A systematic review of literature was performed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (13). The review was not registered, and a protocol was not prepared. This article also incorporates a case report (Supplementary Data) relevant to the topic, to enhance the findings of the systematic review. The study selection process is summarized in the PRISMA flowchart (Figure 1).

To identify existing literature providing different local treatment options for metastatic renal cell carcinoma and their associated outcomes, a systematic search was conducted. We identified peer-reviewed studies published no earlier than 2009, January 1st by using the following search terms alone or combined: “renal cell carcinoma”, “metastatic”, “local”, “treatment”, “metastasectomy”, “cryotherapy”, “ablation”, “SBRT”. The terms were applied in the electronic databases PubMed and ScienceDirect, with filters used to narrow the search, followed by a manual review of reference lists for additional studies. PubMed and ScienceDirect were selected for their ability to provide a broad selection of studies pertinent to this review. Only articles written in English or containing an English abstract were eligible.

The search strategy included a range of terms, and their combinations related to local treatment modalities, including “SBRT”. Although “SBRT” was among the search terms, we did not limit the search to this term alone. During the screening phase studies, we used alternative terms such as stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT), to ensure comprehensive coverage of these treatment techniques.

Studies were considered if they included patients with metastatic renal cell carcinoma affecting any organ, except adrenal glands only. This criterion allowed inclusion of the studies that examined various metastatic sites, rather than those limited to the adrenal glands alone. Accepted interventions included metastasectomy, cryotherapy, thermal ablation, stereotactic radiosurgery, stereotactic body radiation therapy, whole brain radiotherapy, and image-guided radiation therapy. To be eligible, studies had to analyze local treatment either as a standalone approach or in combination with other non-systemic treatment modalities. Study types included retrospective, prospective studies, clinical trials and case reports.

Studies were excluded if they focused on treatments for non-metastatic kidney cancer, if systemic treatments were either the sole treatment or were administered before non-systemic approaches, or if local treatments were combined with systemic therapies and couldn’t be analyzed separately. Additionally, studies focusing primarily on cytoreductive nephrectomy were excluded, as this intervention targets the primary tumor and falls outside the scope of our analysis, which focuses on local treatments directed at metastatic lesions. Studies lacking outcome data for non-systemic treatments, those using local therapies solely for palliative or analgesic purposes, and reviews, conference abstracts, letters, editorials or comments were also excluded. Studies involving children were not considered.

Titles and abstracts of studies were imported into the reference manager software (Mendeley). Results from PubMed and ScienceDirect databases were manually screened, and the full text was retrieved as required.

Data were extracted from each identified paper, including details on the type of study, site of metastasis, treatment modality, and outcome measures. A descriptive review was performed.

Titles and abstracts of studies were imported into the reference manager software Mendeley. After screening the title list, abstracts were then reviewed for all relevant studies, and full texts were retrieved as required for all potentially relevant studies. Full papers and relevant abstracts were formally assessed to ensure they met the inclusion criteria for the systematic review. A peer-review process involving three authors was used to discuss studies with questionable eligibility for inclusion in the review. Data were extracted from each identified eligible paper. The extracted data included information on publication details (authors, title, year, and study design), trial design participants (age, sex, metastatic setting), type of treatment, and outcome measures. A descriptive review was conducted, and data were recorded in an Excel spreadsheet.

The risk of bias for each included study was assessed independently by three authors based on seven categories:

Each category was assessed as having low, unknown, or high risk of bias using specific questions.

Selection bias was identified when inclusion and exclusion criteria were unclear or inconsistently applied.

Confounding was considered present if important baseline characteristics (e.g., patient demographics, disease stage, prior treatments) were either not reported, unevenly distributed between comparison groups, or not adjusted for in the analysis.

A study was classified as being at risk of information bias if outcomes such as overall survival or progression-free survival were not clearly defined, inconsistently measured, or if the measurement methods lacked standardization.

Treatment details were evaluated based on clarity and completeness in describing interventions such as metastasectomy or radiotherapy techniques.

A study was rated at risk in sample size justification if no rationale for sample size determination was provided.

