See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/368845360

Metastases-directed stereotactic body radiotherapy in combination with

targeted therapy or immunotherapy: systematic review and consensus
recommendations by the EORTC-ESTRO OligoCa...

Article  in  The Lancet Oncology · February 2023

DOI: 10.1016/S1470-2045(22)00752-5

CITATIONS READS

0 259

38 authors, including:

S.G.C. Kroeze Karin Stellamans

Cantonal Hospital Aarau AZ Groeninge
95 PUBLICATIONS   953 CITATIONS    33 PUBLICATIONS   257 CITATIONS   

SEE PROFILE SEE PROFILE

Yolande Lievens Carlotta Becherini

Ghent University University of Florence
356 PUBLICATIONS   8,093 CITATIONS    121 PUBLICATIONS   566 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

upper abdominal SBRT View project

Multimodal Magnetic Resonance Imaging (MRI) for diagnosis of spinal metastases and response assessment after Stereotactic Body Radiation Therapy (SBRT) View
project

All content following this page was uploaded by Hossein Hemmatazad on 28 February 2023.

The user has requested enhancement of the downloaded file.

 Policy Review

Metastases-directed stereotactic body radiotherapy in

combination with targeted therapy or immunotherapy:
systematic review and consensus recommendations by the
EORTC–ESTRO OligoCare consortium
Stephanie G C Kroeze*, Matea Pavic*, Karin Stellamans, Yolande Lievens, Carlotta Becherini, Marta Scorsetti, Filippo Alongi, Umberto Ricardi,
Barbara Alicja Jereczek-Fossa, Paulien Westhoff, Jasna But-Hadzic, Joachim Widder, Xavier Geets, Samuel Bral, Maarten Lambrecht,
Charlotte Billiet, Igor Sirak, Sara Ramella, Ivaldi Giovanni Battista, Sergi Benavente, Almudena Zapatero, Fabiola Romero, Thomas Zilli,
Kaouthar Khanfir, Hossein Hemmatazad, Berardino de Bari, Desiree N Klass, Shaukat Adnan, Heike Peulen, Juan Salinas Ramos, Michiel Strijbos,
Sanjay Popat, Piet Ost, Matthias Guckenberger

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low Lancet Oncol 2023; 24: e121–32
tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently *Authors contributed equally
practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is Department of Radiation
little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of Oncology, University Hospital
Zurich, Zurich, Switzerland
high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity
(S G C Kroeze PhD MD,
profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the M Pavic MD,
basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the Prof M Guckenberger MD);
European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment Department of Radiation
Oncology, AZ Groeninge
of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-
Campus Kennedylaan, Kortrijk,
directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to Belgium (K Stellamans MD);
targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and Department of Radiation
fractionation. Results of this systematic review and consensus process compile the best available evidence for safe Oncology, Ghent University
Hospital and Ghent University,
combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or
Gent, Belgium
oligometastatic cancer and aim to guide today’s clinical practice and the design of future clinical trials. (Prof Y Lievens PhD MD);
Department of Radiation
Introduction palliation in patients with a good prognosis with, for Oncology, Careggi University
Hospital, Florence, Italy
An increasing number of patients with metastatic cancer, example, painful spine metastases.3,4
(C Becherini MD); Radiotherapy
especially when characterised by a low tumour burden Despite the increasing use in routine clinical practice, and Radiosurgery Department,
(ie, oligometastatic disease), are treated with a combin­ there is little information on the safety of combining IRCCS Humanitas Research
ation of targeted therapy (ie, small molecule anticancer SBRT with modern targeted therapy or immunotherapy Hospital, Milan, Italy
(Prof M Scorsetti MD); Advanced
drugs and monoclonal antibodies) or immunotherapy and a paucity of high-level evidence to guide clinical Radiation Oncology
and metastases-directed stereotactic body radiotherapy management. Few prospective studies have been department, IRCCS Sacro Cuore
(SBRT). Compared with traditional chemotherapy, many published and most data focus on the combination of don Calabria Hospital, Negrar di
targeted therapy and immunotherapy drugs achieve intracranial stereotactic radiotherapy with targeted Valpolicella, Italy
(Prof F Alongi MD); Department
substantially improved overall survival for patients with therapy or immunotherapy.5 Moreover, the heterogeneity of Radiation Oncology,
metastatic cancer with several cancer types (eg, metastatic of extracranial SBRT with respect to the location of University of Brescia, Brescia,
melanoma or metastatic non-small-cell lung cancer). metastases in various organs, combined with the rapidly Italy (Prof F Alongi);
Despite these improvements, many patients will develop growing number of novel targeted therapies and Department of Oncology,
University of Turin, Turin, Italy
disease progression because of initial or acquired immunotherapies with different biological mechanisms (Prof U Ricardi MD); Department
drug resistance. This resistance leads to the frequent of action and toxicity profiles, makes prospective testing of Radiation Oncology,
observation of only a small number of progressive of all variations difficult. European Institute of
or persistent metastases at radiological imaging, so- To extend our knowledge on the practice of metastases- Oncology, IRCCS, Milan, Italy
(Prof B A Jereczek-Fossa PhD MD);
called oligometastatic disease.1 Metastases-directed local directed SBRT in combination with targeted therapy Department of Oncology and
therapy of such drug-resistant lesions with the aim to or immunotherapy, a consensus process was initiated Hemato-oncology, University
continue the same line of systemic therapy beyond within the European Society for Radiotherapy and of Milan, Milan, Italy
oligoprogression has become a frequently practised Oncology (ESTRO) and European Organisation for (Prof B A Jereczek-Fossa);
Department of Radiation
treatment strategy in several tumour types, such as non- Research and Treatment of Cancer (EORTC) OligoCare Oncology, Radboud University
small-cell lung cancer and renal cell carcinoma, project consortium (NCT03818503), involving an inter­ Medical Center, Nijmegen,
recommended by the National Comprehensive Cancer national and interdisciplinary group of experts in the field Netherlands
(P Westhoff PhD MD);
Network guidelines.2 Another potential reason for the of SBRT for patients with metastatic cancer. The goal was
Department of Radiation
integration of SBRT into targeted-therapy or immuno­ to perform a systematic literature review and establish a Oncology, Institute of
therapy delivery is the aim for long-term control of consensus on risk mitigation strategies to safely combine Oncology, Ljubljana, Slovenia
symptoms and metastases instead of short-term metastases-directed SBRT with targeted therapy or (Prof J But-Hadzic PhD MD);

www.thelancet.com/oncology Vol 24 March 2023 e121

 Policy Review
Department of Radiation
Oncology, Comprehensive
Cancer Center, Medical
University of Vienna, Vienna,
Austria (Prof J Widder PhD MD);
Department of Radiation
Oncology, Cliniques
universitaires Saint-Luc, MIRO-
IREC Lab, Université catholique
de Louvain, Brussels, Belgium
(Prof X Geets PhD MD);
Department of Radiation
Oncology, Onze-Lieve-
Vrouwziekenhuis, Aalst,
Belgium (S Bral PhD MD);
Department of Radiotherapy-
Oncology, Leuvens Kanker
Instituut, Universitair
Ziekenhuis Leuven, Leuven,
Belgium
(Prof M Lambrecht PhD MD);
Department of Radiation
Oncology, Iridium Netwerk,
Antwerp, Belgium
(C Billiet PhD MD,
Prof P Ost PhD MD); Department
of Oncology and Radiotherapy,
University Hospital, Hradec
Králové, Czech Republic
(Prof I Sirak PhD MD);
Department of Radiation
Oncology, Campus Bio-Medico
University of Rome, Rome, Italy
(Prof S Ramella MD);
Department of Radiation
Oncology, Istituti Clinici
Scientifici Maugeri, IRCCS,
Pavia, Italy
(I Giovanni Battista MD);
Department of Radiation
Oncology, Vall d’Hebron
University Hospital, Barcelona,
Spain (S Benavente PhD MD);
Department of Radiation
Oncology, Hospital
Universitario de La Princesa,
Health Research Institute,
Madrid, Spain
(A Zapatero PhD MD);
Department of Radiation
Oncology, Hospital
Universitario Reina Sofia,
Cordoba, Spain (F Romero MD);
Department of Radiation
Oncology, Oncology Institute
of Southern Switzerland, Ente
Ospedaliero Cantonale,
Bellinzona, Switzerland
(Prof T Zilli MD); Faculty of
Medicine, University of Geneva,
Geneva, Switzerland
(Prof T Zilli); Department of
Radiation Oncology, Hôpital
Valais, Sion, Switzerland
(K Khanfir MD); Department of
Radiation Oncology, Inselspital
University Hospital, Bern,
Switzerland
(H Hemmatazad MD);
Department of Radiation
Oncology, University
e122 www.thelancet.com/oncology Vol 24 March 2023
immunotherapy in patients with metastatic cancer, of targeted therapy or immunotherapy without SBRT
especially when characterised by a low tumour burden (ie, (appendix p 6), drug elimination half-life as reported by
oligometastatic disease), to guide current SBRT practice the US Food and Drug Administration (appendix p 7), and
and the design of future clinical trials. the toxicity tables of included literature (appendix pp 8–23)
were provided to all experts to update the participants with
Methods the latest evidence before the Delphi consensus process.
This project originates from the ESTRO and EORTC A total of 28 interdisciplinary experts, who are active
OligoCare registry project (EORTC 1822, first cohort of the members of the OligoCare consortium, participated in this
joint EORTC–ESTRO Radiation Infrastructure for Europe consensus process (appendix pp 24–25).7 The survey was
EORTC 1811 study; NCT03818503), which aims to identify divided into two sections: questions to assess institutional
patient, tumour, staging, and treatment characteristics that patterns of care related to SBRT experience and SBRT dose
affect overall survival of patients treated with metastases- prescription, and questions to achieve consensus about
directed radiotherapy for oligometastatic disease. Our goal risk mitigation strategies to optimise the safety profile
was to generate consensus recommendations to achieve of concomitant metastases-directed SBRT and targeted
safe practice of metastases-directed SBRT in patients with therapy or immunotherapy (appendix pp 26–27). Three
metastatic cancer who are also receiving targeted therapy risk mitigation strategies were addressed in the survey:
or immunotherapy. This consensus does not address the (1) whether systemic therapy can be delivered on the same
indication for such a combination treatment, which should day as SBRT or not; (2) whether there is a preferred time
be based on international guidelines, multidisciplinary interval between the delivery of SBRT and the delivery
discussions, and recommendations. of systemic therapy and for antibodies administered via
The systematic literature search model, in accordance intravenous infusion (ie, anti-VEGF, anti-HER2, anti-
with the PRISMA criteria,6 is available (figure 1). See the EGFR, and immune checkpoint inhibitors), it was
Search strategy and selection criteria panel for inclusion discussed whether administration of one cycle is shifted by
and exclusion criteria. The results of the systematic review a certain time interval or whether one or two cycles are
(appendix pp 2–5), an overview of grade 3–5 toxicity omitted; and (3) whether the dose of SBRT is reduced
when delivered concomitantly with systemic therapy, or
whether the same biological effective dose is distributed
4338 records identified through 3 additional records identified over a larger number of SBRT fractions when combined
database searching through other sources
with systemic therapy.
Two medical oncologists supervised what targeted
therapy or immunotherapy was to be included in the
1483 duplicates excluded survey and the systematic review. In the first round of the
Delphi survey, a draft was reviewed by 11 expert panellists
from the centres that enrolled the most patients to the
2858 records screened
OligoCare study and edited according to their comments.
The final survey consisted of 54 questions (appendix
2473 records excluded pp 28–69). The online survey was sent to all participating
OligoCare centres, which anonymously responded to the
predefined questions. Before answering the Delphi
385 full-text articles assessed
for eligibility survey, the institutional representatives were advised
to seek an interdisciplinary consensus within their
respective institutions in the various combinatory
277 full-text articles excluded
11 in the same cohort treatments. After the first round was completed, the
38 in which toxicity was answers were evaluated by three investigators (MG,
not described
144 received no SRT
SGCK, and MP). In the second round, a structured
46 in which patient started overview of the results of the first round was provided
targeted therapy to the panel. All specific questions were asked for
>1 month before, or not
clearly described a second time after adjustment of the questions
1 patient aged <18 years according to responses of the first round, and consensus
37 received cerebral SRT
only
was defined as agreement with at least 75% (appendix
pp 70–96). The final manuscript was endorsed by the
ESTRO scientific council and the EORTC board.
108 studies included in
qualitative synthesis
Results
Systematic literature review
Figure 1: PRISMA diagram of the systematic literature review search The systematic literature search identified 4338 articles,
SRT=stereotactic radiotherapy. reduced to 108 articles that met all inclusion criteria

