The Current State of Biological and Clinical

Implications of Human Papillomavirus-

Related Oropharyngeal Cancer
Shao Hui Huang, MD, MSc, MRT(T), Brian O'Sullivan, MD, and
John Waldron, MD

In the effort to control human papillomavirus-related oropharyngeal cancer, the head and neck
oncology community has devoted much effort to understanding its disease biology and clinical
behavior, and refining strategies to address early diagnosis and optimal management for the
affected population. This review identifies articles published up to March 2017 on tumor
biology and clinical implications of human papillomavirus-related oropharyngeal cancer, and
summarizes the findings in some key areas. These include potential screening strategies,
possible anatomical features responsible for early lymph node involvement and its implication
for staging, biological mechanisms to explain superior outcomes compared to traditional
nonviral-related mucosal cancers, re-appreciation of traditional prognostic factors (eg, hypoxia,
extranodal extension, and smoking), and current efforts to optimize management for this
patient population. The review reflects the global effort to mitigate the influence of this
burgeoning disease.
Semin Radiat Oncol 28:17-26 C 2017 Elsevier Inc. All rights reserved.

Introduction and treatment response and outcomes.16,17 In essence, tumor

HPV status has emerged as a “diagnostic” biomarker to identify

T he rapid emergence of human papillomavirus-related

(HPVþ) oropharyngeal cancer (OPC) has changed the
head and neck cancer (HNC) landscape significantly in many
a new disease rather than a “prognostic” biomarker within a
“homogeneous” disease entity. The eighth edition TNM staging
includes a new TNM classification for HPVþ OPC. The 2017
Western countries,1-5 and the current trend appears to show World Health Organization/International Agency for Research
no sign of slowing down in high HPV prevalence jurisdic- on Cancer Classification of Head and Neck Tumors (fourth
tions.6,7 Although HPVþ OPC mostly occurs in a relatively edition) has also introduced “SCC, HPV-positive” for HPVþ
young population (median age: 55-60 years), a rising trend is OPC recognizing its distinction as a new disease.18 Clinical
also observed in elderly patients.8,9 In fact, HPVþ OPC now trials are now addressing HPVþ and HPV– diseases separately.
comprises most of the head and neck squamous cell carcinoma In response to the “quandary” of the rising tide of HPVþ
referral in North America. OPC, significant progress has been made in understanding
Although arising in the same anatomical location as smok- tumor biology and clinical behavior, and in developing
ing-related or HPV-negative (HPV–) OPC, HPVþ OPC is now preventative strategies. For example, HPVþ OPC tumors often
recognized as a distinct disease entity, with very different lack p53 mutations; they also involve cervical lymph nodes
molecular profile,10-13 clinical-radiological presentation,14,15 earlier and are frequently accompanied by a cystic nodal
architecture. They also may exhibit a more prolonged nodal
regression after (chemo-)radiation19 with paradoxically supe-
Department of Radiation Oncology, Princess Margaret Cancer Centre, rior outcomes. Current research directions have shifted from
University of Toronto, Toronto, ON, Canada. observational studies describing unique clinical behavior to
Conflict of interest: none. understanding biological mechanisms and refining manage-
Address reprint requests to Shao Hui Huang, MD, MSc, MRT(T), Department
of Radiation Oncology, The Princess Margaret Cancer Centre, University of
ment strategies accordingly. This review aims to summarize
Toronto, 610 University Ave, Toronto, ON, Canada M5G 2M9. E-mail: current understanding of HPVþ tumor biology to uncover its
shaohui.huang@rmp.uhn.on.ca (S.H. Huang) clinical implication on the natural course of the disease, risk

http://dx.doi.org/10.1016/j.semradonc.2017.08.007 17
1053-4296/& 2017 Elsevier Inc. All rights reserved.
18 S.H. Huang et al.

