International Journal of Otolaryngology and Head & Neck Surgery, 2013, 2, 263-270
Published Online November 2013 (http://www.scirp.org/journal/ijohns)
http://dx.doi.org/10.4236/ijohns.2013.26055
Open Access IJOHNS
Does Surgery Have a Relevant Role in the Primary
Treatment of Locoregionally Advanced Oropharyngeal
Carcinomas?
Joana Guimarães, Sara Cruz, Eduardo Breda, Eurico Monteiro
Department of Otorhinolaryngology and Head and Neck Surgery, Portuguese Institute of Oncology—Francisco Gentil,
Oporto, Portugal
Received August 26, 2013; revised September 25, 2013; accepted October 5, 2013
Copyright © 2013 Joana Guimarães et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Background: Treatment concepts for oropharyngeal squamous cell carcinomas are controversial. Th is review compares
the results obtained by distinct treatment options in locoregionally oropharyng eal advanced carcinomas: primary surgi-
cal resection followed by concurrent chemoradiotherapy and concurrent chemoradiotherapy alone. Methods: 57 pa-
tients with stage III and IV oropharyngeal squamous cell carcinoma were selected. 17 patients were treated with pri-
mary surgical resection followed by concurrent chemoradiotherapy and 40 patients were treated only with concurrent
chemoradiotherapy. Statistical analysis was performed regarding survival rates according to tumor location, stage,
treatment regimen and recurrence. Results: Two-year loco-regional control rates were 94% after surgery plus chemora-
diotherapy and 55% after chemoradiotherapy (p = 0.016). Progression free survival rates were 88% and 27%, respec-
tively (p < 0.001). Overall sur vival rates were 88% and 45%, respectively (p = 0.002) . Conclusions: In this study, pri-
mary surgical resection followed by concurrent chemoradiotherapy showed better clinical o utco mes with a lower risk of
death associated with tumor and tumor progression.
Keywords: Oropharyngeal Carcinoma; Treatment; Concurrent Chemoradiotherapy; Primary Surgical Resection;
Survival Rates
1. Introduction
Seventy percent of oropharyngeal tumors are squamous
carcinoma and they represent the third most frequent
head and neck cancers, following laryngeal and oral cav-
ity cancers. It accounts for 10 - 15 percent of all head and
neck tumors and has an annual incidence in the UK
population of approximately ten per million per year [1].
A significant increase in the incidence has been observed
in the United States and Western Europe in people <45
years old in the last few years [2]. During the period in
analysis, around 85 patien ts per year, appear in our insti-
tution, a reference center for oncologic patients for a
population of approximately 3,300,000 habitants [3].
Although tobacco an d alcohol abuse ar e th e major f actors
related to the development of these malignancies, sub-
stancial molecular and epidemiologic evidence has sug-
gested that human papillomavirus (HPV) is an emerging
etiologic factor [4].
Squamous cell carcinoma of the oropharynx is an ag-
gressive malignancy with a high propensity for locore-
gional tumor infiltration. The rich lymphatic network of
the oropharynx predisposes tumors in this area to mani-
fest early regional lymph node involvement. The achieve-
ment of locoregional control is central to the successful
outcome in oropharynx cancer and relates directly to
overall survival [5].
The optimal treatment for these cancers is disputed,
but it is generally accepted that for early stage disease,
surgery or radiotherapy (RT) alone achieves similar sur-
vival rate s .
Considerable controversy exists about the appropriate
treatment modality for locoregionally advanced oro-
pharyngeal squamous cell carcinomas (LAOSCC). Nowa-
days, chemoradiotherapy is generally considered as an
effective option when thinking about a functional pres-
ervation and RT is usually recommended as an adjuvant
treatment option after surgical resection of these tumors,
in patients with advanced stage cancers [6]. However, the

J. GUIMARÃES ET AL. 264
toxicity of concurrent chemoradiotherapy (CCRT) is a
major concern, sometimes with the necessity of hospi-
talization and nutritional support [7]. On the other hand,
surgical management of persistent or recurrent LAOSCC
after failure of chemoradiotherapy is associated with high
complication rates [8].
Currently, in our institution, the main approach in
LAOSCC in patients with favorable medical conditions
consists of concurrent chemoradiotherapy with a regimen
of taxane, platinum and fluorouracil.
