Your activity: 6 p.v.

Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx

Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx
Authors:
Bruce E Brockstein, MD
Kerstin M Stenson, MD, FACS
David J Sher, MD, MPH
Section Editors:
David M Brizel, MD
Marshall R Posner, MD
Marvin P Fried, MD, FACS
Deputy Editor:
Sonali Shah, MD
Literature review current through: Dec 2022. | This topic last updated: Dec 13, 2022.

INTRODUCTION — Worldwide, there are over 180,000 new laryngeal cancer cases and approximately 100,000 deaths annually [1]. In the United States, there are approximately 12,500 cases and 3800 deaths due to laryngeal cancer annually [2]. Glottic, supraglottic, and subglottic cancers represent approximately two-thirds, one-third, and 2 percent of laryngeal cancers, respectively. Hypopharyngeal cancer is less common than laryngeal cancer, with approximately one-fourth as many cases.

Tumors of the glottic larynx commonly present with hoarseness and are most often diagnosed at an early stage. However, patients with supraglottic and subglottic laryngeal cancers, as well as hypopharyngeal cancers, usually present with advanced disease due to a paucity of symptoms, propensity for local extension (subglottis), and rich lymphatics resulting in a high incidence of lymph node metastases (supraglottis).

The management of locoregionally advanced laryngeal and hypopharyngeal cancer is presented here. The approach presented here is consistent with guidelines from the American Society of Clinical Oncology (ASCO) [3]. The treatment of early stage laryngeal and hypopharyngeal cancers is discussed separately.

(See "Treatment of early (stage I and II) head and neck cancer: The larynx".)

(See "Treatment of early (stage I and II) head and neck cancer: The hypopharynx".)

ANATOMY AND STAGING

Larynx — The larynx is divided into three anatomic regions (figure 1A-B):

Supraglottis – Suprahyoid epiglottis, infrahyoid epiglottis, aryepiglottic folds (laryngeal aspect), arytenoids, and ventricular bands (false cords). A fraction of supraglottic carcinomas may be arising from the oropharynx in continuity with the supraglottic larynx, and p16/HPV testing should be considered on all supraglottic cancers, especially those arising in nonsmokers.

Glottis – True vocal cords, including anterior and posterior commissures.

Subglottis – Subglottis, extending from the lower boundary of the glottis to the lower margin of the cricoid cartilage.

Hypopharynx — The hypopharynx lies beside and behind the larynx and extends to the esophageal inlet. It contains the paired pyriform sinuses, the posterior pharyngeal wall, and the postcricoid area (figure 2). Cancers arising in the oropharynx may appear to be hypopharyngeal; therefore, p16/HPV testing should be considered for those hypopharynx cancers contiguous with oropharyngeal sites, especially those arising in nonsmokers.

The eighth tumor, node, metastases (TNM) staging system of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) is used to classify cancers of the larynx (table 1) and hypopharynx (table 2A-B) [4,5]. For laryngeal cancers, staging of the primary tumor (T) is defined separately for supraglottic, glottic, and subglottic tumors. (See "Overview of the diagnosis and staging of head and neck cancer".)

OVERVIEW OF MANAGEMENT — All patients with advanced (stage III and IV) cancer of the larynx or hypopharynx should be seen prior to treatment by a multidisciplinary team with experience in the treatment of head and neck cancer, with the goals of education of the patient and family about surgical approaches and nonsurgical approaches, and evaluation by team members who would be involved in either a primary surgical or nonsurgical approach. A multidisciplinary tumor board can potentially change management and improve survival [6-8].

The treatment approach depends on tumor extent and location, patient-specific factors (eg, age, performance status, comorbidity, psychosocial support), clinician expertise, and availability of rehabilitation services. Treatment-related toxicity associated with chemoradiation and surgery must also be considered. Patient selection should consider a patient's ability to actively participate in speech and swallowing rehabilitation, regardless of treatment approach.

Functional organ preservation is widely recommended and generally utilizes a combination of chemotherapy plus radiation therapy (RT). However, advances in surgical techniques, such as laryngeal preservation surgery and minimally invasive surgery, offer alternative options for larynx preservation in carefully selected patients. These surgical approaches have not been directly compared with chemoradiation [9]. (See 'Larynx preservation surgery' below.)

Although functional organ-sparing approaches (ie, chemoradiation) can permit larynx preservation in patients with locoregionally advanced cancer of the larynx and hypopharynx, they do not provide a survival advantage over total laryngectomy. When feasible, most patients with locally advanced (T3, T4 disease) should be offered the option of organ preservation through combined chemotherapy and radiation (or radiation alone) to preserve the natural speech and swallowing function of the larynx, without compromising overall survival [10]. However, for other selected patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function, better survival rates and quality of life may be achieved with total laryngectomy [11]. This approach is consistent with clinical guidelines from the American Society of Clinical Oncology (ASCO).

