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Advances in Diagnosis and Multi-
disciplinary Management of Oro-
pharyngeal Squamous Cell Carci-
noma: State of the Art
Upendra Parvathaneni, MB, BS,
 FRANZCR
Pierre Lavertu, MD, FRCS(C)
Michael K. Gibson, MD, PhD
Christine M. Glastonbury, MB, BS
Abbreviations: CRT = chemoradiation ther-
apy, ENE = extranodal extension, HPV = hu-
man papillomavirus, IMRT = intensity-modu-
lated RT, OPSCC = oropharyngeal squamous
cell carcinoma, PEG = percutaneous endoscopic
gastrostomy, RT = radiation therapy
RadioGraphics 2019; 39:0000–0000
https://doi.org/10.1148/rg.2019190007
Content Codes:
From the Department of Radiation Oncology,
University of Washington, 1959 NE Pacific Ave,
Seattle, WA 98195-6043 (U.P.); Ear Nose and
Throat Institute, University Hospitals Seid­
Cancer Center, Case Western Reserve University,
Cleveland, Ohio (P.L.); Department of Medi-
cine, Vanderbilt-Ingram Cancer Center, Vander-
bilt University Medical Center, Nashville, Tenn
(M.K.G.); and Department of Radiology, Univer-
sity of California, San Francisco, San Francisco,
Calif (C.M.G.). Received January 20, 2019; revi-
sion requested April 17 and received May 12; ac-
cepted May 24. For this journal-based SA-CME
activity, the author M.K.G. has provided disclo-
sures (see end of article); all other authors, the edi-
tor, and the reviewers have disclosed no relevant
relationships. Address correspondence to U.P.
(e-mail: upendra@uw.edu).
© RSNA, 2019 • radiographics.rsna.org
RSNA, 2019
SA-CME Learning Objectives
After completing this journal-based SA-CME
activity, participants will be able to:
■■Discuss the differences between
HPV-related OPSCC and the historical
tobacco-related type and the significance
of these differences.
■■Listthe recent changes in the staging
system in response to the prognostic dif-
ferences between HPV-related p16-posi-
tive OPSCC and the p16-negative type.
■■Describe multidisciplinary manage-
ment of OPSCC including surgery, RT,
and systemic therapy along with strate-
gies for treatment de-intensification.
See rsna.org/learning-center-rg.
1
Neurologic/Head and Neck Imaging
During the past decade and a half, the most common cause of oro-
pharyngeal squamous cell carcinoma (OPSCC) has shifted from
tobacco and alcohol to the human papillomavirus (HPV). HPV-
driven p16-positive OPSCC and tobacco-related OPSCC differ in
their underlying molecular and genetic profiles, socioeconomic de-
mographics, and response to treatment. HPV-related OPSCC tends
to occur in younger patients and has a significantly better response
to treatment and excellent prognosis. The stark contrast in prog-
nosis—with around 90% overall 5-year survival for HPV-related
p16-positive OPSCC and 40% for non–HPV-related p16-negative
OPSCC—has prompted major changes in the eighth edition of
the staging manual of the AJCC (American Joint Committee on
Cancer). The past 10–15 years have also witnessed major advances
in surgery, radiation therapy (RT), and systemic therapy. Minimally
invasive surgery has come of age, with transoral robotic proce-
dures and laser microsurgery. Intensity-modulated RT (IMRT)
man
and more recently proton-beam RT have markedly improved the
conformity of RT, with an ability to precisely target the cancer and
cancer-bearing regions while sparing normal structures and signifi-
cantly reducing long-term treatment-related morbidity. Progress
in systemic therapy has come in the form of immunotherapy and
targeted agents such as cetuximab. Owing to the better prognosis
of HPV-driven OPSCC as well as the morbidity associated with
treatment, de-escalation of therapy via multiple strategies is being
explored. The article reviews the advances in diagnosis and multi-
disciplinary management of OPSCC in the HPV era.
©
Introduction
Oropharyngeal squamous cell carcinoma (OPSCC) is the most
common head and neck cancer diagnosed in the Western world (1).
Historically, tobacco and alcohol were the leading causes of OP-
SCC; however, in the past decade and a half, the oncogenic human
papillomavirus (HPV) has emerged as a recognized causative agent
(2). Moreover, with a decrease in the incidence of tobacco use and
tobacco-related OPSCC, there has been a concurrent increase in
the incidence of HPV-driven OPSCC, almost to epidemic propor-
tions (3).
HPV-driven OPSCC and tobacco-related OPSCC differ in the
underlying molecular and genetic profiles, socioeconomic demo-
graphics, and response to treatment. HPV-related OPSCC tends
to occur in younger patients and has a significantly better response
2 November-December 2019 radiographics.rsna.org
Teaching Points
■■ Despite the presence of multiple metastatic nodes, the prog-
nosis is not as poor for these HPV-related p16-positive tumors,
resulting in reevaluation of the nodal tables and a substantially
altered table for these tumors that now more closely resem-
bles that of nasopharyngeal carcinoma.
■■ The prognosis of smoking-related OPSCC is significantly
worse than that of the HPV-driven type. Nonsmokers (≤10
pack-years of smoking) with HPV-positive OPSCC have the
best prognosis with 3-year overall survival of 93%, while
smokers (>10 pack-years of smoking) with HPV-negative
OPSCC have 3-year survival of 46.2%.
■■ The most common source of a metastatic cervical lymph
node in level II is a p16-positive squamous cell carcinoma
arising from the tonsil-like tissue of the palatine and lingual
tonsils. These are respectively what we call the tonsils and the
base of the tongue.
■■ Addition of platinum-based chemotherapy to RT in resected
tumors with ENE and/or positive resection margins has been
shown to improve disease control and survival in randomized
controlled studies.
■■ Given both the validation of p16 status as a marker of better
overall survival in OPSCC and the availability of a proven ra-
diosensitizer (cetuximab) with less toxicity than cisplatin, NRG
Oncology Protocol RTOG 1016 was initiated. This was a ran-
domized, two-arm, phase III, noninferiority study that com-
pared RT (accelerated IMRT) plus cisplatin (100 mg/m2 days 1
and 22) with RT (accelerated IMRT) plus cetuximab (400 mg/
m2 load then 250 mg/m2 weekly) for treatment of locally ad-
vanced p16-positive OPSCC. A similarly designed study was
simultaneously completed in Europe. Perhaps surprisingly
and certainly disappointingly, both of these studies revealed
that RT plus cetuximab was inferior, and cisplatin (with RT)
remains the standard of care in this setting of locally advanced
HPV-related p16-positive OPSCC.
to treatment and excellent prognosis (4) (Table
1). It is most often caused by HPV subtype 16,
which is the same sexually transmitted viral sub-
type responsible for cervical and many anogenital
malignancies. Two HPV oncoproteins—E6 and
E7—degrade p53 tumor suppressor protein and
retinoblastoma protein pRB and interfere with
DNA repair and apoptosis. To restore cell cycle
control, there is upregulation of cyclin-dependent
kinase inhibitor p16, which can be detected in
HPV-related tumors with immunohistochemistry.
Non–HPV-driven tobacco-related OPSCC
typically has TP53 mutations, does not have up-
regulation of p16, and has a significantly poorer
prognosis than HPV-related p16-positive OPSCC
(4). The stark contrast in prognosis—with around
90% overall 5-year survival for HPV-related
p16-positive OPSCC versus 40% for non–HPV-
related p16-negative OPSCC—has prompted
major changes in the eighth edition of the staging
manual of the AJCC (American Joint Committee
on Cancer) (5). This article explains the changes
to staging and illustrates how accurate imaging
evaluation helps tumor management.
The past 10–15 years have also witnessed major
advances in surgery, radiation therapy (RT), and
systemic therapy. Minimally invasive surgery has
come of age, with transoral robotic procedures
and laser microsurgery (6). Intensity-modulated
RT (IMRT) and more recently proton-beam RT
have made RT a highly conformal and precise
treatment tool, with opportunities to spare salivary
glands and swallowing structures (7). Immuno-
therapy and other targeted therapies such as ce-
tuximab have been added to the armamentarium
of systemic therapy. Owing to the better prognosis
of HPV-driven OPSCC as well as the morbidity
associated with treatment, de-escalation of therapy
via multiple strategies is being explored (8–12).
This article reviews the current management of
OPSCC in the HPV era.
Imaging and Staging of
Oropharyngeal Cancers
With the new eighth edition AJCC-UICC (Union
for International Cancer Control) manual,
OPSCC staging requires knowledge of p16 and/
or HPV status, since HPV-related and non–HPV-
related tumor types have vastly different nodal
criteria and prognostic stage groupings (5). The
tumor designation (T) tables are nearly identical;
however, for HPV-related p16-positive OPSCC,
since there is no difference in prognosis for T4a
and T4b tumors, these are combined to be T4.
The T criteria for non–HPV-related p16-negative
OPSCC are unchanged from the seventh edition
(Tables 2, 3).
The most significant changes are to the nodal
designation (N) and criteria, so that there are now
two separate clinical (c) nodal criteria tables plus
two distinct pathologic (p) nodal criteria tables
that are used after resection of neck nodes (Tables
2–5). HPV-related p16-positive tumors tend to
manifest with multiple nodes with a trend for
cystic nodes, particularly in level II (13). Despite
the presence of multiple metastatic nodes, the
prognosis is not as poor for these HPV-related
p16-positive tumors, resulting in reevaluation of
the nodal tables and a substantially altered table
for these tumors that now more closely resembles
that of nasopharyngeal carcinoma (14–17).
With clinical staging for HPV-related p16-
positive OPSCC, unilateral nodal disease of any
number and size less than 6 cm is now designated
N1 (Figs 1, 2), bilateral nodes of size less than 6
cm are now designated N2 (Fig 3), and N3 disease
is defined as a nodal mass larger than 6 cm. When
nodes are resected, the pathologic nodal table for
HPV-related p16-positive OPSCC is used. This
does not require surgical evaluation of bilateral
neck nodes. pN1 disease is designated as four or
fewer positive nodes and pN2 disease as greater
RG  •  Volume 39  Number 7 Parvathaneni et al  3

