This article reviews the evidence behind surgical innovations and effect on treatment-related morbidity to examine how they may be integrated into modern management strategies for oral cavity and oropharyngeal squamous cell carcinoma (SCC). Technologic advances, including transoral laser microsurgery and transoral robotic surgery, along with the application of sentinel lymph node biopsy for oral cavity and oropharyngeal SCC are discussed.
| HPV | Human papilloma virus |
| SCC | Squamous cell carcinoma |
| SLNB | Sentinel lymph node biopsy |
| TLM | Transoral laser microsurgery |
| TORS | Transoral robotic surgery |
Key points
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In preliminary studies, minimally invasive approaches to the oropharynx, including transoral laser microsurgery and transoral robotic surgery, show improved functional outcomes and similar oncologic outcomes to primary radiation.
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The application of sentinel lymph node biopsy techniques to oral cavity cancer may reduce the need for elective neck dissection and its associated morbidity.
Introduction
In 2012, an estimated 40,250 people in the United States were diagnosed with oral cavity or oropharyngeal squamous cell carcinoma (SCC), and 7850 people died of these diseases. Although the overall incidence of oral cavity SCC has been decreasing by approximately 1% per year, the incidence of oropharyngeal SCC is rising, particularly in middle-aged patients, likely because of the increasing incidence of human papilloma virus (HPV)-associated oropharyngeal SCC. Treatment of oral cavity and oropharyngeal SCC is particularly challenging, as these sites are involved in many crucial functions, including breathing, deglutition, and speech, and impairment of any of these functions may significantly affect quality of life. Thus, both functional and oncologic outcomes are important considerations in the treatment of oral cavity and oropharyngeal SCC.
Although surgical excision has always been a mainstay of treatment for oral cavity SCC, the treatment of oropharyngeal SCC in recent decades has been notable for the use of primary nonsurgical approaches, namely radiation or chemoradiation. Publication of the Veterans Affairs study in 1991 heralded an era of organ-preservation strategies that were extrapolated from the larynx to the oropharynx. Traditional surgical approaches to the oropharynx (eg, mandibulotomy) entailed significant morbidity, thus making nonsurgical approaches the more attractive treatment option. However, recent technological advances, including transoral laser microsurgery (TLM) and transoral robotic surgery (TORS), have afforded improved access to pathology and the opportunity for decreased treatment-related morbidity. The application of sentinel lymph node biopsy (SLNB) for oral cavity and oropharyngeal SCC may also allow for more minimally invasive management of the neck. Here, we review the evidence behind these surgical innovations to examine how they may be integrated into modern management strategies for oral cavity and oropharyngeal SCC.
Introduction
In 2012, an estimated 40,250 people in the United States were diagnosed with oral cavity or oropharyngeal squamous cell carcinoma (SCC), and 7850 people died of these diseases. Although the overall incidence of oral cavity SCC has been decreasing by approximately 1% per year, the incidence of oropharyngeal SCC is rising, particularly in middle-aged patients, likely because of the increasing incidence of human papilloma virus (HPV)-associated oropharyngeal SCC. Treatment of oral cavity and oropharyngeal SCC is particularly challenging, as these sites are involved in many crucial functions, including breathing, deglutition, and speech, and impairment of any of these functions may significantly affect quality of life. Thus, both functional and oncologic outcomes are important considerations in the treatment of oral cavity and oropharyngeal SCC.
Although surgical excision has always been a mainstay of treatment for oral cavity SCC, the treatment of oropharyngeal SCC in recent decades has been notable for the use of primary nonsurgical approaches, namely radiation or chemoradiation. Publication of the Veterans Affairs study in 1991 heralded an era of organ-preservation strategies that were extrapolated from the larynx to the oropharynx. Traditional surgical approaches to the oropharynx (eg, mandibulotomy) entailed significant morbidity, thus making nonsurgical approaches the more attractive treatment option. However, recent technological advances, including transoral laser microsurgery (TLM) and transoral robotic surgery (TORS), have afforded improved access to pathology and the opportunity for decreased treatment-related morbidity. The application of sentinel lymph node biopsy (SLNB) for oral cavity and oropharyngeal SCC may also allow for more minimally invasive management of the neck. Here, we review the evidence behind these surgical innovations to examine how they may be integrated into modern management strategies for oral cavity and oropharyngeal SCC.