(figure 1): 47 prospective studies with 1333 patients,
37 retrospective studies with 1313 patients, and 24 case
reports with 29 patients. The most evidence about
the toxicity of metastases-directed SBRT and targeted
therapy or immunotherapy was available for immune
checkpoint inhibitors (1150 [43%] of 2675 patients),
followed by multikinase inhibitors (615, 23%) and EGFR
inhibitors (508, 19%), whereas no evidence was avail­
able for almost all other small molecule anticancer
drugs and HER2 antibodies (table 1). SBRT-treated
metastases were most frequently located in the thorax
(985 [38%] of 2585 SBRT-treated metastases), abdomen
(646, 25%) and bones (594, 23%). Overall, grade 3
toxicity was observed in 560 (21%) of 2675 patients,
grade 4 toxicity was observed in 28 (1%) patients,
and grade 5 toxicity (ie, death) was observed in
26 (1%) patients (table 2). About one third of these
adverse events (180, 7%) were reported to be related to
SBRT, whereas most adverse events were attributed
to the targeted therapy or immunotherapy with the
toxicity located outside the radiation field or SBRT-
treated organ. SBRT-induced toxicity was most
frequently observed in combination with ipilimumab in
the thorax (17 [12%] of 145 patients) and abdomen
(9 [10%] of 86), nivolumab–ipilimumab in the thorax
(10 [26%] of 38), multikinase inhibitors (39 [22%] of 175)
and bevacizumab (4 [12%] of 38) in the abdominal area
and cetuximab in the cervical area (36 [15%] of 235).
Detailed results are summarised in the following
sections. The risk of severe in-field toxicity was
categorised as: grade 3–5 toxicity of 0–10% was defined
as low risk, 11–20% was defined as intermediate risk,
and above 20% was defined as high risk. Literature was
rated according to the rating system by the Oxford
Centre for Evidence-based Medicine Levels of Evidence.8
Delphi consensus process
The Delphi panel consisted of 26 radiation oncologists
and two clinical oncologists. The majority (19 [68%] of
28 specialists) worked in university hospitals, were
fully trained specialists with over 10 years of clinical
experience (20, 71%), and had a minimum of 10 years’
experience with SBRT (16, 57%). The Delphi process
resulted in a consensus on the management of the
majority of immunotherapy (figure 2A, B) or targeted
therapy (figure 3). All participants confirmed that
responses to the survey were based on institution-specific
interdisciplinary standards, which were complemented
in 17 (61%) of 28 clinics with formal multidisciplinary
meetings or ad-hoc dis­ cussions addressing specific
questions of the survey, involving mostly medical
oncologists and pneumologists.
Concurrent SBRT and Immune checkpoint inhibitors
Anti-CTLA4 monotherapy (ipilimumab)
Relevant data of 215 patients,9–18 predominantly based
on prospective studies (211 [98%] patients in seven
www.thelancet.com/oncology Vol 24 March 2023 e123
Policy Review
prospective studies, one retrospective study, and two case of Bern, Bern, Switzerland
reports), treated with SBRT and concurrent ipilimumab (H Hemmatazad); Service Radio-
Oncologie Neuchâtel Hôpital
for metastases located in the abdomen or thorax were Network, La Chaux-de-Fonds,
identified, reporting an inter­ mediate risk (10–20%) of Switzerland (B de Bari MD);
severe intrathoracic and intra-abdominal SBRT-induced Institute of Radiation
toxicity (level of evidence: 2b). Oncology, Cantonal Hospital
Graubünden, Chur, Switzerland
Regarding the expert consensus: (1) most experts (D N Klass MD); Department of
(20 [71%] of 28; did not reach consensus) voted not to Oncology, Aberdeen Royal
administer ipilimumab on the same days as SBRT delivery; Infirmary, UK (S Adnan MD);
(2) a consensus to continue ipilimumab uninterrupted Department of Radiation
Oncology, Catharina Hospital,
without omission of treatment cycles during SBRT delivery Eindhoven, Netherlands
was closely missed (20 votes, 71%) and a consensus on a (H Peulen PhD MD); Radiation
minimum time interval of 1 week between administration Oncology Department, Santa
of ipilimumab and SBRT was also closely missed (20 votes, Lucia General University
Hospital, Cartagena, Spain
71%); and (3) when combining ipilimumab with SBRT, (J Salinas Ramos MD);
there was a consensus for all treated organs (24–27 votes, Department of Oncology,
86–96%) that SBRT is performed without dose reduction GasthuisZusters Antwerpen,
Antwerpen, Belgium
and without the use of more SBRT fractions compared
(M Strijbos PhD MD); Lung Unit,
with SBRT without concomitant systemic therapy. The Royal Marsden, London, UK
(Prof S Popat PhD MD); Faculty
Anti-PD-1 or PD-L1 monotherapy of Medicine, University of
Ljubljana, Ljubljana, Slovenia
Relevant data of 910 patients, from 22 prospective studies,
(Prof J But-Hadzic); Centre for
ten retrospective studies, and 15 case reports,10,14,19–63 treated Radiation Oncology KSA-KSB,
with concurrent SBRT and anti-PD-L1 or anti-PD-1 Cantonal Hospital Aarau,
treatment are available. Data are predominantly based on Aarau, Switzerland
(S G C Kroeze); Department of
prospective studies (755 [83%] of 910 patients). The
Oncology and Hemato-
observed risk of severe toxicity was low (0–10%; level of oncology, University of Milan,
evidence 2a). Milan, Italy
Regarding the expert consensus: (1) most experts (Prof B A Jereczek-Fossa)
voted (16–18 votes, 57–64%) that anti-PD-L1 or anti- Correspondence to:
Prof Matthias Guckenberger,
PD-1 treatment is not administered on the same day
Department of Radiation
as SBRT delivery, but no consensus was reached; Oncology, University Hospital
(2) a consensus was reached (23–26, 82–93%) that anti- Zurich, CH 8091 Zürich,
PD-L1 or anti-PD-1 treatment without omission of Switzerland
matthias.guckenberger@usz.ch
treatment cycles continues during SBRT delivery and
no consensus was reached (1–12, 4–43%) regarding a See Online for appendix
minimum time interval between delivery of anti-PD-L1
or anti-PD-1 and SBRT; and (3) when combining anti-
PD-L1 or anti-PD-1 with SBRT, there was a consensus
for all treated organs (24–27, 86–96%) that SBRT is
performed without dose reduction and without the use
of more SBRT fractions compared with SBRT without
concomitant systemic therapy.
Anti-CTLA4 (ipilimumab) plus anti-PD-1 (nivolumab)
Few data of 37 prospectively analysed patients (table 1)
who were treated with 62 courses of SBRT9 indicate that
the combination of SBRT and dual-checkpoint blockade
might be associated with an increased risk (>20%) of
severe thoracic toxicity (level of evidence: 2a).
Regarding the expert consensus: (1) a consensus
was reached (21 votes [75%] of 28) that nivolumab
plus ipilimumab is not administered on the same day
as SBRT; (2) no consensus was reached to continue
nivolumab plus ipilimumab uninterrupted or omit
one or more cycles during SBRT delivery (17, 61%) and
a consensus was reached (an average of 21∙28 votes
 Policy Review

