvant therapy for this group. The pembrolizumab group exhibited a significant improvement in disease-free survival compared to the placebo group, with 24month estimates of 77.3% versus 68.1% (HR, 0.63; 95% CI, 0.50–0.80). Additionally, there was a trend toward improved outcomes, with 4year OS estimates of 91.2% for the pembrolizumab group and 86.0% for the placebo group. In terms of safety, the pembrolizumab group experienced a higher incidence of grade 3–4 adverse events (18.6% vs. 1.2%) and treatment-related adverse events (12% vs. <1%). However, no deaths attributable to pembrolizumab were reported. During a median followup period of 30.1 months, most subgroups showed consistent effects from pembrolizumab. These findings provide the first evidence that pembrolizumab plays a beneficial role as an adjuvant therapy for patients at high risk of RCC recurrence, including those who have undergone complete metastasectomy [47]. Notably, the inclusion criteria permitted the recruitment of patients who had undergone complete metastasectomy. Reports have also suggested that pembrolizumab may be particularly effective as an adjuvant therapy in patients with mRCC eligible for complete metastasectomy. Subgroup analyses from the phase 3 KEYNOTE-564 trial demonstrated that pembrolizumab significantly improved disease-free survival compared to placebo in patients with advanced clear cell RCC. This survival benefit was particularly pronounced in patients with the M1 stage who underwent complete metastasectomy, highlighting important implications for future studies on pembrolizumab as an adjuvant therapy following metastasectomy [47,48]. Recently, a phase 3, multicenter, randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of atezolizumab as an adjuvant therapy in patients at high risk of metastasis following nephrectomy. The trial failed to demonstrate that atezolizumab improved clinical outcomes compared to placebo. Therefore, this study did not support the use of atezolizumab to treat RCC in this setting [49]. In the ECOG-ACRIN E2810 study, a phase III, randomized, double-blind trial comparing pazopanib with placebo in patients with mRCC who achieved a disease-free state after metastasectomy, pazopanib did not improve disease-free survival. Moreover, the pazopanib group tended to have an unfavorable OS. These results are consistent with those of the PROTECT study on pazopanib use after nephrectomy for locally advanced RCC and underscore the need for further research on post-metastasectomy systemic therapy for RCC [50].
Further prospective randomized controlled trials are necessary to validate these findings. Currently, additional clinical trials are being conducted to assess the efficacy of nivolumab alone or in combination with bevacizumab or ipilimumab as neoadjuvant therapy in patients with mRCC, as indicated by ClinicalTrials.gov identifiers NCT02210117 and NCT02595918. It is advisable to promote patient enrollment in relevant clinical trials to identify the most effective immunotherapy strategies in suitable treatment contexts for each type of cancer and to ensure thorough data collection. In light of these findings, future research should concentrate on refining the integration of surgery and systemic therapy, developing biomarkers for selecting appropriate patients, and exploring the potential synergies between immunotherapy and surgical interventions.
CONCLUSIONS
Novel immunotherapies have dramatically transformed the treatment landscape for certain solid tumors, necessitating a reevaluation of the role of metastasectomy in improving patient survival and quality of life.
Without consensus guidelines, decisions regarding metastasectomy in patients with metastatic disease from various primary sites should be individualized. These decisions should be discussed within a multidisciplinary environment that includes surgical and medical oncologists, radiologists, and pathologists.
Although numerous reports have highlighted improvements in oncological outcomes through neoadjuvant and adjuvant therapies, as well as metastasectomy in mRCC, a definitive conclusion has yet to be reached. However, recent studies have shown promising results, suggesting that future research findings warrant close attention.
Notes
Grant/Fund Support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts of Interest
The authors have nothing to disclose.
Author Contribution
Conceptualization: JK, KSC; Data curation: JK, SB, KSC; Formal analysis: JK, SB, KSC; Methodology: JK, SB, KSC; Project administration: KSC; Visualization: JK, SB, KSC; Writing - original draft: JK; Writing - review & editing: SB, KSC.