Clinical and Translational Oncology

https://doi.org/10.1007/s12094-020-02293-y

RESEARCH ARTICLE

Hypofractionated volumetric modulated arc therapy (VMAT) for fragile

patients with oesophageal cancer
Letizia Deantonio1   · Simona Cima1 · Stefano Leva1 · Antonella Richetti1 · Mariacarla Valli1

Received: 7 October 2019 / Accepted: 7 January 2020

© Federación de Sociedades Españolas de Oncología (FESEO) 2020

Abstract
Purpose  To evaluate the feasibility, safety, and dosimetric results of volumetric modulated arc therapy (VMAT) to deliver
hypofractionated radiotherapy (RT) in oesophageal cancer patients, unfit for a multimodality curative strategy.
Patients/methods  From 2010 to 2017, 22 patients were treated with hypofractionated VMAT for palliative/symptomatic
setting. The prescription dose was 40 Gy in 16 fractions (EQD2 41.7 Gy considering an α/β ratio of 10 Gy, and 44 Gy con-
sidering an α/β ratio of 3 Gy).
Results  Eight patients (36%) were symptomatic for grade 3 baseline dysphagia. RT was generally well tolerated, and no
patient interrupted the daily treatment. Acute toxicity was generally mild; no G3 acute toxicities were reported. At the end
of treatment, 5 patients (22.7%) experienced a stable dysphagia and 14 (63.6%) an improvement of baseline dysphagia,
while 3 patients (13.7%) reported a worsening of oesophagitis. At a mean follow-up of 8.7 months, 15 patients (79%) had a
complete clinical recovery (G0–1) of the symptomatic moderate/severe dysphagia. At 3 months after the end of RT, seven
patients (31.8%) achieved a partial or complete response. Two coplanar arcs were employed for VMAT delivery. Dosimetric
results were consistent in terms of both target coverage and normal tissue sparing. Finally, 1-year progression-free and overall
survival was 20% and 27.3%, respectively.
Conclusions  Hypofractionated VMAT was feasible, safe, and effective to deliver symptomatic radiation in locally advanced
oesophageal cancer patients, non-suitable for a standard curative treatment.

Keywords  Oesophageal cancer · Hypofractionation · Volumetric modulated radiotherapy · Toxicity

Introduction disappointing because of a very low 5-year overall survival

Oesophageal cancer has generally a poor prognosis and is
diagnosed in more than 50% of patients when unsuitable for
solely surgery. Neoadjuvant chemo-radiotherapy followed by
surgery is considered the gold standard in locally advanced
adenocarcinoma, whereas definitive concurrent chemo-
radiotherapy is considered the standard of care in squamous
cell carcinoma [1]. Patient co-morbidities, advanced age,
significant weight loss due to symptomatic lesions or poor
general conditions could preclude multimodality treatments
inducing clinicians to a personalized treatment approach.
The results of RTOG 94-05 and 85-01 trials have been
* Letizia Deantonio
letizia.deantonio@eoc.ch
1
Radiation Oncology Clinic, Oncology Institute of Southern
Switzerland, Bellinzona‑Lugano, Via Ospedale,
6500 Bellinzona, Switzerland
(OS) (0–20%) and high rate of 5-year loco-regional failures
(50–55%) in patients treated with conventionally fraction-
ated exclusive radiotherapy (RT) [2, 3]. Mild hypofrac-
tionated schedules have been implemented for improving
the tumoricidal effects in this radio-resistant cancer. Some
authors [4–6] have reported their experiences and, even in
a limited number of patients, demonstrated a better loco-
regional control and OS in comparison to conventional frac-
tionated RT schedules.
Moreover, RT techniques for oesophageal cancer are
moving from conformal three-dimensional RT (3D CRT) to
intensity modulated RT (IMRT) and ultimately to volumetric
modulated arc therapy (VMAT) [7–10].
When a curative intent is precluded because of patient
conditions or tumour stage, patient quality of life and symp-
tom palliation should be the clinician’s aims. In this regard,
within the Oncology Institute of Southern Switzerland,
the standard of care for fragile symptomatic patients with