Preservation of the larynx is not the exclusive determinant of quality of life; maintenance of speech, swallowing, and airway patency are critical endpoints of any functional organ-preservation treatment. An international consensus panel has recommended that a new endpoint of laryngoesophageal dysfunction-free survival is a more useful objective [12,13]. Events in this endpoint include death, local relapse, total or partial laryngectomy, tracheotomy at two or more years, and the presence of a feeding tube at two or more years. Salvage of a dysfunctional larynx with inadequate airway (requiring a tracheotomy) or swallow function (requiring a feeding tube) may not serve the patient well.

In addition, patients should be counseled about smoking cessation; ongoing tobacco use during RT has been associated with reduced survival in patients with locally advanced head and neck cancer [14,15].

COMBINED MODALITY THERAPY — For most good performance status patients with potentially operable, locally advanced cancer of the larynx or hypopharynx, functional organ-preserving approaches using combinations of chemotherapy and radiation therapy (RT) have replaced total laryngectomy plus postoperative RT. These approaches include chemotherapy given at the same time as RT (concurrent chemoradiation), induction chemotherapy followed by RT alone, or sequential therapy with induction chemotherapy followed by concurrent chemoradiation. RT alone may also be considered an organ-preservation strategy for those who cannot tolerate chemoradiation or sequential chemotherapy, although this approach is associated with a lower rate of larynx preservation. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

The choice of a functional organ-preserving alternative requires that the patient be able to withstand the prolonged course of treatment and associated toxicities and participate in rehabilitation, especially swallowing therapy, after treatment [16]. These combined modality approaches are also used to provide definitive treatment for patients who are inoperable because of extensive locoregional disease. (See "Speech and swallowing rehabilitation of the patient with head and neck cancer".)

While combined RT plus chemotherapy approaches usually maintain laryngeal function in patients with resectable disease, they are associated with considerable toxicity that, in some cases, may compromise the airway (edema or stenosis) or the patient's ability to protect the airway, and thus, may not achieve the goal of functional larynx preservation.

Organ function-preserving chemoradiation approaches are not appropriate for all patients with locoregionally advanced cancer of the larynx and hypopharynx. Examples include:

Older adults and patients with poor performance status – Older adults and those with a poor performance status may not be suitable candidates for chemoradiation approaches because of the upfront morbidity associated with this treatment and/or the inability to rehabilitate from these potentially life-threatening toxicities. Definitive RT alone for organ preservation or total laryngectomy followed by postoperative RT may be preferable in this setting. Laryngectomy typically offers rapid control of symptoms and prompt swallowing recovery. (See 'Older and poor performance status patients' below.)

Vocal cord destruction – Patients with destruction of both vocal cords may not recover vocal or airway protective function with larynx-preservation approaches and may function better after total laryngectomy rather than chemoradiation. (See 'Total laryngectomy' below.)

Outer cortex cartilage invasion – Tumors with cartilage outer cortex penetration or destruction (ie, T4a or T4b disease) should typically undergo total laryngectomy with postoperative RT or CRT. This operative approach provides better locoregional control and survival than nonsurgical approaches [17]. In addition, cartilage destruction limits the likelihood of adequate functional recovery with larynx-preserving approaches and increases the probability of radiation-induced necrosis.

By contrast, tumors with limited inner cortex cartilage invasion are classified as T3 in the American Joint Committee on Cancer (AJCC) 8th edition staging system and are appropriate to evaluate for nonsurgical treatment. Such patients were included in a randomized trial comparing various organ-function preserving chemoradiation approaches (RTOG 91-11), the results of which are discussed below. (See 'Comparison of combined chemotherapy and radiation therapy approaches' below.)

Nonsurgical functional organ preservation versus surgery — The feasibility of nonsurgical functional organ preservation using induction chemotherapy prior to definitive RT was established by the Department of Veterans Affairs (VA) Laryngeal Cancer Study Group larynx trial. Similar results were seen in a European Cooperative Group trial (EORTC 24891) of patients with cancers of the hypopharynx mostly (piriform sinus and some with hypopharyngeal aspect of the aryepiglottic fold).

In the VA trial, 332 patients with stage III or IV laryngeal cancer were randomly assigned to three cycles of induction chemotherapy with cisplatin plus fluorouracil, followed by definitive RT or primary surgery (typically total laryngectomy), followed by postoperative RT [18]. Patients without at least a partial response and those with any evidence of disease progression during or after induction chemotherapy were treated with surgery and postoperative RT.

At a median follow-up of 33 months, the two-year survival rate was equal in both treatment groups (68 percent), and the larynx was successfully preserved in 64 percent of patients treated with induction chemotherapy [18]. A subsequent publication reported that the three-year survival rates were 53 and 56 percent for chemotherapy plus RT and surgery plus RT, respectively [19].

In the European trial, 194 patients with stage II through IV squamous cell carcinoma of the pyriform sinus or aryepiglottic fold were randomly assigned to receive induction chemotherapy with cisplatin plus fluorouracil, followed by definitive RT or surgery (total laryngectomy with partial pharyngectomy), followed by postoperative RT [20,21]. Patients who failed to achieve a complete response to induction chemotherapy underwent salvage surgery and postoperative RT.