Table 1: Clinical and Biologic Features of HPV-negative and HPV-posi-

tive OPSCC

HPV-positive
Feature HPV-negative OPSCC OPSCC
Age >60 y Middle-aged
Risk factors Tobacco use with or without alcohol use Sexual behavior
Field cancerization Yes Unknown
Predilection site None Oropharynx
T stage Higher Lower
Nodal burden Lower Multiple nodes
TP53 mutations Frequent Infrequent

Table 2: Tumor and Clinical Nodal Designations for p16-positive HPV-related OPSCC

T or N Category Criteria
T0 No primary tumor identified
T1 Tumor ≤ 2 cm in greatest dimension
T2 Tumor > 2 cm but ≤ 4 cm in greatest dimension
T3 Tumor > 4 cm in greatest dimension or extension to lingual surface of epiglottis
T4 Moderately advanced local disease: tumor invades larynx, extrinsic muscles of
tongue, medial pterygoid, hard palate, or mandible or beyond
cNx Regional lymph nodes cannot be assessed
cN0 No regional lymph node metastasis
cN1 One or more ipsilateral lymph nodes, none > 6 cm
cN2 Contralateral or bilateral lymph nodes, none > 6 cm
cN3 Lymph node(s) > 6 cm
Note.—Reprinted, with permission, from reference 5.

than four nodes. There is no pN3 designation for
the pathologic tables, which supersede any clinical
nodal designation (Table 4).
When OPSCC is p16 negative at immunohis-
tochemistry or otherwise shown to not be HPV re-
lated, then different clinical and pathologic nodal
tables are used. The clinical N criteria are similar
to those in the seventh edition of the AJCC man-
ual with an important new criterion added. The
designation of clinical extranodal extension (ENE)
as determined by physical examination findings
of skin invasion, infiltration of musculature, dense
tethering or fixation, or specific nerve invasion
with dysfunction (brachial plexus, sympathetic
trunk, or cranial or phrenic nerve) is required.
Clinical ENE determines a nodal designation of
cN3b for p16-negative OPSCC (Table 3). How-
ever, ENE does not influence the staging of p16-
positive OPSCC (Table 2) (Fig 4). It is important
when evaluating CT or MR images to look for
ENE, with the features most helpful for detecting
ENE being indistinct nodal margins, irregular cap-
sular enhancement, and infiltration of surrounding
fat or muscles (18–20) (Fig 5). While imaging fea-
tures may be suggestive of ENE, imaging evidence
alone is not sufficient for this designation, and the
final nodal ENE designation is determined with
clinical examination.
When there is resection of neck nodes, then the
non-HPV non-EBV (Epstein-Barr virus)–related
pathologic nodal table is used. This is a new table
that is also used for squamous cell carcinoma else-
where in the larynx, hypopharynx, and oral cavity
and for cutaneous squamous cell carcinoma. It also
includes pathologic ENE (pENE). An ipsilateral
node smaller than 3 cm with pENE is designated
pN2a. Metastasis with pENE to a contralateral
node smaller than 3 cm, an ipsilateral node larger
than 3 cm, or multiple ipsilateral, contralateral, or
bilateral nodes is designated pN3b (Table 5).
These changes to the staging of OPSCC neces-
sitate careful reporting of imaging results, with
particular attention to the presence of unilateral or
bilateral nodal disease. The nodal designation will
differ depending on the p16 status of the tumor;
in the absence of knowledge of this important
pathologic information, it is best to give a thor-
ough description of the tumor, the nodal number
4 November-December 2019 radiographics.rsna.org

Table 3: Tumor and Clinical Nodal Designations for p16-negative OPSCC

T or N
Category Criteria
T1 Tumor ≤ 2 cm in greatest dimension
T2 Tumor > 2 cm but ≤ 4 cm in greatest dimension
T3 Tumor > 4 cm in greatest dimension or extension to lingual surface of epiglottis
T4a Moderately advanced local disease: tumor invades larynx, extrinsic muscles of tongue, medial ptery-
goid, hard palate, or mandible
T4b Very advanced local disease: tumor invades lateral pterygoid, pterygoid plates, lateral nasopharynx, or
skull base or encases carotid artery
cNx Regional lymph nodes cannot be assessed
cN0 No regional lymph node metastasis
cN1 Metastasis in single ipsilateral lymph node ≤ 3 cm in greatest dimension and ENE negative
cN2a Metastasis in single ipsilateral lymph node > 3 cm but ≤ 6 cm in greatest dimension and ENE negative
cN2b Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension and ENE negative
cN2c Metastasis in bilateral or contralateral lymph node(s), none > 6 cm in greatest dimension and ENE
negative
cN3a Metastasis in lymph node > 6 cm in greatest dimension and ENE negative
cN3b Metastasis in any node(s) with clinically overt ENE (clinical ENE)
Note.—Reprinted, with permission, from reference 5. Midline nodes are considered ipsilateral nodes. Clinical extra-
nodal extension (ENE) is defined as invasion of skin, infiltration of musculature, dense tethering or fixation to adja-
cent structures, or invasion of cranial nerve, brachial plexus, sympathetic trunk, or phrenic nerve with dysfunction.

