REVIEWS

The changing therapeutic landscape

of head and neck cancer
John D. Cramer1, Barbara Burtness2, Quynh Thu Le3 and Robert L. Ferris4,5,6*
Abstract | Head and neck cancers are a heterogeneous collection of malignancies of the upper
aerodigestive tract, salivary glands and thyroid. In this Review , we primarily focus on the changing
therapeutic landscape of head and neck squamous cell carcinomas (HNSCCs) that can arise in the
oral cavity , oropharynx, hypopharynx and larynx. We highlight developments in surgical and
non-​surgical therapies (mainly involving the combination of radiotherapy and chemotherapy),
outlining how these treatments are being used in the current era of widespread testing for the
presence of human papillomavirus infection in patients with HNSCC. Finally , we describe
the clinical trials that led to the approval of the first immunotherapeutic agents for HNSCC, and
discuss the development of strategies to decrease the toxicity of different treatment modalities.

1
Department of
Otolaryngology, Wayne State
University School of Medicine,
Detroit, MI, USA.
2
Department of Medicine
and Yale Cancer Center,
Yale School of Medicine,
New Haven, CT, USA.
3
Department of Radiation
Oncology, Stanford
University, Palo Alto, CA,
USA.
4
Department of
Otolaryngology, University of
Pittsburgh, Pittsburgh, PA,
USA.
5
Department of Immunology,
University of Pittsburgh,
Pittsburgh, PA, USA.
6
UPMC Hillman Cancer
Center, Pittsburgh, PA, USA.
*e-​mail: ferrisrl@upmc.edu
https://doi.org/10.1038/
s41571-019-0227-z
Worldwide, >830,000 individuals are diagnosed with
head and neck cancer and >430,000 patients die from
this disease each year1; the annual incidence in the USA
is ~65,000 patients2. Head and neck squamous cell carci-
nomas (HNSCCs) account for 90% of all head and neck
cancers3 and can be detected at various anatomical sites
(Fig. 1). Approximately 75% of HNSCCs are associated
with tobacco and alcohol use4,5; however, a minority of
HNSCCs are caused by human papillomavirus (HPV)
infection6,7. In the USA, the declining use of cigarettes
has been associated with a decrease in HNSCC inci-
dence, with the exception of HPV-​driven (HPV+) oro-
pharyngeal squamous cell carcinoma (OPSCC), which
has a rapidly increasing incidence8.
HPV infection has been established to have a causal
role in the development of HNSCC, primarily of the
oropharynx9. The epidemiology, pathophysiology and
response to treatment of HPV+ OPSCC differ sharply
from that of HPV− disease10,11. The demographic charac-
teristics of patients with HPV+ OPSCC are also different,
including a higher incidence in men and a younger mean
age at diagnosis12. The prevalence of HPV+ OPSCC var-
ies substantially by geographical location, with 60–70%
of OPSCCs in the USA13 and Western Europe14 but
<10% in low-​income and middle-​income countries15.
HPV infection might have a role in a small proportion
of HNSCCs located outside the oropharynx. Although
the effect of HPV in cancers in these sites is less well
understood, HPV positivity is also associated with more
favourable outcomes16,17.
The latency period between HPV infection and clin-
ical presentation with HPV+ OPSCC is estimated to be
10–30 years12. HPV+ OPSCC arises in deep crypts in the
tonsil and the base of the tongue (BOT) and is not asso-
ciated with a pre-​malignant clinical lesion. Therefore,
screening cannot be conducted by a corollary of the Pap
smear test used for the early detection of uterine cer-
vical cancer18. HPV vaccines are 90–100% effective at
preventing anogenital HPV infections and precancer-
ous lesions19. In 2018, the FDA extended the approved
age range of candidates for the vaccine against HPV,
GARDASIL 9, to include men and women <45 years
of age19,20. Epidemiological data suggest that prophy-
lactic HPV vaccination reduces the prevalence of oral
HPV infection by 88–93%. Vaccination is expected to
reduce the incidence of oropharyngeal cancer by 2060,
on the basis of slow uptake and the latency period from
infection to clinical presentation with OPSCC12,21,22.
Patients with HPV+ OPSCC typically present with
small primary tumours and cervical lymphadeno­
pathy23, and might initially be diagnosed with squamous
cell carcinoma of unknown primary (SCCUP) of the
head and neck. Despite the high frequency of spread
to cervical lymph nodes, HPV+ OPSCC is associated
with a significantly more favourable prognosis than
HPV− OPSCC (3-year overall survival (OS) 82.4%
versus 57.1%; P < 0.001)10. In contrast to patients with
HPV− HNSCC, those with HPV+ OPSCC presenting
with cervical lymph node metastases have excellent
survival outcomes (5-year OS of 80–87% for patients
with N1–N2c HPV + OPSCC versus 37–58% for
those with N1–N2c HPV− OPSCC)24. The staging groups
defined by the American Joint Committee on Cancer
(AJCC) in 2010 (ref.25) failed to provide an accurate
prognosis of patients with HPV+ OPSCC23. As a result,
the eighth edition of the AJCC staging manual uses a
unique staging system for HPV+ OPSCC26. Application of
the new staging system resulted in the downstaging
of 92% of patients with HPV+ OPSCC, and the propor-
tion of patients with stage I disease increased from 3% to

