Current Status and Future Directions of

Treatment Deintensification in Human

Papilloma Virus-associated Oropharyngeal
Squamous Cell Carcinoma
Bhishamjit S. Chera, MD,*,† and Robert J. Amdur, MD‡,§

The prevalence of patients with human papilloma virus (HPV)-associated oropharyngeal

squamous cell carcinoma (OPSCC) is rapidly increasing, and it is now well known that these
patients have a significantly better prognosis than patients with HPV-negative OPSCC.
Though standard treatments result in excellent cancer control, they are also associated with
substantial long-term toxicity. There is now great interest in evaluating less intensive (ie,
deintensified) treatment regimens to improve the therapeutic ratio (maintain excellent cancer
control and decrease toxicity). There are many different approaches that are being studied, and
each have their own caveats, with varying degrees of actual deintensification. In this article, we
critically review the current landscape of emerging deintensified treatment paradigms and
future direction of the treatment of HPV-associated OPSCC.
Semin Radiat Oncol 28:27-34 C 2017 Elsevier Inc. All rights reserved.

Introduction stratification based on HPV status, tobacco smoking history,

and nodal stage is now standardly used in clinical practice

T he prevalence of oropharyngeal squamous cell carcinoma

(OPSCC) has been rapidly increasing over the past 20-30
years and is thought to be directly related to the corresponding
increasing incidence of high-risk human papilloma virus
(HPV) infection of the oropharynx.1-3 Retrospective analyses
of several clinical trials have shown that patients with HPV-
associated OPSCC have a better response rate to chemotherapy
and radiation and a significantly better local-regional control
and overall survival (OS) with standard treatments as
compared to patients with HPV-negative tumors.4-7 Risk
*Department of Radiation Oncology, University of North Carolina School of
Medicine, Chapel Hill, NC.
†
Lineberger Comprehensive Cancer Center, University of North Carolina
‡
Hospitals, Chapel Hill, NC.
Department of Radiation Oncology, University of Florida Hospitals,
Gainesville, FL.
§
Shands Cancer Center, University of Florida Hospitals, Gainesville, FL.
Funding source: University of North Carolina School of Medicine, Department
of Radiation Oncology and University of Florida School of Medicine,
Department of Radiation Oncology.
Conflicts of interest: none.
Address reprint requests to Bhishamjit S. Chera, MD, Department of Radiation
Oncology, University of North Carolina Hospitals, 101 Manning Dr, CB
#7512, Chapel Hill, NC 27599-7512. E-mail: bchera@med.unc.edu
when counseling patients on their prognosis. Patients with the
most favorable prognosis are those with HPV-associated
OPSCC, ≤ 10 pack years, and oN2c/N3 stage.6,8
There are 3 standard definitive treatment paradigms for
OPSCC: (1) transoral surgery followed by pathological risk-
adapted radiotherapy (RT) and chemotherapy, (2) concurrent
RT and chemotherapy (ie, chemoradiotherapy [CRT]), and (3)
neoadjuvant chemotherapy followed by CRT. The “preferred”
standard treatment depends on institutional biases; however,
overall the most used organ preservation approach is con-
current CRT (without surgery and neoadjuvant chemo).
These standard treatments result in excellent cancer control
and survival in patients with HPV-associated OPSCC; how-
ever, they are associated with substantial toxicity.9-13 Thus, we
may be “over treating” many patients with HPV-associated
OPSCC. There is now great interest in reducing the intensity of
treatment with the goal of decreasing toxicity while maintain-
ing cancer control (ie, improving the therapeutic ratio). There
are many ways to deintensify treatment each with their own
“pros” and “cons,” and often the reduction in treatment
intensity is small or reduction in 1 treatment modality is
offset with an increase in another.14 We here-in review and
discuss the various ongoing deintensification approaches and

http://dx.doi.org/10.1016/j.semradonc.2017.08.001 27
1053-4296/& 2017 Elsevier Inc. All rights reserved.
28
forecast the future direction of deintensification for HPV-
associated OPSCC.
