This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada. Key Words Competing Interests Article Information Renal cancer, immunotherapy, systematic review None declared. Received on May 9, 2022 Accepted on June 12, 2022 This article has been peer reviewed. Soc Int Urol J. 2022;3(5):341–352 DOI: 10.48083/ WIXM2804 Adjuvant Systemic Treatment for Renal Cancer After Surgery: A Network Meta-Analysis Niranjan J. Sathianathen,1,2 Marc A. Furrer,1 Christopher J. Weight,3 Declan G. Murphy,4 Shilpa Gupta,5 Nathan Lawrentschuk1,2,4 1 Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia 2 Department of Surgery, University of Melbourne, Parkville, Victoria, Australia 3 Department of Urology, Cleveland Clinic, Cleveland, United States 4 Department of Uro-Oncology, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia 5Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, United States Abstract Background Approximately 15% to 20% of patients will experience disease recurrence following surgical removal of renal cell carcinoma. A range of pharmacological agents is prescribed for metastatic renal cell carcinoma, but there are trials testing whether these have an earlier role in the adjuvant setting. We aim to assess the efficacy of adjuvant systemic treatment following surgery in patients with renal cell carcinoma and to determine the most effective treatment. Methods The protocol for this review was published in PROSPERO (CRD42021281588). We searched multiple databases up to August 2021. We included only randomized trials of patients with renal cell carcinoma that had been completely resected. We included patients with locoregional nodal disease if it was surgically removed, and excluded all cases of metastatic disease. We included all adjuvant systemic therapies that were commenced within 90 days of renal surgery. A network meta-analysis was performed using a frequentist approach. Results A total of 13 studies with 8103 patients were included for analysis. Only pembrolizumab (HR 0.74; 95%CI 0.57 to 0.96) and pazopanib (HR 0.80; 95%CI 0.68 to 0.95) improved disease-free survival compared with observation. These 2 treatments were the 2 highest ranked comparisons with a P-score of 0.87 and 0.80. No agent improved overall survival. All agents increased the risk of severe adverse events compared with observation. Conclusions Pembrolizumab and pazopanib were the only 2 adjuvant agents that improved time to disease recurrence compared with observation, with the former likely being the more efficacious. None of the treatments improved overall survival and almost all increased severe adverse events. Introduction There has been an increased incidence of renal cell carcinoma, especially in developed countries[1]. Most of these cancers are localized to the kidney at the time of presentation and are curable by surgery. However, approximately 20% of patients will experience disease recurrence following surgery[2]. Overall prognosis for advanced disease is poor with a median survival time of 21 months after recurrence[3]. 341SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 REVIEW mailto:niranjan19%40gmail.com?subject=SIUJ http://SIUJ.org A range of pharmacological agents has been used to treat metastatic renal cell carcinoma (mRCC) with varying efficacy, including chemotherapy, immuno- therapy, tyrosine kinase inhibitors, monoclonal anti- body against circulating vascular endothelial growth factor, and mTOR inhibitors. A network meta-anal- ysis found that combination immunotherapy likely represents the current best available treatment[4]. The European Association of Urology guidelines support this by suggesting that immunotherapy (including combinations) should be used as first-line treatment in this setting[5]. As immunotherapy has come to the fore- front of mRCC management, there has been increasing interest in employing these treatments at earlier stages of disease. Many of the aforementioned treatments have been trialled in the adjuvant setting with varying results, and there are recent reports of