Front. Oncol. Frontiers in Oncology Front. Oncol. 2234-943X Frontiers Media S.A. 10.3389/fonc.2024.1478245 Oncology Systematic Review Effectiveness of systemic treatments for advanced non-clear cell renal cell carcinoma: a systematic review and meta-analysis Zhang Yaping 1 Chen Jian 2 Wang Xiaoyan 1 Wang Hui 1 Chen Xiaoli 1 Hong Jianfeng 1 Fang Hongming 1 * 1 Department of Oncology, Affliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China 2 Department of GCP, Affliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China

Edited by: Lothar Bergmann, University Hospital Frankfurt, Germany

Reviewed by: Shiying Tang, Peking University Third Hospital, China

Francisco Cezar Aquino de Moraes, Federal University of Pará, Brazil

*Correspondence: Hongming Fang, fanghongming0412@163.com

18 12 2024 2024 14 1478245 09 08 2024 03 12 2024 Copyright © 2024 Zhang, Chen, Wang, Wang, Chen, Hong and Fang 2024 Zhang, Chen, Wang, Wang, Chen, Hong and Fang

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 Background

Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous group of malignancies with substantial differences in morphology, genetic profiles, clinical behavior, and prognosis. Optimal treatment for nccRCC remains unclear, largely extrapolated from evidence available for clear cell renal cell carcinoma (ccRCC). This study aimed to compare the efficacy of current mainstream drug treatments for nccRCC to provide clinical treatment guidance for advanced cases.

 Methods

We systematically searched PubMed, Embase, and Cochrane databases for trials published up to January 2, 2024, including controlled and single-arm trials. Primary outcomes included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

 Results

We selected six randomized controlled trials (RCTs) comparing mammalian target of rapamycin inhibitors (mTORi) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). These trials included four first-line and two second-line studies, with a total of 398 advanced nccRCC patients. Pooled results showed that VEGFR-TKIs significantly improved PFS compared to mTORi in first-line treatment (relative risk [RR] = 1.387; 95% confidence interval [CI]: 1.04-1.85; p = 0.026). In a single-arm meta-analysis, we included 22 VEGFR-TKI trials, three mTORi trials, 12 immune checkpoint inhibitor (ICI) therapies, five chemotherapy trials, and 10 combination therapy trials. The pooled ORR ranged from 6% (95% CI: 0–16%) to 36% (95% CI: 27–44%), and the pooled DCR ranged from 54% (95% CI: 50–58%) to 81% (95% CI: 70–91%). Subgroup analysis of ICI showed a higher ORR in the PD-L1 positive group compared to the PD-L1 negative group (RR = 3.044; 95% CI: 1.623-5.709; p = 0.001).

 Conclusion

This systematic review and meta-analysis demonstrate that VEGFR-TKIs improve PFS in first-line treatment compared to mTORi. The single-arm meta-analysis suggest that combination therapies with different mechanisms result in better ORR and DCR. Furthermore, PD-L1 positive patients showed significantly better therapeutic responses with ICI treatment than PD-L1 negative patients.

 non-clear cell renal cell carcinoma vascular endothelial growth factor receptor tyrosine kinase inhibitors mammalian target of rapamycin inhibitors chemotherapy immune checkpoint inhibitor section-in-acceptance Genitourinary Oncology Introduction

Renal cell carcinoma (RCC) is a common malignancy of the urinary and reproductive systems, making up 2-3% of systemic malignancies and 80-90% of renal malignancies (1). According to the 2016 World Health Organization (WHO) guidelines, RCC is classified histologically into renal clear cell carcinoma (ccRCC) and non-clear cell carcinoma (nccRCC) (2). NccRCC accounts for 15-30% of renal tumor, and includes various malignancies with significant differences in morphology, genetic profiles, immunohistochemical features, and clinical behaviors (3). Notable subtypes of nccRCC include papillary, chromophobe, collecting duct carcinoma (CDC), renal medullary, spindle cell, mucinous tubular, Xp11.2 translocation, carcinoma associated with neuroblastoma, and other rare entities (2). Papillary RCC (pRCC) and chromophobe RCC (chRCC) are the most prevalent, accounting for 10-15% and 4-5% of renal tumors, respectively (2). The sarcomatoid variant is not a distinct histologic entity but a high-grade transformation seen in various RCC subtypes, characterized by frequent metastasis to the lungs and bones and associated with poor prognosis (4).

Recent advancements in targeted therapy and immunotherapy have significantly improved ccRCC treatment outcomes (5–7). However, due to the heterogeneity and rarity of nccRCC, most RCC clinical trials primarily include ccRCC patients or a small subset of nccRCC patients. As a result, systemic therapy options for nccRCC are largely derived from ccRCC trials and retrospective studies (8, 9). Despite these efforts, nccRCC patients have significantly lower survival rates compared to those with ccRCC (1, 3). The National Comprehensive Cancer Network (NCCN) guidelines recommend clinical trials as the preferred treatment option for nccRCC patients (1), highlighting it as a critical and challenging research area.

Numerous endeavors have focused on developing mesenchymal-epithelial transition (MET) inhibitors, given that MET proto-oncogene has been found to have mutations and copy number changes of pRCC (10). A systematic review and meta-analysis evaluated the efficacy and safety of MET inhibitor (METi) in advanced pRCC, results indicated that the objective response rate (ORR) was 36.38% for MET+ pRCC, and an overall population ORR of 20.56% (11). Subgroup analysis of drugs showed that patients on cabozantinib had an ORR of 26.14%, on savolitinib had an ORR of 15.35% (11). METi represents a promising target for precision therapies, nevertheless, the available data remains limited, requiring further validation of this approach.

Due to the limited clinical trial data and guidance for nccRCC therapy selection, we conducted a systematic review and meta-analysis of existing data. This study aimed to evaluate the antitumor efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), mTORi, chemotherapy, immune checkpoint inhibitors (ICIs), and combination therapies in treating nccRCC to provide clinical treatment guidance. Additionally, we analyzed single-arm studies due to the scarcity of controlled trials.

