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EDITORIAL

Beyond the HILUS Trial: How Can We Improve the

Safety of SABR for Ultracentral Thoracic Tumors?
Amir H. Safavi, MD, MSc,* David A. Palma, MD, PhD,y and Meredith E. Giuliani, MBBS, PhD*,z
*
Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; yDepartment of Radiation Oncology, London
Health Sciences Centre, London, Ontario, Canada; and zRadiation Medicine Program, Princess Margaret Cancer Centre, University
Health Network, Toronto, Ontario, Canada

Received Jul 31, 2023; Accepted for publication Aug 1, 2023

“Learn from yesterday, live for today, hope for tomorrow.
The important thing is to not stop questioning.”
Albert Einstein (attributed)
Learn From Yesterday
SABR for ultracentral thoracic tumors is a double-edged
sword: it affords the opportunity to aggressively control
inevitably morbid, often unresectable disease abutting the
central airway and mediastinal structures, at the risk of iat-
rogenic high-grade toxicity and fatality.1 The outcomes of
HILUS,2 the first completed phase 2, single-arm, multi-insti-
tutional trial of SABR for ultracentral lung and thoracic
nodal (35%) tumors, have inspired both cautious optimism
and apprehension. How can we improve the safety of SABR
for ultracentral disease?
In the International Journal of Radiation Oncology  Biol-
ogy  Physics, Lindberg et al present the outcomes of a
pooled analysis of the HILUS trial (65 patients) and a retro-
spective expansion cohort (165 patients) treated with the
same prescription (56 Gy in 8 fractions, allowing maximum
point dose [Dmax] of 150%) to lesions (20% lymph nodes)
within 2 cm of the tracheobronchial tree.3 The investigators
should be congratulated for increasing the sample size of
patients treated with the HILUS regimen to identify risk
factors for high-grade toxicity. Furthermore, the initiative of
the investigators to both provide granular detail and state
uncertainties regarding the radiation therapy planning
should be commended. The rates of grade 3 to 4 (15%) and
grade 5 (13%) toxicity were high in this study, as they were
in the original HILUS study, with the majority of fatal
events being bronchopulmonary hemorrhage (66%). On
multivariable analysis, maximum dose to the mainstem
bronchi or bronchus intermedius and tracheobronchial
compression were independent predictors for grade 5 hem-
orrhage. These data contrast with favorable toxicity out-
comes (pooled incidences of 6% and 4% for grade 3-4 and 5
toxicity, respectively) from 1183 patients in a recent system-
atic review and study-level meta-analysis.1 Recently pre-
sented long-term data from Tekatli et al (127 patients, 60
Gy in 8-12 fractions, allowing Dmax of 140%) and the Lung-
Tech trial (31 patients, 60 Gy in 8 fractions, allowing Dmax
of 130%) report grade 3+ toxicity rates of 24% to 40%,4−7
also contrasting with the summarized outcomes.1
Live for Today
We can reconcile these conflicting data in the clinic by criti-
cally appraising radiation therapy planning and patient
selection factors in these studies and improving our own
practice of SABR for patients with ultracentral thoracic
tumors. Important factors to optimize in daily management

Corresponding author: Meredith E. Giuliani, MBBS, PhD; E-mail:
meredith.giuliani@rmp.uhn.ca
DOI of original article: http://dx.doi.org/10.1016/j.ijrobp.2023.06.246.
David A. Palma and Meredith E. Giuliani made equal contributions to
this editorial.
Disclosures: D.A.P. reports a Clinician-Scientist Grant from the
Ontario Institute for Cancer Research, royalties from UpToDate.com, and
a consultant role with equity from Need Inc, all unrelated to the present
work. M.E.G. has received funding from Bristol-Myers Squibb, AstraZe-
neca, and Eli Lilly. A.H.S. declares no conflicts of interest.