Traditional surgical approaches
Surgical resection has long been a mainstay of treatment for head and neck cancer, including oral cavity and oropharyngeal SCC. Given the complex 3-dimensional anatomy and functional roles of the oral cavity and oropharynx, a variety of surgical approaches have been explored.
Direct Transoral Surgery
A direct transoral approach provides the quickest and most direct route to the oral cavity and oropharynx with the least potential for morbidity. As such, transoral surgery remains important for the treatment of oral cavity SCC and many oropharyngeal SCCs. The primary disadvantage of this approach can be related to exposure. Most oral cavity cancers, and some oropharyngeal cancers, can be adequately visualized via a direct transoral approach; however, larger cancers may be difficult or impossible to reach through the mouth without specialized techniques and/or instrumentation. Patient factors (trismus, kyphosis, dental obstruction) and tumor characteristics (tumor size, location) can limit direct line-of-site visualization of areas in the oral cavity and oropharynx, thereby preventing a traditional direct transoral approach from being used.
Mandibulotomy/Mandibulectomy Approach
The mandible can represent a barrier to exposure for resection of oral cavity and oropharyngeal SCC. Several techniques have been developed to improve access to the posterior oral cavity and oropharynx. Using either a visor flap or lip-splitting approach, the mandible may be divided and retracted laterally to allow broad access to the oral cavity and oropharynx. Internal fixation may be used to restore the mandibular arch at completion of the procedure. Alternatively, a section of involved mandible may be removed during extirpation and then reconstructed with or without restoration of the entire mandibular arch. Although these approaches greatly expand the scope of tumors that may be resected, they also entail significant additional morbidity. Complications from mandibulotomy or mandibulectomy range from 10% to 60%, and include difficulty with speech and swallowing, malocclusion, temporomandibular joint pain, and cosmetic deformity.
Pharyngotomy Approach
As an alternative to mandibulotomy or mandibulectomy, tumors of the tongue base, inferior tonsillar fossae, or pharyngeal wall may be approached via a pharyngotomy. Depending on the location of the tumor and the extent of exposure needed, a lateral pharyngotomy, transhyoid pharyngotomy, and/or suprahyoid pharyngotomy may be used. Acceptable oncologic outcomes have been reported using each of these approaches. Although these approaches avoid many of the complications inherent in mandibulotomy and mandibulectomy, the access afforded is substantially more limited. In addition, patients undergoing pharyngotomy are at increased risk of pharyngocutaneous fistula formation and severe dysphagia, which have been reported to occur in 7% to 38% of patients.
Neck dissection and SLNB for oral cavity SCC
Oral cavity SCC spreads via regional lymphatics. Metastasis to the cervical lymph nodes is an early event in the progression of oral cavity SCC, particularly of the oral tongue and oropharynx, and has important prognostic implications. This is reflected in the major contribution of cervical metastases in American Joint Committee on Cancer TNM Classification System for oral cavity SCC. Thus, management of cervical lymph nodes, and possible metastases, is critical to proper risk stratification and application of therapy. There is little controversy surrounding the need for neck dissection for advanced primary (T3 and T4) oral cavity SCC, and in patients who are clinically node positive (N+). Good evidence also exists to define the appropriate use of neck dissection for early primary (T1 and T2) clinically node-negative (N0) oral cavity SCC, particularly when located in the oral tongue or floor of mouth. Selective neck dissection is now widely accepted for elective management of the neck in early-stage oral cavity SCC. Recently, SLNB has been investigated as an even less invasive method of staging the clinically N0 neck in early-stage oral cavity SCC.
Neck Dissection in Early-Stage Oral Cavity SCC
Current imaging technologies, including positron emission tomography/computed tomography, cannot accurately identify metastatic disease smaller than 5 mm. Therefore, pathologic evaluation of cervical lymph nodes is necessary for the detection of microscopic disease. Tumor thickness can accurately predict the risk of nodal cervical metastases. In particular, oral tongue SCC with thickness greater than 4 mm has been shown to have a significantly increased risk of occult metastasis, regional recurrence, worse disease-specific survival, and worse overall survival. Furthermore, elective neck dissection at or near the time of resection of oral cavity SCC, rather than after a period of failed observation, improves locoregional control and survival. Finally, it has been shown that selective neck dissection of levels I to III is as effective as radical or modified radical neck dissection. Based on these studies, elective selective neck dissection (levels I–III) is the current gold standard for management of the clinically N0 neck in early-stage oral cavity SCC with tumor thickness greater than 4 mm.
