Abstract
Background: The new severe acute respiratory syndrome coronavirus 2 has emerged as a global pandemic that threatens thousands around the world. Observational cohort studies have demonstrated that cancer patients have inferior outcomes due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. We aimed to examine the representation of cancer patients (hematological malignancies and solid tumors) in COVID-19 therapeutic and prophylactic interventional trials. Methods: In this review, all randomized controlled trials (RCTs) published between December 2019 and August 2021 were included. We included only trials evaluating medications that were recommended by NIH guidelines: steroids, tocilizumab, remdesivir, and REGN-COV2. Results: The search yielded 541 potentially relevant RCTs, 22 of which were considered suitable. All trials included patients with solid cancer and hematological malignancies in the formal reported inclusion criteria. However, only two trials reported the accurate number of cancer patients included. Ten trials excluded neutropenic patients and seven trials excluded thrombocytopenic patients. Eleven trials excluded patients that were treated with any immunosuppression treatment. None of the two trials that included cancer patients reported separate outcomes for this population. Conclusion: Our systematic review shows that cancer patients are underrepresented in COVID-19 interventional therapeutic trials, and evidence regarding outcomes are lacking.
References
1.
Wu
Z
, McGoogan
JM
. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention
. JAMA
. 2020 07
;323
(13
):1239
–42
. .2.
Yang
J
, Zheng
Y
, Gou
X
, Pu
K
, Chen
Z
, Guo
Q
, Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis
. Int J Infect Dis
. 2020
;94
:91
–5
. .3.
Guan
WJ
, Liang
WH
, Zhao
Y
, Liang
HR
, Chen
ZS
, Li
YM
, Comorbidity and its impact on 1590 patients with Covid-19 in China: a nationwide analysis
. Eur Respir J
. 2020
;55
(5
):2000547
. .4.
Dai
M
, Liu
D
, Liu
M
, Zhou
F
, Li
G
, Chen
Z
, Patients with cancer appear more vulnerable to SARS-CoV-2: a Multicenter Study during the COVID-19 outbreak
. Cancer Discov
. 2020
;10
:783
–91
. .5.
Kuderer
NM
, Choueiri
TK
, Shah
DP
, Shyr
Y
, Rubinstein
SM
, Rivera
DR
, Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study
. Lancet
. 2020
;395
:1907
–18
.6.
Fu
C
, Stoeckle
JH
, Masri
L
, Pandey
A
, Cao
M
, Littman
D
, COVID 19 outcomes in hospitalized patients with active cancer: experiences from a major New York City health care system
. Cancer
. 2021
;127
(18
):3466
–75
. .7.
Mohseni Afshar
Z
, Hosseinzadeh
R
, Barary
M
, Ebrahimpour
S
, Alijanpour
A
, Sayad
B
, Challenges posed by COVID-19 in cancer patients: a narrative review
. Cancer Med
. 2022 Feb
;11
(4
):1119
–35
.8.
Moher
D
, Liberati
A
, Tetzlaff
J
, Altman
DG
; PRISMA Group
. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
. BMJ
. 2009 Jul 21
;339
(7
):b2535
. .9.
National Institutes of Health
. Coronavirus disease 2019 (COVID-19) treatment guidelines
. 2021
. Available from: https://covid19treatmentguidelines.nih.gov/ (accessed on May 27, 2021).10.
Higgins
JPT
, Green
S
, editors. Cochrane handbook for systematic reviews of interventions: version 5.1.0
. The Cochrane Collaboration
. 2011
. Available from: http://www.cochranehandbook.org.11.
Tomazini
BM
, Maia
IS
, Cavalcanti
AB
, Berwanger
O
, Rosa
RG
, Veiga
VC
, Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial
. JAMA
. 2020 Oct 6
;324
(13
):1307
–16
.12.
Angus
DC
, Derde
L
, Al-Beidh
F
, Annane
D
, Arabi
Y
, Beane
A
, Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial
. JAMA
. 2020 Oct 6
;324
(13
):1317
–29
.13.