VEGF antibody administration; and (3) when anti-VEGF

Head and neck Thorax Abdomen Bone Body
antibodies are combined with SBRT, there was a consensus
Immune checkpoint inhibitors for all treated organs (24–28, 86–100%) that SBRT is
Anti-CTLA-4 ·· 145 86 12 13 performed without dose reduction and without the use
Anti-PD-L1 and anti-PD-1 3 375 276 147 29 of more SBRT fractions compared with SBRT without
Anti-PD-L1 plus anti-CTLA-4 or ·· 38 12 12 ·· concomitant systemic therapy.
anti-PD-1 plus anti-CTLA-4
Monoclonal antibodies
Anti-EGFR
Anti-VEGF 14 ·· 34 ·· ··
Relevant data on cetuximab combined with SBRT
Anti-EGFR 235 ·· ·· ·· ··
have only been published for stereotactic re-irradiation
Anti-HER2 ·· ·· ·· ·· ··
of patients with recurrent head and neck squamous-cell
Small molecules cancer.63–73 Based on a total of 235 patients analysed
mTKI or mTOR 1 59 175 333 41 prospectively (119, 51%) and retrospectively (116, 49%),
EGFR inhibitor ·· 360 61 75 22 an intermediate risk (10–20%) of severe toxicity in the
ALK inhibitor ·· 7 2 5 2 head and neck area was observed (level of evidence: 2a).
ROS1 inhibitor ·· ·· ·· ·· ·· Regarding the expert consensus: (1) a consensus was
NTRK inhibitor ·· ·· ·· ·· ·· reached (24 votes [86%] of 28) that anti-EGFR antibodies
RET inhibitor ·· ·· ·· ·· ·· are not administered on the same day as SBRT; (2) no
MET inhibitor ·· ·· ·· ·· ·· consensus was reached (11, 39%) on whether or not to
BRAF inhibitor and MEK inhibitor ·· ·· ·· 5 ·· continue anti-EGFR antibodies uninterrupted or whether
PARP inhibitor ·· ·· ·· ·· ·· to omit one or more cycles during SBRT delivery and
HER2 inhibitor ·· ·· ·· ·· ·· a consensus was reached (an average of 23∙24 votes
CDK4/6 inhibitor ·· 1 ·· 5 ·· when all options taken together, 83%) that SBRT is not
In the body group, location was not further specified. 0–10 patients is defined as limited data, 11–50 patients is defined performed within one week of the administration of anti-
as few data, and >50 cumulative patients in all studies is defined as relevant data. SBRT=stereotactic body EGFR antibody); and (3) when anti-EGFR antibodies are
radiotherapy. combined with SBRT, there was a consensus for all treated
Table 1: Systematic review with total number of SBRT-treated metastases per targeted agent group and organs (21–27, 75–96%) that SBRT is performed without
anatomical location of SBRT-treated metastases dose reduction and without the use of more SBRT
fractions compared with SBRT without concomitant
systemic therapy.
when all options taken together, 76%) that SBRT is
not performed within one week of nivolumab plus Anti-HER2
ipilimumab administration); and (3) when combining Our literature search did not identify any studies
nivolumab plus ipilimumab with SBRT, there was a reporting the safety of SBRT combined with anti-HER2
consensus for all treated organs (24–27, 86–96%) that antibodies.
SBRT is performed without dose reduction and without Regarding the expert consensus: (1) a consensus was
the use of more SBRT fractions compared with SBRT reached (21 [75%] of 28) that trastuzumab and pertuzumab
without concomitant systemic therapy. can be administered on the same day as SBRT delivery and
consensus was nearly missed (20, 71%) for ado-trastuzumab
Concurrent SBRT and monoclonal antibodies emtansine; (2) a consensus was reached (24–26, 86–93%)
Anti-VEGF to continue anti-HER2 antibodies uninter­rupted without
There are limited data (48 patients from one prospective omission of treatment cycles during SBRT delivery, and a
study and two retrospective studies) on combining consensus was reached for trastuzumab and pertuzumab
SBRT and bevacizumab,64–66 and data are mostly about (both 21, 75%) and was nearly missed for ado-trastuzumab
intra-abdominal SBRT. The results indicate that this emtansine (an average of 20∙2 votes when all options taken
combination might be associated with an intermediate together, 72%) that there is no minimum time interval
risk (11–20%) of severe toxicity when performing SBRT between delivery of SBRT and antibody administration;
within the abdominal region (level of evidence 2b). and (3) when anti-HER2 antibodies are combined with
Regarding the expert consensus: (1) a consensus SBRT, there was a consensus for all treated organs (24–28,
was reached (an average of 23∙24 votes when all options 86–100%) that SBRT is performed without dose reduction
taken together, 83%) that anti-VEGF antibodies are and without the use of more SBRT fractions compared
not administered on the same day as SBRT delivery; with SBRT without concomitant systemic therapy.
(2) a consensus was reached that a minimum of one cycle
is omitted (23, 82%) when anti-VEGF antibodies are given Concurrent SBRT and small-molecule anticancer drugs
in combination with SBRT and a consensus (an average of Multitargeted multikinase inhibitors and mTOR inhibitors
23∙24 votes when all options taken together, 83%) was also Relevant data are available for the combination of
reached that SBRT is not performed within one week of multikinase inhibitors or mTOR inhibitors with SBRT,

e124 www.thelancet.com/oncology Vol 24 March 2023

 Policy Review

which are predominantly based on retrospective

Head and neck Thorax Abdomen Bone Body
studies (351, 75% of 468 patients).30,74–86 Results indicate
that SBRT of the bone concurrent with multikinase Immune checkpoint inhibitors

inhibitors and mTOR inhibitors is not associated Anti-CTLA-4 ·· 12% 10% 8% 23%
with added toxicity. However, data indicate that SBRT Anti-PD-L1 and anti-PD-1 0% 6% 5% 1% 3%
of intra­ hepatic targets combined with sorafenib is Anti-PD-L1 plus anti-CTLA-4 or ·· 26% 0% 8% ··
anti-PD-1 plus anti-CTLA-4
associated with an increased risk (>20%) of severe
Monoclonal antibodies 
toxicity (level of evidence: 2b).
Anti-VEGF 0% ·· 12% ·· ··
Regarding the expert consensus on mTOR inhibitors:
Anti-EGFR 15% ·· ·· ·· ··
(1) no consensus (11 votes [39%] of 28) was reached on
Anti-HER2 ·· ·· ·· ·· ··
whether or not mTOR inhibitors can be administered
on the same day as SBRT; (2) no consensus was Small molecules

reached (1–8 votes for all interval options, 4–29%) mTKI 0% 0% 22% 1% 0%

regarding a minimum time interval between the mTOR inhibitor ·· 0% 0% 0% 0%

delivery of mTOR inhibitors and SBRT; and (3) when EGFR inhibitor ·· 7% 0% 1% 0%
combining mTOR inhibitors with SBRT, there was a ALK inhibitor ·· 0% 0% 0% 0%
consensus for all treated organs (26–28, 93–100%) that ROS1 inhibitor ·· ·· ·· ·· ··
SBRT is performed with­ out dose reduction and NTRK inhibitor ·· ·· ·· ·· ··
without the use of more SBRT fractions compared RET inhibitor ·· ·· ·· ·· ··
with SBRT without concomitant systemic therapy. MET inhibitor ·· ·· ·· ·· ··
Regarding the expert consensus on multikinase BRAF inhibitor and MEK inhibitor ·· ·· ·· 0% ··
inhibitors: (1) there was a consensus (21–23 votes PARP inhibitor ·· ·· ·· ·· ··
[75–82%] of 28) that all multikinase inhibitors are not HER2 inhibitor ·· ·· ·· ·· ··
administered on the same day as SBRT; (2) a consensus CDK4 or CDK6 inhibitor ·· 0% ·· 0% ··
(21, 75%) was reached about an interruption of In the body group, location was not further specified. 0–10% of toxicity is defined as low risk, 11–20% of toxicity is
sunitinib and sorafenib for maximum of 2 weeks defined as intermediate risk, and >20% of toxicity is defined as increased risk. SBRT=stereotactic body radiotherapy.
before or after the delivery of SBRT and no consensus
Table 2: Percentage of systematic review with severe in-field toxicity events (toxicity ≥grade 3) per SBRT
was reached (1–20, 4–71%) on a minimum interval treated lesion by targeted agent group and anatomical location of SBRT-treated metastases
between delivery of other multikinase inhibitors and
SBRT; and (3) when combining multi­kinase inhibitors
with SBRT, there was a consensus for all treated ALK, ROS1, NTRK, RET, and MET inhibitors
organs (24–28, 86–100%) that SBRT is performed Available data on SBRT concurrent with ALK inhibitors
without dose reduction and without the use of are limited (30 patients in two retrospective studies).105,106
more SBRT fractions compared with SBRT without These data do not indicate a risk for severe toxicity (level
concomitant systemic therapy. of evidence: 2b). Currently, no information on the safety
of SBRT combined with ROS1, NTRK, RET, and MET
EGFR inhibitors inhibitors is available.
Relevant data on SBRT concurrent with EGFR-inhibitors Regarding the expert consensus: (1) no consensus
are available, which are primarily based on retrospective was reached on whether or not ALK inhibitors can be
studies (229, 66% of 451 patients).16,29,87–104 Results indicate administered on the same day as SBRT delivery
that the combination is associated with a low risk (11–12 [39–43%] of 28 votes for the different ALK inhibitors);
(<10% risk) of severe pulmonary, intra-abdominal, or (2) no consensus was reached regarding a minimum time
bone toxicity (level of evidence: 2a). interval between delivery of ALK inhibitors and SBRT
Regarding the expert consensus: (1) although (1–10 [4–36%] for the different time interval options); and
consensus was nearly missed, most experts (an average (3) when combining ALK inhibitors with SBRT, there was a
of 20∙2 [72%] of 28 votes when all options taken together) consensus for all treated organs (24–27, 86–96% for the
voted that EGFR inhibitors are not administered on different time interval options) that SBRT is performed
the same day as SBRT; (2) no consensus regarding a without dose reduction and without the use of more SBRT
minimum time interval between delivery of EGFR fractions compared with SBRT without concomitant
inhibitors and SBRT (1–13 votes [4–46%] of 28 was systemic therapy.
reached for all different time interval options for
the different EGFR inhibitors); (3) when combining BRAF and MEK inhibitors
EGFR inhibitors with SBRT, there was a consensus for Data on SBRT concurrent with BRAF and MEK inhibitors
all treated organs (23–28, 82–100%) that SBRT is are limited (one retrospective study with four patients).107
performed with­out dose reduction and without the use Results indicate that the combination of SBRT to bone
of more SBRT fractions compared with SBRT without metastases with BRAF inhibitors is not associated with
concomitant systemic therapy. an increased risk of severe toxicity (level of evidence: 2b).