use of adjuvant immu- notherapy. However, these trials have primarily been conducted using observation or placebo as a compara- tor arm, which has not permitted direct comparisons of active agents. We therefore aimed to perform a systematic review and network-meta-analysis of systemic agents used in the adjuvant setting after surgery for kidney cancer. Methods We registered the protocol of this systematic review in PROSPERO (CRD42021281588). We searched multiple databases (MEDLINE , EMBASE , ScienceDirect, Cochrane Libraries, HTA database, and Web of Science) up to 20 August 2021, with a range of keywords associated with “renal carcinoma” and “adjuvant therapy.” We also searched the abstracts from leading urological and oncological meetings, including those of the European Association of Urology, American Urological Association, American Society of Clinical Oncology, and European Society of Medical Oncology in the last 5 years. We also searched trial registries such as ClinicalTrials.gov. We did not place any restriction on language or date of publication. We included only randomized studies. Our population of interest was patients with RCC that had been completely resected. Surgical treatment included both radical and partial nephrectomy. We included patients with locoregional nodal disease if they underwent surgical removal at the time of kidney extir- pation, ie, N+ cases were eligible. We included all histo- logical subtypes of renal carcinoma. We excluded all patients with distant metastatic disease even if they had undergone metastectomy, ie, M1 cases were not eligible for inclusion. We included all adjuvant systematic therapies that were commenced within 90 days of renal surgery. We excluded autologous vaccine-based treatments because they are not widely available in clinical practice. We did not include adjuvant radiotherapy. Control arms eligible for analysis were observation, placebo, and active treat- ments, although we did not find any studies with the last. Following our search, titles and abstracts were screened by 2 independent authors according to the inclusion/exclusion criteria. Full texts of relevant abstracts were then reviewed by 2 independent authors to confirm eligibility. Any disagreements were resolved by a third senior author. Data were then extracted inde- pendently. The efficacy outcomes of interest were disease-free survival (DFS), defined as time from randomization to disease recurrence (local or distant) and/or death; and overall survival (OS), defined as time from randomiza- tion to death from any cause. The safety outcome of interest was severe adverse events defined as incidence of grade III to V events per patient. We also intended to perform subgroup analysis on the efficacy outcome according to histological subtype (clear-cell versus other subtypes) and nodal disease (no nodal disease [N0] versus nodal disease [N1]). Statistical analysis We first performed traditional pairwise meta-analysis of the included studies (data not shown). To do this, we applied the model proposed by Woods et al. by extracting hazard rates for DFS and OS and number of severe adverse events from each of the included studies[6]. We then performed a network meta-analysis of all included trials which enables indirect comparisons of treatments based on a common comparator arm. We adopted a frequentist approach and performed a fixed-effect consistency network meta-analysis. As a sensitivity analysis, we used the same approach with a random-effects model. We used P-scores that estimate the extent that one treatment is superior to another, averaged over all competing treatments, to determine which agent is the most efficacious. All analyses were performed using RJAGS and R (R Foundation for Statistical Computing, Vienna, Austria) version 3.4. Risk of bias was performed accord- ing to the Cochrane framework[7]. Results Our search retrieved 4088 abstracts of which 41 proceeded to full text review. After inclusion/exclusion criteria were applied, 13 studies were eligible and included for analysis (Online Supplementary Figure 1). The details of included studies are shown in Table 1. 