Critical Reviews in Oncology / Hematology 167 (2021) 103500

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Critical Reviews in Oncology / Hematology

journal homepage: www.elsevier.com/locate/critrevonc

Thoracic re-irradiation with 3D-conformal or more advanced techniques: A

systematic review of treatment safety by the Re-irradiation Study Group of
the Italian Association of Radiation and Oncology AIRO
Marta Maddalo a, 1, Elisa D’Angelo b, *, 1, Francesco Fiorica c, Angela Argenone d,
Melissa Scricciolo e, Salvatore Cozzi f, Alessia Nardangeli g, Francesco Dionisi h,
Gianluca Costantino a, Stefano Vagge i, Antonio Pontoriero j, Vittorio Donato k, 2,
Mariangela Massaccesi l, on behalf of the Re-irradiation Study Group of the Italian Association of
Radiation Oncology
a
Department of Radiation Oncology, ASST Spedali Civili of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy
b
Department of Radiotherapy, University Hospital of Modena, L. del Pozzo 71, 41121, Modena, Italy
c
Department of Radiation Oncology and Nuclear Medicine, State Hospital Mater Salutis AULSS 9, 37045, Legnago (VR), Italy
d
Radiotherapy Unit, AORN San PIO, Via dell’Angelo, 82100, Benevento, Italy
e
Radiation Therapy Unit, Ospedale dell’Angelo, Via Paccagnella 11, 30174, Venezia, Italy
f
Radiation Therapy Unit, Azienda USL-IRCCS di Reggio Emilia, 42122, Reggio Emilia, Italy
g
Fondazione Policlinico Universitario "A. Gemelli" IRCCS, UOC di Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed
Ematologia, L. Gemelli 1, 00168, Roma, Italy
h
Department of Research and Advanced Technology, Radiation Oncology Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144, Roma, Italy
i
Department of Radiation Oncology, Azienda Ospedaliera Universitaria San Martino di Genova-IST, Istituto Nazionale Ricerca sul Cancro, Genoa, Italy
j
Dept. of Radiation Oncology, University of Messina, 98125, Messina, Italy
k
Radiation Oncology Division, Oncology and Speciality Medicine Department, San Camillo-Forlanini Hospital, 00152, Roma, Italy
l
Radiation Oncology Department, Gemelli-ART, Università Cattolica S. Cuore, L. Gemelli 1, 00168, Roma, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Re-irradiation (re-RT) is a treatment modality that has been actively investigated in recurrent lung cancer or in
Re-irradiation lung metastases appeared in previously irradiated areas. A literature search, according PRISMA recommenda­
Recurrent lung cancer tions and a meta-analysis technique were performed with the aims to identify possible factors related to the
Lung metastases
toxicity incidence and severity of ≥ G3 acute toxicity. 1243 patients and 36 studies, met inclusion criteria. Our
Stereotactic body radiotherapy
3D conformal radiotherapy
results, showed that there was no difference in ≥ G3 acute (10,5%) toxicity rate with respect to different ra­
Carbon ion radiotherapy diation techniques, cumulative dose and re-irradiation total dose and fractionation. Factors eventually related to
Proton therapy severe toxicity were described. The frequent lack of a sufficient description of the treatment’s intent, the het­
Toxicity erogeneity in technique and radiotherapy regimen, makes balancing risk and benefit of re-RT based on published
data even more difficult.

1. Introduction systemic therapies has led to a substantial change in the natural history
of lung cancer. Nowadays a substantial number of patients can be
The development of increasingly effective and selective local and treated with more than a purely palliative approach, resulting into an

* Corresponding author at: Radiation Oncology Unit, University Hospital of Modena, Via del pozzo, 71, 41124, Modena, Italy.
E-mail addresses: marta.maddalo@aol.com (M. Maddalo), dangelo.elisa@policlinico.mo.it (E. D’Angelo), francesco.fiorica@aulss9.veneto.it (F. Fiorica), angela.
argenone@ao-rummo.it (A. Argenone), melissa.scricciolo@aulss3.veneto.it (M. Scricciolo), salvatore.cozzi@ausl.re.it (S. Cozzi), alessia.nardangeli@guest.
policlinicogemelli.it (A. Nardangeli), francescodionisi2@gmail.com (F. Dionisi), stefano.vagge@hsanmartino.it (S. Vagge), antonio.pontoriero@unime.it
(A. Pontoriero), vdonato@scamilloforlanini.rm.it (V. Donato), mariangela.massaccesi@policlinicogemelli.it (M. Massaccesi).
1
Equally contribute.
2
President of AIRO (Italian Association of Radiotherapy and Clinical Oncology), Italy.

