Tomeh, Chafeek; Holsinger, F. Christopher
Despite the advent of new and innovative approaches in radiation, chemotherapy, and surgery, the multidisciplinary treatment of patients with intermediate to advanced laryngeal cancer remains a challenging clinical problem. For a century, total laryngectomy was considered the only curative approach to this disease. In 1991, the Veterans Affairs study shifted the pendulum of treatment away from primary surgery toward ‘organ preservation’, relying on induction chemotherapy and radiation therapy. The Radiation Therapy Oncology Group (RTOG) 91–11 later established the efficacy of radiation therapy with concurrent chemotherapy for ‘laryngeal preservation’, but showed that concurrent chemoradiation was associated with diminished overall survival and higher long-term toxicity, compared to induction chemotherapy and radiation. The era of chemoradiation ushered in by RTOG 91–11 has led many to reconsider the notion of laryngeal preservation. Whereas many patients have achieved ‘anatomical preservation’ of the larynx, functional organ preservation has been sometimes elusive. Here, we review the swing of the pendulum in treatment selection for this disease, focusing on pivotal clinical trials and concluding with a discussion of surgical options for functional organ preservation, such as the supracricoid partial laryngectomy (SCPL) and transoral microsurgery.
SURGICAL MANAGEMENT OF LARYNGEAL CANCER
Total laryngectomy was first successfully performed for a patient with laryngeal cancer in 1873 by Theodor Billroth . The procedure evolved as the definitive treatment for the disease providing wide surgical margins and good swallowing function, yet leaving patients with postoperative aphonia and reliance upon permanent tracheostoma. Many methods of postlaryngectomy speech rehabilitation have been developed. The tracheoesophageal puncture was proposed by Singer and Blom in 1980 . The reported success rate of speech production is between 50 and 90%, which is higher than the results noted for esophageal speech . Despite the advances in vocalization, total laryngectomy was still associated with decreased quality of life. Burns et al. reported on quality-of-life measures in total laryngectomy patients, noting that only 56% would undergo total laryngectomy again, 29% would not, and 15% were unsure. Additionally, Harwood and Rawlinson  reported that quality of life for patients with advanced laryngeal cancer was higher for patients treated successfully with radiation therapy compared to surgically treated patients in all categories except throat dryness. In contrast, Morton et al. reported no significant difference in depression, pain, psychological well being, or life satisfaction when comparing laryngectomy patients to patients treated successfully with radiation. Despite excellent opportunities for rehabilitation, alternatives to total laryngectomy have been sought, due to the impact of this surgery on social, emotional, and psychological well being. Laccourreye et al.[7▪] performed a prospective survey regarding the trade-off between survival and larynx preservation of 309 patients presenting to his clinic without a diagnosis of laryngeal cancer. He reported that 12.9% of those surveyed were unable to decide between total laryngectomy and chemoradiation, 24.6% preferred improved survival with total laryngectomy, and 62.5% would consider preserving the larynx even if that compromised survival.
Conservation laryngeal surgery has played an important role in the management of selected early and intermediate-stage cancers. Techniques in vertical partial laryngectomy and the supraglottic partial laryngectomy were refined in the United States in the 1950s by Som , Norris , and Conley . The limited indications for the vertical partial laryngectomy confined its utility to T1 and T2 cancers of the glottic larynx.
For supraglottic tumors, Huet  described a procedure resecting a portion of the supraglottis without resection of the thyroid cartilage in 1938. Alonso  presented his technique for supraglottic laryngectomy, to include resection of the upper portion of the thyroid cartilage, leading to the supraglottic partial laryngectomy known today. Ogura , Som , and Kirchner and Som  popularized this technique in the United States. Supraglottic laryngectomy also has limited indications, confining it to T1 to very selected T3 tumors of the supraglottic larynx, and often excluding chemoradiation failures. The widespread use of these partial laryngectomies was limited by narrow indications, often confined to early-stage tumors, need for temporary and sometimes permanent tracheostomy tube, and risk of aspiration. Given these limitations, total laryngectomy remained the mainstay of treatment for intermediate to advanced-stage laryngeal cancer.