www.thelancet.com/oncology Vol 24 March 2023 e125

 Policy Review

A
CDK4/6 inhibitors
2 cycles 1 cycle None
The limited retrospective data (12 patients in four retro­
Anti-VEGF
spective studies and one case report) on the combination
Ramucirumab* of CDK/6 inhibitors and SBRT to thoracic and bone
Bevacizumab* metastases in patients with metastatic breast cancer108–112
Anti-HER2
Pertuzumab*
did not observe severe toxicity of the combination
Ado-trastuzumab emtansine* treatment (level of evidence: 2b).
Trastuzumab* Regarding the expert consensus: (1) no consensus was
Anti-EGFR reached on whether or not CDK4/6-inhibitors can be
Panitumumab
Cetuximab administered on the same days as SBRT delivery (13 votes
ICI [46%] of 28); (2) no consensus was reached regarding a
Nivolumab–ipilimumab minimum time interval between delivery of CDK4/6
Ipilimumab
Cemiplimab* inhibitors and SBRT (2–8 votes [7–29%] for the different
Atezolizumab* time interval options); and (3) when combining CDK4/6
Avelumab*
Durvalumab*
inhibitors with SBRT, there was a consensus for all treated
Pembrolizumab* organs (26–28, 93–100%) that SBRT is performed without
Nivolumab* dose reduction and without the use of more SBRT
fractions compared with SBRT without concomitant
B systemic therapy.
2 drug half-lives 1 drug half-life >2 weeks >1 week No defined
interval
HER2 inhibitors
Anti-VEGF Our literature search did not identify any study that
Ramucirumab*
Bevacizumab* reports the safety of the combination of SBRT with
Anti-HER2 HER2 inhibitors.
Pertuzumab* Regarding the expert consensus: (1) no consensus was
Ado-trastuzumab emtansine
Trastuzumab* reached on whether or not HER2 inhibitors can be
Anti-EGFR administered on the same day as SBRT delivery (17 votes
Panitumumab* [60%] of 28); (2) no consensus was reached regarding
Cetuximab*
ICI
a minimum time interval between delivery of HER2
Nivolumab–ipilimumab* inhibitors and SBRT (1–6 [4–21%] for all different time
Ipilimumab interval options); and (3) when combining HER2
Cemiplimab
Atezolizumab inhibitors with SBRT, there was a consensus for all treated
Avelumab organs (24–28, 86–100%) that SBRT is performed without
Durvalumab dose reduction and without the use of more SBRT
Pembrolizumab
Nivolumab fractions compared with SBRT without concomitant
0 25 50 75 100 systemic therapy.
% consensus
PARP inhibitors
Figure 2: Results of the Delphi consensus questions regarding intravenously administered drugs.
Our literature search did not identify any study that
Consensus was defined as ≥75% agreement. (A) Results of the Delphi consensus process on the preferred time
interval between delivery of SBRT and delivery of monoclonal antibodies and immune checkpoint inhibitors. Drug reports the safety of the combination of SBRT with
elimination half-lives are available in appendix p 7. (B) Results of the Delphi consensus process on whether PARP inhibitors.
treatment with monoclonal antibodies and immune checkpoint inhibitors is interrupted by omission of one or Regarding the expert consensus: (1) although no con­
two treatment cycles before and after SBRT delivery or whether systemic therapy is uninterrupted. ICI=immune
sensus was reached, most experts voted (18–20 votes
checkpoint inhibitor. SBRT=stereotactic body radiotherapy. *Drugs for which consensus was reached.
[64–71%] of 28) that PARP inhibitors are not administered
on the same day as SBRT delivery; (2) no consensus was
Regarding the expert consensus: (1) a consensus reached regarding a minimum time interval between
(24–27 [86–96%] of 28) was reached that BRAF and delivery of PARP inhibitors and SBRT (1–8, 4–29%); and
MEK inhibitors are not administered on the same day (3) when combining PARP inhibitors with SBRT, there
as SBRT delivery; (2) a consensus (25, 89%) was reached was a consensus for all treated organs (23–27, 82–96%)
about an interruption of BRAF and MEK inhibitors for that SBRT is performed without dose reduction and
a maximum of 2 weeks before or after SBRT delivery; without the use of more SBRT fractions compared with
and (3) when combining BRAF and MEK inhibitors SBRT without concomitant systemic therapy.
with SBRT, there was a consensus for all treated organs
(25–28, 89–100%) that SBRT is performed without Discussion
dose reduction and without the use of more SBRT The treatment of patients with metastatic cancer with
fractions compared with SBRT without concomitant novel immunotherapy or targeted therapy is character­
systemic therapy. ised by a favourable risk–benefit ratio when given as

e126 www.thelancet.com/oncology Vol 24 March 2023

 Policy Review

mono­therapies, especially when compared with chemo­ 2 drug half-lives 1 drug half-life >2 weeks <2 weeks <1 week
therapy. However, severe toxicities have been docu­ No interruption
mented with ipilimumab, multikinase inhibitors, mTOR HER2 inhibitors
inhibitors, EGFR inhibitors, and anti-VEGF antibodies, Lapatinib
CDK4/6 inhibitors
among others. Simultaneously, an increasing number of Ribociclib
patients with cancer are treated with metastases-directed Palbociclib
SBRT due to an oligometastatic disease state or because BRAF and MEK inhibitors
Encorafenib*
durable control of local metastases by use of intensified Dabrafenib*
local therapy is the intended outcome of intensified local Vemurafenib*
therapy, which will result in increasing numbers of PARP inhibitors
Talazoparib
patients treated with concomitant metastases-directed Niraparib
SBRT and immunotherapy or targeted therapy. Although Rucaparib
the toxicity profile of metastases-directed SBRT is Olaparib
mTOR inhibitors
favourable in most situations,113 there are concerns Temsirolimus
and uncertainties about potential interactions between Everolimus
radiation and immunotherapy or targeted therapy and mTKI
Pazopanib*
consequent additional toxicities. Regorafenib*
Our systematic literature review on the safety profile Sorafenib*
of metastases-directed SBRT given concurrently with Sunitinib*
Cabozantinib*
immunotherapy or targeted therapy showed that the data Axitinib*
currently available are scarce or even absent for many Lenvatinib*
combinations, especially when a site-specific analysis on ALK inhibitors
Larotrectinib
the location of SBRT-treated metastases is performed. Lorlatinib
Most data available are for metastases-directed SBRT Crizotinib
Ceritinib
combined with immune checkpoint inhibitors, multi­ Brigatinib
kinase inhibitors, and EGFR inhibitors. There was a Alectinib
clinically relevant increased risk of SBRT-induced thoracic EGFR inhibitors
Dacomitinib
and abdominal toxicity when SBRT was combined with Afatinib
ipilimumab and when SBRT in the thoracic area was Gefitinib
combined with nivolumab plus ipilimumab. For both Osimertinib
Erlotinib
bevacizumab and sorafenib in combination with SBRT
0 25 50 75 100
of abdominal targets, increased rates of intra-abdominal
% consensus
SBRT-induced toxicity were reported. The combination
of EGFR, ALK, and mTOR inhibitors with metastases- Figure 3: Results of the Delphi consensus process on the timing of administration of orally administered,
directed SBRT appears not to be associated with increased small-molecule anticancer drugs and delivery of SBRT
Consensus was defined as ≥75% agreement. Drug elimination half-lives are available in appendix p 7.
rates of toxicity. No literature is available for metastases-
mTKI=multitargeted kinase inhibitors. *Drugs for which consensus was reached.
directed SBRT combined with most other small molecules
(eg, ROS1, NTRK, RET, and MET or HER2 inhibitors).
The Delphi consensus process followed the systematic combined modality treatment in the current literature as
review and involved a large international and multi­ presented in this systematic review. Although no
disciplinary group of experts from the EORTC and consensus was reached, most respondents would not
ESTRO OligoCare consortium. The consensus process administer EGFR inhibitors and PARP inhibitors on the
focused on the question of integrating metastases- same day as SBRT delivery. No consensus was reached
directed SBRT into a systemic therapy backbone with on whether or not all other small molecules can be
immunotherapy or targeted therapy, and evaluated administered on the same day as SBRT delivery. The
strategies to mitigate a potential risk of added toxicity of disparity between responses and inability to obtain
the concomitant treatment. consensus for these systemic therapies reflect the current
There was consensus that systemic treatment with scarcity of evidence and experience in this field.
anti-VEGF antibodies, anti-EGFR antibodies, nivolumab The second risk mitigation strategy addressed the
plus ipilimumab, BRAF and MEK inhibitors, and duration of the interruption to immunotherapy or targeted
multikinase inhibitors is not administered on the same therapy before and after metastases-directed SBRT,
day as metastases-directed SBRT. Consensus was also aiming to achieve a wash-out of systemic therapy (ie,
reached that trastuzumab and pertuzumab can be systemic therapy leaving the body) during the time
administered on the same day as SBRT delivery and of SBRT. A consensus was reached that multikinase
consensus was nearly missed for ado-trastuzumab inhibitors and BRAF and MEK inhibitors are interrupted
emtansine to be delivered on the same day. This for a maximum of two weeks and anti-EGFR antibodies
consensus agrees with the observed toxicity profiles of and ipilimumab plus nivolumab for a minimum one week