Sentinel Node Biopsy for Oral Cavity SCC
The concept of the sentinel lymph node as the initial site of lymphatic tumor spread, and therefore a predictor of the metastases within the remainder of the nodal basin, was first introduced more than 50 years ago. SLNB is most widely used in clinical practice for the treatment of cutaneous malignant melanoma. SLNB has also been adopted into treatment algorithms for breast cancer, colon cancer, and vulvar cancer.
Given the complex lymphatic drainage of the oral cavity and oropharynx, SLNB has the potential to detect micrometastatic disease in oral cavity SCC with less morbidity than elective neck dissection. Furthermore, finer specimen sectioning and immunohistochemistry routinely used with SLNB may improve the detection of micrometastasis. The first studies of SLNB in head and neck SCC compared the pathologic results of SLNB to the gold standard treatment: elective neck dissection. The SLN was identified in 90% to 100% of patients, and false-negative pathology results were 0% to 6%, suggesting that SLNB alone may be sufficient for accurate neck nodal classification. These encouraging results have been replicated in a recent large-scale multi-institutional clinical trial. Observational studies have also validated the efficacy of SLNB biopsy in oral cavity SCC. For example, a long-term study found a negative predictive value of 90%, and a disease-free survival of 96% in patients with initial negative SLNB. A multicenter European trial of 134 patients showed that 5-year overall survival was comparable between patients receiving SLNB alone versus SLNB and elective neck dissection. Finally, SLNB has been shown to be less morbid than elective neck dissection, validating the primary rationale for the approach.
Based on the available literature, guidelines for the use of SLNB in oral cavity SCC have been proposed by the European Association of Nuclear Medicine and the Sentinel European Node Trial Committee. SLNB should be confined to patients with early-stage (T1-2N0) oral cavity SCC. Larger primary cancers are considered large enough to drain to multiple nodal basins, and therefore not recommended for SLNB. Floor-of-mouth SCC is also potentially problematic, as the sentinel nodes can be obscured by close proximity to the primary tumor site. Indications for use of SLNB include staging of the ipsilateral N0 neck for a unilateral primary oral cavity SCC, staging of the ipsilateral and contralateral N0 neck for primary oral cavity SCC involving the midline, or staging of the contralateral N0 neck for an oral cavity SCC near the midline with an ipsilateral N+ neck. It is important to note that randomized studies comparing oncologic outcomes of SLNB to elective neck dissection in oral cavity SCC have not yet been performed. Thus, SLNB for oral cavity SCC is currently not advised outside the setting of a clinical trial but may be incorporated into standard practice algorithms for oral cavity SCC in the near future.
Surgical innovations in oropharyngeal cancer
Until recently, radiation or chemoradiation was the treatment of choice for the vast majority of oropharyngeal SCCs. However, recent technological advances have expanded transoral access to the oropharynx, reinvigorating the use of primary surgical treatment for selected oropharyngeal SCCs. Two primary innovations have been at the forefront in this shift: TLM and TORS.
TLM
TLM was first introduced in the 1970s for the treatment of laryngeal papillomas, and is now accepted for the treatment of early-stage laryngeal SCC with good oncologic results. More recently, TLM has been applied to oropharyngeal SCC. One early series of 48 patients treated with TLM for base-of-tongue SCC yielded an 85% 5-year local control rate. A retrospective review of 166 patients treated for tonsillar SCC also found an 82% 5-year local control rate. Excellent oncologic results have been replicated by groups performing TLM for oropharyngeal SCC treated with and without neck dissection and without adjuvant radiation therapy. Despite these encouraging results, no randomized studies have been performed comparing TLM with or without adjuvant treatment to nonsurgical approaches. TLM requires the use of rigid laryngoscopes with a narrow field of view to provide line-of-sight access to the site of resection. This makes the technique technically challenging to perform in the complex anatomy of the oropharynx. Thus, TLM is largely restricted to a few high-volume centers with extensive experience and may not be easily adapted into widespread clinical use.
TORS
The use of robotic assistance in surgery was first pioneered in the 1980s in neurosurgical and urological surgery. Over the past 2 decades, robotic surgery has proliferated, and several indications have been approved by the Food and Drug Administration (FDA), including applications in prostate surgery, gynecologic surgery, laparoscopic surgery, cardiac surgery, and head and neck surgery. The use of surgical robotic systems provides several advantages, including increased instrument degrees of freedom of movement, improved visualization (particularly outside of line-of-site), potential reduction of hand tremor, and a relatively short learning curve. These advantages are partially offset by the lack of haptic feedback. Nevertheless, TORS has recently emerged as a viable technique for the initial treatment of oropharyngeal SCC.
