Cancer/Radiothérapie 26 (2022) 916–920

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Review article

Head and neck cancers volume reduction: should we reduce our

prophylactic node radiation to spare the antitumor immune
response?
Cancers ORL : faut-il diminuer le volume prophylactique ganglionnaire pour
impacter la réponse immunitaire ?
Y. El Houat a , L. Bouvier a , M. Baty a , X. Palard-Novello b , Y. Pointreau c , R. de Crevoisier a ,
J. Castelli a,∗
a
Département de radiothérapie, centre Eugène-Marquis, 35000 Rennes, France
b
Département de médecine nucléaire, centre Eugène-Marquis, 35000 Rennes, France
c
Institut inter-régional de cancérologie (ILC), centre Jean-Bernard, 9, rue Beauverger, 72000 Le Mans, France

a r t i c l e i n f o a b s t r a c t

Keywords: Radiotherapy for locally advanced head and neck cancer classically include large prophylactic node vol-
Elective neck irradiation ume. However, the use of these large volumes can be responsible for significant toxicity. Furthermore,
Radiotherapy the disappointing results of radioimmunotherapy combinations in head and neck tumors raise concerns
Head and neck cancer
about radiotherapy’s potential negative impact on the immune response when large lymph node volumes
Immunotherapy
are treated. Besides, in other tumor locations, such as lung cancers, the volumes of elective irradiation
have been considerably reduced, with the same local control as before. This opinion piece reviews the
current state of radiation volumes in head and neck cancers, the rationale for these volumes, the potential
impact of radiotherapy on immune response, and the volume changes that would improve the efficacy
of radioimmunotherapy combinations.
© 2022 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All
rights reserved.

r é s u m é

Mots clés : La radiothérapie des cancers localement évolués de la sphère ORL comprend classiquement un large vol-
Reduction volume ume ganglionnaire prophylactique. Cependant, cette irradiation large peut être à l’origine d’une toxicité
Radiothérapie importante. De plus, les résultats décevants des combinaisons de radiothérapie et d’immunothérapie dans
Cancers tête et cou les cancers ORL soulèvent des questions au sujet d’un impact négatif de la radiothérapie sur la réponse
Immunothérapie
immunitaire. Par ailleurs, dans d’autres localisations tumorales, pourtant très lymphophyles, comme les
cancers pulmonaires, l’irradiation ganglionnaire élective a profondément été réduite, sans dégradation
du taux de contrôle local. L’objectif de cet article est de réaliser un point sur le rationnel actuel concernant
les volumes d’irradiation ganglionnaires pour les cancers ORL, l’impact de la radiothérapie sur la réponse
immunitaire, et les modifications potentielles de volumes qui permettraient d’améliorer l’efficacité des
combinaisons de radiothérapie et d’immunothérapie.
© 2022 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous
droits réservés.

1. Introduction

∗ Corresponding author. Radiotherapy department, centre Eugène-Marquis, Cancers of the head and neck (H&N) are the 9th most common
avenue de la Bataille-Flandres-Dunkerque, 35000 Rennes, France. cancer in the world. Approximately 60% of patients present with
E-mail address: j.castelli@rennes.unicancer.fr (J. Castelli).