https://doi.org/10.1016/j.critrevonc.2021.103500
Received 24 March 2021; Received in revised form 20 August 2021; Accepted 10 October 2021
Available online 21 October 2021
1040-8428/© 2021 Elsevier B.V. All rights reserved.
M. Maddalo et al.
increasing number of long-term survivors. These patients can develop
during the follow-up metachronous oligometastatic progression, local
recurrent cancer or a second primary tumor and can be treated a second
time either with a curative purpose or with palliative intent.
Radiation therapy represents a mainstay of local lung cancer treat­
ment, both in the curative and the palliative settings, with or without
combined systemic therapy. Approximately 20 %–50 % of patients with
Non Small Cell Lung Cancer (NSCLC) and 36–52 % of patients with
Small Cell Lung Cancer (SCLC) develop a loco-regional failure after
primary radiotherapy (O’Rourke et al., 2010; Auperin et al., 2006;
Turrisi et al., 1999).
Radiation oncologists frequently face recurrences, second primary
tumors or metastasis developed within a previously irradiated thoracic
area (Jeremic et al., 2001).
Local treatments for patients already irradiated for chest malig­
nancies include radical surgery, radiofrequency ablation (RFA), and
radiation therapy. Re-irradiation has become an effective option, both
for palliative and radical treatment intent in patients not suitable for
surgery. Usually thoracic re-irradiation is defined as at least two courses
of thoracic radiotherapy with an overlap of at least the 50 % isodose
levels between the two courses. Recent advances in radiation techniques
and technology, such as image-guided radiotherapy (IGRT), stereotactic
body radiotherapy (SBRT) and particle therapy (in particular proton
beam therapy - PBT), have the potential to widen the therapeutic win­
dow and thus facilitate thoracic re-irradiation. Nevertheless, the toler­
ance of repeated exposure of previously irradiated organs at risk (OARs)
Fig. 1. Flow chart of studies screened, excluded, and identified for analysis according PRISMA.
2
Critical Reviews in Oncology / Hematology 167 (2021) 103500
remains an issue when considering thoracic re-irradiation.
A wide heterogeneity of indications, techniques and treatment reg­
imens makes it difficult to easily draw definitive safety considerations
from currently available clinical data. The aim of this review, performed
within the framework of the AIRO Re-irradiation Study Group, is to
systematically analyze the most recent literature in order to obtain a
clearer picture of re-irradiation-induced toxicity focusing on identifi­
cation of the incidence and severity of radiation pneumonitis/pulmo­
nary fibrosis (RP/PF), esophagitis, chest wall pain/rib fracture,
radiation dermatitis and any severe/fatal adverse events G4-G5 (AE).
Survival and local control data will also be reported, to clarify
whether thoracic re-irradiation provides sufficient tumor control with
acceptable toxicity.
2. Methods
2.1. Selection of studies
Using recommendations of the Preferred Reporting Items for Sys­
tematic Reviews and Meta-Analyses (PRISMA) (Moher et al., 2009) a
literature search on MEDLINE, EMBASE, OVID, and Cochrane databases,
published from January 1995 to October 2019, was performed (Fig. 1).
Key words used were (‘reirradiation’/exp OR‘re-irradiation’ OR ‘reir­
radiation’ AND ‘thoracic’) and (re irradiation/exp OR re irradiation OR
re irradiation AND lung).
M. Maddalo et al.
2.2. Selection criteria and data extraction
Retrospective and prospective studies with at least 10 patients were
included in the analysis. English language, full-text articles and presence
of detailed toxicity data were the other inclusion criteria. References
listed in the screened articles were also evaluated and cross-referenced
to ensure completeness. Abstracts, letters, proceedings from scientific
meetings, editorials, reviews without original data and duplicate studies
were excluded during the initial database screening. Thoracic re-
irradiation was reported for recurring primary, lymph node recur­
rence, or both.
Five authors (MM, AA, MS, AN and ED) performed the selection of
studies independently, then the decision for full-text articles eligible for
quantitative analysis was performed by three reviewers (FF, MM, ED)
and any disagreement was resolved by discussing the issues that led to
disagreement.
2.3. Review of the trials
Studies were first reviewed for pertinence of patients and treatments
characteristics. Methodological quality of studies was assessed with a
checklist for quality appraisal of case series studies produced by the
Institute of Health Economics (IHE) after modification to improve
applicability (www.ihe.ca/research-programs/rmd/cssqac/cssqac-abo
ut). The following items were evaluated for each study: a clearly
stated aim, prospective data collection, multi-center study, consecutive
patients, described characteristics of patients, clearly stated eligibility
criteria, described intervention, reported losses to follow-up and adverse
events, conclusions of the study supported by the results. Studies
reporting data on re-irradiation with different intent (palliative versus
curative) and techniques (conventional fractionation, SBRT, proton or
carbon ion radiotherapy) were equally accepted and included. To
improve the comparability of the different re-irradiation regimens and
to assess the relationship between radiation dose and toxicity, when the
nominal treatment dose was not reported in the study, equivalent dose
in 2 Gy fractions (EQD2) was calculated according to D × (D/n + α/β)/(2
+ α/β), derived from the linear-quadratic model. The α/β-value used for
the target volume was 10, while it was 3 for organs at risk. We calculated
cumulative equivalent dose assuming no repair between irradiation se­
ries (Abusaris et al., 2012). To determine the pooled G≥3 toxicity rate,
overall survival at 1 and 2 years, locoregional progression free survival
at 1 and 2 years and symptom relief, an established meta-analysis
technique over single arm studies was performed. For this purpose, we
calculated the estimated population proportion of toxicity, 1 and 2 year
overall survival, 1 and 2 year locoregional control and symptom relief
with 95 % CI for each separate study (Julious and Campbell, 1998).
Pooled effect size aided the general evaluation of re-irradiation risk and
effect. Heterogeneity across studies was examined by the Cochran Q
chi-square test and the I 2 statistic. Studies with an I 2 statistic of 25–50
%, 50–75 %, and >75 % were considered to have low, moderate, and
high heterogeneity, respectively (Higgins et al., 2003). We used ran­
dom-effects models because there was great subjectivity given the lack
of related control groups in the non-comparative studies, and a tendency
towards high heterogeneity.
3. Results
The literature search yielded 293 citations. After duplicates removal,
272 articles were evaluated, of these 232 were excluded with reasons
(Fig. 1): treatment was not radiotherapy (n = 61) or re-irradiation (23),
data available only for technique (n = 12) or radiobiology (n = 16),
other re-irradiation site (n = 76), treatment in pediatric population (n =
4), other exclusion criteria (n = 36). Reviews without original data (n =
3), 1 tox reported out of review’s criteria (n = 1), were excluded after a
second screening. Thirty-six studies met the inclusion criteria. The main
features of the included trials are shown in Table 1. These studies were
3
Critical Reviews in Oncology / Hematology 167 (2021) 103500
published between 2002 and 2019 in 10 different countries. Only 2
studies had a prospective design while the remaining 34 were retro­
spective (Chao et al., 2017; Wu et al., 2003). The analyzed population of
each study varied greatly, ranging from 10 (Chao et al., 2017; Wegner
et al., 2018) to 102 patients (McAvoy et al., 2014) with a total number of
1283 patients who had been treated with re-irradiation in the thoracic
region. Treatment intent (i.e. palliation versus cure) was generally not
well defined. Median follow-up after re-irradiation was 15 months
(range 6.5–47.3 months), with six (Chao et al., 2017; McAvoy et al.,
2014; Ebara et al., 2007; Ceylan et al., 2017; Ren et al., 2018; Schlampp
et al., 2019) of thirty-six studies reporting a median follow up of <10
months.
3.1. Re-irradiation site, dose and time interval from first radiotherapy
In our selection, the degree of volume overlap between the previous
and re-irradiation plans was often not well detailed. When available, the
reported locations of re-irradiated lesions indicated that the re-
irradiation volumes were likely to have been fully encompassed by at
least the 50 % isodose of the previous radiotherapy plan and most often,
wholly or partially, within the high dose region.
Previous radiotherapy was delivered with a median dose of 60 Gy,
ranging from 28.8 to 80 Gy using a conventional treatment (2D or 3D
radiotherapy, with a fraction dose ≤ 3 Gy/die) in 15 studies (Wu et al.,
2003; Ebara et al., 2007; Ren et al., 2018; Schlampp et al., 2019; Oka­
moto et al., 2002; Tada et al., 2005; Kelly et al., 2010; Liu et al., 2012;
Reyngold et al., 2013; Kruser et al., 2014; Trovo et al., 2014; Owen et al.,
2014; Hong et al., 2019; Sumodhee et al., 2019) and a combination of
conventional treatment and stereotactic radiotherapy in 8 studies
(Ceylan et al., 2017; Trakul et al., 2012; McAvoy et al., 2013; Meijneke
et al., 2013; Griffioen et al., 2014; Kilburn et al., 2014; Patel et al., 2015;
Binkley et al., 2016). In the remaining studies, stereotactic radiotherapy
alone was used in five studies (Hearn et al., 2014; Peulen et al., 2011;
Yoshitake et al., 2013; Caivano et al., 2018; Ogawa et al., 2018),
carbon-ion or proton therapy in two studies (Karube et al., 2017a;
Hayashi et al., 2018), brachytherapy in two (Wegner et al., 2018; Gill
et al., 2015) and in two other studies (McAvoy et al., 2013; Ohguri et al.,
2012) a combination of conventional and proton therapy was used while
in 3 studies (Chao et al., 2017; Tada et al., 2005; Ohguri et al., 2012) the
technique of previous radiotherapy was not described. The mean time
elapsed since previous irradiation ranged from 7.9 to 51 months, the
median interval time was 18 months.
A stereotactic radiotherapy technique was used to re-irradiate pa­
tients in fourteen studies (Wegner et al., 2018; Ceylan et al., 2017; Kelly
et al., 2010; Liu et al., 2012; Reyngold et al., 2013; Trovo et al., 2014;
Owen et al., 2014; Trakul et al., 2012; Patel et al., 2015; Hearn et al.,
2014; Peulen et al., 2011; Caivano et al., 2018; Ogawa et al., 2018; Gill
et al., 2015), while in ten studies (Wu et al., 2003; Ebara et al., 2007;
Schlampp et al., 2019; Okamoto et al., 2002; Tada et al., 2005; Kruser
et al., 2014; Griffioen et al., 2014; Yoshitake et al., 2013; Ohguri et al.,
2012; Cetingoz et al., 2009) a conventional treatment (2D or 3D
radiotherapy with a fraction dose ≤ 3 Gy/die) was used. In four studies
(Chao et al., 2017; McAvoy et al., 2013; Hayashi et al., 2018; Karube
et al., 2017b) radiation was delivered using proton or carbon ion ther­
apy, while in eight studies (McAvoy et al., 2014; Ren et al., 2018; Hong
et al., 2019; Sumodhee et al., 2019; Meijneke et al., 2013; Kilburn et al.,
2014; Binkley et al., 2016; Sumita et al., 2016) various re-irradiation
techniques were used (conventional, stereotactic, proton therapy).
Re-irradiation prescription doses were variable across different studies,
but also between patients in the same study (see Table 1). Chemotherapy
was given concurrently with re-irradiation in 187 patients (14.6 %). In
27 patients (2.1 %) re-irradiation was delivered after surgery and in 6
patients (0.5 %) re-irradiation was given concomitantly with
hyperthermia.
 Table 1

M. Maddalo et al.
Characteristics of the included studies in the meta-analysis.
First Author Study type: Accrual Median FU Previous RT Previous total dose Time elapsed Re-RT Re-RT total dose Gy CHT Relevant toxicity (N◦ of pts)
Journal Retrospective (R) period (months) technique Gy (months) technique median (range) (%)
Year Prospective (P) median (range) between RT
N◦ Patients/N◦ and re-RT
Treatments* median (range)

Okamoto, Int. J. R 1979– 2000 15 2D 60 (30− 80) 23 (5–87) 2D 3D 50 (10− 70) 15 7 G3 radiation pneumonitis
Radiation 34/34
Oncology Biol.
Phys. 2002
Wu, Int. J. Radiation P 1999− 2001 15 3D 66 (30− 78) 13 (6− 42) 3D 51 (46− 60) 0 2 G3 pulmonary fibrosis
Oncology Biol. 23/23
Phys. 2003
Tada, Int. J. Clin. R 1992− 2002 unknown unknown (50− 69.6) 16 (5–60) unknown 50 1 1 G3 radiation pneumonitis
Oncol. 2005 19/19
Ebara, Anticancer R 1990− 2004 6,5 2D (50− 70) 13 (6− 47) 2D (30− 60) 36 3 G3 pulmonary toxicity
Research 2007 44/44
Cetingoz, Journal of R 1992− 2006 135 2D (28,8− 67,2) 8 (4− 44) 2D (5− 30) 3 1 G3 acute esophagitis
BUON 2009 38/38
Kelly, Int. J. R 2004− 2008 15 3D IMRT 61.5 (30–79.2) 22 (0–92) SBRT 50 0 7 G3 pneumonitis 3 G3 esophagitis 2 G3 chest
Radiation 36/36 wall ulcers 2 G3 cough
Oncology Biol.
Phys. 2010
Peulen, R 1994− 2004 12 SBRT various (see original 14 (5–54) SBRT various (see original 0 3 G3 Cough 4 G3 Dyspnea 1 G3 Pneumonitis 1 G3
Radiotherapy and 29/32 article) article) Stenosis of airway 3 G5 Bleeding 1 G3 Pleural
Oncology 2011 effusion G3 Dermatitis G3 Pain 2 G4 Other
(fistula, VCS fibrosis)
Ohguri,Lung Cancer R 1992− 2009 11 unknown 70 (30− 85) 8 (1− 28) unknown 50 (29− 70) 46 1 neuropathy brachial plexus
2012 33/33
4