stratification and prognostication, investigational treatment who otherwise have a relative lack of risk factors.15,27 Cervical
approaches, and potential screening and preventative nodal metastasis presenting without an obvious primary
strategies. (termed “unknown primary”) most often originates from an
HPVþ OPC.28,29
The earlier nodal involvement in HPVþ OPC has also
The Quest for HPV-Induced changed the prognostic value of the traditional N-category
Precursor Lesions in Oropharynx within the TNM classification that has relied on size, number,
and side of neck affected.30 The multi-institutional study of
HPV-related precancerous lesions have been identified in 1907 HPV-positive OPC by the International Collaboration on
cervical, anal, penile, vaginal, and vulvar regions. Recognizing Oropharyngeal cancer Network (ICON-S) demonstrated that,
these characteristics has enabled implementation of cancer while prognosis worsens in line with higher T category, the
screening in these disease sites. However, whether similar seventh edition N classification was inadequate in depicting
precancerous lesion exist in the oropharynx remains debatable. prognosis. In fact, there is minimal separation in overall
A multi-institutional study of tonsil tissue from 4095 healthy survival (OS) among N1, N2a, and N2b subsets, and the
individuals in the United Kingdom (UK) did not find any ICON-S study consequently reclassified them into a single
precursor lesion.20 Fakhry et al evaluated the feasibility of category as “N1,” while bilateral or contralateral neck nodes are
conducting a “Pap smear equivalent” cytology test (collected by now termed “N2.”26 The ICON-S N classification has now
bilateral tonsil “brushing”) from patients presenting with been adopted in the eighth edition TNM for HPVþ OPC. It is
oropharyngeal abnormalities and human immunodeficiency the first time in the head and neck cancer TNM classification
virus-infected individuals. Among those with oropharyngeal that T4 or N3 M0 disease is not classified as stage IV in this
abnormalities, both oral HPV16 infection and the presence of unique disease setting.31
cytologic abnormalities were strongly associated with the It is interesting that although nodal involvement is often
presence of invasive OPC. In contrast, cytologic abnormalities evident earlier in HPVþ OPC, the topographic distribution of
were rare and were not associated with oral HPV16 infection involved lymph nodes is not different between HPVþ and
among human immunodeficiency virus-infected individuals. HPV– OPC.14,32,33 This strongly suggests that the lymphatic
The absence of detectable precancerous lesions among indi- drainage pathways are similar for both diseases. Therefore,
viduals without clinical disease probably reflects the difficulty there is no indication to modify treatment of candidate lymph
in accessing deep tonsillar crypts.21 The French “Split” trial also node regions with either surgery or radiotherapy based on
showed that tonsil “brushing” appeared to be less reliable in tumor HPV status.
detecting HPV22 compared to an oral rinse method,23 and
furthermore, neither are OPC-specific. Thus, the lack of an
identifiable HPV-induced precursor lesion in the oropharyng-
eal mucosa together with the unavailability of a reliable Potential Role of HPV16 E6
noninvasive measure to detect abnormal cytology poses a Serology for Screening and
challenge for screening and early diagnosis.24
Surveillance
Recently, HPV E6 serum antibody has shown a promising role
Earlier Nodal Involvement and Its in early detection of HPVþ OPC. The E6 antibody is rarely
Implication in Diagnosis and detected in healthy individuals34 but is very high in patients
with HPVþ OPC (490% of patients with HPVþ OPC, 0% of
Staging partners, and 7.4% of healthy volunteers),35 and it is much
The HPV carcinogenesis process occurs at the basal cell layer of lower in non-OPC (oral cavity, larynx) and genital HPVþ
the oropharyngeal mucosa. This anatomical location is clin- cancers (eg, cervix, vagina, vulva, and penis), excepting anal
ically relevant. Electron microscopy studies of this epithelial cancer.36 These differences in host-immune response might
layer have revealed that the basement membrane of the reflect variations in the tumor microenvironment across
tonsillar crypt is discontinuous and rich in intraepithelial anatomical locations. In addition, serum HPV16 E6 antibody
capillaries,25 which might facilitate tumor cell foci accessing was detectable in 490% of patients with HPVþ OPC 2-10
underlying lymphatics resulting in lymph node involvement years before their cancer diagnosis.36 For this reason, it is
earlier in the course of tumor progression. Thus, it could alluring to consider the use of this biomarker to design a
partially explain the clinical observation that most (490%) screening algorithm for HPVþ OPC and anal cancers.37
HPVþ OPCs have clinical nodal involvement, even when However, the choice of study endpoint and monitoring
primary tumors are small (T1-T2).26 method in seropositive patients presents a dilemma as there
The disproportionally earlier nodal involvement relative to is no visible precancerous lesion to screen, even though severe
the size of the primary tumor presents a diagnostic dilemma. dysplasia can exist. Bilateral tonsillectomy is not an ideal
Reports have shown that about two-thirds of HPVþ OPC detection procedure for E6 seropositive patients as it is invasive
patients present with an asymptomatic neck mass as the first and would be unable to address the risk of tumor in the base of
sign requiring medical attention, and often results in misdiag- tongue (BOT) which accounts for nearly 50% of HPVþ OPC
nosis as a benign condition in generally healthy individuals [14]. One possible solution is the use of ultrasound to identify
Biological and clinical implications of HPV-mediated OPC 19