13
Vol.:(0123456789)

oesophageal cancer unfit for a potentially curative treatment
is hypofractionated RT.
The aim of this retrospective study was to evaluate com-
pliance and symptom recovery with hypofractionated RT,
local control, and dosimetric results of VMAT (RapidArc)®.
As secondary end point, we evaluated progression-free sur-
vival (PFS) and OS.
Materials and methods
Since 2010, all fragile patients with a symptomatic or
advanced oesophageal cancer and unsuitable for chemo-radi-
otherapy with neoadjuvant or exclusive intent have received
hypofractionated RT. We collected information on patients
treated from 2010 to 2017 via an informatics query. Patients
who underwent a previous surgery or RT for a previous tho-
racic cancer were excluded.
The study was performed in accordance with the Dec-
laration of Helsinki in its latest version, and all patients
signed a written informed consent, following the roles of
our institution.
Twenty-two patients were treated with hypofractionated
V-MAT in the exclusive setting. All patients underwent an
oesophageal endoscopy for staging and histological con-
firmation, and a complete workup with contrast-enhanced
computed tomography (CT) and 18 fluorodeoxyglucose
(FDG)-positron emission tomography (PET).
A 3-mm-slice thickness simulation helical computed
tomography (CT) (Siemens, Big Bore) of the thorax and
upper abdomen was acquired with patients in the supine
position and immobilized with both arms above the head
using a customizable support (Posiboard TM; CIVCO Medi-
cal Solutions, Kalona, Iowa, USA) in free breathing (FB).
A total dose of 40 Gy in 16 fractions (equivalent dose in
2 Gy per fraction EQD2 = 41.7 Gy considering an α/β ratio
of 10 Gy, and 44 Gy considering an α/β ratio of 3 Gy) was
prescribed. Radiotherapy was administered once daily for
5 days per week in all cases.
We defined the gross tumour volume of the primary
tumour (GTV-T) and the GTV of the involved lymph nodes
(GTV-N) on CT and PET/CT. To include the area of subclin-
ical involvement around the GTVs (i.e. clinical target vol-
ume, CTV), 1 cm radial and 3 cm cranium–caudal margins
to the GTV-T and an isotropic 1 cm margin to the GTV-N
were provided. Performing a kilovoltage cone-beam CT on
daily basis for treatment verification, a margin of 0.5 cm
was provided to create the planning target volume (PTV) to
compensate for tumour motion and set up variations [11].
Considering the aim of the treatment, we did not perform an
elective nodal irradiation [12].
The dose was prescribed considering that the 95% isodose
encompassed the entire PTV, a consideration of tissue
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Clinical and Translational Oncology
heterogeneity was applied and the maximum dose to PTV
did not exceed the 7% of the maximum dose.
The lungs, heart, spinal cord, kidneys, stomach, small
bowel and large bowel, and liver were contoured on all cuts.
Because the moderate hypofractionated schedule here
performed had an EQD2 less damaging to the organs at
risks (EQD2 = 41.7 Gy considering an α/β ratio of 10 Gy,
and 44 Gy considering an α/β ratio of 3 Gy) than the dose
prescribed for a definitive treatment (i.e. 50.4  Gy in 28
fractions), the following conventional dose constraints
for OARs were considered: V20 Gy < 30% to the lung;
V25Gy < 10%, mean dose < 15 Gy, and V30 < 46% to the
heart; maximum dose < 50  Gy to the spinal cord; mean
dose < 15 Gy to the kidneys; maximum dose < 45 Gy to
the stomach; V15 < 120 cc to individual small bowel loops;
mean dose < 30 Gy to the whole liver [13, 14].
Treatment planning was performed by Varian Eclipse
system (TPS, version 13.7) and delivered by a Varian Cli-
nac IX (Varian Inc., Palo Alto, CA) and T ­ ruebeam® (Var-
ian Inc., Palo Alto, CA) Linac equipped with a 120 leaves
Millennium Multileaf Collimator. The geometrical approach
consisted of two VMAT arcs.
Toxicity data were retrieved from medical records graded
according to RTOG/EORTC toxicity scale and CTCAE ver-
sion 4.02 [15, 16].
Follow-up included clinical assessment at 1 and 3 months
and imaging at 3 months after the end of treatment. Fur-
ther follow-up was personalized according to the clinical
assessment.
Statistical analysis
A descriptive analysis was performed to assess treatment
feasibility and to report adverse event.
A Student’s t test was performed to assess any difference
of dosimetric parameters between upper/middle and lower/
junctional oesophageal cancers.
Kaplan–Meier curves were performed to evaluate sur-
vival curves. PFS was defined as the time interval from the
first day of RT until tumour progression as local or distant
failure; OS was defined as the time from the date of diag-
nosis until death.
Statistical analysis was performed using the software
SYSTAT version 11.0 (SPSS, Chicago, IL, USA). A p value
of ≤ 0.05 was considered statistically significant.
Results
Eight patients were in stage IV (36%) and the other 14 (64%)
were in stage II–III. Eight patients (36%) presented a grade
3 baseline dysphagia according to the CTCAE, and four
patients needed enteral feeding support (18%). No patient
Clinical and Translational Oncology