and location, and the greatest diameter of a nodal
mass (17). If imaging findings suggest ENE, this
information may be valuable to confirm a clinical
suspicion or direct the clinician to reexamine the
neck for clinical evidence of this, as it will change
nodal designation for p16-negative tumors.
Formal staging of a tumor should be per-
formed by the managing oncologist or surgeon
with combination of all clinical (including imag-
ing) and pathologic findings. Then, a prognostic
stage grouping is assigned, which reflects the
overall prognosis and may be important for
management, guiding treatment, and clinical trial
eligibility. There are distinct prognostic staging
tables for p16-positive HPV-related OPSCC and
for p16-negative OPSCC, and these are greatly
different (Tables 6, 7).
For example, for p16-negative tumors with a
T1 or T2 primary, the presence of one metastatic
node is designated N1 for a prognostic grouping
of stage III, while for p16-positive tumors mul-
tiple ipsilateral nodes are still designated N1 for a
prognostic grouping of stage I. Similarly, for T0,
T1, T2, or T3 p16-positive tumors,the presence
of bilateral nodal metastases is designated N2 for
a prognostic grouping of stage II. For p16-nega-
tive tumors with the same T categories, bilateral
nodes are designated N2c for a prognostic group-
ing of stage IVA (Fig 3). There is no stage IV for
p16-positive OPSCC unless there is metastatic
disease (M1).
Table 4: Pathologic Nodal Designations for HPV-
related p16-positive OPSCC
N
Category Criteria
pNx Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis in ≤ 4 lymph nodes
pN2 Metastasis in > 4 lymph nodes
Note.—Reprinted, with permission, from reference 5.
Treatment and Prognosis
The optimal management of patients with
OPSCC is in a multidisciplinary setting. For
early-stage primary tumors with a low nodal
burden of involvement (T1–T2, N0–N1), single-
modality treatment with minimally invasive
surgery or RT is usually used. Advanced-stage
disease (T3–T4 or N2–N3) requires combined-
modality treatment, typically with concurrent
chemoradiation therapy (CRT) with or without
surgery. In the nonsurgical setting (definitive or
organ preservation), cytotoxic therapy is usu-
ally added as a radiosensitizer, with the optimal
agent being cisplatin. Multiple randomized
studies have demonstrated that the addition of
systemic therapy to RT improves tumor control
and overall survival, albeit with increased toxic
effects (21–23).
RG  •  Volume 39  Number 7 Parvathaneni et al  5

Table 5: Pathologic Nodal Designations for p16-negative OPSCC

N Category Criteria
pNx Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis in single ipsilateral node ≤ 3 cm in greatest dimen-
sion and ENE negative
pN2a Single ipsilateral node > 3 cm but ≤ 6 cm in greatest dimension
and ENE negative or single node ≤ 3 cm but ENE positive
pN2b Multiple ipsilateral nodes, none > 6 cm in greatest dimension
and ENE negative
pN2c Bilateral or contralateral node(s), none > 6 cm in greatest di-
mension and ENE negative
pN3a Metastasis in lymph node > 6 cm in greatest dimension and ENE
negative
pN3b Metastasis in single ipsilateral node > 3 cm in greatest dimen-
sion and ENE positive or multiple ipsilateral, contralateral, or
bilateral nodes with ENE in any node
Note.—Reprinted, with permission, from reference 5.

Figure 1.  p16-positive OPSCC in a 66-year-old man with a large mobile left neck mass that was non-
responsive to homeopathy and at fine-needle aspiration was determined to be SCC. Axial contrast-en-
hanced CT image (a) and corresponding PET/CT image (b) show a large solid level IIA nodal mass (* in
a) and asymmetric focal intense fluorodeoxyglucose (FDG) avidity (arrow in b) in the left glossotonsillar
sulcus, which biopsy showed to be the primary site, designated T1. For p16-negative OPSCC without
clinical evidence of extranodal extension (ENE), the large ipsilateral node (which is >3 cm but ≤6 cm)
would be designated N2a with final prognostic grouping of stage IVA. For p16-positive OPSCC, as the
tumor was determined to be at pathologic analysis, the unilateral large node is N1, the final staging is
T1N1, and the prognostic grouping is stage I.

For patients treated with up-front surgery,
adjuvant treatment usually involves RT with or
without platinum-based chemotherapy, depend-
ing on the presence of adverse pathologic risk
factors. Postoperative RT is indicated for the
following pathologic features (24): involvement of
multiple nodes, close resection margins (typically
<3 mm), perineural invasion, and lymphovascular
space invasion. Postoperative CRT is indicated
for the following pathologic features (25–27):
ENE and positive surgical margins.
The prognosis of OPSCC depends largely on
the stage of the disease, assuming that the patient
can tolerate standard therapy. The prognosis of
smoking-related OPSCC is significantly worse
than that of the HPV-driven type. Nonsmokers
6 November-December 2019 radiographics.rsna.org

Figure 2.  p16-positive OPSCC in a 68-year-old nonsmoking man with dysphagia and a palpable mobile
right upper neck lymph node, which fine-needle aspiration demonstrated to be p16-positive OPSCC.
(a) Axial contrast-enhanced CT image at the level of the oropharynx shows a mildly enhancing tongue
base mass (*) larger than 4 cm with involvement of the epiglottis and an ipsilateral abnormal level IIA
node (arrow). (b) Axial contrast-enhanced CT image at the level of the glottis shows an additional het-
erogeneous level III nodal mass (arrow) with a necrotic center. The TNM designation for this p16-positive
OPSCC is cT3N1M0 with a final prognostic grouping of stage II. If it had been a p16-negative OPSCC, the
TNM designation would have been cT3N2bM0 with a final prognostic grouping of stage IVA.

(≤10 pack-years of smoking) with HPV-positive

OPSCC have the best prognosis with 3-year
overall survival of 93%, while smokers (>10
pack-years of smoking) with HPV-negative
OPSCC have 3-year survival of 46.2% (28). In
the setting of HPV-related disease, given the
excellent prognosis, the optimal sequencing and
combination of these modalities remain under
investigation (8–12).
Immunohistochemistry is used to measure
the p16 protein, which is upregulated in HPV-
infected cells (its overexpression is caused by the
viral E7 protein) and is the clinically used marker
for HPV positivity in OPSCC. However, as with
any surrogate, p16 expression is neither 100%
sensitive nor specific for the presence of the HPV
genome, and p16 positivity is not limited to
HPV-positive tumors. As such, the test may be a Figure 3.  p16-positive OPSCC in a 69-year-old non-
false-positive representation of HPV infection. In smoking man with right ear pain, which was suspected
addition, not all HPV-infected cells express p16, to be referred pain. Nasoendoscopic examination re-
which may exclude such patients from HPV- vealed a tongue base mass, which biopsy demonstrated
to be p16-positive OPSCC. Axial contrast-enhanced CT
specific trials and treatment. image shows bilateral heterogeneous ill-defined level
This dual definition of HPV infection, in IIA lymph nodes (arrows) and a solid enhancing mass
addition to having implications for trial and larger than 4 cm in the midline tongue base (*). The
treatment inclusion, also may have a direct ef- TNM designation for this p16-positive OPSCC with bi-
lateral adenopathy is T3N2 with a prognostic grouping
fect on survival. One study demonstrated a 2 3 of stage II. If it had been a p16-negative OPSCC, the
2 interaction of p16 at immunohistochemistry final designation would have been T3N2c with a prog-
and polymerase chain reaction, showing that nostic grouping of stage IVA.
patients negative for both have the worst sur-
vival (29). Nonoropharyngeal squamous cell
carcinoma in the head and neck region may also Surgery
express p16, but the clinical implications of this The head and neck surgeon is involved in evalua-
are unknown. tion, primary management, follow-up, and salvage
RG  •  Volume 39  Number 7 Parvathaneni et al  7

Table 6: Prognostic Stage Groupings for p16-

negative OPSCC

N Category

T Category N0 N1 N2 N3
T1 I III IVA IVB
T2 II III IVA IVB
T3 III III IVA IVB
T4a IVA IVA IVA IVB
T4b IVB IVB IVB IVB
Note.—Reprinted, with permission, from reference 5.

