]
It has been shown that concurrent CT sensitizes the
effects of RT. Given the high rates of toxicity and still
under-desired response rates, immunotherapy opens
as a secret door to higher efficacy with less toxicity. The
aim of this review is to present the recent data on the
results of SBRT and immunotherapy in the treatment
of recurrent HNC.
1. SBRT in Recurrent HNC
The critical organs are in close proximity to the target
volume, and the response of these organs to irradiation
differs from the response of the main tumor in HNC.
Using SBRT, a very steep dose gradient is achieved, allowing
a higher chance of tumor control without increasing
toxicity. The shorter overall treatment time
increases the LC rate by preventing the accelerated
repopulation of tumor clonogens.[] However, hypofractionation
may also impair the sublethal damage
repair leading to an increased rate of late toxicity.
Therefore, it is crucial to identify the target volume
with high conformality and precision. SBRT typically
delivers 1-5 fractions, and it has several advantages
over conventional fractionation, such as shorter overall
treatment duration and lower resource burden, as well
as improved patient convenience and a shorter interval
to systemic therapy.
Different dose and fractionation schemes have been
used in the studies of SBRT in recurrent HNC, ranging
from 30-36 Gy in 6 fractions to 44-50 Gy in 5 fractions
with a biologically equivalent dose given in 2-Gy fractions
(EQD2) between 40 Gy and 101.1 Gy. Studies on
SBRT in recurrent HNC are mostly retrospective and
single-institution reports. The retrospective studies with
>20 patients are summarized in Table 1. Table 2 shows
the prospective studies on SBRT in recurrent HNC. The
rate of 1-year LC and OS ranges between 37% and 79%,
and 38% and 83%, respectively, in these studies.
Table 1: Retrospective studies of re-irradiation via SBRT in recurrent HNC
Table 2: Prospective studies of re-irradiation via SBRT in recurrent HNC
The definition of gross tumor volume (GTV), clinical
target volume (CTV) and planning target volume
(PTV) vary in the published studies. While some authors
did not add any margin to the GTV to create
CTV and PTV,[,] Roh et al.[] added 2-3 mm,
and Unger et al.[] added 2-10 mm to the GTV to create
CTV. Wang et al.[] recommended a 5-mm margin
to the GTV to adequately cover the microscopic
disease after evaluating the areas under high risk for recurrence.
The authors reported that more than 60% of
the recurrences occurred as overlapped or marginal to
the PTV, whereas only <20% occurred inside the PTV.
Compared to traditional RT techniques, re-irradiation
using SBRT provides improved LC and reduced
toxicity. The predominant pattern of failure is local or
marginal.[,] Local recurrence (LR) often develops inside the RT field, which constitutes a clear proof
that recurrent parts of tumors are radio-resistant.[]
Another pattern is a marginal recurrence, which arises
from a geometric miss. LR usually develops as multi-
-centric and multifocal sites, with mostly undifferentiated
histopathology. Therefore, the more precise the
RT delivery is, the more successful the treatment concludes.
Thus, elective nodal irradiation is not recommended
unless the neck is involved.
The total prescription dose varies widely among
studies. The study of Rwigema et al.[] is the only
SBRT study to show a higher rate of loco-regional
control (LRC) with a higher dose. In this study, the
2-year LRC rate was found 58% with doses 40-50 Gy
compared to 32% with 15-36 Gy. In addition, Heron et
al.[] reported a higher OS with >40 Gy SBRT compared
to doses ≤40 Gy. Based on these studies, SBRT
doses of ≥40 Gy can be recommended in the treatment
of recurrent HNC to obtain better survival and LC.
In addition to the total dose, tumor volume is also
important for the outcomes of SBRT. The smaller the
tumor volume is, the higher the LRC and OS rates
have been reported. However, the threshold of the
GTV varies between <15 and 25 cm3 [,-], and
the PTV is ≤40 cm3 in SBRT studies.[] On the other
hand, increased toxicity is inevitable with increased tumor
volumes.[,]
Toxicity of SBRT
As expected, the re-irradiation of HNC comes with a
price. The most common acute toxicities include mucositis,
nausea, fatigue, dermatitis and odynophagia.[]
Studies on SBRT in HNC have reported ≥grade 3 late
toxicity rates up to 25%, and grade 5 late toxicity rates
up to 15%, predominantly due to carotid blow-out syndrome
(CBOS). Other common late toxicities include
fibrosis, fistula formation, aspiration, dysphagia, permanent
feeding tubes, trismus, osteoradionecrosis, bone or
soft tissue necrosis, otitis media, cranial nerve palsies,
and brain necrosis.[,] The reason for the high rates
of serious late toxicity is the close proximity of critical
structures to the target. Prior RT dose, re-irradiation
dose, treatment volume, and re-irradiation technique
also affect the risk of severe late complications.