was palliated with an endoluminal stent before treatment. Table 1  Patient and tumour characteristics
Patient characteristics are summarized in Table 1. Variables 22 patients (N) (%)
RT was generally well tolerated; no patient interrupted
the daily treatment. Age
Acute toxicity was generally mild. According to the  Mean (years) 76.5
RTOG/EORTC toxicity scale, G1 gastrointestinal toxic-  Range (years) 55–91
ity with weight loss and nausea was reported in 27.3% and Sex
13.6% of patients, respectively. According to the CTCAE,  Female 6 27.30
G1 fatigue was experienced by 59% of patients. At the end of  Male 16 72.70
treatment, 5 patients (22.7%) experienced a stable dysphagia PS (ECOG)
and 14 (63.6%) an improvement of baseline dysphagia, while  1 10 45.50
only 3 (13.7%) patients reported a worsening of oesophagitis  2 12 54.50
(G2). No patients developed a grade 3 acute toxicity. Histology
At 1 month after treatment completion, the 4 patients  Squamous cell 8 57.10
requiring enteral feeding nutrition achieved a complete clini-  Adenocarcinoma 14 42.90
cal recovery. Grading
There were two deaths within 30 days of treatment, both  1 0 0
due to local tumour progression.  2 10 45.50
Among the 19 patients suitable for follow-up (mean  3 12 54.50
follow-up 8.7 months ± 10), 15 (79%) had a complete clini- Tumour Location*
cal recovery of the baseline symptomatic moderate/severe  Upper 3 13.60
dysphagia at the last follow-up visit. No patient needed to be  Middle 5 22.70
palliated with an endoluminal stent during follow-up.  Lower/GEJ 14 63.70
At 3 months, seven patients (31.8%) achieved a partial or Clinical stage AJCC
complete tumour response.  II 6 27.40
Dosimetric data are detailed in Tables 2, 3. Among all  III 8 36.30
patients, the mean PTV was 249.22 cc. As the mean V95  IV 8 36.30
(volume of PTV that received the 95% of the prescribed Time between biopsy and RT
dose) was 98.42% (SD 4.6), the mean V105 (volume of PTV  116 days (median)
that received the 105% of the prescribed dose) was 0.24%  Range 17–539
(SD 1.83), and the target coverage was consistent (Fig. 1). Follow-up
Exploring the possible volumes and dosimetric differences  Mean 8.7 months
between the upper/middle and lower/GEJ tumours, no dif-  SD SD ± 10
ferences (p = ns) were shown. Middle oesophagus: the middle thoracic oesophagus extends from
As shown in Fig.  2, median time to progression was the lower border of the azygos vein to the inferior pulmonary veins,
5.4  months (range 1–35  months). 6 months PFS was extending from approximately 25–30 cm
50%, and 1-year PFS was 20%. Finally, median OS was Lower oesophagus/gastrointestinal junction (types I and II): the lower
9.6 months (range 3–44 months). 1-year OS was 27.3% thoracic oesophagus extends from the inferior pulmonary veins and
to the stomach and is inclusive of the gastroesophageal junction, typi-
(Fig. 3). cally extending from approximately 30–40 cm. If the tumour center is
located from > 1 cm up to 5 cm above the gastroesophageal junction
(Z-line), the tumour is classified as a type I adenocarcinoma of the
distal oesophagus. If the tumour centre is located within 1 cm ceph-
alad to 2 cm caudal to the gastroesophageal junction, it is classified as
Discussion type II [31]
N number, PS performance status according to Eastern Coopera-
Although neoadjuvant radio-chemotherapy followed by radi- tive Oncology Group (ECOG), GEJ gastrointestinal junction, AJCC
cal surgery has become the standard of care in case of locally American Joint Committee on Cancer, RT radiotherapy, SD standard
advanced stage [17], traditionally, a definitive chemo-radio- deviation
*
therapy regimen is recognized as the standard non-surgical  Upper oesophagus: the upper thoracic oesophagus is bordered supe-
riorly by the thoracic inlet and inferiorly by the lower border of the
approach [3]. In such a scenario, elderly and polymorbid
azygos vein, extending from approximately 20 to 25 cm
patients represent a growing population and may be unfit for
such intensive treatment.
This is a significant area of interest in which different
therapeutic strategies need to be explored.