ORGAN PRESERVATION APPROACHES
The era of chemoradiation as primary treatment for laryngeal cancer began in 1991 with the publication of the Veterans Affairs Laryngeal Cancer Study . In this study, 332 patients with stage III or IV laryngeal cancer were randomized into two treatment groups: those patients treated with either induction chemotherapy with cisplatin and fluorouracil followed by radiation or surgery followed by radiation therapy. Overall 2-year survival rates were 68% for both groups, with a median follow-up period of 33 months. Laryngectomy was avoided in 64% of patients in the induction chemotherapy arm. Statistically significant differences between the two groups were seen with fewer local recurrences in the surgery group (P = 0.0005) and fewer distant metastases in the chemotherapy group (P = 0.016). These results validated the use of induction chemotherapy followed by radiation in the treatment of advanced laryngeal cancer and led to a shift in advanced-stage laryngeal cancer treatment toward a primary nonsurgical approach, leaving total laryngectomy for relapse.
The RTOG 91–11 study, built on the strengths of the Veterans Affairs study, sought to compare three nonoperative approaches to the treatment of advanced laryngeal cancer: induction chemotherapy (cisplatin and fluorouracil) followed by radiation, concurrent cisplatin with radiation therapy, and radiation therapy alone . In this three-arm randomized trial, 547 patients with stage III or IV laryngeal cancer were stratified by primary tumor site, N stage, and primary tumor stage prior to randomization. It was designed to build on the success of the Veterans Affairs study, and to determine proper timing of chemotherapy (induction vs. concurrent). The statistical design of RTOG 91–11 was powered to determine differences in laryngectomy-free survival, or ‘survival with preservation of laryngeal function’. This endpoint was a bold attempt to characterize a unique and heretofore undescribed composite endpoint, including both disease-specific survival and ‘laryngeal preservation’. At 2 years, all three treatment arms had similar laryngectomy-free survival rates, thus the study should have been considered a negative study for the primary endpoint; however, the authors promoted findings that were developed from secondary endpoints. The proportion of patients who maintained an intact larynx was greatest in the concomitant chemoradiation group (88%), compared to the induction chemotherapy group (75%; P = 0.005) and the radiotherapy group (70%; P < 0.001). Locoregional control was also significantly better in the concurrent chemoradiation group at 78% vs. the induction chemotherapy group at 61%, and the radiotherapy-alone group at 56%. Although there was no difference in overall survival among the three treatment arms, both chemotherapy arms had longer disease-free survival compared to radiation alone. This improvement in disease-free survival did come with an increase in serious or severe toxicity; specifically there was nearly twice the occurrence of mucosal toxicity in the concurrent chemoradiation arm compared to either other arm.
In 2012, the long-term results from patients treated on RTOG 91–11 were published [17▪▪]. Overall survival did not differ significantly between groups. Interestingly, deaths not attributed to larynx cancer were higher in the concomitant chemoradiation group at 30.8% (20.8% among the induction chemotherapy arm and 16.9% among the radiation-only arm). Whereas the investigators feel this difference in death rates was not related to cancer treatment, the exact cause was unknown. As such, it is possible there is an underappreciated toxicity from concurrent chemotherapy, which leads to an increase in death. Further investigation into this subset of patients would be necessary to definitively determine the causative differences.
Quality-of-life outcomes reported in the 10-year follow-up study to the RTOG 91–11 noted similar rates of impaired speech between all three groups, in the range of 3–9% of patients reporting moderate difficulty during years 2–5 after treatment. Swallowing dysfunction classified as ‘can only swallow soft foods’ or worse was highest in the concurrent chemotherapy group (17–24%) compared to the induction chemotherapy group (13–14%) and the radiation-alone group (10–17%). Whereas swallowing assessment may be a proxy assessment for aspiration, the RTOG 91–11 study did not report on aspiration specifically nor did it report on the need for long-term tracheostomy or feeding tube.
TRANSORAL MINIMALLY INVASIVE ENDOSCOPIC HEAD AND NECK SURGERY
With the evolution in our understanding of transoral anatomy and the advent of new computer-assisted technologies, transoral minimally invasive endoscopic head and neck surgery (eHNS) is the natural progression of treatment of head and neck cancer patients . This is particularly true for treatment of early to intermediate and sometimes advanced-stage laryngeal cancer [19,20]. Whereas Jako and Strong first introduced transoral laser microsurgery in 1972 for treatment of early-stage glottic cancer, Steiner expanded the use of transoral laser microsurgery (TLM) to treatment of tumors beyond the glottic larynx to other areas of the upper aerodigestive tract including the pyriform sinus and base of tongue [21–24].
