2017 Section 7 Green Book

standard fraction or accelerated fraction radiotherapy. The

authors provided strong evidence that HPV-related oro-

pharyngeal SCC is a unique disease entity with improved

survival outcomes. They also classified patients with oro-

pharyngeal SCC as having either a low, intermediate, or

high-risk of death dependent upon HPV status, smoking

history, neck disease, and primary tumor classification

(all of which were independent predictors of survival).

The 3-year survival rates were 93.0%, 70.8%, and 46.2%,

respectively. The data from RTOG 0129 suggests that

less intense therapy may be warranted for the low-risk

group of patients and more intense therapy may be

needed for the high-risk group. The intermediate group of

patients, which includes 36% of all HPV-positive patients,

should not be deintensified but clearly have poorer overall

survival outcomes than the low-risk group because of

their smoking status and extensive neck disease.

Nonsurgically treated patient survival and functional

outcomes for oropharyngeal SCC have been well-

documented; however, outcomes data for patients treated

with primary surgery is sparse. Since the reports by Par-

sons et al,

5,6

surgical and reconstructive technology has

dramatically advanced and improved functional outcomes.

The use of transoral laser microsurgery and transoral

robotic surgery (TORS) have allowed surgeons to access

tumors without disrupting normal anatomy, while provid-

ing superior visualization of tumor margins.

27–32

Further-

more, when open procedures are necessary, free flap

surgeons are able to provide superior cosmetic and func-

tional outcomes. In addition, surgical resection may be a

way to deintensify therapy for patients in the lowest or

intermediate risk categories by obviating the need for

concurrent chemoradiotherapy.

The purpose of this study was to determine the impact

of primary surgery in the treatment of oropharyngeal

SCC. Predictors of survival will be determined and func-

tional outcomes will be reported. In addition, survival and

functional outcomes will be compared between open sur-

gery and transoral surgical approaches for tumor

extirpation.

MATERIALS AND METHODS

After institutional review board approval, a prospective

database of patients with head and neck cancer treated

with primary surgery was assembled and continually

maintained. This study was retrospective in nature and

exempt from consent. The database was searched for

patients with oropharyngeal SCC treated from January 1,

2002, to August 31, 2012. Patients who were treated with

primary surgery for histologically confirmed SCC were

assessed for eligibility. Patients who were previously

untreated, had tissue available for analysis, and had avail-

able clinical follow-up data were included in the study.

For each patient, demographic data, complete medical

history, pathology, and follow-up were recorded and veri-

fied in real time. Survival data was ascertained through

medical record review and confirmed through tumor

registry files and the Social Security Death Index data.

The type of surgery performed was recorded and classi-

fied as: (a) TORS; (b) transoral nonrobotic; (c) open

transcervical (ie, suprahyoid pharyngotomy, lateral phar-

yngotomy); (d) mandibulotomy; or (e) composite resec-

tion (ie, mandibulectomy with pharyngectomy and/or base

of tongue removal). For analysis purposes, this was con-

densed into groups of transoral (a or b) and open (c, d, or

e) surgical approaches. All patients underwent neck dis-

sections at the time of their primary resections, according

to therapeutic guidelines.

Most patients were treated

with adjuvant radiotherapy or adjuvant chemoradiotherapy

based on standard National Comprehensive Cancer Net-

work guidelines, which notably changed over time. After

the publication by Bernier et al,

most high-risk patients

were treated with postoperative concurrent chemoradio-

therapy, whereas patients before 2004 were treated with

radiation alone.

Multiple studies have shown gastrostomy tube depend-

ence to be a major negative predictor of quality of life in

the head and neck cancer population.

35–37

In this study,

gastrostomy tube presence was assessed and defined as

the presence of a gastrostomy tube that was used for at

least a portion of the diet. Gastrostomy tube presence was

assessed at 0, 6, and 12 months postsurgery, and at last

follow-up visit.

A high density tissue microarray was created with rep-

resentative samples from patients in the study.

Tumor

p16 expression was evaluated by means of immunohisto-

chemical staining using a mouse monoclonal antibody

(MTM Laboratories CINTEC, Westborough, MA) and

visualized with a Ventana XT autostainer (Ventana Medi-

cal Systems, Tucson, AZ). Positive p16 expression was

defined as diffuse nuclear and cytoplasmic staining in

50% or more of the tumor cells. All samples were further

evaluated for HPV positivity via in situ hybridization for

HPV16 (GenPoint HPV DNA Probe) or for high-risk

HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,

and 66 (INFORM HPV III Family 16 Probe (B); Ventana

Medical Systems). Any definitive nuclear staining in the

tumor cells was considered positive. Low-, intermediate-,

and high-risk patients were defined as in the article by

Ang et al.

Statistical methods

Overall survival was defined as the time from the date

of surgery to the date of death, with patients alive at the

date of the last observation censored. Cox proportional

hazards models were used to assess univariate associa-

tions of biomarkers as predictors for death. Unadjusted

hazard ratios (HRs) and 95% confidence intervals (CIs)

are reported. Predictors of both clinical and statistical sig-

nificance were evaluated in multivariable models for the

entire cohort and within the HPV-negative and HPV-

positive subgroups. These predictors included: surgical

approach (transoral vs open), HPV status (positive vs neg-

ative), extranodal extension (no vs yes), mucosal margins

(free of carcinoma vs positive), perineural invasion (no vs

yes), smoking status ( 10 pack-years vs

10 pack-years),

and tumor classification (T1/T2 vs T3/T4).

To profile the risk of death, a recursive partitioning

analysis (RPA) was used as an exploratory analysis. The

“rpart” library in the R package was used to fit a regres-

sion tree with the overall survival data.

39,40

In evaluating

prognostic factors for overall survival, the predictors used

in the multivariable Cox proportional hazards model were

included in the building of the tree. All analyses were

URGICAL MANAGEMENT OF OROPHARYNGEAL

SCC

HEAD & NECK—DOI 10.1002/HED APRIL 2016

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