Trakul, Journal of R 2004− 2010 15 3D IMRT BED 87.5 16 (5–80) SBRT various (see original 0 9 Pneumonitis > G2
Thoracic 15/17 SBRT (60–112.5) article)
Oncology 2012
Liu, Int. J. Radiation R 2004− 2010 16 CFRT 63 (30− 79.2) 21 (0− 106) SBRT 50 0 14 G3 radiation pneumonitis 1 G5 radiation
Oncology Biol. 72/72 pneumonitis
Phys. 2012
Reyngold, Radiation R 2004− 2011 126 2D 3D IMRT 61 (30–80) 37 (1− 180) SBRT various (see original 0 G3 pulmonary toxicity 2 G3 chest wall pain 1 G4
Oncology 2013 39/39 article) skin toxicity
Yoshitake, R 2004− 2011 126 SBRT 48 12 (6− 36) unknown (60− 70) 24 All G1-G2
Anticancer 17/17

Critical Reviews in Oncology / Hematology 167 (2021) 103500

Research 2013
McAvoy, R 2006− 2011 11 unknown 63 (40–74) 36 (2–376) Proton RBE 66 (16.4− 75) 24 3 G3 esophageal toxicity 7 G3 pulmonary toxicity
Radiotherapy and 33/33 1 G3 cardiac toxicity 1 G4 esophagitis (fistula) 2
Oncology 2013 G4 pulmonary toxicity
Meijneke, R 2005− 2012 12 SBRT CFRT various (see original 17 (2–33) SBRT CFRT various (see original 0 All G1-G2
Radiotherapy and 20/20 article) article)
Oncology 2013
McAvoy, Int. J. R 2006− 2013 6,5 2D 3D IMRT EQD2 70 (33− 276) 17 (0− 376) Proton EQD2 60.5 33 3 early discontinuation
Radiation 102/102 SBRT (25.2− 155) 7 > G3 esophageal toxicity 10 > G3 pulmonary
Oncology Biol. Proton toxicity 1 G3 cardiac toxicity
Phys. 2014
Griffioen, Lung R 2004− 2013 193 unknown 59.8 (24–70) 51 (5− 189) IMRT 60 (39–66) 8 1 G3 esophagitis 1 G3 dermatitis 3 G5 bleeding
Cancer 2014 24/24
Kruser, Am. J. Clin. R 2004− 2010 265 3D IMRT NSCLC 57 19 2D 3D IMRT NSCLC 30 (12–60) 0 3 G3 acute pulmonary toxicity 1 G4 late
Oncol. 2014 48/48 (30–80.5) SCLC 45 SCLC 375 (25− 45) pulmonary toxicity
(12–54)
Trovò, Int. J. R unkown 18 3D IMRT (50− 60) 18 (1− 60) SBRT 30 0 4 G3 radiation pneumonitis 1 G5 radiation
Radiation 17/17 pneumonitis 1 G5 hemoptysis
(continued on next page)
 Table 1 (continued )

M. Maddalo et al.
First Author Study type: Accrual Median FU Previous RT Previous total dose Time elapsed Re-RT Re-RT total dose Gy CHT Relevant toxicity (N◦ of pts)
Journal Retrospective (R) period (months) technique Gy (months) technique median (range) (%)
Year Prospective (P) median (range) between RT
N◦ Patients/N◦ and re-RT
Treatments* median (range)

Oncology Biol.
Phys. 2014
Hearn, Int. J. R 2004− 2012 138 SBRT various (see original 15 (10− 26) SBRT (50− 60) 0 All G1-G2
Radiation 10/10 article)
Oncology Biol.
Phys. 2014
Kilburn, R 2001− 2012 17 3D SBRT CFRT 66 (45–80.5) 18 (6− 61) 3D IMRT various (see original 0 1 G3 dyspnea (oxygen) 1 G5 aorta-esophageal
Radiotherapy and 33/33 SBRT 50 (22.5–60) SBRT article) fistula
Oncology 2014
Patel, J. Radiat. R 2008- 2011 unknown CFRT SBRT 612 8 (3− 26) SBRT 30 (15–50) 0 All G1-G2
Oncol. 2015 26/29
Binkley, Int. J. R 2008- 2014 17 CFRT HFRT SBRT 40 (25− 54) 16 (1− 71) SBRT HFRT SBRT 40 (25− 54) 26 3 G>2 acute esophagitis 2 G>2 acute chest wall
Radiation 38/38 SBRT HFRT (49,5− 51 Gy) CFRT HFRT 60(60− 64,5) tox 2 G > 2 late rib fracture 2 recurrent laryngeal
Oncology Biol. CFRT 66 (45− 71.6 hypoFRT CFRT 66 (60− 72) neuropathy 1 late brachial plexopathy 1 late
Phys. 2015 Gy) hypoFRT 60 (50− 60) Horner’s syndrome
Gill, Frontiers in R unkown 252 post-op BRT unkown 46 (11− 114) SBRT various (see original 0 1 G3 esophageal stricture
Oncology 2015 13/13 article)
Owen, Frontiers in R 2006- 2012 212 CFRT EQD2 60 (42.3− 70) 18 (2− 113) SBRT various (see original 17 All G1-G2
Oncology 2015 18/27 article)
Sumita, Radiation R 2007- 2014 221 CFRT NSCLC: 60 SCLC: 27 (11− 92) CFRT NSCLC: 60 SCLC: 50 5 1 acute G3 pneumonitis
Oncology 2016 21/21 Proton (1) 43.1 Proton
Ceylan, Oncol. Res. R 2005- 2015 9 2D 3D IMRT 54 (40–57) 14 (4− 56) SBRT various (see original 57 All G1-G2
Treat. 2017 28/28 VMAT SBRT article)
Chao, Journal of P, multi- 2010- 2015 7,8 unknown unknown 19 (4− 151) Proton 66.6 (30–74) 68 3 G4 neutropenia 1 G4 pericardial effusion 1 G5
5

Thoracic institutional bronchial hemorrhage 1 G5 neutropenic sepsis 1

Oncology 2017 57/57 G5 Anorexia 1 G5 Pneumonitis 1 5 Hypoxic
respiratory failure/pleural effusion 1 G5
Tracheoesophageal fistula
Karube, R 2007− 2014 29 carbon-ion various (see original 20 (8− 99) carbon-ion 66 0 All G1-G2
Radiotherapy and 29/29 article)
Oncology 2017
Caivano, Radiation R 2011− 2016 13 SBRT BED 97.2 Gy 18 (6− 66) SBRT BED 100.6 0 1 G3 acute dyspnea 1 G3 late dyspnea 1 G3 late
Oncology 2018 22/27 (40− 120) (48− 151.2) chest pain 2 G3 pulmonary fibrosis
Ogawa Radiation R 2004− 2017 26 SBRT (48− 52) 18 (4− 80) SBRT (48− 60) All G1-G2
Oncology 2018 31/31

Critical Reviews in Oncology / Hematology 167 (2021) 103500

Wegner, Lung R unkown 465 BRT 120 41 (2− 85) SBRT 50 0 All G1-G2
Cancer 10/10
Management
2018
Hayashi, Cancer R 2006− 2016 18 carbon-ion RBE (28− 68,4) 17 (6− 139) carbon-ion (48− 72) 0 All G1-G2
Science 95/95 stage I (68− 76)
stage IIA-IIIB
Ren, Radiation R 2010− 2017 9 3D IMRT 56 (30− 120) 16 (2− 96) 3D SBRT 3D (40− 60) SBRT 28 18 G3 Pneumonitis 1 G4 Pneumonitis
Oncology 67/67 (40− 50)
Hong, Cancer res. R 2005 174 3D IMRT 60 (45− 66) 15 (4− 56) IMRT 50 (35− 65) 10 All G1-G2
treat. 31/31 Helical Helical
SBRT
Schlampp, Strahler R 2010− 2015 8,2 3D 60 14 (3− 103) IMRT 385 (20− 60) 0 2 G3 and 1 G5 Pneumonitis 1 tracheal fistula
Onkology 62/62
Sumodhee, BMC R 2007− 2015 473 3D 66 (44− 70) 23 (6− 102) SBRT (50− 60) 22 All G1-G2
Cancer 46/46

*Number of patients treated or number of lesion treated.