Transoral Surgery Paradigm
Performing surgery first provides pathological information that
can be used to tailor the use of adjuvant treatment, with the
goal of reducing or omitting radiation and chemotherapy.
Proponents of the definitive surgery approach believe that the
toxicities of surgery ± radiation and chemotherapy are fewer
than definitive CRT. Conventional surgery for OPSCC has
been open en bloc resection with free flap reconstruction
which, when compared with CRT, has similar outcomes but
higher severe or fatal complications.13
Newer transoral surgical approaches (ie, transoral laser
microsurgery [TLM] and transoral robotic surgery [TORS])
are garnering much interest for the treatment of HPV-
associated OPSCC because these techniques are less invasive
and thus have less toxicity. In fact, the toxicity of TLM and
TORS ± CRT or RT has been suggested to be less than
definitive CRT.15,16 Because of the use of magnification and the
transection of the tumor during surgery (TORS allows for en
bloc resection), the “host-tumor” interface is better visualized,
allowing for more precise negative margin resections, max-
imizing tumor removal, and limiting removal of normal
healthy tissue, resulting in “surgically targeted therapy.16,17”
Furthermore, similar to CRT, HPV-associated OPSCC is also
associated with a better prognosis when treated with primary
surgery.7 The major potential benefits of primary TLM and
TORS are reduction in surgical morbidity and reduction in the
intensity of CRT without compromising oncologic outcomes.
Primary surgery provides pathologic information that influen-
ces adjuvant treatment recommendations. RT and chemo-
therapy may be omitted or at least the RT dose may be reduced.
The deintensification of RT and chemotherapy after TLM or
TORS has been arbitrary, institution specific, and has not been
studied in a controlled manner. The eastern cooperative
oncology group (ECOG) is currently conducting a prospective
randomized phase II study (ECOG3311) in which patients
with HPV-associated T1-2, N1-N2b OPSCC all have transoral
surgery followed by risk-adapted adjuvant radiation and
chemotherapy.18
Omission of Radiation
There is no question that single modality treatment with TLM
and TORS alone will significantly reduce toxicity. Interestingly,
most patients (70%-80%) who receive TLM and TORS receive
adjuvant RT.16 Currently on the ECOG3311, only ~11% of
enrolled patients are being observed after transoral surgery (ie,
not receiving postoperative radiation and chemotherapy).18
Thus, omission of RT may be a reality for only a small number
of patients.
Grant et al19 reported on 69 patients treated with TLM alone
at the Mayo Clinic; 44 patients who did not have indications
for RT and 25 patients who did have indications for RT in the
neck, but refused. The 5-year local control for the entire group
B.S. Chera and R.J. Amdur
was 94% and the 5-year local-regional control for those with
and without RT indications was 84% vs 74%. However, in a
multicenter TLM study, patients who did not receive adjuvant
RT had worse overall and disease-free survival.16 One may
argue that all patients with node-positive OPSCC require
adjuvant RT because of the risk of occult disease in the
ipsilateral retropharyngeal (~20%)20 and cranial level II nodes
that are not surgically treated. Even in those who are node
negative, the retropharyngeal nodes may still be at risk.
What about excluding the primary site from the RT treat-
ment volume? Many patients do not have indications for
postop RT related to the primary site (margin not close and no
perineural invasion). In patients with indications for RT to the
neck (multiple positive nodes or extranodal tumor extension)
but no indications at the primary site, it is reasonable to
exclude the primary site operative bed from the RT target
volume.
Historically, a negative margin was considered to be
≥5 mm, close margins were o5 mm, and positive was tumor
on the inked en bloc specimen. The definition of pathologic
margins is different with transoral surgical procedure. There is
no close margin designation and a negative margin is defined
as a negative inked margin, regardless of distance.21 Margins
are defined and interpreted differently with transoral surgeries
because margins are carefully mapped intraoperatively under
better visualization (as compared to conventional surgical
techniques). Furthermore, for resection of the tonsil, the
superior constrictor muscle is taken with the resection and is
considered a natural barrier of spread. The mean superior
constrictor thickness is ~2 mm, and even though tumor often
abuts this muscle, because it is considered a barrier to spread,
what historically would be considered a close margin is
considered negative with transoral surgery. Thus, close mar-
gins are not defined with transoral surgeries and the reported
rate of positive margins is low o10%, and therefore one could
argue that the primary site need not be treated with RT.
