reviewarticle · 2021. 1. 5. · y66]x6yl6“6(kih –676”6(kif gx6¨6(ki-total (95% ci) g6 uz6...

Review ArticleCombination of Immune Checkpoint Inhibitors andRadiotherapy for Advanced Non-Small-Cell Lung Cancer andProstate Cancer: A Meta-Analysis

Zexi Xu , Jia Feng , Yiming Weng , Yao Jin , and Min Peng

Department of Oncology Center, Renmin Hospital of Wuhan University, Wuhan 430060, China

Correspondence should be addressed to Min Peng; [email protected]

Received 10 October 2020; Revised 6 December 2020; Accepted 18 December 2020; Published 5 January 2021

Academic Editor: Nicola Silvestris

Copyright © 2021 Zexi Xu et al.-is is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objectives. Immune checkpoint inhibitors (ICI) combined with radiotherapy (RT) have emerged as a breakthrough therapy in thetreatment of various cancers. -e combination has a strong rationale, but data on their efficacy and safety are still limited. Hence,we comprehensively searched the database and performed this study to elucidate the clinical manifestations of this combinedstrategy. Methods. We performed a meta-analysis of randomized trials that compared ICI plus RT with placebo plus RT or ICIalone for the treatment of advanced nonsmall-cell lung cancer (NSCLC) and prostate cancer. -e outcomes included overallsurvival (OS), progression-free survival (PFS), disease control rate (DCR), and treatment-related adverse events. A fixed-effects orrandom-effects model was adopted depending on between-study heterogeneity. Results. -ree trials involving 1584 patients wereincluded. ICI plus RT was significantly associated with improvement of OS (hazard ratio [HR]� 0.81, 95% confidence interval[CI]� 0.70–0.94, P � 0.004), PFS (HR� 0.64; 95% CI 0.56–0.72, P< 0.00001), and DCR (relative risk [RR]� 1.38; 95% CI1.03–1.84, P � 0.03). A significant predictor for PFS with the combination of ICI and RTwas age, as a significant improvement inPFS (HR� 0.49; 95% CI 0.37–0.64, P< 0.00001) was observed in NSCLC patients aged under 65 years. In safety analyses, patientsreceiving ICI plus RT had a significantly higher incidence of dyspnea (RR� 2.43; 95% CI 1.16–5.08, P � 0.02) and pneumonitis ofgrade 3 or higher (RR� 2.78; 95% CI 1.32–5.85, P � 0.007). Conclusion. -e combination of ICI and RT was associated withimproved OS, PFS, and DCR. Patients under 65 years will be the dominant beneficiaries. However, the incidence of dyspnea andpneumonia of grade 3 or higher also increased, which deserves our vigilance.

1. Introduction

Over recent decades, immune checkpoint inhibitors (ICI) areconsidered a major advance in the treatment of various ad-vanced cancers. Targets of ICI therapy include cytotoxicT lymphocyte antigen-4 (CTLA-4), programmed cell deathprotein 1 (PD1), and programmed death-ligand 1 receptor(PD-L1). However, actually, the majority of patients treatedwith ICI do not achieve objective responses, and most neo-plasm regressions are partial rather than complete [1].With therecent success of radiotherapy (RT) combined with immu-notherapy in animal models of various types of cancer, therehas been renewed interest in the combination of ICI with RT[2–7]. However, it is not clear whether RT can enhance theeffects of ICI in human patients, and the safety of combined

therapy has not been fully confirmed. We performed a sys-tematic review of the literature and reported the outcomes ofpatients with solid neoplasm treated with ICI and RT.

2. Materials and Methods

We conducted this meta-analysis on the basis of thePRISMA statement [8]. All analyses were conducted basedon previously published studies; thus, no ethical approvaland patient consent are required.

2.1. Search Strategy. Two reviewers independently com-pleted the search. -ey were searched, with no time re-strictions, the following databases for relevant English

HindawiJournal of OncologyVolume 2021, Article ID 6631643, 10 pageshttps://doi.org/10.1155/2021/6631643

mailto:[email protected]://orcid.org/0000-0002-7984-5211https://orcid.org/0000-0001-9365-4940https://orcid.org/0000-0001-9716-7576https://orcid.org/0000-0002-3969-5562https://orcid.org/0000-0001-6648-945Xhttps://creativecommons.org/licenses/by/4.0/https://doi.org/10.1155/2021/6631643

language literature: PubMed (MEDLINE), Embase, theCochrane Central Register of Controlled Trials (CENTRAL),US-clinical trials, and China National Knowledge Infra-structure Database (CNKI). -e following keywords wereused: “Neoplasms,” “Neoplasia,” “Cancer,” “Immunother-apy,” “Programmed Cell Death 1 Receptor,” “ProgrammedCell Death 1 Ligand 1,” “CTLA-4 Antigen,” “Durvalumab,”“Pembrolizumab,” “Atezolizumab,” “Nivolumab,” “Trem-elimumab,” “Ipilimumab,” “Radiotherapy,” “randomizedcontrolled trial.” -e electronic database search will besupplemented by a manual search of the reference lists ofincluded articles.