342 SIUJ • Volume 3, Number 5 • September 2022 SIUJ.ORG REVIEW http://siuj.org http://SIUJ.org The included trials tested a range of adjuvant treatments: axitinib[8], girentuximab[9], interferon-alpha[10–14], interleukin-2[10, 11], pazopanib[15], pembrolizumab[16], sorafenib[17,18], sunitinib[17,19], and thalidomide[20]. Two of the trials tested combination adjuvant therapies of interleukin-2+interferon-alpha[10] and interleukin- 2+interferon-alpha+5-f lurouracil[11]. The PROTECT trial that compared pazopanib with placebo included patients who received either 600 mg or 800 mg, and we included both in this analysis[15]. The trials were overall of moderate quality, and the detailed risk of bias classification can be found in Online Supplementary Table 1. We also found a further 6 trials in progress (Table 2). Disease-free survival All eligible studies reported on DFS and were included in this analysis of 8103 patients. Only the 2016 study by Haas et al. reported on direct comparison between active agents[17]. The forest plot of HRs compared with control arm for each agent is shown in Figure 1A. Only pembrolizumab (HR 0.74; 95% CI 0.57 to 0.96) and pazopanib (HR 0.80; 95% CI 0.68 to 0.95) prolonged DFS compared with observation. These 2 treatments were the FIGURE 1. Treatment versus control for (A) DFS and (B) OS A B TABLE 1. Characteristics of included studies Author/ Year Adjuvant treatment Number of participants Inclusion criteria Number of participants with ≤T2 disease, n Number of participants with clear- cell RCC Number of participants with nodal disease Gross-Goupil et al. 2018[8] Axitinib: 5 mg BD up to 3 years 724 • ≥pT2 and/or N+ • Any Fuhrman grade • ECOG performance status 0/1 80 NR 36 Chamie et al. 2017[9] Girentuximab: IV 50mg week 1 followed by IV 20 mg week 2–24 864 Histologically confirmed ccRCC pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/ N0M0 with nuclear grade 3 or greater 139 834 65 Passalacqua et al. 2014[10] IL-2 + IFN-a: IL-2 SC 1 mil IU/m2 5 days per week for 4 weeks; INF-a SC 1.8 mil IU/m2 on day 3 and 5 each week. Cycles repeated every 4 months for 2 years and 6 months for 3 years 310 Partial or radical nephrectomy with no residual disease and free surgical margins: pT2-3b pN0-3 M0 182 254 12 NR: not reported , Cont’d continued on page 344 343SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 Adjuvant Systemic Treatment for Renal Cancer After Surgery: A Network Meta-Analysis http://siuj.org http://siuj.org http://SIUJ.org TABLE 1. Characteristics of included studies Author/ Year Adjuvant treatment Number of participants Inclusion criteria Number of participants with ≤T2 disease, n Number of participants with clear- cell RCC Number of participants with nodal disease Aitchison et al.2014[11] IL-2 + IFN-a + 5-FU: IL-2 SC 20 mil IU/m2 on days 3-5 in weeks 1 and 4 and SC 5 mil IU/m2 on days 1, 3 and 5 in weeks 2 and 3; IFN-a SC 6 mil IU/m2 in weeks 2 and 3 and increasing to SC 9 mil IU/m2 in weeks 5-8 given on days 1, 3 and 5; 5-FU IV 750mg/m2 weekly in weeks 5-8 309 Histologically proven stage T3b, T3c, T4 tumour or any pT stage and nodal status pN1 or 2, or any pT stage Clinical N+ disease removed and had no metastatic disease or macroscopic residual disease as confirmed within 2–4 weeks prior to randomization by CT or MRI plus CXR 65 NR 49 Messing et al. 2003[12] Interferon α-NL: SC 5 days every 3 weeks (3 mil IU/m2 day 1, 5 mil IU/m2 day 2, 20 mil IU/m2 day 3-5) up to 12 cycles 283 Unilateral, locally advanced (pT3-4a) and/ or node-positive renal cancer following radical nephrectomy No disseminated disease 36 176 44 Pizzocaro et al.2001[13] Interferon α: IM 6 mil IU 3 times per week for 6 months 247 Radical nephrectomy with suggested unilateral para- aortic nodal dissection Patients with pathologic stages II and III RCC (1987 tumour-node-metastasis categories T3aN0M0 and T3bN0M0 or T2/3N1-3M0) were eligible for the study 16 NR 43 Hinotsu et al.2013[14] Interferon