Table 1 Selected Studies Exploring the Role of HPV16 E6 Serology in Prognosis and Surveillance
Study/HPVþ Case No. HPV16 E6 Antibody Findings
Testing
Rubenstein et al41 Enzyme-linked • HPV16 E6 seropositive at diagnosis: 20/27 (91%) OPC (no data on HPV
• OPC: 27; oral cavity: 73 immunosorbent assay status for these 20 OPC patients)
• Larynx/hypopharynx: 9 (ELIZA) • Posttreatment E6 level decreased; HPV E6 seroconversion rate was 5%
• No data on exact number • Unknown value of pretreatment or posttreatment seropositivity in HPVþ
of HPVþ OPC OPC

Koslabova et al40 ELIZA • Pretreatment HPV16 E6 seropositive in tumor HPV16þ: 67/78 (86%)
• 118 OPC and 24 oral • Majority (99%) HPV16 E6 or E7 remains seropositive at 1-year follow-up
cavity but the level was lower in most (64%) cases
• 78 HPV16þ • Posttreatment antibody level reduction was more frequently seen in
those disease-free vs recurrent patients [5/6 recurrent patients did not
have decline in posttreatment E6 antibody levels]

Dahlstrom et al38 Magnetic programmable • Pretreatment HPV16 E6 seropositivity: 76/96 (79%)

• N ¼ 96 bead ELISA • Pretreatment HPV16 E6 seropositivity was associated with reduced risk
of recurrence/death (HR ¼ 0.3, 95% CI: 0.1-0.9)
• The posttreatment HPV16 E6 antibody level was nonsignificantly lower in
those with (n ¼ 8) vs without recurrence (n ¼ 23, randomly selected)

Fakhry et al39 ELIZA using the GST • Level of HPV16 E6 antibody declined over time after treatment
• N ¼ 60 capture method • Higher pretreatment HPV16 E6 antibody level was associated with
increased risk of recurrence
• Higher E6 antibody level at 3-month posttreatment was associated with
nonsignificant increased risk of recurrence

Zhang, et al42 Multiplex assay • HPV16 E6 seropositive at diagnosis: 98/115 (85%)

• N ¼ 115; 64 had • 0/7 seronegative cases had recurrence
posttreatment blood • Higher antibody level at diagnosis was associated with nonsignificant
sample higher risk of recurrence
• Posttreatment seronegative conversion rate was low (3/53)
• Posttreatment antibody level did not predict recurrence
HR, hazard ratio.