 Methods Search strategy

This systematic review and meta-analysis evaluated the efficacy of VEGFR-TKIs, mTORi, chemotherapy, ICIs, and combination therapies for advanced nccRCC. Comprehensive searches were performed in the PubMed, Embase, and Cochrane databases for reports published up to January 2, 2024. Only English-language articles and abstracts from all available years were included, while case reports, case series, and review articles were excluded. The primary search term was “renal cell carcinoma”.

 Inclusion and exclusion criteria

All trial designs were included, comprising randomized controlled trials (RCTs), non-randomized controlled trials, and single-arm studies.

Inclusion criteria: (1) Adult patients diagnosed histologically or cytologically with advanced nccRCC; (2) Controlled trials or single-arm studies assessing interventions such as VEGFR-TKIs, mTORi, chemotherapy, ICIs, or combination therapies; (3) Studies published in English; (4) Reports of at least one of the following outcomes: ORR, disease control rate (DCR), progression-free survival (PFS), or overall survival (OS); (5) When multiple reports were available from the same investigator for the same patient population, the most recent or comprehensive report was selected.

Exclusion criteria: (1) In vitro or in vivo studies; (2) Case reports, case series, or studies with fewer than 10 participants; (3) Reviews, abstracts, or letters; (4) Re-challenge therapies; (5) Non-English publications.

 Literature screening and data extraction

Two researchers (Y.P.Z. and X.Y.W) independently screened titles and abstracts based on predefined inclusion and exclusion criteria. Data extraction adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (12). Discrepancies were resolved through discussion; if consensus was not reached, a third investigator (J.C.) was consulted to arbitrate, with final decisions determined by majority vote. If inclusion could not be established from the abstract or if essential data were missing, the full text was reviewed. A standardized data extraction form was created to collect the following information: study characteristics (first author, publication year, identifier, study design, study phase, treatment type, histological subgroups of nccRCC, treatment line), patient characteristics (number of evaluable patients, number of treatment arms, number of control arms, median age, sex), and outcome assessments (complete response [CR], partial response [PR], stable disease [SD], disease progression [PD], ORR, DCR, PFS, or OS).

 Quality assessment

Two investigators (X.L.C. and J.F.H) independently performed the quality assessment. The risk of bias was evaluated in duplicate, with any discrepancies resolved by consensus or by consulting a third reviewer (H.W.). The methodological quality of the included RCTs was assessed using the Cochrane Risk of Bias Tool, as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (13). A risk of bias summary was compiled using Review Manager Version 5.4 (Copenhagen: Nordic Cochrane Centre, Cochrane Collaboration, 2020).

 Statistical analysis

Statistical analyses were performed using Stata 12.0 software (Stata Corporation, College Station, TX). Dichotomous data, including ORR and DCR, were compared using relative risk (RR). Hazard ratios (HR) for OS and PFS, along with their 95% confidence intervals (CIs), were extracted from each RCT. Summary HRs were calculated using either random or fixed-effects models, depending on the heterogeneity of the studies. Heterogeneity was assessed using the I² statistic and Chi-squared test, with I² ≥ 50% indicating significant heterogeneity. The random-effects model was employed when heterogeneity was substantial (I² > 50% or P < 0.05); otherwise, the fixed-effects model was applied (14). Additionally, the Begg test and funnel plots were used to assess potential publication bias among the studies. A two-tailed p-value of less than 0.05 was considered statistically significant.

 Results Literature selection

The electronic search identified 16,438 citations published between September 1994 and January 2024. After screening abstracts and titles, 576 full-text articles were reviewed, and 58 studies were included in the systematic review. These comprised six RCTs comparing the efficacy of mTORi and VEGFR-TKIs, 22 single-arm studies on VEGFR-TKIs, three on mTORi, 12 on immunotherapy, five on chemotherapy, and ten on combination therapy. The literature screening process is illustrated in the flowchart in Figure 1 .

The flowchart of the study selection process for the meta-analysis.

 Characteristics of six RCTs comparing mTORi and VEGFR-TKIs

Four studies compared mTORi with VEGFR-TKIs as first-line treatments (15–18), while two studies focused on second-line treatments (15, 19). The ESPN trial provided data for both first-line and second-line treatments separately (15), and we analyzed them as distinct studies. The meta-analysis included 398 patients, with 203 receiving mTORi and 195 receiving VEGFR-TKIs. Among the VEGFR-TKI group, 45 patients were treated with sorafenib, and the rest received sunitinib. Five of the six studies were randomized phase II trials (15–18), and one was a randomized phase III trial (19). Four studies exclusively recruited nccRCC patients (15–17), while two included both ccRCC and nccRCC patients (18, 19), providing separate data for each subgroup. In the three RCTs that reported pathological subgroups (15–17), papillary histology was the most common nccRCC type (113 out of 198 patients). The characteristics and main outcomes of the six RCTs are summarized in Table 1 and Table 2 , separately.

General characteristics of the included randomized controlled trials (RCTs).

First author(year) Identifier Study design Studyphase Patients(n) Histological subgroups Comparator Treatmentline
Bergmann(2020) / RCT 2 22 Papillary 16Chromophobe 2Renal medullary 1Unclassified 3 TemsirolimusvsSunitinib First
Armstrong(2016) ASPEN RCT 2 108 Papillary 70Chromophobe 16Unclassified 22Translocation 8Minor clear cell component 13Sarcomatoid differentiation 16 SunitinibvsEverolimus First
Tannir(2015) ESPN RCT 2 68 Papillary 27Clear cell with sarcomatoid features 12Chromophobe 12Translocation 7Unclassified 10 EverolimusvsSunitinib First
Motzer(2014) RECORD-3 RCT 2 66 / EverolimusvsSunitinib First
Tannir(2015) ESPN RCT 2 44 / EverolimusvsSunitinib Second
Hutson(2014) INTORSECT RCT 3 90 / TemsirolimusvsSorafenib Second

RCT, randomized controlled trial; n, number.

Summary of main outcomes of the included RCTs: Response Evaluation Criteria in Solid Tumors (RECIST), progression - free survival (PFS) and overall survival (OS).