Omission of the primary site in intensity-modulated radio-
therapy (IMRT) plans will reduce the mean dose to the primary
site to ~40 Gy.22 Mean doses to the contralateral parotid and
pharyngeal constrictors are not significantly reduced; however,
the mean dose to the oral cavity is reduced by a mean of
20 Gy.22 With primary site avoidance IMRT plans, swallowing
function may not be improved. From the prospective series
from Haughey et al, patients with swallowing function scores
of 0-2 (normal swallowing to mild dysphagia) were not
significantly different between patients treated with TLM alone
(47/52 patients) or TLM plus adjuvant RT (103/117); P ¼
0.79. Thus, even the complete omission of RT did not improve
swallowing function. This suggests that sparing the primary
site with IMRT may not result in less dysphagia.
The low-dose radiation bath associated with IMRT techni-
ques makes it difficult to completely avoid or spare the primary
site. Proton RT (especially intensity-modulated proton
therapy) has the advantage of eliminating the low-dose bath
resulting in better avoidance of the primary site. The Mayo
clinic is currently conducting an observational study of patients
with OPSCC who have indications for RT only to the neck after
transoral resection, and neck dissection will be treated with
Treatment deintensification in HPV-associated OPSCC carcinoma
postoperative mucosal-sparing proton beam therapy
(NCT02736786, clinicaltrials.gov).
Lowering the Radiation Dose
Transoral surgery will, at the very least, allow for a reduction in
RT dose. For patients with indications for RT, the standard
adjuvant RT doses have been 60 Gy (close margins, ≥2
positive nodes, perineural invasion, and lymphovascular space
invasion) or 66 Gy (positive margins or extracapsular spread
[ECS]). Thus, on average, patients with indications for RT
would be spared 4-10 Gy. It is debatable whether a TLM or
TORS procedure is less intensive than 10 Gy. Proponents of
transoral surgery suggest that a 10-Gy reduction in dose to the
pharyngeal constrictors will have a significant effect on long-
term dysphagia.16 The available data (ie, definitive CRT) for the
dose-effect relationship for dysphagia suggest that doses
≥50 Gy to the pharyngeal constrictors correlate with late
dysphagia.23,24 The dose-response may be different in patients
undergoing transoral surgery. In general, though, partial
sparing of pharyngeal constrictors should be more feasible
when treating the oropharynx to a total dose of 60 vs 70 Gy.
It is unknown whether lower adjuvant RT doses
(ie, ≤60 Gy) may be equally efficacious in HPV-associated
OPSCC. Ma and colleagues at the Mayo Clinic (Rochester,
MN) have recently completed a phase II study evaluating a
de-escalated adjuvant therapy regimen of 30 Gy (1.5 Gy/fx
twice a day; intermediate pathological risk) or 36 Gy
(1.8 Gy/fx, twice a day; high pathological risk) with concurrent
weekly docetaxel 15 mg/m2. Preliminary results (verbal com-
munication with Ma) show excellent local-regional control and
preservation of swallowing function. They are currently
conducting a phase III study comparing this experimental
arm to standard of care 60 Gy (2 Gy/fx, 4 times a day) with
concurrently weekly cisplatin 40 mg/m2 (NCT02908477,
clinicaltrials.gov). The primary endpoint is grade 3-5 toxicity.
Omission of Chemotherapy
Based on the individual Radiation Therapy Oncology Group
(RTOG) and European Organization for Research and Treat-
ment of Cancer (EORTC) randomized studies and the
subsequent exploratory combined analysis, patients with
positive margins and extracapsular extension derive the great-
est benefit from the concurrent addition of cisplatin to post-
operative RT.25-27 Interestingly, chemotherapy is used less
often than expected after transoral surgery. This is in part
explained by the low rates of positive margins (see above
section on lowering the RT dose) and absence of the “close
margin” historical convention. However, the incidence of
nodal extracapsular extension has not changed from historical
en bloc open surgeries. For example, only 16% of patients in
the multicenter TLM study received adjuvant CRT, even
though 64% had ECS and 7% had positive margins.16 Despite
the deintensification of chemotherapy, the overall local-
regional control rate was 93%. Proponents of transoral surgery
do not consider ECS to be a poor prognostic factor and have
published retrospective analyses showing that the presence of
29
ECS does not adversely affect disease control and survival in
patients with HPV-associated OPSCC.28 Adjuvant chemo-
therapy may not be needed because of the enhanced radio-
curability of HPV-associated OPSCC.