3D: three dimensional conformal radiotherapy; IMRT: intensity modulated radiation therapy; SBRT: Sterotactic body radiotherapy; HFRT: hyperfractionated radiotherapy; CFRT: conformal radiotherapy; hypoFRT:
hypofractionated radiotherapy.
M. Maddalo et al.
Fig. 2. Pooled rate of ≥G3 toxicity in re-irradiated patients for included
studies.
Abbreviations: Q: cochran’s Q-statistic, I2: I2-statistic (both are used to evaluate
heterogeneity across studies), ES: Effect Size.
Fig. 3. Pooled objective 1 y overall survival in re-irradiated patients for
included studies.
Abbreviations: Q: cochran’s Q-statistic, I2: I2-statistic (both are used to evaluate
heterogeneity across studies), ES: Effect Size.
3.2. Toxicity and Radiation tolerance of organ at risk
All studies reported the organs at risk (OARs) constraints either as
6
Critical Reviews in Oncology / Hematology 167 (2021) 103500
Fig. 4. Pooled objective 2 y overall survival in re-irradiated patients for
included studies.
Abbreviations: Q: cochran’s Q-statistic, I2: I2-statistic (both are used to evaluate
heterogeneity across studies), ES: Effect Size.
Fig. 5. Pooled objective 1 y local control in re-irradiated patients for included
studies.
Abbreviations: Q: cochran’s Q-statistic, I2: I2-statistic (both are used to evaluate
heterogeneity across studies), ES: Effect Size.
maximum point doses or as cumulative doses from the previous irradi­
ation and the re-irradiation. Data on acute toxicity were analyzed in all
studies: ≥ G3 acute toxicity was observed in 135 patients (10.5 %).
There was no difference in ≥ G3 acute toxicity rate with respect to
different radiation techniques, cumulative dose and re-irradiation total
dose and fractionation. Fourteen patients (1.09 %) died because of likely
treatment related acute toxicities such as neutropenia, fatal hemor­
rhages and pneumonia. Globally, the pooled effect size for toxicity ≥ G3
M. Maddalo et al.
Fig. 6. Pooled objective 2 y local control in re-irradiated patients for included
studies.
Abbreviations: Q: cochran’s Q-statistic, I2: I2-statistic (both are used to evaluate
heterogeneity across studies), ES: Effect Size.
Fig. 7. Pooled objective symptoms relief in re-irradiated patients for included
studies.
Abbreviations: Q: cochran’s Q-statistic, I2: I2-statistic (both are used to evaluate
heterogeneity across studies), ES: Effect Size.
was 9.1 % (95 %CI: 6.3–13.1 %) with high heterogeneity (I2 = 87.063, P
< 0.001) (Fig. 2). No difference in heterogeneity was evident analyzing
studies using the different modalities of re-irradiation.
3.3. Outcomes
Thirty-three studies reported data on 1-yr OS and the pooled 1-yr OS
rate was 60.9 % (95 %CI: 54.8–67.6 %) with high heterogeneity (I 2 =
85.5 %, P = 0.001) (Fig. 3). No difference in heterogeneity was observed
analyzing studies using the different modalities of re-irradiation. Two-
year OS was reported by 33 studies. The pooled effect size for 2-yr OS
was 43.9 % (95 %CI: 38.7–49.9 %) with moderate heterogeneity (I 2 =
74.7 %, P = 0.001) (Fig. 4). Analyzing only studies using stereotactic
radiotherapy and proton/carbon ion, the pooled result was respectively
50.8 % (95 % CI: 42–61.6 %) with a moderate heterogeneity (I2 = 65.2
%, P = 0.001) and 50.4 % (95 % CI: 38.8–65.5 %) with a moderate
heterogeneity (I2 = 60.6 %, P = 0.055). No difference in heterogeneity
was observed analyzing studies using the other different modalities of
re-irradiation.
Locoregional progression free survival at 1 and 2 year was reported
by 27 and 26 studies, respectively. The pooled 1-yr locoregional pro­
gression free survival rate was 65.1 % (95 % CI: 59.7–71.1 %) with high
heterogeneity (I 2 = 83.7 %, P = 0.001) (Fig. 5). Instead, the pooled 2-yr
locoregional progression free survival rate was 47.2 % (95 % CI:
40.4–55.1 %) with high heterogeneity (I 2 = 83.7 %, P = 0.001) (Fig. 6).
Only six studies evaluated improvements in symptoms (Ebara et al.,
7
Critical Reviews in Oncology / Hematology 167 (2021) 103500
2007; Okamoto et al., 2002; Tada et al., 2005; Kruser et al., 2014;
Ohguri et al., 2012; Cetingoz et al., 2009). The pooled analysis showed
that 79.5 % of patients who experienced symptoms obtained relief (95 %
CI: 72–87.8 %) (Fig. 7).
4. Discussion
The advent of more efficient local interventions and increasingly
multimodal therapies has led to an improvement in lung cancer treat­
ment outcome. Therefore, an increasing number of patients may need
re-treatment for recurrent or metastatic disease and re-irradiation is
among the possible approaches. Thoracic re-irradiation is one of the
most significant challenges for modern radiotherapy, as the control of
symptoms, the possibility for cure and the risk of side effects has to be
carefully balanced. The major issue in this context is the difficulty to
predict the probability for severe toxicity for a given patient due to the
lack of knowledge of normal tissue complication probabilities (NTCP)
and data on organ at risk (OARs) tolerance in the heterogeneous cohort
of patients that undergo re-irradiation. Currently, dosimetric constraints
are only available for patients that underwent SBRT, as first treatment
approach (Benedict et al., 2010; Grimm et al., 2011; Milano et al., 2008).
This review attempts to extract useful information regarding severe
toxicity after thoracic re- irradiation from available clinical data.
First, some issues should be considered when thoracic toxicity is
reported. The majority of the studies included in the analysis scored
toxicity according to Common Terminology Criteria for Adverse Event
(CTCAE), but there were 5 series in which the scale used was either the
RTOG/EORTC (Wu et al., 2003; Ebara et al., 2007; Okamoto et al., 2002;
Cetingoz et al., 2009) or the WHO (Tada et al., 2005) and 2 studies in
which the scale was not specified (Wegner et al., 2018; Trakul et al.,
2012). The use of different toxicity scores has an impact on the
comparability of toxicity data and limits the accuracy of results’
comparison.
As a second issue, thoracic re-irradiation has so far mainly performed
with palliative intent, which results in a median follow up of only 15
months (range 6.5–47.3 months) and as a consequence in a paucity late
toxicity data. This limits the extrapolation of existing data to patient
cohorts where re-irradiation is performed in a fully or quasi-curative
intent.
Only few studies in this review explicitly reported symptom relief,
but an albeit ill defined “benefit” was seen globally in 795% of cases. In a
meta-analysis (Drodge et al., 2014) published in 2014 collecting data of
older studies with a smaller proportion of patients treated with
radical-intent re-irradiation the authors reported a similar overall
average symptom improvement of 69.2 %. Thus, even if the description
of symptoms varied across different studies the benefit of re-irradiation
in the palliative setting seems well documented.
Over the recent past, a shift towards SBRT higher doses per fraction
accentuated the uncertainties on late toxicities prediction. In a recent
meta-analysis (Viani et al., 2020) on effectiveness and safety of SBRT
re-irradiation the authors found a correlation between the cumulative
EQD2 dose and the development of any grade 3 toxicity. The risk of
toxicity was significantly higher (3% vs. 15 %, P = 0.03) when the EQD2
was stratified into EQD2 ≤ 145 Gy or EQD2 > 145 Gy.
In a further attempt to provide the appropriate “flavor” of the results
reported as quantitative global data based on the meta-analysis in the
results section, we here discuss these data adding more specific infor­
mation and conclusions on three peculiar topics: severe acute toxicity,
particle therapy and the combination of re-irradiation with
chemotherapy.
4.1. Severe acute toxicity
A review published in 2011 by Jeremic (Jeremic et al., 2001) on
chest re-irradiation reported low rates of severe acute toxicity, mainly
esophagitis (4–6 %) and pneumonitis (5–21 %), but the authors specified
M. Maddalo et al.
that many of the studies included that covered a pre-1990 therapy were
particularly limited by the absence of formal toxicity scoring systems.
In the present review, data about the safety of re-irradiation with
conventional techniques were collected from different studies (see
Table 1). However, many of these works collected data from re-
