Acta Oncologica

ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: https://www.tandfonline.com/loi/ionc20

Clinical results of proton therapy reirradiation for

recurrent nasopharyngeal carcinoma

F. Dionisi, S. Croci, I. Giacomelli, M. Cianchetti, A. Caldara, M. Bertolin, V.

Vanoni, R. Pertile, L. Widesott, P. Farace, M. Schwarz & M. Amichetti

To cite this article: F. Dionisi, S. Croci, I. Giacomelli, M. Cianchetti, A. Caldara, M. Bertolin, V.

Vanoni, R. Pertile, L. Widesott, P. Farace, M. Schwarz & M. Amichetti (2019) Clinical results of
proton therapy reirradiation for recurrent nasopharyngeal carcinoma, Acta Oncologica, 58:9,
1238-1245, DOI: 10.1080/0284186X.2019.1622772

To link to this article: https://doi.org/10.1080/0284186X.2019.1622772

Published online: 03 Jun 2019.

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ACTA ONCOLOGICA
2019, VOL. 58, NO. 9, 1238–1245
https://doi.org/10.1080/0284186X.2019.1622772

ORIGINAL ARTICLE

Clinical results of proton therapy reirradiation for recurrent

nasopharyngeal carcinoma
F. Dionisia, S. Crocib, I. Giacomellia, M. Cianchettia, A. Caldarac, M. Bertolinc, V. Vanonid, R. Pertilee ,
L. Widesottf, P. Faracef, M. Schwarzf and M. Amichettia
a
Proton Therapy Unit, APSS, Trento, Italy; bRadiation Oncology Unit, University of Siena, Siena, Italy; cOncology Unit, APSS, Trento, Italy;
d
Radiation Oncology Unit, APSS, Trento, Italy; eEpidemiology Unit, APSS, Trento, Italy; fMedical Physics Unit, APSS, Trento, Italy

ABSTRACT ARTICLE HISTORY

Background and purpose: Recurrent nasopharyngeal carcinoma (NPC) has limited curative treatment Received 4 February 2019
options. Reirradiation is the only potential definitive treatment in advanced stages at a cost of sub- Accepted 17 May 2019
stantial severe and often life-threatening toxicity. Proton therapy (PT) reduces irradiated volume com-
pared with X-ray radiotherapy and could be advantageous in terms of safety and efficacy in a
population of heavily pretreated patients. We report the retrospective results of PT reirradiation in
recurrent NPC patients treated at our Institution
Methods: All recurrent NPC patients treated since the beginning of clinical activity entered the pre-
sent analysis. Clinical target volume consisted of Gross Tumor volume plus a patient-specific margin
depending on disease behavior, tumor location, proximity of organs at risk, previous radiation dose.
No elective nodal irradiation was performed. Active scanning technique with the use of Single Field
Optimization (SFO) or Multifield Optimization (MFO) was adopted. Cumulative X-ray -PT doses were
calculated for all patients using a dose accumulation tool since 2016. Treatment toxicity was retro-
spectively collected.
Results: Between February 2015, and October 2018, 17 recurrent NPC patients were treated. Median
follow-up (FUP) was 10 months (range 2–41). Median PT reirradiation dose was 60 Gy RBE (range
30.6–66). The majority of patients (53%) underwent concomitant chemotherapy. Acute toxicity was
low with no
G3 adverse events. Late events
G3 occurred in 23.5% of patients. Most frequent late
toxicity was hearing impairment (17,6%). G2 soft tissue necrosis occurred in two patients. Fatal bleed-
ing of uncertain cause (either tumor recurrence or G5 carotid blowout) occurred in one patient.
Kaplan–Meier 18 months Overall Survival (OS) and Local control (LC) rates were 54.4% and 66.6%,
respectively.
Conclusions: Our initial results with the use of modern PT for reirradiation of recurrent NPC patients
are encouraging. Favorable LC and OS rates were obtained at the cost of acceptable severe
late toxicity.