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Key points
• Current treatments for human papillomavirus-​driven (HPV+) oropharyngeal squamous
cell carcinoma (OPSCC), primarily derived from those for the more aggressive HPV−
head and neck squamous cell carcinoma (HSNCC), might be more intensive than
necessary for patients with favourable risk features and an excellent prognosis.
• Multiple prospective studies have investigated various treatment de-​intensification
strategies with promising early results; however, pending definitive conclusions, HPV+
OPSCC should continue to be treated with established standard-​of-care therapies,
known to yield very high survival.
• Minimally invasive transoral surgical techniques provide an alternative treatment
option for OPSCC; retrospective evidence is promising, but results from prospective
randomized trials are required to fully integrate these approaches into the treatment
armamentarium.
• More-​precisely targeted radiotherapy (with incorporation of intensity-​modulated
radiation therapy, molecular imaging-​guided therapy, adaptive therapy and proton
beam therapy) has the potential to decrease the long-​term toxicity of radiotherapy.
• Anti-​EGFR therapy with cetuximab improves survival in the curative and recurrent
and/or metastatic settings; however, no other molecularly targeted approach has
prolonged survival in HNSCC.
• Anti-​programmed cell death 1 (PD-1) therapies, currently approved for platinum-​
refractory recurrent and/or metastatic HNSCC, offer the prospect of long-​term
remissions with fewer toxicities than traditional cytotoxic chemotherapy for a
minority of patients, and are expected to advance to earlier lines of therapy.
64%27. Of note, 98% of patients from the cohort in which
the new staging criteria were developed and validated
received non-​surgical therapy with definitive radio-
therapy or chemoradiotherapy24. Importantly, while
the guidelines for HPV+ OPSCC in the eighth edition
of the AJCC staging manual were designed to improve
prognostication, they are based on multimodal therapy
and do not provide sufficient data to support treatment
de-​intensification on the basis of revised stage groups
alone. Treatment decisions should be driven by the clin-
ical criteria used to select patients for inclusion in land-
mark trials of definitive therapy, rather than by novel
stage-​defined groups. Consequently, the identification
of clinical risk categories and/or biomarkers that can be
used to modify the dose and duration of therapies in
patients with HPV+ OPSCC is a major interest of several
research groups10,28,29.
In the setting of HPV− HNSCC, treatment with pri-
mary surgery or radiotherapy improves the cure rate
of patients with early-​stage disease, with a 5-year OS of
70–90%30. Unfortunately, two-​thirds of patients present
with advanced-​stage disease, with large primary disease
(T3–T4) and/or cervical adenopathy31. The survival
outcomes of patients with locoregionally advanced dis-
ease are modest, ranging from a 5-year OS of 49% for
patients with laryngeal cancer to 25% for those with
hypopharyngeal cancer32. The standard-​of-care treat-
ment for locoregionally advanced disease is multimodal.
Many studies have demonstrated that the addition of
concurrent chemotherapy to radiotherapy results in
modest improvements in survival33. The awareness that
more-​intense multimodal therapy regimens result in a
higher incidence of severe acute and late toxicities34 has
generated renewed interest in therapeutic strategies that
minimize toxicity while maintaining disease control.
In this Review, we focus on treatment advances from
clinical trials with results published in the past few years
that offer the possibility to limit the toxicity of treatment
and further improve outcomes of patients with HNSCCs
in one of the four major sites: the oral cavity, oropharynx,
hypopharynx or larynx. Noteworthy advances in head
and neck cancers of other histologies are also discussed.
Surgery
Surgery remains the preferred treatment for oral cavity
squamous cell carcinomas (OCSCCs)35 and advanced-​
stage (T4a) laryngeal or hypopharyngeal cancers36.
Surgical treatment has improved dramatically over
the past 30 years. For advanced-​stage primary cancers,
microvascular reconstruction has become the standard-​
of-care modality; this approach enables cancer resection
with improved restoration of function37. For early-​stage
cancers, minimally invasive surgical treatment options
have similarly improved and have now become a surgi-
cal option associated with reduced morbidity for many
patients.
Minimally invasive transoral surgery
Definitive chemoradiotherapy was widely adopted
in the late 1990s in an effort to avoid the morbidities
associated with open surgery38,39. Transoral robotic sur-
gery (TORS) and transoral laser microsurgery (TLM)
are surgical modalities that have emerged as promising
alternatives with far fewer morbidities than open surgery
(reduction in feeding tube support at 1 year from 31%
to 3% and reduction in length of hospital stay from 8.0 to
3.8 days)40. These approaches enable improved visuali-
zation of deep regions of the upper airway while using
the mouth as a natural orifice41. Transoral surgery is
primarily used to access primary OPSCCs of small-​to-­
moderate size (T1–T2) and T1–T2 cancers of the larynx
and hypopharynx42.
A retrospective analysis of records from several cen-
tres using TLM supports this modality as an effective
and safe approach43. Several prospective trials of TLM
from cooperative groups are ongoing (NCT01898494
and NCT02215265), but no results have been published
yet. Since the FDA approval of the da Vinci surgical
robotic system for transoral resection in the orophar-
ynx in 2009 (ref.44), TORS has been rapidly adopted by
the surgical community for OPSCC45. A second robotic
device by Medrobotics was approved in 2015 (ref.46).
Compared with open approaches, transoral surgery
improves the safety, efficacy and tolerability of surgery47.
Most of the published evidence on transoral surgery
comes from single-​institution series (with pooled results
published in ref.47). The indications for upfront surgi-
cal treatment of OPSCC are controversial. Proponents
of surgery point out that, when selected appropriately,
69–83% of patients who undergo surgery avoid the
need for adjuvant chemotherapy and 11–47% also
avoid the need for radiotherapy42,43,48,49. Retrospective
studies have further suggested improved functional
results, including decreased dependency on a gastro­
stomy tube for patients who undergo upfront transoral
surgery compared with those who receive definitive
chemoradiotherapy 47,50,51. However, proponents of
definitive chemoradiotherapy point out that 17–31%
of patients who undergo surgery eventually need therapy
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 Reviews

Cancer subtype Annual incidence Annual mortality

Worldwide USA Worldwide USA

Oral cavity and lip 358,864 33,950 177,384 6,800

Nasopharynx
Laryngeal 177,422 13,150 94,771 3,710

Oral Nasopharyngeal 129,079 Rare 72,987 NA

cavity Oropharynx
Oropharyngeal 92,887 NA 51,005 NA

Hypopharyngeal 80,608 NA 34,984 NA

Hypopharynx
Larynx

Fig. 1 | incidence rates and mortality for patients with head and neck squamous carcinoma 1,2.  Results of worldwide
and US investigations of the epidemiology of head and neck squamous cell carcinoma are shown; national databases
frequently group different subtypes together (for example, oral cancers and pharyngeal cancers). For this reason, some
oropharyngeal cancers of the base of the tongue can be misclassified as cancers of the oral cavity. Furthermore, the
incidence of human papillomavirus-​associated oropharyngeal cancer is regionally specific: human papillomavirus
accounts for 70% of oropharyngeal cancers in the USA and for 10% in low-​income and middle-​income countries5,7,9.
The incidence of nasopharyngeal cancer is included as it significantly impacts the global burden of head and neck cancer,
particularly in Southeast Asia, although the incidence is low in the USA. NA , not applicable.

intensification to triple-​modality therapy (involving sur- reduces morbidity35. Historically, elective neck dissection
gery, chemotherapy and radiotherapy)52. The lack of data (END) has been advocated for patients with neck dis-
from prospective studies of transoral surgery led to the ease and no lymph node involvement (N0) and a >20%
development of several trials investigating TORS and risk of occult nodal disease62, although this approach is
TLM in patients with HPV+ OPSCC. not supported by data from randomized studies. D’Cruz
et al.63 performed a randomized trial of END versus
SCCUP of the head and neck observation in 500 patients with stage I/II OCSCC.
SCCUP accounts for 1–4% of all HNSCCs, and 69% Patients in the observation arm who developed recur-
of SCCUPs are attributable to HPV53,54. Historically, rent disease in the neck underwent salvage therapy with
if physical examination, fibre-​optic examination and therapeutic neck dissection63. At 3 years of follow-​up,
imaging were non-​revealing, patients underwent patients treated with END had a 12.5% improvement
examination under anaesthesia involving biopsy of the in OS compared with those in the observation group63.
nasopharynx, BOT, and pyriform sinus and palatine ton- Subgroup analysis showed that the improvement in
sillectomy55. This approach enabled the identification of OS was restricted to patients with a depth of tumour
a primary tumour in 24–39% of patients but many BOT invasion of >3 mm. Importantly, patients in the END
cancers were not detected54. Before examination under group were more likely to receive adjuvant radiotherapy
anaesthesia, tissue specimens should be tested for HPV than those in the observation group (48.6% versus 34%).
(either with p16 immunohistochemistry and/or PCR-​ The relative therapeutic contribution of END versus
based HPV testing) to provide an indication of the pri- adjuvant radiotherapy to survival was not explored in
mary site56. In single-​institution and multi-​institution this study. Nevertheless, a small prospective study of
retrospective studies, transoral surgery to excise lingual single-​modality elective neck treatment with radio-
tonsillar tissue in the BOT led to a twofold-​to-threefold therapy for patients with OCSCC demonstrated a high
improvement in the rates of detection of SCCUP to locoregional recurrence rate (23%), suggesting that adju-
72–89%57–61. Nevertheless, the addition of lingual ton- vant radiotherapy alone does not lead to a substantial
sillectomy increases the risk of acute morbidities and OS benefit64. Overall, these results provide important
can impair swallowing, and thus requires prospective level 1 evidence supporting END as the standard-​
evaluation. of-care approach in patients with node-​n egative
OCSCC with a depth of invasion of >3 mm.
Regional metastatic disease D’Cruz et al.63 did not evaluate alternative methods
Over the past 30 years, radical neck dissection has largely for the pathology-​based assessment of regional meta­
been supplanted by selective dissection as a therapeu- static disease, such as sentinel lymph node biopsy
tic procedure to eradicate lymph node metastases in (SLNB). While END is a safe operation, even the mor-
both the elective and the therapeutic settings; the latter bidities associated with selective neck dissections might
approach spares critical non-​lymphatic structures and be under-​appreciated65,66. In the upper aerodigestive