asymptomatic neck adenopathy together with clinical or distant failure, which has clinical implications in terms of up-
endoscopic examination for screening, as cervical adenopathy front treatment strategies and subsequent approaches to
is often an early finding in patients with HPVþ OPC. Notably, surveillance.
early identification of enlarged unilateral lymph nodes with In summary, the role of HPV16 E6 in surveillance seems to
T0-T2 tumor is considered stage I disease by the eighth edition be limited, and its prognostic role at diagnosis remains to be
TNM classification and has a very high cure rate.31 confirmed.
Another potential role for HPV E6 serology is in surveillance.
Several small studies (Table 1)38-42 have explored this domain
but have yielded inconsistent findings. All available studies Tonsillectomy and Risk of HPVþ
have observed a high proportion (480%) of HPV16 E6
seropositivity at diagnosis and a significant decline but still
OPC
detectable antibody level after treatment in most (490%) Most HPVþ OPC occurs in the tonsil and BOT regions. This
HPVþ OPC cases. Higher pretreatment HPV16 E6 antibody raises the hypothesis that tonsillectomy might reduce the risk
level has been nonsignificantly associated with a higher risk of of HPVþ OPC. Fakhry et al43 explored the association
recurrence.39,42 However, results concerning higher posttreat- between tonsillectomy and the incidence of OPC in the Danish
ment antibody levels have not been consistent; for example, Cancer Registry and found that remote tonsillectomy signifi-
high levels were nonsignificantly associated with higher cantly reduced the risk of diagnosis with tonsil carcinoma
recurrence risk in 2 studies,39,40 but an opposite observation (relative risk ¼ 0.40) but did not affect the risk of OPC overall.
was found in 1 study38 and no effect was seen in yet another A large nationwide cohort study of 225,718 patients in Sweden
study42 (Table 1). All of these studies suffer from small sample by Chaturvedi et al44 also showed similar findings. Another
size and low recurrence rates with consequent low event study of 1378 controls, 108 BOT cancer cases, and 198 tonsil
rates and insufficient power. There also was no obvious cancer cases45 showed that previous tonsillectomy reduced the
consideration to differentiate locoregional failure from odds of HPVþ tonsil cancer (OR ¼ 0.17); however, the risk of
20 S.H. Huang et al.

