Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: a systematic review

Abstract

Head and neck cancer (HNC) is a fatal malignancy with an overall long-term survival of about 50% for all stages. The diagnosis is not rarely delayed, and the majority of patients present with loco-regionally advanced disease. The rate of second primary tumors after a diagnosis of HNC is about 3–7% per year, the highest rate among solid tumors. Currently, a single-modality or a combination of surgery, radiotherapy and chemotherapy (CHT), is the standard treatment for stage III–IV HNC. For the recurrent/metastatic setting, in the last 40 years great efforts have been made in order to develop a more effective CHT regimen, from the use of methotrexate alone, to the combination of cisplatin (CDDP) and 5-fluorouracile (5FU) or paclitaxel. Recently, the introduction of cetuximab, an anti-EGFR monoclonal antibody, to the CDDP–5FU doublet (EXTREME regimen) has improved the overall response rate, the progression-free survival and the overall survival (OS) compared to CHT alone. Nowadays, the EXTREME regimen is the standard of care for the first-line treatment of recurrent/metastatic head and neck carcinoma (RMHNC). In the last years, new promising therapies for RMHNC such as immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials, gained special interest. Nivolumab and pembrolizumab are the first two ICIs able to prolong OS in the second-, later-line and platinum-refractory setting, with tolerable toxicities. This review summarizes the current state of the art in RMHNC treatment options.

Full text

Vol.:(0123456789)
1 3
Medical Oncology (2018) 35:37
https://doi.org/10.1007/s12032-018-1096-5
REVIEW ARTICLE
Chemotherapy andimmunotherapy forrecurrent andmetastatic head
andneck cancer: asystematic review
AlessandroGuidi1 · CarlaCodecà1· DarisFerrari1
Received: 11 January 2018 / Accepted: 5 February 2018 / Published online: 13 February 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Head and neck cancer (HNC) is a fatal malignancy with an overall long-term survival of about 50% for all stages. The
diagnosis is not rarely delayed, and the majority of patients present with loco-regionally advanced disease. The rate of
second primary tumors after a diagnosis of HNC is about 3–7% per year, the highest rate among solid tumors. Currently,
a single-modality or a combination of surgery, radiotherapy and chemotherapy (CHT), is the standard treatment for stage
III–IV HNC. For the recurrent/metastatic setting, in the last 40years great efforts have been made in order to develop a more
effective CHT regimen, from the use of methotrexate alone, to the combination of cisplatin (CDDP) and 5-fluorouracile
(5FU) or paclitaxel. Recently, the introduction of cetuximab, an anti-EGFR monoclonal antibody, to the CDDP–5FU doublet
(EXTREME regimen) has improved the overall response rate, the progression-free survival and the overall survival (OS)
compared to CHT alone. Nowadays, the EXTREME regimen is the standard of care for the first-line treatment of recurrent/
metastatic head and neck carcinoma (RMHNC). In the last years, new promising therapies for RMHNC such as immune
checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials, gained special interest.
Nivolumab and pembrolizumab are the first two ICIs able to prolong OS in the second-, later-line and platinum-refractory
setting, with tolerable toxicities. This review summarizes the current state of the art in RMHNC treatment options.
Keywords Immunotherapy· Chemotherapy· Monoclonal antibodies· Recurrent/metastatic head and neck cancer
Introduction
Head and neck cancer (HNC) represents the sixth leading
cancer by incidence worldwide [1], and it is defined as a
heterogeneous variety of malignant tumors which includes
oral cavity, oropharynx, hypopharynx, nasopharynx, larynx,
nasal fossa, paranasal sinuses, thyroid, salivary glands and
vermilion surfaces. This kind of cancer constitutes about 3%
of all newly diagnosed malignant tumors in humans, and this
percentage is likely to increase in the future. All over the
world head and neck tumors account for more than 550,000
new cases and 380,000 deaths annually. (In Europe, this
statistics declines to 250,000 new cases and 63,500 deaths
annually in 2012.) [2] Nearly all the cases of head and neck
malignancies (95%) are represented by squamous cell car-
cinoma (HNSCC) arising in the oral cavity and pharynx.
Adenocarcinomas, adenoid cystic carcinomas and mucoepi-
dermoid varieties are more frequent in the salivary glands,
while in the thyroid gland the most frequent histological
subtypes include papillary, follicular giant cell, Hürthle cell
carcinomas and lymphomas.
Despite the recent advances in treatment, including chem-
otherapy (CHT), radiotherapy (RTX) and the most promis-
ing immunotherapy, the global, long-term survival rate is
still under 50%, and this rate decreases to 19% if patients
are diagnosed in very advanced stage [3]. This trend can
be attributed to various causes, first of all the persistence
of inescapable and strong risk factors such as smoking and
alcohol, the new outbreak of human papillomavirus (HPV)
infection, the diagnostic delay of this kind of cancers and the
frequent onset of multiple primary tumors. Indeed, the rate
of second primary tumor is near 3–7% per year. No other
malignancies have a rate as higher as this [4, 5].