Morbidity of Neck Dissection
The reported long-term outcomes of transoral surgery studies
focus on reporting excellent overall quality of life, preservation
of swallowing function, and low rates of permanent feeding
tube use. Neck dissections are standardly part of the transoral
surgical paradigm, which have associated known moderate
rates of morbidity, especially with the addition of postoperative
RT. Many patients experience lymphedema, fibrosis, and
worsening cosemsis after a neck dissection and postoperative
RT. Marginal mandibular and cranial nerve eleven (among
other nerves) injuries can occur as well. Proponents of transoral
surgery paradigm do not discuss or comment on the morbidity
of neck dissections. Historically, avoidance of neck dissections
was thought to be important; however, the side effects of neck
dissection are not considered in the transoral surgery
approach.
Neoadjuvant Chemotherapy
Paradigm
HPV-associated OPSCC has been observed to have a better
response rate to neoadjuvant chemotherapy4 compared to
HPV-negative disease, thus reducing the radiation dose
and volume after which neoadjuvant chemotherapy may
be possible. The trade-off is an additional 9 weeks of
intensive chemotherapy for a reduction of 1 week (ie,
10 Gy) of RT. A disadvantage of this approach is that the
overall treatment time is increased, thus prolonging the
duration, frequency, and severity of toxicities. The net
deintensification may be “zero” because 1 modality (ie, RT)
is being minimally decreased, while the other (ie, chemo-
therapy) is maximally intensified.
Although the local-regional control of HPV-associated
OPSCC is excellent, approximately 10%-15% will develop
distant metastases.6,8 In fact, most patients who die of HPV-
associated OPSCC die from distant recurrence. This clinical
observation has led to the false conclusion that patients with
HPV-associated OPSCC have a higher rate of distant recur-
rence and that their distant recurrences are more aggressive.
These conclusions are used to support the argument that the
neoadjuvant chemotherapy deintensification approach has the
advantage of reducing the radiation dose while still intensively
treating distant metastases. However, the objective data have
shown similar distant recurrent rates for HPV-negative and
HPV-positive OPSCC6,8,29 and that the survival after develop-
ment of distant metastases is better in patients with HPV-
associated OPSCC.29
ECOG recently published its results of a phase II trial
(E1308) of neoadjuvant chemotherapy followed by reduced-
dose RT and weekly cetuximab.30 Eighty patients were
enrolled. Patients received 3 cycles of neoadjuvant
30
chemotherapy (cisplatin 75 mg/m2, paclitaxel 90 mg/m2, and
cetuximab 250 mg/m2) followed by clinical response adjusted
RT with concurrent cetuximab. If patients had a complete
clinical response to neoadjuvant chemotherapy at the primary
site (manual palpation and endoscopic evaluation) or nodal
sites (palpation), they received reduced-dose RT to 54 Gy. If
there was a partial clinical response, the RT dose was 69.3 Gy.
RT dose specification was done separately for primary and
nodal sites: for example, patient could have complete response
at the primary site which would receive 54 Gy and a partial
response in the neck which would receive 69.3 Gy. Seventy
percentage of patients had complete responses at the primary
site and 58% at the nodal sites. Thirteen (16%) patients
received the incorrect RT doses (protocol violations): for
example, patient with complete response at primary site
received 69.3 Gy. With a median follow-up of 35 months,
the 2-year progression-free survival (PFS) and OS was 78%
and 91%, respectively, for the intent to treat analysis. All
recurrences occurred in patients with 410 pack years smok-
ing history. The subset of patients with the best outcomes were
those with ≤10 pack years and oT4, N2c (2-year PFS 95%,
2-year OS 95%).