www.thelancet.com/oncology Vol 24 March 2023 e127

 Policy Review
before or after SBRT. The observed toxicity in the literature
around anti-VEGF antibodies was based on two small
retrospective studies that observed severe toxicity when
bevacizumab was paused for a month or first applied
several months after SBRT.64,66 The prospective study with
SBRT of the liver, in which bevacizumab was applied
concurrently, did not report any toxicity.65 Unlike the clear
evidence of increased toxicity after treatment with
bevacizumab before or after surgery, there is no clear
evidence that recommends how long bevacizumab is
interrupted during SBRT. The consensus we reached
was the recom­mendation that anti-VEGF antibodies are
interrupted for a minimum of one week before or after
SBRT. Additionally, a consensus was reached that SBRT
can be performed at any time interval around the
administration of the anti-HER2 antibodies trastuzumab
and pertuzumab, although consensus was narrowly
missed for ado-trastuzumab emtansine. For all other
small molecules there was no consensus regarding the
time interval, which reflects the current scarcity of clinical
data in this rapidly growing field.
Reduction of SBRT dose, or whether the same
biological effective dose is distributed over more SBRT
fractions, was evaluated as another potential risk-
mitigation strategy in concurrent treatment with
Search strategy and selection criteria
Literature for the systematic review was identified through searches of PubMed and
Embase for articles published between Jan 1, 2010, and Oct 31, 2021, with the MeSH and
free-text search terms “radiosurgery”, “local ablative therapy”, “gamma knife”, and
“stereotactic” combined with the terms “CTLA-4”, “MEK”, “PARP”, “ICI”, “ALK”, “ROS-1”,
“EGFR”, “BRAF”, “Tyrosine Kinase Inhibitors”, “PD1”, “immune checkpoint inhibitor”, “TKI”,
“NTRK”, “RET”, “MET”, “ado-trastuzumab”, “afatinib”, “alectinib”, “atezolizumab”,
“avelumab”, “axitinib”, “binimetinib”, “bevacizumab”, “brigatinib”, “cabozantinib”,
“ceritinib”, “cetuximab”, “crizotinib”, “cemiplimab”, “cetuximab”, “dabrafenib”,
“dacomitinib”, “durvalumab”, “encorafenib”, “erlotinib”, “everolimus”, “gefitinib”,
“imatinib”, “ipilimumab”, “lapatinib”, “larotrectinib”, “lenvatinib”, “loratinib”, “niraparib”,
“nivolumab”, “olaparib”, “osimertinib”, “pazopanib”, “pembrolizumab”, “pertuzumab”,
“sorafenib”, “sunitinib”, “talazoparib”, “temsirolimus”, “trametinib”, “trastuzumab”,
“vemurafenib”, “panitumumab”, “PLX4032”, “ribociclib”, “palbociclib”, “panitumumab”,
“dacomitinib”, “pertuzumab”, “larotrectinib”, “ramucirumab”, “trametinib”, “regorafenib”,
“rucaparib”, and “talazoparib”. The search was limited to original articles published in
English. We included targeted drugs were approved for use by US Food and Drug
Administration and the European Medicines Agency up to 2022 in solid tumour types
that are also regularly treated with oligometastasis-directed SBRT. SBRT was defined by a
single fraction of at least 5 Gy and maximum 10 fractions. Studies that used palliative,
low-dose radiotherapy with, for example, 1 × 8 Gy and 5 × 4 Gy were excluded. No ablative
cutoff dose of minimum 100 Gy biologically effective dose was used for study selection
because lower stereotactic body radiotherapy (SBRT) doses are allowed in prospective
clinical trials in the field of oligometastastic disease. Additionally, we excluded papers that
met the dose definition but did not clearly report stereotactic treatments
(eg, neoadjuvant rectal cancer irradiation). Other eligibility criteria were a clear
description that targeted drugs were given concurrently or within 30 days before or after
SBRT, patient age of ≥18 years, and toxicity graded or properly described according to the
National Cancer Institute’s Common Terminology Criteria for Adverse Events.
e128 www.thelancet.com/oncology Vol 24 March 2023
metastases-directed SBRT and immunotherapy or
targeted therapy. There was a strong consensus for every
targeted therapy or immunotherapy that no dose
reduction of SBRT or change of fractionation is
performed, irrespective of the location of the metastasis
and involved organ at risk. The expert panel did not
advocate to decrease the SBRT dose and possibly
jeopardise the probability of local control, but advocated
instead to separate the delivery of systemic treatment
and SBRT. Several studies reported that ablative doses of
at least 100 Gy biologically effective dose (BED₁₀) are
associated with durable long-term local tumour control.114
The real-world practice from the institutions in our
Delphi panel suggested that lung and liver metastases
are regularly treated with a BED₁₀ above 100 Gy; however,
metastases in all other organs are regularly treated with
lower SBRT doses (appendix p 7). Metastases-directed
SBRT with doses below the ablative threshold of 100 Gy
BED₁₀ is supported by prospective studies, especially in
the situation of induced oligometastatic disease, when
SBRT is combined with effective systemic therapy.
The aim of a Delphi consensus is to fill gaps of knowledge
by the use of expert opinion and to provide guidance in
daily clinical practice for which prospective data are scarce
and the field is rapidly evolving. Randomised controlled
trials are considered as the gold standard to guide clinical
management. However, randomised clinical trials appear
especially difficult in the context of the large and rapidly
growing number of approved targeted therapy or immuno­
therapy drugs; the heterogeneity of targeted therapy or
immunotherapy with respect to their effects on specific
organs; the heterogeneity of SBRT with respect to planning
and delivery; and the number of SBRT-treated metastases,
their size, and anatomical location individual to each
patient. These combinations are too numerous to be
investigated in separate comparative studies. The
prospective EORTC and ESTRO OligoCare registry trial
(NCT03818503) and similar projects are valuable to
generate real-world evidence in this dynamic field at the
multidisciplinary interface of local and systemic therapy
and provide the necessary data for the design of
interventional and randomised clinical trials that address
fundamental clinical questions and strategies.
In conclusion, a Delphi process by international and
multidisciplinary experts of the ESTRO and EORTC
OligoCare consortium achieved consensus regarding the
management of safely combining metastases-directed
SBRT with several drug classes in daily clinical practice.
Because of a paucity of high-level evidence, large
international registry trials are recommended to generate
timely, prospective, real-world data on patients that
receive combination treatment.
Contributors
SGCK, MP, PO, and MG conceptualised the study and developed the
methods. SGCK, MP, and MG did the administration for the project.
SGCK and MP selected the data, conducted the formal analysis, and
wrote the original draft of the manuscript. MG, MSt, SP, and PO