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 Clinical and Translational Oncology

Table 2  Planning target volume (PTV) dose parameters (total dose prescribed 40 Gy)
Tumour location N pts PTVcc (mean ± SD) D2 (Gy) (mean ± SD) D98 (Gy) (mean ± SD) V95 (%) (mean ± SD) V105 (%) (mean ± SD)

All 22 249.22 ± 142.32 41.21 ± 0.92 39.2 ± 0.01 98.42 ± 4.6 0.24 ± 1.83

Upper/middle 8 210.27 ± 139.18 41.25 ± 0.33 39.2 ± 0.01 98.96 ± 1.27 0.21 ± 0.29
Lower/GEJ 14 271.47 ± 150.73 41.19 ± 0.29 39.2 ± 0.01 98.11 ± 2.13 0.26 ± 0.67
p = 0.35 p = 0.65 p = 0.39 p = 0.32 p = 0.84

N number, Pts patients, Gy gray, cc cubic centimetres, D2 dose received by 2% of the PTV, D98 dose received by 98% of the PTV, V95 volume of
the PTV receiving 95% of the prescribed dose, V105 volume of the PTV receiving 105% of the prescribed dose, P t test p value

Table 3  Organs at risk (OAR) Volumes Dose parameter All (mean + SD) Upper/middle Lower/GEJ (mean + SD)
dose parameters (total dose (mean + SD)
prescribed 40 Gy)
Spinal cord D1cc Gy 18.92 ± 0.24 20.98 ± 6.54 17.75 ± 0.24 p = 0.08
Lungs MLD Gy 4.95 ± 4.32 5.36 ± 0.24 4.72 ± 4.32 p = 0.59
V5 (%) 36.28 ± 27.33 43.83 ± 10.39 31.96 ± 27.33 p = 0.2
V20 (%) 3.6 ± 5.3 4.21 ± 6.09 3.25 ± 5.3 p = 0.52
V30 (%) 1.14 ± 0.93 1.47 ± 2.86 0.94 ± 0.93 p = 0.3
Heart Dmean Gy 10.14 ± 1.88 9.65 ± 0.8 10.35 ± 1.89 p = 0.8
D1cc (Gy) 32.62 ± 1.85 29.47 ± 0.34 33.98 ± 1.85 p = 0.43
V30 (%) 4.9 ± 4.77 4.16 ± 0.94 5.21 ± 4.77 p = 0.72