* Alessandro Guidi
alessandro.guidi@live.com
Carla Codecà
carla.codeca@asst-santipaolocarlo.it
Daris Ferrari
daris.ferrari@asst-santipaolocarlo.it
1 Department ofMedical Oncology, San Paolo Hospital, Via
Antonio di Rudinì, 8, 20142Milan, Italy

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Risk factors andbiological behavior
ofHNSCCs
Risk factors
The major risk factors for HNSCC are cigarette smoking
and alcohol consumption; for this reason, European and
North America males are more frequently affected than
females with a ratio ranging from 2:1 to 4:1. The propor-
tion of incidence due to alcohol and tobacco use is near
72, 4% of which due to alcohol alone, 33% due to tobacco
alone and 35% due to the combined action of alcohol and
tobacco [6]. Another important risk factor associated with
oropharyngeal carcinoma is represented by HPV [7]. In
particular, HPV-16 genotype has been identified as a caus-
ative agent in almost 50% of oropharyngeal malignancies
in patients with no other classical risk factors, especially
when localized at the base of the tongue and in the tonsil-
lar region. HPVs-18, 31 and 33 are also responsible for
HNSCC, but they are less frequent than genotype 16 [7].
Nowadays, the demographic pattern of HNC is chang-
ing. In the last 30years, there was a steady decline in the
number of HNSCC caused by tobacco and alcohol, but on
the contrary, there was an increase in the number of HPV-
related cases, for which sexual behavior is the most accred-
ited risk factor. For this reason, at present, patients affected
by HNSCC are more likely to be younger adults aged
40–50years [8]. While tobacco- and alcohol-related oro-
pharyngeal tumors are more frequent in African-Americans,
malignancies caused by HPV are diagnosed more frequently
among Caucasians. Overall survival (OS) is higher for HPV-
related HNSCC (about 79–82% of patients is still alive at
5years) than for tobacco-related ones (46%).
Also in the recurrent and/or metastatic context, the OS
for HPV-positive tumors is better than their HPV-negative
counterparts, with a 2-year OS rate of about 55 versus
28%. This favorable trend is likely explained by the fact
that carcinomas associated with HPV are more responsive
to treatment than those HPV-unrelated.
Other known risk factors for HNC include familiarity,
poor oral hygiene, chronic irritation of mucous membranes
(e.g., irritation from dental prostheses), actinic radiation
and pipe smoke for lip cancer, malnutrition (vitamin A
deficiency), high consumption of salted meat or fish,
immunosuppression (HIV, GVHD, transplant) and, within
the Asian population, betel mastication [9].
Recurrent HNSCCs
“Field cancerization” or “condemned mucosa” is an
expression, coined in 1953 by Slaughter [10], that is
referred to the presence of transformed stem cells near
the area of the primary tumor and well explains the natu-
ral trend of head and neck tumors to recur. According to
this theory, multiple primary tumors are the expression of
multiple independent foci of altered-by-carcinogens stem
cells. According to the “field cancerization,” a patient who
has survived for 5years from the diagnosis has a prob-
ability of developing one other primary tumor of about
35% in the same time lapse [3]. Therefore, the diagnosis of
premalignant lesions, such as leukoplakia or erythroplakia,
should be as earlier as possible.
Metastatic process
To better understand the reasoning behind the use of tradi-
tional and innovative therapies, it is important to know how
the metastatic behavior is acquired by cancer cells. The most
frequent sites where HNSCC metastasizes are the lymph
nodes of the cervical region and the lungs. The involvement
of different anatomical sites is much less frequent.
The so-called permeation mode was a common thought
in the past which was used to explain how primary tumor
cells spread to other organs. Following the “permeation
mode” theory, the metastatic process of HNSCC is the result
of tumor cells migration into lymphatic vessels. Regional
lymph nodes act as filters in order to prevent distant metas-
tasis [11]. This theory was accepted only for a short period
because several studies in the 1960s demonstrated that
lymph nodes could be easily overcome by tumor cells even
when they were not saturated [12, 13]. Nowadays it is gen-
erally accepted that the metastatic process is an active and
complex process rather than a passive one as described in the
1960s [14]. The first step is tumor cell detachment followed
by degradation of the extracellular matrix (ECM). This
process is regulated by matrix metalloproteinases (MMPs)
produced by cancer cells and stromal cells (e.g., fibroblasts
and inflammatory cells), and it is called epithelial-to-mes-
enchymal transition (EMT). The following step is tumor cell
dissemination, which can be local, lymphatic or blood dis-
semination. The interactions between receptors of both can-
cer cells and target organs are most important in the last step
of metastatic invasion, and they are the reason why a tumor
preferentially metastasizes to certain organs rather than oth-
ers. With regard to HNSCC, cell-surface receptors such as
epidermal growth factor receptor (EGFR) and neurotrophin
receptor B (TrkB), as well as the presence of inflammatory
cytokines such as interleukin-1b, have all been implicated in
the induction of EMT [14]. Cytokines such as interleukin-8
(IL-8), platelet-derived growth factor (PDGF), hepatocyte
growth factor (HGF) and vascular endothelial growth factor
(VEGF) are expressed by HNSCC tumor cells secondary to
constitutive activation of mitogen-activated protein kinase,
nuclear factor-kappa B and signal transducer and activator

Medical Oncology (2018) 35:37
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of transcription 3 intracellular signaling cascades, as well as
by immune and other stromal cells within the tumor micro-
environment. VEGF family members, in particular, seem to
correlate with elevated lymphatic vessel density in tumor
specimens and the presence of cervical metastasis [14].