α: IM 3-6 mil IU 3 times per week for 1 year 107 Histopathological diagnosis of renal cell carcinoma resection of the primary tumour by nephrectomy, for which open or laparoscopic surgery could have been selected and lymph node dissection was possible no metastatic disease 40 82 5 NR: not reported , Cont’d continued on page 345 344 SIUJ • Volume 3, Number 5 • September 2022 SIUJ.ORG REVIEW http://SIUJ.org TABLE 1. Characteristics of included studies Author/ Year Adjuvant treatment Number of participants Inclusion criteria Number of participants with ≤T2 disease, n Number of participants with clear- cell RCC Number of participants with nodal disease Motzer et al.2017[15] Pazopanib: 600 mg or 800 mg once daily 1538 Resected non-metastatic (M0) clear-cell or predominant clear-cell RCC histology within the following TNM classification and Fuhrman grades: pT2G3- 4N0, pT3-T4 GanyN0, or pTanyGanyN1 235 1057 90 Choueiri et al. 2021[16] Pembrolizumab: IV 200 mg once every 3 weeks up to 17 cycles 994 Histologically confirmed locoregional renal cell carcinoma with a clear- cell component that is at high risk of recurrence (ie, tumour stage 2 with nuclear grade 4 or sarcomatoid differentiation, tumour stage 3 or higher, regional lymph node metastasis, or stage M1 with NED) Surgery (partial or radical nephrectomy or metastasectomy) with negative surgical margins In those with M1 NED status, M1 disease was present in addition to the primary tumour at diagnosis, and metastases had to be completely resected at the time of nephrectomy or within 1 year after nephrectomy 86 994 62 Eisen et al. 2020[18] Sorafenib: 400 mg BD PO 1711 Histologically confirmed RCC No evidence of residual macroscopic disease on postoperative CT scan after resection of RCC 604 1455 74 NR: not reported , Cont’d continued on page 346 345SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 Adjuvant Systemic Treatment for Renal Cancer After Surgery: A Network Meta-Analysis http://SIUJ.org http://SIUJ.org , Cont’d TABLE 1. Characteristics of included studies Author/ Year Adjuvant treatment Number of participants Inclusion criteria Number of participants with ≤T2 disease, n Number of participants with clear- cell RCC Number of participants with nodal disease Haas et al. 2016[17] Sunitinib: 50 mg PO daily for first 28 days of each 6-week cycle 1943 Histologically proven, completely resected high- risk clear-cell or non-clear- cell RCC within 12 weeks of removal of the primary tumour. High-risk features: pT1b G3–4 N0 (or pNX where clinically N0) M0 to T(any) G(any) N + (fully resected) M0 Sorafenib: 400 mg BD PO daily NR 1541 NR Ravaud et al. 2016[19] Sunitinib: 50 mg PO daily 4 weeks on, 2 weeks off schedule for 1 year 615 Locoregional RCC (tumour stage 3 or higher, regional lymph node metastasis, or both) Histologic confirmation of clear-cell RCC The absence of macroscopic residual or metastatic disease after nephrectomy, as confirmed on blinded independent central review of CT images NR 615 49 Margulis et al. 2009[20] Thalidomide: 100 mg/day for 2 weeks then 200 mg/day for 2 weeks followed by 300 mg/day 46 Completely resected locally advanced high-risk RCC, as defined by one of the following criteria: pT2 (Fuhrman grade 3 or 4), pT3a-c, T4, or N1–2 disease resected to no evidence of residual disease All tumour subtypes were eligible 7 34 13 NR: not reported 346 SIUJ • Volume 3, Number 5 • September 2022 SIUJ.ORG REVIEW http://SIUJ.org TABLE 2. Trials in progress Trial name/ number Interventions Inclusion criteria Current progress Estimated completion date EVEREST NCT01120249 Everolimus Histologically or cytologically confirmed renal cell carcinoma Considered pathologically either intermediate high-risk or very high-risk disease No history of distant metastases Have undergone a full surgical resection (radical nephrectomy or partial nephrectomy) including removal of all clinically positive nodes No evidence of residual or metastatic renal cell cancer on CT scan of the chest, abdomen, and pelvis (all with oral and IV contrast) performed