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tract, SLNB has primarily been evaluated in patients
with OCSCC who had primary tumours that were eas-
ily accessible with radiotracer injections. Prospective,
single-​arm trials have found SLNB to be highly effec-
tive for stage I/II OCSCC67–69, and a meta-​analysis
has shown that the sensitivity and negative predictive
value of this approach are 95% and 96%, respectively70.
Unfortunately, no direct randomized comparison of
END versus SLNB for OCSCC has fully examined the
risks and benefits of these approaches, although one
such study is currently under development by the NRG
Oncology group. A rando­mized controlled trial of neck
dissections based on sentinel lymph node navigation
versus standard selective neck dissections in N0 oral
cancers conducted by a Japanese group has completed
accrual, but the results are not yet available.
Assessment after chemoradiotherapy
Evidence from retrospective studies suggests that
patients with a complete response to definitive chemo-
radiotherapy detected on post-​t reatment PET–CT
imaging might be able to avoid post-​treatment neck
dissection, but no prospective data are available. In a
phase III non-​inferiority trial, 564 patients with HNSCC
of an advanced nodal stage were randomly assigned to
receive definitive chemoradiotherapy followed by either
END within 4–8 weeks or PET–CT at 12 weeks71. In the
PET–CT group, only patients with an incomplete or
equivocal response on imaging underwent neck dissec-
tion. Following definitive chemoradiotherapy, patients
in the PET–CT group had non-​inferior 2-year OS com-
pared with those in the END group (84.9% versus 81.5%;
P = 0.004)71. In addition, patients in the PET–CT group
underwent fewer surgical procedures (19.1% versus
78.4%) and, correspondingly, had fewer surgical compli-
cations (7.8% versus 29.4%), with a lower cost (savings of
US$2,190). Two important caveats merit emphasis. First,
the proportion of patients with N3 disease (>6 cm in any
dimension) included in this study was <4%; therefore,
the results cannot be extrapolated to this disease setting.
Second, 85% of patients enrolled had OPSCC, and the
majority of those patients had HPV+ disease; therefore,
these results should be interpreted cautiously when
considering patients with HPV− disease. Nonetheless,
these results indicate that END after definitive chemo-
radiotherapy can be avoided in the majority of patients.
The American College of Radiology Imaging Network
(ACRIN) 6685 trial assessed the accuracy of PET–CT in
the preoperative management of N0 neck disease72. This
trial demonstrated a 92.2% negative predictive value of
PET–CT for each side of the neck and also indicated a
role of PET–CT in preoperative nodal staging, with an
improved negative predictive value of 94.2% demon-
strated by setting the threshold standardized uptake
value intensity to 1.8 (ref.73).
Radiotherapy
Altered fractionation
Conventional fractionated radiotherapy for patients with
HNSCC involves the use of 2 Gy fractions delivered once
daily to a total dose of 70 Gy. A major focus of investiga-
tion has been to determine whether altered fractionation
schedules can enhance efficacy. Altered fractionation
includes hyperfractionation, in which the total radi-
ation dose is increased by administering twice-​daily
fractions while keeping the overall treatment duration
the same at ~7 weeks, and accelerated fractionation, in
which the total dose is unchanged but delivered over a
shorter duration (for example, 5–6 weeks). The updated
MARCH meta-​analysis74 of data from 34 trials testing
altered fractionation schedules in HNSCC showed an
improvement in 5-year OS favouring altered fraction-
ation over conventional fractionation without chemo-
therapy74. The OS benefit was restricted primarily to
hyperfractionation, with a 5-year absolute OS benefit
of 8.1%, according to data from 8 trials involving 1,733
patients74. In a separate analysis of data from 5 trials
including 986 patients comparing conventional radio-
therapy fractionation plus concomitant chemotherapy
versus altered fractionation alone, the latter was associ-
ated with inferior outcomes74. Of note, these five trials
primarily tested accelerated fractionation (shortening
the radiation course by 1–2 weeks), which has not been
shown to increase OS compared with conventional frac-
tionation74. Unfortunately, hyperfractionation has never
been tested in comparison with or as a component of
chemoradiotherapy and thus its efficacy and safety com-
pared with chemoradiotherapy are unclear. Moreover,
hyperfractionation schedules using intensity-​modulated
radiotherapy (IMRT) techniques are time-​consuming,
both in terms of institutional resources and for patients,
and have not been widely adopted.
Intensity-​modulated radiotherapy
Technological advances focusing on more precise delin-
eation of targets and more accurate delivery of radio-
therapy that enables sparing of non-​malignant tissues
can reduce the morbidity of treatment. IMRT enables
the delivery of high doses per fraction of radiation
to the tumour while constraining the dose delivered to
adjacent tissues. Several randomized trials, includ-
ing the PARSPORT trial75, have revealed a lower inci-
dence of xerostomia with IMRT than with conventional
radiotherapy75–77. In addition, a large randomized trial
conducted in China73 demonstrated an OS benefit
and reduced toxicities with IMRT versus conven-
tional radiotherapy78. Owing to these improvements
and other quality of life (QOL) benefits, IMRT has
become a routine modality in the treatment of patients
with HNSCC79.
Adaptive radiotherapy
Radiotherapy treatment plans are traditionally designed
using a single pretreatment time point that does not take
into account anatomical changes during the course of
treatment. During treatment, tumour and nodal vol-
umes might contract by up to 3% per day80. Adaptive
radiotherapy is designed to alter treatment on the basis
of such changes in tumour and non-​malignant tissues
during the course of treatment. A prospective trial
involving 22 patients with OPSCC who received adap-
tive radiotherapy showed improved dosimetry but no
differences in locoregional control (lack of disease recur-
rence at the primary site or regional lymph nodes)81.
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While an appealing possibility for further investiga- High-​dose versus low-​dose cisplatin. Low-​dose weekly
tions, adaptive radiotherapy is not currently used on a cisplatin offers several advantages over high-​dose cis-
routine basis. platin, including ease of administration and reduced
toxicity90. Despite widespread use, this regimen has only
Proton beam therapy been evaluated previously in small-​cohort prospective
IMRT delivered using a photon beam can result in a trials88,91. Quon et al.92 investigated the safety and effi-
large volume of low-​dose radiation becoming deposi­ cacy of the addition of 20 mg/m2 weekly cisplatin to
ted in non-​malignant tissues located along the beam radiotherapy. This trial is important because it showed
path. Protons behave differently to photons, releasing that low-​dose radiosensitizers do not have a role in the
the greatest amount of energy at a defined depth, thus treatment of unresectable HNSCC. Between 1982 and
enabling reductions in the dose delivered to adjacent 1987, 308 eligible patients were accrued to this study,
non-​malignant tissues. Advances in the technology of which had a median follow-​up duration of 62 months.
proton beam delivery and planning during the past few Median failure-​f ree survival was 6.5 months and
years might enable further sparing of radiation to non-​ 7.2 months in the radiotherapy and radiotherapy plus
malignant tissue. Currently available proton beam treat- cisplatin groups, respectively (P = 0.30), and median
ments can use a combination of different beam angles OS was 13.3 months and 11.8 months, respectively
and/or intensity modulation similar to that used in pho- (P = 0.81). The incidence of expected acute toxicities
ton therapy, known as intensity-​modulated proton beam was significantly higher with the addition of cispla-
therapy (IMPT). Multiple comparative studies of treat- tin (for example, the incidences of grade 3–4 acute
ment planning approaches have shown that protons pro- haematological toxicities were 4% with radiotherapy
duce dose distributions that would deliver less radiation and 11% with radiotherapy plus cisplatin; P < 0.001).
to structures that are important for salivary function and Oesophageal and laryngeal late toxicities were more
swallowing (reviewed previously82). This observation has frequent in the radiotherapy plus cisplatin group (9%
resulted in widespread enthusiasm for proton therapy; versus 3%, P = 0.03; and 11% versus 4%, respectively,
however, evidence of the comparative effectiveness of P = 0.05). The results of this trial demonstrate that
IMPT versus standard IMRT is limited. With IMRT, the inadequate radiation sensitization with low-​dose plati-
incidence of chronic severe dysphagia in treated patients, nating agents can worsen toxicities without improving
including those with OPSCC, remains low (7–8% feed- survival; indeed, OS was shorter on a numerical basis
ing tube dependency 1 year after IMRT versus 2% with in those receiving low-​dose cisplatin, but this difference
IMPT)83,84. Some investigators have hypothesized that was not statistically significant.
this result is related to the dose delivered to the constric- Noronha et al.93, in a single-​centre randomized trial,
tor muscles and the oral cavity81,85,86. Therefore, a large compared low-​dose weekly cisplatin (30 mg/m2) and
multi-​institutional randomized phase II/III trial designed high-​dose cisplatin (100 mg/m2) every 3 weeks both
to determine whether IMPT is superior to IMRT concurrently with radiotherapy in 300 patients with
(NCT01893307) in decreasing late severe toxicities, and stage III/IV HNSCC. The primary end point of the
thus improving the QOL of survivors, is currently ongo- trial was non-​inferior locoregional control at 2 years
ing. These lines of investigation are important for the in a population of patients with OCSCC who predo­
integration of proton therapy into treatment algorithms. minantly received postoperative chemoradiotherapy
(93%). High-​dose cisplatin every 3 weeks resulted in a
Systemic therapy superior 2-year locoregional control rate (15% improve-
Cytotoxic chemotherapy ment; P = 0.014), although OS was not significantly
Over the past three decades, considerable effort has worse93. The doses used in the weekly cisplatin arm,
been devoted to understanding the benefit of adding however, might not have been adequate, as a retrospec-
systemic therapy to radiotherapy in the curative setting tive study88 comparing the efficacy of weekly 40 mg/m2
in patients with HNSCC. Cytotoxic chemotherapy can cisplatin and 100 mg/m2 cisplatin every 3 weeks demon-
be employed as induction, concurrently with definitive strated equivalent OS and locoregional control rates for
radiotherapy, or combined with adjuvant radiotherapy. the two regimens and fewer incidences of neutropenia,
A meta-​analysis of data from 93 randomized trials of nephrotoxicity and ototoxicity with low-​dose cisplatin
chemoradiotherapy81 identified a 6.5% absolute 5-year (unspecified grade of toxicities)94. Furthermore, the
OS benefit for concurrent chemoradiotherapy versus question as to whether the cumulative or peak dose
radiotherapy87. In this analysis, concurrent cisplatin is the more important variable remains to be defini-
monotherapy provided the same magnitude of benefit tively answered. In the RTOG 0129 trial, the efficacy
as combination chemoradiotherapy87,88. As a radiosen- of two doses of 100 mg/m2 cisplatin (cumulative dose of
sitizer, high-​dose cisplatin (100 mg/m2) administered 200 mg/m2) during accelerated radiotherapy was com-
every 3 weeks on days 1, 22 and 43 concurrently with pared with that of three doses of 100 mg/m2 cisplatin
conventionally fractionated radiotherapy over 7 weeks in (cumulative dose of 300 mg/m2) with conventional
the definitive setting, or on days 1 and 22 for accelerated fractionation. No significant difference was detected,
fractionation radiotherapy or as adjuvant radiotherapy albeit 30% of patients in the standard-​of-care arm did
over 6 weeks89, remains the gold standard. Nevertheless, not receive a third dose of cisplatin89. Higher dosing
the adverse effects of high-​dose cisplatin are substan- (40–50 mg/m2 per week) might improve the efficacy of
tial, thus fuelling the search for better-​tolerated dosing weekly cisplatin and is being investigated in an ongoing
schedules or agents. study90,95,96.