Introduction reirradiation among Canadian radiation oncologists revealed

Radiotherapy represents the mainstay in the treatment of
nasopharyngeal carcinoma (NPC), rare cancer with an age-
standardized rate of 1.2 per 100,000 in 2012; in endemic
areas such as Eastern-Southern Asia NPC accounts for 43.6%
of head and neck (HN) cancers [1].
Cure rates are high also in advanced stages, where che-
moradiation is the standard of care allowing an Overall
Survival (OS) at 5 years of around 60% [2].
Local failure can occur in up to 40% of the patients [3,4].
In this setting, treatment options with curative intent still
exist but are limited to surgery, when feasible, in early recur-
rence stages [5] and reirradiation [6].
Reirradiation combined with chemotherapy improves dis-
ease-free survival (DFS) compared to surgery alone in recur-
rent HN cancer, as demonstrated in the randomized trial by
Janot et al. [7] A survey of patterns of practice regarding
that almost 80% of the respondents would offer reirradiation
in case of recurrent NPC [8]. The rationale lies in the high
rates of local control (up to 85% at 3 years in recent series
[9]) that can be achieved with modern reirradiation of NPC.
The risk of severe toxicity, however, is relevant, with around
30–50% of the patients experiencing
G3 late effects even
with the use of advanced radiation techniques such as inten-
sity-modulated radiotherapy (IMRT) [10].
Proton therapy (PT) represents a unique method to
deliver RT which exploits protons physical properties of a
finite range in tissue to ensure low entrance dose and zero
dose beyond the end of their path [11]. These features make
this treatment particularly suitable for specific clinical chal-
lenging settings such as reirradiation with curative intent,
where normal tissue tolerance limits the administration of
curative doses [12]. A recent systematic review by Verma
et al. regarding the use of PT for reirradiation posited that

CONTACT F. Dionisi francesco.dionisi@apss.tn.it Proton therapy Unit, Azienda Provinciale per i Serivizi Sanitari, Via al Desert, 14, 38123, Trento, Italy
ß 2019 Acta Oncologica Foundation