Recently, the focus has centered on CCRT protocols,
[7,9] but only a few anatomic site-specific randomized
trials evaluating the outcomes after primary surgical
treatment vs. nonsurgical treatment of LAOSCC are
available.
The aim of the present study was to compare retro-
spectively the results obtained by different treatment
strategies in our Institution for LAOSCC: primary surgi-
cal resection followed by concurrent chemoradiotherapy
and concurrent chemoradiotherapy alone.
2. Methods
2.1. Study Design
A total of 57 patients stage III/IV (American Joint Com-
mittee of Cancer (AJCC), 7th edition, 2010) were treated
with isolated or postoperative chemoradiotherapy for
squamous cell carcinoma of the oropharynx at the Por-
tuguese Institute of Oncology of Oporto between January
2005 and December 2009 and included in this analysis.
The data of these patients were obtained from a database
of 204 oropharynx cancer patients. Excluded from the
study were those who presented a previous history of
head and neck cancer, stage I and II disease, distant me-
tastasis or irresectable disease, synchronous primary le-
sions, patients who had palliativ e treatment or part of the
treatment in another institution, Karnofsky performance
status <60%, those who had surgery or radiotherapy
alone or surgery followed only by radiotherapy, incom-
plete information or no follow-up available.
Treatment options depended mainly on the patient’s as
well as on the physician’s preference according to mul-
tidisciplinary group decision. Data from 17 patients
treated with surgery plus chemoradiotherapy were com-
pared with 40 patients treated with definitive chemora-
diotherapy. The two groups were selected according to
five similar characteristics: age, gender, tumor site (tonsil
and soft palate vs. tongue base and vallecula), N-cate-
gory (N0 vs. N+) and AJCC stage (III vs. IV, according
to AJCC classification, 7th edition).
2.2. Pretreatment and Post-Treatment
Evaluation
Prior to the first treatment and after any treatment modal-
ity all patients were evaluated by our multidisciplinary
group of physicians, including head and neck surgeons,
radiation oncologists, medical oncologists and radiolo-
gists.
All patients were initially evaluated by complete
physical examination, head and neck computed tomo-
graphy (CT) and magnetic resonance imaging (MRI) in
selected cases. In advanced N stages, patients were sub-
mitted to positron emission tomography in order to detect
distant metastasis leading to different treatment options.
The routine follow-up prog ram in our in stitution consists
of a clinical observation every 3 months. CT scan and/or
MRI were performed between 8 - 12 weeks after treat-
ment.
2.3. Treatment
2.3.1. Surgery plus Chemoradio th erapy
Surgery was performed to resect the primary tumor. Dif-
ferent types of neck dissections were associated accord-
ing to the stage of the disease: in 4 cases no lymph node
dissection was performed, ipsilateral and bilateral neck
dissections were performed in 4 and 9 cases, respec-
tively.
Three-dimensional conformal radiotherapy with a
multileaf collimator was performed in all patients using 4
- 6 MV photons from a linear accelerator with conven-
tionally fractionation (2 Gy/fraction, once daily, five
times weekly), 6 - 8 weeks after surgery. The treatment
field included the entire primary tumor area, all exten-
sions of the surgical scar and the upper and middle lym-
phatic drainage areas. Total dose at the primary site was
60 - 66 Gy, according to the limits of the surgical mar-
gins. In the lymph node area, doses were between 50 and
66 Gy, according to the type of nodal invasion observed
surgically and on histopathological diagnosis following
neck dissection.
All these patients had high risk factors such as positive
surgical margins, extracapsular spread of lymph nodes
metastasis and lympho-vascular or perineural invasion
and consequently all received concurrent chemotherapy
in addition to radiotherapy. Concurrent chemotherapy
consisted of 100 mg/m2 of cisplatin on radiotherapy days
1, 22 and 43. All patients eligible for chemotheraphy
received prophylatic hydration and antiemetic agents.