Table 7: Prognostic Clinical Stage Groupings for

p16-positive HPV-related OPSCC

Figure 4.  p16-positive OPSCC in a 51-year-old man
with a 30 pack-year smoking history who presented
with an immobile or fixed left neck mass. Axial contrast-
enhanced CT image shows the primary OPSCC to be
an endophytic mass at the left tongue base (*) infiltrat-
ing the extrinsic tongue musculature of the floor of the
mouth. A large left level II conglomerate nodal mass
(arrow) infiltrates the sternocleidomastoid muscle. For
this p16-positive OPSCC, the final designation is T4N1
with a prognostic grouping of stage III. If the tumor
had been p16 negative, the ENE at clinical examination
would have warranted cN3b designation. The final des-
ignation would have been cT4aN3b with a prognostic
grouping of stage IVB.
Figure 5.  p16-negative OPSCC in a 60-year-old
woman with a 40 pack-year smoking history who pre-
sented with a small left palatine tonsillar OPSCC, which
was shown to be p16 negative. Axial contrast-en-
hanced T1-weighted fat-suppressed MR image shows
a left tonsillar primary mass (*). There is also a necrotic
left level II nodal conglomerate (arrow) with irregular
margins and infiltration of fat planes, suggesting ENE.
Clinically, this was a fixed left neck mass representing
cN3b disease with stage IVB prognostic grouping.
N Category
T Category N0 N1 N2 N3
T0 … I II III
T1 I I II III
T2 I I II III
T3 II II II III
T4 III III III III
Note.—Reprinted, with permission, from reference 5.
of patients with oropharyngeal cancers. These
patients often present with a neck mass, most
often in level II with or without throat symptoms.
The examination includes evaluation of the oral
cavity, oropharynx, hypopharynx, larynx, and
neck, including a flexible endoscopic examination.
Palpation is often used to detect a small lesion or
determine the extent of a known lesion.
It is not uncommon to have a patient present
with a level II neck mass and not find an obvious
primary tumor at initial examination. This occurs
most often with HPV-related OPSCC. Patients
often present with a small primary lesion and a
large cystic neck mass. The small primary lesion
is often not seen at initial examination. This is
referred to as an unknown primary tumor. In that
situation, fine-needle aspiration of the neck mass
is often performed in the office.
It is important to perform p16 testing when
squamous cell carcinoma is identified. The most
common source of a metastatic cervical lymph node
in level II is a p16-positive squamous cell carcinoma
arising from the tonsil-like tissue of the palatine and
lingual tonsils. These are respectively what we call
the tonsils and the base of the tongue (13).
The next step in the evaluation is imaging.
CT with contrast material is usually the first
imaging test performed. When the diagnosis of
8 November-December 2019 radiographics.rsna.org
cancer is established, it is not uncommon to
also perform PET. This is especially important
in the presence of an unknown primary tumor.
A primary lesion not seen at examination or CT
can often be seen at PET.
The next step is to bring the patient to the
operating room and perform laryngoscopy and
biopsy of the primary site. This is completed
with bronchoscopy and esophagoscopy to look
for a second primary lesion. A percutaneous
endoscopic gastrostomy (PEG) tube can also
be inserted at the time if thought appropriate.
When the primary lesion is not obvious, the
area can be examined with the microscope in
the operating room. The next step is to remove
the tonsils and proceed to random biopsies of
the tongue base. With the advent of transoral
surgery, bilateral lingual tonsillectomy is now
recommended by some authors (30).
The options available for primary treatment
of these oropharyngeal tumors are surgery, RT,
and chemotherapy. Because of its morbidity,
traditional open surgery gave way to the combi-
nation of RT and chemotherapy. Some surgeons
prefer to have surgery performed first. In a
retrospective review, Seikaly et al (31) showed
better survival results in comparison with CRT
when surgery preceded any other modality. On
further analysis, the survival advantage was not
significant for p16-positive nonsmokers but was
significant for p16-positive smokers and even
more so for p16-negative smokers.
A recent study by Kelly et al (32) showed no
survival difference in patients with HPV-nega-
tive OPSCC treated with surgery versus CRT.
In general, however, at most centers, patients are
treated with CRT. It was later recognized that
patients with p16-positive tumors—especially
nonsmokers—had an especially good course.
However, the long-term complications of CRT
became obvious, especially in patients treated
with historical RT techniques (33–35). There
was a need to try to minimize complications.
At about the same time, transoral resection
techniques were developed. Use of robotic sur-
gery for management of oropharyngeal cancer
was reported by Weinstein et al (36) in 2010.
Selected early-T-stage tumors were removed
transorally, and neck dissection was performed.
This resulted in more accurate staging and more
tailored postsurgical therapy.
In 2012, Weinstein et al (37) reported use of
robotic surgery alone in some selected patients
with early-stage tumors. Other patients under-
went only postoperative irradiation with reduced
dosage and fields. Some patients with adverse
features still received chemotherapy in addi-
tion to RT. Authors have reported that transoral
robotic surgery (TORS) reduced complications
without affecting survival (38–42).
On the basis of these results, numerous ran-
domized trials have been designed. Recently, the
ECOG (Eastern Cooperative Oncology Group)
3311 trial completed accrual (12). On the basis
of pathology findings after TORS, 515 patients
with T1–T2 N0–N2 tumors were determined to
be at low, intermediate, or high risk. The low-
risk group did not receive any further therapy.
Intermediate-risk patients were randomized to
the standard 60 Gy of RT versus 50 Gy. The
high-risk group underwent postoperative CRT
with weekly cisplatin.
The results of this trial should be available
in a few years. Note that in this trial, 11% of
patients did not receive any further therapy and
68% did not receive chemotherapy. The results
of this trial and other de-escalation trials will
determine if treatment reduction is appropri-
ate in patients with HPV-positive oropharyn-
geal cancers. Sadeghi et al (43) reported use of
TORS after induction chemotherapy without
any RT in 17 patients; this treatment failed in
only one patient.
Surgery for salvage after RT or CRT is
reserved for selected patients. Patel et al (44)
reviewed 1163 patients treated with RT or CRT.
Of these, 122 (10.5%) had a recurrence. Only
34 of these (28%) underwent salvage surgery;
the other 88 were not considered candidates for
a variety of reasons or refused surgery. Salvage
surgery failed in 27 of the 34 (79%). Among
those who were candidates for salvage surgery,
there was a significant benefit compared with
the nonsalvageable group, with 5-year overall
survival of 25% compared with 2%, respectively.
Interestingly, HPV status did not seem to influ-
ence these results. These patients were almost
exclusively treated with open surgery. A recent
review of 18 articles showed similar results (45).
Favorable results have also been reported using
TORS for salvage surgery in a selected group of
patients with early-stage recurrence.
In conclusion, use of surgery and especially
TORS in management of selected early-stage
oropharyngeal tumors—especially HPV-positive
ones—is promising. Data from prospective ran-
domized trials are needed to support this early
enthusiasm.
Radiation Therapy
Oropharyngeal cancers respond well to RT,
and the majority of early-stage cancers (T1–T2
N0–N1) are cured with RT alone with excel-
lent functional outcomes (46). Garden et al (46)
reported 5-year local-regional tumor control
rates of 98% and overall survival of 90% in 217
RG  •  Volume 39  Number 7 Parvathaneni et al  9
Figure 6.  Typical IMRT treatment plan for a p16-
positive left tonsillar squamous cell carcinoma. Axial CT
image shows the primary tumor (*) (purple area). This
is treated with a “safety margin” to account for setup
uncertainties, generating a planning target volume (red
area) that is treated with 70 Gy. The lymph nodal re-
gions in levels II–IV are at risk for disease spread and are
treated with 50–60 Gy bilaterally. Note the sparing of
the right submandibular salivary gland (arrow), which is
made possible by use of a highly conformal IMRT plan-
ning technique.
patients with T1–T2 N1–N2a oropharyngeal
cancers treated at a single institution with RT
alone without concurrent chemotherapy. The
long-term gastrostomy (PEG dependence) rate
in this population was only 2%.
Although there are no published randomized
studies comparing RT with minimally invasive
surgery at the time of submission of this ar-
ticle, the oncologic and functional outcomes for
early-stage tumors are believed to be equivalent
between the two modalities. The choice between
minimally invasive surgery and RT is based on
the location of the tumor and patient preference.
Tumors that extensively involve the palate and
those that straddle the midplane of the tongue
base are generally better candidates for RT. Ad-
vanced tumors (T3–T4 N2–N3) are generally
managed with primary CRT; surgery is reserved
for salvage of unresponsive or recurrent disease.
In the postoperative setting, RT is added to
minimize the risk of local-regional recurrence
for adverse pathologic features including mul-
tiple nodal involvement, close margins, perineu-
ral invasion, and lymphovascular space invasion
(24). Addition of platinum-based chemotherapy
to RT in resected tumors with ENE and/or
positive resection margins has been shown to
improve disease control and survival in random-
ized controlled studies (25–27). However, these
studies were designed and conducted at a time
when HPV was not a widely recognized cause of
OPSCC.
The standard dose of RT to treat gross tumor
visible at imaging or examination is 66–70 Gy
in 33–35 daily fractions over 6.5–7 weeks. Most
OPSCCs have a significant risk of spreading
bilaterally to the level II–IV regional lymph nodes
of the neck. These nodal regions are electively
targeted with a subclinical dose of RT (50–60
Gy), even if they are not overtly involved on the
basis of clinical examination or imaging (Fig 6).
Well-lateralized tumors confined to the pala-
tine tonsil without significant involvement of the
tongue or palate have a low (<5%) risk of spread-
ing to the contralateral neck lymph nodes. In
these special cases, elective RT to the uninvolved
contralateral neck may be omitted to reduce
treatment morbidity (47,48) (Fig 7).
For postoperative RT, the target volume
includes the operative bed to a dose of 60 Gy
in 30 fractions over 6 weeks. ENE and close or
positive margins are boosted by an additional
3–6 Gy. The undissected neck is electively
treated with 50–54 Gy, if it is deemed to be at
risk for lymph nodal spread. Optimally, the in-
terval between surgery and postoperative RT is
limited to less than 6 weeks to minimize tumor
repopulation (24).
The complexity of treating patients with head
and neck cancer cannot be overemphasized. Con-
touring of target volumes requires a thorough
familiarity with the anatomy of the region and
knowledge of the patterns of failure. While the
contouring is performed on a CT image acquired
during simulation, additional imaging with PET/
CT and/or MRI could help with the process. The
beginner is strongly encouraged to seek the help
of a neuroradiologist until he or she develops a
comfort level with the anatomy of the region. In
addition to imaging, a detailed physical examina-
tion including nasoendoscopy is essential to accu-
rately delineate the gross tumor.
Robust external and internal immobilization
is required for a reproducible setup lasting for
6–7 weeks of treatment. In addition to stan-
dard immobilization with an Aquaplast (Qfix;
Avondale, Pa) mask, a customized dental stent
provides considerable internal immobilization of
the tongue as well as deviation of it away from
the primary path of the radiation beams and
helps with sparing of oral mucosa (49). A strong
quality assurance program involving other radia-
tion oncology colleagues treating head and neck
cancer is necessary to maintain a high level of
consistency and accuracy. International consen-
sus guidelines for contouring the primary tumor
10 November-December 2019 radiographics.rsna.org