The authors do not provide details on how many patients
were able to receive reduced-dose RT to both the primary and
nodal sites. It is likely that there were very few patients who had
a complete response in both their primary and nodal sites and
thus truly received deintensified RT. Complete response rates
to neoadjuvant chemotherapy did not correlate with smoking
status (complete response rate was only 45% in never
smokers). This study does not answer the question whether
neoadjuvant chemotherapy is needed to deintensify RT—is this
trade-off necessary?
Targeted Therapy Paradigm
Cetuximab, in conjunction with RT, has been shown to
improve survival in locally advanced head and neck cancer
while not increasing the rate of ≥grade 3 mucositis or
dysphagia, late effects, or worsening quality of life.31 The
prevailing opinion is that cetuximab is less toxic than cisplatin
and cetuximab is used, standardly, as an alternative to cisplatin.
As a way to deintensify therapy, NRG Oncology
(NCT01302834) and Tasman Radiation Oncology Group
(TROG) (NCT01855451) are conducting phase III studies
evaluating the noninferiority of cetuximab compared with
high-dose cisplatin in HPV-associated OPSCC. The RT dose
will not be decreased in this study; thus, the major long-term
toxicities related to RT (ie, xerostomia and dysphagia) may not
be reduced.
The assertion that concurrent cetuximab is less toxic than
concurrent chemotherapy is being challenged. An Italian
randomized phase II study of RT with concurrent weekly
cisplatin 40 mg/m2 vs weekly cetuximab 250 mg/m2 showed
similar rates of ≥grade 3 mucositis between the 2 arms, with
more treatment breaks (410 days) and severe or fatal adverse
events associated with the cetuximab arm.32
B.S. Chera and R.J. Amdur
The efficacy of cetuximab in HPV-associated OPSCC is
also being questioned. Epidermal growth factor receptor
expression is lower in HPV-positive OPSCC as compared
to HPV-negative OPSCC,33,34 and emerging data suggest
that cetuximab may be less efficacious than cytotoxic
chemotherapy when combined with definitive RT.32,35,36
Proton Paradigm
The promise of protons is in its dosimetric advantages of
reducing the low-radiation dose beam path-related toxicity,
namely reductions in anterior oral cavity and posterior neck/
brainstem/brain incidental irradiation.37,38 It is reasonable to
hypothesize that the dosimetric benefits of protons could
translate to lower symptom burden and better quality of life in
patients with HPV-associated OPSCC. Early, preliminary data
from a retrospective comparison of patients treated at MD
Anderson Cancer Center with IMRT vs intensity-modulated
proton therapy showed no clinically meaningful differences in
patient-reported outcomes. Unfortunately, mucositis, pain,
xerostomia, and dysphagia, the most important and ubiqui-
tous toxicities oropharyngeal cancer patients experience, were
similar between the 2 cohorts.37,38 We interpret these negative
results to support the rationalization that it is the total-dose and
high-dose volume that are most associated with toxicity, and
that deintensification efforts that reduce the total-dose and
high-dose treatment volumes will have the biggest impact. MD
Anderson Cancer Center and others are currently conducting a
randomized control trial to further assess the possible benefits
of proton therapy in patients with OPSCC (NCT01893307
clinicaltrials.gov).