validated the data. MG, SGCK, and MP supervised the project. SGCK,
MP, KS, YL, CBe, MSc, FA, UR, BAJ-F, PW, JB-H, JW, XG, SB, ML, CBi,
IS, SR, IGB, SB, AZ, FR, TZ, KK, HH, BdB, DNK, SA, HP, and JSR
conducted the investigation. All authors were involved in the review and
edit of the manuscript.
Declaration of interests
FA declares payment or honoraria for lectures, presentations, speakers
bureaus, manuscript writing, or educational events from Varian, Elekta,
Brainlabs, outside of this Policy Review. CBe declares payment or
honoraria for lectures, presentations, speakers bureaus, manuscript
writing, or educational events from Novartis. CBe also declares support
for attending meetings and travel from Pfizer and Eli Lilly, unrelated to
this Policy Review. CBi declares payment or honoraria for lectures,
presentations, speakers bureaus, manuscript writing, or educational
events from SPCC congress, unrelated to this Policy Review.
BdB declares payment or honoraria for lectures, presentations, speakers
bureaus, manuscript writing, or educational events from Debiopharma,
Ipsen, and Astellas; support for attending meetings and travel from
Debiopharma and Micropos medical; and leadership or fiduciary role in
the board, society, committee, or advocacy group of ESTRO, SAKK, and
SASRO, unrelated to this Policy Review. BAJ-F declares grants or
contracts from Italian Association for Cancer Research, FIEO-CCM and
FUV, Accuray, and IBA Dosimetry; payment or honoraria for lectures,
presentations, speakers bureaus, manuscript writing, or educational
events from Janssen, Bayer, Roche, Astellas, Ipsen, and Accuray; and
participation on a data safety monitoring board or advisory board for
Bayer, unrelated to this Policy Review. XG declares a grant from Varian
paid to their institution; payment or honoraria for lectures, presentations,
speakers bureaus, manuscript writing, or educational events for
Congress Care and Sanofi; and a leadership or fiduciary role in the board,
society, committee, or advocacy group for RIZIV–INAMI and FANC–
AFCN. YL declares grants or contracts from ImmunoSABR, EU Project,
and HERO–VBHC; consulting fees paid to the institution by
AstraZeneca; and a leadership or fiduciary role in the board, society,
committee, or advocacy group of ESTRO, Belgian College of Oncology,
and EORTC–ESTRO Radiation Infrastructure for Europe project,
unrelated to this Policy Review. PO declares grants or contracts from
Varian and Bayer; consulting fees from Bayer, AAA, Curium, Janssen,
Telix, MSD, and Ferring; and support for attending meetings and travel
from Ferring, unrelated to this Policy Review. SP declares personal fees
from Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer
Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly,
Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics,
Turning Point Therapeutics, and EQRx; payment or honoraria for
lectures, presentations, speakers bureaus, manuscript writing,
or educational event from AstraZeneca, Bayer, Guardant Health, Janssen,
Merck Sereno, Roche, Takeda, and Pfizer; payment for expert testimony
from Roche and Merck Sereno; support for attending meetings and travel
from Janssen and Roche; participation on a data safety monitoring board
or advisory board for Amgen, AstraZeneca, Bayer, Beigene, Blueprint,
BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte,
Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer,
and Seattle Genetics; and leadership or fiduciary role in the board,
society, committee, or advocacy group of British Thoracic Oncology
Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation,
Mesothelioma Applied Research Foundation, and ETOP–IBCSG Partners
Foundation Board, unrelated to this Policy Review. SR declares payment
or honoraria for lectures, presentations, speakers bureaus, manuscript
writing, or educational events from MSD Italia, Genetec, and Istituto
Gentili Amgen; and participation on a data safety monitoring board or
advisory board for Roche and AstraZeneca, unrelated to this Policy
Review. UR declares payment or honoraria for lectures, presentations,
speakers bureaus, manuscript writing, or educational events from Elekta
and Accuray, unrelated to this Policy Review. MS declares payment or
honoraria for lectures, presentations, speakers bureaus, manuscript
writing, or educational events from Janssen, Roche, and Merck;
participation on a data safety monitoring board or advisory board for
Janssen, Ipsen, and Merck; and a leadership or fiduciary role in the
board, society, committee, or advocacy group for ESMO, unrelated to this
Policy Review. TZ declares grants or contracts from Varian Medical
Systems and Debiopharm; consulting fees from Janssen and Astellas;
www.thelancet.com/oncology Vol 24 March 2023 e129
Policy Review
payment or honoraria for lectures, presentations, speakers bureaus,
manuscript writing, or educational events from Janssen, Astellas,
Debiopharm, Bayer, and Ferring; support for attending meetings and
travel from Debiopharm; and participation on a data safety
monitoring board or advisory board for SAKK scientific board and
GFRU, unrelated to this Policy Review. All other authors report no
conflict of interest.
Acknowledgments
We thank Nicollo Giajlevra of IRCCS Sacro Cuore don Calabria Hospital
and the University of Brescia for their support and contribution.
References
1 Guckenberger M, Lievens Y, Bouma AB, et al. Characterisation and
classification of oligometastatic disease: a European Society for
Radiotherapy and Oncology and European Organisation for
Research and Treatment of Cancer consensus recommendation.
Lancet Oncol 2020; 21: e18–28.
2 Gillessen S, Armstrong A, Attard G et al. Management of patients
with advanced prostate cancer: report from the Advanced Prostate
Cancer Consensus conference 2021. Eur Urol 2022; 82: 115–41.
3 Guckenberger M, Sweeney RA, Hawkins M et al. Dose-intensified
hypofractionated stereotactic body radiation therapy for painful
spinal metastases: results of a phase 2 study. Cancer 2018;
124: 2001–09.
4 Sahgal A, Myrehaug SD, Siva S et al. Stereotactic body radiotherapy
versus conventional external beam radiotherapy in patients with
painful spinal metastases: an open-label, multicentre, randomised,
controlled, phase 2/3 trial. Lancet Oncol 2021; 22: 1023–33.
5 Kroeze SG, Fritz C, Hoyer M et al. Toxicity of concurrent
stereotactic radiotherapy and targeted therapy or immunotherapy:
a systematic review. Cancer Treat Rev 2017; 53: 25–37.
6 Page MJ, McKenzie JE, Bossuyt PM et al. The PRISMA 2020
statement: an updated guideline for reporting systematic reviews.
Int J Surg 2021; 88: 105906.
7 McMillan SS, King M, Tully MP. How to use the nominal group
and Delphi techniques. Int J Clin Pharm 2016; 38: 655–62.
8 Centre For Evidence-Based Medicine. Oxford Centre for Evidence-
Based Medicine: levels of evidence (March 2009). https://www.
cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-
evidence-based-medicine-levels-of-evidence-march-2009 (accessed
July 1, 2022).
9 Bestvina CM, Pointer KB, Karrison T, et al. A phase 1 trial of
concurrent or sequential ipilimumab, nivolumab, and stereotactic
body radiotherapy in patients with stage IV NSCLC study.
J Thorac Oncol 2022; 17: 130–40.
10 Chen D, Menon H, Verma V, et al. Response and outcomes after
anti-CTLA4 versus anti-PD1 combined with stereotactic body
radiation therapy for metastatic non-small cell lung cancer:
retrospective analysis of two single-institution prospective trials.
J Immunother Cancer 2020; 8: e000492.
11 Formenti SC, Rudqvist NP, Golden E, et al. Radiotherapy induces
responses of lung cancer to CTLA-4 blockade. Nat Med 2018;
24: 1845–51.
12 Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC.
An abscopal response to radiation and ipilimumab in a patient with
metastatic non-small cell lung cancer. Cancer Immunol Res 2013;
1: 365–72.
13 Hiniker SM, Chen DS, Reddy S, et al. A systemic complete
response of metastatic melanoma to local radiation and
immunotherapy. Transl Oncol 2012; 5: 404–07.
14 Maity A, Mick R, Huang AC, et al. A phase I trial of pembrolizumab
with hypofractionated radiotherapy in patients with metastatic solid
tumours. Br J Cancer 2018; 119: 1200–07.
15 Sundahl N, De Wolf K, Kruse V, et al. Phase 1 dose escalation trial
of ipilimumab and stereotactic body radiation therapy in metastatic
melanoma. Int J Radiat Oncol Biol Phys 2018; 100: 906–15.
16 Tang C, Welsh JW, de Groot P, et al. Ipilimumab with stereotactic
ablative radiation therapy: phase I results and immunologic
correlates from peripheral T cells. Clin Cancer Res 2017;
23: 1388–96.
17 Theurich S, Rothschild SI, Hoffmann M, et al. Local tumor
treatment in combination with systemic ipilimumab
