Background: Older cancer patients with locally advanced or metastatic disease may benefit from chemotherapy alone or combined with radiotherapy. However, chemotherapy is often omitted either because of physician bias or because of its underlying comorbidity, thus compromising their survival. The coronavirus disease 19 (COVID-19) pandemic is compounding this issue because of the fear of immunosuppression induced by chemotherapy on the elderly which makes them more vulnerable to the virus. Summary: Immunotherapy has less effect on the patient bone marrow compared to chemotherapy. The potential synergy between radiotherapy and immunotherapy may improve local control and survival for older patients with selected cancer. Preliminary data are encouraging because of better survival and local control in diseases which are traditionally resistant to radiotherapy and chemotherapy such as melanoma and renal cell carcinoma. Key Message: We propose a new paradigm combining immunotherapy at a reduced dose and/or extended dosing intervals and hypofractionated radiotherapy for older patients with selected cancer which needs to be tested in future clinical trials.

1.
Handforth
C
,
Clegg
A
,
Young
C
,
Simpkins
S
,
Seymour
MT
,
Selby
PJ
, et al.
The prevalence and outcomes of frailty in older cancer patients: a systemic review
.
Ann Oncol
.
2015
;
26
(
6
):
1091
101
.
2.
Nguyen
NP
,
Karlsson
U
,
Oboite
E
,
Alvarenga
J
,
Godinez
J
,
Zamagni
A
, et al.
Older breast cancer undertreatment: unconscious bias to undertreat-potential role for the international geriatric radiotherapy group
.
Transl Cancer Res
.
2020
;
9
(
S1
):
S228
35
.
3.
Shahrokni
A
,
Wu
AJ
,
Carter
J
,
Lichtman
SM
.
Long-term toxicity of cancer treatment in older patients
.
Clin Geriatr Med
.
2016
;
32
(
1
):
63
80
. .
4.
Zhou
F
,
Yu
T
,
Du
R
,
Fan
G
,
Liu
Y
,
Liu
Z
, et al.
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study
.
Lancet
.
2020
;
395
(
10229
):
1054
62
. .
5.
Liu
K
,
Chen
Y
,
Lin
R
,
Han
K
.
Clinical feature of COVID-19 in elderly patients: a comparison with young and middle-age patients
.
J Infect
.
2020 Jun
;
80
(
6
):
e14
8
.
6.
Grasselli
G
,
Zangrillo
A
,
Zanella
A
,
Antonelli
M
,
Cabrini
L
,
Castelli
A
, et al.
Baseline and characteristics and outcome of 1,591 patients infected with SARS-COVI-2 admitted to ICUs of the Lombardo Región, Italy
.
JAMA
.
2020 Apr 28
;
323
(
16
):
1574
81
.
7.
Chavez-Mac Gregor
M
,
Clarke
CA
,
Lichzensztajn
DY
,
Giordano
SH
.
Delayed initiation of adjuvant chemotherapy among breast cáncer patients
.
JAMA Oncol
.
2016
;
2
(
3
):
322
9
.
8.
McArthur
K
,
D’Cruz
AA
,
Segal
D
,
Lackovic
K
,
Wilks
AF
,
O’Donnell
JA
, et al.
Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia
.
Oncotarget
.
2017
;
8
(
35
):
57948
63
. .
9.
Reynders
K
,
Illidge
T
,
Siva
S
,
Chang
JY
,
De Ruysscher
D
.
The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant
.
Cancer Treat Rev
.
2015
;
41
(
6
):
503
10
. .
10.
Britschgi
C
,
Riesterer
O
,
Burger
IA
,
Guckenberger
M
,
Curioni-Fontecedro
A
.
Report of an abscopal effect induced by stereotactic body radiotherapy and nivolumab in a patient with metastatic non-small cell lung cancer
.
Radiat Oncol
.
2018
;
13
(
1
):
102
. .
11.
Xu
MJ
,
Wu
S
,
Daud
AI
,
Yu
SS
,
Yom
SS
.
In field and abscopal response after short course radiotherapy in patients with metastatic Merkel cell cáncer progressing on PD-1 check point blockade: a case series
.
J Immunother Cancer
.
2018
;
6
(
1
):
43
.
12.
Finazzi
T
,
Rordorf
T
,
Ikenberg
K
,
Huber
GF
,
Guckenberger
M
,
Garcia Schueler
HI
.
Radiotherapy-induced anti-tumor immune response and immune-related adverse events in a case of recurrent nasopharyngeal carcinoma undergoing anti-PD-1 immunotherapy
.