However, further studies to assess the metastatic phenotype
of HNSCC malignant cells are needed.
Pathology ofmetastatic HNSCCs
Like any other cancer, HNSCC is the result of cumulative
mutations that cause the activation of oncogenes and the
inactivation of tumor suppressor genes in a clonal cell popu-
lation. HNSCCs normally arise from premalignant lesions,
such as leukoplakia or erythroplakia. Leukoplakia is defined
by World Health Organization as a “predominantly white
lesion of the oral mucosa that cannot be characterized as any
other definable lesion.” About 50% of these lesions contain
a loss of heterozygosity (LOH) in the 3p and 9p21 chro-
mosome arms. This LOH causes the inactivation of p16,
a cyclin-dependent kinase inhibitor (CDKI), and the con-
sequent alteration of cell cycle. A subsequent LOH of the
chromosomal region p13 on chromosome 17 leads to the
loss of tumor suppressor gene p53, the so-called guardian of
the genome, and is associated with progression from hyper-
plasia/mild dysplasia to advanced dysplasia/CIS (carcinoma
insitu) [3]. About 60% of HNSCCs carry the genetic muta-
tion which leads to the suppression of p53; the remaining
cases are supposed to be deleted in other proteins involved
in the same p53 pathway, or to undergo p53-independent
malignant progression. Since 2011, when the first exome
sequencing of HNSCC was published, different altered
pathways of growth have been identified in the cells. Apart
from the herein mentioned deletion of p53, mutations in
phosphoinositide 3-kinase (PI3K)–PTEN–AKT pathway
have been discovered in 10–20% of HNSCCs, especially in
those infected by HPV, whereas the inactivation of NOTCH1
(which encodes for a homonymous cell-surface receptor)
was found in 10–19% of head and neck malignancies. A
smaller proportion of HNSCCs, about 8–9%, is carrier of
mutations in caspase 8 (CASP8), which lead to dysregula-
tion of apoptosis and to the immortal profile acquired by
malignant cells [15].
Genetic alterations and deletions on chromosome 4q, 6p,
8p, 13q, 14q and amplification on 11q13, which causes the
overexpression of cyclin D1, are also responsible for the
metastatic potential acquired by HNSCC cells [3].
EGFR
Since 1960s, when growth factors were first discovered [16],
a large number of studies have been conducted in order to
better understand their involvement in tumor cell growth and
their role as targets of new therapies. In particular, EGFR
(ErbB1 or HER1) has been identified in many human can-
cers, such as lung and breast cancers. Also in HNSCCs, both
EGFR and transforming growth factor alpha (TGF-α, one of
EGFR ligands) have been observed to be overexpressed. In
particular, EGFR is elevated in 38–47% of HNSCCs [17].
EGFR is a cell-surface tyrosine-kinase receptor, and it is a
member of the ErbB family receptors which also includes
HER2/neu (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). The
activation of EGFR by ligands such as EGF or TGF-α leads
to DNA synthesis and cell proliferation through the MAPK,
Akt or IP3 pathways.
Elevated expression of EGFR in HNSCC was observed
in advanced-stage and poorly differentiated tumors, and the
highest levels of EGFR correlate with poor prognosis. It was
also observed that EGFR is upregulated even in the normal
tissue surrounding the tumor, further supporting the field
cancerization theory [18].
Chemotherapy (CHT)
The history of medical treatment for recurrent/metastatic
head and neck cancer (RMHNC) began in 1970 with tra-
ditional drugs, methotrexate (MTX) above all, that offered
limited results to the patients in terms of response rate
(RR) and survival [19–21]. In subsequent years, different
drugs such as 5-fluorouracil (5FU), bleomycin, doxoru-
bicin, cyclophosphamide, hydroxyurea and carboplatin
demonstrated good activity with 15–45% RR in phase II
studies [22–24], but unfortunately, no phase III trials were
performed to evaluate any advantage versus best support-
ive care (BSC). Then, cisplatin (CDDP) was studied in
this patient population and demonstrated high RR and an
improvement in OS compared to BSC and MTX [25–29].
In order to ameliorate efficacy, the association of CDDP
and 5FU was tested in different trials because of its activ-
ity and favorable safety profile [30, 31]. The combination
therapy yielded higher rate of objective response, without
prolonging OS, compared to single-agent treatment. As a
consequence, CDDP plus 5FU became the main regimen
used worldwide, because response may be so important in
these often symptomatic patients, and moreover, toxicity
was manageable with appropriate supportive care. More
complex regimens combining CDDP, MTX, vincristine
and bleomycin were studied and compared with CDDP
alone or in combination with 5FU, with poorer survival
results and high rate of toxicity, so they warranted no
further studies [32]. With the introduction of taxanes,
demonstrating promising activity in terms of RR in HNC
[33–37], investigators tried to improve the efficacy of
treatment with paclitaxel and CDDP in combination. A
phase III trial that compared CDDP plus 5FU and CDDP

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plus paclitaxel showed no difference in survival between
the two arms, with similar toxicity [38]. The same group
tried to get better results with high-dose paclitaxel and
CDDP, but the trial showed no survival advantage and
excessive toxicity in the experimental arm [39]. The effi-
cacy of paclitaxel was also evaluated in a phase II study
in combination with carboplatin and demonstrated a
disease control rate (DCR) of 51.8% and few G3–4 side
effects [40]. Recently, buparlisib, a pan-PI3K inhibitor,
was studied in a phase II trial with paclitaxel [41]. In this
trial, patients with RMHNC resistant to platinum-based
CHT were randomly assigned to receive second-line treat-
ment with paclitaxel plus buparlisib or placebo. Median
progression-free survival (PFS) was 4.6months in the
buparlisib group and 3.5months in the placebo group
(P=0.011, hazard ratio [HR] 0.65). The treatment with
buparlisib was associated with a manageable safety pro-
file with hyperglycemia being the most common adverse
event. This study suggests that buparlisib plus paclitaxel
could be an effective second-line treatment, but a phase III
trial is warranted to confirm these promising results. Nab-
paclitaxel (paclitaxel bound to nanoparticle albumin as a
delivery vehicle) is a new taxane with good clinical activ-
ity in many solid tumors. There are no data about its activ-
ity as monotherapy in RMHNC neither about efficacy in
patients that progressed during treatment with a different
taxane. Nonetheless, a retrospective analysis of patients
treated with nab-paclitaxel monotherapy, conducted in a
single institution, showed clinical benefit for patients with
taxane-resistant disease [42].