2.3.2. Definitive Chemoradi otherapy
Forty patients received conventionally fractionated ra-
diotherapy (5 fractions per week) with doses per fraction
of 2.0 Gy. Radiotherapy was performed with a linear
accelerator and 4 - 6 MV photons. The total dose deliv-
ered to the primary tumor and the involved lymph nodes
was 70 Gy. In clinically uninvolved cervical and supra-
clavicular lymph nodes total dose administered was 50 -
60 Gy. Concurrent chemotherapy consisted of 100 mg/
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J. GUIMARÃES ET AL. 265
m2 of cisplatin on radiotherapy days 1, 22 and 43.
2.4. Study End-Points and Statistical
Considerations
All the variables were evaluated using the Pearson chi-
square test, fisher’s exact test, Mann-Whitney test and
the student t test to determine any significant differences
between the two groups.
Both treatment groups were compared for one-year
and two-years loco-regional control (LC), disease-free
survival (DFS) and overall survival (OS), referenced
from the last day of radiotherapy.
LC, DFS and OS estimate rates were calculated using
the Kaplan-Meier method. Differences between the
Kaplan-Meier curves were calculated with the Wilcoxon
test. Prognostic factors found to be significant (p < 0.05)
in the univariate analysis were included in a multivariate
analysis, performed with the Cox proportional hazards
model. The primary goal of this study was to compare
the results of definitive chemoradiotherapy to surgery
followed by chemoradiotherapy.
The levels of statistical significance were calculated at
the 5% level of probability (p < 0.05). Statistical analyses
were conducted using the Statistical Package for Social
Sciences, version 19.0 for Windows (SPSS, Chicago,
IL).
3. Results
3.1. Demographics
A total of 17 patients with LAOSCC treated by primary
surgical resection followed b y CCRT were matched to 40
patients treated only with CCRT according to gender, age,
tumor site, nodal status and overall stage. The character-
istics of the two groups are listed in Tables 1 an d 2. All
patients were men with an age range of 38 - 74 years.
The median age was 57 years for surgical patients and 53
years for CCRT patients (p = 0.474). The two groups did
not differ significantly with respect to N-category (p =
0.633) and T-category (p = 0.015).
3.2. Surgery plus Chemoradiotherapy Group
In the surgical group, four patients underwent unilateral
and nine bilateral neck dissection. The remaining four
did not undergo neck dissection.
After surgery, patients were restaged according to the
histopatological results (Table 3).
3.3. Survival Analysis
On univariate analysis, treatment regimen (p = 0.016,
Figure 1) and AJCC-stage (p = 0.035) were associated
with LC. The results of the uni variate analysis for LC are
summarised in Table 4. On multivariate analysis directed
Table 1. Patients characteristics of both treatment groups.
Characteristic Surgery + CCRT
(n = 17) CCRT (n = 40) p
Gender n (%)
Male 17 (100.0) 40 (100.0) 1.000
Age n (%)
<55 years 7 (41.2) 22 (55.0)
55 - 59 years 3 (17.6) 7 (17.5)
>59 years 7 (41.2) 11 (27.5)
0.561
Subsite n (%)
Palatine tonsil and
soft palate 11 (64.7) 21 (52.5)
Base of the tongue
and vallecule 6 (35.3) 19 (47.5) 0.396
Nodal status n (%)
Negative 6 (35.3) 15 (37.5)
Positive 11 (64.7) 25 (62.5)
0.874
AJCC-stage n (%)
III 10 (58.8) 17 (42.5)
IV 7 (41.2) 23 (57.5) 0.259
T-category n (%)
T1 1 (5.9) 0 (0.0)
T2 6 (35.3) 3 (7.5)
T3 7 (41.2) 20 (50.0)
T4 3 (17.6) 17 (42.5)
0.015
N-category n (%)
N0 6 (35.3) 15 (37.5)
N1 5 (29.4) 14 (35.0)
N2 6 (35.3) 9 (22.5)
N3 0 (0.0) 2 (5.0)
0.633
Follow-up of
survivors (months)
Median (range) 31 (22 - 58) 39.5 (22 - 70)0.123
Abbreviations: CCRT = concurrent chemoradiotherapy.
Table 2. Distribution of patients by T and N.
N Stage
Treatment N0 N1 N2 N3 Total
Surgery + CCRT
T1 0 0 1 0 1
T2 0 4 2 0 6
T3 6 0 1 0 7
T4a 0 1 2 0 3
Total 6 5 6 0 17
CCRT
T2 0 1 1 1 3
T3 10 6 3 1 20
T4a 5 7 5 0 17
Total 15 14 9 2 40
Abbreviations as in Table 1.