D1 dose received by 1% volume of the considered organ

SD standard deviation, Gy gray, cc cubic centimetres, MLD mean lung dose, V5, V20, V30 relative volume
of the considered organ receiving 5, 20, 30 Gy, respectively, P t test p value

Fig. 1  Isodose distribution for an oesophageal cancer patient treated with VMAT

When palliation of dysphagia is the aim of the therapy,
physicians may offer many therapy modalities such as RT
(i.e. external beam RT and brachytherapy) or endoscopic
techniques (i.e. endoluminal stents, endoscopic ablation).
Among these approaches, RT and endoluminal stents are
frequently discussed and proposed to patients. Interestingly,
a recent review [18], analysing randomized trials compar-
ing RT and endoscopic techniques, showed better dyspha-
gia-free survival and quality of life in patients treated with
brachytherapy. With RT, dysphagia relief occurred later than

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Clinical and Translational Oncology
Fig. 2  Oncological results for treatment: progression-free survival
(PFS)
Fig. 3  Oncological results for treatment: overall survival (OS)
with endoluminal stent; however it was longer with less risk
of complications.
In such symptomatic patients, an early symptom relief
by stent placement and then RT may be considered, but the
available data do not reveal a standard of care [18].
International guidelines suggest considering RT when a
patient has at least a life expectancy of 4 months [18, 19].
Overcoming the concept of standard RT fractionation [20,
21], some authors proposed hypofractionated schedules of
external beam RT or brachytherapy in selected series of
patients [4, 5, 18]. Available data did not show witch one
was better and hospital policy and equipment may influence
treatment choice [18]. Moreover, hypofractionated schedules
are used in a wide range of treatments and may be supported
through the use of more precise RT techniques such as IMRT
and VMAT and modern system of treatment verification (i.e.
image-guided RT) [9, 22–25]. Therefore, the present retro-
spective study showed the feasibility of a hypofractionated
regimen for symptomatic fragile patients unfit for a multi-
modal curative treatment. This moderate hypofractionation
using 2.5 Gy per fraction was chosen taking into account
that the treatment is completed in 3 weeks and the results
of hypofractionated schedules on symptom relief for fragile
patients [26].
The schedule used was well tolerated, with mild acute
toxicity, none grade 3 events, and a satisfactory symptom
recovery in 79% of patients during the follow-up. In particu-
lar, the four patients with feeding tube achieved a complete
dysphagia recovery within 1 month from the end of RT. In
contrast, Jones et al. [6] experienced enteral feeding support
in 6.6% of elderly patients treated with a mild hypofraction-
ated RT schedule to a total dose of 50 Gy in 16 fractions
(EQD2 = 54.1 Gy).
Our patients had a mean age of 76.5 years and all per-
formed the daily treatment without interruption. In this
regard, Walter et al. [27] addressed a definitive conventional
fractionation RT schedule ± chemotherapy to a sample of
elderly patients (mean age 76 years) with oesophageal can-
cer. 80% of patients experienced acute toxicity of grade 3 or
more, and the majority of them were treated with 3D-CRT
technique. Moreover, 44% were not be able to receive the
full course of planned chemotherapy. The high risk of severe
toxicity and the difficulty of administering the planned treat-
ment may suggest performing a more tolerable treatment in
such a scenario. Unfortunately, elderly patients are usually
excluded from clinic trials, but need to be taken into account
as a fragile population constantly growing.
For several diseases, the IMRT technique has been
proven to be more effective than 3D-CRT in target cover-
age, dose homogeneity, and reducing doses to normal tis-
sues [8]. Although 3D-CRT has been considered the stand-
ard approach for oesophageal cancer, the implementation
of IMRT suggests that organs at risk may be significantly
speared [8]. The comparison between 3D-CRT and IMRT
showed significantly less average percent volumes of irradi-
ated lung and heart with IMRT. Interestingly, a dosimetric
benefit did not correspond with a clinical benefit in terms of
toxicity [8, 9, 24]. Moreover, IMRT seems to be superior to
3D-CRT in the OS [8].
From the first demonstration of the superiority of IMRT
in oesophageal cancer [28], other RT strategies were imple-
mented, such as VMAT. Such rotational technique offered
the opportunity of reducing the treatment time and monitor-
ing units with a continuous beam on during the treatment.
Additionally, dose rate, field shape, and gantry rotational
speed may be changed [9, 29]. In our experience, the VMAT
guaranteed homogeneous PTV coverage with a mean V95
of 98.42% and a very low risk of overdosage with a mean
V105 of 0.24%. VMAT achieved also an effective sparing
of the spinal cord (D1 mean dose 18.9 Gy), a low mean lung
dose (MLD 4.95 Gy SD 4.3 Gy) and a safe heart sparing
(V30 = 4.9 Gy).
For what concerns PFS and OS, the 1-year PFS and OS
were 20% and 27.3%, respectively. Jones et al. [6] reported
13