First author(year) Comparator Age(range) Sexmale/female Patients(n) ResponseRECIST (n) PFS(mo) PFS HR(95% CI) OS(mo) OS HR(95% CI)
Bergmann(2020) Temsirolimus 59.5(29–85) 8/4 12 CR:0PR:2SD:5PD:2 9.3 1.76(0.7-4.46) 19.4 0.98(0.31-3.09)
Sunitinib 65.5(46–80) 8/2 10 CR:0PR:3SD:6PD:1 13.2 19.8
Armstrong(2016) Everolimus 64(29–90) 44/13 57 CR:1PR:4SD:30PD:13 5.6 1.41(0.88-2.26) 13.2 1.12(0.7-2.1)
Sunitinib 59(24–100) 37/14 51 CR:0PR:9SD:30PD:10 8.3 31.5
Tannir(2015) Everolimus 58(23–73) 24/11 35 CR:0PR:1SD:26PD:8 4.1 1.16(0.67-2.01) 14.9 /
Sunitinib 60(28–76) 19/14 33 CR:0PR:3SD:21PD:9 6.1 16.2
Motzer(2014) Everolimus / / 31 / 5.1 1.5(0.9-2.8) / /
Sunitinib / / 35 / 7.2 /
Tannir(2015) Everolimus / / 23 PR:2SD:15PD:6 2.8 / / /
Sunitinib / / 21 SD:13PD:8 1.8 /
Hutson(2014) Temsirolimus / / 45 / / 0.88(0.53-1.45) 1 .42(0.86-2.35)
Sorafenib / / 45 / /

HR, hazard ratio; CI, confidence interval; n, number; CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease.

 Assessment of study quality and risk of bias

A total of 398 patients were included in the six RCTs. Five studies reported PFS (15–19), four reported ORR and DCR (15–17), and three reported OS (16, 17, 19). The studies exhibited some risks of bias, primarily in blinding of participants and personnel (15–17, 19), random sequence generation (15, 17, 19) and allocation concealment (15, 17, 19). Figure 2 presents the risk of bias summary and graph.

Risk of bias. (A) Graph: review authors’ judgments about each risk of bias item presented as percentages across all RCTs. (B) Summary: review authors’ judgments about each risk of bias item for each included RCT.

 PFS and OS

A comparative meta-analysis of six RCTs examined the PFS of mTORi versus VEGFR-TKIs. Four of these trials were first-line treatments (15–18). The overall analysis showed no significant difference in PFS between the two treatment groups (RR = 1.240; 95% CI, 0.966-1.592; P = 0.091). However, a subgroup analysis revealed a significant PFS benefit for sunitinib over mTORi in first-line treatment (RR = 1.387; 95% CI, 1.040-1.850; P = 0.026) ( Figure 3A ). There was no significant heterogeneity among the studies.

The forest plot comparing of PFS, OS, ORR, DCR between mTORi and VEGFR-TKIs. (A) PFS, (B) OS, (C) ORR, (D) DCR.

Three articles provided specific OS data: two compared mTORi to VEGFR-TKIs in first-line treatment (16, 17), and one in second-line treatment (19). The results showed no significant difference in OS between mTORi and VEGFR-TKIs (RR = 1.243; 95% CI, 0.874-1.769; P = 0.227) ( Figure 3B ). Similar results were observed in the subgroup analysis of first- and second-line treatments.

ORR and DCR

The meta-analysis results for ORR and DCR are shown in Figures 3C , D . Statistical tests indicated low heterogeneity for both ORR (I² = 0%, P = 0.885) and DCR (I² = 0%, P = 0.720). Sunitinib did not demonstrate a significant advantage over mTORi in ORR (RR = 0.597; 95% CI, 0.289-1.232; P = 0.163) or DCR (RR = 0.983; 95% CI, 0.837-1.153; P = 0.830). Subgroup analysis for first-line and second-line treatments also showed no significant differences in ORR (RR = 0.548; 95% CI, 0.248-1.209; P = 0.136) or DCR (RR = 0.960; 95% CI, 0.817-1.127; P = 0.616).

 Single-arm trials with VEGFR-TKIs Characteristics

All included studies evaluated the efficacy of VEGFR-TKIs for advanced nccRCC. Among the 22 clinical trials, 12 were prospective (20–31) and 10 were retrospective (32–41), comprising a total of 1,597 patients. Of the 18 studies that specified pathological subgroups (21, 24–39, 41), papillary histology was the most common, accounting for 607 of 914 patients. The most frequently used VEGFR-TKI was sunitinib (1,025 patients), followed by sorafenib (192 patients), pazopanib (111 patients), axitinib (58 patients), and tivozanib (46 patients). Five studies involved only first-line treatments (20, 21, 32–34), while the remaining 17 either included patients with prior anti-tumor treatments or did not specify treatment history. Detailed information on these 22 single-arm experiments is provided in Table 3 and Table 4 .

General characteristics of the included single-arm trials.