TLM requires meticulous microscopic technique and instrumentation, performed under suspension direct laryngoscopy with the carbon dioxide (CO2) laser . The technique popularized by Steiner and Ambrosch  was instrumental in broadening the use of TLM though it challenged a basic tenet of oncologic surgery, namely en-bloc resection. Transecting the tumor reveals the depth of tumor penetration, which provides clear visualization of tumor margins during resection. Function is preserved using Steiner's techniques by maintaining at least one valve of the larynx for airway protection, swallowing, and vocalization.
After expanding the use of TLM to multiple sites in the aerodigestive tract, Canis et al.[25▪▪] in 2013 reported on their experience with more advanced-stage T2 to T3 tumors in a retrospective study of 391 previously untreated patients. After a median follow-up of 71 months, 5-year overall, recurrence-free, and disease-specific survival rates were 72.2, 76.4, and 93.2% for pT2a tumors; 64.9, 57.3, and 83.9% for pT2b tumors; and 58.6, 57.8, and 84.1% for pT3 tumors, respectively. They noted a 93% larynx preservation rate among pT2a tumors and 83% among pT3 tumors. These results compare favorably to open partial laryngectomies, total laryngectomies, or chemoradiation. Functionally, 84% of patients never required a nasal feeding tube; only one patient in the pT2a group temporarily required a feeding tube, whereas in the pT3 group, three patients required a temporary feeding tube.
Patient selection is an important factor for determining feasibility of TLM, as exposure through a laryngoscope dictates whether this approach is possible [22,26]. Involvement of the anterior commissure was thought to be a limitation to transoral surgery; however, recent studies have shown favorable results in these patients . Steiner et al. reported a 79% 5-year local control rate and a 93% laryngeal preservation rate in patients with pT2a glottic tumors involving the anterior commissure. This compared favorably to patients without anterior commissure involvement in whom he reported a 74 and 97% 5-year local control rate and laryngeal preservation rate, respectively. Hinni et al. in 2007 reported a 92% laryngeal preservation rate in patients treated with TLM, supporting Steiner et al.'s results.
TLM has been proven to be effective in treatment of tumors of the glottic as well as the supraglottic larynx. Supraglottic tumors are more difficult to control compared to glottic tumors, given their presentation at a later stage and a much higher incidence of cervical nodal metastasis . Despite these negative characteristics, Davis et al. reported on his series of 38 patients selected for TLM with T2 and T3 primary supraglottic tumors and noted a 97% primary site control rate among patients who received TLM and radiation after a mean follow-up of 66 months. This is better than the quoted control rates for T2 and T3 tumors by radiation alone at 70–80% and 40–60%, respectively [32,33].
The functional outcomes of TLM are excellent, with Steiner  showing no patients requiring long-term feeding or tracheostomy tube placement. Voice quality can vary depending on the depth and extent of resection, essentially correlating with stage of the tumor . In 2012 and 2013, Kerr et al.[34▪▪] and Vilaseca et al.[35▪▪] reported on voice outcomes of patients after TLM. Kerr et al. noted that the TLM patients had inferior voice quality for the first 48 months after treatment compared to the 91 patients who were treated with primary radiation despite a stage bias in favor of TLM. However, given the higher laryngeal preservation rate among the TLM patients (near 100% for TLM and between 88 and 92% for primary radiation), the benefits of TLM outweigh the poorer voice quality. Vilaseca et al. noted an improvement in quality of life 1 year after treatment of laryngeal cancer with TLM using the University of Washington Questionnaire. Although voice quality improves with time after treatment with TLM, speech remains the most important quality of life variable in 46% of patients. Tumor location, postoperative radiation, and neck dissection were all independent factors affecting quality-of-life measures. Vilsaseca et al. reinforced the necessity for preoperative counseling and postoperative rehabilitation.
TRANSORAL ROBOTIC SURGERY
The daVinci Surgical System (Intuitive Surgical, Sunnyvale, California, USA) is composed of a surgeon's console, separated by several feet from the patient, and a robotic tower with four articulating arms containing the microsurgical instruments controlled virtually through the surgeon console. The surgeon's console includes a high-definition three-dimensional monitor. The microsurgical instruments are positioned within the robotic arms and controlled robotically with 540 degrees of wristed instrumentation. Movements of the surgeon's hands in the virtual environment are translated into instrument movements with dampening of the surgeon's native tremor as the robot tracks the surgeon's movements 1300 times per second. Motion is also scaled, translating larger movements of the surgeon's hands into finer movements, making this application perfect for microsurgery.