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J. GUIMARÃES ET AL. 266
Table 3. Distribution of surgical patients by pre and post-
operative stage.
Palatine tonsil and
soft palate Base of the tongue and vallecule
AJCC stage III IV III IV
Pre-operative 8 2 3 4
Postoperative 1 10 1 5
Table 4. Univariate analysis for loco-regional control.
At 1-year (%) p At 2-years (%)p
Treatment
Surgery + CCRT 94.1 94.1
CCRT 62.5
0.015 55.0 0.016
Age
<55 years 65.5 62.1
55 - 59 years 80.0 80.0
>59 years 77.8
0.544
77.8
0.764
Subsite
Palatine tonsil and
soft palate 75.0 68.8
Base of the tongue
and vallecule 68.0
0.559
64.0
0.514
T-category
T1-2 80.0 80.0
T3 77.8 70.4
T4 60.0
0.335
55.0
0.089
Nodal status
Negative 85.7 81.0
Positive 63.9
0.077 58.3 0.196
AJCC-stage
III 85.2 81.5
IV 60.0
0.035 53.3 0.069
Entire cohort 71.9 66.7
Abbreviations as in Table 1.
Figure 1. Comparison of both treatment groups (surgery
plus chemoradiotherapy and chemoradiotherapy) with re-
spect to loco-regional control.
to LC, treatment regimen (risk ratio [RR] 9.43; 95%-
confidence interval [CI] 1.25 - 71.28; p = 0.030), main-
tained significance. AJCC-grade (RR 2.67; 95%-CI 0.95
- 7.50; p = 0.063) was almost significant.
On univariate analysis, treatment regimen (p < 0.001,
Figure 2) and AJCC-stage (p = 0.05) were associated
with DFS. The results of the univariate analysis of DFS
are summarized in Table 5. On multivariate analysis to
DFS treatment regimen (RR 6.54; 95%-CI 1.98 - 21.61;
Table 5. Univariate analysis for disease free survival.
At 1-year (%) p At 2-years (%)p
Treatment
Surgery + CCRT88.2 88.2
CCRT 37.5
<0.001 27.5 <0.001
Age
<55 years 55.2 44.8
55 - 59 years 40.0 40.0
>59 years 55.6
0.678
50.0
0.872
Subsite
Palatine tonsil and
soft palate 53.1 50.0
Base of the tongue
and vallecule 52.0 0.933 40.0 0.452
T-category
T1-2 70.0 70.0
T3 55.6 48.1
T4 40.0
0.275
30.0
0.109
Nodal status
Negative 57.1 57.1
Positive 50.0
0.602 38.9 0.182
AJCC-stage
III 63.0 59.3
IV 43.3
0.138 33.3 0.050
Entire cohort 52.6 45.6
Abbreviations as in Table 1.
Figure 2. Comparison of both treatment groups (surgery
plus chemoradiotherapy and chemoradiotherapy) with re-
spect to progression free survival.
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J. GUIMARÃES ET AL. 267
p = 0.002) option was significant as AJCC-stage (RR
2.00; 95%-C I 0. 97 - 4.13; p = 0.062).
In the surgical group, one patient developed locore-
gional recurrence and another lung metastatis (Table 6).
In the CCRT group a total of 4 patients suffered dis-
ease progression. After treatment, 6 patients presented
persistence of the disease. Three of these patients under-
went neck dissection and one patient underwent salvage
surgery. Recurrence or another tumor developed in a
total of 17 patients (Table 6).
Follow-up time of the survival group was 22 - 70
months (with a median of 31 months for the surgery plus
CCRT group and 39.5 months for the CCRT group). Al-
though the median follow-up of survivors was longer in
the CCRT group, the difference did not reach statistical
significance (Table 2).
On univariate analysis, treatment regimen (p = 0.002,
Figure 3), age (p = 0.012) and T-category (p = 0.012)
were associated with better OS. The results of the uni-
variate analysis of OS are summarized in Table 7. On
multivariate analysis, treatment regimen (RR 3.86;
95%-CI 1.09 - 13.61; p = 0.036) maintained significance.