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Induction chemotherapy. Induction chemotherapy
followed by radiotherapy alone has been extensively
investigated in patients with locoregionally advanced
HNSCC. Meta-​analyses of data from randomized
trials of intensive chemotherapy81,91 have identified
a non-​s ignificant 2.2% OS benefit with induction
chemotherapy before radiotherapy compared with
radiotherapy alone87,97. Randomized trials have since
established that the combination of docetaxel, cisplatin
and 5-fluorouracil is a more active regimen than cispla-
tin and 5-fluorouracil; however, no level 1 evidence is
available to support the routine use of either regimen as
induction therapy98,99. Three phase III trials in patients
with locoregionally advanced disease compared the
addition of taxane-​containing induction chemotherapy
to cetuximab plus radiotherapy or to cisplatin plus radio­
therapy on the effect of OS100–102. None of these stud-
ies revealed a significant survival benefit of induction
chemotherapy100–102. These studies were slightly under-
powered because baseline statistical assumptions had
not accounted for the lower event rate associated with
HPV+ disease, and two studies closed early; however,
the results consistently showed a lack of effect on OS,
with HRs of 0.91–1.12. Induction chemotherapy might
have lowered the rate of distant metastases102, although
the morbidity rate increased (the incidence of serious
adverse events increased from 28% to 47%)101. The
utility of induction chemotherapy for chemoselection
in patients with highly locally advanced disease, in which
patients with a >50% response to one cycle of induction
chemotherapy are selected for organ preservation and
patients with a <50% response are selected for surgery,
and its utility to tailor chemotherapy and radiotherapy
regimens remains to be fully explored.
Targeted therapies
Anti- ​ E GFR therapy. EGFR is overexpressed in up
to 90% of HNSCCs; high levels of this protein are
correlated with decreased survival103,104. Cetuximab
is a chimeric IgG1 monoclonal antibody that com-
petitively inhibits ligand binding to EGFR, fostering
EGFR internalization and altering EGFR-​dependent
signalling. Cetuximab also mediates antigen-​specific
immune responses, leading to cell death105. Cetuximab
is approved by the FDA for the treatment of HNSCC
in multiple settings. Treatment with cetuximab mono­
therapy is associated with a 13% response rate in
patients with recurrent and/or metastatic HSNCC106.
The addition of cetuximab to first-​line chemother-
apy improves response rates, progression-​f ree sur-
vival (PFS) and OS (median OS of 10.1 months versus
7.4 months; P = 0.04) in patients with recurrent and/or
metastatic HNSCC107,108. Finally, in patients with loco­
regionally advanced disease, cetuximab plus radiother-
apy improves OS compared with radiotherapy alone
(49.0 months versus 29.3 months; P = 0.03)109. Impor­
tantly, numerous other anti-​EGFR agents (such as pani-
tumumab, zalutumumab, gefitinib, afatinib or lapatinib)
have failed to demonstrate notable clinical activity in
patients with HNSCC. Whether differences in tumour
penetration, immunological effects or toxicity pro-
files contribute to the apparent differences in efficacy
between cetuximab and these other agents remains to
be determined110–112.
In the curative setting, the addition of anti-​EGFR
agents to chemoradiotherapy has yielded conflict-
ing results. The phase III RTOG 0522 trial106 failed to
demonstrate improved outcomes with the addition of
cetuximab to cisplatin and radiotherapy. Conversely,
an abstract presented in 2018 from a large phase III
trial conducted in India involving 536 patients suggests
that nimotuzumab, which has lower EGFR-​binding
affinity and a more favourable toxicity profile than
cetuximab, improved both PFS and disease-​free sur-
vival (DFS) when added to radiotherapy plus weekly
cisplatin (30 mg/m2)113. The trial did not demonstrate
an improvement in OS and can be criticized for having
a potentially inadequate control arm (weekly cisplatin
with radiotherapy)113. Other combination strategies
involving cetuximab have shown promising results; for
example, the 2-year OS in a randomized phase II study
was higher for patients receiving postoperative chemo-
radiation who were treated with docetaxel plus cetuxi-
mab than for those treated with cisplatin plus cetuximab
(79% versus 69%; P = 0.04)114.
Other targeted agents. Chung et al.115, The Cancer
Genome Atlas Network116 and others109,112,113 have delin-
eated the different genomic subtypes of HNSCC and
provided guidance for the development of targeted
therapies for these cancers115–119. These data confirmed
the widespread prevalence of loss-​of-function muta-
tions in TP53 and CDKN2A in HPV− HNSCCs116 (Fig. 2).
In HPV+ HNSCCs, these groups identified deletions and
point mutations in TRAF3, PIK3CA and E2F1 (ref.116).
Overall, the most promising actionable targets in
HNSCC include proteins involved in the PI3K pathway
and cyclin-​dependent kinases 4/6 (refs120–122), although
the most common genomic alterations affected tumour
suppressor genes, for which targeted therapies have had
little success.
Therapy de-​intensification in HPV+ OPSCC
Given the generally favourable prognosis of patients
with HPV+ OPSCC and the considerable morbidities
associated with current treatments, multiple studies
have investigated whether therapy de-​intensification
could provide similar levels of disease control to
those achieved with conventional therapy, but with
fewer acute and/or chronic toxicities (Table  1). De-​
intensification is probably most appropriate in patients
with HPV+ OPSCC with the lowest risk of disease
recurrence, such as those with a smoking history of
<10 pack-​years and non-​T4 cancer10,123–126. Several strate-
gies are currently used to reduce the toxicity of treatment.
The first possible strategy is reliance on resection alone
in patients with HPV+ T1N0M0 OPSCC. The second
approach involves the omission of cisplatin chemotherapy
from definitive radiotherapy regimens to reduce the
risk of both acute and late effects. This exclusion can be
achieved by omitting systemic therapy (NCT02254278;
ongoing) or by substituting cetuximab for cisplatin
(NCT01302834; completed and published)127 or inhibi-
tors of programmed cell death 1 (PD-1) (NCT02764593;
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 Reviews