Treatment group First author Identifier Study design Studyphase Patients(n) Histological subgroups Treatment Treatmentline
VEGFR-TKIs Ravaud(2015) SUPAP Prospective 2 61 Papillary type I 15Papillary type II 46 Sunitinib First
Procopio(2022) Meet-URO 2/NCT03354884 Prospective 2 23 Collecting duct 23 Cabozantinib First
Gore(2009) a NCT00130897 Prospective / 588 / Sunitinib Unselected
Kim(2011) a / Prospective / 18 / Sunitinib Unselected
Barata(2023) / ProspectiveRandomized 2 46 Papillary 11Chromophobe 2Collecting duct 2Mixed/unclassified 31 Tivozanib FirstSecond
Tannir(2012) NCT00465179 Prospective 2 57 Papillary 27Chromophobe 5Collecting duct or medullary carcinoma 6Sarcomatoid 7Unclassified 8Others 4 Sunitinib FirstSecondThird
Molina(2012) / Prospective 2 23 Papillary 8Chromophobe 2 Collecting duct 4 Medullary 1Unclassified 5 HLRCC-related 3 Sunitinib Unselected
Lee(2012) / Prospective 2 31 Papillary 22Chromophobe 3Unclassified 5Xp11.2 translocation type 1 Sunitinib Unselected
Jung(2018) / Prospective Multicenter 2 26 Papillary 19 Chromophobe 3 Unclassified 2Unknown 5 Pazopanib Unselected
Park(2018) / Prospective Multicenter 2 40 Papillary 26Chromophobe 4MiT family translocation 7Others 3 Axitinib Unselected
Procopio(2007) / Prospective / 23 Papillary 14Chromophobe 3Bellini ducts 1Sarcomatoid variants 1Mixed or unknown 4 Sorafenib Unselected
Stadler(2010) NCT00111020 Prospective / 127 Papillary 107Chromophobe 20 Sorafenib Unselected
Poprach(2019) a / Retrospective / 93 Papillary 87Chromophobe 6 Sunitinib or pazopanib First
Buti(2021) / Retrospective / 48 Papillary 24Chromophobe 9Xp11 translocation 1Unclassified 6Mixed 8 Pazopanib First
Koguchi(2023) a b / Retrospective / 60 / Sunitinib or sorafenib or axitinib or pazopanib First
SHI(2015) / Retrospective / 37 Papillary 25Chromophobe 2Spindle cell type 2Unclassified 8 Sunitinib Unselected
Paglino(2012) / Retrospective / 21 Papillary type I 4Papillary type II 2Chromophobe 4Tubular, mucinous and spindle cell 1Bellini’s collecting duct carcinoma 4Mixed 1Sarcomatoid component ≥20% 5 Sunitinib Unselected
YILDIZ(2014) / Retrospective / 63 Papillary 46 Chromophobe 10Undifferentiated 7 Sunitinib Unselected
Campbell(2018) / Retrospective / 30 Papillary 17Chromophobe 6 Unclassified 3 Translocation 2Sarcomatoid 1Mucinous tubular/spindle cell 1 Cabozantinib Unselected
Chanzá(2019) / Retrospective / 112 Papillary 66Xp11-2 translocation 17 Unclassifid 15Chromophobe 10 Collecting duct 4 Cabozantinib Unselected
Matrana(2016) c / Retrospective / 17 / Pazopanib Not first-line
Choueiri(2008) / Retrospective / 53 Papillary 41Chromophobe 12 Sunitinib orsorafenib Unselected
mTORi Escudier(2016) RAPTOR Prospective 2 88 Papillary 88 Everolimus First
Koh(2013) NCT00830895 Prospective 2 49 Papillary 29Chromophobe 8Collecting duct 2Sarcomatoid 4Unclassifiable 6 Everolimus Unselected
Lee(2019) / ProspectiveRetrospective 44 Papillary 24Chromophobe 11Collecting duct 2Xp11.2 translocation 1Others 6 Temsirolimus Unselected
ICIs Vogelzang(2020) a CheckMate 374 Prospective 3b/4 44 / Nivolumab Unselected
Atkins(2023) d NCT03117309 Prospective 2 35 Papillary 19Chromophobe 6 Unclassified 10 Nnivolumab First
Albiges(2020) NCT03012581 Prospective 2 50 Papillary type I 5Papillary type II 20Chromophobe 9pRCC unclassified 4Collecting duct 4Others 8 Nivolumab FirstSecondThird
Conduit(2023) d NCT03177239 Prospective 2 83 Papillary 37Chromophobe 15Other 31 Ipilimumab Unselected (no prior ICIs)
McDermott(2021) KEYNOTE-427 study (cohort B) Prospective 2 165 Papillary 118Chromophobe 21Unclassifified 26 Pembrolizumab First
Tykodi(2022) CheckMate 920 (NCT02982954) Prospective 3b/4 52 Papillary 18Chromophobe 7Translocation-associated 2Collecting duct 2Renal medullary 1Unclassified 22 Ipilimumab plus nivolumab First
Koguchi(2023) b / Retrospective / 16 / Nivolumab Second
Koshkin(2018) / Retrospective / 41 Papillary 16Unclassified 14Chromophobe 5Collecting duct 4Ranslocation 1Mucinous Tubular and spindle cell carcinoma 1 Nivolumab Unselected
CHAHOUD(2019) / Retrospective / 40 Papillary 12Chromophobe 5Unclassified 11 Other 12 Nivolumab Unselected
Vries-Brilland(2020) / Retrospective / 57 Papillary type I 16Papillary type II 34Papillary unclassified 7 PD-1/PD-L1 inhibitors Unselected
McKay(2018) / Retrospective / 43 Papillary 14Chromophobe 10Unclassified 9Other 10 PD-1/PD-L1 inhibitors Unselected
Gupta(2019) / Retrospective / 18 Papillary 6Chromophobe 5Unclassified 3Other 4 Ipilimumab +nivolumab Unselected
Chemotherapy Tsimafeyeu(2012) NCT01182142 Prospective 2 51 Papillary 39Chromophobe 7Collecting duct 5 Capecitabine Unselected
Oudard(2007) GETUG Prospective 2 23 Collecting duct 23 Gemcitabin plus platinum salt First
Bylow(2009) / Prospective 2 17 Collecting duct 1Papillary 16 Carboplatin plus paclitaxel First
Richey(2013) / Prospective 2 15 Papillary 5Collecting duct 3Chromophobe 2 Unclassified 3Translocation carcinoma 2 Pemetrexed plus gemcitabine Unselected (no prior chemotherapy)
Rizzo(2022) / Retrospective / 36 Collecting duct 36 Cisplatin-based chemotherapy First
Combination therapy Hutson(2021) / Prospective 2 31 Papillary 20Chromophobe 9Unclassified 2 Lenvatinib pluseverolimus First
Feldman(2020) / Prospective 2 39 Unclassified RCC, Papillary features 24Papillary 14Translocation-associated RCC, papillary features 1 Everolimus plusbevacizumab First
Albiges(2023) KEYNOTE-B61 Prospective 2 158 Papillary 93Chromophobe 29Unclassified 21Translocation 6Other 9 Pembrolizumab plus lenvatinib First
Mahoney(2016) a / Prospective 2 13 Papillary 6Unclassifified 5Chromophobe 1Poorly differentiated RCC which was included as nccRCC 1 Bevacizumab plus temsirolimus Not first-line
McGregor(2019) / Prospective 2 60 Papillary 12Chromophobe10Collecting duct 5Medullary 1Translocation 5Unclassified RCC with or without sarcomatoid differentiation 9ccRCC With 20% sarcomatoid differentiation 18 Atezolizumab plus bevacizumab Unselected
Suarez(2023) NCT02819596 Prospective 2 41 Papillary 41 Savolitinib plus durvalumab Unselected
Sheng(2018) NCT01762150 Prospective 2 26 collecting duct carcinoma 28 Sorafenib in combination with gemcitabine plus cisplatin Unselected (no prior chemotherapy)
Srinivasan(2023) NCT01130519 Prospective 2 83 HLRCC 42Sporadic 41 Bevacizumab plus erlotinib Unselected
Lee(2022) NCT03635892 Prospective 2 40 Papillary 32Unclassified without papillary features 6Translocation-associated 2 Cabozantinib plus nivolumab FirstSecond
Stellato(2023) Meet-URO 23a Prospective retrospective / 32 Chromophobe 13Papillary 19 Pembrolizumab plus axitinib First

VEGFR-TKIs, vascular endothelial growth factor receptor tyrosine kinase inhibitors; mTORi, mammalian target of rapamycin inhibitors; ICI, immune checkpoint inhibitors; n, number.