2.2. Inclusion Criteria. All relevant articles underwentevaluation for eligibility by two investigators independently.-e relevant clinical trials were selected carefully based onthe following criteria: (1) population: participants withhistologically confirmed solid tumors; (2) intervention: PD-1/PD-L1/CTLA-4 Inhibitors combined with RT (or che-moradiotherapy), RT were applied prior to immunotherapyor during immunotherapy, and the types of RT includeconventional radiotherapy and stereotactic radiotherapy; (3)comparison: ICI or RT alone; (4) outcomes: overall survival(OS), progression-free survival (PFS), clinical efficacy andtreatment safety; (5) study design: randomized controlledtrials (RCTs). -e following exclusion criteria were con-sidered: insufficient data were available to estimate theoutcomes; the size of each arm was less than ten patients;animal studies and nonrandomized studies.

2.3. Data Extraction. Literature screening and data extrac-tion were carried out by two independent reviewers. -ediscrepancy was resolved by discussion between the two ofus. If the two authors could not reach a consensus, anotherauthor made the decision. For each study, the followingdetails were extracted: the name of the first author, year ofpublication, cancer type, treatment arm and control arm,sample size, dose, the hazard ratio (HR), and 95% confidenceinterval (CI) for PFS (defined as the time from randomi-zation to the first documented disease progression or death),and OS (defined as the time from randomization to death),disease control rate (DCR), number of patients who expe-rienced adverse effects (AEs). We also extracted HR and 95%CI for PFS of the intention-to-treat population and thefollowing predefined subgroups: age ( 50%,the random effect models were chosen. Otherwise the fixedeffect models were used. -e possibility of publication biaswas estimated by funnel plots. A P value

PRISMA 2009 flow diagram

Records identified through database searching (n = 590)

(Pubmed (n = 138); Embase (n = 290);Cochrane (n = 187); CNKI (n = 0))

Scre

enin

gIn

clud

edEl

igib

ility

Iden

tifica

tion

Additional records identified through other sources

(n = 25)(US-clinical trials (n = 25))

Records a�er duplicates removed(n = 556)

Records screened(n = 64)

Studies excluded based on screening of titles and

abstracts no relevant (n = 492)

Full-text articles assessed for eligibility

(n = 3)

Studies excluded (n = 61)(Not randomized (n = 15)

Different interventions (n = 11)Not relevant (n = 35))

Studies included in qualitative synthesis

(n = 3)

Studies included in quantitative synthesis

(meta-analysis)(n = 3)

Figure 1: Flow diagram of included and excluded studies. After successively applying the inclusion and exclusion criteria, 3 RCTs wereincluded, but no clinical trials with usable data.

Table 1: Characteristics of the 3 studies included in the meta-analysis.

Study RCTphase Pathology Line AgeMale(%)

Treatmentcomparison Case ICI

RTsite

Follow-up of

ICI + RT(months)

HR (95% CI) for ICI +RT

OS PFS

Antoniaet al. [12] 3 NSCLC 1

recurrence and metastasis by 36% in patients with NSCLCand prostate cancer (HR � 0.64; 95% CI 0.56–0.72,P< 0.00001).

3.4.2. Disease Control Rate. RR for the DCR was availablefor three trials. -e pooled analysis of DCR using therandom-effects model is shown in Figure 5. -ere wasstatistical heterogeneity among the studies (I2 � 90%). -e

results showed that RT combined with ICI significantlyincreased the DCR (RR� 1.38; 95% CI 1.03–1.84, P � 0.03).

3.4.3. Subgroup Analysis. We performed a subgroup anal-ysis by grouping NSCLC patients based on whether theywere older than 65 years. A significant improvement wasobserved in PFS (HR� 0.49; 95% CI 0.37–0.64, P< 0.00001)in patients aged under 65 years who received ICI combined

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

25 50 75 1000(%)

Low risk of biasUnclear risk of biasHigh risk of bias

Figure 2: Risk of bias graph.

