PMID- 36713467
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230202
IS  - 2589-5370 (Electronic)
IS  - 2589-5370 (Linking)
VI  - 56
DP  - 2023 Feb
TI  - The likelihood of being helped or harmed as a patient-centred tool to assess 
      cyclin dependent kinase 4/6 inhibitors clinical impact and safety in metastatic 
      breast cancer: a systematic review and sensitivity-analysis.
PG  - 101824
LID - 10.1016/j.eclinm.2023.101824 [doi]
LID - 101824
AB  - BACKGROUND: In hormone-receptor positive/HER2-negative metastatic breast cancer 
      (mBC) no randomized comparisons are available between CDK4/6 inhibitors. We 
      undertook this systematic review and meta-analysis to assess the reliability of 
      the likelihood of being helped or harmed (LHH). METHODS: PubMed, CENTRAL, Embase 
      and oncological meetings websites were searched to September 13th, 2022. We 
      included phase III randomized controlled trials (RCTs) investigating palbociclib, 
      ribociclib and abemaciclib in addition to endocrine therapy (ET) compared to 
      placebo in hormone-receptor positive/HER2-negative advanced or mBC. Outcomes were 
      progression-free survival (PFS), overall survival (OS), adverse events (AEs), 
      dose reductions and discontinuations. Hazard ratios (HRs) and risk differences 
      were computed with a random effect model to estimate the number needed to 
      treat/harm (NNT/NNH). LHH was computed as (1/NNT)/(1/NNH). PROSPERO registration 
      number: CRD42022362417. FINDINGS: 2204 records were screened and seven RCTs (4415 
      patients) were included. A significant PFS benefit was observed in patients 
      treated with a CDK4/6 inhibitor compared to placebo (HR 0.549; 0.508-0.594, I (2) 
       = 0). Palbociclib, ribociclib and abemaciclib had similar NNTs (4.4, 5.0 and 
      4.4). Palbociclib and ribociclib showed lower LHHs for grade 3-4 neutropenia 
      (0.33 and 0.35) and febrile neutropenia ([FN], 14.27 and 15.52), while 
      abemaciclib the lowest LHH for any grade diarrhea (0.42). Abemaciclib had a lower 
      LHH for grade 3-4 fatigue (9.92) and the highest LHH for all grade 3-4 AEs 
      (0.62), while ribociclib the lowest LHH (1.75) for grade 3-4 hepatotoxicity. 
      Palbociclib had the highest LHH for dose reductions and discontinuations (0.65 
      and 6.17). Considering OS, an overall benefit was observed (HR 0.788, 
      0.727-0.856, I (2)  = 0%); ribociclib and abemaciclib had lower NNTs (9.7 and 
      10.0). Ribociclib showed the highest LHH for diarrhea (1.29), fatigue (7.37), 
      dose reductions (0.28) and discontinuations (2.40), while abemaciclib the highest 
      LHHs for neutropenia (0.40), FN (12.53) and hepatotoxicity (2.23). 
      INTERPRETATION: Palbociclib and ribociclib showed lower LHHs for haematological 
      toxicities and abemaciclib for diarrhea. Palbociclib confirmed to be a manageable 
      drug. The LHH appears to be a reliable synthesis tool for balancing risks and 
      benefits of experimental drugs when head-to-head comparisons are missing. 
      FUNDING: None.
CI  - (c) 2023 The Authors.
FAU - Mastrantoni, Luca
AU  - Mastrantoni L
AD  - Medical Oncology, Universita Cattolica del Sacro Cuore, Rome, Italy.
FAU - Orlandi, Armando
AU  - Orlandi A
AD  - Medical Oncology, Universita Cattolica del Sacro Cuore, Rome, Italy.
AD  - Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino 
      Gemelli IRCCS, Rome, Italy.
FAU - Palazzo, Antonella
AU  - Palazzo A
AD  - Medical Oncology, Universita Cattolica del Sacro Cuore, Rome, Italy.
AD  - Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino 
      Gemelli IRCCS, Rome, Italy.
FAU - Garufi, Giovanna
AU  - Garufi G
AD  - Medical Oncology, Universita Cattolica del Sacro Cuore, Rome, Italy.