https://doi.org/10.1016/j.canrad.2022.06.014
1278-3218/© 2022 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
Y. El Houat et al.
locally advanced cancer. The relapse rate varies from 35 to 65%
according to the location, stage, and resectability [1].
In the case of H&N cancers, intensity-modulated radiotherapy
has been shown to be beneficial in terms of reduced toxicity,
especially for xerostomia [2]. Due to the high risk of lymph node
metastasis, it is standard practice to perform wide cervical irra-
diation in order not to miss microscopic disease. Generally, two
volumes will be defined, a first one including the macroscopic dis-
ease (tumor and lymph nodes), with a margin to cover a potential
microscopic extension (high dose CTV), and a second volume, much
larger, which will correspond to all the lymph node drainage areas
(low dose CTV).
However, the use of these large volumes can be responsible
for significant toxicity. Furthermore, the disappointing results of
radioimmunotherapy combinations in H&N tumors raise concerns
about radiotherapy’s potential negative impact on the immune
response when large lymph node volumes are treated [3]. Besides,
in other tumor locations, such as lung cancers, the volumes of elec-
tive irradiation have been considerably reduced, with the same
local control as before.
The objective of this opinion piece is to review the current state
of radiation volumes in H&N cancers, the rationale for these vol-
umes, the potential impact of radiotherapy on immune response,
and the volume changes that would improve the efficacy of radio-
immunotherapy combinations.
2. Targeted node volumes in H&N radiation
It is routine, in clinical standard practice, that irradiation of
H&N cancers includes a large cervical volume to increase locore-
gional control. This historical approach is based on the findings
of surgical series that revealed a high percentage of lymph node
metastases not visible on imaging, as well as the fact that lym-
phatic dissemination into neck lymph nodes is fairly consistent and
follows predictable pathways [4].
Advances in imaging, and in particular the use of 18 FDG PET and
multiparametric MRI, have significantly improved the diagnostic
accuracy of lymph node involvement. According to some papers,
the combination of different imaging modalities utilized in clinical
practice provides for diagnosis reliability for lymph node metasta-
sis ranging from 92 to 97% [5]. This improvement leads to a more
tailored treatments where some lymph node areas, that, histor-
ically, would have been treated as N0 (and therefore treated at
50 Gy) are now included in the high dose volume.
The analysis of relapse sites after radiotherapy shows that the
majority of recurrences occur around the GTV + 1 cm margin, thus
in the high dose volume [6]. These results are also in line with three
studies that have analyzed peritumor infiltration on surgical speci-
mens [7–9]. Even though these investigations only included a small
number of patients, the findings are consistent with microscopic
peri-tumoral recurrence between 0 and 10 mm from the GTV’s
edge. This notion of microscopic infiltration was thus retained in
the inter-group recommendations for defining H&N target volumes
[10].
Moreover, the risk of cervical invasion varies depending on the
primary tumor and the lymph node areas concerned. For exam-
ple, the histological analysis of 103 oropharyngeal patients’ neck
dissection showed that the risk of invasion of Ib and V areas was
very low (<5%) [11]. Meanwhile, risk of II area involvement was
high despite negative CT imaging and the rate of occult metasta-
sis in III area was about 15%. Two major limitations of this study
are the limited number of patients and the absence of multimodal
imaging (PET, MRI) that could further reduce the number of these
occult metastases. Similarly, in the case of hypopharyngeal cancer,
the risk of involvement of IV area is low in the absence of lymph
917
Cancer/Radiothérapie 26 (2022) 916–920
node involvement, whereas it can reach 40% in the case of lymph
node involvement in another territory [12].
3. Effect of radiation on the immune response
We know now that the anti-tumor immune response is
a cornerstone of the anti-tumor response overall [13]. In the
past, our understanding of radio-induced cell death was mostly
DNA-centered but current biomolecular technology shows that
radiotherapy has an effect on virtually all cellular organelles and
can cause apoptosis, autophagy or senescence without DNA dam-
age [14]. One of the mechanisms of such radio-induced cell deaths
is by mobilizing the immune system, also known as immunogenic
cell death or in situ vaccination.
Understanding our immune system’s involvement in the anti-
tumor response has had concrete clinical repercussions with the
use of checkpoint inhibitors (CPIs) and there is strong preclini-
cal data that hints at an enhanced response rate to such drugs
with radiation via the in situ vaccination [15]. Although there is
substantial encouraging information on a synergic action between
radiotherapy and immunotherapy, a systematic and predictable
response has yet to be found, and one of the reasons might be
radio-induced lymphopenia (RIL).
Immune cells and specifically lymphocytes are one of the most
radiosensitive cells in the body and it has been known by biolo-
gists and radio-oncologists since the 1950s. Overall, the scientific
literature concurs that immune cells die at doses greater than
2 Gy per fraction. This innate radio-sensitivity of immune cells has
clinical repercussion on radiated patients. Indeed radio-induced
lymphopenia was first noticeably studied in cerebral irradiation,
in the early 1980s. As this phenomenon was more described in
other location, a trend towards inferior clinical outcomes (overall
survival and progression-free survival) in patients treated for solid
cancers and presenting RIL was observed. Moreover, several pub-
lished studies found that radio-induced lymphopenia’s association
with overall survival was independent of pretreatment prognostic
factors, tumour histology, chemotherapy regimen or corticosteroid
use [16].
In head and neck cancers specifically, a few studies have already
linked RIL to OS, showing its poor prognostic value. To our knowl-
edge, Table 1 identifies all the available data involving H&N cancers
with lymphopenia during radiation therapy and overall survival.
Ten papers were published between 2016 and 2020. Of the ten
studies, three are prospective; most of the papers dealt with
oropharyngeal or nasopharyngeal cancer probably because those
two locations are the richest in lymphoid structures and almost all
treated their patients with concurrent chemoradiotherapy. All but
two studies showed that lymphopenia during treatment is a poor
prognostic factor for death. These results must be interpreted with
cautions since chemotherapy was used with radiotherapy in most
of the studies but in other location, radiotherapy has been proven
to be an independent factor of lymphopenia regardless of the use
of systemic agents. On paper sought out if RIL was associated with
unilateral vs. bilateral neck radiation in palatine tonsil squamous
cell cancer patients. Acute grade 3-4 lymphopenia occurred in 79%
of bilateral neck radiation patients and in 58% of unilateral neck
radiation patients, P = 0.03. Acute grade 4 lymphopenia occurred
in 15% of bilateral neck radiation patients and none of the unilat-
eral neck radiation patients, P = 0.04. Unilateral neck radiation was
associated with reduced acute grade 3-4 lymphopenia (OR = 0.05,
95% CI (0.005–0.468)). In this study, radiation volumes rather than
chemotherapy was associated with acute hematological toxicity
[17].
Lymphopenia has been shown to be a poor prognostic fac-
tor for patients receiving immunotherapy. Some data suggests
Y. El Houat et al. Cancer/Radiothérapie 26 (2022) 916–920

