2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Management of Human Papillomavirus–Induced
Oropharynx Cancer
Overview: Oropharynx cancer (OPC) constitutes the most
common location for squamous-cell head and neck cancer,
and most OPC is caused by the human papilloma virus (HPV).
Early-stage (American Joint Committee on Cancer [AJCC]
stage I and II) disease should be treated with single modality
surgery or radiotherapy whenever possible. More advanced
presentations generally require combined-modality therapy
with various combinations of surgery, radiotherapy, and che-
THE VAST majority (� 90%) of squamous-cell head and
neck cancers (HNCs) that are induced by the human
papillomavirus (HPV) originate within the oropharynx. This
anatomic region comprises the tonsils, soft palate, and base
of tongue. Understanding the general management principles
of oropharynx cancer (OPC) is central to comprehending
the development of new therapeutic options for HPVpositive
OPC. The first step in this process is to recognize
that OPC can be clinically divided into early-stage and
advanced-stage presentations. Early-stage presentations
typically include T1N0 and T2N0 presentations (stage I and
II), whereas advanced-stage disease is more heterogeneous,
with presentations ranging from T1N1 to T4N3 (stage III to
IVB).
The fundamental management tenet for early-stage disease
is to adopt a strategy that maximizes the likelihood
that the disease can be treated with single-modality therapy—either
surgery or radiotherapy (RT) alone. These two
modalities have equivalent efficacy in the early-stage setting.
The rationale for the use of a single modality is to
minimize morbidity, which invariably increases in step with
the use of multiple therapeutic modalities. Surgical management
consists of resection of the primary site, most often
with an ipsilateral neck dissection, whereas definitive RT
treats the same primary tumor site and ipsilateral lymph
nodes as surgery. The advent of minimally invasive surgical
techniques including transoral robotic resection and transoral
laser excision and the increasing adoption of intensitymodulated
RT (IMRT) have all led to substantial reductions
in the long-term functional morbidity of treating early-stage
OPC. The National Comprehensive Cancer Center Network
(NCCN) Head and Neck Cancer Guidelines provide additional
detail regarding the choices for radiation fractionation
schemes (www.nccn.org). Postoperative irradiation for
early-stage disease should be used only on the basis of
adverse histopathology including perineural invasion, positive
margins, the presence of multiply involved lymph nodes,
or the presence of extracapsular nodal extension. Conversely,
when RT is used as the primary modality, surgery
should be used only for the presence of persistent disease or
for the salvage of recurrent disease. Primary RT is usually
preferred for tumors originating in the base of tongue or
extending from the tonsil onto the soft palate close to the
midline because of the higher risk of occult contralateral
lymph node involvement, which necessitates treatment of
both sides of the neck. These regions can usually be treated
with less long-term functional morbidity by using RT as
opposed to bilateral neck dissection.
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By David Brizel, MD
motherapy or molecularly targeted therapy. All of these approaches
expose patients to a substantial risk of serious
long-term functional morbidity. HPV-induced OPC has a very
favorable prognosis compared with its HPV-negative counterpart
irrespective of the treatment platform that is used.
Current clinical trials are investigating the concept of therapeutic
deintensification with the dual objectives of decreasing
toxicity and maintaining efficacy.
T1N1 and T2N1 presentations are classified as stage III
and technically advanced disease, but the management
principles for stage I/II presentations are still generally
applicable, namely treatment with primary surgery or RT as
single modality with an understanding, however, that the
larger burden of disease increases the probability that the
addition of adjuvant neck dissection or postoperative irradiation
will be necessary. Traditionally, primary nonsurgical
management has assumed the most prominent role for the
management of more extensive stage III and IV presentations,
with surgery being used more in an adjuvant setting
(neck dissection or salvage role for residual/recurrent disease
at the primary site). Three different strategies can
be considered as standards of care for management of
advanced-stage disease: RT alone using modified fractionation,
RT plus concurrent epidermal growth factor receptor
(EGFR) blockade, and RT and concurrent chemotherapy.
Randomized trials have confirmed improvements in locoregional
control with the use of both hyperfractionation
and accelerated fractionation by means of improvement in
locoregional disease control. 1-3 A recent meta-analysis from
Bourhis and colleagues evaluated updated individual patient’s
data from 6,515 patients in 15 randomized trials of
patients with stage III/IV oropharynx and larynx carcinoma.
4 It showed an 8.2% absolute difference in 5-year
survival for patients who received altered fractionation RT
compared with conventional once-daily RT (36.7% vs. 28.5%,
respectively).
EGFR is overexpressed in the majority of patients with
head and neck squamous-cell carcinoma. Bonner and colleagues
conducted a prospective randomized trial that
tested the value of adding EGFR blockade to a course of
RT. 5,6 Four hundred twenty-four patients were randomly
assigned to receive either RT alone or RT plus weekly
cetuximab, a chimeric monoclonal antibody to the EGFR
receptor. The majority of these patients had oropharynx
primary tumors, and 75% of them received treatment with
accelerated or hyperfractionated irradiation. The RT/cetuximab
patients had significant improvements in median survival
(49 months vs. 29 months; hazard ratio [HR] � 0.73;
p � 0.02), and 5-year overall survival (46% vs. 36%). Subset
From the Duke University Cancer Institute, Durham, NC.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to David Brizel, MD, Duke University Cancer Institute, Box 3085
DUMC, Durham, NC 27710; email: david.brizel@duke.edu.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10