AD  - Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino 
      Gemelli IRCCS, Rome, Italy.
FAU - Fabi, Alessandra
AU  - Fabi A
AD  - Precision Medicine Breast Unit, Scientific Directorate, Department of Women, 
      Children and Public Health Sciences, Fondazione Policlinico Universitario 
      Agostino Gemelli IRCCS, Rome, Italy.
FAU - Daniele, Gennaro
AU  - Daniele G
AD  - UOC Phase I, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 
      Italy.
FAU - Giannarelli, Diana
AU  - Giannarelli D
AD  - Biostatistic, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 
      Italy.
FAU - Tortora, Giampaolo
AU  - Tortora G
AD  - Medical Oncology, Universita Cattolica del Sacro Cuore, Rome, Italy.
AD  - Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino 
      Gemelli IRCCS, Rome, Italy.
FAU - Bria, Emilio
AU  - Bria E
AD  - Medical Oncology, Universita Cattolica del Sacro Cuore, Rome, Italy.
AD  - Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino 
      Gemelli IRCCS, Rome, Italy.
LA  - eng
PT  - Journal Article
DEP - 20230120
PL  - England
TA  - EClinicalMedicine
JT  - EClinicalMedicine
JID - 101733727
PMC - PMC9874016
OTO - NOTNLM
OT  - CDK4/6 inhibitors
OT  - LHH
OT  - Metastatic breast cancer
OT  - NNH
OT  - NNT
COIS- L.M., G.G., G.D. declare no conflict of interest. A.O. has declared consulting 
      fees/advisory role for 10.13039/100004336Novartis, 10.13039/100004337Roche, 
      Eli-Lilly, 10.13039/100002429Amgen, Daiichi Sankyo, travel and accommodation by 
      Daiichi Sankyo, 10.13039/100004336Novartis, 10.13039/100004337Roche, 
      10.13039/100004319Pfizer. A.P. has declared consulting fees/advisory role for 
      10.13039/100002429Amgen, MSD, 10.13039/100004336Novartis, travel and 
      accommodation by 10.13039/100004319Pfizer. D.G. received educational courses fee 
      from MSD and 10.13039/100002429Amgen. A.F. has declared consulting fees/advisory 
      role for Astra Zeneca, Daiichi Sankyo, 10.13039/501100003769Eisai, Eli-Lilly. 
      Epionpharma, exact science, MSD, 10.13039/100004336Novartis, Pierre Fabre, 
      10.13039/100004337Roche, Seagen. G.T. is supported by funds of 
      10.13039/501100003196Ministero della Salute (Ricerca Corrente 2022). E.B. is 
      currently supported by the 10.13039/501100005010Associazione Italiana per la 
      Ricerca sul Cancro (AIRC) under Investigator Grant (IG) No. IG20583. E.B. is 
      supported by Institutional funds of Universita Cattolica del Sacro Cuore 
      (UCSC-project D1). E.B. is supported by funds of 10.13039/501100003196Ministero 
      della Salute (Ricerca Corrente 2022). E.B. received speakers' and travels' fee 
      from MSD, Astra-Zeneca, 10.13039/100004319Pfizer, Eli-Lilly, BMS, 
      10.13039/100004336Novartis and 10.13039/100004337Roche. E.B. received 
      institutional research grants from Astra-Zeneca, 10.13039/100004337Roche.
EDAT- 2023/01/31 06:00
MHDA- 2023/01/31 06:01
PMCR- 2023/01/20
CRDT- 2023/01/30 04:15
PHST- 2022/12/08 00:00 [received]
PHST- 2022/12/29 00:00 [revised]
PHST- 2022/12/30 00:00 [accepted]
PHST- 2023/01/30 04:15 [entrez]
PHST- 2023/01/31 06:00 [pubmed]
PHST- 2023/01/31 06:01 [medline]
PHST- 2023/01/20 00:00 [pmc-release]
AID - S2589-5370(23)00001-9 [pii]
AID - 101824 [pii]
AID - 10.1016/j.eclinm.2023.101824 [doi]
PST - epublish
SO  - EClinicalMedicine. 2023 Jan 20;56:101824. doi: 10.1016/j.eclinm.2023.101824. 
      eCollection 2023 Feb.