Development of TORS
In 2003, the first potential head and neck applications for robotic surgery were reported, including neck dissection and salivary gland surgery in a porcine model. However, TORS, as it is known today, originated with studies performed at the University of Pennsylvania, where Hockstein and colleagues demonstrated in an airway mannequin that the da Vinci surgical system (Intuitive Surgical, Inc, Sunnyvale, CA.) could be safely manipulated to access the oropharynx and larynx. Furthermore, this group showed that multiple oropharyngeal and laryngeal procedures were technically feasible and refined the proper use of oral retractors and surgical instrumentation in both canine and cadaveric models, thereby paving the way for the use of this technique in humans.
The first use of TORS for oropharyngeal SCC was reported by O’Malley and colleagues, whereby they demonstrated the importance of oral retractor use and detailed the steps of tongue-base resection using this approach. In this initial series of 3 patients, 2 patients received planned tracheotomies and were successfully decannulated after surgery, and all patients tolerated a regular diet within 6 weeks of surgery. Shortly thereafter, robot-assisted supraglottic laryngectomy was reported with good postoperative functional results and no complications.
The first larger series of the use of TORS in oropharynx SCC included 27 patients, all of whom received prophylactic gastrostomy tube placement, and showed an overall complication rate of 19%. Early oncologic results were promising at 6-month follow-up, with no patients having evidence of locoregional recurrence. Three independent groups then reported initial case series ranging from 20 to 45 patients. Oncologic results from these studies were similarly encouraging, with negative margins in all patients and high rates of locoregional disease control and no life-threatening perioperative complications reported. However, it must be pointed out that most patients in these TORS retrospective series received postoperative radiation as part of the treatment package. Functional results were also promising, with temporary tracheostomy needed in 10% to 31% of patients and temporary enteral feeding needed in 31% to 48%. Those with prolonged feeding tube dependence and tracheostomy tube dependence tended to have advanced (T3-T4) disease. Based on these encouraging results at multiple institutions, TORS was approved by the FDA (December 2009) for resection of tumors of the oral cavity and oropharynx.
Functional Results
The primary rationale for the shift from a primary surgical approach to a primary nonsurgical approach for the treatment of oropharyngeal SCC over the past several decades was the significant functional morbidity entailed with most traditional surgical approaches to the oropharynx; however, the application of chemoradiation to the oropharynx is not without risk of significant functional impairment. The rate of severe late toxicity from chemoradiation for oropharyngeal cancer ranges from 35% to 43%. A prospective study of 104 patients with head and neck cancer treated with chemoradiation found that 26% remained feeding tube dependent at 1 year, and 14% remained tracheostomy dependent. In addition, there is a small but real risk of death in patients treated with chemoradiation. However, in a recent prospective multi-institutional trial specifically for oropharyngeal cancer and using modern radiotherapy techniques, long-term toxicities were quite modest. Proponents of TORS argue that functional outcomes may be significantly improved without compromising oncologic control.
Several studies have assessed the early functional outcomes following TORS ( Table 1 ). In these studies, 0% to 31% of patients received temporary tracheostomy. Of the patients who required tracheostomy, most were decannulated within 14 days of TORS. Of a total of 204 patients treated with TORS, 1 (0.5%) patient remained tracheostomy dependent at 1 year after surgery. Importantly, 83% to 100% of patients returned to an oral diet within 2 weeks after TORS. The rate of temporary feeding tube use varies significantly across studies, depending on surgeon preference and possible need for postoperative radiation. However, only 0% to 17% of patients required a feeding tube at 1 year, and many of these patients already had impaired swallowing before TORS. A case-control study comparing quality of life between patients receiving TORS and patients receiving primary chemoradiation found that patients receiving TORS scored significantly higher in swallowing, eating, and diet domains 2 weeks after treatment, although these differences disappeared at 3 to 6 months after treatment. At 1 year, patients who received TORS had returned to baseline scores on subjective measures of swallowing and oral intake, whereas patients who received chemoradiation continued to score below pretreatment levels. These early functional results compare favorably with previously reported functional outcomes of primary chemoradiation; however, further prospective, large-scale and long-term data comparing a primary TORS approach with a primary chemoradiation approach are necessary to better define potential differences in functional outcomes.