Study or subgroup

Antonia, S. J 2017

Eugene D Kwon 2015Theelen, W 2019

Total (95% CI)Total eventsHeterogeneity: chi2 = 1.64, df = 2 (P = 0.44); I2 = 0%Test for overall effect: Z = 2.85 (P = 0.004)

0

00

0

0

00

0

0

00

0

Events Total0

00

0

O-E

–10.47907542

–23.14166411–4.74698682

Variance

27.1716227

142.393653411.42433305

Weight(%)

15.0

78.76.3

100.0

0.68 [0.47, 0.99]

0.85 [0.72, 1.00]0.66 [0.37, 1.18]

0.81 [0.70, 0.94]

Events TotalExperimental Control Peto odds ratio

Exp[(O-E)/V], fixed, 95% CIPeto odds ratio

Exp[(O-E)/V], fixed, 95% CI

Favours (experimental) Favours (control)0.1 1 10 1000.01

Figure 3: Forest plot for the meta-analysis of HR of OS for ICI+RT in solid tumors. HR: hazard ratio; ICI: Immune checkpoint inhibitors;OS: overall survival; RT: radiotherapy.

Antonia, S. J 2017Eugene D Kwon 2015�eelen, W 2019

Total (95% CI)

Total eventsHeterogeneity: chi2 = 5.85, df = 2 (P = 0.05); I2 = 66%Test for overall effect: Z = 7.48 (P < 0.00001)

000

0

000

0

000

0

000

0

–56.073–62.62

–4.9318

83.2759175.56714.3999

30.564.35.3

100.0

0.51 [0.41, 0.63]0.70 [0.60, 0.81]0.71 [0.42, 1.19]

0.64 [0.56, 0.72]

Study or subgroupEvents Total

O-E Variance Weight(%)Events TotalExperimental Control Peto odds ratio



0.1 1 10 1000.01Favours (experimental) Favours (control)

Figure 4: Forest plot for the meta-analysis of HR of PFS for ICI+RT in solid tumors. HR: hazard ratio; ICI: Immune checkpoint inhibitors;PFS: progression-free survival; RT: radiotherapy.

4 Journal of Oncology

with RT (Figure 6), but no significant difference in PFS wasobserved in patients older than 65 years (HR� 0.86; 95% CI0.65–1.16, P � 0.43) (Figure 7). -ere was no significantdifference in PFS between genders or pathological types ofNSCLC.

3.5. Statistical Analysis of Safety Outcomes

3.5.1. Any Grade Adverse Events and Grade 3–5 AdverseEvents. -e meta-analysis pooled results of any grade AEsare presented in Figure 8. -e heterogeneity test indicatesthat a fixed-effects model can be selected. -ere wasminimal statistical heterogeneity in pruritus (I2 � 40%) andno heterogeneity in fatigue, cough, dyspnea, nausea, andpneumonitis (I2 �15%, I2 �18%, I2 � 0, I2 � 20%, I2 � 0,respectively). -e results indicated that ICI plus RT led to ahigher risk of fatigue (RR� 1.19; 95% CI 1.01–1.41,P � 0.04), cough (RR � 1.55; 95% CI 1.06–2.27, P � 0.02),pruritus (RR � 3.65; 95% CI 2.52–5.28, P< 0.00001), andpneumonitis (RR� 2.66; 95% CI 1.64–4.31, P< 0.00001)than RT with placebo/ICI alone. Differences were notstatistically significant with respect to dyspnea (RR � 1.37;95% CI 0.98–1.90, P � 0.06) and nausea (RR� 1.05; 95% CI0.86–1.29, P � 0.60) between the two groups. -e results ofgrade 3–5 AEs are described in Figure 9. More dyspnea(RR� 2.43; 95% CI 1.16–5.08, P � 0.02) and pneumonitis(RR� 2.78; 95% CI 1.32–5.85, P � 0.007) might occur inpatients treated with ICI combined with RTcompared withpatients treated with RT with placebo/ICI alone, but therates of fatigue, cough, nausea, and pruritus were notsignificantly different between the two groups.

4. Discussion

-ere are strong preclinical and clinical reasons for com-bining ICI with RT in the treatment of tumors. -e aim oftreatment is to achieve local and systemic disease control,which may lead to improvements in PFS and OS. However,data on the safety and efficacy of this strategy are still limited.We have conducted a systematic review of studies to explorethe efficacy and safety of immunotherapy combined with RTin the treatment of solid tumors. To the best of ourknowledge, this is the first systematic review and meta-

analysis explicitly assessing this topic. However, the publi-cations in this systematic review mainly report data frompatients with lung cancer and prostate cancer, so these re-sults cannot be directly translated to patients with otherprimary tumors.