Reduction Elective Nodal
Radiation Volume or Dose
Paradigm
Omitting contralateral neck radiation significantly improves
patient-reported quality of life. Ipsilateral radiation can be
safely done in patients with well-lateralized tonsil primaries
that neither invade the base of tongue nor have significant soft
palate invasion (extent of invasion is ≥1 cm away from the
uvula).39 Though the extent of the primary tonsil cancer
dictates the risk of contralateral nodal involvement, most of the
patients reported in the retrospective unilateral tonsil irradi-
ation studies had N0 to N2b disease, with the majority having
N0 to N2a disease and those with N2b having low volume of
neck disease.39-42 These data were generated in the pre-HPV
era; they are applicable to patients with well-lateralized HPV-
associated OPSCC. Though the burden of nodal disease is
higher in HPV-associated OPSCC, the increase in N-stage
designation has primarily been N2a-N2b (not bilateral, N2c) in
the HPV era, suggesting that regional spread patterns have not
changed and, in appropriately selected patients, ipsilateral RT
is safe.43
Nevens et al44 have conducted a randomized study inves-
tigating the reduction of the dose to elective nodal levels. Two
Treatment deintensification in HPV-associated OPSCC carcinoma
hundred patients were randomized to either 50 Gy (control) or
40 Gy (experimental) elective nodal radiation doses. Both
nonoropharynx and oropharynx primaries were allowed,
and only ~10% of enrolled patients had HPV-associated
OPSCC. The primary endpoint was dysphagia at 6 months,
which was not significantly (clinically or statistically) different
between the 2 arms. The local failure rate was similar between
each arm; however, the regional failure rate was 5.5% in the
50 Gy arm vs 13.4% in the 40 Gy arm (P ¼ 0.08).
These same researchers have also presented preliminary data
on another randomized phase II study investigating a reduc-
tion in the irradiated volume of the elective neck.45 Based on
the results of the aforementioned study, the elective nodal
radiation dose was 40 Gy. In the experimental arm, contrala-
teral levels 3 and 4 were omitted. One hundred patients were
randomized, and both oropharynx and nonoropharynx pri-
mary sites were allowed. Fifty percentage of enrolled patients
had OPSCC; however, the HPV status was unknown for most
of them. Primary objective was toxicity at 6 and 12 months,
which were not significantly different (grade ≥ 2 dysphagia,
xerostomia, and fibrosis). With a minimum follow-up of
1 year, there were no statistical difference in local control
(86% vs 90%, P 4 0.05) or regional control (84% vs 92%,
P 4 0.05), with 8 regional failures (1 in the nontreated elective
neck) in the experimental arm vs 4 in the control arm.
Taken together, these 2 prospective studies provide insuffi-
cient data to support the use of reducing the elective nodal
radiation dose and volume as a means of deintensification.
Long-term toxicity was not significantly reduced, and though
not statistically significant, there were more regional failures in
the electively irradiated neck.
The University of Chicago has investigated the use of
intensive induction chemotherapy followed by limiting radi-
ation volume to the original sites of gross disease at the primary
site and neck.46 Ninety-four patients were enrolled in a phase
2 clinical trial and 59 patients (76%) had OPSCC of which
83% were HPV-associated. All patients received induction
chemotherapy (cisplatin, paclitaxel, cetuximab, and
±evorlimus) followed by THFX (paclitaxel, fluorouracil,
hydroxyurea, and 1.5 Gy twice daily RT every other week).
Patients who were good responders to induction chemo-
therapy had 450% radiographic response to targeted lesions.
Patients with good response to chemotherapy only had their
gross tumor (plus 1.5 cm margin) treated to 75 Gy (no elective
nodal radiation). Patients with ≤50% (nonresponders) radio-
graphic response had their gross tumor treated to 75 Gy and
the first uninvolved nodal echelon to a dose of 45 Gy. Thirty-
seven of 89 assessable patients had good responses to
induction chemotherapy, 30 of whom had HPV-associated
OPSCC (ie, 30/59, 51% of HPV-associated OPSCC had good
response). With a mean follow-up of 2 years, the 2-year PFS
and OS for HPV-associated OPSCC with good response were
93.1% and 92.1%, respectively. Two-year PFS and OS for
HPV-associated OPSCC with ≤ good response were 74.0%
and 95.2%, respectively. As far as toxicity, patients with good
response were less likely to have percutaneous endoscopic
gastrostomy placement during treatment, though long-term
percutaneous endoscopic gastrostomy dependence was similar
31
between good and nonresponders. Long-term patient-
reported quality of life and xerostomia scores were not
clinically significantly different.