HPVþ BOT cancer was unexpectedly increased (odds ratio: mechanistic explanation for this hinges on the requirement for
2.46) compared to controls. The authors speculated that a oxygen to be present to indelibly “fix” free radical–mediated
tonsillectomy procedure could result in increased lymphoid DNA damage. In the absence of oxygen, the same radiation
tissue in the residual lingual tonsil and the BOT. dose results in less radical-mediated net DNA damage due to
In summary, current available data do not support using easier repair which leads to radioresistance.65 Hypoxia could
tonsillectomy as a prophylactic method for HPVþ OPC in also limit chemotherapy drug diffusion resulting in insufficient
general because of potential increased susceptibility to HPV effective killing. In addition, prolonged hypoxia can lead to cell
infection in the BOT as well as the morbidity of tonsillectomy. cycle inhibition and decreases in the growth fraction. Because
HPV vaccination is conceptually a safer and a potentially more the most chemotherapeutic agents have most effect on pro-
effective preventative strategy. liferating cells, the diminished kinetics could lead to
chemoresistance.64
The importance of hypoxia in HPVþ OPC has been
Molecular Basis for Favorable questioned. A re-analysis of the Danish Head and Neck Cancer
Study 5 trial based on tumor HPV status revealed that hypoxic
Outcomes of HPVþ OPC modification (using the antihelminthic compound Nimora-
Improved prognosis in patients with HPVþ OPC has been zole) improved outcome in HPV– patients but without
unequivocally demonstrated in many studies.16,17 The biologic apparent benefit in HPVþ patients, suggesting that hypoxic
basis of favorable outcomes of HPVþ OPC has not been fully radioresistance may not be as clinically relevant in the
elucidated. One hypothesis is that the HPVþ OPC tumors are latter.66,67 However, the lack of benefit from Nimorazole in
intrinsically radiosensitive or chemosensitive, possibly related the HPVþ patients appears not related to inherent differences
to lack of p53 mutations (wild type p53). Intact p53 in HPVþ in hypoxia sensitivity or response to Nimorazole. An in vitro
cells might have rendered them sensitive to treatment restoring study had shown that HPVþ and HPV– cell lines have the
apoptotic function. Increased intrinsic radio-chemo-sensitivity same resistance under hypoxic conditions and the same
for HPVþ OPC has been reported in many in vitro and in vivo relative sensitizer effect from Nimorazole.68 Therefore, it is
studies. Increased apoptosis after radiation has been observed possible that the lack of difference in clinical outcomes by
in many HPVþ OPC cell lines,46-49 likely related to compro- hypoxia modification in HPVþ patients is due to its overall
mised DNA repair capacity (intact p53) and cell cycle dysre- higher radiosensitivity offsetting the adverse consequences
gulation (increased G2/M cell cycle arrest by E7 protein).50 from hypoxia. Similar observations have also been made
Another hypothesis is that the presence of HPV viral protein recently for the hypoxic cell cytotoxin tirapazamine.69
may induce an increased immune response targeting HPVþ
tumor cells and may be responsible for a more favorable
prognosis.51 Spanos et al52 showed that there was no difference Extranodal Extension
in radiation sensitivity between HPVþ and HPV– xenografts in Historical data have shown that the presence of extranodal
immune-deficient mice, whereas HPVþ xenografts in immu- extension (ENE) is a high-risk adverse feature warranting
nocompetent mice were more sensitive than their HPV- addition of chemotherapy, at least in the postoperative setting
unrelated counterparts. The study highlighted the importance in HNC in general.70,71 However, its prognostic importance in
of host-immune response. Increased tumor-infiltrating lym- HPVþ OPC has been questioned as several recent studies
phocytes in HPVþ OPC compared to HPV– tumors have been failed to detect differences in outcomes by presence or absence
demonstrated in many studies.53-58 The level of tumor- of ENE in HPVþ OPC managed surgically.72-75 Admittedly,
infiltrating lymphocytes appeared to be highly correlated with most cases in published series also received adjuvant radio-
improved outcomes, even within HPVþ OPC, suggesting the therapy, but no difference was observed in disease-free survival
importance of host-immune response in cancer outcomes. between those who received postoperative chemoradiotherapy
Some studies59 have shown that radiotherapy resulted in a (POCRT) or radiotherapy alone (PORT) in HPVþ OPC with
dose-dependent decrease of surface expression of CD47, ENE, raising the potential that chemotherapy may be withheld
which led to increased phagocytosis and interferon gamma as a component of deintensification in HPVþ OPC with ENE
production to facilitate tumor clearance. when managed surgically.
In summary, the superior outcomes of HPVþ OPC is likely A recent study76 of 1043 surgically treated patients with
attributable to both intrinsic tumor factors and extrinsic HPVþ OPC, of whom 72% received POCRT, 16% received
microenvironmental factors60-62 and is notably also observed PORT, and 12% received no adjuvant treatment. The authors
with other treatments, including surgery. observed worse OS in ENEþ patients (confirmed in multi-
variable analysis [MVA]), but, among ENEþ patients, there
was no difference in 3-year OS between POCRT (n ¼ 305)
Revisiting Determinants of compared to PORT (n ¼ 66) [3-year OS: 89.3% vs 89.6%)].
Prognosis The lack of prognostication of ENE in POCRT over PORT
might reflect the radiosensitive nature of HPVþ OPC without
Hypoxia additional benefit of chemotherapy. However, the aforemen-
Hypoxia is a well-known adverse prognostic factor for tioned analyses were all retrospective, and it seems premature
HNC.63,64 Hypoxia could affect the efficacy of radiation. The to change practice based on these level 3-4 evidence. This
Biological and clinical implications of HPV-mediated OPC 21