Although recent IMRT series have reported the rate
of CBOS 0-3%, the rate increases to 9-18% in SBRT
studies. The risk factors for CBOS were reported as
tumor encasing ?180° around the carotid artery, total
dose to the carotid artery, presence of ulceration, and
lymph node irradiation.[,,] A simple strategy to
decrease the rate of grade 5 CBOS is to administer RT
every other day and to keep the carotid artery dose below
34 Gy.[]
Hacettepe University Experience of SBRT in Recurrent
HNC
We, as Hacettepe University Department of Radiation
Oncology, have a more than 10-year experience of
re-irradiation of HNC using SBRT. In 2011, we compared
our treatment results in 51 patients with recurrent
nasopharyngeal cancer that were re-irradiated
using SBRT and 3-D conformal RT with or without
brachytherapy.[] The median re-irradiation dose
was 30 Gy in 5 fractions, and 57 Gy in 2 Gy/day, respectively.
After a median follow-up of 24 months, the
rate of 2-year cancer-specific survival was 64% and
47%, and actuarial LC was 82% and 80%, respectively.
Although the LC and survival rates were similar, the rate of ≥ grade 3 late toxicity was significantly higher in
the 3-D conformal RT arm (48% vs. 21%). Upon these
results, we recommended using SBRT in the treatment
of recurrent HNC if the patient was already irradiated.
We also presented our results of re-irradiation in 46
patients with recurrent HNC treated using Cyberknife
(Accuray, Sunnyvale, CA, USA).[] The median SBRT
dose was 30 Gy (18?35 Gy) in a median of 5 (1-5) fractions.
At the last follow-up, 10 patients had a complete
response, 11 had a partial response, and 10 had stable
disease with an actual LC rate of 83.8%. We found the
median OS 11.93 months and the median progressionfree
survival (PFS) 10.5 months. The rate of 1-year OS
and PFS was 46 % and 41%, respectively, with a rate of 13.3% ≥ grade 2 late toxicity. CBOS was observed in 8
(17.3%) patients, and 7 of them were succumbed to this
complication. When we evaluated further, we discovered
that death was observed only when the tumor was
surrounding the carotid artery and the carotid artery
received 100% of the prescribed dose.
Based on the high rate of CBOS, we changed our
treatment policy and started to irradiate recurrent HNC
patients every other day, and published the results in
2013.[] We compared the results of 43 patients irradiated
on consecutive days with the results of 32 patients
irradiated every other day. Median OS was 11 months
and 23 months, respectively (p=0.006). CBOS was observed
in a total of 11 patients with a mortality of 86% in
consecutive treatment and 50% in the every-other-day
treatment. The median CBOS-free OS was nine months
and 23 months, respectively (p=0.002). The threshold
dose for CBOS was detected 34 Gy, with no patients developing
CBOS when received under this dose. Based on
these studies, we have been treating recurrent HNC patients
every other day since 2013, and trying to keep the
maximum dose to the carotid artery <34 Gy.
2. Immunotherapy in Recurrent HNC
It has been shown that concurrent systemic therapy sensitizes
the effects of radiation in the treatment of primary
HNC at the expense of increased toxicity rate. However,
to our knowledge, there are no prospective trials on the
comparison of re-irradiation with and without concurrent
systemic therapy, although a retrospective study on
re-irradiation of HNC using SBRT reported increased
serious toxicity with concurrent chemotherapy.[] The
use of concurrent targeted agents, such as cetuximab, an
epidermal growth factor receptor (EGFR) inhibitor, has
been shown to improve the outcomes without increasing
toxicity in the primary treatment of HNC.[-]
Cetuximab is the first targeted agent used in the
treatment of HNC. Dysregulation of the EGFR pathway
is common in HNC, and it has been shown that high
EGFR expression leads to worse outcomes.[] Cetuximab
inhibits the proliferation of tumor cells and stimulates
the pro-apoptotic pathways within these cells by
preventing the ligand-mediated activation and dimerization
of EGFR.[-] It also limits the translocation
of EGFR into the nucleus and prevents the activation of
the deoxyribonucleic acid (DNA)-dependent protein kinase
resulting in the inhibition of the repair of doublestrand
DNA break which may also affect the pathways
of distant metastasis (DM).[,] Another mechanism
is the induction of antibody-dependent cell-mediated
cytotoxicity (ADCC), which targets and kills the cells
coated in immunoglobulin (Ig)-G1 and other antibodies
and maximizes antitumor effects using natural killer
(NK) cells.[,,] The stimulation of ADCC is the
main mechanism that makes cetuximab adequate for
the treatment of recurrent HNC, which differentiates it
from panitumumab, an IgG2 antibody with lower clinical
activity in recurrent HNC.[,] In the first-line
treatment of recurrent and metastatic HNC, adding
cetuximab to cisplatin/carboplatin and 5-fluorouracil
followed by maintenance cetuximab (the EXTREME
regimen) resulted in better outcomes concerning overall
response rate, OS, and PFS compared to the chemotherapy-
only-arm, independent from the human papillomavirus
(HPV) status.[,] The addition of cetuximab
also resulted in improved social functioning and quality
of life.[] However, the 80% rate of grade 3-4 toxicity in
both arms of this study should not be overlooked.
