2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

HPV-INDUCED OROPHARYNX CANCER
analysis demonstrated the most pronounced therapeutic
benefit in patients with oropharynx primaries, N� presentations,
and treatment with accelerated fractionation.
Concurrent chemoradiation represents the largest experience
in the nonsurgical management of advanced HNC.
Pignon and colleagues performed an extensive metaanalysis
of individual patient data from 17,346 patients
enrolled on 93 randomized controlled trials comparing RT
alone against RT and chemotherapy. 7,8 These trials were
published from 1965 to 2000, and it is important to recognize
that this era was before the use of taxane-based chemotherapy
in HNC. Their analysis demonstrated a 21% reduction
in the risk of recurrence or death as a result of the addition
of concurrent chemotherapy to RT. This risk reduction
corresponded to a 6.5% absolute improvement in 5-year
survival (33.7 vs. 27.2%). The majority of this improvement
was attributable to a 13% absolute improvement in locoregional
disease control. A more modest 2.9% absolute
improvement in distant failure was attributable to concurrent
therapy. The analysis also showed that the use of
concurrent cisplatin was most important. Induction chemotherapy
did not provide an improvement in locoregional
disease control.
The role of induction chemotherapy continues to be investigated.
Several phase III trials have confirmed that the
addition of a taxane to a platinum and flurorouracil (FU)–
based induction regimen yields superior survival compared
with induction with platinum and FU only. Most of these
trials administered substandard locoregional therapy, however.
9-11 Whether taxane-based induction followed by stateof-the-art
concurrent chemoradiation is superior to concurrent
chemoradiation alone, however, remains unknown.
Toxicity considerations must be incorporated into the
treatment decision-making process for HNC in general and
OPC in particular. The standard investigational treatment
paradigm has been one of therapeutic intensification via the
combination of multiple modalities with increasing disease
stage and tumor burden. Concurrent chemoradiation programs
do improve overall efficacy, but at the price of a
considerable increase in toxicity. The incidence of grade 3
confluent mucositis approximately doubles with the addi-
KEY POINTS
● The incidence of oropharynx cancer is increasing even
as the incidence of head and neck cancer (HNC) in
other locations is decreasing.
● This increase is attributable to the human papillomavirus
(HPV), which causes the majority of cases of
oropharynx cancer.
● The prognosis of HPV-associated HNC is much more
favorable than that of HPV-negative HNC.
● The favorable prognostic effect of HPV positivity is
independent of treatment platform, although a history
of cigarette smoking appears to negate some of
the benefit.
● Trials under development for HPV-positive HNC will
explore the concept of therapeutic de-escalation designed
to reduce treatment-associated morbidity with
preservation of thereapeutic efficacy.
tion of concurrent chemotherapy to RT-alone regimens. The
percentage of patients experiencing serious late toxicities
including cervical fibrosis, dental disease, and neuropathy
increases by approximately 50%. 12 The addition of neck
dissection after concurrent chemoradiation also substantially
increases the risk of late toxicity after concurrent
chemoradiation. 13 Recent developments in the use of postchemoradiation
computed tomography and positron emission
tomography scanning, however, have substantially
improved the ability to separate those patients who do
require adjuvant neck dissection from those who do not. 14
Bentzen and Trotti analyzed the Radiation Therapy Oncology
Group (RTOG) portfolio of randomized trials in HNC
that have either compared different RT schedules against
one another or compared RT and chemotherapy against RT
alone. 15 They showed that both induction chemotherapy and
concurrent chemotherapy approaches increased the overall
burden of severe toxicity on the patient by five-fold compared
with conventionally fractionated irradiation. Moreover,
their data clearly demonstrated that a single patient
can have more than one severe toxicity event, something
that is not routinely captured in conventional toxicity scoring
systems.
The toxicity of a given treatment strategy can also be
judged by the probability that a patient will be able to
complete the entire prescribed course of treatment. Sequential
chemoradiation regimens (induction chemotherapy followed
by concurrent chemoradiotherapy) sound a cautionary
note in this regard. Compliance rates with an entire course
of treatment in the published clinical trials range from
only 50% to 73%. 10,16 Sequential therapy regimens that use
state-of-the-art concurrent chemoradiation schemes appear
to be particularly problematic from a compliance standpoint.
9,17
A recent evaluation of tissue obtained through the Surveillance,
Epidemiology and End Results (SEER) registries
of patients with OPC receiving treatment from 1984 to 2004
shows an increasing incidence of OPC even as the overall
incidence of HNC is declining. 18 OPC now constitutes the
most prevalent subtype of HNC within the United States.
Moreover, the majority (approximately 70%) of these OPCs
are HPV positive. Current estimations are that by the year
2020 the annual number of HPV-positive OPCs will exceed
the annual number of HPV-positive uterine cervix carcinomas.
Additional projections are that there will be more than
15,000 cases of HPV-positive OPC per year by 2030.
The SEER analysis included patients who received various
types of treatment. The overall 5- and 10-year survivals
were approximately two times better for those patients with
HPV-positive disease. HPV-positive disease appears to convey
this more favorable prognosis in a platform-independent
fashion. RTOG-0129 was a phase III trial that compared
standard fractionation RT against accelerated fractionation
RT, with both arms receiving concurrent cisplatin chemotherapy.
19 The accelerated fractionation arm received two
cycles, and the standard fractionation arm received three
cycles. There was no difference in overall outcome. Therefore,
the patients from the two arms were pooled, and
outcomes were reanalyzed as a function of HPV positivity as
determined by p16 immunohistochemistry. The probability
of long-term survival was more than three times greater for
HPV-positive patients than for their HPV-negative counterparts
(HR � 0.29; p � 0.001). A history of cigarette smoking
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