question is currently being addressed in an ongoing clinical Clinical Oncology used a 20 pack-year cutoff.83 A subsequent
trial, Adjuvant De-escalation, Extracapsular Spread, P16þ, risk stratification analysis of 573 patients with HPVþ OPC84
Transoral Trial (ADEPT, NCT01687413). objectively derived 20 pack-years as the best cutoff, which
mirrors the earlier iteration of the RTOG 0129 data.83
Another aspect of smoking effect is the “smoking status,”
Smoking often classified as current smoker, former smoker, and non-
It is undisputable that smoking has a detrimental effect on smoker. The definition of “current” smoker has varied across
survival of all individuals and obviously by extension in OPC many studies. Some have defined it as smoking at the initiation
patients as well. However, the effect on oncologic outcome of of radiotherapy85 or at first follow-up after completion of
HPVþ OPC and the underlying mechanisms remain elusive. radiotherapy,81 while others also included smoking cessation
Potential hypotheses include the following: (1) Increased 3 months86 to 1 year87 before radiotherapy.
competing mortalities owing to smoking-related comorbidities
and second primary cancers77,78; (2) reduced treatment Choice of Outcome Endpoints
efficacy of radiotherapy due to hypoxia79; (3) impaired treat- Choice of outcome endpoint largely relies on the purpose of
ment tolerance due to associated comorbidity and side effects; the study. Progression-free survival is not an ideal endpoint for
(4) increased treatment-related mortality due to increased late understanding the smoking effect on disease control and how
toxicities80; and (5) possible effects on tumor biology. Uncov- it may guide treatment strategies as it is confounded by
ering these mechanisms is important as it will affect manage- all-cause mortality events. Although studies have shown that
ment strategies for HPVþ OPC smokers which account for smoking pack-years affects progression-free survival and
nearly 50% of the HPVþ population.16,17 Currently, patients OS,16,81 its effect on disease control and treatment efficacy
with HPVþ OPC with 410 pack-year smoking are excluded remains uncertain. If the unfavorable outcome of smokers is
from deintensification trials and the potential also exists to treat due to ineffectiveness of current treatment, a novel and
them with additional intensification though they may repre- possibly more intensified treatment is warranted. However,
sent the population least able to tolerate such approaches. as noted earlier, if it is due to impaired tolerance of smokers,
Contemporary studies of smoking effect on HPVþ OPC exposing them to more intensified treatment could worsen
population have suffered from several important methodology outcome.
problems and need to be interpreted in the light of a number of
caveats. Inadequate Event or Variable Ratio for Multivariable
Analysis
Combining HPVþ and HPV– in 1 Prognostic Model Construction of a reliable multivariable Cox regression prog-
In an earlier unplanned analysis of smoking effect,16,81 the nostic model generally requires ≥10 events per independent
study population comprised both HPVþ and HPV– patients, variable.88 Too small an event-variable ratio may affect the
and HPV status was used as prognostic factor for MVA and risk accuracy of regression coefficients for independent variables
stratification analysis. However, heavy smoking is unevenly and derive inadequate conclusions.89 A recent study showed
distributed in HPVþ and HPV– patients where 495% HPV– an increased risk of distant metastasis (DM) in active smokers,
patients are heavy smokers. Using HPV status in 1 multi- but the MVA included 5 variables for 31 events, thereby raising
variable model to address smoking effect might be problematic concerns about reliability.
as confounding prognostic contribution from HPV– disease A recent study of 82 HPVþ patients reported a compro-
may not be totally adjusted by HPV status, and other mised locoregional control (LRC) in current smokers. How-
prognostic effect related to HPV– disease might also not be ever, the event-variable ratio (o20 events for 5 variables) in
adequately accounted for. For example, the prognostic impor- MVA is concerning. In addition, potential misclassification of
tance of N classification26,30,31 and cisplatin dose intensity82 is tumor HPV status is a concern. The study used a polymerase
known to be different for these 2 diseases. There is no chain reaction method to determine HPV status. Such a
significant survival difference among seventh edition N0, N1, method is known to be oversensitive and unable to differ-
N2a, and N2b subsets in HPVþ but significant differences entiate “passenger” from “driver” HPV infection.90 In fact,
exist in HPV– disease.26 Effect of cisplatin dose is also different 4 HPV subtype 6 (a low-risk HPV subtype) cases were
between these 2 diseases.82 Using the same cutoff in 1 model classified as HPVþ, which is generally considered a misclassi-
would be unlikely to equally adjust for the relative contribution fication in this context. The possibility of misclassification of
of these 2 diseases. HPV– as HPVþ may partially explain a surprisingly low LRC
(only 78%) in the HPVþ cohort.
Variation in Definition of Smoking Variables (Smoking
Pack-Years and Smoking Status)
Accumulated tobacco exposure, quantified by smoking pack- Optimizing Therapeutic Ratio:
years, has been used in the 2 unplanned analyses of Radiation
Therapy Oncology Group (RTOG) trials (0129 and 9003) and
Work in Progress
a 10 pack-year cutoff has been used.16,81 Whether 10 pack- Most patients with HPVþ OPC have excellent oncologic
year is the optimal cutoff remains uncertain, and indeed the outcomes with current treatment algorithms. Refining treat-
earlier presentation of the 0129 study at American Society of ment to augment the therapeutic ratio according to a specific
22 S.H. Huang et al.