immunotherapy prolongs overall survival in patients with advanced
malignant melanoma. Cancer Immunol Res 2016; 4: 744–54.
 Policy Review
18 Welsh JW, Tang C, de Groot P, et al. Phase II trial of ipilimumab
with stereotactic radiation therapy for metastatic disease: outcomes,
toxicities, and low-dose radiation-related abscopal responses.
Cancer Immunol Res 2019; 7: 1903–09.
19 Altorki NK, McGraw TE, Borczuk AC, et al. Neoadjuvant
durvalumab with or without stereotactic body radiotherapy in
patients with early-stage non-small-cell lung cancer: a single-centre,
randomised phase 2 trial. Lancet Oncol 2021; 22: 824–35.
20 Amin NP, Zainib M, Parker SM, Agarwal M, Mattes MD.
Multi-institutional report on toxicities of concurrent nivolumab and
radiation therapy. Adv Radiat Oncol 2018; 3: 399–404.
21 Bonfante G, Fantinel E, Masini C, Bergamaschi F, Micali S,
Rocco B. Exceptional response to immunotherapy in association
with radiotherapy in patient with breast metastasis from
urothelial carcinoma: a case report. Urol Case Rep 2020;
34: 101444.
22 Britschgi C, Riesterer O, Burger IA, Guckenberger M,
Curioni-Fontecedro A. Report of an abscopal effect induced by
stereotactic body radiotherapy and nivolumab in a patient with
metastatic non-small cell lung cancer. Radiat Oncol 2018; 13: 102.
23 Callaghan T, Margrain TH, Binns AM. The effect of systemic
hyperoxia and hypoxia on scotopic thresholds in people with early
and intermediate age-related macular degeneration. Curr Eye Res
2020; 45: 1273–82.
24 Cannon JGD, Russell JS, Kim J, Chang ALS. A case of metastatic
basal cell carcinoma treated with continuous PD-1 inhibitor
exposure even after subsequent initiation of radiotherapy and
surgery. JAAD Case Rep 2018; 4: 248–50.
25 Chiang CL, Chan ACY, Chiu KWH, Kong FS. Combined
stereotactic body radiotherapy and checkpoint inhibition in
unresectable hepatocellular carcinoma: a potential synergistic
treatment strategy. Front Oncol 2019; 9: 1157.
26 Cousin F, Desir C, Ben Mustapha S, Mievis C, Coucke P,
Hustinx R. Incidence, risk factors, and CT characteristics of
radiation recall pneumonitis induced by immune checkpoint
inhibitor in lung cancer. Radiother Oncol 2021; 157: 47–55.
27 Desideri I, Francolini G, Scotti V, et al. Benefit of ablative versus
palliative-only radiotherapy in combination with nivolumab in
patients affected by metastatic kidney and lung cancer.
Clin Transl Oncol 2019; 21: 933–38.
28 Floudas CS, Brar G, Mabry-Hrones D, et al. A pilot study of the
PD-1 targeting agent AMP-224 used with low-dose
cyclophosphamide and stereotactic body radiation therapy in
patients with metastatic colorectal cancer. Clin Colorectal Cancer
2019; 18: e349–60.
29 Higa J, Wilenius K, Savino S, Larsen C, Scholz M, Vogelzang N.
Real world experience with pembrolizumab in recurrent or
advanced prostate cancer. Clin Genitourin Cancer 2020;
18: e397–401.
30 Kroeze SGC, Fritz C, Schaule J, et al. Stereotactic radiotherapy
combined with immunotherapy or targeted therapy for metastatic
renal cell carcinoma. BJU Int 2021; 127: 703–11.
31 Kwan EM, Spain L, Anton A, et al. Avelumab combined with
stereotactic ablative body radiotherapy in metastatic castration-
resistant prostate cancer: the phase 2 ICE-PAC clinical trial. Eur Urol
2022; 81: 253–62.
32 Li D, He C, Xia Y, Du Y, Zhang J. Pembrolizumab combined with
stereotactic body radiotherapy in a patient with human
immunodeficiency virus and advanced non-small cell lung cancer:
a case report. J Med Case Rep 2018; 12: 104.
33 Linge A, Rauschenberg R, Blum S, Spornraft-Ragaller P, Meier F,
Troost EGC. Successful immunotherapy and irradiation in a HIV-
positive patient with metastatic Merkel cell carcinoma.
Clin Transl Radiat Oncol 2018; 15: 42–45.
34 Liu C, Piao J, Shang Z. Hyperprogressive disease after
radiotherapy combined with anti-PD-1 therapy in renal cell
carcinoma: a case report and review of the literature. BMC Urol
2021; 21: 42.
35 Liu J, Li C, Seery S, Yu J, Meng X. Identifying optimal first-line
interventions for advanced non-small cell lung carcinoma according
to PD-L1 expression: a systematic review and network meta-
analysis. OncoImmunology 2020; 9: 1746112.
36 Luke JJ, Lemons JM, Karrison TG, et al. Safety and clinical activity of
pembrolizumab and multisite stereotactic body radiotherapy in
patients with advanced solid tumors. J Clin Oncol 2018; 36: 1611–18.
e130 www.thelancet.com/oncology Vol 24 March 2023
37 Masini C, Iotti C, De Giorgi U, et al. Nivolumab in combination
with stereotactic body radiotherapy in pretreated patients with
metastatic renal cell carcinoma: results of the phase II NIVES study.
Eur Urol 2022; 81: 274–82.
38 Mattes MD, Eubank TD, Almubarak M, et al. A prospective trial
evaluating the safety and systemic response from the concurrent
use of radiation therapy with checkpoint inhibitor immunotherapy
in metastatic non-small cell lung cancer. Clin Lung Cancer 2021;
22: 268–73.
39 McBride S, Sherman E, Tsai CJ, et al. Randomized phase II trial of
nivolumab with stereotactic body radiotherapy versus nivolumab
alone in metastatic head and neck squamous cell carcinoma.
J Clin Oncol 2021; 39: 30–37.
40 Miyamoto S, Nomura R, Sato K, et al. Nivolumab and stereotactic
radiation therapy for the treatment of patients with stage IV
non-small-cell lung cancer. Jpn J Clin Oncol 2019; 49: 160–64.
41 Ni J, Zhou Y, Wu L, et al. Sintilimab, stereotactic body radiotherapy
and granulocyte-macrophage colony stimulating factor as second-
line therapy for advanced non-small cell lung cancer: safety run-in
results of a multicenter, single-arm, phase II trial. Radiat Oncol
2021; 16: 177.
42 Papachristofilou A, Hipp MM, Klinkhardt U, et al. Phase Ib
evaluation of a self-adjuvanted protamine formulated mRNA-based
active cancer immunotherapy, BI1361849 (CV9202), combined with
local radiation treatment in patients with stage IV non-small cell
lung cancer. J Immunother Cancer 2019; 7: 38.
43 Papadopoulos KP, Johnson ML, Lockhart AC, et al. First-in-human
study of cemiplimab alone or in combination with radiotherapy
and/or low-dose cyclophosphamide in patients with advanced
malignancies. Clin Cancer Res 2020; 26: 1025–33.
44 Perna M, Scotti V, Ciammella P, et al. The NIPRO study:
an observational, retrospective, multicenter study on the safety of
the radiotherapy and immunotherapy combination for advanced-
stage NSCLC. Clin Lung Cancer 2021; 22: e767–73.
45 Pizarro G, Pinto MP, Muñoz-Medel M, et al. Complete response to
immunotherapy plus chemotherapy after an unusual clinical
response to afatinib and stereotactic radiosurgery in a patient with
metastatic EGFR-mutant non-small-cell lung cancer.
Clin Lung Cancer 2020; 21: e250–54.
46 Ratnayake G, Reinwald S, Shackleton M, et al. Stereotactic radiation
therapy combined with immunotherapy against metastatic melanoma:
long-term results of a phase 1 clinical trial. Int J Radiat Oncol Biol Phys
2020; 108: 150–56.
47 Schubert P, Rutzner S, Eckstein M, et al. Prospective evaluation of
all-lesion versus single-lesion radiotherapy in combination with
PD-1/PD-L1 immune checkpoint inhibitors. Front Oncol 2020;
10: 576643.
48 Sharabi A, Kim SS, Kato S, et al. Exceptional response to nivolumab
and stereotactic body radiation therapy (SBRT) in neuroendocrine
cervical carcinoma with high tumor mutational burden:
management considerations from the center for personalized
cancer therapy at UC San Diego Moores Cancer Center. Oncologist
2017; 22: 631–37.
49 Sotelo MJ, Cabezas-Camarero S, Riquelme A, Bueno C. Long-term
survival of a patient with programmed death ligand 1-negative lung
adenocarcinoma and oligoprogressive disease treated with
nivolumab and stereotactic body radiation therapy. J Cancer Res Ther
2020; 16: 941–45.
50 Sundahl N, Seremet T, Van Dorpe J, et al. Phase 2 trial of nivolumab
combined with stereotactic body radiation therapy in patients with
metastatic or locally advanced inoperable melanoma.
Int J Radiat Oncol Biol Phys 2019; 104: 828–35.
51 Sundahl N, Vandekerkhove G, Decaestecker K, et al. Randomized
phase 1 trial of pembrolizumab with sequential versus concomitant
stereotactic body radiotherapy in metastatic urothelial carcinoma.
Eur Urol 2019; 75: 707–11.
52 Theelen WSME, Peulen HMU, Lalezari F, et al. Effect of
pembrolizumab after stereotactic body radiotherapy vs
pembrolizumab alone on tumor response in patients with advanced
non-small cell lung cancer: results of the PEMBRO-RT phase 2
randomized clinical trial. JAMA Oncol 2019; 5: 1276–82.
53 Tian S, Switchenko JM, Buchwald ZS, et al. Lung stereotactic body
radiation therapy and concurrent immunotherapy: a multicenter
safety and toxicity analysis. Int J Radiat Oncol Biol Phys 2020;
108: 304–13.