Table 1
Head and neck studies involving lymphopenia during radiotherapy and overall survival.

Authors Year Type of study Localization Treatment n n with RIL HR

Campian et al. 2014 Retrospective 70% of oropharyngeal, 95% received 56 34 5.75 (1.04–31.59);
[28] 30% other H&N CDDP + RT, 5% received P = 0.045
localization RT only
Moon et al. [29] 2016 Prospective 33.3% oropharynx, CDDP + RT (70.0 Gy; 153 76 3.22 (1.41–7.09);
31.4% nasopharynx, range: 60.0–74.8 Gy) P = 0.005
18.3% larynx, 17%
hypopharynx
Li et al. [30] 2017 Prospective Nasopharyngeal 95% treated by 249 100 1.90 (1.004–3.80);
CDDP + RT, 5% RT only P = 0.049
(70.0 Gy; range:
60.0–74.8 Gy)
Jensen et al. 2017 Retrospective Oropharyngeal 47% had induction CT, 150 16 2.34 (0.77–7.06);
[31] 69% had concurrent CT P = 0.13
Liu et al. [32] 2018 Prospective Nasopharyngeal CDDP + RT 181 86 3.79 (1.75–8.19);
P = 0.001
Lin et al. [17] 2018 Retrospective Oropharyngeal 69% CDDP + RT, 31% RT 99 16 12.02
only (3.024–47.778);
P = 0.001
Lin et al. [33] 2019 Retrospective Oropharyngeal 31.5% RT only, 39.8% 108 19 2.60 (1.3–5.5)
CDDP + RT, 28.7%
Inudction CT and
CDDP + RT
Ng et al. [34] 2020 Retrospective Oropharyngeal 87% CDDP + RT, 13% RT 850 703 1.3 (0.86–2.01)
only
Liu et al. [35] 2020 Retrospective Nasopharynx CDDP + RT (IMRT) 207 44 2.89 (1.334–2.784);
P = 0.001
Patil et al. [36] 2020 Retrospective 0.5% oral cavity 50% CDDP + RT, 50% 532 73 1.32; P = 0.11
49.8% oropharyngeal CDDP + RT + IO
28.7% larynx (nimotuzumab)
20.14% hypopharynx