Radiation-Alone Paradigm
There are multiple studies demonstrating very high cure rates
with RT alone in patients with stage T1-2, N0-1 OPSCC with
and without consideration of HPV or smoking status.8,47
Because of the enhanced radiocurability of HPV-associated
OPSCC, omitting chemotherapy even for higher-staged
patients is another approach that has been proposed to
deintensify therapy.48 This may be more appropriate for the
more favorable risk patients, specifically those with ≤ 10 pack
years smoking histories.48
The concern of a radiation-alone approach is that the occult
distant metastatic disease is not being treated. Though it is
debatable whether systemic chemotherapy is effective at
treating micrometastatic distant disease, in the HPV-associated
OPSCC subset, it may be more efficacious as the response rate
to chemotherapy is better.
University of North Carolina/
University of Florida Paradigm
Our approach has been to substantially reduce both RT and
chemotherapy without using definitive surgery or induction
chemotherapy. In our first phase II study, we enrolled 44
patients with HPV-associated OPSCC, of which 64% were
HPV and p16 positive and 82% were never smokers.49 Patients
with T4 and N3 disease were not eligible. All patients received
60 Gy (2 Gy/fx, daily) IMRT with concurrent weekly cisplatin
of 30 mg/m2. Compared to the standard of 70 Gy and
cumulative cisplatin dose of 300 mg/m2, radiation was
reduced to 10 Gy and cisplatin by 40%. The primary endpoint
was pathological complete response (pCR), and all patients
had a biopsy of their primary site and supraselective neck
dissections (nodal pluck or removal of initial involved nodal
level) 6-14 weeks after completing deintensified CRT. Our null
hypothesis was that the pCR rate would be ~87% (the reported
3-year local-regional control rate in RTOG 0129).6 We
observed a pCR rate of 86% (98% at the primary site and
84% in the neck).49 With a median follow-up of 36 months
(88% have at least 2 years follow-up), the 2-year OS is 95%
(1 patient died from cerebrovascular accident and another died
from a glioblastoma multiforme) and 2-year cause-specific
survival is 100%. Six patients had partial pathological
response, all of which were micrometastatic (o1 mm) resid-
ual, equivocal foci. One of these 6 patients had an equivocal
focus in the base of tongue (biopsy) and neck node for which
he had a transoral resection (no further additional neck
dissection) showing no residual cancer. The other 5 patients
only had microscopic residual in a lymph node(s) and did not
have further surgery. All 6 patients are alive with no evidence of
disease. Global quality of life (assessed by EORTC QLQ C30)
returned to baseline and patients reported (assessed by
32
PRO-CTCAE) mild-to-moderate xerostomia and none-to-mild
dysphagia at 24 months posttreatment. Thirty-nine percentage
required a feeding tube (median duration of 15 weeks)
of which none were permanent. The results of our first study
are encouraging as the pCR was very high and the 2-year
clinical outcomes and patient-reported outcome were excel-
lent. Based on our results, the NRG oncology group is
conducting a phase II randomized trial comparing 60 Gy
IMRT with concurrent weekly cisplatin 40 mg/m2 (6 weeks)
vs accelerated 60 Gy IMRT (5 weeks) (NCT02254278,
clinicaltrials.gov).
We have completed accrual (n ¼ 100) to our second-
generation phase II trial that has the more traditional endpoint
of 2-year PFS. A 12-week post deintensified CRT PET/CT is
used to guide surgical evaluation. Other major differences
included the following: (1) chemotherapy is omitted in
patients with T0-T2, N0-N1 stages (ie, 60 Gy IMRT alone),
(2) patients with moderate, remote smoking histories are
eligible (≤30 pack years and 5 years abstinence), and
(3) genomic sequencing of pretreatment biopsies are
performed.
Our ongoing third-generation deintensification phase II
study is investigating whether tumor genomics can be used
to select patients with 410 pack years histories in whom
deintensification may be safely done. Patients with HPV-
associated OPSCC regardless of smoking history are eligible
(excluding T4 and N3). Tumor genomics are performed on
tumor samples of patients who have 410 pack years smoking
histories and if P53 is wild-type, they will receive deintensified
CRT (60 Gy IMRT þ weekly cisplatin 30 mg/m2). The results
of the genetic analysis is available by week 2 or 3 of radiation,
and if P53 is found to be mutated, patients will receive an
additional 10 Gy and another week of cisplatin 30 mg/m2
(70 Gy IMRT þ cumulative cisplatin 200 mg/m2). Mutations
in P53 are rarely seen in HPV-associated OPSCC and are
indicative that tobacco may have been the major driver of
carcinogenesis.50 We are also prospectively analyzing plasma
circulating HPV tumor DNA (baseline, weekly during treat-
ment, and with each follow-up visit) to evaluate its predictive
and prognostic value.
