Does Surgery Have a Relevant Role in the Primary Treatment of Locoregionally Advanced Oropharyngeal Carcinomas?

doi:10.4236/ijohns.2013.26055

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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

Email: [email protected]

Received August 26, 2013; revised September 25, 2013; accepted October 5, 2013

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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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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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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