PT “may be the safest option … .and … may be the best
approach for offering select patients a new chance of
cure” [13].
In this paper, we retrospectively analyzed the clinical
results of all the patients affected by recurrent NPC that
were reirradiated with PT at our Institution since the begin-
ning of our clinical activity.
Material and methods
Patients
All cases were discussed in the Institutional multidisciplinary
HN tumor board. Patients were considered for PT reirradia-
tion in case of M0 disease, Eastern Cooperative Oncology
Group (ECOG) Performance Status (PS) 2, absence of severe
comorbidities. Written consent was signed by all the
patients; the analysis was conducted according to the
Institutional Ethical Committee policy.
Previous treatment information
A detailed documentation of previous radiochemotherapy
treatment, including radiation volumes, dose distributions,
fractionations, chemotherapy regimens and tolerance was
mandatory. Initially, the retrieval of previous treatment
plan’s DICOM files were requested but not mandatory.
Since 2016, with the implementation of a new treatment
planning software allowing for deformable registration, the
retrieval of previous treatment DICOM files
became mandatory.
Proton therapy
Setup procedures consisted of patient immobilization on
base of skull (BOSTM) specific headframe with an individual
three-point thermoplastic mask. A mouth bite to increase
setup position reproducibility was suggested but not man-
datory. The planning computed tomography (CT) scan
(1.5 mm slice thickness) was registered with diagnostic MR
and or PET-CT for target volume and organ at risk (OAR)
delineation. A margin of 0.5–1.5 cm around the gross tumor
volume (GTV) (according to disease behavior, tumor recur-
rence volume, OAR location, site of recurrence with respect
of previous treatment volumes), corrected for anatomical
barriers was used to create the clinical target volume
(CTV). No elective nodal irradiation was performed.
Simulation CT scan was repeated at least once during
treatment in order to verify consistent target coverage and
OAR sparing.
Proton plans were generated using the XIOV planning sys-
R
tem (XioV Proton; Elekta AB, Stockholm, Sweden) or, since
R
2016, Raystation planning system (#Raysearch Laboratories,
Sweden) using actively scanned protons (energy range
70–230 MeV, spot sigma @ 32 g/cm2  2.65 mm) accelerated
by a cyclotron and delivered by a 360 rotational gantry (Ion
Beam Application, IBAV). Single field optimization technique
R
(SFO), which employs individually optimized PT fields that
ACTA ONCOLOGICA 1239
each delivers a homogeneous dose to the target, or
Multifield optimization technique (MFO), which optimizes all
spots from all fields simultaneously, were used. For the SFO
technique, an isotropic margin from CTV to PTV of 4 mm was
applied, thus accounting for both setup and range uncertain-
ties. For the multi-field optimization (MFO) technique, an
hybrid approach was implemented to allow combining MFO
planning with a Monte Carlo dose calculation algorithm in a
clinical context: i.e. planning dose coverage on isotropic
PTVMFO (with 3 mm CTV-PTV margin) compensating for
setup errors, whereas range calibration uncertainties of
±3.5% are incorporated into PTVMFO robust optimization
process (submitted paper).
Available DICOM files of previous treatment were
imported into proton-planning software; X-ray simulation CT
was deformed and registered with PT simulation CT. Then, X-
ray dose distribution was deformed into PT CT for proton-X-
ray dose summation and evaluation. Maximum cumulative
dose to the carotid arteries (CA) was set at 120 Gy; case by
case evaluation was made between target coverage and
carotid sparing prioritization. A 30–50% brainstem recovery
from previous radiotherapy was assumed. Maximum cumula-
tive (considering recovery) dose constraints for the brainstem
were v60 < 0.9cc [14] and maximum dose < 64 Gy [15]. Due
to the lack of robust clinical data, no recovery was consid-
ered for optic structures; cumulative maximum dose was set
at 60 Gy. Temporal lobe and inner ears doses were not con-
strained with the exception of avoiding hotspots. Plan
robustness analyses were performed for MFO plans; combi-
nations of possible range and setup errors were simulated.
Specifically, range uncertainty due to CT calibration errors
was considered by scaling the mass density of the treatment
volume by ±3.5%, while to account for setup errors, ±2mm
shifts (simultaneously in each orthogonal direction) of the
isocenter were introduced. The robustness analysis consisted
in the calculation of eight perturbed doses for each of the
two range uncertainties considered, with the total shift corre-
sponding to the eight vertexes of a cube centered at the
nominal isocenter. A total of 16 perturbations are thus calcu-
lated, that represent a set of worst-case (but physically pos-
sible) scenarios. Proton relative biological effectiveness (RBE)
was set at 1.1 [16].
Chemotherapy
The use of chemotherapy, chemotherapy drug and regimen
depended on patient comorbidity, age, recurrence volume,
recurrence location, PS and previous chemother-
apy treatments.
Clinical evaluation and follow-up
Toxicity and patient treatment compliance were evaluated
weekly during PT and at every follow-up visit; imaging
examinations (MR, PET) were performed three months after
the end of the treatment and then every 3–6 months.
Treatment-related acute and late toxicities were scored
1240 F. DIONISI ET AL.

Table 1. Patients characteristics. Table 2. Reirradiation treatment details.