Figure 7.  (a) Standard IMRT plan to treat a small and well-lateralized left tonsillar SCC (red area) that
does not involve the tongue or palate. Only the ipsilateral neck lymph nodes (green area) are treated.
Isodose lines shown include 10 Gy (yellow) (arrows), 52.92 Gy (green), 58.8 Gy (dark blue), and 64.68 Gy
(red). (b) Comparative plan for proton-beam RT in the same patient shows lack of the spillover “exit dose”
into the contralateral neck and oral cavity seen in the IMRT plan. Isodose lines shown include 5 Gy (white)
(arrows), 10 Gy (yellow), 52.92 Gy (green), 58.8 Gy (dark blue), and 64.68 Gy (red). Note the ipsilateral
parotid gland (*) in relation to the left tonsil and that it is partially spared from the low-dose spillover.

and lymph nodal volumes are available to guide
radiation oncologists caring for patients with can-
cers in this complex disease site (50,51).
During the past 15–20 years, technical ad-
vances in hardware with multileaf collimators and
computing software with inverse planning pro-
grams has led to highly conformal RT treatment
techniques, with IMRT being the poster child for
this movement. IMRT allows precise targeting of
the tumor and lymph nodal regions of potential
tumor spread, while sparing salivary glands and
swallowing structures and dramatically reducing
the morbidity associated with historical tech-
niques (7,52–58) (Fig 6). IMRT is the current
standard of care for treating head and neck can-
cers, based on multiple randomized studies that
demonstrated improved parotid gland sparing,
thus reducing xerostomia (dry mouth) compared
with historical techniques (56–58).
Gensheimer et al (52) reported a further
reduction in long-term xerostomia from 36% to
3% by sparing the submandibular salivary glands
in addition to parotid gland sparing with use of
IMRT. They also reported a significant decrease
in PEG dependence at 6 months—from 30% to
3%—and a reduction in duration of PEG depen-
dence with submandibular gland (and parotid
gland)–sparing IMRT compared with parotid
gland–sparing IMRT (54). Other comparable
examples of conformal techniques using x-ray–
based treatment include volumetric modulated
arc therapy (VMAT) and tomotherapy. With the
advent of cone-beam CT scanners that are at-
tached to the head of the treatment unit, image-
guided RT (IGRT) has became incorporated into
routine practice, allowing volumetric verification
and alignment of the patient before each treat-
ment, which are required for safe and accurate
delivery of an IMRT plan.
By virtue of its physical property of the
Bragg peak effect, proton-beam therapy can be
modulated to stop the beam within a very short
distance after treating the desired target volume.
Thus, compared with an x-ray beam, there is no
exit dose with proton therapy; this feature could
be used to minimize unnecessary radiation to
normal structures that are not at risk for being
involved by cancer (Fig 7). In the past 5–7 years,
pencil beam scanning technology has been intro-
duced in the clinic, and it is now possible to treat
head and neck cancers requiring bilateral neck
irradiation with proton-beam RT.
Riding this wave, more than 30 centers have
become operational or are in the final stages of
development in the United States and around
the world. Compared with x-ray–based units, the
availability of proton-beam RT is still limited.
In addition, this technology is expensive, and its
cost-effectiveness has been questioned (7,59).
While there are no randomized trials to compare
outcomes, according to early results proton-beam
RT appears to compare favorably with IMRT,
RG  •  Volume 39  Number 7 Parvathaneni et al  11
with reduced feeding tube dependency; improved
treatment-related head and neck symptoms in-
cluding painful mucositis, dysgeusia, and nausea;
and improved quality of life, especially during the
subacute phase (60–63).
In summary, several technical advances during
the past 10–15 years in the equipment used for
RT treatment planning, delivery, and verifica-
tion, along with careful contouring skills, have
eliminated most of the toxic effects reported with
RT techniques of the previous era (7,46,52,54).
Finally, the outcomes in patients with head and
neck cancers treated at high-volume centers with
expertise have been found to be demonstrably su-
perior to outcomes in patients treated at low-vol-
ume centers, especially when complex techniques
that produce steep dose gradients such as IMRT
are used to minimize morbidity (64,65).
Boero et al (64) identified RT providers from
Medicare claims of 6212 Medicare beneficiaries
with head and neck cancers treated between
2000 and 2009. Among patients treated with
IMRT, they found significantly improved sur-
vival and decreased risk of aspiration pneumonia
in those who received treatment from higher-
volume radiation oncologists compared with
those who received treatment from lower-volume
radiation oncologists. Among the patients treated
with conventional or historical techniques, there
was no difference in outcomes on the basis of
provider volume.
Systemic Therapy
With accumulating biologic and survival data
regarding HPV-related OPSCC, there is ongo-
ing interest in tailoring definitive CRT for these
patients, with the goal of preserving a high sur-
vival rate while reducing treatment-related toxic
effects. These de-escalation approaches involve
updates or modifications to all three treatment
modalities (8–12). The current paradigm for cu-
rative treatment of locally advanced HPV-related
p16-positive OPSCC as well as HPV-related p16-
negative OPSCC is definitive CRT with standard
dose-fractionation IMRT plus cisplatin, given
every 3 weeks (21–23).
On first principles, there are underlying bio-
logic factors that support the study of different
treatment approaches to HPV-negative and HPV-
positive OPSCC. Field cancerization due to envi-
ronmental exposures (tobacco and alcohol) that
cause HPV-negative head and neck squamous
cell cancer (HNSCC) results in multiple genetic
hits that create genomically unstable cancers that
occur at later stages in older patients, who are of-
ten less healthy owing to comorbidities (3,4,66).
HPV-associated OPSCC results from dysregula-
tion of the cell cycle and apoptosis due to the
oncogenic E6 and E7 proteins (4,67). This virally
associated carcinogenesis leads to lower-stage
tumors in younger patients that have a mark-
edly higher cure rate than similar stage non-HPV
HNSCC (Table 1).
The paradigm study that evaluated the role of
HPV (measured using immunohistochemistry-
detected surrogate marker p16) as a prognostic
marker of survival in locally advanced p16-pos-
itive HNSCC treated with definitive CRT with
cisplatin was RTOG (Radiation Therapy Oncol-
ogy Group) 0129 (68). Patients with locally ad-
vanced (stage III–IV) squamous cell carcinoma of