Study includes ccRCC and nccRCC, with some data extracted.

Two sets of data from the same study.

This study includes 9 cases of first-line treatment, but not included because of less than 10 cases.

This study includes combination of nivolumab/ipilimumab treatment after immunotherapy for PD, but was not included.

Summary of main outcomes of the included studies: Response Evaluation Criteria in Solid Tumors (RECIST), progression-free survival (PFS) and overall survival (OS).

Treatment group First author Treatment Age(Range) Sexmale/female Patients(n) Patientsfor response/survival analysis(n) ResponseRECIST (n) PFS(mo)(95% CI) OS(mo)(95% CI)
VEGFR-TKIs Ravaud(2015) Sunitinib 64(32-81) 51/10 61 60/60 CR: 0PR: 7SD: 35PD: 18 6.6(2.8-14.8) 17.8(5.7-26.1)
Procopio(2022) Cabozantinib 66(53-74) 19/4 23 23/23 CR: 1PR: 7SD: 3 4(3-13) 7(3-31)
Gore(2009) Sunitinib / / 588 437/588 CR: 2PR: 46SD: 250PD: 139 7.8 (6.3–8.3) 13.4(10.7–14.9)
Kim(2011) Sunitinib / / 18 18/18 CR: 0PR: 3SD: 13PD: 2 5.8(4.0-7.6) /
Barata(2023) Tivozanib 55(26-75) 34/12 46 46/46 PR: 7SD: 22PD: 12NE: 5 6.7(3.9-12) /
Tannir(2012) Sunitinib 57(22-85) 38/19 57 55/55 CR: 0PR: 3SD: 29PD: 23 2.7(1.4-5.4) 16.8(10.7-26.3)
Molina(2012) Sunitinib 55(21-80) 17/6 23 23/23 PR: 1SD: 15PD: 6NE: 1 5.5(2.5-7.1) /
Lee(2012) Sunitinib 53(18-76) 23/8 31 31/31 PR: 11SD: 17PD: 1NE: 2 6.4(4.2-8.6) /
Jung(2018) Pazopanib 58(27-76) 21/8 29 28/28 CR: 0PR: 8SD: 17PD: 3 16.5 (10.9-22.1) /
Park(2018) Axitinib 59(22-84) 26/14 40 40/40 PR: 15SD: 12PD: 11NE: 2 7.4(5.2-9.5) 12.1(6.4-17.7)
Procopio(2007) Sorafenib / / 23 23/23 CR: 0PR: 1SD: 4PD: 18 / /
Stadler(2010) Sorafenib / / 127 127/127 CR: 0PR: 4SD: 104PD: 19 / /
Poprach(2019) Sunitinib or pazopanib 63(33-82) 68/25 93 83/93 CR: 1PR: 11SD: 28PD: 31 NE: 12 6.5(2.5−10.5) 22(14.6−29.4)
Buti(2021) Pazopanib 70(27-86) 36/12 48 48/48 CR: 0PR: 13SD: 27PD: 6 NE: 2 12.3 (3.6-20.9) 27.7 (18.2-37.1)
Koguchi(2023) Sunitinib or sorafenib or axitinib or pazopanib 63(24–89) 38/22 60 / 5.4( 2.5-7.1) /
SHI(2015) Sunitinib 50(29–74) 26/11 37 37/37 CR: 0PR: 5SD: 22PD: 10 6(3.6−8.4) 9 (6.9−11.1)
Paglino(2012) Sunitinib 54.9 (35–74) 20/1 21 21/21 CR: 1PR: 2SD: 8PD: 10 4.08(average:10.60; range: 1.38-73.1) e 14.60 (average: 27.62;range:2.04-78.1) e
YILDIZ(2014) Sunitinib 63(25–82) 38/25 63 63/63 CR: 0PR: 7SD: 33PD: 23 7.6(5.5-9.7) 22(13.4-30.6)
Campbell(2018) Cabozantinib 58.4(25-81) 26/4 30 28/30 PR: 4SD: 18PD: 6 8.6(6.1-14.7) 25.4(15.3-35.4)
Chanzá(2019) Cabozantinib 60(48–66) 85/27 112 112/112 CR: 1PR: 29SD: 53PD: 25 NE: 4 7.0 (5.7–9.0) 12.0 (9.2–17.0)
Matrana(2016) Pazopanib / / 17 17/17 PR: 1SD: 14PD: 2 4.0 (2.1–9.9) 13.6 (6.4–NA)
Choueiri(2008) Sunitinib orsorafenib 59(24-83) 34/19 53 53/53 CR: 0PR: 5SD: 36 8.6 (5.3-11.9) /
mTORi Escudier(2016) Everolimus 60(23-84) f 72/20 f 88 88/88 CR: 0PR: 1SD: 57PD: 28Unknown: 2 4.1 (3.6-5.5) 21.4(15.4-28.4)
Koh(2013) Everolimus 57.0(23.8-75.5) 37/12 49 49/49 PR: 5SD: 25PD: 16Unable: 3 5.2 e 14.0 e
Lee(2019) Temsirolimus 52(17-84) 32/12 44 35/44 CR: 3PR: 1SD: 25PD: 6 7.6(5.0-10.2) 17.6 (0-39.1)
ICIs Vogelzang(2020) Nivolumab 62.0 (32-89) 32/12 44 44/44 CR: 1PR: 5SD: 16PD: 18 Unable to determine: 4 2.2(1.8-5.4) 16.3 (9.2-NE)
Atkins(2023) Nivolumab 63 (35–84) 31/4 35 35/35 CR: 2PR: 3SD: 16PD: 14 4.0 (2.7-4.3) /
Albiges(2020) Nivolumab 61.4 35/15 50 50/50 CR+PR: 5SD+PD: 45 3.9(2.9-8.3) /
Conduit(2023) Ipilimumab 64(21–88) 57/26 83 83/83 CR: 3PR: 11SD: 39PD: 27Unknown: 3 4.0 (3.6-7.4) 24(16–28)
McDermott(2021) Pembrolizumab 62(22-86) 109/56 165 165/165 CR: 11PR: 33SD: 51PD: 60NE: 2NA: 8 4.2 (2.9-5.6) 28.9(24.3–NR)