irradiation addressed both with symptomatic and “radical” intent.
Cetingoz et al. (2009) reported the outcome of 38 patients. Of the 26
patients who showed toxicity, only 1 had G3 esophagitis (3%). Ac­
cording to Ebara et al. (2007) in 44 patients, 3 G3 pulmonary toxicity
were observed (7%), and 14 % of patients experienced a pulmonary
toxicity of any grade. Tada et al. (2005) in a series of 19 patients
mentioned only 1 G3 pneumonitis in the oldest patient of the series (84
year’s old), and a 20 % of cumulative G2-G3 lung toxicity. A study from
Wu et coll. (Wu et al., 2003), showed similar rates (< 10 %) of severe
lung toxicity with 2 G3 pulmonary fibrosis. Only one study by Okamoto
et al. (2002) reported a higher rate of G3 pneumonitis in 7/34 (21 %). In
our pooled analysis acute toxicity ≥ G3 was observed in 135 patients
(10.5 %). There was no difference in ≥ G3 acute toxicity rate with
respect to different radiation techniques.
In 2015 De Bari et al. (2015) performed a review on the feasibility of
SBRT after high dose radiotherapy for lung cancer. They reported a ≥ G3
pulmonary toxicity of 3–28 %. This wide range of toxicity reflects the
heterogeneity of studies due to the intent of treatment, schedules, and
patients’ characteristics.
In our analysis, severe toxicity such as pneumonitis/pulmonary
fibrosis (RP/PF), esophagitis, chest wall pain/rib fracture, radiation
dermatitis and severe/fatal G4-G5 adverse events (AE) were reported by
different studies.
Different predictive factors for severe toxicity were identified. One of
the most important factors seems to be the location of the treatment site.
A Swedish retrospective analysis (Peulen et al., 2011) of 32 patients that
underwent high-dose SBRT, reported that 5 patients died of massive
hemorrhage, but the authors didn’t found a correlation with the
maximum dose to vessel wall or the dose to the entire circumference of
large mediastinal vessels. In the same report 8 patients experienced G3
lung toxicity and the authors concluded that a larger clinical target
volumes (CTV) and central tumour localization were associated with an
increased rate of severe toxicity. The correlation between the central
position of the tumor and re-irradiation toxicity has also been docu­
mented by Schlapp and Sumodhee (Schlampp et al., 2019; Sumodhee
et al., 2019). Sumodhee et al. reported that hilar tumors and tumor size
> 33 mm correlated with G5 hemoptysis and alveolitis. According to
Binkley et al. (2016), re-irradiation of non-peripheral lesions was asso­
ciated with increased toxicity, but no patient experienced a severity >
G3.
In 2012, Liu et al. (2012) published the results on re-irradiation with
SBRT in 72 pts initially treated with conventional fractionation (median
dose of 63 Gy). Fourteen and one patients experienced G3 and G5 ra­
diation pneumonitis respectively. The dosimetric analysis of composite
plans showed that V10 and mean lung dose (MLD) of the previous plan
and the V10-V40 and MLD were related to lung toxicity. Also Hong et al.
(2019) reported a statistically significant difference in the cumulative
MLD for patients with and without acute pulmonary symptoms (p =
0.004).
Interestingly, pulmonary severe toxicity could also be related to the
dose received by other OARs. In a retrospective study on 17 pts re-
treated with relatively low doses (30 Gy in 5–6 fractions), Trovò et al.
(Trovo et al., 2014) identified that heart maximum dose, D5 mean of 10
Gy and D10 mean of 3 Gy were correlated with higher risk of > G3
pneumonitis and hemoptysis. A retrospective analysis in definitive
treatment of lung malignancies, established the role of heart dosimetric
parameters in predicting the post-radiotherapy pneumonitis, although
the mechanism of this effect remains unclear (Huang et al., 2011).
In contrast with what was reported thus far, a group from the MD
Anderson Cancer Center published the results on 36 patients (Kelly
et al., 2010) and showed that the G3 lung toxicity was only associated
8
Critical Reviews in Oncology / Hematology 167 (2021) 103500
with treatment for out-of-field relapses (28 % of patients). The authors
hypothesized a protective role of inflammation induced by first course of
radiotherapy to explain the high rate of pulmonary toxicity out of field.
However, looking more closely at the available data, the cumulative
G2-G3 rate of radiation pneumonitis was similar for patients treated for
in-field (5 of the 11 patients, 45 %) and out-of-field relapses (13 of the 25
patients, 52 %). In the same paper, the Authors reported that chest wall
pain was associated with in-field recurrence.
The combined approach of radiotherapy and Hyperthermia (Ohguri
et al., 2012) or brachytherapy, as part of initial course of treatment, does
not seem to further enhance toxicity (Gill et al., 2015).
Schröder et al. (Schroder et al., 2020) in a retrospective analysis (not
included in the present systematic review due to the recent publication)
attempted to estimate the tolerance of thoracic organs-at-risk (OAR) to
re-irradiation by calculating accumulated dose distributions using
deformable image registration and dose conversion to EQD2. In their
series of 40 patients, even if most OARs received cumulative EQD2 doses
between 70 and 100 Gy and maximum doses to individual OARs above
100 Gy, only one patient suffered from a high-grade complication.
4.2. Particle therapy
Proton beam therapy (PBT) has emerged as a potentially promising
lung re-treatment modality, given its reduced integral dose and thus
ideally improved normal tissue sparing. Nevertheless, few studies have
analyzed the role of PBT in thorax re-irradiation.
Chao et al. (2017) in a prospective multi-institutional trial reported
acute and late > G3 toxicity in a high proportion (42 %) of patients. The
paper also reported a consistent rate of G4-G5 toxicity (four cases of
grade 4 toxicity and 6 cases of grade 5 toxicity were observed, see
Table 1). This higher rate of severe toxicity in comparison with all the
other series of the present selection could be explained by the pro­
spective nature of the study and the consequent more accurate adverse
event report. The authors observed a correlation of the proximity of
re-irradiated lesions to the bronchial tree, the mean doses to heart and
esophagus obtained from the composite dose to these organ and con­
current chemotherapy (p = 0.003) with higher toxicity and were
therefore advocating a cautious selection of patients in relation to the
predictive factors identified. Notably, authors had selected patients
based on treatment volume, those with high volume >250 cm3 were
considered untreatable.
McAvoy et al. (2014, 2013) registered a G3 or higher esophageal and
pulmonary toxicity in 9% and 21 % pts respectively. Toxicity was related
to the high cumulative doses to these organs (significant Dmax (p =
0.001) and larger esophageal V60 (p < 0.001)), but not with concomi­
tant chemotherapy. Peripheral lesions had significantly lower cardiac
toxicity rates (p = 0.02) than central ones.
Overall, the crude rates of toxicity reported for PBT are similar to
what has been reported for conventional radiation therapy modalities
(Wu et al., 2003; Okamoto et al., 2002; Cetingoz et al., 2009), keeping in
mind, that the latter was usually performed with a more palliative
intent, thus with lower doses and hypothetical smaller irradiated
volumes.
Only two studies on re-irradiation with Carbon Ion Radiotherapy
(CIRT) had been included in our analysis, both showing the feasibility of
the treatment with only few cases of > G3 toxicity (Hayashi et al., 2018;
Karube et al., 2017b).
Hayashi et coll. (Hayashi et al., 2018) reported the data of 95 pa­
tients treated for primary or metastatic lung tumors: one patient
developed Pneumonitis G4, 1 reported chest pain G3, and 1 developed a
bronchopleural fistula G5. This patient had received long-term Bev­
acizumab before and after CIRT and the fistula was detected in the re­
gion exposed to >70.0 Gy of relative biological effectiveness (RBE).
Based on their experience, the authors suggested the criteria for selec­
tion of appropriate patients for CIRT: solitary recurrent, metastatic or
secondary tumors in the lung or mediastinum, not suitable for surgery,
M. Maddalo et al.
no previously treatment with Bevacizumab, with at least 24 months