the oral cavity, oropharynx, larynx, or hypophar-
ynx received standard fraction RT with cisplatin
at 100 mg/m2 3 3 or accelerated fractionation
with a concomitant boost with cisplatin at 100
mg/m2 3 2. Overall survival was equivalent. In
a follow-up analysis, Ang and colleagues (28)
retrospectively stratified overall survival by tumor
HPV and p16 status. The hazard ratio for death
in the overall survival model was 0.29 (confi-
dence interval: 0.20, 0.43; P < .001), suggesting a
strong survival benefit in p16-positive patients.
Concurrent with the emergence of the data
regarding improved overall survival in p16-posi-
tive tumors was the introduction of cetuximab, a
monoclonal antibody against the human epider-
mal growth factor receptor that gained approval
as single-agent therapy for advanced HNSCC
(69,70). Compared with standard-of-care chemo-
therapies such as paclitaxel, cisplatin, and metho-
trexate, the side effect profile of cetuximab was
greatly reduced. Given the lower toxicity as well
as clinical activity in locally advanced HNSCC,
cetuximab was then evaluated for curative intent
in locally advanced disease. In the landmark
study by Bonner et al (71), RT alone was com-
pared with RT plus cetuximab in patients with
locally advanced HNSCC (41% HPV positive).
The 5-year absolute survival benefit was 9.2%
for cetuximab; in a follow-up analysis, overall sur-
vival was better in p16-positive patients, and the
cetuximab effect benefited both groups (72).
Given both the validation of p16 status as a
marker of better overall survival in OPSCC and
the availability of a proven radiosensitizer (ce-
tuximab) with less toxicity than cisplatin, NRG
Oncology Protocol RTOG 1016 was initiated.
This was a randomized, two-arm, phase III, non-
inferiority study that compared RT (accelerated
IMRT) plus cisplatin (100 mg/m2 days 1 and
22) with RT (accelerated IMRT) plus cetux-
imab (400 mg/m2 load then 250 mg/m2 weekly)
for treatment of locally advanced p16-positive
OPSCC (73). A similarly designed study was si-
multaneously completed in Europe (74). Perhaps
surprisingly and certainly disappointingly, both
12 November-December 2019 radiographics.rsna.org
of these studies revealed that RT plus cetuximab
was inferior, and cisplatin (with RT) remains the
standard of care in this setting of locally ad-
vanced HPV-related p16-positive OPSCC.
Despite these data, efforts continue to find
a regimen that is equal to or better than cispla-
tin but less toxic. RT technology continues to
progress (eg, proton-beam RT), while additional
radiosensitizing agents are under study, primar-
ily immunotherapy—which holds promise as an
improvement over cetuximab (75,76).
Conclusion
Patients with OPSCC are ideally managed in
a multidisciplinary setting to optimize cancer
control and minimize morbidity. HPV-driven
OPSCC has an excellent prognosis, prompting
changes in the staging system. While treatment
de-intensification strategies are being explored
for these cancers, the current standard of care
provides high cure rates with acceptable morbid-
ity at experienced centers.
Disclosures of Conflicts of Interest.—M.K.G. Activities related
to the present article: disclosed no relevant relationships. Activi-
ties not related to the present article: speaker for Bristol-Myers
Squibb; royalties from UpToDate. Other activities: disclosed no
relevant relationships.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA
Cancer J Clin 2017;67(1):7–30.
2. Gillison ML, Koch WM, Capone RB, et al. Evidence for
a causal association between human papillomavirus and
a subset of head and neck cancers. J Natl Cancer Inst
2000;92(9):709–720.
3. Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C.
Epidemiology of human papillomavirus-positive head
and neck squamous cell carcinoma. J Clin Oncol 2015;33
(29):3235–3242.
4. Bhatia A, Burtness B. Human papillomavirus-associated
oropharyngeal cancer: defining risk groups and clinical
trials. J Clin Oncol 2015;33(29):3243–3250.
5. Amin MB, Edge SB, Greene FL, et al, eds. AJCC cancer
staging manual. 8th ed. New York, NY: Springer, 2017.
6. Holsinger FC, Ferris RL. Transoral endoscopic head and
neck surgery and its role within the multidisciplinary treat-
ment paradigm of oropharynx cancer: robotics, lasers, and
clinical trials. J Clin Oncol 2015;33(29):3285–3292.
7. Parvathaneni U, Laramore GE, Liao JJ. Technical ad-
vances and pitfalls in head and neck radiotherapy. J Oncol
2012;2012:597467.
8. NRG-HN002: a randomized phase II trial for patients
with p16 positive, non-smoking associated, locoregionally
advanced oropharyngeal cancer. https://clinicaltrials.gov/
ct2/show/NCT02254278. Accessed September 2019.
9. Chera BS, Amdur RJ, Tepper JE, et al. Mature results of
a prospective study of deintensified chemoradiotherapy
for low-risk human papillomavirus-associated oropha-
ryngeal squamous cell carcinoma. Cancer 2018;124(11):
2347–2354.
10. Chen AM, Felix C, Wang PC, et al. Reduced-dose radio-
therapy for human papillomavirus-associated squamous-cell
carcinoma of the oropharynx: a single-arm, phase 2 study.
Lancet Oncol 2017;18(6):803–811.
11. Marur S, Li S, Cmelak AJ, et al. E1308: Phase II Trial
of Induction Chemotherapy Followed by Reduced-Dose
Radiation and Weekly Cetuximab in Patients With HPV-
Associated Resectable Squamous Cell Carcinoma of the
Oropharynx—ECOG-ACRIN Cancer Research Group. J
Clin Oncol 2017;35(5):490–497.
12. EGOG 3311: transoral surgery followed by low-dose or
standard-dose radiation therapy with or without chemo-
therapy in treating patients with HPV positive stage III-IV
oropharyngeal cancer. https://clinicaltrials.gov/ct2/show/
NCT01898494. Accessed January 2019.
13. Cantrell SC, Peck BW, Li G, Wei Q, Sturgis EM,
Ginsberg LE. Differences in imaging characteristics of
HPV-positive and HPV-negative oropharyngeal cancers:
a blinded matched-pair analysis. AJNR Am J Neuroradiol
2013;34(10):2005–2009.
14. O’Sullivan B, Huang SH, Su J, et al. Development and
validation of a staging system for HPV-related oropharyngeal
cancer by the International Collaboration on Oropharyngeal
Cancer Network for Staging (ICON-S): a multicentre cohort
study. Lancet Oncol 2016;17(4):440–451.
15. Huang SH, Xu W, Waldron J, et al. Refining American
Joint Committee on Cancer/Union for International Can-
cer Control TNM stage and prognostic groups for human
papillomavirus-related oropharyngeal carcinomas. J Clin
Oncol 2015;33(8):836–845.
16. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck
cancers: major changes in the American Joint Committee on
Cancer eighth edition cancer staging manual. CA Cancer J
Clin 2017;67(2):122–137.
17. Glastonbury CM, Mukherji SK, O’Sullivan B, Lydiatt
WM. Setting the Stage for 2018: How the Changes in the
American Joint Committee on Cancer/Union for Inter-