Jeronimo
CMP
, Farias
MEL
, Val
FFA
, Sampaio
VS
, Alexandre
MAA
, Melo
GC
, Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease 2019 (COVID-19; metcovid): a randomized, double-blind, phase IIb, placebo-controlled trial
. Clin Infect Dis
. 2021 May 4
;72
(9
):e373
–81
. .14.
Dequin
PF
, Heming
N
, Meziani
F
, Plantefève
G
, Voiriot
G
, Badié
J
, Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial
. JAMA
. 2020 Oct 6
;324
(13
):1298
–306
.15.
Tang
X
, Feng
YM
, Ni
JX
, Zhang
JY
, Liu
LM
, Hu
K
, Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-intensive care unit patients with COVID-19 pneumonia: a multicenter, single-blind, randomized control trial
. Respiration
. 2021
;100
(2
):116
–26
. .16.
Jamaati
H
, Hashemian
SM
, Farzanegan
B
, Malekmohammad
M
, Tabarsi
P
, Marjani
M
, No clinical benefit of high dose corticosteroid administration in patients with COVID-19: a preliminary report of a randomized clinical trial
. Eur J Pharmacol
. 2021 Apr 15
;897
:173947
. .17.
Corral-Gudino
L
, Bahamonde
A
, Arnaiz-Revillas
F
, Gómez-Barquero
J
, Abadía-Otero
J
, García-Ibarbia
C
, Methylprednisolone in adults hospitalized with COVID-19 pneumonia: an open-label randomized trial (GLUCOCOVID)
. Wien Klin Wochenschr
. 2021 Apr
;133
(7–8
):303
–11
. .18.
Edalatifard
M
, Akhtari
M
, Salehi
M
, Naderi
Z
, Jamshidi
A
, Mostafaei
S
, Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial
. Eur Respir J
. 2020 Dec 24
;56
(6
):2002808
. .19.
RECOVERY Collaborative Group
; Horby
P
, Lim
WS
, Emberson
JR
, Mafham
M
, Bell
JL
, Dexamethasone in hospitalized patients with covid-19
. N Engl J Med
. 2021 Feb 25
;384
(8
):693
–704
. .20.
Weinreich
DM
, Sivapalasingam
S
, Norton
T
, Ali
S
, Gao
H
, Bhore
R
, REGN-COV2, a neutralizing antibody cocktail, in outpatients with covid-19
. N Engl J Med
. 2021 Jan 21
;384
(3
):238
–51
. .21.
Wang
Y
, Zhang
D
, Du
G
, Du
R
, Zhao
J
, Jin
Y
, Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial
. Lancet
. 2020 May 16
;395395
(10236
):1569
–78
. .22.
Beigel
JH
, Tomashek
KM
, Dodd
LE
, Mehta
AK
, Zingman
BS
, Kalil
AC
, Remdesivir for the treatment of covid-19: final report
. N Engl J Med
. 2020 Nov 5
;383
(19
):1813
–26
. .23.
Spinner
CD
, Gottlieb
RL
, Criner
GJ
, Arribas López
JR
, Cattelan
AM
, Soriano Viladomiu
A
, Effect of remdesivir versus standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial
. JAMA
. 2020 Sep 15
;324
(11
):1048
–57
. .24.
Stone
JH
, Frigault
MJ
, Serling-Boyd
NJ
, Fernandes
AD
, Harvey
L
, Foulkes
AS
, Efficacy of tocilizumab in patients hospitalized with covid-19
. N Engl J Med
. 2020 Dec 10
;383
(24
):2333
–44
. .25.
Salama
C
, Han
J
, Yau
L
, Reiss
WG
, Kramer
B
, Neidhart
JD
, Tocilizumab in patients hospitalized with covid-19 pneumonia
. N Engl J Med
. 2021 Jan 7
;384
(1
):20
–30
. .26.
Hermine
O
, Mariette
X
, Tharaux
PL
, Resche-Rigon
M
, Porcher
R
, Ravaud
P
, Effect of tocilizumab versus usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial
. JAMA Intern Med
. 2021 Jan 1
;181
(1
):32
–40
. .27.
Salvarani
C
, Dolci
G
, Massari
M
, Merlo
DF
, Cavuto
S
, Savoldi
L
, Effect of tocilizumab versus standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial
. JAMA Intern Med
. 2021 Jan 1
;181
(1
):24
–31
. .28.