that patients with lymphopenia during and before treatment with
immunotherapy, demonstrate significantly poorer outcomes [18].
These results question whether a decline in the number and func-
tion of lymphocytes may therefore result in a decrease in the
efficacy of immunotherapeutic agents.
In head and neck cancers, avelumab held a lot of promises and
two major trials tested it combination to standard of care chemora-
diotherapy. The Javelin head and neck 100 trial aimed to assess of
adding avelumab to chemoradiotherapy could improve treatment
outcome for unresected locally advanced squamous cell carcinoma
of the head and neck. The study was stopped at the time of the
preplanned interim analysis after the test statistic crossed the futil-
ity boundary. The authors cite a possible dysfunction or depletion
of circulating T cells or changes in the tumour microenvironment
after radiotherapy as one of the reasons for these results. They
also added the hypothesis that the prophylactic bilateral cervical
radiation might impair the function et number of lymphocytes [3].
The same year, the Reach trial announced the same disappointing
results: the trial tested the combination of avelumab to either stan-
dard of care chemoradiotherapy or cetuximab with radiotherapy.
The combination did not improve outcome for patients fit for cis-
platin and the futility boundary was crossed, favoring standard of
care over CPI-based combination. The authors suggested the same
hypothesis as the Javelin’s to explain these results [19].
The mechanisms of interaction between the immune stim-
ulatory (in situ vaccination) and suppressive (radio-induced
lymphopenia) remain to be fully understood. However, there are
strong suggestions that minimizing radio-induced lymphopenia
could tilt the balance to finding significant clinical outcome.
It can be argued that RIL is first a function of field size, frac-
tionation, and overall treatment time. Second, RIL could also be
explained by the radiation dose received by hematopoietic, lym-
phopoietic organs and specifically lymph nodes and in head and
neck cancer, maybe by target volume reduction strategies.
4. Modifying our habits?
In view of these elements, a modification of radiation volumes
can be discussed. In the next section, the work on volume modi-
fications and their results will be discussed, followed by ongoing
trials.
4.1. Published data
Average doses of 40 Gy appear to be sufficient to sterilize
metastatic nodes with a diameter of less than 5 mm. This was evalu-
ated in a trial comparing two different dose levels for prophylactic
cervical volume (a standard dose of 50 Gy and a reduced dose of
40 Gy) [20]. Toxicity was decreased in the 40 Gy arm, while achiev-
ing identical regional control to the 50 Gy arm. In case of N0 tumors,
exclusive irradiation of the GTV also seems feasible. In a cohort of
331 patients with supraglottic cancer, radiation doses of 50 to 55 Gy
in 16 fractions, without prophylactic irradiation, resulted in a high
rate of regional control (90%), without acute toxicity [21].
It should be noted that for other highly lymphophilic cancers
which present a very high risk of microscopic dissemination, such
as non-small cell lung cancer or lymphoma, it has been shown that
prophylactic lymph node irradiation does not improve clinical out-
comes. There is strong data that proves that irradiation of only the
invaded lymph nodes provides the same locoregional control as
elective irradiation, while significantly reducing toxicity [22] and
it transcribes in the consensus of delineation of lung tumors which
does not advocate prophylactic lymph node irradiation [23].
Another approach to reduce the volumes consists in unilateral
cervical irradiation. In a cohort of 154 patients treated by surgery for
tonsillar cancer, unilateral cervical radiotherapy achieved the same
rate of locoregional control as for patients who had received bilat-
eral irradiation, while having a lower rate of toxicity [24]. This result
was confirmed in a systematic review of 11 studies that included