after nephrectomy Active, not recruiting October 2021 SPARC-1 NCT04028245 Spartalizumab and Canakinumab Histologically confirmed clear-cell or predominantly clear-cell RCC Non-metastatic (localized) RCC that is clinical stage T2 and above, or clinical N1 disease with any T stage Scheduled to undergo either radical or partial nephrectomy Recruiting December 2022 PROSPER NCT03055013 Nivolumab – neo-adjuvant and adjuvant Patients must have a renal mass consistent with a clinical stage ≥T2Nx renal cell carcinoma (RCC) or TanyN+ RCC for which radical or partial nephrectomy is planned Patients must have no clinical or radiological evidence of distant metastases (M0) unless the presumed M1 disease is planned to be resected/definitively treated (eg, thermal ablation, stereotactic radiation) Active, not recruiting November 2023 IMmotion010 NCT03024996 Atezolizumab Pathologically confirmed RCC with a component of either clear-cell histology or sarcomatoid histology that has not been previously treated in the adjuvant or neoadjuvant setting and classified as being at high risk of RCC recurrence Radical or partial nephrectomy with lymphadenectomy in select participants Absence of residual disease and absence of metastasis, as confirmed by a negative baseline CT of the pelvis, abdomen, and chest Absence of brain metastasis, as confirmed by a negative CT with contrast or MRI scan of the brain Active, not recruiting February 2024 NR: not reported continued on page 348 347SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 Adjuvant Systemic Treatment for Renal Cancer After Surgery: A Network Meta-Analysis http://SIUJ.org TABLE 2. Trials in progress Trial name/ number Interventions Inclusion criteria Current progress Estimated completion date CheckMate 914 NCT03138512 Nivolumab Nivolumab + ipilimumab Kidney tumour has been completely resected with negative surgical margins obtained Pathologic TNM staging meeting one of the following: pT2a, G3 or G4, N0 M0; pT2b, G any, N0 M0; pT3, (a, b, c), G any, N0 M0; pT4, G any, N0 M0; pT any, G any, N1 M0 Post-nephrectomy tumour shows RCC with a predominantly clear-cell histology, including participants with sarcomatoid features Participants must have no clinical or radiological evidence of macroscopic residual disease or distant metastases after nephrectomy Recruiting July 2025 RAMPART NCT03288532 Durvalumab Durvalumab + Tremelimumab Histologically proven RCC (all cell types of RCC are eligible, except for pure oncocytoma, collecting duct, medullary and transitional cell cancer [TCC]); no evidence of residual macroscopic disease on postoperative CT scan after resection of RCC Patients with microscopically positive resection margins after radical nephrectomy at the nephrectomy bed, renal vein, or inferior vena cava are eligible provided the postoperative CT scan shows no evidence of residual macroscopic disease Recruiting December 2034 NR: not reported 2 highest ranked comparisons with a P-score of 0.87 and 0.80, respectively. Thalidomide was the lowest ranked treatment with a P-score of 0.03. Interferon-alpha was inferior to axitinib, pazopanib, pembrolizumab and sunitinib. Comparisons of all treatments are shown in Table 3. These findings were the same in the sensitivity analysis when using a random-effects model (data not shown). Overall survival The OS analysis included 7063 patients from all the studies from above except Margulis et al. (thalidomide, 2009)[20] and Choueiri et al. (pembrolizumab, 2021) [16]. The forest plot of HRs compared with the control arm for each agent is shown in Figure 1B. None of the agents demonstrated a survival benefit compared with observation. Pazopanib was the highest ranked treatment with a P-score of 0.83. Comparisons of all treatments are shown in Online Supplementary Table 2. There was no difference between any of the treatment comparisons. These findings were the same in the sensitivity analysis when using a random-effects model (data not shown). Severe adverse events Data from 8 trials using the following interventions