There are data on the positive effects of adding concurrent
cetuximab on LC and survival compared to
re-irradiation via SBRT alone.[,,,] Heron et
al.[20] retrospectively observed a complete response in 34% and 46% of patients that underwent SBRT alone
and SBRT with concurrent cetuximab, respectively,
with similar toxicity rates. This study led the way to
prospective trials on the use of cetuximab in the re-irradiation
of recurrent HNC. In a phase I trial, Comet et
al.[] showed the feasibility of cetuximab concurrent
with SBRT in recurrent HNC with a response rate of
75% and mild toxicity. In the phase II trial of Vargo
et al.[], concurrent cetuximab with SBRT resulted
in a 1-year OS 40%, local PFS 60%, loco-regional PFS
37%, and distant PFS 71% with a late grade 3 toxicity
of 6%. In another phase II trial, Lartigau et al.[] administered
concurrent cetuximab with an SBRT dose
of 36 Gy in 6 fractions and reported the 1-year OS rate
47.5%, LC rate 92%, and grade 3 toxicity 30%.
In recent years, interest in immunotherapy has risen.
Immune checkpoint inhibitors (ICI) interrupt the immunosuppressive
pathways, which are called inhibitory
checkpoints. These checkpoints are used by tumor cells
to hide from the detection and elimination by the immune
system of the host.[,] The molecular targets
of ICIs on T cells include cytotoxic T-lymphocyte
antigen-4 (CTLA-4), programmed cell death protein 1
(PD-1) receptor, and this PD-1"s corresponding ligand,
PD-L1, which is found on both tumor and immune
cells.[45,46] The examples are ipilimumab and tremelimumab,
which are anti-CTLA-4 antibodies, nivolumab
and pembrolizumab, which are anti-PD-1 antibodies,
and durvalumab and avelumab, which are anti-PD-L1
antibodies. The higher the levels of endogenous PD-L1
expression, the more successful these antibodies are.[]
PD-1 inhibitors are shown to be effective in HNC
patients with DM.[-] A randomized phase III trial
compared nivolumab and standard systemic therapy
in recurrent HNC and reported increased OS rate with
nivolumab.[] The KEYNOTE-028 trial on the effects
of pembrolizumab in recurrent and metastatic nasopharyngeal
cancer patients with ≥1 PD-L1 expression reported
an overall response rate of 74.1%.[] A phase
I trial of pembrolizumab for recurrent and metastatic
HNC in 56 patients with ≥1 PD-L1?positive staining
reported a 20% overall response rate, regardless of HPV
status.[] However, the rate of long-term durable response
and survival was achieved in <5% of the patients.
There is evidence that RT and ICI have synergistic
effects in the treatment of HNC given that ICI can overcome
the negative effects of RT on the tumor microenvironment.[,] Besides, the antigenic response to RT
may also increase the effectiveness of ICI. In the ongoing
CheckMate 651 trial, nivolumab and ipilimumab together
are compared to the EXTREME regimen. In the
KEYNOTE-048 trial, pembrolizumab is under investigation
either alone and in combination with systemic chemotherapy. Durvalumab is also being examined
either alone and in combination with in the KESTREL
study. While waiting for the results of these trials, the use
of ICIs as a first-line treatment in recurrent or metastatic
HNC is not recommended outside of clinical trials.
The potential synergy between SBRT and concurrent
systemic targeted and immunotherapeutic agents
have been reported in lung cancer and melanoma patients.[] The high dose-per-fraction in SBRT may
affect as a potential immune stimulant and induce an
abscopal effect in patients treated simultaneously with
PD-1 checkpoint inhibitors by increasing T cell activity.
As patients with recurrent HNC are at high risk for
regional and DM, this may particularly be important in
patients that will be re-irradiated with limited volumes.
The KEYSTROKE trial (RTOG 3507) is currently ongoing
to compare SBRT re-irradiation alone to SBRT
re-irradiation and pembrolizumab.
There are several challenges regarding the timing
of RT, timing of immune checkpoint blockade and RT,
and optimal site for treatment in metastatic cases. In this
context, Vanpouille-Box et al.[] published a promising
study showing that exonuclease TREX1 abrogated
the immunogenicity of irradiated cancer cells by degrading
interferon-stimulatory cytosolic double-strand
DNA. TREX1 upregulation by radiation dose per fraction
beyond a threshold of 10-12 Gy resulted in poor
synergy with immune checkpoint blockers. They also
showed that 24 Gy in three fractions seems to be stimulating
the immune response more efficiently compared
to lower doses, similar to one fraction-based schemes,
such as 20 Gy in one fraction. Based on this preclinical
study, we administered an SBRT dose of 24 Gy in three
fractions and immunotherapy to our two patients with
recurrent/metastatic sinonasal cancer.[] We achieved
excellent local responses in both cases without any significant
side effects with such a low SBRT dose regimen.
To our knowledge, those two cases are the first clinical
proof supporting the findings of Vanpouille-Box et al.