918
Y. El Houat et al.
patients treated with unilateral irradiation, with a contralateral
recurrence rate of 2.4% [25].
However, despite the very lymphophilic character of non-small
cell lung cancers and H&N cancers, differences exist in the natural
history of these two cancers which could limit similar treatment
strategies. For example, H&N cancers are less likely to present
a metastatic extension, potentially reflecting a difference in the
tumor microenvironment.
Some authors have reported a high rate of lymph node recur-
rence in case of homolateral neck radiation in oropharyngeal
tumours [26]. In a series of 53 patients with a well lateralized tonsil
tumor treated with homolateral radiotherapy (no contralateral cer-
vical radiation), the authors found a contralateral recurrence rate
of 7.5% (four patients). Of note, these four patients all had a p16
positive tumor and N2b lymph node involvement. In this subgroup
of patients with N2b involvement (28 patients), the contralateral
recurrence rate was 14.3%. Particular attention should also be paid
to tumors of the hypopharynx because of the increased risk of sub-
mucosal extension, which could be up to 20-30 mm craniocaudal.
This demonstrates that volume de-escalation schemes should be
done in the context of clinical trials. Moreover, combining volume
de-escalation with immunotherapy, due to the potential benefits
discussed above, can represents a promising avenue of research.
4.2. Ongoing trials and in the pipeline
Several radioimmunotherapy trials are underway, with the goal
of optimizing radiotherapy volumes to potentiate the immune
response.
The REWRITe trial (GORTEC 2018-02) seeks to assess regional
control in patients with locally advanced H&N tumors (T1-T4, N0-
N2b), unfit for concomitant chemoradiotherapy and treated by
durvalumab and radiotherapy. The initial workup included cervical
CT, cervical MRI and 18 FDG PET. The primary endpoint is cervical
control at 1 year outside the irradiated neck. Treatment consists
of radiation therapy at a dose of 69.96 Gy (33 fractions of 2.12 Gy)
on the macroscopic tumor volume (GTV + 5 mm) and a second dose
level (optional) of 52.8 Gy (33 × 1.6 Gy) on the nearest lymph node
areas, combined with durvalumab concomitantly (1125 mg every
3 weeks) and then as maintenance (1500 mg every 4 weeks for 6
months). The study began in June 2019. Sixty patients are expected,
for 14 French centers are participating.
The Lymphocyte-Sparing Radio-Immunotherapy in Head and
Neck Carcinoma (LySAIRI) trial is a multicentric phase III trial
evaluating reduced-volume radiotherapy in conjunction with
immune-stimulating interleukin 15. This study will focus on
patients with oropharyngeal, hypopharynx or larynx tumors, with
ipsilateral lymph node involvement. This trial focuses on the con-
cept of spatial lymphocyte sparing (modification of the volume
of cervical irradiation), guided by lymphatic node mapping, and
chemical stimulation by an analog of interleukin 15, allowing an
increase in the number of CD8+ and CD56+ lymphocytes [27]. This
trial should thus make it possible to evaluate the synergy between
immune response stimulation and lymph node volume sparing. The
trial plans for 460 patients and is expected to end by 2025.
Volume reduction with no immunotherapy is also considered,
for example, the Personalized Management of the Neck in Can-
cer of the Upper Aerodigestive Tract: Radiotherapy to the PRIMary
Tumor Only (Primo) trial (NCT05333523) is a Dutch trial that will
compare standard radiotherapy (including elective cervical irradia-
tion) with adapted radiotherapy using the sentinel node technique.
The study has a dual primary objective of non-inferiority for lymph
node recurrence rate and superiority for xerostomia-related qual-
ity of life. The Primo trial is planned for 242 patients and is expected
to start in October 2023.
919
Cancer/Radiothérapie 26 (2022) 916–920
The question of volume reduction also arises in the adjuvant
setting. The Preservation of Swallowing in Respected Oral Cavity
Squamous Cell Carcinoma: Examining Radiation Volume Effects
(PRESERVE) trial aims to evaluate the possibility of no neck radi-
ation in pN0 patients after surgery for oral cavity cancer. In the
experimental arm, only the surgical bed will be irradiated. The
primary endpoint is the 5-year locoregional relapse rate.
5. Conclusion
The question of volume de-escalation in H&N cancers is very
current, whether with the objective of reducing toxicity, but also
of potentiating the immune response, in particular in the era of
immunotherapy. The hypotheses that radiotherapy impairs lym-
phocytes count, function and the anti-tumor immune response,
as well as the promising idea that irradiation of only the invaded
lymph nodes provides the same locoregional control as elective
irradiation, while significantly reducing toxicity, seem to suggest
that volume reduction is possible.
Relapse in a non-radiated area should be limited to lymph node
relapse only, without relapse of the primary tumor. This change
of paradigm must be done through randomized trials, to ensure
the necessary framework for clear answers, without risks for the
patients. The contribution of new equipment such as MRI linear
accelerators also opens the possibility of more targeted radiother-
apy, with the dual objective of improving locoregional control and
patient quality of life.
Credit authors statement
Y.E. and J.C. wrote the manuscript. All authors helped, read, cor-
rected and approved the final manuscript.
Disclosure of interest
The authors Y.E., L.B., M.B., X.P.-N. declare that they have no
competing interest.
Y.P.: MSD, BMS, Merck Serono, Lilly, Pierre Fabre médica-
ment, Seagen, Novartis, Ipsen, Kyowa Kirin, MundiPharma, Amgen,
Takeda.
R. d-C.: Amgen, Bayer, Astellas, Sanofi, Ipsen, Takeda, Janssen-
Cilag, Kyowa Kirin, MSD, Roche.
J.C.: Merck, BMS, Nanobiotix, Astellas.
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