Table 2 Selected Clinical Trials for Nonmetastatic HPVþ OPC

Low-risk: deintensification treatment strategies
• Substitution of cisplatin by Cetuximab (eg, RTOG 1016, NCT01302834)
• Reduction of radiotherapy dose or chemotherapy intensity for definitive treatment (eg, NRG HN-002 and NCT02254278)
• Response adaptive approach
– Induction chemotherapy followed by lower radiation dose in good responders (eg, ECOG 1308 NCT01084083100)
– RT dose reduction to lymph nodes for those with no pretreatment hypoxia or resolution of hypoxia 1 week after chemoradiation
(NCT00606294)99
• Surgical resection with or without adjuvant chemoradiotherapy (eg, ECOG 3311 and NCT01898494)
• Proton therapy focusing on improvement of functional outcome by spatial sparing normal tissue:
– IMPT vs IMRT for improving swallowing function in OPC (NCT01893307)
High-risk: novel approach
• Immunotherapy102
– HPVþ T4 and N3 OPC Window Study: immunotherapy biomarker study followed by definitive chemoradiotherapy þ HPV
vaccine þ anti-PD-1/PD-L1 monoclonal antibody
IMPT, intensity-modulated proton therapy; IMRT, intensity-modulated radiotherapy.

risk profile and failure pattern has become one of the most (n ¼ 28). However, a recent study82 suggests less evidence of
active research areas. Investigational risk-adapted approaches benefit for delivering more than 2 cycles of high-dose cisplatin for
include deintensification of “low-risk” patients and novel HPVþ with the exception of T4 or N3 disease, thereby under-
approaches (generally additive) for “high-risk” patients. pinning another potential deintensification for many patients.
However, uncertainty exists regarding who is “low-risk” and The current eighth edition TNM for HPVþ OPC has
“high-risk,” which “risk” (risk of death or risk of DM) is most classified T1-2 with no nodes or with only ipsilateral neck
relevant, and finally what contemporary treatment options disease (seventh edition N0-N2b) as early stage (lowest risk for
should be considered for these different groups. Several death), based on the ICON-S study irrespective of smoking
deintensification and novel strategies are currently under status. It may be worth considering this group for investiga-
evaluation (Table 2). tional single modality approach, such as radiotherapy alone or
natural orifice minimal invasive surgery (transoral robotic
surgery or transoral laser microsurgery).
Defining Low Risk and High Risk
Ang et al16 classified mortality risk for RTOG 0129 patients
using HPV status and classified all patients with HPVþ OPC Investigational Deintensification Approaches
(including those with T4 or N3 disease), except 410 pack- Chemotherapy is considered a major contributor to late
year smokers with seventh edition N2b-N3 disease, as the toxicity, and deintensification approaches include reduction
“low-risk” group and suggested this category be considered a or omission of chemotherapy. One of the earlier approaches
deintensification trial candidate. However, concerns remain considered (eg, RTOG 1016, NCT01302834) was to replace
about whether the excellent outcomes seen can be retained cisplatin with cetuximab on the assumption that cetuximab
with deintensified approach in this “low-risk” group, some of had a putatively more favorable toxicity profile compared to
whom might be considered higher risk (ie, the aforementioned chemotherapy. More recently, concerns have emerged with
T4 or N3 groups) by contemporary criteria, as they had all this approach that include uncertainty regarding the efficacy of
received intensified treatment. cetuximab on DM in HPVþ OPC, the observation that HPVþ