Characteristics N (%) Characteristics N (%, range)
Gender Treatment intent
M/F 10 (58.8)/ 7 (42.2) Definitive 16 (94.1)
Age Palliative 1 (5.9)
Median (range) 58 (37–76) GTV
Histology Median (range) 15.4 cc (5–43.3)
Squamous cell carcinoma 6 (35.3) PT technique
Non-keratinizing carcinoma 4 (23.5) SFO 13 (76.5)
Undifferentiated carcinoma 7 (42.2) MFO 4 (23.5)
Recurrence site N of beams
Skull base 16 (94.1) Median (range) 4 (2–5)
nodal 1 (5.9) Reirradiation total dose (Gy)
rT STAGE Median (Range) 60 (30.6–66)
T2 1 (5.9) Reirradiation fractionation (Gy)
T3 3 (17.6) Median (Range) 2 (1.8–2)
T4 12 (70.6) OAR doses
rTNM STAGE Maximum cumulative carotid artery 118.5 (109–129)
II 1 (5.9) Maximum optic nerve PT 16.5 (0.3–49)
III 4 (23.5) Maximum cumulative optic nerve 47 (4–60)
IV 12 (70.6) Maximum chiasm PT 25 (0.3–50)
PS (ECOG) Maximum cumulative chiasm 49 (5–58)
0 4 (23.5) MaximumP cumulative temporal lobe 80.8 (30.5–117)
1 7 (42.2) BED2,5 1cc temporal lobe 145.5 (54.9–210)
2 6 (35.3) Avg dose inner ear PT 20 (3.7–61.5)
Time elapsed since previous irradiation (months) Avg cumulative inner ear 61.9 (33.7–98.6)
Median(range) 30 (11–108) Replanning during reirradiation
N of previous RT treatments Yes 3 (17.6)
Median (range) 1 (1–2) No 14 (82.4)
Previous treatment course technique Chemotherapy regimen
3D CRT 6 (35.3) Induction 1 (5.9)
IMRT 11 (64.7) Induction þ concomitant 1 (5.9)
Brachytherapy 1 (5.9) Concomitant (CDDP) 3 (17.6)
Previous treatment course RT total dose (Gy) Concomitant (CBDCA) 4 (23.5)
Median (range) 70 (60–74) No chemotherapy 8 (47.1)
Previous treatment course RT fractionation (Gy) In case of paired organ, the organ receiving the maximum dose was
Median (range) 2 (1.8–2.5) P
reported. OAR: organ a at risk; PT: proton therapy; BED2,5_ 1cc: cumulative
Previous chemotherapy regimen biological equivalent dose, a/b 2,5; Avg: average; CDDP: cisplatin; CBCDA:
Induction þ concomitant 12 (70.6) carboplatin.
Concomitant 4 (23.5)
No chemotherapy 1 (5.9)
r: recurrence; 3DCRT: 3D conformal radiotherapy; IMRT: intensity modulated Treatment
radiotherapy.
Table 2 describes reirradiation treatment details. All but one
patients were treated with definitive intent; median PT reirra-
according to Common Terminology Criteria for Adverse
diation dose was 60 GY RBE. Median GTV was 15.4 cc. MFO
Events, CTCAE Version 5.0.
technique was implemented since the end of 2017 and was
used for four patients. Three patients (17.6%) underwent
Statistical analysis replanning during treatment due to anatomical changes
Local control (LC) and overall survival (OS) were estimated resulting in not negligible shift between planned and deliv-
from the end of the treatment with the Kaplan–Meier method. ered dose. The majority of patients (53%) underwent inte-
Fisher exact test was used to compare patients’ characteristics grated PT plus chemotherapy treatment. Concomitant
and outcome. p  .05 was considered statistically significant. carboplatin was the most adopted chemotherapy regi-
Statistical analysis was performed using SASV v 9.1, Milan, Italy. men (23.6%).
R

Results Outcome

Between February 2015 and October 2018, 17 patients
affected by recurrent NPC and reirradiated at our Institution
entered the present analysis. The patients’ clinical character-
istics are detailed in Table 1. The median age was 58 years.
The majority of the patients (94%) were affected by
advanced stage (III–IV) recurrence stage. Median interval time
between treatments was 30 months. IMRT was used in the
1st treatment course for most patients (64.7%). One patient
underwent two course of radiation therapy (one delivered
with IMRT and the latest with brachytherapy) before PT
reirradiation.
Median follow-up was 10 months (range 2–41). At the time
of the present analysis, seven patients (41%) have died. Four
patients died for the consequences of local cancer progres-
sion at 6, 11, 14 and 22 months, respectively. One patient
died for oropharyngeal cancer not susceptible for other
active treatment at 10 months. Another patient died for
other causes at 6 months. Kaplan–Meier 18 months OS and
LC rates were 54.4% and 66.6%, respectively (Figure 1).
When excluding the patient treated with palliative intent, the
18 m OS and LC probability for the remaining 16 patients
were 59.3% and 72.9%, respectively. No significant
 ACTA ONCOLOGICA 1241

Figure 1. Kaplan–Meier OS and LC analysis for all patients.

associations between the treatment parameters examined Table 3. Acute toxicities.