between primary treatments and re-irradiation, CTV volume for new
irradiation <80.0 mL.
Even if our analysis does not support the use of one technique over
the others in terms of incidence of adverse events, a comparison between
CIRT and photon or proton therapy is challenging because differences in
physical dose deposition but more importantly because of significant
uncertainties in the precise estimation of the α/β ratio of high-linear
energy transfer (LET) radiation (CIRT), and, thus, RBE.
4.3. Chemotherapy
The impact of concomitant chemotherapy on the development of
serious toxicity in the re-irradiation setting is not clear as the results are
heterogeneous. In our analysis, concurrent chemotherapy was admin­
istered in 11/36 studies (Chao et al., 2017; McAvoy et al., 2014; Ebara
et al., 2007; Ceylan et al., 2017; Okamoto et al., 2002; Tada et al., 2005;
McAvoy et al., 2013; Binkley et al., 2016; Ohguri et al., 2012; Cetingoz
et al., 2009; Sumita et al., 2016).
Only in the study of Chao et al. (2017), there seem to be a correlation
with an increase in severe toxicity with concomitant chemotherapy,
while, in the reports by McAvoy et al. (2014, 2013) and Binkley et al.
(2016), this was not confirmed.
Interestingly, Yang et al. (2020) in a recent paper not included in the
present selection reported a significant association between subsequent
chemotherapy following thoracic re-irradiation (p = 0.009) with lethal
lung events, and a trend in favor of taxane-based regimens versus those
not receiving taxane-based regimens.
In the era of a preferentially integrated and multidisciplinary treat­
ment approach, even though the goal of re-irradiation is still mostly
palliation, the combined approach could provide durable local control
and potentially improve progression-free and overall survival in an
increasing number of patients.
Recently, in clinical practice, despite a lack of unequivocal preclin­
ical and clinical experimental data, patients with recurrent or metastatic
NSCLC and SCLC have frequently been referred to targeted therapy and
immunotherapy in association with re-irradiation in order to gain
greater efficacy and increase survival (Evans et al., 2017; Arcangeli
et al., 2019a; Arcangeli et al., 2019b). Although existing data on efficacy
are encouraging, long-term result, particularly acute and late toxicity,
are not yet enough, and combined treatments should be performed with
caution.
5. Conclusion
This is a comprehensive and systematic review on thoracic re-
irradiation. A meta-analysis technique has been used to address sur­
vival and toxicity outcomes, but its clinical and scientific validity is
limited by the heterogeneity of the included studies. Different treatment
paradigms (palliative versus curative intent, in field recurrence versus
edge of field recurrence, local relapse versus separate primary versus
oligometastatic lung metastases) makes it even harder to draw reliable
conclusions.
The inconsistency of the data is also due to the retrospective nature
of the majority of the studies analyzed - many of these including a small
number of patients - the possible role of chemotherapy and the hetero­
geneity of radiation therapy modalities, volumes treated, and
scheduling.
This analysis shows that the main problem of the existing data is the
frequent lack of a sufficient description of the treatment’s intent, which
makes balancing risk and benefit of re-irradiation based on published
data even more difficult.
Thus the 10–25 % rate of acute severe pulmonary toxicity could be
reasonable in the curative setting of re-irradiation both with photon RT
techniques and highly conformal techniques such as IMRT, SBRT, PBT,
or CIRT.
9
Critical Reviews in Oncology / Hematology 167 (2021) 103500
The high rate of symptoms relief could still justify the use of re-
irradiation with lower doses in a palliative scenario. However, dose
schedules, both for palliative and curative intent are yet to be
investigated.
Importantly the conclusions regarding the comparison of the
different treatment modalities, given that different NTCP model might
have to be applied. To offer the best therapeutic option to patients
referred to re-irradiation in loco-regional recurrence or metastatic dis­
ease, great attention should be paid to comorbidities and age to more
precisely predict the benefit of thoracic re-irradiation over systemic
therapy or best supportive care.
Besides, unknown factors such as genetic susceptibility could also
affect OAR tolerance to radiotherapy (Tang et al., 2020; Xu et al., 2019).
To achieve reliable results from retrospective series an accurate se­
lection of patients and a proper indication about intent, dose and tech­
nique are warranted. Prospective clinical trials evaluating molecular
predictors to assess the real advantages of re-irradiation in terms of
disease control and toxicity with different techniques and in different
populations, above all in oligometastic disease, are needed to provide
more accurate selection criteria for thoracic re-irradiation. Defining a
standard shared nomenclature to be used in re-irradiation prospective
and retrospective data collection would be welcomed.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors certify that they have NO affiliations with or involve­
ment in any organization or entity with any financial interest (such as
honoraria; educational grants; participation in speakers’ bureaus;
membership, employment, consultancies, stock ownership, or other
equity interest; and expert testimony or patent- licensing arrangements),
or non-financial interest (such as personal or professional relationships,
affiliations, knowledge or beliefs) in the subject matter or materials
discussed in this manuscript.
Acknowledgments
The Authors thank the Scientific Committee and Board of the AIRO
for the critical revision and final approval of the paper.
References
Abusaris, H., Hoogeman, M., Nuyttens, J.J., 2012. Re-irradiation: outcome, cumulative
dose and toxicity in patients retreated with stereotactic radiotherapy in the
abdominal or pelvic region. Technol. Cancer Res. Treat. 11, 591–597.
Arcangeli, S., Jereczek-Fossa, B.A., Alongi, F., Aristei, C., Becherini, C., Belgioia, L., et al.,
2019a. Combination of novel systemic agents and radiotherapy for solid tumors -
part i: an airo (italian association of radiotherapy and clinical oncology) overview
focused on treatment efficacy. Crit. Rev. Oncol. Hematol. 134, 87–103.
Arcangeli, S., Jereczek-Fossa, B.A., Alongi, F., Aristei, C., Becherini, C., Belgioia, L., et al.,
2019b. Combination of novel systemic agents and radiotherapy for solid tumors -
part ii: an airo (italian association of radiotherapy and clinical oncology) overview
focused on treatment toxicity. Crit. Rev. Oncol. Hematol. 134, 104–119.
Auperin, A., Le Pechoux, C., Pignon, J.P., Koning, C., Jeremic, B., Clamon, G., et al.,
2006. Concomitant radio-chemotherapy based on platin compounds in patients with
locally advanced non-small cell lung cancer (nsclc): a meta-analysis of individual
data from 1764 patients. Ann. Oncol. 17, 473–483.
Benedict, S.H., Yenice, K.M., Followill, D., Galvin, J.M., Hinson, W., Kavanagh, B., et al.,
2010. Stereotactic body radiation therapy: the report of aapm task group 101. Med.
Phys. 37, 4078–4101.
Binkley, M.S., Hiniker, S.M., Chaudhuri, A., Maxim, P.G., Diehn, M., Loo Jr., B.W., et al.,
2016. Dosimetric factors and toxicity in highly conformal thoracic reirradiation. Int.
J. Radiat. Oncol. Biol. Phys. 94, 808–815.
Caivano, D., Valeriani, M., De Matteis, S., Bonome, P., Russo, I., De Sanctis, V., et al.,
2018. Re-irradiation in lung disease by sbrt: a retrospective, single institutional
study. Radiat. Oncol. 13, 87.
Cetingoz, R., Arican-Alicikus, Z., Nur-Demiral, A., Durmak-Isman, B., Bakis-Altas, B.,
Kinay, M., 2009. Is re-irradiation effective in symptomatic local recurrence of non
M. Maddalo et al.
small cell lung cancer patients? A single institution experience and review of the
literature. J. B.U.O.N. 14, 33–40.
Ceylan, C., Hamaci, A., Ayata, H., Berberoglu, K., Kilic, A., Guden, M., et al., 2017. Re-
irradiation of locoregional nsclc recurrence using robotic stereotactic body
radiotherapy. Oncol. Res. Treat. 40, 207–214.
Chao, H.H., Berman, A.T., Simone 2nd, C.B., Ciunci, C., Gabriel, P., Lin, H., et al., 2017.