Reporting of hypotheses was assessed by examining whether studies clearly stated their primary outcomes and research questions.

Any disagreements between reviewers were resolved through discussion and consensus.

Six studies evaluated the effectiveness of metastasectomy for renal cell carcinoma metastases, reporting outcomes of complete metastasectomy alone or in comparison to no-metastasectomy or incomplete metastasectomy (Table 2) (17, 18, 20, 22, 23, 26). Nevertheless, in one study, complete metastasectomy was performed in 90% of cases, with incomplete resections occurring due to reasons such as unresectable metastases (18). Complete metastasectomy was associated with significantly improved survival measurements in all six studies, including overall survival (OS), median survival, cumulative survival rates, and cancer-specific survival (CSC). These studies reported better outcomes for the complete metastasectomy groups in these various survival measures.

Two studies found that complete metastasectomy notably improved median OS (Table 2). One of the two studies revealed a significantly different median OS of 81 months (interquartile range [IQR]: 58−NR) compared to 61 months (IQR: 26−NR) between complete metastasectomy and no metastasectomy groups, respectively (p=0.0001) (22). Another study presented a median OS of 24.1 months versus 18.9 months (p<0.001). The 1-, 2-, 5-year OS rates of 68.4%, 50%, and 24.4% for the metastasectomy group, versus 64.1%, 43.0%, and 19.5% for the no metastasectomy groups (log-rank p<0.001) (27). One of the six studies also revealed significant relationships between disease-free intervals of less than 2 years versus 2 years or more, solitary versus multiple metastases, and completeness of resection (p<0.05). The 5-year survival rates were 50% and 20% for the complete and incomplete resection groups, respectively (18).

Another three studies specifically examined metastasectomy outcomes for metastases to lungs, liver and pancreas (Table 2). Pulmonary metastasectomy was associated with the cumulative survival rates of 60% at 3 years, 47% at 5 years, and 18% at 10 years (p=0.009). The majority of patients underwent resection of a solitary lung lesion, although some had 2, 3, or ≥4 resected (18). A study evaluating liver metastasectomy showed that the 5-year OS rate was 62.2% ± 11.4% (SEM), with a median survival of 142 months (95% CI: 115–169), which was significantly higher than the 29.3% ± 22.0% (SEM) and median survival of 27 months (95% CI: 16–38) seen in the no-metastasectomy group (p=0.003). In addition, metastasectomy of synchronous metastases did not significantly improve medial survival, which was 29 months (95% CI: 14-55) compared to 15 months (95%, CI 0-34) in the no metastasectomy group (p=0.593) (20). One study specifically focusing on pancreatic metastasectomy reported that patients with metastases smaller than 2.5 cm had a significantly longer survival after resection than those with metastases larger than 2.5 cm, (100.9 vs 44.0 months, respectively; p<0.01). Furthermore, a statistically significant difference was found when comparing survival between patients with solitary versus multiple metastasis, with survival of 111 months versus 49 months, respectively (p=0.04) (17). One study that focused on multiple metastatic sites also provided separate data on patients with lung-only metastases, revealing a 5-year CSS rate of 73.6% for complete metastasectomy group, compared to 19% for patients who did not undergo complete resection of all metastases (p<0.001) (26).

The use of systemic therapy and its impact varied across the studies (Table 2). In one study, a lower percentage of patients who underwent metastasectomy received targeted therapy during follow-up compared with those who did not (36.5% vs 47.2% respectively; p=0.0026), with a median time to first-line targeted treatment without prior exposure of 49 months and 38 months for the metastasectomy and no-metastasectomy groups, respectively (p=0.0057) (22). Another study demonstrated a survival benefit in patients treated with metastasectomy and targeted therapy (HR:0.86, 95% CI: 0.76–0.96, p=0.008) compared to those who received targeted therapy alone without metastasectomy. Additionally, a survival advantage was also found in patients who underwent metastasectomy without targeted therapy versus no-metastasectomy and no targeted therapy group (HR: 0.84, 95% CI: 0.75–0.94, p=0.004). The exact number of metastases per patient was not reported in the study, as the data captured metastatic sites only (23). One study pointed out that systemic treatment significantly improved survival only for patients who did not receive complete metastasectomy, showing a median CSS of 1.6 years for those who received systemic therapy versus 1.1 years for those who did not (p=0.01). Additionally, there was no significant difference observed in patients who underwent complete metastasectomy, with the median CSS being 4.5 years and 5.7 years with and without systemic therapy, respectively (p=0.98) (26).