BMC Cancer
.
2018
;
18
(
1
):
395
. .
13.
Popescu
T
,
Karlsson
U
,
Vinh-Hung
V
,
Trigo
L
,
Thariat
J
,
Vuong
T
, et al.
Challenges facing radiation oncologists in the management of older cancer patients: consensus of the International Geriatric Radiotherapy Group
.
Cancers
.
2019
;
11
(
3
):
371
.
14.
Copes
N
,
Edwards
C
,
Chaput
D
,
Saifee
M
,
Barjuca
I
,
Nelson
D
, et al.
Metabolome and proteome change with aging in Caenorhabditis elegans
.
Exp Gerontol
.
2015
;
72
:
67
84
.
15.
Connor
KM
,
Hsu
Y
,
Aggarwal
PK
,
Capone
S
,
Colombo
AR
,
Ramsingh
G
.
Understanding metabolic changes in aging bone marrow
.
Exp Hematol Oncol
.
2018
;
7
(
1
):
13
. .
16.
Kovtonyuk
LV
,
Fritsch
K
,
Feng
X
,
Manz
MG
,
Takizawa
H
.
Inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment
.
Front Immunol
.
2016
;
7
:
502
13
. .
17.
Chambers
SM
,
Shaw
CA
,
Gatza
C
,
Fisk
CJ
,
Donehower
LA
,
Goodell
MA
.
Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation
.
PLoS Biol
.
2007
;
5
(
8
):
e201
. .
18.
Ferrucci
L
,
Corsi
A
,
Lauretani
F
,
Bandinelli
S
,
Bartali
B
,
Taub
DD
, et al.
The origins of age-related proinflammatory state
.
Blood
.
2005
;
105
(
6
):
2294
9
. .
19.
Guralnik
JM
,
Eisenstaedt
RS
,
Ferrucci
L
,
Klein
HV
,
Woodman
RC
.
Prevalence of anemia in adults 65 years and older in the United States: evidence for a high rate of unexplained anemia
.
Blood
.
2004
;
104
(
8
):
2263
8
.
20.
Penninx
BW
,
Pahor
M
,
Woodman
RC
,
Guralnik
JM
.
Anemia in old age is associated with increased mortality and hospitalization
.
J Gerontol A Biol Sci Med Sci
.
2006
;
61
(
5
):
474
9
. .
21.
Penninx
BW
,
Pahor
M
,
Cesari
M
,
Corsi
AM
,
Woodman
RC
,
Bandinelli
S
, et al.
Anemia is associated with disability and decreased physical performance and muscle strength in the elderly
.
J Am Geriatr Soc
.
2004
;
52
(
5
):
719
24
. .
22.
Zakai
NA
,
Katz
R
,
Hirsch
C
,
Shlipak
MG
,
Chaves
PHM
,
Newman
AB
, et al.
A prospective study of anemia status, hemoglobin concentration, and mortality in the elderly cohort: the Cardiovascular Health Study
.
Arch Int Med
.
2005
;
165
(
19
):
2214
20
.
23.
Gardner
RV
,
Lerner
C
,
Astle
CM
,
Harrison
DE
.
Assessing permanent damage to primitive hematopoietic stem cells after chemotherapy using the competitive repopulation assay
.
Cancer Chemother Pharmacol
.
1993
;
32
(
6
):
450
4
. .
24.
Gardner
RV
,
Astle
CM
,
Harrison
DE
.
Hematopoietic precursor cell exhaustion is a cause of proliferative defect in primitive hematopoetic stem cells (PFSC) after chemotherapy
.
Exp Hematol
.
1997
;
25
(
6
):
495
501
.
25.
Nurgalieva
Z
,
Liu
CC
,
Du
XL
.
Chemotherapy use and risk of bone marrow suppression in a large population-based cohort of older women with breast and ovarian cancer
.
Med Oncol
.
2010
;
28
(
3
):
716
25
. .
26.
Muss
HB
,
Berry
DA
,
Cirrincione
C
,
Budman
DR
,
Henderson
IC
,
Citron
M
, et al.
Toxicity of older and younger patients treated with adjuvant chemotherapy for node positive breast cancer: the cancer and leukemia group B experience
.
J Clin Oncol
.
2007
;
25
(
24
):
3699
704
.
27.
Hamaker
ME
,
Seynaeve
C
,
Wymenga
AN
,
van Tinteren
H
,
Nortier
JW
,
Maartense
E
, et al.