-e overarching message of our analysis is the findingthat the combination of ICI with RT is effective. -is isconsistent with the conclusions from several studies thathave examined the combination of ICI and RT. -e phaseIII Pacific trial confirmed that the addition of durvalumabto chemoradiotherapy significantly improves both OS andPFS in lung cancer patients. -erefore, the standardtreatment for stage III NSCLC now includes consolidativedurvalumab [9, 12]. In a secondary analysis of the KEY-NOTE-001 phase trial, patients were divided into sub-groups comparing patients who had previously received RTand those who had not received RT. PFS and OS withpembrolizumab were significantly longer in patients whohad previously received RT than in patients who had notpreviously received RT [13]. A phase I study conducted byKelly et al. explored the efficacy and safety of atezolizumabplus stereotactic ablative radiation therapy (SBRT) formedically inoperable patients with early-stage NSCLC. -epreliminary results showed that the combined treatmentwas a feasible option without obvious additional toxicity[14]. Moreover, the results of phase II prospective trial inpatients with metastatic NSCLC reported that the com-bination of SBRT with concurrent pembrolizumab led toincreased PFS, with a systemic response rate of 9.52% and aDCR of 57.14% [15]. At present, the results of many clinicalstudies, such as NCT02562625 and NCT02730130, have notbeen fully published [16]. -e results of our meta-analysismay provide guidance for the current clinical work.

In addition, our meta-analysis of elderly subjectsrevealed that the risk of recurrence and metastasis was re-duced by 51% upon the addition of RT to ICI in NSCLCpatients aged under 65 years. -ese results are similar tothose of previous studies of ICI [17, 18]. A previous meta-analysis explored the differential efficacy of ICI in olderpatients compared to young adults. In that analysis, thepatients were divided into younger and older groups using acut-off age of 65 years. PFS was not significantly differentbetween ICI and controls for the older group (HR� 0.77;

Study or subgroup

Antonia, S. J 2017Eugene D Kwon 2015�eelen, W 2019

Total (95% CI)Total eventsHeterogeneity: tau2 = 0.05; chi2 = 19.99, df = 2 (P < 0.0001); I2 = 90%Test for overall effect: Z = 2.17 (P = 0.03)

35926926

654

Events Total

44338736

866

15317119

343

21339240

645

Weight(%)

38.837.523.7

100.0

1.13 [1.03, 1.24]1.59 [1.40, 1.82]1.52 [1.04, 2.23]

1.38 [1.03, 1.84]

ExperimentalEvents Total

Control Risk ratioM-H, random, 95% CI

Risk ratioM-H, random, 95% CI


Figure 5: Forest plot for the meta-analysis of RR of DCR for ICI+RT in solid tumors. DCR: disease control rate; ICI: Immune checkpointinhibitors; RR: relative risk; RT: radiotherapy.

Journal of Oncology 5

95% CI 0.58–1.01, P � 0.06) [17]. -e potential correlationbetween old age and primary drug resistance in immuno-therapy may be related to immunosenescence, which is aphenomenon of decreased immune function as a result ofage-associated alterations to the immune system [19, 20].-emajority of cancer morbidity and mortality occur in ≥65year-olds, but older patients were “strikingly underrepre-sented” in a set of RCTs [21, 22]. Most elderly patients whoare excluded from RCTs have comorbid conditions, reducedperformance status, organ dysfunction, etc. [23]. -erefore,combination therapy should be used cautiously in geriatricpatients.

In assessing the benefits of treatment, it is important toconsider the possible side effects of immunotherapy and RT.In ourmeta-analysis, the incidence of fatigue, cough, pruritus,and pneumonitis of any cause and grade upon combinedtreatment was higher than with any single treatment strategy,and the incidence of grade 3–5 dyspnea and pneumonitis was2.43 times and 2.78 times higher, respectively. Overall, AEsare generally tolerable. Given the risk of pneumonitis, thiscombination should continue to be evaluated in clinical trials.A retrospective study found that the incidence of pneumonitiswas highest after the integration of hypofractionated body RTinto ICI [24]. Barron et al. observed an increase in the risk andseverity of pneumonitis in patients with previous RT andsubsequent treatment with immunotherapy (OR� 6.8; 95%CI 1.6–28.5, P � 0.009) [25]. In their prospective study ofSBRT with concurrent ICI, Tian et al. reported that con-current lung SBRTwith ICI is safe, but the risk of pneumoniashould be monitored more closely [26]. Zhang et al. suggestedthat the application of ICI before or during thoracic RT

increases the incidence of radiation pneumonia [27]. Cui et al.showed that the risk of immunotherapy-related pneumonitiswas associated with prior thoracic RT and combinationtherapy [25, 28]. -us, clinicians should be aware of theoccurrence of pneumonitis when RTand immunotherapy arecombined.