T-category (RR 1.508; 95%-CI 0.88 - 2.58; p = 0.134)
and age (RR 1.26; 95%-CI 0.84 - 1.89; p = 0.253) were
not significant.
Three patients of the group treated with surgery plus
CCRT died. In the group treated with CCRT, 26 patients
died. Of these 29 patients, 18 died of disease, 2 of second
primary tumors and 9 from unrelated causes.
Two patients from the surgery plus CCRT group suf-
fered tumor recurrence compared with 27 from the
CCRT group, who experienced recurrence or p rogression.
The 3-year DFS estimate rate was 78.4% for the surgical
group and 23.0% for the CCRT group. Figure 2 shows
the Kaplan-Meier PFS curve for the surgery plus CCRT
group versus the CCRT group. Significant difference was
found in the mean PFS between the 2 groups (p < 0.001).
Table 6. Distribution of patients by type of recurrence.
Surgery + CCRT
n = 17 CCRT n = 40
Recurrence
n (%) Deaths (n) n (%) Deaths (n)
No relapse 14 (82.3) 0 13 (32.5) 4
Primary site 0 (0.0) 0 6 (15.0) 6
Neck 0 (0.0) 0 1 (2.5) 1
Simultaneous
primary site and neck 1 (5.9) 1 3 (7.5) 3
Distant
metastases 1 (5.9) 1 4 (10. 0) 4
Secondary ENT
localization 0 (0.0) 0 1 (2.5) 0
Secondary no ENT
localization 1 (5.9) 1 2 (5.0) 1
Abbreviations as in Table 1.
Table 7. Univariate analysis of overall survival.
At 1-year (%) p At 2-years (%)p
Treatment
Surgery + CCRT 94.1 88.2
CCRT 70.0
0.047 45.0 0.002
Age
<55 years 86.2 62.1
55 - 59 years 60.0 40.0
>59 years 72.2
0.195
61.1
0.012
Subsite
Palatine tonsil and
soft palate 68.8 59.4
Base of the tongue
and vallecule 88.0 0.086 56.0 0.798
T-category
T1-2 100.0 90.0
T3 77.8 63.0
T4 65.0
0.098
35.0
0.012
Nodal status
Negative 81.0 66.7
Positive 75.0
0.605 52.8 0.306
AJCC-stage
III 81.5 70.4
IV 73.3
0.464 46.7 0.070
Entire cohort 77.2 57.9
Abbreviations as in Table 1.
Figure 3. Comparison of both treatment groups (surgery
plus chemoradiotherapy and chemoradiotherapy) with re-
spect to overall survival.
The 3-year OS estimate rate was 88.2% for those who
had undergone surgery plus CCRT and 26.9% for the
patients who received CCRT. Figure 3 shows the Kap-
lan-Meier OS curve for the surgery plus CCRT group
versus the CCRT group. The difference in mean OS be-
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J. GUIMARÃES ET AL. 268
tween the 2 groups was statistically significant (p =
0.003).
4. Discussion
Squamous cell carcinoma of the oropharynx represents a
great therapeutic challenge. Historical approaches to the
management of this disease included initially radical
surgery. Surgical approaches for these tumors can pro-
foundly affect crucial daily activities, su ch as respiration,
speech, chewing, swallowing and facial cosmesis with
the respective emotional and social hardships.
Since the 1960s, RT alone has been considered the
standard for oropharyngeal cancer treatment in many
institutions, regardless of tumor stage [10,11].
In the past decade, several trials were consistent in
showing a significant increase in locoregional control
and organ preservation rates in patients randomized to
receive CCRT compared with those who received RT
alone [12,13].
Until today, chemoradiotherapy-based regimens have
been increasingly integrated into first-line therapy for
advanced oropharyngeal carcinomas. However, no ran-
domized trials have been conducted comparing oncologic
results of surgery vs. CCRT in patients with LAOSCC.
One nonanatomic site-specific randomized comparison
of surgery plus postoperative radiotherapy (PORT) vs.
CCRT was done, including only 21 patients with oro-
pharyngeal carcinoma. Although this study showed no
significant differences in the 3-year disease-free survival
rate between surgery and CCRT, a subset analysis of
patients with oropharyngeal cancer was not performed
[14].