In the intensity-modulated radiotherapy era, locoregional OPC rarely express epidermal growth factor receptor93,94 as
failure is no longer an overwhelming problem while DM has well as uncertainty about the toxicity profile when cetuximab is
emerged as the most common cause of death for this popula- combined with accelerated radiotherapy. The initial analysis
tion91,92 and merits attention when considering reduction or of the randomized IMCL-9815 Trial (Bonner et al,
omitting systemic approaches. O'Sullivan et al17 stratified NCT00004227)95 showed better LRC (50% vs 41%) but
patients with HPVþ by risk of DM and identified T1-T3, similar DM at 2-years (16% vs 17%) for radiotherapy with vs
N0-N2c as having a low risk for DM. Within this low-risk subset, without cetuximab. HPV status was not analyzed. A recent
they further showed an equivalent excellent outcome with unplanned analysis for the same study96 showed improved
radiotherapy alone vs chemoradiation in T1-3N0-N2a and LRC with cetuximab in HPVþ patients. However, the critical
N2b minimal smoker subgroup and proposed this subgroup DM comparison was not reported, notwithstanding the over-
as most suitable for chemo-omission trial candidates; the whelming nature of this endpoint on the survival of HPVþ
observation became the basis for the population studied in the OPC. Notably, the trial was conducted in the preintensity-
recently completed 2-arm trial HN-002 (NCT02254278). modulated radiotherapy era, and the LRC was quite low (65%
Whether N2b heavy smokers can be considered for radio- at 3-years) for RT alone compared to 490% LRC in
therapy-alone trials was uncertain owing to the small sample size contemporary series.97,98
Biological and clinical implications of HPV-mediated OPC 23

Besides reduction or omission of chemotherapy, other Conclusions

approaches under investigation include reducing radiotherapy
dose or radiotherapy volume (eg, NRG HN-002 and In response to the rapid emergence of HPVþ OPC, which
NCT02254278), and response-adapted approaches99,100 as essentially surprised the medical community initially, head and
well as the use of transoral robotic surgery or transoral laser neck oncology practitioners have now achieved rapid progress
microsurgery. in understanding the biological mechanisms underpinning its
unique clinical behavior and are developing strategies that
address prevention, screening, and early detection, and are
Investigational Novel Approach for High-Risk optimizing the therapeutic ratio for this disease. Obviously, the
HPVþ OPC – Immunotherapy ultimate goal through these strategies is to eradicate this disease
The current intensified treatment approach for high-risk (T4 or entirely.
N3) HPVþ patient remains unsatisfactory. The 3-year OS was
only 79% even with high-dose chemotherapy combined with
concurrent radiotherapy.82 Further intensified treatment by References
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combining cetuximab with chemotherapy seems unlikely to be
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Though studies are underway, there are no results available 2. Marur S, D'Souza G, Westra WH, et al: HPV-associated head and neck
to support modifying first-line treatment for this patient cancer: A virus-related cancer epidemic. Lancet Oncol 11:781-789, 2010
population. A novel approach under investigation is 3. Ang KK, Sturgis EM: Human papillomavirus as a marker of the natural
history and response to therapy of head and neck squamous cell
immunotherapy.102,103
carcinoma. Semin Radiat Oncol 22:128-142, 2012
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