Although data supporting the use of transoral robotic surgery (TORS) for oropharyngeal carcinoma are abundant, data supporting robotic surgery in laryngeal carcinoma are, however, lacking. Hockstein et al. and Weinstein et al. first reported on the use of the daVinci Surgical System for the treatment of laryngeal cancer, demonstrating the feasibility of this technique in a small series of patients. Solares and Strome  reported in 2007 on the feasibility of coupling the CO2 laser with the daVinci Surgical System in cadaveric models and attempts in live patients for the treatment of supraglottic tumors. Although the technique seemed feasible in the cadaveric and animal models, exposure was only adequate in one out of the three selected patients. In 2012, Alon et al.[39▪] reported on seven supraglottic cancers staged T1 to T3 treated with TORS. All seven patients were resected to negative margins, four patients underwent tracheostomy tube placement with three successfully decannulated, and two patients required long-term gastrostomy tube placement during adjuvant radiation therapy. There was one intraoperative complication in which a patient sustained thermal injury to the anterior cervical skin. This series illustrates the limitations of TORS for the treatment of supraglottic carcinoma.
Similarly, TORS for glottic cancers lacks supporting data with a few case series in the head and neck literature. Blanco et al. reported successful treatment of a T1a glottic cancer coupling the laser with the daVinci Surgical System. Kayhan et al.[41▪] presented a case series of 10 patients with T1 glottic cancers treated using the daVinci robot. He noted negative margins in all patients, short operative time (mean of 21.6 min), and only one patient requiring a short-term tracheostomy and nasal feeding tube with the remaining nine patients starting oral nutrition within 6–24 h postop.
SUPRACRICOID PARTIAL LARYNGECTOMY
In 1959, Majer  described the supracricoid laryngectomy in which the entire thyroid cartilage, true folds, false folds, all or a portion of the epiglottis and pre-epiglottic space are resected. Patients with advanced tumors from T2 to select T4 lesions with anterior commissure or transglottic spread may be candidates for SCPL. In SCPL, the paraglottic space is resected and the hyoid bone is impacted onto the cricoid cartilage in order to reconstruct the larynx . In SCPL with cricohyoidoepiglottopexy (CHEP), a segment of the epiglottis is preserved and this segment is included in the cricoid–hyoid impaction. Although the vocal cords are resected in SCPL, speech and swallowing are maintained through preservation of a cricoarytenoid unit [43,44]. SCPL is thus a function-sparing procedure for treatment of advanced laryngeal cancer; physiologic speech and swallowing are retained without the need for long-term tracheostomy.
Supracricoid partial laryngectomy produces a high level of functional outcomes and has replaced near-total laryngectomy as an organ-sparing surgical option. It is associated with local control rates greater than 96%, and when compared with total laryngectomy has improved swallowing and speech quality-of-life measures . Benito et al. reported swallowing outcomes on a series of 457 patients who underwent SCPL, noting normal swallowing without aspiration in 259 out of 457 (58.9%), subclinical grade 1 aspiration in 87 patients (19%), and severe grade 2 or 3 aspiration in 101 patients (22.1%). They predicted that patients most at risk for severe aspiration were above 70 years old and underwent cricohyoidopexy with partial or total arytenoid resection. Aspiration was managed with temporary gastrostomy, permanent gastrostomy, and completion total laryngectomy in 34.5, 1.6, and 3.7%, respectively.
In patients with T2 and select T3 tumors, local control rates exceed 90% and are comparable with rates seen with chemoradiation or total laryngectomy [15,16,46,47]. Functionally, although speech and swallowing are preserved, voice quality is different postoperatively. Restoration of swallowing may require intensive rehabilitation over several weeks. Despite these obstacles, 80–90% of patients will have swallowing function restored within the first year . Additionally, SCPL can be considered in the salvage setting; however, proper patient selection is of utmost importance as there is an increase in postoperative complications including delayed wound healing and prolonged rehabilitation of speech and swallowing .