In a region with an incidence of 85 new cases of oro-
pha ryngeal tumors, our institution treats nearly 40 cases
per year. We decided to conduct a retrospective study to
evaluate survival outcomes in patients with LAOSCC
treated with surgery and CCRT vs. CCRT alone. The two
groups of patients were selected according to similar
potential confounding variables known to influence the
prognosis.
In the present analysis, treatment with CCRT alone
was associated with an increased risk of death and pro-
gression, compared with surgery plus CCRT. Data from
patients undergoing surgery and CCRT were impressive,
with a 3-year OS and DFS rate of 88% and 78%, respec-
tively. The 2-year actuarial LRC rate was 94%. On the
other hand, the CCRT group showed a 3-year OS and
DFS rate of 27% and 23%, respectively and a 2-year ac-
tuarial LRC rate of 55%. These differences were statisti-
cally significant.
A recent matched-pair study was conducted in Italy
toevaluate survival outcomes in patients with LAOSCC
treated with surgery and PORT vs. induction chemo-
therapy/CCRT. The clinical efficacy of chemoradiother-
apy was as good as surgical resection and PORT, with a
3-year OS and DFS rate of 71% and 73%, respectively.
The 3-year actuarial rate of local control was 79% and
regional control was 80% [15].
In a trial of CCRT for LAOSCC, Calais et al. [12] also
reported a h igher 3-y e a r overall survival rate (51%).
This might have resulted because in our study more
patients with advanced stage (Stage T4 and N3) were
included in the CCRT group. Also, the differences in
treatment protocols might have some influence, since our
protocol did not consist of a sequential chemoradiother-
apy and did not include 5-fluorouracil, with potential
systemic effect on distant micrometastases [16].
Furthermore, we did not evaluate comorbidities which
can also be a prognostic factor. Although it is difficult to
determine whether the cause of death was related or not
to the type of cancer therapy, treatment-related mortality
should not be underestimated in patients undergoing ag-
gressive multimodality regimens. Argiris et al. [17] re-
ported a death rate of 15% related to treat ment compl ica-
tions after CCRT.
The advent of new targeted therapies and the emerging
role of HPV in oropharyngeal carcinoma might influence
the choice of therapeutic approach. Patients with HPV-
positive oropharyngeal tumors tend to have a better
prognosis than those with tobacco- and/or alcohol-related
tumors. This has been attributed to enhanced radiation
sensitivity [18]. In our geographic region, tobacco- and
alcohol-related oropharyngeal cancers remain dominant
and the standard use of aggressive multimodality regi-
mens for the treatment of LAOSCC may represent over-
treatment in regions with a high incidence of HPV-re-
lated oropharyngeal carcinoma [19].
The primary limitations of the present study are the
relatively small sample size and the different size of the
two groups, which limited the statistical power, its non-
randomized nature and retrospective comparison. Al-
though the matching procedure can limit the bias result-
ing from potential confounders, this was not a matched-
pair analysis, so it had some intrinsic limits. Patients
were similar with respect to age, gender, nodal status,
subsite and overall stage. However, an imbalance was
still present in these variables. Other variables that might
have prognostic significance, including T and N category,
had a different distribution in the two groups. In the case
of T category it was statistically significant, with the
proportion o f Stage T4 disease in the CCRT greater than
that of the surgical group.
With respect to distant failure, the 2-year rate of pa-
tients who developed distant metastases was greater in
the CCRT group (10% vs. 6%).
Although currently the most widely accepted treatment
for LAOSCC is a sequential chemoradiotherapy, this
study showed that surgery has an important role as a
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J. GUIMARÃES ET AL. 269
primary therapeutic modality in th e treatment of selected
cases of LAOSCC and is related with a significant better
overall survival, progression-free survival and locore-
gional control rates.
5. Conclusion
According to this study, including surgery as an initial
therapeutic option in the treatment of selected cases of
LAOSCC, followed by CCRT may lead to better overall
survival, progression-free survival and locoregional con-
trol rates and an apparent lower risk of death or tumor
progression. For this reason, surgery has an important
role as a primary therapeutic choice in the treatment of
LAOSCC.
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