national Cancer Control Cancer Staging Manual Eighth
Edition Impact Radiologists. AJNR Am J Neuroradiol
2017;38(12):2231–2237.
18. King AD, Tse GM, Yuen EH, et al. Comparison of CT and
MR imaging for the detection of extranodal neoplastic spread
in metastatic neck nodes. Eur J Radiol 2004;52(3):264–270.
19. Lodder WL, Lange CA, van Velthuysen ML, et al. Can
extranodal spread in head and neck cancer be detected on
MR imaging. Oral Oncol 2013;49(6):626–633.
20. Prabhu RS, Magliocca KR, Hanasoge S, et al. Accuracy
of computed tomography for predicting pathologic nodal
extracapsular extension in patients with head-and-neck
cancer undergoing initial surgical resection. Int J Radiat
Oncol Biol Phys 2014;88(1):122–129.
21. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase
III comparison of standard radiation therapy and two
schedules of concurrent chemoradiotherapy in patients with
unresectable squamous cell head and neck cancer. J Clin
Oncol 2003;21(1):92–98.
22. Denis F, Garaud P, Bardet E, et al. Final results of the
94-01 French Head and Neck Oncology and Radiotherapy
Group randomized trial comparing radiotherapy alone
with concomitant radiochemotherapy in advanced-stage
oropharynx carcinoma. J Clin Oncol 2004;22(1):69–76.
23. Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis
of chemotherapy in head and neck cancer (MACH-NC):
a comprehensive analysis by tumour site. Radiother Oncol
2011;100(1):33–40.
24. Ang KK, Trotti A, Brown BW, et al. Randomized trial
addressing risk features and time factors of surgery plus
radiotherapy in advanced head-and-neck cancer. Int J Radiat
Oncol Biol Phys 2001;51(3):571–578.
25. Bernier J, Domenge C, Ozsahin M, et al. Postoperative
irradiation with or without concomitant chemotherapy
for locally advanced head and neck cancer. N Engl J Med
2004;350(19):1945–1952.
26. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative
concurrent radiotherapy and chemotherapy for high-risk
squamous-cell carcinoma of the head and neck. N Engl J
Med 2004;350(19):1937–1944.
27. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels
in locally advanced head and neck cancers: a comparative
analysis of concurrent postoperative radiation plus che-
motherapy trials of the EORTC (#22931) and RTOG (#
9501). Head Neck 2005;27(10):843–850.
28. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus
and survival of patients with oropharyngeal cancer. N Engl
J Med 2010;363(1):24–35.
RG  •  Volume 39  Number 7 Parvathaneni et al  13
29. Geißler C, Tahtali A, Diensthuber M, Gassner D, Stöver
T, Wagenblast J. The role of p16 expression as a predic-
tive marker in HPV-positive oral SCCHN: a retrospective
single-center study. Anticancer Res 2013;33(3):913–916.
30. Fu TS, Foreman A, Goldstein DP, de Almeida JR. The
role of transoral robotic surgery, transoral laser microsur-
gery, and lingual tonsillectomy in the identification of head
and neck squamous cell carcinoma of unknown primary
origin: a systematic review. J Otolaryngol Head Neck Surg
2016;45(1):28.
31. Seikaly H, Biron VL, Zhang H, et al. Role of primary surgery
in the treatment of advanced oropharyngeal cancer. Head
Neck 2016;38(suppl 1):E571–E579.
32. Kelly JR, Park HS, An Y, et al. Comparison of Survival
Outcomes Among Human Papillomavirus-Negative cT1-2
N1-2b Patients With Oropharyngeal Squamous Cell Cancer
Treated With Upfront Surgery vs Definitive Chemora-
diation Therapy: An Observational Study. JAMA Oncol
2017;3(8):1107–1111.
33. Machtay M, Moughan J, Trotti A, et al. Factors associated
with severe late toxicity after concurrent chemoradiation for
locally advanced head and neck cancer: an RTOG analysis.
J Clin Oncol 2008;26(21):3582–3589.
34. Wilson JA, Carding PN, Patterson JM. Dysphagia after non-
surgical head and neck cancer treatment: patients’ perspec-
tives. Otolaryngol Head Neck Surg 2011;145(5):767–771.
35. Francis DO, Weymuller EA Jr, Parvathaneni U, Merati AL,
Yueh B. Dysphagia, stricture, and pneumonia in head and
neck cancer patients: does treatment modality matter? Ann
Otol Rhinol Laryngol 2010;119(6):391–397.
36. Weinstein GS, O’Malley BW Jr, Cohen MA, Quon H.
Trans­ oral robotic surgery for advanced oropharyngeal
carcinoma. Arch Otolaryngol Head Neck Surg 2010;
136(11):1079–1085.
37. Weinstein GS, Quon H, Newman HJ, et al. Transoral
robotic surgery alone for oropharyngeal cancer: an analy-
sis of local control. Arch Otolaryngol Head Neck Surg
2012;138(7):628–634.
38. Ling DC, Chapman BV, Kim J, et al. Oncologic outcomes
and patient-reported quality of life in patients with oropha-
ryngeal squamous cell carcinoma treated with definitive
transoral robotic surgery versus definitive chemoradiation.
Oral Oncol 2016;61:41–46.
39. Sinha P, Pipkorn P, Thorstad WL, Gay HA, Haughey
BH. Does elimination of planned postoperative radiation
to the primary bed in p16-positive, transorally-resected
oropharyngeal carcinoma associate with poorer outcomes?
Oral Oncol 2016;61:127–134.
40. Routman DM, Funk RK, Tangsriwong K, et al. Relapse
rates with surgery alone in human papillomavirus-related
intermediate- and high-risk group oropharynx squamous cell
cancer: a multi-institutional review. Int J Radiat Oncol Biol
Phys 2017;99(4):938–946. [Published correction appears
in Int J Radiat Oncol Biol Phys 2018;100(5):1304.] https://
doi.org/10.1016/j.ijrobp.2017.06.2453.
41. Sharma A, Patel S, Baik FM, et al. Survival and gastrostomy
prevalence in patients with oropharyngeal cancer treated
with transoral robotic surgery vs chemoradiotherapy. JAMA
Otolaryngol Head Neck Surg 2016;142(7):691–697.
42. Kumar B, Cipolla MJ, Old MO, et al. Surgical manage-
ment of oropharyngeal squamous cell carcinoma: survival
and functional outcomes. Head Neck 2016;38(suppl
1):E1794–E1802.
43. Sadeghi N, Li NW, Taheri MR, Easley S, Siegel RS. Neo-
adjuvant chemotherapy and transoral surgery as a defini-
tive treatment for oropharyngeal cancer: a feasible novel
approach. Head Neck 2016;38(12):1837–1846.
44. Patel SN, Cohen MA, Givi B, et al. Salvage surgery for locally
recurrent oropharyngeal cancer. Head Neck 2016;38(suppl
1):E658–E664.
45. Kao SS, Ooi EH. Survival outcomes following salvage sur-
gery for oropharyngeal squamous cell carcinoma: systematic
review. J Laryngol Otol 2018;132(4):299–313.
46. Garden AS, Kies MS, Morrison WH, et al. Outcomes and
patterns of care of patients with locally advanced oropha-
ryngeal carcinoma treated in the early 21st century. Radiat
Oncol 2013;8(1):21.
47. O’Sullivan B, Warde P, Grice B, et al. The benefits and
pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar
region. Int J Radiat Oncol Biol Phys 2001;51(2):332–343.
48. Jensen K, Overgaard M, Grau C. Morbidity after ipsilateral
radiotherapy for oropharyngeal cancer. Radiother Oncol
2007;85(1):90–97.
49. Johnson B, Sales L, Winston A, Liao J, Laramore G, Par-