were included in the safety analysis: axitinib, girentuximab, interferon-alpha, pazopanib, pembrolizumab, sorafenib, su n it i n ib, a nd t ha l idom ide[8,9,12 ,15 –17,19, 20]. The forest plots of ORs compared with control are shown in Online Supplementary Figure 2. All of the active treatments except girentuximab significantly increased the likelihood of severe adverse events compared with observation. These findings were the same in the sensitivity analysis when using a random-effects model. Subgroup analyses There were insufficient data to perform a network meta- analysis on the planned subgroups. , Cont’d 348 SIUJ • Volume 3, Number 5 • September 2022 SIUJ.ORG REVIEW http://siuj.org http://siuj.org http://siuj.org http://SIUJ.org Discussion Ou r net work meta-a na lysis repor t fou nd t hat pembrolizumab is likely the most efficacious adjuvant agent in prolonging time to disease recurrence compared with other tyrosine k inase inhibitors, monoclonal antibody against circulating vascular endothelial growth factor, and/or chemotherapies. The only other therapy that was shown to improve DFS compared with observation was pazopanib. However, the absolute difference in recurrence-free survival at 3 years was only 3% between pazopanib and placebo[15]. We used data from patients who received both 600 mg and 800 mg where there were discrepancies in the results related to dose. Although patients receiving the lower dose did not experience improved DFS, those receiving the higher dose were noted to have a prolonged disease- free survival. Therefore, it is likely that the benefit of pazopanib 800 mg is greater than the overall estimates in this review. It should also be noted that the sunitinib did show an improvement in DFS in the S-TRAC trial, although the estimates from this meta-analysis were not significant when including the ECOG trial. The results from this network meta-analysis are consistent with those of previously published meta-analyses on the topic[21, 22]. Despite these positive findings in delaying disease recurrence, none of the treatments improved overall survival. We acknowledge that the overall survival data have not matured for most of the recent studies and that there may still be a benefit with adjuvant therapy. Importantly, there was an increased risk of severe adverse events with adjuvant treatment compared with observation. It should be considered that there are several factors that impact the use of adjuvant treatment and choice of agent. This review represented a population of patients with locoregional renal cancer who had undergone surgery, but there are sub-populations within this group in whom treatment effect may differ. For example, we believed there may have been differences based on histological subtype and nodal status but were unable to perform the pre- planned subgroup analyses due to a lack of data. The POLAR-01 trial reported that patients with N0 disease had better outcomes with combination IL-2 and IFN-alpha treatment than did those with N+ disease[10]. In contrast, the ATLAS trial demonstrated that patients with highest risk (pT3 with grade ≥ 3 or pT4 and/or N+, any T, any grade) benefitted with axitinib treatment compared with those with low risk (pT2 or pT3 with grade ≤ 2) who had no difference in outcomes with axitinib[8]. The wider literature, especially in the metastatic setting, highlights the increasing use of molecular biomarkers to tailor treatment choices[23]. This will increase in importance as immunotherapies are used more in this setting. Therefore, patient selection is key in determining the benefit of adjuvant therapy and the choice of agent. The findings of this meta-analysis should be contextualised within its limitations. As mentioned above, there is heterogeneity within the popula- tions of the included studies, and we were unable to perform the pre-planned subgroup analyses. There were also individual study limitations, especially with respect to blinding, that may have introduced bias into the estimates. Additionally, we did not