Multi-institutional prospective study of reirradiation with proton beam radiotherapy
for locoregionally recurrent non-small cell lung cancer. J. Thorac. Oncol. 12,
281–292.
De Bari, B., Filippi, A.R., Mazzola, R., Bonomo, P., Trovo, M., Livi, L., et al., 2015.
Available evidence on re-irradiation with stereotactic ablative radiotherapy
following high-dose previous thoracic radiotherapy for lung malignancies. Cancer
Treat. Rev. 41, 511–518.
Drodge, C.S., Ghosh, S., Fairchild, A., 2014. Thoracic reirradiation for lung cancer: a
literature review and practical guide. Ann. Palliat. Med. 3, 75–91.
Ebara, T., Tanio, N., Etoh, T., Shichi, I., Honda, A., Nakajima, N., 2007. Palliative re-
irradiation for in-field recurrence after definitive radiotherapy in patients with
primary lung cancer. Anticancer Res. 27, 531–534.
Evans, T., Ciunci, C., Hertan, L., Gomez, D., 2017. Special topics in immunotherapy and
radiation therapy: reirradiation and palliation. Transl. Lung Cancer Res. 6, 119–130.
Gill, B.S., Clump, D.A., Burton, S.A., Christie, N.A., Schuchert, M.J., Heron, D.E., 2015.
Salvage stereotactic body radiotherapy for locally recurrent non-small cell lung
cancer after sublobar resection and i(125) vicryl mesh brachytherapy. Front. Oncol.
5, 109.
Griffioen, G.H., Dahele, M., de Haan, P.F., van de Ven, P.M., Slotman, B.J., Senan, S.,
2014. High-dose, conventionally fractionated thoracic reirradiation for lung tumors.
Lung Cancer 83, 356–362.
Grimm, J., LaCouture, T., Croce, R., Yeo, I., Zhu, Y., Xue, J., 2011. Dose tolerance limits
and dose volume histogram evaluation for stereotactic body radiotherapy. J. Appl.
Clin. Med. Phys. 12, 3368.
Hayashi, K., Yamamoto, N., Karube, M., Nakajima, M., Tsuji, H., Ogawa, K., et al., 2018.
Feasibility of carbon-ion radiotherapy for re-irradiation of locoregionally recurrent,
metastatic, or secondary lung tumors. Cancer Sci. 109, 1562–1569.
Hearn, J.W., Videtic, G.M., Djemil, T., Stephans, K.L., 2014. Salvage stereotactic body
radiation therapy (sbrt) for local failure after primary lung sbrt. Int. J. Radiat. Oncol.
Biol. Phys. 90, 402–406.
Higgins, J.P., Thompson, S.G., Deeks, J.J., Altman, D.G., 2003. Measuring inconsistency
in meta-analyses. BMJ 327, 557–560.
Hong, J.H., Kim, Y.S., Lee, S.W., Lee, S.J., Kang, J.H., Hong, S.H., et al., 2019. High-dose
thoracic re-irradiation of lung cancer using highly conformal radiotherapy is
effective with acceptable toxicity. Cancer Res. Treat. 51, 1156–1166.
Huang, E.X., Hope, A.J., Lindsay, P.E., Trovo, M., El Naqa, I., Deasy, J.O., et al., 2011.
Heart irradiation as a risk factor for radiation pneumonitis. Acta Oncol. 50, 51–60.
Jeremic, B., Shibamoto, Y., Acimovic, L., Nikolic, N., Dagovic, A., Aleksandrovic, J.,
et al., 2001. Second cancers occurring in patients with early stage non-small-cell
lung cancer treated with chest radiation therapy alone. J. Clin. Oncol. 19,
1056–1063.
Julious, S.A., Campbell, M.J., 1998. Sample size calculations for paired or matched
ordinal data. Stat. Med. 17, 1635–1642.
Karube, M., Yamamoto, N., Shioyama, Y., Saito, J., Matsunobu, A., Okimoto, T., et al.,
2017a. Carbon-ion radiotherapy for patients with advanced stage non-small-cell lung
cancer at multicenters. J. Radiat. Res. 58, 761–764.
Karube, M., Yamamoto, N., Tsuji, H., Kanematsu, N., Nakajima, M., Yamashita, H., et al.,
2017b. Carbon-ion re-irradiation for recurrences after initial treatment of stage i
non-small cell lung cancer with carbon-ion radiotherapy. Radiother. Oncol. 125,
31–35.
Kelly, P., Balter, P.A., Rebueno, N., Sharp, H.J., Liao, Z., Komaki, R., et al., 2010.
Stereotactic body radiation therapy for patients with lung cancer previously treated
with thoracic radiation. Int. J. Radiat. Oncol. Biol. Phys. 78, 1387–1393.
Kilburn, J.M., Kuremsky, J.G., Blackstock, A.W., Munley, M.T., Kearns, W.T., Hinson, W.
H., et al., 2014. Thoracic re-irradiation using stereotactic body radiotherapy (sbrt)
techniques as first or second course of treatment. Radiother. Oncol. 110, 505–510.
Kruser, T.J., McCabe, B.P., Mehta, M.P., Khuntia, D., Campbell, T.C., Geye, H.M., et al.,
2014. Reirradiation for locoregionally recurrent lung cancer: outcomes in small cell
and non-small cell lung carcinoma. Am. J. Clin. Oncol. 37, 70–76.
Liu, H., Zhang, X., Vinogradskiy, Y.Y., Swisher, S.G., Komaki, R., Chang, J.Y., 2012.
Predicting radiation pneumonitis after stereotactic ablative radiation therapy in
patients previously treated with conventional thoracic radiation therapy. Int. J.
Radiat. Oncol. Biol. Phys. 84, 1017–1023.
McAvoy, S.A., Ciura, K.T., Rineer, J.M., Allen, P.K., Liao, Z., Chang, J.Y., et al., 2013.
Feasibility of proton beam therapy for reirradiation of locoregionally recurrent non-
small cell lung cancer. Radiother. Oncol. 109, 38–44.
McAvoy, S., Ciura, K., Wei, C., Rineer, J., Liao, Z., Chang, J.Y., et al., 2014. Definitive
reirradiation for locoregionally recurrent non-small cell lung cancer with proton
beam therapy or intensity modulated radiation therapy: predictors of high-grade
toxicity and survival outcomes. Int. J. Radiat. Oncol. Biol. Phys. 90, 819–827.
Meijneke, T.R., Petit, S.F., Wentzler, D., Hoogeman, M., Nuyttens, J.J., 2013.
Reirradiation and stereotactic radiotherapy for tumors in the lung: dose summation
and toxicity. Radiother. Oncol. 107, 423–427.
Milano, M.T., Constine, L.S., Okunieff, P., 2008. Normal tissue toxicity after small field
hypofractionated stereotactic body radiation. Radiat. Oncol. 3, 36.
Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., Group P, 2009. Preferred reporting
items for systematic reviews and meta-analyses: the prisma statement. J. Clin.
Epidemiol. 62, 1006–1012.
10
Critical Reviews in Oncology / Hematology 167 (2021) 103500
O’Rourke, N., Roque, I.F.M., Farre Bernado, N., Macbeth, F., 2010. Concurrent
chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst. Rev.,
CD002140
Ogawa, Y., Shibamoto, Y., Hashizume, C., Kondo, T., Iwata, H., Tomita, N., et al., 2018.
Repeat stereotactic body radiotherapy (sbrt) for local recurrence of non-small cell
lung cancer and lung metastasis after first sbrt. Radiat. Oncol. 13, 136.
Ohguri, T., Imada, H., Yahara, K., Moon, S.D., Yamaguchi, S., Yatera, K., et al., 2012. Re-
irradiation plus regional hyperthermia for recurrent non-small cell lung cancer: a
potential modality for inducing long-term survival in selected patients. Lung Cancer
77, 140–145.
Okamoto, Y., Murakami, M., Yoden, E., Sasaki, R., Okuno, Y., Nakajima, T., et al., 2002.
Reirradiation for locally recurrent lung cancer previously treated with radiation
therapy. Int. J. Radiat. Oncol. Biol. Phys. 52, 390–396.
Owen, D., Olivier, K.R., Song, L., Mayo, C.S., Miller, R.C., Nelson, K., et al., 2014. Safety
and tolerability of sbrt after high-dose external beam radiation to the lung. Front.
Oncol. 4, 376.
Patel, N.R., Lanciano, R., Sura, K., Yang, J., Lamond, J., Feng, J., et al., 2015. Stereotactic
body radiotherapy for re-irradiation of lung cancer recurrence with lower biological
effective doses. J. Radiat. Oncol. 4, 65–70.
Peulen, H., Karlsson, K., Lindberg, K., Tullgren, O., Baumann, P., Lax, I., et al., 2011.
Toxicity after reirradiation of pulmonary tumours with stereotactic body
radiotherapy. Radiother. Oncol. 101, 260–266.
Ren, C., Ji, T., Liu, T., Dang, J., Li, G., 2018. The risk and predictors for severe radiation
pneumonitis in lung cancer patients treated with thoracic reirradiation. Radiat.
Oncol. 13, 69.
Reyngold, M., Wu, A.J., McLane, A., Zhang, Z., Hsu, M., Stein, N.F., et al., 2013. Toxicity
and outcomes of thoracic re-irradiation using stereotactic body radiation therapy
(sbrt). Radiat. Oncol. 8, 99.
Schlampp, I., Rieber, J., Adeberg, S., Bozorgmehr, F., Heussel, C.P., Steins, M., et al.,
2019. Re-irradiation in locally recurrent lung cancer patients. Strahlentherapie und
Onkologie : Organ der Deutschen Rontgengesellschaft … [et al] 195, 725–733.
Schroder, C., Stiefel, I., Tanadini-Lang, S., Pytko, I., Vu, E., Guckenberger, M., et al.,
2020. Re-irradiation in the thorax - an analysis of efficacy and safety based on
accumulated eqd2 doses. Radiother. Oncol. 152, 56–62.
Sumita, K., Harada, H., Asakura, H., Ogawa, H., Onoe, T., Murayama, S., et al., 2016. Re-
irradiation for locoregionally recurrent tumors of the thorax: a single-institution,
retrospective study. Radiat. Oncol. 11, 104.