Future Directions
There are several questions that remain to be answered. We
now have a biomarker that we can reliably use in the practice of
head and neck oncology, but it is not perfect. Though HPV
status, smoking status, and T and N stage do a “pretty good”
job at providing prognostic information and define risk groups
in a way that we can (with relative confidence) select patients
who would most benefit (ie, not compromise tumor control)
from deintensification—there are still patients with favorable
risk disease (≤10 pack years) who do not experience cancer
control and there are patients with unfavorable risk disease
(≥ 10 pack years, T4, N3) who may benefit from deintensi-
fication. Our ability to risk stratify can be refined with the use
of other biomarkers. In our third-generation phase II, we are
studying tumor genomics and circulating tumor DNA as
B.S. Chera and R.J. Amdur
potential adjunctive biomarkers that can help us better select
patients for deintensification.
Another area of future research would be adaptive treatment
using imaging biological correlates early during treatment to
help in deciding when to deintensify. Lee and colleagues
performed a pilot study in 33 patients in whom they
performed pretreatment 18F-fluorodeoxyglucose and
dynamic18F-fluoromisonidazole positron emission tomo-
graphy (PET) scans. For patients with pretreatment hypoxia
on 18F-fluoromisonidazole PET, a repeat scan was done
1 week after chemoradiation. Patients without pretreatment
hypoxia or with resolution of hypoxia on repeat scan
received a 10-Gy dose reduction to metastatic lymph node
(s). All 33 patients had pretreatment hypoxia, and 30% met
criteria for 10 Gy dose reduction to lymph node(s). With a
median follow-up of 32 months, the 2-year local-regional
control rate was 100%.
Early results have shown that deintensification is possible in
carefully selected patients; however, the optimal level of
deintensification is not known. Can we go lower than 60 Gy
in the definitive setting (without induction) or lower than
54 Gy after induction chemotherapy? Assessment of bio-
markers pretreatment (eg, tumor genomics) and during treat-
ment (eg, circulating tumor DNA, tumor hypoxia using
functional radiographic imaging techniques) may allow us to
super-select patients in whom it may be safe to undergo ultra-
deintensification.
Future studies may not be able to define the optimal
deintensification paradigm or strategy. Patient, physician,
and institutional biases will influence the field of deintensified
treatments for HPV-associated OPSCC, and just as there are
now 3 major “preferred” treatment paradigms for oropharynx
cancer (surgery first, radiation first, and induction first), in the
future (we project) there will be 3 acceptable deintensification
paradigms. Purist will call for phase III randomized controlled
trials to find the best paradigm. Conducting these gold
standard studies may be difficult as patient aversion to
randomization and their desire for faster discovery of newer
treatments increase and physicians growing lack of equipoise
influence their willingness to participate in phase III studies.
Conclusions
There are several deintensified treatment strategies for HPV-
associated OPSCC, each with their unique caveats and
controversies. There are several phase II studies with excellent
outcomes. In the near future, there will be several accepted
deintensified approaches centered around (1) transoral surgi-
cal followed by pathological risk-adapted, reduced-dose radi-
ation and chemotherapy, (2) neoadjuvant chemotherapy
followed by reduced-dose (and possibly volume) radiation,
and (3) reduced-dose radiation ± chemotherapy. Bastions of
excellence in surgery, chemotherapy, and radiation will favor
one of these 3 paradigms. Though the results of large
randomized studies are often required to change medical
practice, patient expectations as health care consumers (risk
adverse to randomization) and physician biases (lack of
Treatment deintensification in HPV-associated OPSCC carcinoma
equipoise) may impede the conduction of traditional phase III
trials. Further, the excellent results of well conducted phase II
studies may be enough to change medical practice.
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