assess patient-reported outcomes, which is crit- ical in determining whether adjuvant treatment improves quality in life[24]. Future studies will need to assess the cost-effectiveness of these treat- ments because immunotherapies are expensive and thus may not be cost-effective[25]. Health econom- ics studies of advanced RCC have reported that a significant decrease in the cost of immunotherapy is required for it to be cost-effective at generally accepted thresholds[26]. It is likely that these would be generalizable to the use of immunotherapy in the adjuvant setting as the absolute benefits of treatment are small, albeit statistically significant, and come at significant cost. Furthermore, this study will need to be updated following the publication of trials in progress. Conclusions Pembrolizumab and pazopanib were the only 2 adjuvant agents that improved time to disease recurrence compared with observation, with the former likely being the more efficacious. None of the treatments improved overall survival, and almost all increased severe adverse events. While it is promising to see these agents show efficacy in this setting, the duration and cost of treatment also need to be considered when determining utility. 349SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 Adjuvant Systemic Treatment for Renal Cancer After Surgery: A Network Meta-Analysis http://SIUJ.org TABLE 3. Matrix comparing hazard ratios [confidence intervals] for DFS between all therapies Axitinib 1.15 [0.87; 1.52] 1.11 [0.79; 1.57] 0.97 [0.57; 1.63] 0.97 [0.65; 1.44] 1.45 [1.00; 2.10] 0.92 [0.67; 1.27] 0.85 [0.58; 1.24] 1.12 [0.82; 1.53] 1.07 [0.78; 1.47] 2.69 [1.04; 7.01] 0.87 [0.66; 1.15] Control 0.97 [0.79; 1.19] 0.84 [0.54; 1.31] 0.84 [0.63; 1.12] 1.26 [0.99; 1.61] 0.80 [0.68; 0.95] 0.74 [0.57; 0.96] 0.97 [0.84; 1.13] 0.93 [0.80; 1.09] 2.34 [0.94; 5.86] 0.90 [0.64; 1.26] 1.03 [0.84; 1.26] Girentuximab 0.87 [0.53; 1.41] 0.87 [0.61; 1.23] 1.30 [0.95; 1.79] 0.82 [0.64; 1.07] 0.76 [0.55; 1.06] 1.00 [0.78; 1.29] 0.96 [0.74; 1.24] 2.42 [0.95; 6.17] 1.04 [ 0.61; 1.75] 1.19 [0.76; 1.85] 1.15 [0.71; 1.88] IL-2 + Interferon 1.00 [0.59; 1.70] 1.50 [0.90; 2.49] 0.95 [0.59; 1.53] 0.88 [0.53; 1.47] 1.16 [0.73; 1.85] 1.11 [0.69; 1.77] 2.79 [1.01; 7.72] 1.04 [0.70; 1.54] 1.19 [0.89; 1.59] 1.15 [0.81; 1.64] 1.00 [0.59; 1.70] IL-2 + Interferon +5-FU 1.50 [1.03; 2.19] 0.95 [0.68; 1.33] 0.88 [0.60; 1.30] 1.16 [0.84; 1.60] 1.11 [0.80; 1.54] 2.79 [1.07; 7.28] 0.69 [0.48; 1.00] 0.79 [0.62; 1.01] 0.77 [0.56; 1.06] 0.67 [0.40; 1.11] 0.67 [0.46; 0.97] Interferon-alpha 0.63 [0.47; 0.85] 0.59 [0.41; 0.84] 0.77 [0.58; 1.03] 0.74 [0.55; 0.99] 1.86 [0.72; 4.80] 1.09 [0.79; 1.50] 1.25 [1.06; 1.48] 1.21 [0.93; 1.57] 1.05 [0.65; 1.69] 1.05 [0.75; 1.46] 1.58 [1.17; 2.12] Pazopanib 0.92 [0.68; 1.26] 1.22 [0.98; 1.52] 1.16 [0.93; 1.46] 2.93 [1.16; 7.43] 1.18 [0.80; 1.72] 1.35 [1.04; 1.75] 1.31 [0.94; 1.82] 1.14 [0.68; 1.90] 1.14 [0.77; 1.67] 1.70 [1.19; 2.44] 1.08 [0.79; 1.47] Pembrolizumab 1.32 [0.98; 1.77] 1.26 [0.93; 1.71] 3.17 [1.22; 8.21] 0.89 [0.65; 1.22] 1.03 [0.89; 1.19] 1.00 [0.78; 1.28] 0.86 [0.54; 1.37] 0.86 [0.62; 1.19] 1.29 [0.97; 1.72] 0.82 [0.66; 1.02] 0.76 [0.56; 1.02] Sorafenib 0.96 [0.77; 1.18] 2.41 [0.95; 6.08] 0.93 [0.68; 1.28] 1.07 [0.92; 1.26] 1.04 [0.81; 1.34] 0.90 [0.56; 1.44] 0.90 [0.65; 1.25] 1.35 [1.01; 1.81] 0.86 [0.68; 1.08] 0.79 [0.59; 1.08] 1.05 [0.85; 1.29] Sunitinib 2.52 [0.99; 6.37] 0.37 [0.14; 0.97] 0.43 [0.17; 1.07] 0.41 [0.16; 1.06] 0.36 [0.13; 0.99] 0.36 [0.14; 0.94] 0.54 [0.21; 1.39] 0.34 [0.13; 0.87] 0.32 [0.12; 0.82] 0.42 [0.16; 1.05] 0.40 [0.16; 1.01] Thalidomide Light blue shading shows superiority, and dark blue shading shows inferiority of the row compared with the column. 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JAMA Oncol.2017;3(7):913-920. 10. Passalacqua R, Caminiti C, Buti S, Porta C, Camisa R, Braglia L, et al. Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC). J Immunother.2014;37(9):440-447. 