vathaneni U. Fabrication of customized tongue-displacing
stents: considerations for use in patients receiving head and
neck radiotherapy. J Am Dent Assoc 2013;144(6):594–600.
50. Grégoire V, Evans M, Le QT, et al. Delineation of the pri-
mary tumour clinical target volumes (CTV-P) in laryngeal,
hypopharyngeal, oropharyngeal and oral cavity squamous
cell carcinoma: AIRO, CACA, DAHANCA, EORTC,
GEORCC, GORTEC, HKNPCSG, HNCIG, IAG-KHT,
LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS,
SBRT, SOMERA, SRO, SSHNO, TROG consensus
guidelines. Radiother Oncol 2018;126(1):3–24.
51. Grégoire V, Ang K, Budach W, et al. Delineation of the
neck node levels for head and neck tumors: a 2013 update.
DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI,
RTOG, TROG consensus guidelines. Radiother Oncol
2014;110(1):172–181.
52. Gensheimer MF, Liao JJ, Garden AS, Laramore GE,
Parvathaneni U. Submandibular gland-sparing radiation
therapy for locally advanced oropharyngeal squamous cell
carcinoma: patterns of failure and xerostomia outcomes.
Radiat Oncol 2014;9(1):255.
53. Dijkema T, Raaijmakers CP, Ten Haken RK, et al. Parotid
gland function after radiotherapy: the combined Michigan
and Utrecht experience. Int J Radiat Oncol Biol Phys
2010;78(2):449–453.
54. Gensheimer MF, Nyflot M, Laramore GE, Liao JJ, Par-
vathaneni U. Contribution of submandibular gland and
swallowing structure sparing to post-radiation therapy PEG
dependence in oropharynx cancer patients treated with
split-neck IMRT technique. Radiat Oncol 2016;11(1):151.
55. Eisbruch A, Kim HM, Feng FY, et al. Chemo-IMRT of
oropharyngeal cancer aiming to reduce dysphagia: swallow-
ing organs late complication probabilities and dosimetric
correlates. Int J Radiat Oncol Biol Phys 2011;81(3):e93–e99.
56. Nutting CM, Morden JP, Harrington KJ, et al. Parotid-
sparing intensity modulated versus conventional radio-
therapy in head and neck cancer (PARSPORT): a phase
3 multicentre randomised controlled trial. Lancet Oncol
2011;12(2):127–136.
57. Kam MKM, Leung SF, Zee B, et al. Prospective randomized
study of intensity-modulated radiotherapy on salivary gland
function in early-stage nasopharyngeal carcinoma patients.
J Clin Oncol 2007;25(31):4873–4879.
58. Pow EHN, Kwong DLW, McMillan AS, et al. Xerostomia
and quality of life after intensity-modulated radiotherapy vs.
conventional radiotherapy for early-stage nasopharyngeal
carcinoma: initial report on a randomized controlled clinical
trial. Int J Radiat Oncol Biol Phys 2006;66(4):981–991.
59. Sher DJ, Tishler RB, Pham NL, Punglia RS. Cost-effective-
ness analysis of intensity modulated radiation therapy versus
proton therapy for oropharyngeal squamous cell carcinoma.
Int J Radiat Oncol Biol Phys 2018;101(4):875–882.
60. Blanchard P, Garden AS, Gunn GB, et al. Intensity-
modulated proton beam therapy (IMPT) versus intensity-
modulated photon therapy (IMRT) for patients with oro-
pharynx cancer: a case matched analysis. Radiother Oncol
2016;120(1):48–55.
61. Sio TT, Lin HK, Shi Q, et al. Intensity modulated pro-
ton therapy versus intensity modulated photon radiation
therapy for oropharyngeal cancer: first comparative results
of patient-reported outcomes. Int J Radiat Oncol Biol Phys
2016;95(4):1107–1114.
62. Romesser PB, Cahlon O, Scher E, et al. Proton beam
radiation therapy results in significantly reduced toxicity
compared with intensity-modulated radiation therapy for
head and neck tumors that require ipsilateral radiation.
Radiother Oncol 2016;118(2):286–292.
63. Sharma S, Zhou O, Thompson R, et al. Quality of Life of
Postoperative Photon versus Proton Radiation Therapy for
Oropharynx Cancer. Int J Part Ther 2018;5(2):11–17.
14 November-December 2019 radiographics.rsna.org
64. Boero IJ, Paravati AJ, Xu B, et al. Importance of Radiation
Oncologist Experience Among Patients With Head-and-
Neck Cancer Treated With Intensity-Modulated Radiation
Therapy. J Clin Oncol 2016;34(7):684–690.
65. Lassig AA, Joseph AM, Lindgren BR, et al. The effect of
treating institution on outcomes in head and neck cancer.
Otolaryngol Head Neck Surg 2012;147(6):1083–1092.
66. Forastiere AA, Ang K, Brizel D, et al. Head and neck cancers.
J Natl Compr Canc Netw 2005;3(3):316–391.
67. Leemans CR, Snijders PJF, Brakenhoff RH. The molecu-
lar landscape of head and neck cancer. Nat Rev Cancer
2018;18(5):269–282. [Published correction appears in Nat
Rev Cancer 2018;18(10):662.] https://doi.org/10.1038/
nrc.2018.11.
68. Nguyen-Tan PF, Zhang Q, Ang KK, et al. Randomized
phase III trial to test accelerated versus standard fractionation
in combination with concurrent cisplatin for head and neck
carcinomas in the Radiation Therapy Oncology Group 0129
trial: long-term report of efficacy and toxicity. J Clin Oncol
2014;32(34):3858–3866.
69. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based
chemotherapy plus cetuximab in head and neck cancer. N
Engl J Med 2008;359(11):1116–1127.
70. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncon-
trolled, multicenter phase II study to evaluate the efficacy
and toxicity of cetuximab as a single agent in patients with
recurrent and/or metastatic squamous cell carcinoma of the
This journal-based SA-CME activity has been approved for AMA PRA Category 1 Credit . See rsna.org/learning-center-rg.
head and neck who failed to respond to platinum-based
therapy. J Clin Oncol 2007;25(16):2171–2177.
71. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus
cetuximab for squamous-cell carcinoma of the head and
neck. N Engl J Med 2006;354(6):567–578.
72. Rosenthal DI, Harari PM, Giralt J, et al. Association of
Human Papillomavirus and p16 Status With Outcomes in
the IMCL-9815 Phase III Registration Trial for Patients
With Locoregionally Advanced Oropharyngeal Squamous
Cell Carcinoma of the Head and Neck Treated With
Radiotherapy With or Without Cetuximab. J Clin Oncol
2016;34(12):1300–1308.
73. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus
cetuximab or cisplatin in human papillomavirus-positive
oropharyngeal cancer (NRG Oncology RTOG 1016):
a randomised, multicentre, non-inferiority trial. Lancet
2019;393(10166):40–50.
74. Mehanna H, Robinson M, Hartley A, et al. Radiotherapy
plus cisplatin or cetuximab in low-risk human papillomavirus-
positive oropharyngeal cancer (De-ESCALaTE HPV): an
open-label randomised controlled phase 3 trial. Lancet
2019;393(10166):51–60.
75. Bauml J, Seiwert TY, Pfister DG, et al. Pembrolizumab
for Platinum- and Cetuximab-Refractory Head and Neck
Cancer: Results From a Single-Arm, Phase II Study. J Clin
Oncol 2017;35(14):1542–1549.
76. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab
for recurrent squamous-cell carcinoma of the head and neck.
N Engl J Med 2016;375(19):1856–1867.
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