Baseline comprehensive geriatric assessment is associated with toxicity and survival in elderly metastatic breast cancer patients receiving single-agent chemotherapy: results from the OMEGA study of the Dutch breast cancer trialists’ group
.
Breast
.
2014
;
23
(
1
):
81
7
. .
28.
Xianglin
L
,
Osborne
C
,
Goodwin
JS
.
Population-based assessment of hospitalization for toxicity from chemotherapy for older women with breast cancer
.
J Clin Oncol
.
2002
;
20
(
24
):
4636
42
.
29.
Quoix
E
,
Zalcman
G
,
Westeel
V
,
Pichon
E
,
Dauba
LA
,
Debieuvre
D
, et al.
Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small cell lung cancer: IFCT-0501 randomised, phase III trial
.
Lancet
.
2011
;
378
(
9796
):
1079
88
.
30.
Austin
D
,
Russell
EM
.
Is there ageism in oncology?
Scott Med J
.
2003
;
48
(
1
):
17
20
. ..
31.
Des Guetz
G
,
Nicolas
P
,
Perret
J
,
Morere
J
,
Uzzan
B
.
Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis
.
Eur J Cancer
.
2010
;
46
(
6
):
1049
55
.
32.
Petrelli
F
,
Ardito
R
,
Borgovono
K
,
Lonati
V
,
Cabiddu
M
,
Ghilardi
M
, et al.
Haematological toxicities with immunotherapy in patients with cancer: a systemic review and meta-analysis
.
Eur J Cancer
.
2018
;
103
:
7
16
.
33.
Lokhorst
HM
,
Plesner
T
,
Laubach
JP
,
Nahi
H
,
Gimsing
P
,
Hansson
M
, et al.
Targeting CD38 with daratumumab monotherapy in multiple myeloma
.
N Engl J Med
.
2015
;
373
(
13
):
1207
19
. .
34.
Zavala
VA
,
Kalergis
AM
.
New clinical advances in immunotherapy for the treatment of solid tumours
.
Immunology
.
2015
;
145
(
2
):
182
201
. .
35.
Yilmaz
MT
,
Emali
A
,
Yazici
G
.
Abscopal effect, from myth to reality: from radiation oncologists’ perspective
.
Cureus
.
2019
;
11
:
e3860
.
36.
Wang
SL
,
Fang
H
,
Song
Y
,
Wang
W
,
Hu
C
,
Liu
W
, et al.
Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high risk breast cancer: a randomized, non-inferiority, open label, phase 3 trials
.
Lancet Oncol
.
2019
;
20
(
19
):
352
60
. .
37.
Hoffman
KE
,
Voong
KR
,
Levy
LB
,
Allen
PK
,
Choi
S
,
Schlemback
PJ
, et al.
Randomized trial of hypofractionated, dose-escalated, intensity-modulated radiotherapy (IMRT) versus conventional fractionated IMRT for localized prostate cancer
.
J Clin Oncol
.
2018
;
36
(
29
):
2943
9
.
38.
Narayan
V
,
Kahlmeyer
NV
,
Dahm
P
,
Skoetz
N
,
Risk
MC
,
Bongiorno
C
, et al.
Pembrolizumab monotherapy versus chemotherapy for treatment of advanced urothelial carcinoma with disease progression during or following platinum-containing immunotherapy
.
Cochrane Database Syst Rev
.
2018
;
7
:
CD012838
.
39.
Khan
M
,
Lin
J
,
Liao
G
,
Tian
Y
,
Liang
Y
,
Li
R
, et al.
Comparative analysis of immune check point inhibitors and chemotherapy in the treatment of advanced non-small cell lung cancer. A metanalysis of randomized controlled trials
.
Medicine
.
2018
;
97
(
33
):
33
.
40.
Hao
C
,
Tian
J
,
Liu
H
,
Li
F
,
Niu
H
,
Zhu
B
.
Efficacy and safety of anti-PD-1 and anti-PD-1 combined with anti-CTLA-4 immunotherapy to advanced melanoma: a systematic review and meta-analysis of randomized controlled trials
.
Medicine
.
2017
;
96
(
26
):
e7325
. .
41.
Ferris
RL
,
Blumenschein
G
,
Fayette
J
,
Guigay
J
,
Colevas
AD
,
Licitra
L
, et al.
Nivolumab for recurrent squamous-cell carcinoma of the head and neck
.
N Engl J Med
.
2016
;
375
(
19
):
1856
67
. .
42.