11. Aitchison M, Bray CA, Van Poppel H, Sylvester R, Graham J, Innes C, et al. Adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: results of a phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/National Cancer Research Institute trial. Eur J Cancer.2014;50(1):70-77. 12. Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, Crawford ED, et al. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol.2003;21(7):1214-1222. 13. Pizzocaro G, Piva L, Colavita M, Ferri S, Artusi R, Boracchi P, et al. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study. J Clin Oncol.2001;19(2):425-431. 14. Hinotsu S, Kawai K, Ozono S, Tsushima T, Tokuda N, Nomata K, et al. Randomized controlled study of natural interferon α as adjuvant treatment for stage II or III renal cell carcinoma. Int J Clin Oncol.2013;18(1):68-74. 15. Motzer RJ, Haas NB, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol.2017;35(35):3916-3923. TABLE 3. Matrix comparing hazard ratios [confidence intervals] for DFS between all therapies Axitinib 1.15 [0.87; 1.52] 1.11 [0.79; 1.57] 0.97 [0.57; 1.63] 0.97 [0.65; 1.44] 1.45 [1.00; 2.10] 0.92 [0.67; 1.27] 0.85 [0.58; 1.24] 1.12 [0.82; 1.53] 1.07 [0.78; 1.47] 2.69 [1.04; 7.01] 0.87 [0.66; 1.15] Control 0.97 [0.79; 1.19] 0.84 [0.54; 1.31] 0.84 [0.63; 1.12] 1.26 [0.99; 1.61] 0.80 [0.68; 0.95] 0.74 [0.57; 0.96] 0.97 [0.84; 1.13] 0.93 [0.80; 1.09] 2.34 [0.94; 5.86] 0.90 [0.64; 1.26] 1.03 [0.84; 1.26] Girentuximab 0.87 [0.53; 1.41] 0.87 [0.61; 1.23] 1.30 [0.95; 1.79] 0.82 [0.64; 1.07] 0.76 [0.55; 1.06] 1.00 [0.78; 1.29] 0.96 [0.74; 1.24] 2.42 [0.95; 6.17] 1.04 [ 0.61; 1.75] 1.19 [0.76; 1.85] 1.15 [0.71; 1.88] IL-2 + Interferon 1.00 [0.59; 1.70] 1.50 [0.90; 2.49] 0.95 [0.59; 1.53] 0.88 [0.53; 1.47] 1.16 [0.73; 1.85] 1.11 [0.69; 1.77] 2.79 [1.01; 7.72] 1.04 [0.70; 1.54] 1.19 [0.89; 1.59] 1.15 [0.81; 1.64] 1.00 [0.59; 1.70] IL-2 + Interferon +5-FU 1.50 [1.03; 2.19] 0.95 [0.68; 1.33] 0.88 [0.60; 1.30] 1.16 [0.84; 1.60] 1.11 [0.80; 1.54] 2.79 [1.07; 7.28] 0.69 [0.48; 1.00] 0.79 [0.62; 1.01] 0.77 [0.56; 1.06] 0.67 [0.40; 1.11] 0.67 [0.46; 0.97] Interferon-alpha 0.63 [0.47; 0.85] 0.59 [0.41; 0.84] 0.77 [0.58; 1.03] 0.74 [0.55; 0.99] 1.86 [0.72; 4.80] 1.09 [0.79; 1.50] 1.25 [1.06; 1.48] 1.21 [0.93; 1.57] 1.05 [0.65; 1.69] 1.05 [0.75; 1.46] 1.58 [1.17; 2.12] Pazopanib 0.92 [0.68; 1.26] 1.22 [0.98; 1.52] 1.16 [0.93; 1.46] 2.93 [1.16; 7.43] 1.18 [0.80; 1.72] 1.35 [1.04; 1.75] 1.31 [0.94; 1.82] 1.14 [0.68; 1.90] 1.14 [0.77; 1.67] 1.70 [1.19; 2.44] 1.08 [0.79; 1.47] Pembrolizumab 1.32 [0.98; 1.77] 1.26 [0.93; 1.71] 3.17 [1.22; 8.21] 0.89 [0.65; 1.22] 1.03 [0.89; 1.19] 1.00 [0.78; 1.28] 0.86 [0.54; 1.37] 0.86 [0.62; 1.19] 1.29 [0.97; 1.72] 0.82 [0.66; 1.02] 0.76 [0.56; 1.02] Sorafenib 0.96 [0.77; 1.18] 2.41 [0.95; 6.08] 0.93 [0.68; 1.28] 1.07 [0.92; 1.26] 1.04 [0.81; 1.34] 0.90 [0.56; 1.44] 0.90 [0.65; 1.25] 1.35 [1.01; 1.81] 0.86 [0.68; 1.08] 0.79 [0.59; 1.08] 1.05 [0.85; 1.29] Sunitinib 2.52 [0.99; 6.37] 0.37 [0.14; 0.97] 0.43 [0.17; 1.07] 0.41 [0.16; 1.06] 0.36 [0.13; 0.99] 0.36 [0.14; 0.94] 0.54 [0.21; 1.39] 0.34 [0.13; 0.87] 0.32 [0.12; 0.82] 0.42 [0.16; 1.05] 0.40 [0.16; 1.01] Thalidomide Light blue shading shows superiority, and dark blue shading shows inferiority of the row compared with the column. 351SIUJ.ORG SIUJ • Volume 3, Number 5 • September 2022 Adjuvant Systemic Treatment for Renal Cancer After Surgery: A Network Meta-Analysis http://SIUJ.org 16. 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Quality of patient-reported outcome reporting across cancer randomized controlled trials according to the CONSORT patient- repor ted outcome extension: a pooled analysis of 557 trials. Cancer.2015;121(18):3335-3342. 25. Chien C-R, Geynisman DM, Kim B, Xu Y, Shih Y-CT. Economic burden of renal cell carcinoma-par t I: an updated review. Pharmacoeconomics.2019;37(3):301-331. 26. Watson TR, Gao X, Reynolds KL, Kong CY. Cost-effectiveness of pembrolizumab plus axitinib vs nivolumab plus ipilimumab as first-line treatment of advanced renal cell carcinoma in the US. JAMA Netw Open.2020;3(10):e2016144. 352 SIUJ • Volume 3, Number 5 • September 2022 SIUJ.ORG REVIEW http://SIUJ.org