Int J Radiation Oncol Biol Phys, Vol. 117, No. 5, pp. 1232−1235, 2023
0360-3016/$ - see front matter Ó 2023 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ijrobp.2023.08.002
Volume 117  Number 5  2023
Fig. 1. Factors to optimize SABR for ultracentral thoracic tumors. Abbreviations: 4D-CT = 4-dimensional computed tomog-
raphy; Dmax = maximum point dose; EQD23 = equivalent dose in 2 Gy per fraction, a/b = 3 Gy; ITV = internal target volume;
IV = intravenous; OAR = organ at risk; PBT = proximal bronchial tree; PTV = planning target volume.
include dose fractionation and prescription, motion man-
agement strategies and planning target volume (PTV)
expansions, organ-at-risk (OAR) hotspots, target and OAR
contouring, and mitigation strategies for high-risk patients
(Fig. 1).
Risk-adapted dose fractionations and
prescription practices
Although a heterogeneously prescribed biologically equiva-
lent dose (BED10) ≥ 100 Gy is associated with high local
control and commonly used for SABR to peripheral and
central lung tumors,1 the optimal prescription has yet to be
elucidated for ultracentral lesions. The HILUS regimen
delivers a seemingly risk-adapted BED10 of 95.2 Gy to the
PTV periphery but a high BED10 (172.2 Gy) within the
PTV. The Tekatli et al and LungTech regimens deliver a
similarly high BED10 within the PTV (142.8-172.2 Gy), as
well as a higher BED10 (100 Gy) to the PTV periphery.
Although allowing large degree of inhomogeneity is com-
mon in SBRT, in light of potential uncertainties dose deliv-
ery, hotspots may pose a risk if tumor setup is imperfect. In
a free-breathing patient, it is plausible that a moving bron-
chus could enter the PTV and be subjected to a higher-
than-intended dose. An alternative approach is to limit the
inhomogeneity to safeguard against this occurrence. This
approach was taken in the SUNSET trial, prescribing 60 Gy
in 8 fractions and allowing a Dmax of 120%; oncologic and
toxicity outcomes associated with this risk-adapted prescrip-
tion are pending.8
Beyond the HILUS trial 1233
Optimized motion management strategies and
PTV expansions
By using techniques that encompass and limit breathing-
related tumor motion, accurate target coverage can be achieved
while limiting PTV expansions. The use of motion manage-
ment and PTV expansions is challenging to interpret in the
pooled analysis of the HILUS regimen.3 Abdominal compres-
sion was used if available when free-breathing tumor excursion
exceeded 5 to 10 mm, but it is unclear what strategies were
used if abdominal compression was not available or if com-
pression was insufficient to limit tumor motion. Relatively
large anisotropic PTV expansions of 10 to 15 mm longitudinal
and 5 to 10 mm transverse were allowed with the HILUS regi-
men. If deemed insufficient, PTV margins could be adapted,
but the method by which this was done is difficult to appraise.3
The relatively large expansions would have a substantial effect
on the target size. For a 2 cm tumor, adding 0.5 cm expansion
from GTV to PTV yields a 3 cm PTV (radius 1.5 cm) with a
volume of 14 mL. In contrast, adding a 15 mm longitudinal
and 10 mm transverse margin yields a PTV measuring 5 cm
longitudinally and 4 cm transverse, with a volume of approxi-
mately 42 mL, tripling the irradiated area. PTV overlap with
lobar or intermediate bronchi was a significant predictor of
grade 5 toxicity following the HILUS regimen. However, PTV
volume itself was not significant for toxicity and PTV expan-
sions were not tested for statistical associations. Larger (>5
mm) PTV expansions may increase the risk of higher doses
being delivered to the bronchi than planned; this analysis is
pending from the HILUS group. Motion management
1234 Safavi et al.
strategies to use include 4-dimensional computed tomography
(CT) with internal target volume (ITV) generation, abdominal
compression for free-breathing tumor excursion >8 to 10 mm,
or breath-hold techniques. In turn, an ITV should be isotropi-
cally expanded by only 3 to 5 mm, as in LungTech and
SUNSET.5,8
Limited OAR hotspots
It is prudent to limit hotspots in critical ultracentral OARs,
as there is a dearth of dose-volume data informing normal
tissue complication probabilities for these structures.
Ahmadsei et al report dose-response modeling predicting
low rates of severe toxicity with a peribronchial tree (PBT)
Dmax ≤100 Gy EQD23,9 complementing recommendations
from the International Stereotactic Radiosurgery Society to
limit Dmax < 80 to 90 Gy EQD23.1 Although these PBT con-
straints correspond with that of LungTech (EQD23 = 74.8
Gy),5 they are quite conservative compared with those used
in HILUS (EQD23 = 112 Gy) and SUNSET (EQD23 = 141
Gy).3,8 Adherence to conservative PBT constraints may
result in significant underdosing within the PTV and com-
promised local control. Higher PBT constraints as in SUN-
SET (Dmax < 106.7%) may be reasonable if applied to all
subsegments of the PBT, reducing the risk of unintended
hotspots in the OAR. The bronchus intermedius Dmax was
predictive of fatal hemorrhage following the HILUS regi-
men, underscoring that the omission of constraints for PBT