-e anticancer effect of RT is mainly based on thedisruption of the chemical bonds within the lipid mem-branes and proteins and, most importantly, between thebases in DNA [29]. Apart from direct cell killing, RT has aprofound effect on the tumor microenvironment and in-duces the abscopal effect, which may contribute to triggeringan anticancer immune response [30, 31]. For example, ra-diation can induce immunogenic cell death (ICD) of cancercells. ICD is a way of cell death that releases tumor antigensand causes immune responses [32]. RT upregulates tumor-associated antigens, which are expressed on the cell surfacein association with MHC I antigens; therefore, RT can alsoinduce upregulation of MHC Imolecules, which is the key toT cell activation [33, 34]. Radiation may alter the profile ofMHC class I related peptides to produce new antigens,making the immune system more likely to recognize thesecells [3, 35]. Additionally, RT can also cause ICD, activatedendritic cells, reduce the abundance of regulatory T cells intumors, broaden the T cell repertoire, and increase T celltrafficking [36, 37]. -is radiation property is key to itssynergistic effect with ICI, antibodies targeting T inhibitoryreceptors such as CTLA-4 and PD1. Radiation inducesantitumor Tcells, complementing the activity of ICI [38, 39].Radiation may also activate the antitumor immune responseby triggering the stimulation of the interferon gene

Antonia, S. J 2017Theelen, W 2019

Total (95% CI)


00

0

00

0

00

0

00

0

–38.9110.44443

46.10487.62722

85.814.2

100.0

0.43 [0.32, 0.57]1.06 [0.52, 2.16]

0.49 [0.37, 0.64]






Figure 6: Forest plot for the subgroup analyses of HR of PFS for ICI+RT in NSCLC patients under 65. HR: hazard ratio; ICI: Immunecheckpoint inhibitors; NSCLC: nonsmall-cell lung cancer; PFS: progression-free survival; RT: radiotherapy.

Antonia, S. J 2017Theelen, W 2019

Total (95% CI)

Total events

00

0

00

0

00

0

00

0

–11.8025.14839

39.19536.38381

86.014.0

100.0

0.74 [0.54, 1.01]2.24 [1.03, 4.87]

0.86 [0.65, 1.16]





Heterogeneity: chi2 = 6.73, df = 1 (P = 0.009); I2 = 85%

Test for overall effect: Z = 0.99 (P = 0.32) Favours (experimental) Favours (control)0.1 1 10 500.02

Figure 7: Forest plot for the subgroup analyses of HR of PFS for ICI+RT in NSCLC patients older than 65. HR: hazard ratio; ICI: Immunecheckpoint inhibitors; NSCLC: nonsmall-cell lung cancer; PFS: progression-free survival; RT: radiotherapy.


(STING)-mediated DNA sensing pathway [40, 41]. Houet al. demonstrated that the deficiency of noncanonical NF-κB promotes radiation-induced antitumor immunity byregulating the STING-mediated type I IFN expression [42].Furthermore, radiation regulates immune checkpoint

expression. Wu et al. showed that irradiation upregulatedthe expression of PD-L1 in tumor cells in in vitro and in vivoexperiments, and its increase was related to the irradiationdose [43]. Similarly, Dovedi et al. demonstrated that lowdoses of fractionated RT led to upregulation of tumor cell

Study or subgroup

3.1.1 FatigueAntonia, S. J 2017Eugene D Kwon 2015Theelen, W 2019

Subtotal (95% CI)

Total eventsHeterogeneity: chi2 = 2.36, df = 2 (P = 0.31); I2 = 15%Test for overall effect: Z = 2.05 (P = 0.04)

3.1.2 CoughAntonia, S. J 2017Eugene D Kwon 2015Theelen, W 2019

Subtotal (95% CI)


3.1.3 DyspnoeaAntonia, S. J 2017Eugene D Kwon 2015Theelen, W 2019

Subtotal (95% CI)


3.1.4 NauseaAntonia, S. J 2017Eugene D Kwon 2015Theelen, W 2019

Subtotal (95% CI)


3.1.5 PruritusAntonia, S. J 2017Eugene D Kwon 2015Theelen, W 2019

Subtotal (95% CI)


3.1.6 PneumonitisAntonia, S. J 2017Eugene D Kwon 2015Theelen, W 2019

Subtotal (95% CI)


Total (95% CI)