Tykodi(2022) Ipilimumab +nivolumab 64(23–86) 36/16 52 46/52 CR: 2PR: 7SD: 17PD: 19Unable to determine: 1 3.7(2.7-4.6) 21.2 (16.6-NE)
Koguchi(2023) Nivolumab 64(30–73) 11/5 16 / / 5.6(2.4-10.3)
Koshkin(2018) Nivolumab 58(33–82) 29/12 41 41/41 PR: 7SD: 10PD: 18NE: 6 3.5 (1.9–5.0) NR
CHAHOUD(2019) Nivolumab / / 31 31/31 CR: 2PR: 1SD: 13PD: 9NA: 6 4.3(3.4-7) 11.6(6.1-22.8)
Vries-Brilland(2020) PD-1/PD-L1 inhibitors 65 (19-85) 43/14 57 57/57 CR: 2PR: 4SD: 18PD: 31Unknown: 2 3.1(2.7-5.0) 14.6(9.0-NA)
McKay(2018) PD-1/PD-L1 inhibitors / / 43 30/43 CR: 0PR: 4SD: 11PD: 15 4.6(2.8-6.0) /
Gupta(2019) Ipilimumab +nivolumab 60(32-81) 14/4 18 18/18 PR: 6SD: 3PD: 9 7.1 e /
Chemotherapy Tsimafeyeu(2012) Capecitabine / 37/14 51 51/51 CR: 2PR: 11SD: 24PD: 14 10.1 (8.7-11.5) 18.3 (15.5-21.1)
Oudard(2007) Gemcitabine+platinum Salt 65(18–74) 10/13 23 23/23 CR: 1PR: 5SD: 10PD: 7 7.1(3-11.3) 10.5 (3.8-17.1)
Bylow(2009) Carboplatin +paclitaxel 55(36-67) 15/2 17 17/17 CR: 1PR: 0SD: 8PD: 4 NE: 4 / /
Richey(2013) Pemetrexed +gemcitabine 58.5 (18-77) 12/3 15 14/14 CR: 0PR: 0 3.2(1.9-6+) 23.2(12.9-38.1)
Rizzo(2022) Cisplatin-based chemotherapy 66.6(51-77) 26/10 36 36/36 CR: 0PR: 8SD: 9PD: 19 6(4.95-6.8) 8(7.4-9.8)
Combination therapy Hutson(2021) Lenvatinib pluseverolimus 64(38–85) 20/11 31 31/31 CR: 0PR: 8SD: 18PD: 3NE/unknown: 2 9.2 (5.5–NE) 15.6(9.2–NE)
Feldman(2020) Everolimus plusbevacizumab 54(27-77) 32/7 39 37/39 CR: 0PR: 13SD: 21PD: 3 13.7(10.8-16.4) 33.9(23.3-71.9)
Albiges(2023) Pembrolizumab plus lenvatinib 60(52-69) 112/46 158 158/158 CR: 9PR: 69SD: 52PD: 17NE: 1NA: 10 18(14–NR) NR
Mahoney(2016) Bevacizumab plus temsirolimus / / 13 13/13 PR: 1SD: 10PD: 2 5.6(3.4-13.7) 13.1(5.0-24.6)
McGregor(2019) Atezolizumab plus bevacizumab 61 (22-82) 47/13 60 60/60 CR+PR: 20SD+PD: 40 g 8.3(5.7-10.9) NR
Suarez(2023) Savolitinib plus durvalumab 62(22-77) 34/7 41 41/41 CR: 0PR: 11SD: 4PD: 20NE: 4NA: 2 4.9(2.5-10.0) 14.1(7.3-30.7)
Sheng(2018) Sorafenib in combination with gemcitabine plus cisplatin / 21/5 26 26/26 CR: 0PR: 8SD: 14PD: 4 8.8(6.7-10.9) 12.5(9.6-15.4)
Srinivasan(2023) Bevacizumab plus erlotinib / / 83 83/83 CR+PR: 42 14.2(11.4-18.6) /
Lee(2022) Cabozantinib plus nivolumab 57(33-78) 28/12 40 40/40 PR: 19SD: 20PD: 1 12.5 (6.3-16.4) 28(16.3-NE)
Stellato(2023) Pembrolizumab plus axitinib 68 23/9 32 32/32 CR: 0PR: 14SD: 11PD: 6NE: 1 10.8(7.8–13.7) NR

VEGFR-TKIs, vascular endothelial growth factor receptor tyrosine kinase inhibitors; mTORi, mammalian target of rapamycin inhibitors; ICI, immune checkpoint inhibitors; n, number; CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NA, not available; NE, not estimable; NR, not reached.

The 95% CI for PFS and OS was not provided.

The data is sourced from the safety population (N=92) mentioned in the article.

The literature indicates that the ORR was 33% (n=20)

 ORR and DCR

All studies, except one retrospective trial (32), provided analyzable data for ORR and DCR. Both ORR and DCR exhibited significant heterogeneity, with I² values over 50% and p-values below 0.01 in the Q-test, indicating notable variability among the studies. The ORR ranged from 3.15% to 35.48%, with a pooled ORR of 14% (95% CI: 11–18%) ( Figure 4A ). Subgroup analysis showed a pooled ORR of 14% (95% CI: 9–19%) in prospective studies and 15% (95% CI: 10–20%) in retrospective studies. The DCR varied from 21.74% to 90.21%, with a pooled DCR of 70% (95% CI: 64–76%) ( Figure 5A ). Subgroup analysis revealed a pooled DCR of 69% (95% CI: 61–78%) in prospective studies and 71% (95% CI: 63–80%) in retrospective studies.