Cohen
EEW
,
Soulieres
D
,
Le Tourneau
C
,
Dinis
J
,
Licitra
L
,
Ahn
MJ
, et al.
Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head and neck squamous cell carcinoma (KEYNOTE-040): a randomized open-label, phase 3 study
.
Lancet
.
2019
;
393
(
10167
):
156
67
.
43.
Elias
R
,
Giobbie-Hurder
A
,
Mc Cleary
NJ
,
Ott
P
,
Hodi
S
,
Rahma
O
.
Efficacy of PD-1 and PDL-1 inhibitors in older adults: a meta-analysis
.
J Immunother Cancer
.
2018
;
6
:
26
.
44.
Van Holstein
Y
,
Kapiteijn
E
,
Bastiaannet
E
,
Van den Bos
F
,
Portielje
J
,
De Glas
NA
.
Efficacy and adverse events of immunotherapy with checkpoint inhibitors in older patients with cancer
.
Drugs Aging
.
2019
;
36
(
10
):
927
38
. .
45.
Gomes
F
,
Woolley
S
,
Califano
R
,
Summers
Y
,
Baker
K
,
Burns
K
, et al.
MA10.07 elderly lung cancer patients on immunotherapy: preliminary results of the ELDERS study
.
J Thor Oncol
.
2017
;
12
(
11
):
S1841
2
.
46.
Renner
A
,
Burotto
M
,
Rojas
C
.
Immune check point inhibitor dosing: can we go lower without compromising treatment
.
J Glob Oncol
.
2019
:
1
4
.
47.
Yoo
SH
,
Keam
B
,
Kim
M
,
Kim
SH
,
Kim
YJ
,
Kim
TM
, et al.
Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity
.
Esmo Open
.
2018
;
3
(
5
):
e000332
. .
48.
Mukherjee
S
,
Ibrahimi
S
,
Machiorlati
M
,
Roman
D
,
Saleem
R
,
Hassan
A
, et al.
Personalized dosing versus fixed dosing of immune checkpoint inhibitors
.
Am J Ther
.
2018
;
25
(
6
):
e767
8
.
49.
Chatterjee
M
,
Turner
DC
,
Felip
E
,
Lena
H
,
Cappuzzo
F
,
Horn
L
, et al.
Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer
.
Ann Oncol
.
2016
;
27
(
7
):
1291
8
. .
50.
Agrawal
S
,
Feng
Y
,
Roy
A
,
Kollia
G
,
Lestini
B
.
Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy
.
J Immunother Cancer
.
2016
;
4
:
72
. .
51.
Sehtal
K
,
Costa
DB
,
Rangachari
D
.
Extended-interval dosing strategy of immune checkpoint inhibitors in lung cancer: will it outlast the COVID-19 pandemics?
Frontier Oncol
.
2020
;
10
:
1193
.
52.
Goldstein
DA
,
Ratain
MJ
,
Saltz
LB
.
Weight-based dosing of pembrolizumab every six weeks in the time of COVID 19
.
JAMA
.
2020
. epublication.
53.
Hiniker
SM
,
Reddy
SA
,
Maecker
HT
,
Subrahmanyam
PB
,
Rosenberg-Hasson
Y
,
Swetter
SM
, et al.
A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma
.
Int J Radiat Oncol Biol Phys
.
2016
;
96
(
3
):
578
88
. .
54.
Aboudaram
A
,
Modesto
A
,
Chaltiel
L
,
Gomez-Roca
C
,
Boulinguez
S
,
Sibaud
V
, et al.
Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination
.
Melanoma Res
.
2017
;
27
(
5
):
485
91
. .
55.
Koller
KM
,
Mackley
HB
,
Liu
J
,
Wagner
H
,
Talamo
G
,
Schell
TD
, et al.
Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone
.
Cancer Biol Ther
.
2017
;
18
(
1
):
36
42
. .
56.
Chicas-Sett
R
,
Morales-Orue
I
,
Castilla-Martinez
J
,
Zafra-Martin
J
,
Kannerman
A
,
Blanco
J
, et al.
Stereotactic ablative radiotherapy combined with check point inhibitors rebooted the immune response assisted by immunotherapy in metastatic lung cancer: a systemic review
.
Int J Mol Sci
.
2019
;
20
(
9
):
2173
.
57.
Chicas-Sett
R
,
Morales-Orue
I
,
Rodriguez-Abreu
D
,
Lara-Jimenez
P
.
Combining radiotherapy and ipilumomab induces clinically relevant radiation-induced abscopal effects in metastatic melanoma patients: a systematic review
.