Cabazitaxel is a second-generation taxane that improves
survival in patients with metastatic castration-resistant
prostate cancer resistant to docetaxel [43]. Unfortunately,
a phase II trial showed that cabazitaxel has low activity in
RMHNC previously treated with platinum-based therapy,
and it has an unfavorable toxicity profile [44].
Pemetrexed is a drug with promising activity that was
evaluated in combination with CDDP in a phase III study.
This large trial randomized 795 patients with RMHNC to
CDDP plus pemetrexed versus CDDP plus placebo. The
results were negative as an advantage in OS, the primary
endpoint, was not reached. OS in the pemetrexed–CDDP
arm was 7.3months, while in the placebo–CDDP arm it
was 6.3months (HR 0.87; 95% confidence interval [CI],
0.75–1.02; P=0.082). Looking at subgroups, in patients
with performance status 0 or 1, pemetrexed–CDDP
led to longer OS and PFS than placebo–CDDP (8.4 vs.
6.7months; HR 0.83; P=0.026; 4.0 vs. 3.0months;
HR 0.84; P=0.044, respectively). Also among patients
with oropharyngeal cancers, pemetrexed–CDDP resulted
in longer OS and PFS than placebo–CDDP (9.9 vs.
6.1months; HR 0.59; P=0.002; 4.0 vs. 3.4months; HR,
0.73; P=0.047, respectively). Despite this interesting
result, the combination cannot be considered a standard
treatment [45].
Since the activity of doublet with classical agents was dis-
appointing, investigators tried to get better results in phase
II trials with more complex regimens including paclitaxel,
ifosfamide and platinum analogue, achieving high rate of
objective response and median OS of 9–11months, but tox-
icity has always been a critical issue [46, 47].
Monoclonal antibodies (mAbs)
Cetuximab is a recombinant IgG1 antibody directed against
the external domain of EGFR, which blocks ligand-medi-
ated activation of EGFR pathway and stimulates antibody-
dependent cellular cytotoxicity [48, 49]. The efficacy of
cetuximab in RMHNC was first evaluated as monotherapy
in patients refractory to platinum-based therapy [50]. In this
trial, DCR was 46% and median time to progression 70days;
treatment was well tolerated. On the base of these findings,
a phase III trial was conducted by the Eastern Cooperative
Oncology Group, evaluating the activity of CDDP plus
cetuximab or placebo [51]. The addition of cetuximab to
CDDP significantly improved RR (overall RR was 26% in
experimental arm vs. 10% in placebo arm) without prolong-
ing significantly OS and PFS. In order to optimize the effi-
cacy of treatment, cetuximab was added to a standard dou-
blet with CDDP and 5FU in the EXTREME study [52]. This
trial enrolled 442 patients with untreated RMHNC that were
randomized to CDDP or carboplatin and 5FU or the same
combination plus cetuximab at the standard dose of 400mg
per square meter for the first dose followed by 250mg per
square meter weekly. Patients received up to 6 cycles of
CHT. Cetuximab was maintained until progression or unac-
ceptable toxicity. The primary endpoint was OS, and for the
first time after many years the experimental arm improved
significantly OS with an absolute advantage of 2.6months
(7.4months in the CHT arm vs. 10.1 in the CHT plus cetuxi-
mab arm). The addition of cetuximab also prolonged PFS
and increased the RR. The incidence of grade 3–4 adverse
events was comparable between the two treatments, except
for higher rates of skin toxicity, hypomagnesemia and sepsis
in the cetuximab group. There were no cetuximab-related
deaths. The benefit of cetuximab was greater for patients
younger than 65years, those with Karnofsky performance
status≥80% and those who received CDDP. The results of
this study led to consider CDDP plus 5FU and cetuximab,
the so-called EXTREME regimen, the new standard of care
for patients with RMHNC and good performance status.