Total eventsHeterogeneity: chi2 = 54.26, df = 17 (P < 0.00001); I2 = 69%Test for overall effect: Z = 6.95 (P < 0.00001)Test for subgroup differences: chi2 = 43.63, df = 5 (P < 0.00001), I2 = 88.5%

6215018

230

253612

73

28509

87

26127

5

158

33997

139

43249

76

763

Events Total

47539335

903

47539335

903

47539335

903

47539335

903

47539335

903

47539335

903

5418

2612310

159

4278

39

8368

52

1410610

130

5225

32

893

20

432

23436937

640

23436937

640

23436937

640

23436937

640

23436937

640

23436937

640

3840

Weight(%)

7.527.42.1

37.0

1.26.01.78.9

2.38.01.7

12.0

4.123.62.1

29.8

1.44.91.07.4

2.32.00.64.9

100.0

1.17 [0.76, 1.81]1.15 [0.95, 1.39]1.90 [1.02, 3.54]1.19 [1.01, 1.41]

3.08 [1.08, 8.74]1.25 [0.78, 2.02]1.59 [0.74, 3.41]1.55 [1.06, 2.27]

1.72 [0.80, 3.72]1.30 [0.87, 1.95]1.19 [0.52, 2.73]1.37 [0.98, 1.90]

0.91 [0.49, 1.72]1.12 [0.91, 1.40]0.53 [0.20, 1.39]1.05 [0.86, 1.29]

3.25 [1.29, 8.22]4.23 [2.72, 6.56]1.48 [0.52, 4.23]3.65 [2.52, 5.28]

2.65 [1.27, 5.54]2.50 [1.18, 5.32]

3.17 [0.93, 10.77]2.66 [1.64, 4.31]

1.46 [1.31, 1.62]

ExperimentalEvents Total

Control Risk ratioM-H, fixed, 95% CI

Risk ratioM-H, fixed, 95% CI


Figure 8: Forest plot for the subgroup analyses of RR of any grade adverse events for ICI+RT in solid tumors. ICI: Immune checkpointinhibitors; RR: relative risk; RT: radiotherapy.

Journal of Oncology 7

expression of PD-L1 in multiple syngeneic models [44].-us, it is highly rational to combine RT with ICI.

However, this meta-analysis has some obvious limi-tations. First, there were only three trials that met theeligibility criteria, so the number of included RCTs is low.-is may be because many related studies are underway.

Second, although our main outcome analysis of immu-notherapy plus RT treatment is biologically plausible andsound, significant heterogeneity was observed between theincluded studies. -is may be related to the different ICIand tumor types included in our study. We have minimizedits influence by using the random-effects model. Our

3.2.1 FatigueAntonia, S. J 2017Eugene D Kwon 2015�eelen, W 2019

Subtotal (95% CI)


3.2.2 CoughAntonia, S. J 2017Eugene D Kwon 2015�eelen, W 2019

Subtotal (95% CI)

Total eventsHeterogeneity: not applicableTest for overall effect: Z = 1.00 (P = 0.32)

3.2.3 DyspnoeaAntonia, S. J 2017Eugene D Kwon 2015�eelen, W 2019

Subtotal (95% CI)Total eventsHeterogeneity: chi2 = 0.08, df = 2 (P = 0.96); I2 = 0%Test for overall effect: Z = 2.35 (P = 0.02)

3.2.4 NauseaAntonia, S. J 2017Eugene D Kwon 2015�eelen, W 2019

Subtotal (95% CI)


3.2.5 PruritusAntonia, S. J 2017Eugene D Kwon 2015�eelen, W 2019

Subtotal (95% CI)

Total eventsHeterogeneity: not applicableTest for overall effect: Z = 0.63 (P = 0.53)

3.2.6 PneumonitisAntonia, S. J 2017Eugene D Kwon 2015�eelen, W 2019

Subtotal (95% CI)


Total (95% CI)

Total eventsHeterogeneity: chi2 = 10.54, df = 12 (P = 0.57); I2 = 0%Test for overall effect: Z = 3.09 (P = 0.002)Test for subgroup differences: chi2 = 7.05, df = 5 (P = 0.22), I2 = 29.1%

1401

42

020

2

3184

25

0111

12

010

1

10164

30

112

47539335

903

47539335

903

47539335

903

47539335

903

47539335

903

47539335

903

5418

0350

35

000

0

072

9

072

9

000

0

431

8

61

23436937

640

23436937

640

23436937

640

23436937

640

23436937

640

23436937

640

3840

1.054.10.7

55.8

0.8

0.8

1.010.82.9

14.7

10.82.9

13.7

0.8

0.8

8.04.61.5

14.1

100.0

1.48 [0.06, 36.22]1.07 [0.70, 1.65]