HPV– (n = 243) HPV+ (n = 36)

EGFR 15% v 6%
Receptor tyrosine kinases

FGFR1 10% 0%
ERBB2 5% 3%
IGF1R 4% 0%
EPHA2 4% 3%
DDR2 3% 6%
FGFR2 2% 0%
FGFR3 2% 11%
MET 2% 0%
Oncogenes

CCND1 31% 3%
MYC 14% 3%
HRAS 5% 0%

PIK3CA 34% 56%

PI3K

PTEN 12% 6%
PIK3R1 1% 3%

NF1 3% 0%
TSGs

TP53 84% 3%
CDKN2A 58% 0%

Homozygous Protein Protein EGFR vIII MET exon 14 FGFR3–TACC3

Amplification Mutation v
deletion upregulation downregulation deletion skipping fusion

Fig. 2 | Therapeutic targets and potential driver oncogenes in head and neck squamous carcinoma according to
The Cancer genome atlas network. The genes listed reflect somatic alterations and changes in protein expression
identified as reasonable therapeutic targets. The frequency of each genetic alteration is shown next to the gene name
on the far left for human papillomavirus negative (HPV−) and on the far right for HPV+. TSG, tumour supressor gene.
Reproduced from ref.116, Springer Nature Limited.

completed accrual). The third strategy is a mod-
est reduction in the dose and/or field of radiation
(NCT02254278; ongoing), and the fourth is the admin-
istration of systemic therapy followed by a more marked
reduction in radiation dose delivered to tumours shown
to be chemosensitive (NCT01706939; ongoing). Each
approach has merits and drawbacks, and none has been
compared with the others. Emerging biomolecular128
and clinical risk28 categories and patient preferences will
probably lead to tailored de-​intensification, according
to the paradigm most suited to the individual’s risk of
locoregional recurrence, risk of distant metastases, and
predicted sensitivity to radiotherapy, chemotherapy
and/or immunotherapy.
Induction chemotherapy
In the Eastern Cooperative Oncology Group (ECOG)
1308 phase II trial, patients with HPV+ OPSCC received
induction chemotherapy with cisplatin, paclitaxel and
cetuximab, followed by cetuximab plus radiotherapy
with reduced or full-​dose radiation to the primary
site on the basis of response: patients with a complete
response received a dose of 54 Gy, whereas those with-
out a complete response received a standard dose of
69.3 Gy126. As anticipated, 70% of patients achieved
a clinical complete response at the primary site; these
patients had a longer PFS than those who did not have
a complete response and required full-​dose radiation
(Table 2). Substantial lifetime exposure to tobacco and
the presence of T4 cancer portended worse outcomes
with this approach126. Induction chemoselection with
paclitaxel and carboplatin followed by paclitaxel plus
radiotherapy or radiotherapy alone have confirmed that
induction chemotherapy followed by treatment with a
reduced radiation dose for patients with chemosensi-
tive tumours maintains high cure rates, with 2-year PFS
of 92% and 94.5%129,130, and favourable QOL outcomes
compared with historical controls131.
Concurrent chemoradiotherapy
An alternative attempt at de-​intensification involves
the substitution of concurrent cetuximab for cisplatin
in definitive chemoradiotherapy regimens. The results
of the phase III RTOG 1016 trial127 comparing radio-
therapy plus cetuximab with radiotherapy plus cispla-
tin in 849 patients with HPV+ OPSCC were reported
in 2018. At 5 years, locoregional control, PFS and OS
were superior with cisplatin and no significant dif-
ferences were reported in toxicity rates or swallowing
function (Table 2). However, for patients with preserved
performance status, no significant differences in 5-year
OS were observed between the groups (84.6% versus
84.0%)127. The results of the smaller De-​ESCALaTE
HPV trial132 were also reported in 2018, with similar dif-
ferences in locoregional control observed with cisplatin
plus radiotherapy versus cetuximab plus radiotherapy

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Table 1 | Summary of phase ii/iii trials of therapy de-​intensification in human papillomavirus-​driven oropharyngeal squamous cell carcinoma
Study Phase Patients Disease stage Treatment DFS, PFS and/or OS adverse
(n) locoregional events
control rate
Surgical approaches
Ma et al. IIb 80 <10 pack-​years, TORS + adjuvant 30 Gy radiotherapy 2-year DFS: 89% NR 0% grade 3–4 at
(2017)160a resected with (36 Gy for ENE) + docetaxel 2 years
negative margins
Siegel et al. IIb 20 III–IVac Induction chemotherapy (cisplatin, 21-month DFS: NR NR
(2018)161a docetaxel); if >80% response in 85%
primary site, then TORS + ND
Non-​surgical approaches
RTOG 1016 III 849 III–IVac Cisplatin (100 mg/m2 every PFS: 78.4% versus 5-year OS: Acute grade
(ref.127) 3 weeks) + 70 Gy radiotherapy versus 67.3% (P = 0.0002) 84.6% versus 3–4: 82% versus
cetuximab + 70 Gy radiotherapy 77.9% 77% (P = 0.16)
De-​ III 334 III–IVac Cisplatin (100 mg/m2 every 2-year recurrence 2-year No difference
ESCALaTE 3 weeks) + 70 Gy radiotherapy versus rate: 6% versus OS: 97.5% in acute or
HPV132 cetuximab + 70 Gy radiotherapy 16% (P = 0.0007) versus 89.4% late grade 3–5
(P = 0.001) toxicity
ECOG IIb 80 III–IVac Induction chemotherapy (cisplatin, 2-year PFS: 2-year OS: 1-year solid
1308 paclitaxel and cetuximab); if 96% versus 80% 96% versus food dysphagia:
(ref.126) CR in primary site, then 54 Gy (≤54 Gy versus 94% (≤54 Gy 40% versus
radiotherapy + cetuximab; if less >54 Gy) versus >54 Gy) 89%; P = 0.01
than CR in primary site, then 69.3 Gy (≤54 Gy versus
radiotherapy + cetuximab >54 Gy)
Chen et al. IIb 45 III–IVac Induction chemotherapy (2 cycles 2-year PFS: 92% NR Grade 3:
(2017)129 of carboplatin and paclitaxel); if PR 39% and 0%
or CR in primary site then 54 Gy dependency
radiotherapy + paclitaxel; if less on gastrostomy
than PR in primary site, then 60 Gy tube at
radiotherapy + paclitaxel 6 months
Chera et al. IIb 44 T0–3, N0–2c, M0 Cisplatin (30 mg/m2 weekly) + 60 Gy 3-year 95% at 3 years 0% dependency
(2018)133 and ≤10 pack-​years radiotherapy locoregional on gastrostomy
or >10 pack-​years control: 100% tube
and >5 years
smoke-​free
CR , complete response; DFS, disease-​free survival; ENE, clinical extranodal extension; ND, neck dissection; NR , not reported (can include immature data);
OS, overall survival; PFS, progression-​free survival; PR , partial response; TORS, transoral robotic surgery. aIncludes non-​peer-reviewed data from conference
presentations. bSingle-​arm trial. cRefers to NCCN guidelines, 7th edition25.