54 Welsh J, Menon H, Chen D, et al. Pembrolizumab with or without
radiation therapy for metastatic non-small cell lung cancer:
a randomized phase I/II trial. J Immunother Cancer 2020;
8: e001001.
55 Wu JS, Jen CW, Chen HH, Cheng SH. Stereotactic body
radiotherapy and checkpoint inhibitor for locally recurrent
unresectable nasopharyngeal carcinoma. BMJ Case Rep 2021;
14: e240806.
56 Xiao A, Luke JJ, Partouche J, Karrison T, Chmura SJ,
Al-Hallaq HA. Evaluation of dose distribution to organs-at-risk in
a prospective phase 1 trial of pembrolizumab and multisite
stereotactic body radiation therapy (SBRT). Pract Radiat Oncol
2022; 12: 68–77.
57 Xie C, Duffy AG, Brar G, et al. Immune checkpoint blockade in
combination with stereotactic body radiotherapy in patients with
metastatic pancreatic ductal adenocarcinoma. Clin Cancer Res 2020;
26: 2318–26.
58 Xie G, Gu D, Zhang L, Chen S, Wu D. A rapid and systemic
complete response to stereotactic body radiation therapy and
pembrolizumab in a patient with metastatic renal cell carcinoma.
Cancer Biol Ther 2017; 18: 547–51.
59 Ye H, Pang H, Shi X, et al. Nivolumab and hypofractionated
radiotherapy in patients with advanced lung cancer: ABSCOPAL-1
clinical trial. Front Oncol 2021; 11: 657024.
60 Zhao X, Kong Y, Zhang L. Anti-PD-1 immunotherapy combined
with stereotactic body radiation therapy and GM-CSF as salvage
therapy in a PD-L1-negative patient with refractory metastatic
esophageal squamous cell carcinoma: a case report and literature
review. Front Oncol 2020; 10: 1625.
61 Zhu X, Cao Y, Liu W, et al. Stereotactic body radiotherapy plus
pembrolizumab and trametinib versus stereotactic body
radiotherapy plus gemcitabine for locally recurrent pancreatic
cancer after surgical resection: an open-label, randomised,
controlled, phase 2 trial. Lancet Oncol 2021; 22: 1093–102.
62 Liu X, Yao J, Song L, Zhang S, Huang T, Li Y. Local and abscopal
responses in advanced intrahepatic cholangiocarcinoma with low
TMB, MSS, pMMR and negative PD-L1 expression following
combined therapy of SBRT with PD-1 blockade.
J Immunother Cancer 2019; 7: 204.
63 Morkos M, Jain P, Pavlick AC, Finger PT. Ipsilateral metastatic
choroidal melanoma responds to systemic immunotherapy.
Eur J Ophthalmol 2020; 30: NP69–73.
64 Barney BM, Markovic SN, Laack NN, et al. Increased bowel toxicity
in patients treated with a vascular endothelial growth factor
inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT).
Int J Radiat Oncol Biol Phys 2013; 87: 73–80.
65 Detsky JS, Milot L, Ko YJ, et al. Perfusion imaging of colorectal liver
metastases treated with bevacizumab and stereotactic body
radiotherapy. Phys Imaging Radiat Oncol 2018; 5: 9–12.
66 Haji Mohd Yasin NA, Gray AR, Bevin TH, Kelly LE, Molteno AC.
Choroidal melanoma treated with stereotactic fractionated
radiotherapy and prophylactic intravitreal bevacizumab:
the Dunedin hospital experience. J Med Imaging Radiat Oncol 2016;
60: 756–63.
67 Comet B, Kramar A, Faivre-Pierret M, et al. Salvage stereotactic
reirradiation with or without cetuximab for locally recurrent head-
and-neck cancer: a feasibility study. Int J Radiat Oncol Biol Phys
2012; 84: 203–09.
68 Gebhardt BJ, Vargo JA, Ling D, et al. Carotid dosimetry and the risk
of carotid blowout syndrome after reirradiation with head and neck
stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys
2018; 101: 195–200.
69 Heron DE, Rwigema JC, Gibson MK, Burton SA, Quinn AE,
Ferris RL. Concurrent cetuximab with stereotactic body
radiotherapy for recurrent squamous cell carcinoma of the head
and neck: a single institution matched case-control study.
Am J Clin Oncol 2011; 34: 165–72.
70 Lartigau EF, Tresch E, Thariat J, et al. Multi institutional phase II
study of concomitant stereotactic reirradiation and cetuximab for
recurrent head and neck cancer. Radiother Oncol 2013; 109: 281–85.
71 Quan K, Xu KM, Zhang Y, et al. Toxicities following stereotactic
ablative radiotherapy treatment of locally-recurrent and previously
irradiated head and neck squamous cell carcinoma.
Semin Radiat Oncol 2016; 26: 112–19.
www.thelancet.com/oncology Vol 24 March 2023 e131
Policy Review
72 Vargo JA, Ferris RL, Ohr J, et al. A prospective phase 2 trial of
reirradiation with stereotactic body radiation therapy plus
cetuximab in patients with previously irradiated recurrent
squamous cell carcinoma of the head and neck.
Int J Radiat Oncol Biol Phys 2015; 91: 480–88.
73 Vargo JA, Heron DE, Ferris RL, et al. Examining tumor control and
toxicity after stereotactic body radiotherapy in locally recurrent
previously irradiated head and neck cancers: implications of
treatment duration and tumor volume. Head Neck 2014; 36: 1349–55.
74 Brade AM, Ng S, Brierley J, et al. Phase 1 trial of sorafenib and
stereotactic body radiation therapy for hepatocellular carcinoma.
Int J Radiat Oncol Biol Phys 2016; 94: 580–87.
75 Cheung P, Patel S, North SA, et al. Stereotactic radiotherapy for
oligoprogression in metastatic renal cell cancer patients receiving
tyrosine kinase inhibitor therapy: a phase 2 prospective multicenter
study. Eur Urol 2021; 80: 693–700.
76 De Wolf K, Rottey S, Vermaelen K, et al. Combined high dose
radiation and pazopanib in metastatic renal cell carcinoma:
a phase I dose escalation trial. Radiat Oncol 2017; 12: 157.
77 Dengina N, Mitin T, Gamayunov S, Safina S, Kreinina Y,
Tsimafeyeu I. Stereotactic body radiation therapy in combination
with systemic therapy for metastatic renal cell carcinoma:
a prospective multicentre study. ESMO Open 2019; 4: e000535.
78 Gatto L, Nannini M, Saponara M, et al. Radiotherapy in the
management of gist: state of the art and new potential scenarios.
Clin Sarcoma Res 2017; 7: 1.
79 Goody RB, Brade AM, Wang L, et al. Phase I trial of radiation
therapy and sorafenib in unresectable liver metastases.
Radiother Oncol 2017; 123: 234–39.
80 He L, Liu Y, Han H, et al. Survival outcomes after adding
stereotactic body radiotherapy to metastatic renal cell carcinoma
patients treated with tyrosine kinase inhibitors. Am J Clin Oncol
2020; 43: 58–63.
81 Liu Y, Zhang Z, Han H, et al. Survival after combining
stereotactic body radiation therapy and tyrosine kinase inhibitors
in patients with metastatic renal cell carcinoma. Front Oncol 2021;
11: 607595.
82 Miller JA, Balagamwala EH, Angelov L, et al. Spine stereotactic
radiosurgery with concurrent tyrosine kinase inhibitors for
metastatic renal cell carcinoma. J Neurosurg Spine 2016;
25: 766–74.
83 Myrehaug S, Chan DL, Rodriguez-Freixinos V, et al. A pilot study of
everolimus and radiation for neuroendocrine liver metastases.
Endocr Relat Cancer 2021; 28: 541–48.
84 Roberto M, Falcone R, Mazzuca F, et al. The role of stereotactic
body radiation therapy in oligometastatic colorectal cancer: clinical
case report of a long-responder patient treated with regorafenib
beyond progression. Medicine 2017; 96: e9023.
85 Staehler M, Haseke N, Nuhn P, et al. Simultaneous anti-
angiogenic therapy and single-fraction radiosurgery in clinically
relevant metastases from renal cell carcinoma. BJU Int 2011;
108: 673–78.
86 Straka C, Kim DW, Timmerman RD, Pedrosa I, Jacobs C,
Brugarolas J. Ablation of a site of progression with stereotactic body
radiation therapy extends sunitinib treatment from 14 to 22 months.
J Clin Oncol 2013; 31: e401–03.
87 Bellyei S, Boronkai Á, Pozsgai E, Fodor D, Mangel L. Effective
chemotherapy and targeted therapy supplemented with
stereotactic radiotherapy of a patient with metastatic colon cancer
following renal transplantation: a case report. J Med Case Rep
2021; 15: 125.
88 Blake-Cerda M, Lozano-Ruíz F, Maldonado-Magos F, et al.
Consolidative stereotactic ablative radiotherapy (SABR) to
intrapulmonary lesions is associated with prolonged progression-
free survival and overall survival in oligometastatic NSCLC patients:
a prospective phase 2 study. Lung Cancer 2021; 152: 119–26.
89 Bruno R, Proietti A, Alì G, et al. Squamous cell transformation and
EGFR T790M mutation as acquired resistance mechanisms in a
patient with lung adenocarcinoma treated with a tyrosine kinase
inhibitor: a case report. Oncol Lett 2017; 14: 5947–51.
90 Chan OSH, Lam KC, Li JYC, et al. ATOM: a phase II study to assess
efficacy of preemptive local ablative therapy to residual
oligometastases of NSCLC after EGFR TKI. Lung Cancer 2020;
142: 41–46.
 Policy Review
91 Chan OSH, Lee VHF, Mok TSK, Mo F, Chang ATY, Yeung RMW.
The role of radiotherapy in epidermal growth factor receptor
mutation-positive patients with oligoprogression: a matched-cohort
analysis. Clin Oncol 2017; 29: 568–75.
92 Gomez DR, Blumenschein GR Jr, Lee JJ, et al. Local consolidative
therapy versus maintenance therapy or observation for patients
with oligometastatic non-small-cell lung cancer without
progression after first-line systemic therapy: a multicentre,
randomised, controlled, phase 2 study. Lancet Oncol 2016;
17: 1672–82.
93 Hsu KH, Huang JW, Tseng JS, et al. Primary tumor radiotherapy
during EGFR-TKI disease control improves survival of treatment
naïve advanced egfr-mutant lung adenocarcinoma patients.
OncoTargets Ther 2021; 14: 2139–48.
94 Iyengar P, Kavanagh BD, Wardak Z, et al. Phase II trial of
stereotactic body radiation therapy combined with erlotinib for
patients with limited but progressive metastatic non-small-cell lung
cancer. J Clin Oncol 2014; 32: 3824–30.
95 Jia W, Guo H, Jing W, et al. An especially high rate of radiation
pneumonitis observed in patients treated with thoracic
radiotherapy and simultaneous osimertinib. Radiother Oncol
2020; 152: 96–100.
96 Kroeze SGC, Fritz C, Schaule J, et al. Continued versus interrupted
targeted therapy during metastasis-directed stereotactic
radiotherapy: a retrospective multi-center safety and efficacy
analysis. Cancers 2021; 13: 4780.
97 Kroeze SGC, Schaule J, Fritz C, et al. Metastasis directed
stereotactic radiotherapy in NSCLC patients progressing under
targeted- or immunotherapy: efficacy and safety reporting from the
‘TOaSTT’ database. Radiat Oncol 2021; 16: 4.
98 Pezzuto A, Terzo F, Graziani ML, Ricci A, Bruno P, Mariotta S.
Lung cancer requires multidisciplinary treatment to improve
patient survival: a case report. Oncol Lett 2017; 14: 3035–38.
99 Sedef AK, Sumbul AT, Yildrim BA, Topkan E. Upfront thoracic
radiotherapy to primary lession improve outcomes in patients with
stage IV non-small cell lung cancer harboring EGFR
mutations. J Clin Oncol 2021; 39.
100 Wang X, Zeng Z, Cai J, et al. Efficacy and acquired resistance for
EGFR-TKI plus thoracic SBRT in patients with advanced EGFR-
mutant non-small-cell lung cancer: a propensity-matched
retrospective study. BMC Cancer 2021; 21: 482.
101 Wang Z, Zhu XX, Wu XH, et al. Gefitinib combined with stereotactic
radiosurgery in previously treated patients with advanced non-small
cell lung cancer. Am J Clin Oncol 2014; 37: 148–53.
102 Weiss J, Kavanagh B, Deal A, et al. Phase II study of stereotactic
radiosurgery for the treatment of patients with oligoprogression on
erlotinib. Cancer Treat Res Commun 2019; 19: 100126.
e132 www.thelancet.com/oncology Vol 24 March 2023
View publication stats
103 Xu Q, Liu H, Meng S, et al. First-line continual EGFR-TKI plus
local ablative therapy demonstrated survival benefit in
EGFR-mutant NSCLC patients with oligoprogressive disease.
J Cancer 2019; 10: 522–29.
104 Santarpia M, Altavilla G, Borsellino N, et al. High-dose radiotherapy
for oligo-progressive NSCLC receiving EGFR tyrosine kinase
inhibitors: real world data. In Vivo 2020; 34: 2009–14.
105 Gan GN, Weickhardt AJ, Scheier B, et al. Stereotactic radiation
therapy can safely and durably control sites of extra-central nervous
system oligoprogressive disease in anaplastic lymphoma kinase-
positive lung cancer patients receiving crizotinib.
Int J Radiat Oncol Biol Phys 2014; 88: 892–98.
106 Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of
oligoprogressive disease prolongs disease control by tyrosine kinase
inhibitors in oncogene-addicted non-small-cell lung cancer.
J Thorac Oncol 2012; 7: 1807–14.
107 Stefan D, Popotte H, Stefan AR, et al. Vemurafenib and
concomitant stereotactic radiation for the treatment of melanoma
with spinal metastases: a case report. Rep Pract Oncol Radiother
2016; 21: 76–80.
108 Chowdhary M, Sen N, Chowdhary A, et al. Safety and efficacy of
palbociclib and radiation therapy in patients with metastatic breast
cancer: initial results of a novel combination. Adv Radiat Oncol
2019; 4: 453–57.
109 Ippolito E, Greco C, Silipigni S, et al. Concurrent radiotherapy
with palbociclib or ribociclib for metastatic breast cancer
patients: preliminary assessment of toxicity. Breast 2019;
46: 70–74.
110 Meattini I, Desideri I, Scotti V, Simontacchi G, Livi L. Ribociclib
plus letrozole and concomitant palliative radiotherapy for metastatic
breast cancer. Breast 2018; 42: 1–2.
111 Nardone V, Reginelli A, Vitale C, et al. Feasibility of stereotactic
ablative reirradiation in breast cancer patient undergoing
palbociclib: a case report. Int J Radiat Res. 2021; 19: 479–82.
112 Ratosa I, Orazem M, Scoccimarro E, et al. Cyclin-dependent
kinase 4/6 inhibitors combined with radiotherapy for patients
with metastatic breast cancer. Clin Breast Cancer 2020;
20: 495–502.
113 Lehrer EJ, Singh R, Wang M, et al. Safety and survival rates
associated with ablative stereotactic radiotherapy for patients with
oligometastatic cancer: a systematic review and meta-analysis.
JAMA Oncol 2021; 7: 92–106.
114 Burkon P, Kazda T, Pospisil P, et al. Ablative dose stereotactic body
radiation therapy for oligometastatic disease: a prospective single
institution study. Neoplasma 2019; 66: 315–25.
Copyright © 2023 Elsevier Ltd. All rights reserved.