Veiga
VC
, Prats
JAGG
, Farias
DLC
, Rosa
RG
, Dourado
LK
, Zampieri
FG
, Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial
. BMJ
. 2021 Jan 20
;372
:n84
. .29.
Rosas
IO
, Bräu
N
, Waters
M
, Go
RC
, Hunter
BD
, Bhagani
S
, Tocilizumab in hospitalized patients with severe covid-19 pneumonia
. N Engl J Med
. 2021 Apr 22
;384
(16
):1503
–16
. .30.
Wang
D
, Fu
B
, Peng
Z
, Yang
D
, Han
M
, Li
M
, Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial
. Front Med
. 2021 Jun
;15
(3
):486
–94
. .31.
Soin
AS
, Kumar
K
, Choudhary
NS
, Sharma
P
, Mehta
Y
, Kataria
S
, Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial
. Lancet Respir Med
. 2021 May
;9
(5
):511
–21
. .32.
Kumar
S
, De Souza
R
, Nadkar
M
, Guleria
R
, Trikha
A
, Joshi
SR
, A two-arm, randomized, controlled, multi-centric, open-label phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19
. Expert Opin Biol Ther
. 2021 May
;21
(5
):675
–86
. .33.
Rochwerg
B
, Agarwal
A
, Siemieniuk
RA
, Agoritsas
T
, Lamontagne
F
, Askie
L
. A living WHO guideline on drugs for covid-19
. BMJ
. 2020
;370
:m3379
.34.
Wen
W
, Chen
C
, Tang
J
, Wang
C
, Zhou
M
, Cheng
Y
, Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: a meta-analysis
. Ann Med
. 2022 Dec
;54
(1
):516
–23
.35.
Mehta
V
, Goel
S
, Kabarriti
R
, Cole
D
, Goldfinger
M
, Acuna-Villaorduna
A
, Case fatality rate of cancer patients with COVID-19 in a New York Hospital system
. Cancer Discov
. 2020
;10
(7
):935
–41
.36.
Pufall
MA
. Glucocorticoids and cancer
. Adv Exp Med Biol
. 2015
;872
:315
–33
. .37.
Kotch
C
, Barrett
D
, Teachey
DT
. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome
. Expert Rev Clin Immunol
. 2019 Aug
;15
(8
):813
–22
. .38.
Schiff
MH
, Kremer
JM
, Jahreis
A
, Vernon
E
, Isaacs
JD
, van Vollenhoven
RF
. Integrated safety in tocilizumab clinical trials
. Arthritis Res Ther
. 2011
;13
(5
):R141
. .39.
Wu
JT
, La
J
, Branch-Elliman
W
, Huhmann
LB
, Han
SS
, Parmigiani
G
, Association of COVID-19 vaccination with SARS-CoV-2 infection in patients with cancer: a US Nationwide Veterans Affairs Study
. JAMA Oncol
. 2022 Feb 1
;8
(2
):281
–6
.40.
Gurion
R
, Rozovski
U
, Itchaki
G
, Gafter-Gvili
A
, Leibovitch
C
, Raanani
P
. Humoral serologic response to the BNT162b2 vaccine is abrogated in lymphoma patients within the first 12 months following treatment with anti-CD2O antibodies
. Haematologica
. 2022 Mar 1
;107
(3
):715
–20
.41.
Herishanu
Y
, Avivi
I
, Aharon
A
, Shefer
G
, Levi
S
, Bronstein
Y
, Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia
. Blood
. 2021
;137
(23
):3165
–73
.42.
Benjamini
O
, Rokach
L
, Itchaki
G
, Braester
A
, Shvidel
L
, Goldschmidtet
N
, Safety and efficeffacy of BNT162b mRNA Covid19 Vaccine in patients with chronic lymphocytic leukemia
. Haematologica
. 2022 Mar 1
;107
(3
):625
–34
.43.
Fendler
A
, Shepherd
STC
, Au
L
, Wilkinson
KA
, Wu
M
, Byrne
F
, Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study
. Nat Cancer
. 2021 Dec
;2
:1321
–37
.© 2022 S. Karger AG, Basel
2022
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