(GTV > or < 20cc, use of chemotherapy, target coverage < or Acute toxicity G1 G2 G3 G4 G5
> 90%, tumor histology) and outcome were found (P ¼ NS). Mucositis 4 3
Dysphagia
Cranial nerve disorder 1
Hearing impaired 1
Pain 3 1
Toxicity Radiation dermatitis 3
Fatigue 2
PT was well tolerated without interruptions due to toxicity.
Acute toxicity was mild with no
G3 side effects (Table 3).
Late toxicities are described in Table 4. 23.5% of the patients Table 4. Late toxicities.
registered
G3 toxicities. Hearing impairment was the most Late toxicity G2 G3 G4 G5
frequent G3 late side effect. No temporal lobe injuries were Trismus 1
Dysphagia 1 1
registered at the time of the present analysis. At the present Soft tissue necrosis 2
time one patient developed asymptomatic cervical vertebral Hearing impaired 3
(C1) focal osteonecrosis 21 months after the end of the treat- Osteonecrosis 1
Middle ear inflammation 2
ment. DVH analysis revealed that the bone volume affected Cranial nerve disorder 1
by necrosis received a cumulative maximum dose of 119 Gy Carotid blowout 1
(Figure 2). The patient is alive with no evidence of recurrence See text for details.
at 41 months from the end of the treatment. One patient
developed profuse nasal hemorrhage 11 months after the Discussion
end of reirraidiation given to a recurrent tumor abutting the
NPC is a rare cancer, with a crude incidence rate in Europe
left carotid space (tumor involvement < 1/3 of CA circumfer-
of 0.475 per 100,000 (period 2000–2007) [17]. In Italy, inci-
ence). Time interval between 1st treatment (69.96 Gy in 33
dence is slightly higher than in Europe with 574 new cases
fractions) and PT reirradiation (59.4 Gy RBEin 33 fractions) estimated in 2015 and a crude incidence rate of 0.88 per
was 70 months. Maximum left CA dose for the PT plan was 100,000 [18].
56 Gy RBE. Urgent endoscopical examinations revealed a NPC usually grows silently and is often diagnosed in
bleeding mass in the nasopharynx, suspicious for recurrent advanced stages [19]; nonetheless it remains a curable dis-
tumor; a biopsy was not performed. Previous follow-up imag- ease with OS at 5 years of around 60%. When recurrence
ing (PET, MR) after PT reirradiation did not report any suspi- occurs, in most cases isolated local failure is diagnosed: in
cious signs of recurrence. The patient died due to infarction such cases, patients who receive salvage treatment have sig-
few days after hospitalization, no autopsy was performed nificant better OS than those who do not receive salvage
and even if an unquestionable cause of death (recurrence vs. treatment [20].
G5 carotid blowout) could not be found, death cause was Proton therapy represents one of the most advanced
registered as recurrence. Post hoc deformable registration types of radiotherapy currently available. Dosimetrical and
(not available at the time of treatment) revealed a maximum clinical reports demonstrated dose distribution advantages
cumulative dose to the left CA ¼129 Gy. The median cumula- compared with state of the art X-ray therapy along with
tive dose to CA in our series for patients with DICOM files safety and effectiveness in HN patients [21–23]. In such a
available was 118.5 Gy (range 104–129). challenging scenario as reirradiation with curative intent of
1242 F. DIONISI ET AL.

Figure 2. (a) FDG CT-PET showing recurrence of squamous cell NPC 66 months after definitive chemoradiation treatment. Recurrence stage was T4N0M0. The
patient was treated with induction CHT (2 cycles CDDP-5FU) and reirradiation PT (59, 4 Gy RBE in 33 fractions). (b) PT 95% isodose distribution (orange) encompass-
ing GTV (blue line), CTV (purple line) and PTV (red line). PT 30% isodose distribution is illustrated in blue. (c) FDG CT-PET showing complete response to reirradia-
tion at three months. (d) CT image showing osteonecrosis focal area at cervical vertebra C1 21 months after reirradiation (red arrow). (e) PT isodose distribution of
100% (red area) encompassing osteonecrosis focal area. (f) Photon-PT dose summation via deformable registration showing isodose of 119 Gy and 114 Gy (yellow
and green areas, respectively). Maximum cumulative dose to the osteonecrosis area (orange circle) was 119 Gy. The patient is alive with no evidence of disease 41
months after the end of the treatment.