(Table 2). However, data were available for only 2 years
of follow-​up monitoring and a substantial proportion of
the deaths were not caused by HNSCC, and thus the
efficacy end points were underpowered132. Of note,
the De-​ESCALaTE HPV trial132 included a standard
radiation scheme and three doses of high-​dose cispla-
tin, while the RTOG 1016 trial127 involved the reduced
cumulative cisplatin dose of 200 mg/m2, which had been
validated in the RTOG 0129 trial89 for use with acceler-
ated radiation. These results confirm that cisplatin plus
radiotherapy remains the non-​surgical standard-​of-care
treatment for unselected patients with HPV+ OPSCC.
An alternative trial of de-​intensified standard chemo-
radiotherapy, including definitive radiotherapy alone
compared with chemoradiotherapy and reduction in
the dose of radiotherapy included in the chemoradio-
therapy regimen (NCT02254278), is ongoing. Of note,
several single-​arm trials using reduced-​dose chemo-
radiotherapy have been reported with excellent out-
comes. For example, in a multicentre study involving
44 patients with T0–T3 N0–N2c (defined accord-
ing to ref.25) OPSCC and a minimal smoking history
treated with 60 Gy radiotherapy and weekly cisplatin
(30 mg/m2), the 3-year OS was 95% with excellent QOL
outcomes133.
Transoral surgery
In response to the enthusiasm for transoral surgery
that has emerged, data from several ongoing prospec-
tive trials investigating up-​front surgery followed by
de-​intensified adjuvant therapy should help to clarify
the role of surgery. Early results from an innovative
single-​institution phase II trial129 highlight the potential
of surgical de-​intensification: 80 patients underwent
TORS and neck dissection followed by 30–36 Gy radio-
therapy combined with docetaxel. Patients with clinical
extra­nodal extension (ENE) received a boost to 36 Gy.
At 2 years, DFS was 89% with no grade 3–4 toxicities. This
small-​cohort trial highlights the potential to radically
reduce the toxicity of current treatments.
In the USA, the NCI sponsored the ECOG 3311 trial49,
a large-​cohort phase II trial of de-​intensified adjuvant
therapy after transoral surgery in HPV+ OPSCC. In the
UK, the Postoperative Adjuvant Treatment for HPV-​
positive Tumours (PATHOS) phase II/III trial134 used a
similar design. Both studies investigated the efficacy of

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Table 2 | Summary of data from clinical trials of anti-​PD-1 agents in head and neck squamous carcinoma
Study Phase Eligibility Patients Treatment arms OS ORR grade 3–4
(n) adverse events
First-​line therapy in refractory and/or metastatic disease
KEYNOTE-048 III – 882 Pembrolizumab (200 mg Pembrolizumab versus 17%, 36% 17%, 71%
(ref.150)a every 3 weeks) versus EXTREME: 14.9 months and 36% with and 69% with
pembrolizumab + versus 10.7 months pembrolizumab, pembrolizumab,
cisplatin or carboplatin + (P = 0.0007; patients pembrolizumab pembrolizumab
5-FU versus cetuximab + with CPS of ≥20) and + chemotherapy + chemotherapy
EXTREME 12.3 months versus and EXTREME, and EXTREME,
10.3 months (P = 0.0086; respectively respectively
patients with CPS of (overall
≥1); pembrolizumab + population)
chemotherapy versus
EXTREME: 13.0 months
versus 10.7 months
(P = 0.0034; overall
population)
Monotherapy in platinum-​refractory and/or metastatic disease
CheckMate 141 III – 361 Nivolumab versus 2-year OS: 17% versus 13% versus 6% 15% versus 37%
(refs160,162) investigators’ choice 6%
chemotherapy
KEYNOTE-012 Ibb PD-​L1 expression 60 Pembrolizumab (10 mg/kg Median OS: 8 months 18% 9%
(ref.138) >1% on tumour body weight every
and/or stromal 2 weeks)
cells by immuno-
histochemistry
KEYNOTE-012 Ibb – 132 Pembrolizumab (200 mg 6-month OS: 59% 18% 9%
(expansion every 3 weeks)
cohort)139
KEYNOTE-055 IIb Refractory to 171 Pembrolizumab (200 mg Median OS: 8 months 16% 15%
(ref.141) platinum and every 3 weeks)
cetuximab
KEYNOTE-040 III – 497 Pembrolizumab (200 mg Median OS: 8.4 months 15% versus 10% 13% versus 18%
(ref.142) every 3 weeks) versus versus 6.9 months
investigators’ choice (P = 0.02)
chemotherapy
Segal et al. I/IIb – 62 Durvalumab (10 mg/kg 12-month OS: 62% 11% 7%
(2015)143 body weight every
2 weeks)
HAWK163 IIb – 112 Durvalumab (10 mg/kg Immature data 14% 10%
body weight every
2 weeks)
Combination therapy in platinum-​refractory and/or metastatic disease
CONDOR145 II PD-​L1 expression 267 Durvalumab (20 mg/kg 7.6 months, 6.0 months 8%, 9% and 16%, 12%
<25% on tumour body weight every and 5.5 months 2% with and 17% with
cells by immuno- 4 weeks) + tremelimumab with combination, combination, combination,
histochemistry (1 mg/kg body weight durvalumab and durvalumab and durvalumab and
every 4 weeks) for tremelimumab, tremelimumab, tremelimumab,
four cycles followed respectively respectively respectively
by durvalumab
monotherapy
versus durvalumab
monotherapy versus
tremelimumab
monotherapy
5-FU, 5-fluorouracil; CPS, combined positive score; EXTREME, combination of cetuximab, 5-FU and cisplatin or carboplatin; ORR , overall response rate;
OS, overall survival; PD-1, programmed cell death 1; PD-​L1, programmed cell death 1 ligand 1. aIncludes non-​peer-reviewed data from conference presentation.
b
Single-​arm trial.

transoral surgical resection and neck dissection followed
by pathological risk-​based adjuvant therapy in patients
with resectable HPV+ OPSCC with N0–N2b nodal
status. Patients with low-​risk disease (negative surgi-
cal margins and no adverse pathology) did not receive
adjuvant therapy, those with intermediate-​risk disease
were randomly assigned to 50 Gy versus 60 Gy adjuvant
radiotherapy, and those with high-​risk disease (positive
surgical margins, five or more metastatic lymph nodes,
or >1 mm of ENE (in ECOG 3311) or any ENE (in
PATHOS)) received adjuvant radiotherapy and cispla-
tin (ECOG 3311) or were randomly assigned to adjuvant