no significant differences in PFS and OS between the two
groups analysed (hypofractionated RT vs. standard frac-
tionation RT), with a median time to treatment failure of
25 months and 1-year OS of 85% for patients treated with
hypofractionation. The higher survival and control rate may
be explained by the higher EQD2 and BED gained. The
schedule performed by Jones et al. was equivalent to 54.1 Gy
(EQD2), and had a biological equivalent dose (BED) of
100 Gy, considering an α/β ratio of 10 Gy, while our sched-
ule is equivalent to EQD2 of 41.7 Gy and BED of 73.3 Gy.
Although the reported data are based on retrospective
studies, several important implications may be argued.
Firstly, assuming an α/β of 10 Gy for oesophageal cancer,
hypofractionated schedule that achieved at least an EQD2
of 50 Gy may be considered safe and effective, because the
standard prescription dose for definitive CRT is 50.4 Gy
(EQD2 49.6 Gy) [30]. Moreover, a schedule that applied
a dose escalation may be supported by IMRT or V-MAT
with IGRT. Finally, V-MAT may guarantee an optimal target
coverage with sparing of organs at risk [9].
The present study has some limitations that need to be
taken into account. Firstly, this was a retrospective analysis
and the number of patients was limited, reducing the power
of the conclusions. Secondly, the high burden of comorbidity
and the relative low performance status described a sample
of fragile population, with a relatively short survival. Lastly,
the schedule has an EQD2 lower than 50 Gy that may also
explain survival rates. However, the population received a
homogeneous RT treatment with an optimal compliance
and dysphagia recovery that were the primary aims of our
analysis.
Conclusions
Hypofractionated VMAT was feasible, safe, and effective to
deliver definitive RT in fragile oesophageal cancer patients,
non-suitable for a standard treatment. The concern about
the risk of toxicity using hypofractionated schedule may be
overcame using the newer precision RT technology, such as
V-MAT, and the implementation of IGRT. However, the use
of hypofractionated schedules for the treatment of oesopha-
geal cancer requires prospective and randomized trials.
Looking at our clinical practice, the feasibility of the pre-
sent fractionation prompts evaluating a higher fractionation
to achieve higher biological equivalent doses.
Compliance with ethical standards  pelvic radiotherapy. Radiat Oncol. 2019;14:57.
Conflict of interest  The authors declare that they have no conflict of
interest.
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Clinical and Translational Oncology
Ethical approval  All procedures performed in studies involving human
participants were in accordance with the ethical standards of the insti-
tutional and/or national research committee and with the 1964 Helsinki
Declaration and its later amendments or comparable ethical standards.
Informed consent  Informed consent was obtained from all individual
participants included in the study.
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