heavily pretreated NPC cancer patients, the use of PT could
help in increasing the therapeutic ratio between cure rates
and the risk of toxicity.
To our knowledge, the present paper represents the larg-
est series of recurrent NPC cancer patients reirradiated with
PT. In the multi-institutional retrospective study by Romesser
et al. [24] regarding PT reirradiation for HN cancer, nine
patients were affected by recurrent NPC. Seven recurrent
NPC were reirradiated in the other retrospective analysis of
the use of PT for HN reirradiation by Mcdonald et al. [25].
Another multi-institutional series by Phan et al. included five
patients affected by recurrent NPC [26]. In another series by
Dale et al. [27] of HN and skull base patients reirradiated
with particle therapy, nasopharyngeal site was reirradiated in
15 patients, of whom six patients were reirradiated with pro-
tons; the other nine patients were reirradiated with carbon
ions. Two patients affected by nasopharyngeal tumor recur-
rence were included in the analysis from Heidelberg regard-
ing the use of particles for recurrent HN cancer [28]. No
details regarding recurrent NPC patients’ specific outcome
were provided in all the studies. The historical series of Lin
et al. from Loma Linda analyzed the results of PT for 16
patients affected by recurrent NPC between 1991 and 1997
[29]; double scattering proton therapy technique was used.
Median reirradiation PT dose was 60.1 Gy RBE. OS and LC
were both 50% at 24 months. A significant association
between adequate tumor coverage (defined as
90% of
treated volume receiving
90 of the prescribed dose) and
OS was found. Similar outcome results were found in our ser-
ies with 18 months OS and LC probability of around 60%
and 70%, respectively and long-term survival expectancy for
selected patients.
Differently from the study by Lin, in our series adequate
target coverage was achieved in a higher percentage of
patients (83% vs. 50%). The most reasonable explanation for
this finding lies in the different delivery technique between
the two studies: in the historical series by Loma Linda treat-
ments were delivered with passive scattering technique,
while in the present paper an active scanning technique was
used. The difference in adequate target coverage between
the two series may be explained by the advantage in dose
conformality (i.e., proximal conformality) guaranteed by mod-
ern PT technique such as active scanning [30]. A longer FUP
is needed to evaluate if superiority in dose distribution
would translate in a better outcome.
As already mentioned, the treatment of recurrent NPC
represents a therapeutic dilemma: surgery, when feasible, is
limited to selected, early stages [31], whereas reirradiation
with or without chemotherapy is the only potential curative
option in early stages when surgery is not indicated or not