3.17 [0.13, 75.24]1.11 [0.73, 1.69]

Not estimable4.70 [0.23, 97.48]

Not estimable4.70 [0.23, 97.48]

3.46 [0.18, 66.63]2.41 [1.02, 5.71]

2.11 [0.41, 10.83]2.43 [1.16, 5.08]

Not estimable1.48 [0.58, 3.77]0.53 [0.05, 5.57]1.27 [0.54, 3.00]

Not estimable2.82 [0.12, 68.94]

Not estimable2.82 [0.12, 68.94]

1.23 [0.39, 3.89]5.01 [1.47, 17.05]4.23 [0.50, 36.01]2.78 [1.32, 5.85]

1.60 [1.19, 2.16]

Study or subgroup Events TotalWeight

(%)Experimental

Events TotalControl Risk ratio

M-H, fixed, 95% CIRisk ratio

M-H, fixed, 95% CI


Figure 9: Forest plot for the subgroup analyses of RR of grade 3–5 adverse events for ICI+RT in solid tumors. ICI: Immune checkpointinhibitors; RR: relative risk; RT: radiotherapy.


systematic review still has some strengths: we included allpublished RCTs exploring the efficacy and safety of ICIcombined with RT for the treatment of solid tumors andfound that the association of ICI and RT provides a goodDCR among the subjects, and in particular, we showed thatthe combination of ICI with RT is significantly better thanRT alone or ICI alone, with a 36% reduced risk of recur-rence and metastasis and a 19% reduced risk of death, butthe incidence of pneumonia increased significantly.

5. Conclusion

In conclusion, our meta-analysis showed that ICI with RTsignificantly improved OS and PFS compared with controlsin patients with NSCLC and prostate cancer. A benefit withrespect to PFS was observed in NSCLC patients aged

[17] T. F. Nishijima, H. B. Muss, S. S. Shachar, and S. J. Moschos,“Comparison of efficacy of immune checkpoint inhibitors(ICIs) between younger and older patients: a systematic re-view and meta-analysis,” Cancer Treatment Reviews, vol. 45,pp. 30–37, 2016.

[18] T. Landre, C. Taleb, P. Nicolas, and G. D. Guetz, “Is there aclinical benefit of anti-PD-1 in patients older than 75 yearswith previously treated solid tumour?” Journal of ClinicalOncology, vol. 34, 2016.

[19] G. Pawelec, E. Derhovanessian, and A. Larbi, “Immunose-nescence and cancer,” Critical Reviews in Oncology/Hema-tology, vol. 75, no. 2, pp. 165–172, 2010.

[20] R. Ferrara, L. Mezquita, E. Auclin, N. Chaput, and B. Besse,“Immunosenescence and immunecheckpoint inhibitors innon-small cell lung cancer patients: does age really matter?”Cancer Treatment Reviews, vol. 60, pp. 60–68, 2017.

[21] V. H. Murthy, H. M. Krumholz, and C. P. Gross, “Partici-pation in cancer clinical trials,” JAMA, vol. 291, no. 22,pp. 2720–2726, 2004.

[22] E. B. Ludmir, W. Mainwaring, T. A. Lin et al., “Factors as-sociated with age disparities among cancer clinical trialparticipants,” JAMA Oncology, vol. 5, no. 12, 2019.

[23] G. B. Rocque and G. R.Williams, “Bridging the data-free zone:decision making for older adults with cancer,” Journal ofClinical Oncology, vol. 37, no. 36, pp. 3469–3471, 2019.

[24] O. Mohamad, D. L. A. Diaz, S. Schroeder et al., “Safety andefficacy of concurrent immune checkpoint inhibitors andhypofractionated body radiotherapy,” OncoImmunology,vol. 7, no. 7, Article ID e1440168, 2018.

[25] F. Barron, L. Ramirez-Tirado, O. Macedo-Pérez et al., “P3.14-012 risk of developing pneumonitis increases in patients re-ceiving immunotherapy with a history of lung irradiation,”Journal of :oracic Oncology, vol. 12, no. 11, p. S2335, 2017.

[26] S. Tian, J. M. Switchenko, Z. S. Buchwald et al., “Lung ste-reotactic body radiation therapy and concurrent immuno-therapy: a multicenter safety and toxicity analysis,”International Journal of Radiation Oncology Biology Physics,vol. 108, no. 1, pp. 304–313, 2020.