Nature Reviews | Clinical Oncology

Reviews
chemoradiotherapy or radiotherapy (PATHOS). ECOG
3311 has completed accrual of 519 patients and
PATHOS has completed phase II accrual and is expected
to progress to phase III134. Furthermore, each trial used
a novel process to ensure consistent standards of sur-
gery and patient safety49,134. The robust accrual outcomes
and the existence of surgical quality assurance mecha-
nisms provide proof of the concept that multicentre
trials can be successfully completed with consistent
surgical standards in the setting of head and neck surg­
ical oncology. Additionally, in Ontario, Canada, the
Oropharynx: Radiotherapy Versus Trans-​Oral Robotic
Surgery (ORATOR) and the follow-​up ORATOR2 trials
are single-​centre randomized trials directly comparing
de-​escalated transoral surgery with de-​intensified adju-
vant therapy versus de-​intensified definitive chemo-
radiotherapy (NCT01590355 and NCT03210103)135.
These trials will provide a definitive comparison of
QOL outcomes of primary transoral surgery with those
of non-​surgical treatment. Unfortunately, these results
might not clearly favour any approach. While inter-​
trial comparisons of standardized QOL measures can
be informative, no data from phase III studies directly
comparing the major treatment paradigms are cur-
rently available. Owing to patient preferences, varia-
tions in the availability of expertise and other factors,
the field needs such comparisons to obtain level 1 evi-
dence for de-​intensification with different modalities, to
enable the better-​informed selection of surgical and/or
non-​surgical reduced-​dose therapies.
Immunotherapy
The most remarkable therapeutic development in
HNSCC over the past 10 years has been the advent of
immunotherapy. This therapeutic modality is based
on the premise that alterations in immune surveil-
lance, in cancer cell phenotype and/or in the tumour
microenviron­ment are required for cancers to evade the
immune system and manifest clinically. Indeed,
the immune system has been recognized to be key to the
development, establishment and spread of HNSCC136,137.
This biological rationale is supported by the results of
large-​cohort clinical trials demonstrating consistent
efficacy of immune checkpoint inhibitors (ICIs).
Anti-​PD-1
In 2016, the FDA approved the first anti-​PD-1 agents
for the treatment of patients with HNSCC in the set-
ting of platinum-​refractory recurrent and/or metastatic
disease. The phase Ib trial KEYNOTE-012 (ref.138) and
the expansion cohort of the same study139 showed dura-
ble responses to pembrolizumab (Table 2), leading to
its accelerated FDA approval. Soon after, nivolumab
was approved in the same setting based on data from
the phase III CheckMate 141 trial140, which showed
improved OS and QOL relative to the investigators’
choice of standard-​of-care systemic therapy (Table 2).
In this randomized trial involving 361 patients, OS at
1 year was 36% in those treated with nivolumab com-
pared with 16.6% in those treated with chemotherapy
(HR 0.70, 95% CI 0.51–0.96)137. The phase Ib results
obtained with pembrolizumab in the KEYNOTE-012
trial136 have been bolstered by evidence from an expan-
sion cohort, the phase II KEYNOTE-055 trial141, and
phase III data from the KEYNOTE-040 trial142. Of note,
in the KEYNOTE-040 trial, 497 patients with platinum-​
refractory and/or metastatic HNSCC were randomly
assigned to receive pembrolizumab or standard-​of-care
systemic therapy. Pembrolizumab resulted in improved
OS (8.4 months versus 6.9 months, HR 0.80; P = 0.016)
and a significantly better toxicity profile142. Importantly,
the data for both nivolumab and pembrolizumab demon-
strate durable survival benefits in a substantial minority
of patients137,138. Furthermore, patients receiving anti-​
PD-1 agents reported fewer treatment-​related adverse
events142, and improved QOL outcomes in domains such
as swallowing, talking, eating and xero­stomia compared
with those receiving standard cytotoxic chemotherapy140.
A phase I/II trial138 showed an objective response rate of
11% for durvalumab, an antibody against programmed
cell death 1 ligand 1 (PD-​L1), in the setting of advanced-​
stage disease, but this ICI has not yet been approved for
use in patients with HNSCC143.
Biomarkers and immunotherapy
Clinical response to immunomodulatory agents might
be considerably improved with combination ther-
apy in appropriately selected patients based on data
from other malignancies144, although the experience
with combinational therapy in HNSCC remains nas-
cent145. Biomarkers might also enable the prediction
of the principal immune phenotype (immune-​desert,
immune-​excluded or inflamed) for each patient146.
The immune-​desert phenotype is characterized by a
total absence of an immune response; in the immune-​
excluded phenotype, immune cells are unable to pene­-
trate into the tumour microenvironment; and the
inflamed phenotype is characterized by an active
immune response within the tumour, but with the pres-
ence of inhibitory factors that prevent a fully effective
antitumour immune response. High levels of PD-​L1
expression, typically only seen in the inflamed pheno­
type, are associated with an increased likelihood of
response to anti-​PD-1 therapy. As noted, PD-​L1 is likely
to be adopted as a predictive biomarker for the selection
of patients with HNSCC for immunotherapy137.
PD-​L1 is expressed on 50–60% of HNSCCs147 and
is a key component of mechanisms of evasion of anti­
tumour immunity in HNSCC148. Data suggest that PD-1+
regulatory T cells infiltrate HPV+ HNSCCs more com-
monly than HPV− HNSCCs149. The PD-​L1 positivity of a
tumour can be measured with various scoring methods.
The tumour proportion score is a measure of the per-
centage of PD-​L1-stained tumour cells142. The combined
positive score (CPS) is a measure of the ratio of PD-​L1+
tumour and immune cells to the total number of tumour
cells counted; the CPS has been shown to predict clinical
outcomes150.
The importance of biomarker selection has been
shown in subgroup analyses from several trials. The
survival benefit derived from anti-​PD-1 therapy is
largely restricted to patients with ≥1% intratumoural
PD-​L1 expression137,139: in the CheckMate 141 trial140, the
median OS was 8.7 months with nivolumab treatment
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 Reviews

Paclitaxel inhibits
microtubule disaggregation
HNSCC
tumour cell
HNSCC tumour cell Pembrolizumab
overexpressing EGFR and nivolumab PD-1 MHC class I
block PD-1 and Antigen
Cetuximab PD-L1 interaction TCR
EGFR PD-L1 CTLA-4
Cisplatin inhibits B7
DNA replication and CD8+
mRNA transcription T cell

Ipilimumab DC
Cetuximab and EXTREME regimen
radiotherapy approved da Vinci robotic (cetuximab, 5-FU Pembrolizumab Data presented
in LRA HNSCC and as system approved for and cisplatin or and nivolumab showing superiority
monotherapy in transoral resection carboplatin) are approved in of pembrolizumab
platinum-refractory of oropharyngeal approved for first- platinum-refractory in first-line R/M
R/M HNSCC cancer line R/M HNSCC R/M HNSCC HNSCC

2006 2009 2011 2016 2018

Fig. 3 | Timeline showing the main therapeutic advances for patients with head and neck squamous carcinoma.
Cetuximab was the first major drug approved by the FDA for use in patients with head and neck squamous cell carcinoma
(HNSCC) since the approval of cisplatin in 1978. Cetuximab was approved in 2006 for use in patients with recurrent and/or
metastatic (R/M) HNSCC and as a radiosensitizer in patients with locally advanced HNSCC. In 2011, the EXTREME
regimen was also approved for use in patients with R/M HNSCC. The FDA had approved the da Vinci robotic system for
the resection of T1–T2 oropharyngeal cancer 2 years earlier. In 2016, both nivolumab and pembrolizumab were approved
by the FDA for use in patients with platinum-​refractory R/M HNSCC. In 2018, data were presented showing the superiority
of pembrolizumab over cisplatin as a first-​line treatment for R/M HNSCC; the FDA is currently reviewing these data. 5-FU,
5-fluorouracil; CTL A-4, cytotoxic T lymphocyte antigen 4; DC, dendritic cell; LRA , locoregionally advanced; PD-1,
programmed cell death 1; PD-​L1, programmed cell death 1 ligand 1; TCR , T cell receptor.