One of the included studies analyzed percutaneous microwave ablation as a treatment for metastatic renal cell carcinoma, reporting a 100% immediate technical success rate and durable local control for 93% of the tumors at a median follow-up of 14.7 months (25). However, the study also reported that patients with prior systemic therapy had an OS of 2.0 years, compared to 5.1 years for those who either did not receive systemic therapy or received it after the ablation procedure (p=0.03). This indicates that while percutaneous microwave ablation is effective for local control, the timing of systemic therapy is crucial in survival outcomes.

Image-guided radiotherapy (IGRT) was carried out in one study, using either a hypofractionated regimen or single dose (SD) irradiation (Table 2). The SD group had a significantly lower risk of local relapse, compared to the hypofractionation group (p=0.01). Also, in comparison with hypofractionation, SD treatment was associated with improved local relapse-free survival (p=0.01). To add on, a single dose of 24 Gy was a key predictor of enhanced local progression-free survival (PFS) (p=0.01) (15).

Three studies focused on the treatment of spine metastasis, using different radiotherapy techniques (Table 2). One study reported that the 1-year survival after stereotactic body radiotherapy (SBRT) was 62.2% and the 2-year survival was 37.8%. Among the patients who died, the median survival was 9.1 months (range, 1–43.4 months), and the mean survival was 12.1 ± 8.8 months. The most common regimen administered was a total dose of 27 Gy delivered in 3 fractions, followed by 40 Gy in 5 fractions and 18 Gy in 1 fraction, with regimens categorized as high-dose or low-dose using a BED (biological effective dose) of 50 Gy as a cutoff. There was no significant difference found in the rates of in-field progression between those with a BED > 50 Gy and those with a BED < 50 Gy (p=0.68). Also, the greatest pain reduction was seen in patients who initially reported moderate pain (4-6 out of 10) (14). Another study showed a 1-year spinal tumor progression-free survival rate of 82%. This study also reported that after SBRT, the percentage of pain-free patients increased to 44%, 53% and 64% at 1, 6 and 9 months, respectively, compared to 23% before treatment. No patient’s spinal cord received more than 45 Gy in total in this study (16). In the third spine study, outcomes of stereotactic radiosurgery (SRS) were reported in comparison to external radiation therapy (RT). The mean total margin radiation dose was 38.0 Gy for the SRS group and 29.4 Gy for the RT group (p=0.04), and mean nBED (normalized biological effective dose) was also significantly higher in the SRS group compared to RT (61.7 versus 32.0 Gy2/10, p=0.0001). The median overall survival was 15 months for the SRS group and 7 months for the RT group, but this difference was not statistically significant (p=0.08). When comparing perioperative Visual Analogue Scale (VAS) score changes, the SRS group demonstrated a larger decrease than the RT group (p=0.04) (19).

Another two studies focused on stereotactic radiotherapy (SRT) for multiple metastatic sites, including brain, spine, non-spine bones, soft tissue, viscera, lymph nodes, lung, kidney, adrenal gland, and liver (Table 2). One study performed SRT for oligoprogressive, oligometastatic, and residual tumors following a partial response to systemic treatment. For the entire cohort, median PFS was 8.5 months, local recurrence-free survival (LRFS) was 23.2 months, time to systemic therapy (TTS) was 13.2 months, and OS was 29.2 months. PFS was significantly longer in the residual tumor group compared to those with oligometastatic disease (p=0.036), while those with oligoprogression were more likely to have a better LRFS (local recurrence-free survival) (p=0.02). Also, LRFS was worse with an increased number of systemic treatments (p=0.035) and was higher in males than in females (p=0.0028) (21). In another study, multivariate analysis revealed that only an interval of less than 36 months from initial diagnosis to SBRT was a predictor of further metastatic progression (hazard ratio 2.37, p<0.001). Post SBRT, 50% of patients received systemic therapy, most commonly sunitinib, with a median time between SBRT and systemic therapy of 15.6 months. OS was estimated at 85% at two years, and no deaths occurred among patients who received treatment for all metastatic sites (24).