[27] N. Zhang, X. Zhu, C. Kong et al., “1907P Application of anti-PD1 drugs before or during thoracic radiotherapy increasesthe incidence of radiation pneumonia compared to the ap-plication after radiotherapy,” Annals of Oncology, vol. 31,p. S1081, 2020.

[28] P. Cui, Z. Liu, G. Wang et al., “Risk factors for pneumonitis inpatients treated with anti-programmed death-1 therapy: acase-control study,” Cancer Medicine, vol. 7, no. 8,pp. 4115–4120, 2018.

[29] E. Selzer and A. Hebar, “Basic principles of molecular effectsof irradiation,” Wien Med Wochenschr, vol. 162, no. 3-4,pp. 47–54, 2012.

[30] D. De Ruysscher, K. Reynders, E. Van Limbergen, andM. Lambrecht, “Radiotherapy in combination with immunecheckpoint inhibitors,” Current Opinion in Oncology, vol. 29,no. 2, pp. 105–111, 2017.

[31] Y. Wang, Z. G. Liu, H. Yuan et al., “-e reciprocity betweenradiotherapy and cancer immunotherapy,” Clinical CancerResearch, vol. 25, no. 6, pp. 1709–1717, 2019.

[32] G. Kroemer, L. Galluzzi, O. Kepp, and L. Zitvogel, “Immu-nogenic cell death in cancer therapy,” Annual Review ofImmunology, vol. 31, no. 1, pp. 51–72, 2013.

[33] A. R. Kwilas, R. N. Donahue, M. B. Bernstein, andJ. W. Hodge, “In the field: exploiting the untapped potential ofimmunogenic modulation by radiation in combination with

immunotherapy for the treatment of cancer,” Frontiers inOncology, vol. 2, p. 104, 2012.

[34] B. Zhang, N. A. Bowerman, J. K. Salama et al., “Inducedsensitization of tumor stroma leads to eradication of estab-lished cancer by T cells,” Journal of Experimental Medicine,vol. 204, no. 1, pp. 49–55, 2007.

[35] A. M. Dudek, A. D. Garg, D. V. Krysko, D. De Ruysscher, andP. Agostinis, “Inducers of immunogenic cancer cell death,”Cytokine & Growth Factor Reviews, vol. 24, no. 4, pp. 319–333,2013.

[36] X. Meng, R. Feng, L. Yang, L. Xing, and J. Yu, “-e role ofradiation oncology in immuno-oncology,” :e Oncologist,vol. 24, no. S1, pp. S42–S52, 2019.

[37] V. Longo, O. Brunetti, A. Azzariti et al., “Strategies to improvecancer immune checkpoint inhibitors efficacy, other thanabscopal effect: a systematic review,” Cancers (Basel), vol. 11,no. 4, 2019.

[38] K. A. Pilones, C. Vanpouille-Box, and S. Demaria, “Combi-nation of radiotherapy and immune checkpoint inhibitors,”Seminars in Radiation Oncology, vol. 25, no. 1, pp. 28–33,2015.

[39] A. Sindoni, F. Minutoli, G. Ascenti, and S. Pergolizzi,“Combination of immune checkpoint inhibitors and radio-therapy: review of the literature,” Critical Reviews in Oncol-ogy/Hematology, vol. 113, pp. 63–70, 2017.

[40] Q. Storozynsky and M. M. Hitt, “-e impact of radiation-induced DNA damage on cGAS-STING-mediated immuneresponses to cancer,” International Journal of MolecularSciences, vol. 21, no. 22, 2020.

[41] T. Reisländer, F. J. Groelly, and M. Tarsounas, “DNA damageand cancer immunotherapy: a STING in the tale,” MolecularCells, vol. 80, no. 1, pp. 21–28, 2020.

[42] Y. Hou, H. Liang, E. Rao et al., “Non-canonical NF-κB an-tagonizes STING sensor-mediated DNA sensing in radio-therapy,” Immunity, vol. 49, no. 3, pp. 490–503, 2018.

[43] C. T. Wu, W. C. Chen, Y. H. Chang, W. Y. Lin, andM. F. Chen, “-e role of PD-L1 in the radiation response andclinical outcome for bladder cancer,” Scientific Reports, vol. 6,Article ID 19740, 2016.

[44] S. J. Dovedi, A. L. Adlard, G. Lipowska-Bhalla et al., “Acquiredresistance to fractionated radiotherapy can be overcome byconcurrent PD-L1 blockade,” Cancer Research, vol. 74, no. 19,pp. 5458–5468, 2014.


reviewarticle · 2021. 1. 5. · y66]x6yl6“6(kih –676”6(kif gx6¨6(ki-total (95% ci) g6 uz6...

Documents