This regimen might result difficult to administer for many
patients because of the risk of adverse events related to high
dose of CDDP. As a consequence, some authors tried to find
an alternative combination with the same efficacy. Nakano

Medical Oncology (2018) 35:37
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and colleagues [53] conducted a retrospective analysis of
patients with RMHNC treated with a cetuximab-containing
regimen. The efficacy of weekly paclitaxel plus cetuximab
was compared to the EXTREME regimen. A total of 86
patients were included. Response rates were similar in the
two cohorts (45% in the paclitaxel–cetuximab arm vs. 51%
in the CDDP–5FU–cetuximab arm), while patients treated
with paclitaxel and cetuximab had a significant advantage
in PFS (6.0 vs. 5.0months, P=0.027). This schedule could
represent a useful alternative option for patients refractory
or ineligible to CDDP.
To avoid the risks of toxicity associated with 5FU and the
need of a central catheter for the 96-h infusions, Bossi etal.
[54] tried to substitute 5FU with paclitaxel and compared a
3-drug (CDDP–paclitaxel–cetuximab) with a two-drug regi-
men (CDDP and cetuximab) in the phase II non-inferiority
study B490. A total of 201 patients were randomized 1:1 to
each regimen. For the primary endpoint, PFS, the 2-drug
arm resulted non-inferior to the 3-drug one (6 vs. 7months,
HR 0.99). There were also no differences in OS between
the two groups of patients, with a median OS of 13months
for patients receiving CDDP–cetuximab and 11months for
those treated with CDDP, paclitaxel and cetuximab with an
HR of 0.77. The overall RR was 41.8% with the two drugs
versus 51.7% with the addition of paclitaxel. The results
in terms of all efficacy endpoints were similar or supe-
rior to those reported in the EXTREME study. Grade≥3
adverse events were 76% with CDDP and cetuximab, 73%
with CDDP, paclitaxel and cetuximab. No toxic deaths
were observed, and compared to EXTREME, the rate of
life-threatening toxicities (cardiac and septic) was reduced.
This study showed that 5FU can be substituted by pacli-
taxel, mostly in patients that need a tumor shrinkage, and
that the 2-drug regimen can also be an option with similar
results in terms of PFS and OS. These regimens may repre-
sent a potential less toxic backbone for new combinations
with emerging immunotherapies, such as the new checkpoint
inhibitors.
Panitumumab is a fully humanized anti-EGFR mAb used
for the treatment of metastatic colorectal cancer [55]. In the
SPECTRUM study, patients with RMHNC candidates to a
first-line treatment were randomly assigned to CHT with
CDDP and 5FU or the same treatment plus panitumumab
[56]. Panitumumab was administered on day 1 of each cycle
before cytotoxic drugs at the dosage of 9mg/kg. CHT con-
tinued until disease progression or for a maximum of six
cycles. Patients in the panitumumab group could receive
the mAb until disease progression or unacceptable toxicity.
Unfortunately the trial did not meet OS, its primary end-
point. Median OS was 11.1months in the panitumumab
arm and 9months in CHT only arm (HR 0.873, P=0.14).
Median OS was longer for patients with p16-negative tumors
in the panitumumab arm than in the control arm (11.7 vs.
8.6months, HR 0.73, P=0.015). Grade 3–4 adverse events
were more frequent with CHT plus panitumumab. Panitu-
mumab was then studied in the PARTNER trial, a phase
II study that evaluated the activity of a first-line treatment
with CDDP and docetaxel with or without panitumumab in
patients with RMHNC [57]. In order to limit toxicity, only
patients younger than 70years were enrolled and primary
prophylaxis with granulocyte colony-stimulating factors was
mandatory. PFS, the primary endpoint, was 6.9months in
the experimental arm versus 5.5months in the CHT alone
arm (HR 0.62, P=0.048). There was no difference in OS
between the two treatment groups (12.9months with CHT
plus panitumumab and 13.8months with CHT alone, HR
1.103), while grade 3–4 adverse events were more frequent
with CHT plus panitumumab than with CHT alone. Follow-
ing these data, panitumumab is not indicated in the treatment
of RMHNC.
Bevacizumab is a humanized mAb directed against
VEGF, approved for many solid tumors. VEGF hyper-
expression is correlated to poor prognosis in patients with
HNC. Preclinical and clinical activities of a combined treat-
ment with cetuximab and bevacizumab were evaluated in
human endothelial cells, head and neck and lung cancer
xenografts model systems and, afterward, in patients with
RMHNC [58]. This chemo-free treatment demonstrated
growth inhibition invitro and invivo and reduced tumor vas-
cularization. In the clinical phase II trial of the same report,
46 patients were enrolled. The RR was 16% and the disease
control rate (DCR) 73%; median PFS was 2.8months and
median OS 7.5months. The treatment was well tolerated
and grade 3–4 adverse events occurred in less than 10% of
patients.
Bevacizumab was also studied in combination with pem-
etrexed in patients with RMHNC in first-line setting in a
phase II trial [59]. The 2-drug regimen demonstrated prom-
ising clinical activity. Time to progression, the primary end-
point, was 5months, while OS was 11.3months and DCR
86%. Unfortunately, frequent serious bleeding events (15%),
including two deaths, grade 3–4 neutropenia and sepsis were
indeed a real concern for the safety of the regimen.
Tyrosine‑kinase inhibitors (TKIs)
Gefitinib and erlotinib are the two anti-EGFR TKIs approved
for the treatment of advanced non-small cell lung cancer
patients. These drugs target one of the most important path-
ways in lung and head and neck carcinogenesis and have
been tested in RMHNC.