ORR for patients with nccRCC receiving VEGFR-TKIs, mTORi, ICIs, chemotherapy, and combination therapy. (A) VEGFR-TKIs, (B) mTORi, (C) ICIs, (D) chemotherapy, (E) combination therapy.

DCR for patients with nccRCC receiving VEGFR-TKIs, mTORi, ICIs, chemotherapy, and combination therapy. (A) VEGFR-TKIs, (B) mTORi, (C) ICIs, (D) chemotherapy, (E) combination therapy.

Sensitivity analysis for both ORR and DCR showed no significant interference from any single study, confirming the reliability of the meta-analysis results.

 Single-arm trials with mTORi Characteristics

Three relevant studies were included in this analysis after screening: RAPTOR (42), NCT00830895 (43), and Lee (44). RAPTOR (42) and NCT00830895 (43) were open-label, single-arm, non-randomized, multicenter studies, while Lee (16) integrated both prospective and retrospective data. A total of 215 patients were involved, with 181 in prospective analyses and 34 in retrospective studies. All 88 patients in RAPTOR (42) had pRCC. In the other two studies, pRCC was also the most common, followed by chRCC. Two studies used everolimus, while the third used temsirolimus. Only RAPTOR (42) included patients who had not received previous systemic therapy. Detailed information on these three single-arm studies is presented in Table 3 and Table 4 .

 ORR and DCR

The three articles provided data on ORR and DCR (42–44). The pooled ORR was 6% (95% CI: 0–16%), with significant heterogeneity (I² = 76.10%, P = 0.02) ( Figure 4B ). The pooled DCR was 70% (95% CI: 58–82%), also with high heterogeneity (I² = 68.31%, P = 0.04) ( Figure 5B ).

 Single-arm trials with ICIs Characteristics

A total of 622 patients participated in six prospective (45–50) and six retrospective studies (32, 51–55). Prior treatment with ICIs was excluded. Only three studies received first-line treatment (46–48). Among the prospective studies, two were Phase IIIb/IV trials (45, 48). Two retrospective studies analyzed various PD-1/PD-L1 inhibitors (53, 54). Nivolumab monotherapy was the most commonly used, appearing in six studies (32, 45, 46, 49, 51, 52). Combination therapy with ipilimumab and nivolumab was examined in two studies (48, 55). Both Vogelzang (45) and Koguchi (32) researched ccRCC and nccRCC but did not detail the nccRCC subtypes. Patients with pRCC were the most prevalent. Detailed information on these studies is presented in Table 3 and Table 4 .

 ORR and DCR

ORR was reported in six prospective (45–50) and five retrospective studies (51–55), while DCR was reported in five prospective (45–48, 50) and five retrospective studies (51–55). Both ORR and DCR showed no significant heterogeneity. The overall pooled ORR was 16% (95% CI: 13–19%) ( Figure 4C ). Subgroup analysis showed a pooled ORR of 18% (95% CI: 14–22%) in the prospective group and 13% (95% CI: 8–18%) in the retrospective group. The overall pooled DCR was 54% (95% CI: 50–58%), with a DCR of 58% (95% CI: 53–63%) in the prospective group and 46% (95% CI: 38–53%) in the retrospective group ( Figure 5C ). Additionally, ORR (RR = 3.044; 95% CI: 1.623-5.709%; P = 0.001) was higher in the PD-L1 positive group compared to the PD-L1 negative group ( Figure 6 ).

The forest plot comparing of ORR between PD-L1 positive group and PD-L1 negative group.

 Single-arm trials with chemotherapy Characteristics

A total of 142 patients participated in four phase II trials (56–59) and one retrospective study (60), all excluding prior chemotherapy. Three patients received first-line treatment (56, 59, 60). Tsimafeyeu (58) focused on capecitabine monotherapy, while the other studies used combination chemotherapy. Oudard (56) and Rizzo (60) exclusively studied patients with CDC, whereas the remaining studies included various types of nccRCC. Detailed information is presented in Table 3 and Table 4 .

 ORR and DCR

Both ORR and DCR showed significant heterogeneity, with an I² > 50% in the Q-test. ORR ranged from 0% to 26.09% across studies, resulting in a pooled ORR of 16% (95% CI: 6–28%) ( Figure 4D ). DCR, which was not reported in Richey (57), ranged from 47.22% to 72.55%, with a pooled DCR of 62% (95% CI: 48–75%) ( Figure 5D ).

 Single-arm trials with combination therapy Characteristics

This analysis included ten studies with a total of 523 patients (61–70). Of these, one study incorporated both prospective and retrospective data (66), while the others were prospective phase II trials (61–65, 67–70). All studies investigated anti-angiogenesis therapies, using either small molecule targeted agents, such as VEGFR-TKIs, or large molecule monoclonal antibodies, such as bevacizumab, often in combination with mTORi, ICIs, or chemotherapy. Notably, Suarez (69) focused exclusively on pRCC, and Sheng (70) examined only CDC. The remaining studies included various subtypes of nccRCC, with pRCC being the most common subtype. Detailed information on these ten single-arm studies is presented in Table 3 and Table 4 .

 ORR and DCR

All studies provided data on ORR (61–70), while only eight included DCR (61–64, 67–70). Statistical analysis indicated high heterogeneity for both ORR (I² = 76.59%, P < 0.01) and DCR (I² = 89.75%, P < 0.01). ORR across studies ranged from 7.69% to 50.6%, with a pooled estimate of 36% (95% CI: 27–44%) ( Figure 4E ). DCR varied from 36.59% to 97.50%, resulting in a pooled DCR of 81% (95% CI: 70–91%) ( Figure 5E ). Subgroup analysis revealed five studies using bevacizumab (62–66), seven utilizing VEGFR-TKIs (61, 63, 66, 68, 70), and five based on ICIs (63, 65, 67–69). All subgroups demonstrated significant heterogeneity for ORR. The pooled ORRs were 31% (95% CI: 17–45%) for bevacizumab, 41% (95% CI: 31–50%) for VEGFR-TKIs, and 40% (95% CI: 31–50%) for ICIs.