feasible, and in intermediate and advanced stages. To bal-
ance the risks and the benefits of reirradiation in this setting
is extremely hard: on one hand, indeed, the majority of
deaths occur for cancer local progression [32], and reirradia-
tion can be delivered with curative intent achieving substan-
tial rates of LC and OS. On the other hand, the risk of death
due to radiation-related toxicity is significant.
As expected, the majority of reports with the higher num-
ber of patients comes from endemic area such as Eastern
Asia. In a very recent report by Fudan University, Shanghai,
the records of 184 patients undergoing IMRT reirradiation
with or without chemotherapy between 2005 and 2013 were
reviewed [9]. Despite the high rates of 5-year local recur-
rence-free survival and distant metastases-free survival
(72.8% and 85.7%, respectively), 5 year OS was only 28.8%.
The main cause of death was radiation injury: 54 patients
(29.3% of the entire population) died for treatment toxicities,
the majority (44 patients) for profuse epistaxis due to
internal carotid blowout. Cancer progression represented the
cause of death for 39 patients (21.2%).
Carotid blowout (CB) represents a catastrophic and life-
threatening potential consequence of HN reirradiation, with
limited salvage treatment options and high rates of mortality
in the past [33] with a trend in decreased morbidity and
mortality rates in the recent era due to early diagnosis and
modern technology [34].
As already reported, the rate of blowout in NPC reirradia-
tion is not negligible, and it is higher than the global, low
rate reported when considering all HN subsites [35]. This
finding could be explained by several reasons, such as the
close proximity of CA to nasopharyngeal mucosa, the exist-
ing association between skull base osteoradionecrosis and
the risk of blowout [36], the curative intent of reirradiation
with the use of high doses, the longer life expectancy of reir-
radiated NPC patients compared with other HN subsites [37].
Currently, there is a lack of dosimetric constraints to apply
to reirradiated CA using conventional fractionation in order
to reduce the risk of CB: at the National Center of
Hadrontherapy (CNAO), Italy, the current practice is to avoid
a cumulative dose of 120 Gy to CA. In their already cited
report [27], the incidence of CB between populations strati-
fied according to cumulative dose to CA (± 120 Gy) was 2%
and 4%, respectively. The use of 120 Gy as cumulative dose
limit in HN reirradiation comes from a study by Garg et al.
[38], where the authors reported the chances of developing
a carotid blowout at a maximum dose of <120 Gy and >
120 Gy being 4.6 versus 13.3% at 6 months and 5.9% versus
25% at 12 months, respectively. Of note, the power of this
finding is limited by the paucity of events (one case of CB
where, moreover, tumor-related injury could not be ruled
out as the cause of complication) and the small sample size.
Adopting a 120 Gy cumulative dose limit poses a risk of tar-
get volume underdosage with the potential risk of reduced
local control and survival [29]: it must be said that the major-
ity of studies do not use dose constraints for the cumulative
dose to CAs [7,39]. In our Institution, deformable registration
allowing treatment dose summation is implemented since
2016 and it is mandatory for any HN reirradiation when
ACTA ONCOLOGICA 1243
DICOM files of 1st treatment are available. As already stated,
our policy is to limit CA cumulative dose to 120 Gy whenever
feasible (i.e., not underdosing GTV). The risk of a carotid
blowout is fully acknowledged and consented by any patient
receiving HN reirradiation in our Center. At the time of the
present analysis, in our series severe late toxicities occurred
in 23.5% of the patients; potential life-threatening toxicities
such as soft tissue necrosis occurred in two patients so far.
All the patients undergo regular follow-up imaging and HN
consultations with nasopharyngoscopy for diagnosis and
treatment of soft tissue necrosis [40].
In our Institution, in patients at high risk for CB, in the
absence of clear dosimetric criteria and with the goal of
decreasing radiation-induced life-threatening injuries thus
increasing cure rates, other therapeutic strategies are cur-
rently being evaluated, such as the feasibility of pre-reirradia-
tion stenting or even occlusion of the threatened CA.
Temporal lobe injury (TLI) is another potential complica-
tion affecting patients’ quality of life after NPC reirradiation.
The incidence of symptomatic TLI is variable among studies:
in the already cited report by Kong et al. [9] no symptomatic
TLI was reported, whereas 27% of the patients experienced
symptomatic TLI in the study of Leung et al. [41]. In the
recent study of Chan et al. [42], an inverse relationship
between cumulative biological equivalent dose (BED) to the
temporal lobe and the time of TLI manifestation was
observed. Interestingly, no TLI was registered with a cumula-
tive BED < 150 Gy2,5. In our study, no TLI injuries were regis-
tered at the time of the present analysis. The median
cumulative BED to the temporal lobe was 145,5 Gy2,5 (Table
2). Three patients with a cumulative BED to the temporal
lobe >150 Gy2,5 are still alive and considered at higher risk
of developing TLI.
The use of particle therapy reduces medium, low and
integral doses in comparison with state of the art X-ray
radiotherapy [30]; in silico studies demonstrated a significant
OAR sparing with the use of particles compared with con-
ventional radiotherapy in all HNSCC patients who are candi-
dates for reirradiation [21].
Therefore, such a challenging treatment could be better
tolerated by heavily pretreated patients. Patients’ compliance
with concomitant chemotherapy could also increase; more-
over, elderly patients could be considered for reirradiation
[43,44]. As of outcome, a recent report by Yamzaki et al. [45]
regarding the results of particle or X-ray reirradiation for HN
patients showed a statistically significant better OS in
patients treated with particle therapy. The use of PT for reir-
radiation is currently supported by both national radiation
oncology societies and Health systems [46,47] and national
comprehensive cancer network (NCCN) guidelines [48].
The initial clinical results of our retrospective analysis
regarding unselected patients affected by advanced stage,
recurrent NPC demonstrated the feasibility and the effective-
ness of modern PT in such a critical scenario. Long-term sur-
vival without life-threatening toxicity was achieved. The
small sample size and the retrospective nature of the study
limit, however, the power of our results. A longer follow-up
is needed to confirm in the long-term the encouraging
1244 F. DIONISI ET AL.
findings of our analysis such as OS, LC and the rate of
late toxicity.
Disclosure statement
The authors have no conflict of interest to declare.
ORCID
R. Pertile http://orcid.org/0000-0003-1455-842X
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