and 4.6 months with chemotherapy in the subgroup with
≥1% intratumoural PD-​L1 expression but 5.7 months in
the subgroup with <1% intratumoural PD-​L1 expression,
regardless of treatment.
Anti-​PD-1 therapy may soon be approved as a first-​
line therapy in patients with recurrent and/or metastatic
HNSCC. The KEYNOTE-048 trial (NCT02358031)150, a
phase III randomized trial involving 825 patients, com-
pared the efficacy of pembrolizumab monotherapy or of
a novel combination of pembrolizumab, 5-fluorouracil
and cisplatin or carboplatin versus the EXTREME regi-
men (cetuximab, 5-fluorouracil and cisplatin or carbo­
platin) in the first-​line setting for recurrent and/or
metastatic HNSCC. Interim data presented in 2018
(ref.146) indicate that pembrolizumab monotherapy signi­
ficantly improved OS compared with the EXTREME reg-
imen in patients with a PD-​L1 CPS of ≥20 or CPS of >1,
and the addition of pembrolizumab to chemotherapy
significantly improved OS over the EXTREME regimen
in unselected patients150 (Table 2).
In other solid tumours, tumour mutational load
has been strongly associated with a response to ICIs151.
HNSCCs have a moderate-​to-high mutational load
(the ninth-​highest average mutational load among 30
different tumour types studied)152 and harbour other
genomic alterations (such as frameshifts)116 that might
also be associated with response to ICIs, although this
hypothesis has not been directly tested. HPV status
is another potential biomarker, with data from the
CheckMate 141 trial133 indicating that HPV+ HNSCCs
are more likely to respond to anti-​P D-1 therapy
than HPV− HNSCCs (HR for death of 0.56 and 0.73,
respectively). New strategies to trigger an antitumour
immune response in patients with immune-​excluded
phenotypes are needed.
Combination with radiotherapy
ICIs are rapidly being investigated in trials in the cura-
tive setting, and in various combinations with other
treatment modalities. Radiotherapy has complex effects
on malignant and non-​malignant tissues and might both
enhance and suppress an antitumour immune response.
Under certain conditions, radiotherapy might amplify
the effect of immunotherapy by promoting the release
of cytokines and tumour-​associated antigens. In the
PACIFIC trial, durvalumab after definitive chemoradio-
therapy in patients with stage III non-​small-cell lung car-
cinoma improved 2-year OS compared with definitive
chemoradiotherapy alone (66.3% versus 55.6%; HR 0.68,
CI 0.47–0.99)153. Multiple phase I/II trials in the setting
of locoregionally advanced HNSCC are investigating a
similar strategy, adding anti-​PD-1 antibodies to defini-
tive chemoradiotherapy (NCT02252042, NCT02586207,
NCT02819752, NCT02707588 and NCT02289209).
The published data currently available on the poten-
tial abscopal effect derived from the combination of
immunotherapy and radiotherapy in HNSCC are lim-
ited and emphasize the complex interactions between
radiotherapy and the immune system. In a randomized
phase II study presented at the 2018 ASCO Annual
Meeting154 in the setting of refractory and/or metastatic
HNSCC, the addition of stereotactic body radiotherapy
to nivolumab failed to improve survival compared
with nivolumab alone.

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Combination immunotherapy Other approaches, involving HPV peptide vaccines or

Unfortunately, the majority of patients with HNSCC
do not respond to single-​agent anti-​PD-1 therapy. In
an effort to improve response rates, ongoing trials are
evaluating combinations involving ICIs, therapeutic
vaccines, co-​stimulatory agonists and cytotoxic agents.
Combinations of anti-​cytotoxic T lymphocyte antigen 4
(CTLA-4) and anti-​PD-1 agents have a synergistic
effect in patients with melanoma144 and are being tested
in phase III studies involving patients with HNSCC
(NCT02551159 and NCT027451570). In the phase II
CONDOR study, in which the anti-​CTLA-4 antibody
tremelimumab plus the anti-​PD-L1 antibody dur-
valumab was investigated in patients with refractory
and/or metastatic HNSCC and low or no (<25%) PD-​
L1 tumour cell expression, overall response rates of 8%
and 9% were observed with the combination and dur-
valumab, respectively; a follow-​up phase III trial has
completed accrual (NCT02369874)145.
Multiple therapeutic vaccines are also under inves-
tigation in phase I/II trials involving patients with
HNSCC. In a phase I study involving 16 patients, an
adjuvant peptide-​loaded dendritic cell-​based vaccine
against p53 was well tolerated and the 2-year DFS was
88%155. Another vaccine strategy involves talimogene
laherparepvec, an oncolytic herpes simplex virus 1
vaccine that promotes the release of granulocyte–
macrophage colony-​stimulating factor that was FDA-​
approved for use in patients with recurrent melanoma
in 2015. In a phase I/II study in the setting of loco­
regionally advanced HNSCC, treatment with talimo-
gene laherparepvec in combination with cisplatin and
radio­therapy resulted in an OS of 70.5% at 29 months156.
A phase II study of a combination of nivolumab and
a synthetic long-​p eptide HPV-16 vaccine showed
promising results with an overall response rate of
33% and a median OS of 17.5 months, both of which
are higher than historically observed with anti-​PD-1
therapy alone157.
co-​stimulatory agonists (such as Toll-​like receptor, OX40,
CD40L or CD137), are also being tested (NCT03906526,
NCT02315066 and NCT03792724) 158 . In the
Active8 study, 195 patients were randomly assigned (1:1)
to receive the EXTREME regimen with or without the
Toll-​like receptor 8 agonist motolimod159. No signi­ficant
benefit was derived from motolimod, but, in a prespeci­
fied subgroup analysis, the addition of motolimod
improved PFS (7.8 months versus 5.9 months; P = 0.046)
and OS (15.2 months versus 12.6 months; P = 0.03) in
patients with HPV+ HNSCC159.
Conclusions
The diversity of the therapeutic advances in HNSCC dis-
cussed in this Review is remarkable. These modalities
illustrate important principles that have the potential to
dramatically alter treatment paradigms, improving both
the oncological and functional outcomes of patients with
HNSCC (Fig. 3). Technological advances in surgery and
radiotherapy have provided patients with multiple treat-
ment options and have progressively decreased the risks
of morbidity that were previously associated with these
therapeutic modalities. De-​intensification of treatment
for patients with a favourable prognosis might also have
a major effect on QOL after treatment. Furthermore,
the advent of immunotherapy offers the potential for
long-​term remissions in the setting of refractory and/or
metastatic disease, for which a limited number of treat-
ment options was previously available. In the near future,
immunotherapy might be used to enhance the efficacy
of conventional treatments in the curative setting. To be
fully realized, these advances require continued, careful
evaluation. However, for the first time in decades, the
culmination of these technological advances offers
the prospect of positively affecting the outcomes of
patients with HNSCC.
Published online xx xx xxxx

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Acknowledgements
The work of R.L.F. was supported by the US NIH grant P50
CA097190 and the University of Pittsburgh Cancer Center
support grant P30CA047904.
Author contributions
All authors made a substantial contribution to all aspects of
the preparation of the manuscript.
Reviews
Competing interests
B.B. has received compensation for consulting from Aduro,
Alligator Biosciences, AstraZeneca, Bayer, Boehringer
Ingelheim, Bristol-​Myers Squibb, Celgene, DebioPharma,
Genentech–Roche, Merck and TRM Oncology, has been a
non-​paid consultant of Adlai Norte and Celldex, has received
compensation for serving on data safety monitoring commit-
tees for IDDI (AstraZeneca–Medimmune) and VentiRx, and
for medical education activities from CCO, Chemo Advisor,
PER, Peerview, Practice Update, Prime Oncology and
OncLive, and has received travel support from Boehringer
Ingelheim and Merck. Q.T.L. has received travel support for
serving on the advisory board of Bristol-​Myers Squibb, serves
as a non-​paid consultant of Merck, and serves on the data
safety monitoring committee for a clinical trial sponsored by
Pfizer. R.L.F. has received compensation for consulting and/
or advisory board membership from AstraZeneca–
Medimmune, Bristol-​M yers Squibb, Merck, PER, Pfizer,
Regeneron, Tesaro and TTMS Therapeutics. Through con-
tracts with the UPMC Hillman Cancer Center, his laboratory
has also been funded to perform sponsored research by
AstraZeneca–Medimmune, Bristol-​Myers Squibb and Tesaro.
J.D.C. declares no competing interests.
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Reviewer information
Nature Reviews Clinical Oncology thanks A. Eisbruch and the
other anonymous reviewer(s), for their contribution to the
peer review of this work.
Related links
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