Risk of bias was assessed across seven categories, each of which contained two to three specific questions in order to evaluate potential bias. Three authors independently assessed each study. Based on evaluation, studies were classified as having low, unknown, or high risk of bias, as seen in Figure 2.

This systematic review provides important insights into the management of mRCC, especially by identifying different patient subgroups that benefit the most from specific local treatment methods. The main strength of this review is its comprehensive analysis and inclusion of various treatment modalities, including metastasectomy, various ablative therapies and different radiotherapy methods. Our findings highlight the significant survival advantages that specific patient subgroups can get, such as those with smaller lesions, or those undergoing complete metastasectomy, thereby showing the importance of personalized treatment strategies.

There are some limitations to our review. All included studies were of retrospective nature, apart from one prospective observational study, meaning the review relies on retrospective data. This highlights the need for more prospective studies to strengthen the evidence.

The retrospective nature of nearly all included studies introduces an inherent risk of bias. Retrospective analyses often involve selection bias, unmeasured confounding factors, and incomplete or inconsistent reporting of clinically relevant variables.

In addition, publication bias must be considered, as studies reporting positive or favorable outcomes for local treatment approaches are more likely to be published, while studies with negative or inconclusive findings may remain unpublished. This may result in an overestimation of the true effectiveness of these interventions across the available literature.

Most of the studies showed a low risk of bias in the treatment details and reporting hypothesis categories. However, there was a moderate risk of bias observed overall, with a significant number of included studies classified as having unclear risk of bias across various categories, such as selection bias, confounding adjustment, and information bias. Additionally, the conducted search was limited to studies published from 2009 onwards, and earlier publications might have been missed. For instance, the role of systemic therapy was not consistently addressed across all the included studies, including the unknown treatment timing (prior or after local treatment), potentially changing the survival outcomes. This inconsistency in systemic therapy timing limits our ability to isolate the true impact of local treatment and introduces potential interpretation bias when comparing survival outcomes across the studies. Furthermore, the included studies often lacked detailed reporting on clinically important factors such as the type and sequence of systemic therapy, time to progression, or the presence of brain or other specific metastases, limiting the possibility of performing subgroup comparisons. The inconsistency in reporting reduces the ability to fully explore which treatment conditions have the biggest impact on survival outcomes and represents a major limitation when applying findings to clinical practice.

The findings of our review suggest that specific local treatment modalities, including complete metastasectomy, advanced radiotherapy methods, and ablative techniques, play a significant role in treating mRCC. These local treatment techniques are seen to prolong survival outcomes and enhance the quality of life. However, it is important to note that specific patient and disease factors influence the benefits of local treatment strongly. This shows how complex the treatment for mRCC is highlights that local treatment is becoming more important. Furthermore, the review shows a significant lack of knowledge in understanding how local treatment modalities interact with systemic therapies, emphasizing the need for more evident work to create the best strategies.

Findings of this systematic review highlight the importance of personalized treatment plans for each metastatic RCC patient. Clinicians should carefully consider different factors specific for each patient, such as the number, location and size of metastases, when selecting the type of local treatment. From a policy perspective, it is important to integrate local treatment options for mRCC into standard clinical practice. Future studies should focus on prospective designs to further investigate the role of local treatment in mRCC, particularly focusing on patient subgroups that could benefit the most. Additionally, it is important to explore local treatment in combination with systemic therapy, as the approach remains unclear.

Future research should focus on prospective studies to validate these retrospective findings, particularly analyzing the patient subgroups that respond best to different local interventions for metastatic kidney cancer. Exploration of combination of local treatment and systemic therapy should be done, with an emphasis on the timing. Guidelines should be developed in order to assist clinicians in adjusting treatment based on patient-specific characteristics.