In a phase II study, gefitinib obtained a RR of 10.6%
and a DCR of 53% at the dose of 500mg daily. Median
OS was 8.1months, and the drug was well tolerated [60].
A following trial evaluated the activity of gefitinib at the

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recommended dosage of 250mg daily [61]. The lower dos-
age, as used in lung cancer, had less activity than the dose
of 500mg daily: A partial RR of 1.4% and median OS of
5.5months were reported. Most interesting, a phase III
trial designed to compare gefitinib 250mg daily or 500mg
daily with the old MTX in second-line demonstrated that
gefitinib 250 and 500mg/day did not improve OS com-
pared to MTX, and the primary endpoint of the study was
not reached [62].
Gefitinib was also tested in addition to docetaxel [63].
The study was closed at an interim analysis for inefficacy.
The addition of gefitinib to docetaxel did not improve OS
in these patients.
Erlotinib was also evaluated in this setting and dem-
onstrated modest activity as monotherapy [64]. RMHNC
patients were treated with erlotinib 150mg/day. Objective
response rate was 4.3%. The median PFS was 9.6weeks,
and the median OS was 6months. Rash and diarrhea were
the main adverse events. Erlotinib was also combined with
bevacizumab [65] in a phase II study enrolling 48 patients,
treated with erlotinib 150mg/day and bevacizumab 15mg/
kg every 3weeks. Fifteen percentage of patients obtained
an objective response, and 31% had stable disease. Median
OS was 7.1months, and the treatment was well tolerated.
The trial suggests that blocking both EGFR and VEGF
might have activity in HNSCC, but no further results have
been published yet.
Afatinib is an irreversible pan-human epidermal recep-
tor (pan-HER) inhibitor that downregulates ErbB signal-
ing by covalently binding to the kinase domain of EGFR,
HER2 or HER4. In a phase II study, afatinib demonstrated
anti-tumor activity comparable to cetuximab. In this
trial, 124 pretreated patients were randomized to receive
afatinib 50mg/day or cetuximab 250mg per square meter
weekly until disease progression or intolerable toxicity
(stage I); then, a crossover to the other treatment (stage II)
was permitted. The first stage of the study demonstrated
similar tumor shrinkage, RR, DCR and PFS with the two
drugs. In stage II, DCR was higher with afatinib than with
cetuximab, suggesting that afatinib after cetuximab fail-
ure may be the optimal sequence. This is related to a lack
of cross-resistance between the two agents, but it is still
unclear why afatinib used after and not before cetuximab
yields a better DCR [66].
On the base of these results, the activity of afatinib was
further investigated in a phase III trial of second-line treat-
ment. It was associated with significantly higher DCR and
longer PFS compared to MTX. Moreover, patients treated
with afatinib had less pain and a significant delay in time
to clinical worsening. These favorable outcomes did not
translate into a prolonged OS, a secondary endpoint of
the trial [67].
Immunotherapy
Despite new advances in conventional therapies such as
surgery, RTX and CHT, survival of HNSCC is still poor.
Furthermore, these strategies, although conventional, can
result in serious complications, from pain to dysphagia and
malnutrition, risk of infection and psychological distress
[68, 69]. Patients suffering from advanced HNSCC are
faced with challenging treatments, so researchers have the
tremendous task to discover and develop new therapies
that combine high efficacy as well as low toxicity. Coming
from studies on the molecular biology and immunology of
cancer, immunotherapy has recently opened new interest-
ing perspectives for HNSCC treatment.
It is now well known that cancer cells develop the abil-
ity to evade anti-tumor immune attacks either by inhibiting
recognition of cancer-specific antigens by T cells, or by
causing dysfunction of CD8 cytotoxic T cells (CTL). The
possibility to revert these cellular alterations is the basis
of cancer immunotherapy, working under the regulation
of positive and negative co-signaling pathways, the so-
called immunologic checkpoints. The checkpoints of pro-
grammed cell death 1 (PD-1) and programmed cell death
ligand 1 (PD-L1) have important roles in the formation
of “immune privilege” regions, viral persistence, tumor
development and immune evasion [70–72]. Following
“in vitro” and preclinical tests, various immune check-
point inhibitors (ICIs), such as anti-PD-1 mAbs and anti-
CTLA-4 mAbs, have demonstrated the potential to control
cancer by immune activation [73–80]. Immune checkpoint
blockade is able to reactivate dysfunctional or exhausted T
cells by restoring tumor-specific immunity, a high-quality
program aimed at eliminating cancer cells (Fig.1).
The results of two recently published trials, the open-
label, multicenter, phase Ib trial (KEYNOTE-012) and
the randomized, open-label, phase III trial (CheckMate
141) [81–83], demonstrated the clinical activity of two
antagonists of the PD-1/PD-L1 axis (pembrolizumab and
nivolumab) and led to their approval by the US Food and
Drug Administration (FDA) as first molecular-targeted
therapeutic drugs for HNSCC.
