Key points

Transoral surgery in oropharyngeal cancer treatment

Transoral endoscopic surgery (TOS) encompasses 2 different techniques, transoral laser microsurgery (TLM) and transoral robotic surgery (TORS), both of which provide a minimally invasive surgical approach to the pharynx. TOS offers superior oncologic and functional outcomes compared with the traditional open surgical approach. TLM, originally developed in the 1970s for the ablation of laryngeal papillomas, has expanded into the oropharynx and oral cavity, but its application has been limited by the requirements of line-of-sight visualization and occupation of one hand to operate the laser. Meanwhile, TORS, approved by the US Food and Drug Administration in 2009 for removal of benign and malignant early-stage pharyngeal tumors, has experienced rapid adoption. Advantages of TORS over TLM include improved wide-field visualization, especially useful at the base of tongue, and greater stability and subtlety of movement in a virtual, magnified, 3-dimensional surgical environment. The surgeon is seated at a console remote from a patient-side cart equipped with robotic arms that deliver the surgical instruments and endoscope. TORS allows for bimanual manipulation and en bloc excision of tumors. In the United States, TORS has increasingly been used as part of a curative-intent treatment plan for oropharyngeal squamous cell carcinomas (OPSCC), and its use is increasing in Europe and other parts of the world.

The emergence of transoral surgery as an upfront management strategy has coincided with the recognition of human papillomavirus (HPV) as an etiologic and prognostic factor in OPSCC, leading to several interrelated uncertainties pertinent to postoperative management. At present, single-modality treatment (using either radiation therapy or TOS) is clearly appropriate for early- and intermediate-stage (T1-2, N0-1) OPSCC, but it has proven more complex to identify indications for TOS in the management of advanced-stage cancers, which have been traditionally managed with chemoradiation (CRT) over the past 2 decades. In locally or regionally advanced oropharyngeal cancers, complete extirpation may be more challenging, and by current standards of care, postoperative radiation or CRT is required in most cases. Thus, investigators are rigorously examining the indications for adjuvant therapy following initial surgical management for advanced OPSCC. The hypothesis is that histopathologic information from upfront surgery will result in an improved precision of adjuvant therapy decisions, thereby improving function and quality-of-life outcomes over upfront radiation-based treatment in patients who are pathologically downstaged and receive deintensified adjuvant therapy.

Impact of human papillomavirus on prognosis and staging of oropharyngeal cancer

HPV was confirmed in 2000 by DNA polymerase chain reaction detection to be an etiologic agent of OPSCC. It is now known that greater than 60% of OPSCC are exclusively associated with HPV-16 (which accounts for 86.7% of HPV detected in OPSCC) or HPV-18, although other “high-risk” strains that are detected at a low frequency include HPV-31, -33, -35, -39, -45, and -52, for an overall proportion of greater than 70% of OPSCC that is HPV related. These findings are reinforced by a distinct clinical profile of patients with HPV-associated OPSCC that differs dramatically from patients with conventional head and neck cancer. Patients with HPV-OPSCC have been found more likely to be younger, nonsmokers, and with higher rates of marijuana and sexual exposure than other patients with head and neck cancer. They tend to have a higher socioeconomic status and level of education. HPV-OPSCC has a distinctive molecular profile as well, demonstrating a lack of p53 mutations and overexpression of p16 caused by inhibition of retinoblastoma protein pRB by HPV E7 protein. Unlike the stability or declines seen in the incidence of other head and neck cancers in Western countries consequent to decreases in the rate of cigarette smoking, the incidence of HPV-OPSCC is countering the trend with a rising incidence.

An important recursive partitioning analysis of Radiation Therapy Oncology Group (RTOG) 0129, a CRT-based cooperative group clinical trial, showed that compared with other OPSCC patients, patients with HPV-OPSCC were at “low risk” for death, due to the responsiveness of their cancers to CRT and their lower risk for development of distant metastases. The 3-year overall survival (OS) rates were 82.4% for HPV-OPSCC patients versus 57.1% for patients with HPV-negative tumors, with HPV positivity conferring a 58% reduction in the risk of death and risk of death increasing for each additional pack-year of tobacco smoking. In the low-risk group, defined by HPV positivity and either ≤10 pack-years of smoking or greater than 10 pack-year history with stage N0-N2a, the 3-year OS was 93%. Given the exceptional response of HPV-OPSCC to standard therapy and the lengthy survivorship seen in this patient population with a higher relative risk of long-term morbidity from potential overtreatment, recently conceived clinical trials for this population have focused on “deintensification” of therapies ( Table 1 ). The clinical trial landscape for this category of patients is very active, with a large number of competing proposed interventions and no new singular standard of care that has clearly emerged.

One major change that is universally accepted is that p16 status is now considered a basic mandatory stratification factor in clinical trials for oropharyngeal cancer. Diffuse nuclear and cytoplasmic p16 protein staining set at a cutoff of greater than 70% of tumor cells has approximately 90% correlation with HPV status as determined by in situ hybridization and quantitative and consensus polymerase chain reaction. Because p16 immunohistochemistry is less costly and reliably standardizes across laboratories, p16 graded by H-score, rather than HPV DNA status, has been used for stratification in most clinical trials. A complicating issue is that although p16 remains the most commonly accepted biomarker for HPV status, it is itself a tumor suppressor protein. Therefore, p16 positivity may be reflective of a biological process independent of HPV status. One large study of aggregated clinical trial data showed a prognostic value of p16 in oral, laryngeal, and hypopharyngeal squamous cell carcinomas, but the prognosis of these cancers was not as dramatically improved by p16 positivity as was OPSCC, and p16 positivity in these nonoropharyngeal cancers showed less correlation with HPV DNA status. Therefore, no proposals for changes to standard treatment have been made for nonoropharyngeal head and neck cancers on the basis of either p16 or HPV status. p16 has also been identified in other cancers, which can metastasize to the lymph nodes of the head and neck, such as skin cancer, wherein p16 positivity does not affect prognosis and is not associated with HPV in these cancers.