Sumodhee, S., Bondiau, P.Y., Poudenx, M., Cohen, C., Naghavi, A.O., Padovani, B., et al.,
2019. Long term efficacy and toxicity after stereotactic ablative reirradiation in
locally relapsed stage iii non-small cell lung cancer. BMC Cancer 19, 305.
Tada, T., Fukuda, H., Matsui, K., Hirashima, T., Hosono, M., Takada, Y., et al., 2005.
Non-small-cell lung cancer: reirradiation for loco-regional relapse previously treated
with radiation therapy. Int. J. Clin. Oncol. 10, 247–250.
Tang, Y., Yang, L., Qin, W., Yi, M.X., Liu, B., Yuan, X., 2020. Impact of genetic variant of
hipk2 on the risk of severe radiation pneumonitis in lung cancer patients treated
with radiation therapy. Radiat. Oncol. 15, 9.
Trakul, N., Harris, J.P., Le, Q.T., Hara, W.Y., Maxim, P.G., Loo Jr., B.W., et al., 2012.
Stereotactic ablative radiotherapy for reirradiation of locally recurrent lung tumors.
J. Thorac. Oncol. 7, 1462–1465.
Trovo, M., Minatel, E., Durofil, E., Polesel, J., Avanzo, M., Baresic, T., et al., 2014.
Stereotactic body radiation therapy for re-irradiation of persistent or recurrent non-
small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 88, 1114–1119.
Turrisi 3rd, A.T., Kim, K., Blum, R., Sause, W.T., Livingston, R.B., Komaki, R., et al.,
1999. Twice-daily compared with once-daily thoracic radiotherapy in limited small-
cell lung cancer treated concurrently with cisplatin and etoposide. N. Engl. J. Med.
340, 265–271.
Viani, G.A., Arruda, C.V., De Fendi, L.I., 2020. Effectiveness and safety of reirradiation
with stereotactic ablative radiotherapy of lung cancer after a first course of thoracic
radiation: a meta-analysis. Am. J. Clin. Oncol. 43, 575–581.
Wegner, R.E., Ahmed, N., Hasan, S., Schumacher, L.Y., Colonias, A., 2018. Lung
stereotactic body radiotherapy after past ablative therapy: a single institution case
series. Lung Cancer Manag. 7, LMT05.
Wu, K.L., Jiang, G.L., Qian, H., Wang, L.J., Yang, H.J., Fu, X.L., et al., 2003. Three-
dimensional conformal radiotherapy for locoregionally recurrent lung carcinoma
after external beam irradiation: a prospective phase i-ii clinical trial. Int. J. Radiat.
Oncol. Biol. Phys. 57, 1345–1350.
Xu, L., Jiang, J., Li, Y., Zhang, L., Li, Z., Xian, J., et al., 2019. Genetic variants of sp-
d confer susceptibility to radiation pneumonitis in lung cancer patients undergoing
thoracic radiation therapy. Cancer Med. 8, 2599–2611.
Yang, W.C., Hsu, F.M., Chen, Y.H., Shih, J.Y., Yu, C.J., Lin, Z.Z., et al., 2020. Clinical
outcomes and toxicity predictors of thoracic re-irradiation for locoregionally
recurrent lung cancer. Clin. Transl. Radiat. Oncol. 22, 76–82.
Yoshitake, T., Shioyama, Y., Nakamura, K., Sasaki, T., Ohga, S., Shinoto, M., et al., 2013.
Definitive fractionated re-irradiation for local recurrence following stereotactic body
radiotherapy for primary lung cancer. Anticancer Res. 33, 5649–5653.
Marta Maddalo is a full time radiation oncologist at the university hospital ASST Spedali
Civili di Brescia (Italy). She specialized “cum laude” in May 2015 with a dissertation
entitled “A Patient-Reported Outcome Measure to screen for Symptom in the Head and
Neck Cancer Population: Translation and Pilot Study on Testing Feasibility and Utility of
the Vanderbilt Head and Neck Symptom Survey (VHNSS)”. The thesis followed a period
abroad as a visiting doctor at the Medical Oncology Department of the Vanderbilt Ingram
Cancer Center in Nashville, Tennessee. She gained particular interest in treating cancer of
the head and neck, lung, breast and anal canal, and collaborated as investigator on na­
tional prospective protocols and retrospective data series collections.
M. Maddalo et al.
Elisa D’Angelo is a full-time radiation oncologist at University Hospital of Modena. She’s
involved in about ten national and international clinical controlled trials as principal
investigator or sub-investigator, and author of several peer-reviewed papers. She is a
member and counsellor of Italian and European most important oncological societies, and
reviewer for journals in the oncological field. Major area of interest: lung cancer, head and
neck cancer, radiogenomics, immune-oncology.
Francesco Fiorica, MD, PhD; Head of Department of Radiation Oncology and Nuclear
Medicine, AULSS 9 Scaligera, Verona, Italy. Obtained his MD degree in University of
Palermo (honor’s degree), his radiation oncology certification at University of Modena and
his PhD in Geriatric Oncology in University of Catania. Dr Fiorica‘s interests include
development of biomarkers from tissue and from diagnostic images and translational
research.
Angela Argenone, is a radiation oncologist with more than 10 years of experience. She has
collaborated within multiple Italian medical trials and active member and counsellor of
important scientific societies. She is authors of numerous scientific papers.
Melissa Scricciolo, is a Radiation Oncologist and at present, working at Radiotherapy
Department of Hospital “Ospedale dell’Angelo” of Venice. She deal with head and neck
cancer, lymphoma and lung cancer, and is member of Head and Neck Young Investigator
group of EORTC, of coordination group AIRO Re-irradiation 2020–2021 and of coordi­
nation group AIRO Triveneto 2020–2021.
Salvatore Cozzi, is a radiation oncologist graduated in 2013. Actually working at Radi­
ation Therapy Unit, USL-IRCCS of Reggio Emilia. Major area of interest are lung cancer,
breast cancer and brachytherapy. Author and co-Author of 11 publications.
Alessia Nardangeli is a Radiation Oncologist at the department of Radiation Oncology at
Fondazione Policlinico Universitario “A. Gemelli” IRCSS, Università Cattolica del Sacro
Cuore in Rome, where she attended medical studies and completed residency in Radiation
Oncology in 2016. Her research interest include re-irradiation and gynecologic cancer.
Francesco Dionisi, radiation oncologist with > 10 year of experience in the field. Major
areas of expertise: proton therapy, moving targets, head and neck cancer, liver cancer, re-
11
Critical Reviews in Oncology / Hematology 167 (2021) 103500
irradiation. Active researcher in the field of radiation oncology, author of several peer
reviewed papers. Phd candidate. Reviewer for numerous journals in the field of radiation
oncology.
Gianluca Costantino, August 2012, Master’s Degree in Medicine and Surgery at the
University of Turin 2016–2020, Residency training in Radiation Oncology at the Univer­
sity of Brescia; graduated magna cum laude. January 2021, MD Radiation Oncologist at
Radiation Oncology Department ASST Valcamonica. May 2021 to present MD Radiation
Oncologist Currently at Humanitas-Gavazzeni Bergamo.
Stefano Vagge, MD, PhD is a full-time radiation oncologist at IRCCS Ospedale Policlinico
San Martino, Genoa. He obtained his MD and the RO board certification at the University
of Genoa. He reached a Ph.D. in translational and clinical onco-hematology at the
Department of Internal Medicine (DIMI) at the University of Genoa. His main field of
research and clinical practice are thoracic cancers, onco-hematology, lower G.I. and skin
cancers.
Antonio Pontoriero is Senior Researcher (Assistant Professor) Department of BIOMORF,
Section of Radiological Science, Operative Unit of Radiation Oncology Messina University
School of Medicine, Messina, Italy. July 2007 - present Co-Director, Messina Cyberknife
Program. Authors of many peer-reviewed publications. Main field of research are Re-
Irradiation, Prostate Cancer Gynecological Cancer, Stereotactic Body Radiotherapy,
Cyberknife.
Vittorio Donato, President of Italian Association of Radiotherapy and Clinical Oncology.
Researcher from 1991 to 2006 at University of Rome “La Sapienza”. From 2006 has
become Head of Radiotherapy Department at “San Camillo Forlanini” Hospital of Rome
and from 2017 Chief of Oncology and Specialized Medicine Department.
Mariangela Massaccesi is a Radiation Oncologist at the Department of Radiation
Oncology at the Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Università
Cattolica del Sacro Cuore in Rome, where she attended medical studies, and completed
residency in Radiation Oncology in 2007. Dr. Massaccesi is the author and co-author of
more than 60 peer reviewed paper. Her research interest include reirradiation, lung can­
cer, molecular imaging and new techniques for image guidance and radiation delivery.