The PD‑1/PD‑L1 axis
PD-1 is a surface transmembrane glycoprotein consisting
of 268 amino acids, which belongs to the CD28/CTLA-4/
ICOS co-stimulatory receptor family. Its structure consists
of an extracellular region, a hydrophobic transmembrane
region and an intracellular region. Two independent tyros-
ine residues are located in the intracellular region, at the
tail end [84–86]. The corresponding PD-1 ligands (PD-L1

Medical Oncology (2018) 35:37
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Page 7 of 12 37
and PD-L2) belong to the B7 superfamily, which includes
the important B7–1 (cluster of differentiation [CD]80) [71,
87]. Similar to PD-1, the structures of PD-L1 and PD-L2
mainly comprise an extracellular region, a hydrophobic
transmembrane region and an intracellular region with a
short cytoplasmic tail of unknown function [84, 87]. The
affinity of the PD-L1 extracellular region with PD-1 is
lower than that of the PD-L2 extracellular region, but it
can also bind with the B7-A (CD80) extracellular region
[71, 84, 87].
PD-1 is expressed on activated T cells after induction
by a T cell antigen receptor and cytokine receptor [84],
and it is also expressed at low levels on double-negative
(CD4–CD8–) T cells in the thymus, activated natural
killer T cells, B cells and monocytes [71, 84]. PD-L1 is
expressed constitutively at low levels on antigen-presenting
cells (APCs), but this scanty expression can be enhanced
by inflammatory cytokines such as type I and type II
interferons, tumor necrosis factor α and VEGF [84, 88].
Increased expression of PD-1/PD-L1 in the microenviron-
ment of HNSCC is independent of HPV status [89].
Different mechanisms are involved in the upregulation
of PD-L1 expression by tumor cells. One possibility is the
activation of the EGFR and the PI3K–Akt or Janus kinase
2/signal transducer and activator of transcription 1 signal-
ing pathways [84, 90, 91]. Other mechanisms involved are
the amplification of genes coding PD-L1 (9p24.1) [84, 90]
and the induction of Epstein–Barr virus (EBV). Moreo-
ver, in tumor microenvironment, the stimulatory effects of
inflammatory factors can also induce PD-L1 expression,
interferon-γ being the most important stimulating factor
[72, 84, 88, 91–93].
T cells are activated by a dual control system involving a
specific binding between a T cell receptor and a major his-
tocompatibility complex class and the interaction between
co-stimulatory molecules and the corresponding receptor
Fig. 1 a. Tumor cells can express PDL-1, which is normally
expressed on antigen-presenting cells (APCs) of the immune system
in order to inhibit an exaggerate immune response. b. New antibody
drugs have been developed to prevent the inactivation of immune
system against tumors. Nivolumab and pembrolizumab are the main
humanized antibodies tailored to block PD-1. Durvalumab is an
experimental IgG1 mAb against PDL-1

Medical Oncology (2018) 35:37
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37 Page 8 of 12
on the T cell surface. To prevent T cell overstimulation, T
cell activity is finely regulated at checkpoints [71, 85, 86,
88]. After invasion by tumor cells, these signals are used to
inhibit T cell activation so as to evade attack by the immune
system. At present, a variety of inhibitors of immune check-
points have been studied, mainly mAbs already tested in the
clinical context. The anti-tumor effect is realized by multiple
actions comprising the inhibition of the activity of immune
checkpoints, the blockade of immunosuppression in the
tumor microenvironment and the reactivation of the immune
response of T cells to the tumor [71, 72, 81–84, 86, 88, 94].
Clinical application inHNC
PD‑1‑targeted drugs
The main PD-1-targeted drugs used to treat HNSCC are
pembrolizumab and nivolumab, both of which are human-
ized PD-1-inhibiting IgG4 mAbs with high specificity for
receptors [81–83]. They have been used for the treatment
of patients with recurrent/metastatic HNSCC with disease
progression on or after platinum-containing CHT (Table1).
Pembrolizumab
Seiwert etal. [81] experienced pembrolizumab in a popu-
lation of 60 patients with recurrent/metastatic HNSCC
(KEYNOTE-O12). PD-L1 expression of≥1% was present
in tumor cells of all patients. The majority of cases (62%)
were HPV−, whereas 38% were HPV+. Pembrolizumab
(10mg/kg body weight, intravenous [iv]) was adminis-
tered biweekly for 2years. Median duration of follow-up
was 14 (range 4–14) months. The ORR was 18% (25% for
HPV+ and 14% for HPV−). While the median PFS was
only 2months, interestingly the median OS was 13months.
Treatment-related adverse events were reported in 63% of
the cases (17% grade 3–4), mainly fatigue and skin toxicity,
but there were no treatment-related deaths. Chow etal. [82]
used pembrolizumab in 132 adult patients with recurrent/
metastatic HNSCC irrespective of PD-L1 or HPV status.
Fifty-seven percent of the patients previously received two
or more lines of CHT. Most of them (71%) were HPV−.
Pembrolizumab (200mg, iv) was administered once every
3weeks for 2years. The median duration of follow-up was 9
(range 3–11) months. The ORR was 18%, and the response
rate of HPV+was 32%, while that of HPV−was 14%. A
statistically significant increase in ORR was observed for
PD-L1-positive versus PD-L1-negative patients (22 vs. 4%;
P=0.021). The median PFS was 2months, and the median
OS was 8months. Treatment-related adverse events were
reported in 62% of the patients, 9%≥grade 3. There were
no treatment-related deaths. Bauml etal. [95] used pem-
brolizumab in platinum- and cetuximab-refractory HNC.
