PMID- 37745049
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230926
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 14
DP  - 2023
TI  - Comparative safety of tyrosine kinase inhibitors in the treatment of metastatic 
      renal cell carcinoma: a systematic review and network meta-analysis.
PG  - 1223929
LID - 10.3389/fphar.2023.1223929 [doi]
LID - 1223929
AB  - Objective: This study aimed to compare the safety profile of tyrosine kinase 
      inhibitors (TKIs) approved for use as monotherapy or combination therapy for the 
      first-line treatment of adult patients with metastatic clear cell renal cell 
      carcinoma (RCC). Methods: A systematic review with frequentist network 
      meta-analysis (NMA) was performed according to the Preferred Reporting Items for 
      Systematic Reviews and Meta-Analyses guidelines. We included randomized 
      controlled trials (RCTs) investigating the use of: cabozantinib, pazopanib, 
      sorafenib, sunitinib, tivozanib, cabozantinib + nivolumab, lenvatinib + 
      pembrolizumab, axitinib + avelumab, and axitinib + pembrolizumab in previously 
      untreated adult patients with metastatic clear cell RCC. Eligible studies were 
      identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane 
      Library. The risk of bias for RCTs was assessed using the Cochrane Collaboration 
      tool. The P score was used to determine the treatment ranking. The mean 
      probability of an event along with the relative measures of the NMA was 
      considered with the treatment rankings. Results: A total of 13 RCTs were included 
      in the systematic review and NMA. Sorafenib and tivozanib used as monotherapy 
      were the best treatment options. Sorafenib achieved the highest P score for 
      treatment discontinuation due to adverse events (AEs), fatigue, nausea, vomiting 
      of any grade, and hypertension of any grade or grade >/=3. Tivozanib achieved the 
      highest P score for AEs, grade >/=3 AEs, dose modifications due to AEs, and grade 
      >/=3 diarrhea. Sunitinib was the best treatment option in terms of diarrhea and 
      dysphonia of any grade, while cabozantinib, pazopanib, and axitinib + 
      pembrolizumab-in terms of grade >/=3 fatigue, nausea, and vomiting. TKIs used in 
      combination were shown to have a poorer safety profile than those used as 
      monotherapy. Lenvatinib + pembrolizumab was considered the worst option in terms 
      of any AEs, grade >/=3 AEs, treatment discontinuation due to AEs, dose 
      modifications due to AEs, fatigue of any grade, nausea, vomiting, and grade >/=3 
      nausea. Axitinib + avelumab was the worst treatment option in terms of dysphonia, 
      grade >/=3 diarrhea, and hypertension, while cabozantinib + nivolumab was the worst 
      option in terms of grade >/=3 vomiting. Interestingly, among the other safety 
      endpoints, cabozantinib monotherapy had the lowest P score for diarrhea and 
      hypertension of any grade. Conclusion: The general safety profile, including 
      common AEs, is better when TKIs are used as monotherapy vs. in combination with 
      immunological agents. To confirm these findings, further research is needed, 
      including large RCTs.
CI  - Copyright (c) 2023 Krawczyk, Sladowska, Holko and Kawalec.
FAU - Krawczyk, Kinga
AU  - Krawczyk K
AD  - Faculty of Health Sciences, Institute of Public Health, Jagiellonian University 
      Medical College, Krakow, Poland.
FAU - Sladowska, Katarzyna
AU  - Sladowska K
AD  - Department of Nutrition and Drug Research, Faculty of Health Sciences, Institute 
      of Public Health, Jagiellonian University Medical College, Krakow, Poland.
FAU - Holko, Przemyslaw
AU  - Holko P
AD  - Department of Nutrition and Drug Research, Faculty of Health Sciences, Institute 
      of Public Health, Jagiellonian University Medical College, Krakow, Poland.
FAU - Kawalec, Pawel
AU  - Kawalec P
AD  - Department of Nutrition and Drug Research, Faculty of Health Sciences, Institute 
      of Public Health, Jagiellonian University Medical College, Krakow, Poland.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20230907
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC10512702
OTO - NOTNLM
OT  - meta-analysis
OT  - renal cell carcinoma
OT  - safety
OT  - systematic review
OT  - tyrosine kinase inhibitors
COIS- 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.
EDAT- 2023/09/25 06:42
MHDA- 2023/09/25 06:43
PMCR- 2023/09/07
CRDT- 2023/09/25 04:53
PHST- 2023/05/16 00:00 [received]
PHST- 2023/08/11 00:00 [accepted]
PHST- 2023/09/25 06:43 [medline]
PHST- 2023/09/25 06:42 [pubmed]
PHST- 2023/09/25 04:53 [entrez]
PHST- 2023/09/07 00:00 [pmc-release]
AID - 1223929 [pii]
AID - 10.3389/fphar.2023.1223929 [doi]
PST - epublish
SO  - Front Pharmacol. 2023 Sep 7;14:1223929. doi: 10.3389/fphar.2023.1223929. 
      eCollection 2023.