Parallel to the evolution in clinical trials is a change in the American Joint Committee on Cancer (AJCC) staging system for OPSCC. In the AJCC 8th edition, which will take effect in the national cancer registries on January 1, 2018, HPV-OPSCC has its own unique staging system separate from other OPSCC. HPV-OPSCC patients who would formerly have been considered to have stage IVA oropharyngeal cancer will mostly be reclassified to have stage I or stage II, reflecting that they are at a low risk for death when appropriately treated. Because the staging system is an international system that must be used worldwide, the definition of HPV-OPSCC for staging purposes will rely on p16 immunohistochemistry. It is also important to note that OPSCC staging, whether HPV-associated or not, remains distinct from staging for cancers of the oral cavity.

Safety and oncologic outcomes of transoral robotic surgery for oropharyngeal cancer

TORS represents an interesting case study in the assessment of quality in head and neck cancer care. TORS emerged in a time of close monitoring of outcome measures by health care systems and regulatory agencies. An initial study of TORS using measures from the American College of Surgeons’ National Surgical Quality Improvement Program (NSQIP) revealed a low rate of postoperative complications of 7.9%. However, the NSQIP measures were not ideal to assess TORS, because common complications were not specifically measured. Postoperative bleeding was measured through the surrogate of transfusion requirement, and other metrics of quality, such as need for reoperation, were difficult to assess because of the often-staged nature of TORS operations. Furthermore, metrics of quality specific to head and neck cancer such as speech and swallowing outcomes were not included. This study highlighted the need for specialty-specific NSQIP measures to allow more relevant analyses of quality for TORS.

For TORS, as for many surgical techniques, increased volume has been associated with a lower rate of complications and improved quality outcomes. Multiple case series describe a decreased risk of complications after TORS with increasing experience, and increased TORS experience correlates with decreased operative time, length of intubation, and hospital stay. The risk of complications appears to be lower in surgeons who have performed more than 50 TORS procedures. As a result, there has been considerable effort by the American Academy of Otolaryngology-Head and Neck Surgery and the American Head and Neck Society to set up an independent credentialing committee to standardize training. Previous credentialing methods were institution-dependent and highly reliant on industry. Establishment of national standards will enable follow-up analyses of adherence to guidelines and impact on quality.

At present, TORS has been evaluated most thoroughly in single- and multi-institutional studies conducted by major academic centers. Although the available data suggest very favorable oncologic outcomes, no randomized controlled studies have been completed comparing the outcomes of upfront TOS and upfront CRT or radiation. This direct comparison is the goal of the ORATOR ( NCT01590355 ) randomized phase 2 clinical trial, which is based on a head-to-head randomization of surgery versus radiation-based treatment. One large, influential, multi-institutional series found 2-year locoregional control and OS rates of TOS-treated patients to be 91.8% and 91%, respectively. A systematic review of 11 studies could not clearly report long-term local control due to variable follow-up but identified 9 studies reporting gastrostomy tube dependence for an aggregate 12-month rate of only 5%. On head-and-neck–specific quality-of-life surveys, outcomes of upfront TOS followed by adaptive adjuvant therapy appear to be roughly equivalent to, and in cases when no adjuvant therapy or adjuvant radiation alone can be given, superior to, concurrent CRT. However, attempts at direct comparison may be affected by selection bias given resectability and better performance status of surgically eligible patients.

Complicating the issue of comparative evaluation further is the fact that most patients with OPSCC, even those with locoregionally advanced cancers who receive CRT, tend to experience quite favorable long-term survival outcomes with low rates of severe toxic effects. The differences separating patients treated with variably sequenced forms of multimodal therapy may be subtle and difficult to distinguish. An additional complicating factor is that the standard of CRT is evolving, with large institutional experiences indicating that T1-T2 node-positive HPV-OPSCC patients achieve high 5-year survival rates (90%) when treated with radiation alone, potentially making comparisons of TOS to radiation alone or other “deintensified” radiation-based treatments currently under study more valid in the future than comparisons to standard CRT.

To address these questions, clinical trials such SiRS ( NCT02072148 ), ECOG 3311 ( NCT01898494 ), and PATHOS ( NCT02215265 ), all studies of upfront TOS followed by histopathologically directed adjuvant therapy, are investigating the role of upfront TOS for the purpose of decreasing adjuvant radiation dosage. Other trials such as ADEPT ( NCT01687413 ) are examining the feasibility of decreasing or eliminating adjuvant chemotherapy intensity in surgically staged HPV-OPSCC patients. These clinical trials will record outcomes prospectively in HPV-OPSCC patients treated with TOS, providing a higher-quality evidence base for meaningfully crediting the contribution of surgery in well-controlled clinical scenarios.