DEFINING QUALITY OF LIFE AND FUNCTION AS BENCHMARKS FOR SUCCESS IN TREATING LARYNGEAL CANCER
As the pendulum began to swing towards chemoradiation for advanced laryngeal carcinoma, it became apparent that laryngeal ‘organ preservation’ might not be the best benchmark to determine successful treatment. For patients treated with chemoradiation, quality of life and functional outcomes, especially swallowing, may not always correlate with an anatomically preserved larynx. Murphy et al. evaluated swallowing function with modified barium swallow and longitudinal swallowing function questionnaires in head and neck cancer patients prior to and after chemoradiation. He noted that whereas many patients had an abnormal modified barium swallow prior to chemoradiation, they reported normal swallowing function. After chemoradiation, these patients noted declining swallowing function, suggesting that they were able to compensate for tumor-related dysfunction prior to chemoradiation, but were no longer able to do so after it. However, patients may not be able to accurately perceive their level of swallowing function, as xerostomia may cause a diminished perception of swallowing function, whereas objectively it remains intact . This lack of correlation between patients’ perceptions and objective studies highlights the importance of documenting swallow function before, during, and after chemoradiation treatment .
Whereas acute mucositis is the dose-limiting toxicity of chemoradiation, it is also associated with dysphagia in the long term. However, there are other factors which are also responsible for long-term dysphagia after chemoradiation, such as loss of laryngeal sensitivity [53,54]. Furthermore, the worsening of dysphagia and aspiration years after chemoradiation suggests that submucosal fibrosis as well as vascular and nerve injury may play a role [55▪▪]. Interestingly, there is growing evidence that the targeted agent cetuximab may lead to less mucositis and dysphagia compared to cytotoxic chemotherapeutic drugs; however, further investigation with properly designed studies specifically addressing laryngeal function is needed [55▪▪,56].
The Larynx Preservation Consensus Panel in 2009 reported on the key issues in designing larynx preservation trials, discussing which patients should be considered for organ preservation and which quality-of-life measures should be assessed . They recommended patients with laryngeal dysfunction, defined as pretreatment tracheostomy, tumor-related dysphagia requiring feeding tube, or recurring pneumonia, due to tumor should not be considered for organ preservation approaches. Vocal cord fixation and patients who are eligible for partial laryngectomies should also be excluded from these trials.
In assessing quality-of-life measures, the Larynx Preservation Panel recommended swallowing evaluations at 1 and 2 years after treatment, assessing voice at 1 and 2 years, recording use of a feeding tube and episodes of pneumonia. Esophageal stricture requiring intervention and assessment of vocal cord mobility were also important measures to assess.
Whereas total laryngectomy was the mainstay of treatment years ago, the Veterans Affairs study and RTOG 91–11 introduced the concept of laryngeal preservation into the multidisciplinary treatment approach, while maintaining locoregional control rates similar to total laryngectomy. As an increasing number of patients began to undergo chemoradiation for treatment of advanced laryngeal carcinoma, some limitations of ‘organ preservation’ emerged. Whereas chemoradiation could preserve the larynx, laryngeal function was not always guaranteed. The focus of treatment evolved from improved locoregional control and laryngeal ‘organ’ preservation to preservation of laryngeal function, focusing on swallowing function without aspiration. Around the same time, a new generation of surgeons ushered in a renaissance of conservation laryngeal surgery, from Steiner and Ambrosch to Laccourreye. Multiple studies supported these procedures, demonstrating in single-institution series that locoregional control was maintained and laryngeal function remained intact. Whereas these procedures were viable options for early-stage laryngeal cancer, they were not sufficient for many advanced-stage lesions. Supracricoid laryngectomy emerged as an option for these advanced cancers, once again maintaining locoregional control rates at acceptable levels and maintaining a functional larynx. Future studies will continue to focus on the importance of laryngeal function whenever considering laryngeal preservation, and further investigation is needed in comparing chemoradiation regimens to the emerging methods of conservation of laryngeal surgery.
Conflicts of interest
No financial conflicts of interest to disclose, no funding.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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Demonstrates functional voice outcomes in transoral laser surgery, which is an important consideration for laryngeal conservation surgery.
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Demonstrates important patient-centered factors in determining proper treatment algorithms using transoral laser surgery.
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Demonstrates the feasibility of robotic surgery.
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