Clin Transl Rad Oncol
.
2018
;
9
:
5
11
.
58.
Desideri
I
,
Francolini
G
,
Scotti
V
,
Pezzulla
D
,
Becherini
C
,
Terziani
F
, et al.
Benefit of ablative versus palliative-only radiotherapy in combination with nivolumab in patients affected by metastatic kidney and lung cancer
.
Clin Transl Oncol
.
2019
;
21
(
7
):
933
8
. .
59.
Hubbeling
HG
,
Schapira
EF
,
Horick
NK
,
Goodwin
KEH
,
Lin
JJ
,
Oh
KS
, et al.
Safety of combined PD-1 pathway inhibition and intracranial radiation therapy in non-small cell lung cancer
.
J Thorac Oncol
.
2018
;
13
(
4
):
550
8
. .
60.
Gabani
P
,
Fischer-Valuck
BW
,
Johanns
TM
,
Hernandez-Aya
LF
,
Keller
JW
,
Rich
KM
, et al.
Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: patterns of care and treatment outcomes
.
Radiother Oncol
.
2018
;
128
(
2
):
266
73
. .
61.
Foster
CC
,
Sher
DJ
,
Rusthoven
CG
,
Verma
V
,
Spiotto
MT
,
Weichselbaum
RR
, et al.
Overall survival according to immunotherapy and radiation treatment for metastatic non-small cell lung cancer: a national cancer database analysis
.
Radiat Oncol
.
2019
;
14
:
18
.
62.
Chen
L
,
Douglass
J
,
Kleinberg
L
,
Ye
X
,
Marciscano
AE
,
Forde
PM
, et al.
Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma
.
Int J Radiat Oncol Biol Phys
.
2018
;
100
(
4
):
916
25
. .
63.
Magnuson
WJ
,
Lester-Coll
NH
,
Wu
AJ
,
Yang
TJ
,
Lockney
NA
,
Gerber
NK
, et al.
Management of brain metastases in tyrosine kinase inhibitor-naïve epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis
.
J Clin Oncol
.
2017
;
35
(
10
):
1070
7
. .
64.
D’Andrea
M
,
Reddy
GK
.
The systemic immunostimulatory effects of radiation therapy producing overall tumor control through the abscopal effect
.
J Radiat Oncol
.
2019
;
8
:
143
56
.
65.
D’Andrea
M
,
Reddy
GK
.
Systemic immunostimulatory effects of radiation therapy improves the outcomes of patients with advanced NSCLC receiving immunotherapy
.
Am J Clin Oncol
.
2020
;
43
(
3
):
218
28
.
66.
Smit
HJM
,
Aerts
J
,
van den Heuvel
M
,
Hiltermann
TJN
,
Bahce
I
,
Smit
EF
, et al.
Effects of checkpoint inhibitors in advanced non-small cell lung cancer at population level from the national immunotherapy registry
.
Lung Cancer
.
2020
;
140
:
107
12
. .
67.
Lazarri
G
,
Terlizzi
A
,
Porrazo
G
,
Devicienti
S
,
Perri
F
,
Della
G
, et al.
Effective nivolumab sequential thoracic radiotherapy in elderly patients with advanced squamous cell lung cancer: did radiotherapy play a role: a case report
.
Oncotarget Ther
.
2018
;
11
:
4621
9
.
68.
Verma
V
,
Cushman
TR
,
Selek
U
,
Tang
C
,
Welsh
JW
.
Safety of combined immunotherapy and thoracic radiation therapy: analysis of 3 single institutional phase I/II trials
.
Int J Radiat Oncol Biol Phys
.
2018
;
101
(
5
):
1141
8
.
69.
Murphy
W
,
Pahalyants
V
,
Klebanov
N
,
Theodosakis
N
,
Zubiri
L
,
Klevens
M
, et al.
Risk of COVID-19 infection among patients receiving immune checkpoint inhibitor therapy. A tertiary care hospital system collaboration with the Massachusetts department of health
.
J Immunnother Cancer
.
2020
;
8
(
Suppl 3
):
A656
A959
.
70.
Rogiers
A
,
Tondini
C
,
Grimes
JM
,
Trager
MH
,
Nahm
S
,
Zubiri
L
, et al.
Clinical characteristics and outcomes of coronavirus 2019 disease (COVID-19) in cancer patients treated with immune checkpoint inhibitors
.
Clin Cancer Res
.
2020
;
26
(
18
):
S02
01
.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.