 Discussion

The optimal therapeutic strategy for nccRCC remains contentious. The heterogeneity of nccRCC complicates the establishment of robust evidence for specific therapies, as it hinders the conduct of prospective randomized trials. While systemic treatments effective for ccRCC show some activity in nccRCC, their response rates are significantly lower. Therefore, the panel recommends prioritizing clinical trial enrollment for nccRCC patients (1).

Our analysis of six RCTs compared the efficacy of mTORi and VEGFR-TKIs. Unfortunately, we did not achieve positive results in terms of effectiveness and survival. However, subgroup analysis of the four first-line studies showed that PFS was superior with sunitinib compared to mTORi (RR = 1.387; 95% CI: 1.04-1.85; p = 0.026). This advantage was not reflected in ORR and DCR, possibly due to limited data, as only three articles reported on ORR and DCR. Further validation through large-scale studies is needed.

NccRCC is a heterogeneous disease with significant variability among studies in histological subtypes, populations recruited, and risk factors, complicating comparisons across studies. Despite these challenges, current research suggests sunitinib as a potential treatment option for advanced nccRCC. The ESPN study found that sunitinib tended to prolong OS in first-line treatment of nccRCC without sarcomatoid features (15). Among 49 patients without sarcomatoid features, median OS was 31.6 months with sunitinib compared to 10.5 months with everolimus (p = 0.075) (15). The ASPEN trial highlighted the benefit of VEGFR-TKI therapy in patients with good or intermediate risk according to MSKCC criteria compared to everolimus (16). The RECORD-3 study, through prespecified subgroup analysis of MSKCC prognosis, found that median PFS was longer for patients with favorable and intermediate risk treated with first-line sunitinib compared to everolimus (18). However, this study included both ccRCC and nccRCC, and did not separately report results for the nccRCC group based on MSKCC criteria. These findings indicate that future nccRCC studies should focus on differences in efficacy based on MSKCC risk groups.

Sunitinib is a primary treatment option for nccRCC, but the search for a superior tyrosine kinase inhibitor (TKI) continues. Cabozantinib, an oral inhibitor of MET, VEGFR, and AXL, has shown promise. The randomized phase II SWOG 1500 trial (71) compared cabozantinib, crizotinib, and savolitinib with sunitinib in patients with advanced pRCC who had received up to one prior systemic therapy, excluding VEGFR- and MET-targeted TKIs. Only cabozantinib demonstrated significantly longer PFS and a higher ORR than sunitinib. As a dual VEGF-MET inhibitor, cabozantinib’s efficacy suggests that pRCC may involve both VEGF and MET signaling pathways. Although the SWOG 1500 trial focused on pRCC, the Meet-URO 2/NCT03354884 (20) trial treated 23 patients with CDC using cabozantinib, achieving an ORR of 34.78%, surpassing most previously reported targeted therapies. Consequently, NCCN guidelines now recommend cabozantinib as a preferred option alongside clinical trials (1).

Future research should focus on the genetic and molecular characteristics of nccRCC to better identify the target audience for these therapies. Given the limited number of RCTs, our analysis includes relevant single-arm trials to evaluate drug efficacy more comprehensively. Single-arm trials have shown limited efficacy of monotherapy for nccRCC, with mTORi demonstrating the lowest pooled ORR of only 6% (95% CI: 0-16%). In contrast, VEGFR-TKIs, chemotherapy, and ICIs had monotherapy effective rates of 14-16%. Koh (43) found that patients with chRCC treated with everolimus exhibited longer PFS and better ORR compared to other RCC subtypes. Conversely, Lee (44) reported no significant differences in PFS or OS among histological subtypes treated with temsirolimus, although patients with poor prognosis, as defined by ARCC criteria, had significantly shorter PFS and OS.

The pooled ORR for single-drug treatments with chemotherapy, VEGFR TKIs, and ICIs ranged from 14-16%. While the ORR and DCR of chemotherapy were similar to those of VEGFR-TKIs and ICIs, four of the five chemotherapy-related studies were published between 2007 and 2013, making them somewhat outdated. Additionally, the chemotherapy regimens varied: Tsimafeyeu (58) used oral capecitabine as a single agent for nccRCC, Richey (57) conducted a phase II trial with pemetrexed and gemcitabine, and the other three studies employed platinum-based combination chemotherapy (56, 59, 60).

Retrospective and recent prospective clinical trials have evaluated the antitumor activity of ICIs for nccRCC, either as monotherapy or combined with PD-1/PD-L1 inhibitors. Subgroup analysis revealed that PD-L1 positive patients had significantly better ORRs than PD-L1 negative patients, suggesting that PD-L1 expression levels could guide treatment choices for nccRCC patients. However, only three trials provided relevant data, and there was no standardized method for PD-L1 detection (46–48). Larger and more rigorous studies are needed to identify nccRCC patients who would benefit most from ICIs.

Treatment options for nccRCC are expanding, with drug combinations of different mechanisms entering clinical practice. Examples include lenvatinib plus everolimus, everolimus plus bevacizumab, pembrolizumab plus lenvatinib, and cabozantinib plus nivolumab. Our research indicates that combination therapies with different mechanisms show better ORR and DCR compared to single-agent therapies. Subgroup analysis found that combination therapies based on VEGFR-TKIs and ICIs achieved similar ORRs, both outperforming combination therapies based on bevacizumab.

 Conclusions

In conclusion, the systematic review shows that sunitinib provides superior PFS compared to mTORi as a first-line treatment for advanced nccRCC. Due to limited data, single-arm trials were included to improve clinical guidance. The results indicated that PD-L1 positive patients had better ORR than PD-L1 negative patients, suggesting a need for further investigation. Additionally, combination therapies involving different mechanisms, especially those based on VEGFR-TKIs or ICIs, were more effective than single-agent treatments.

 Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

 Author contributions

YZ: Conceptualization, Data curation, Writing – original draft. HF: Supervision, Visualization, Writing – review & editing. JC: Data curation, Writing – review & editing. XW: Data curation, Writing – review & editing. HW: Data curation, Writing – review & editing. XC: Data curation, Writing – review & editing. JH: Formal analysis, Writing – review & editing.

 Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

 Acknowledgments

We thank all the researchers who contributed to this study.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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