Pembrolizumab (200mg, iv) was administered once every
3weeks for 2years in 50 patients. The median duration of
follow-up was 6.8months. ORR was 16% (95% CI 11–23%),
with a median duration of response of 8months (range 2+
to 12+months); 75% of the patients were still in response at
the time of analysis. RR was similar in all HPV and PD-L1
subgroups. Median PFS was 2.1months, and median OS
was 8months. Sixty-four percent of the patients experienced
a treatment-related adverse event, and 15% experienced a
grade≥3 event. Seven patients (4%) discontinued treatment,
and one treatment-related death was registered. That trial
showed that pembrolizumab demonstrated clinically mean-
ingful anti-tumor activity and an acceptable safety profile in
recurrent/metastatic HNSCC previously treated with plati-
num and cetuximab.
Nivolumab
Nivolumab recently demonstrated to be active in recurrent/
metastatic HNSCC and gained approval by the FDA after
the pivotal phase III trial by Ferris etal. [83]. In that trial,
361 patients with recurrent/metastatic HNSCC were rand-
omized in a 2:1 ratio to nivolumab (3mg/kg, iv) once every
2weeks, or standard therapy (either methotrexate, docetaxel,
or cetuximab of the investigator’s choice) until disease pro-
gression. The median duration of follow-up was 5.1months.
The ORR and partial response rate (PRR) were 13.3 and
10.8% for nivolumab, and 5.8 and 5.0% for standard therapy,
Table 1 Anti-PD-1 drugs currently tested for R/M HNSCC
Authors Drug Year Phase No. of patients mOS (months) mPFS (months)
Seiwert etal. [81] Pembrolizumab 2016 Ib 60 13 2
Chow etal. [82] Pembrolizumab 2016 132 8 2
Bauml etal. [95] Pembrolizumab 2017 50 8 2.1
Ferris etal. [83] Nivolumab versus standard therapy 2016 III 361 7.5—Nivolumab 2—Nivolumab
5.1—Standard therapy 2.3—Standard therapy
Segal etal. [97] Durvalumab (MEDI4736) 2015 I/II 62 Not evaluated Not evaluated
Fury etal. [98] Durvalumab (MEDI4736) 2014 I 50 Not evaluated Not evaluated

Medical Oncology (2018) 35:37
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Page 9 of 12 37
respectively. The median PFS was 2months for nivolumab
and 2.3months for standard therapy. The median OS for
nivolumab was 7.5months and 36% of patients reached
1-year PFS, while for standard therapy it was 5.1months
and 16.6% patients reached 1-year PFS. Treatment-related
adverse events (fatigue, nausea and skin rash) were recorded
in 58.9% of the nivolumab patients compared to 77.5% in the
standard therapy group. Grade>3 treatment-related adverse
events were experienced by 13.1% of the nivolumab patients
and by 35.1% of the standard therapy patients. In conclusion,
nivolumab prolonged survival, as compared with standard
therapy, among patients with platinum-refractory HNSCC,
and was associated with fewer toxic effects of grade 3 or
4 than standard therapy. Moreover, nivolumab delayed the
time to deterioration of patient-reported quality-of-life out-
comes [96] among patients with treatment-refractory cancer
that negatively impacts on quality of life and leads to death.
PD‑L1‑targeted drugs
At present, the main PD-L1-targeted drug for HNSCC treat-
ment is durvalumab (MEDI4736), a human IgG1 mAb that
blocks PD-L1 binding to its receptors [71, 97, 98]. It has
been used for recurrent/metastatic HNSCC in two small tri-
als [97, 98] where it was administered (10mg/kg, iv) once
every 2weeks for 12months. At present, the data have been
published only in abstract form, so it is premature to con-
clude about a possible role of durvalumab in the clinical
practice.
Conclusion
The treatment of RMHNC is a hard task as the disease is
burdened by cumbersome morbidity and high mortality.
Recent trials have demonstrated how useful the advent of
immunotherapy in this dreary landscape could be, high-
lighting superior response and survival rates compared to
standard CHT. Furthermore, a well-defined prerogative of
immunotherapy seems to be a reduced rate of adverse events,
making it a safe and powerful new anticancer treatment.
Pembrolizumab has the highest ORR in HPV+HNSCC
patients and probably has the greatest potential among
PD-1-/PD-L1-targeting drugs. In the effort to find an effec-
tive and less toxic treatment, a promising approach will be
the evaluation of the combination of pembrolizumab and
radiotherapy in the loco-regionally advanced disease, with
the aim of decreasing local and distant relapse in the HPV
subgroup. For the next future, we need more clinical data
on the efficacy of the single agents, but it will be of utmost
interest the unexplored option to combine two or more drugs
together (immunotherapy or CHT), as well as the possibility
to substitute one drug in the standard EXTREME protocol
(5-FU for example) with a PD-1-/PD-L1-targeting drugs.
Finally, it is well known how cetuximab, a mAb directed
to EGFR, can be effective in HNC. As it has been demon-
strated, the blockade of PD-1/PD-L1 signaling can improve
anticancer effects of anti-EGFR agents [99], so the combined
application of PD-1-/PD-L1-targeted drugs and cetuximab
merits further research in order to discover favorable and
long-lasting clinical effects.
Compliance with ethical standards
Conflict of interest All authors declare that they have no conflict of
interest.
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