subsegments contributed to mortality in this study.3 Limita-
tion of the overall plan Dmax also reduces the risk of
unplanned, delivered hotspots in the PBT and increases
confidence in using a higher PBT constraint. Great vessel
Dmax less than the prescription could be considered. HILUS
and LungTech did not specify a Dmax for great vessels, while
SUNSET allows for a hotspot in the great vessels (Dmax <
106.7%, EQD23 = 141 Gy). Furthermore, undercoverage of
the PTV may be acceptable to permit prioritization of ultra-
central OAR constraints during radiation therapy planning,8
thereby lowering the risk of severe toxicity.
Fig. 2. An ultracentral primary lung tumor abutting the pulmonary artery on a computed tomography simulation scan with-
out (A) and with intravenous contrast (B).
International Journal of Radiation Oncology  Biology  Physics
Strategies to improve target and OAR contouring
accuracy and consistency
Ultracentral contouring is challenging and small variations
may lead to substantial OAR overdosage.10 In HILUS, a
SABR-induced tracheoesophageal fistula was noted in a
patient with an undercontoured esophagus, resulting in an
esophageal Dmax of 80 Gy.2 CT simulation with intravenous
contrast (Fig. 2), use of consensus atlases for OAR contour-
ing (ie, PBT, esophagus, great vessels, heart),11 and rigorous
review of volumes in quality assurance rounds may enhance
contouring accuracy for these cases.
Mitigation strategies for treating high-risk
patients
Endobronchial disease is a well-described risk factor for severe
toxicity.1 Following the HILUS regimen, tracheobronchial
compression independently predicted post-SABR fatal hemor-
rhage.3 Close radiographic review of all patients should be con-
sidered to identify potential tracheobronchial compression or
invasion, along with confirmatory bronchoscopy for equivocal
cases. Patients with concern for tracheobronchial compression
or invasion may be better suited for nonablative hypofractio-
nated regimens (eg, 60 Gy in 15 fractions), in lieu of SABR.
Peri-SABR use of anticoagulant/platelet/angiogenic medica-
tions remains a risk factor for severe toxicity,1 notwithstanding
the absence of a statistical interaction in the pooled HILUS
analysis.3 Following a comprehensive clinical assessment, man-
agement options include pausing or discontinuing these medi-
cations, constraining tracheobronchial Dmax below SABR
prescription dose, or using nonablative hypofractionated regi-
mens.1 Hilar and pericarinal lymph nodes may be higher risk
ultracentral targets for SABR with BED ≥ 100 Gy. Lymph
nodes accounted for 35% of targets in the HILUS trial, and 8
of 10 deaths occurred after high-dose SABR to hilar and peri-
carinal targets.2 Although lymph nodes were not identified as a
risk factor for grade 5 toxicity or hemorrhage following the
HILUS regimen,3 modest-dose SABR (eg, 35 Gy in 5 fractions)
Volume 117  Number 5  2023
may be a risk-mitigating alternative,12 accounting for the non-
curative intent of treatment for these targets.
Hope for Tomorrow
The future of SABR for ultracentral disease remains bright. In
the spirit of Ralph Waldo Emerson, we hope SUNSET brings
the promise of a new dawn of safer evidence-based treatment
for patients with ultracentral lung tumors. Adaptive radiation
therapy (ART) is a burgeoning radiotherapeutic strategy which
has the potential to further optimize the therapeutic index of
SABR for these indications. ART uses daily CT or magnetic res-
onance imaging to facilitate precise anatomic delineation and
adaptation before each fraction, thereby managing interfraction
anatomic variability. Additionally, ART allows for real-time
image-guided gated delivery, an ideal SABR strategy that maxi-
mizes OAR sparing by eliminating periodic motion during
beam-on time and reducing PTV margins. Early clinical effec-
tiveness and toxicity outcomes of magnetic resonance−guided
adaptive SABR for ultracentral thoracic lesions are promising;
Sandoval et al report their retrospective experience, including a
4.3% rate of grade 3 toxicity and no grade 4 or 5 adverse
events.13 This study combines ART with a more modest maxi-
mum point dose (125%) than in HILUS (150%), omission of
an ITV, and allowance of longer hypofractionated regimens
(10-15 fractions). Prospective data are pending from LUNG
STAAR (NCT04917224) and STARLUNG (NCT05354596), 2
ongoing nonrandomized phase 2 trials of magnetic resonance
−guided adaptive SABR for ultracentral thoracic lesions.
Although ART is promising, long-term prospective randomized
outcome data and critical appraisal of technical factors will be
required to establish ART as an evidence-based radiotherapeu-
tic strategy and define the attributable benefit of ART-enabling
technologies for optimizing the therapeutic index.
As we move beyond the HILUS trial, we must continue
to accumulate and review prospective evidence, comprehen-
sively report and analyze radiation therapy planning and
patient selection factors, and prioritize safety in daily man-
agement (Fig. 1), thereby advancing the practice of SABR
for ultracentral thoracic tumors.
Beyond the HILUS trial 1235
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