At a median follow-up of 10.5 years, there were no significant differences in survival or patterns-of-failure outcomes. The 10-year progression-free survival probabilities for the chemotherapy plus definitive RT and for the surgery arms were 11 and 9 percent, respectively. Overall survival probabilities at 10 years were 13 and 14 percent, respectively. The 5- and 10-year probabilities of being alive with a functional larynx were 21.9 and 8.7 percent, respectively, on the larynx preservation arm; however, for those patients alive at 5 and 10 years, 59.5 percent (22/37) and 62.5 percent (5/8) maintained a normal larynx, respectively.

Following the demonstration of benefit with induction chemotherapy followed by RT, various subsequent trials evaluated the concurrent administration of chemotherapy with RT (concurrent chemoradiation), induction chemotherapy, and induction chemotherapy followed by concurrent chemoradiation (sequential chemoradiation). (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

Concurrent chemoradiation — Concurrent chemoradiation administers systemic chemotherapy at the same time as definitive RT to improve the likelihood of disease control and laryngeal preservation. This approach is more effective in achieving locoregional control of disease as well as larynx preservation and may be preferable for medically fit patients. However, the Radiation Therapy Oncology Group (RTOG) 91-11 trial suggested that concurrent chemoradiation was associated with more unexplained deaths than induction chemotherapy followed by definitive RT, and induction chemotherapy had better survival and equivalent laryngectomy-free survival (LFS) as late outcomes [22]. (See 'Comparison of combined chemotherapy and radiation therapy approaches' below.)

Data supporting the role of concurrent chemoradiation come from the 2011 update of the Meta-Analysis of Chemotherapy on Head and Neck Cancer (MACH-NC) Collaborative Group, which conducted a comprehensive analysis by tumor site [23]. This analysis was based upon individual patient data for 3216 patients with laryngeal cancer. There was an overall benefit for the addition of chemotherapy to locoregional therapy (hazard ratio [HR] for death 0.87, 95% CI 0.80-0.96); this survival advantage was exclusively restricted to concurrent chemoradiation rather than induction or adjuvant delivery of systemic therapy.

In patients with laryngeal cancer, the survival benefit with concomitant chemoradiation versus RT alone was particularly robust (HR 0.80, 95% CI 0.71-0.90). However, very few of the induction studies included the cisplatin plus fluorouracil regimen, and none incorporated the contemporary standard, docetaxel plus cisplatin and fluorouracil (TPF) (table 3). Furthermore, the data on induction chemotherapy from the largest trial (RTOG 91-11) were not included in the analysis, which is particularly relevant because the update of this trial suggested a non-significant trend favoring the induction chemotherapy group over concomitant chemoradiation. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Concurrent chemotherapy' and 'Comparison of combined chemotherapy and radiation therapy approaches' below.)

For the 2767 patients with hypopharyngeal cancer, a similar benefit in survival with chemotherapy was observed (HR 0.88, 95% CI 0.80-0.96). In contrast to larynx cancer, there was no statistically significant interaction between chemotherapy timing and survival as the benefit of chemotherapy was similar in those given concomitant chemoradiation (HR 0.85) and neoadjuvant chemotherapy (HR 0.88). However, only the HR for concomitant chemotherapy was statistically significant in comparison to local therapy alone, although the analysis may not have had adequate power to detect a difference in this disease site.

Based upon these results, concurrent chemoradiation is widely recommended for good performance status patients with resectable, locally advanced (stage III and carefully selected stage IV) laryngeal and hypopharyngeal cancer, with a platinum-based chemotherapy regimen, such as cisplatin (100 mg/m2 every three weeks). Induction chemotherapy is a reasonable alternative in some patients. (See 'Comparison of combined chemotherapy and radiation therapy approaches' below.)

Induction chemotherapy — Induction chemotherapy followed by definitive RT is an alternative for the functional organ-preservation treatment of locally advanced cancer of the larynx and hypopharynx. Induction chemotherapy may also be preferable for patients with a relatively high risk of distant metastases, such as those with advanced nodal disease. Although this approach may not be as effective as concurrent chemoradiation in initial control of locoregional disease without salvage laryngectomy, induction therapy may decrease the incidence of distant metastases compared with RT alone and had a better, although not statistically significant, survival outcome versus concomitant chemoradiation in RTOG 91-11 [22].

This latter finding is particularly provocative since there were fewer locoregional recurrences in the concurrent arm without an increase in distant failures as first progression, and the study did not show a difference in treatment-associated death between the arms [22]. Patients treated with concomitant chemoradiation were significantly more likely to die from causes not related to the cancer in comparison to the induction arm (69.8 versus 52.8 percent at 10 years), raising the question of whether the study did not capture attribution of late deaths from treatment-associated morbidity (eg, aspiration pneumonia).

In earlier reports of the MACH-NC meta-analysis, there was no statistically significant survival benefit for induction chemotherapy versus definitive locoregional therapy alone when all head and neck subsites were analyzed, although there was a significant benefit for induction chemotherapy in the subset of trials using induction with cisplatin plus fluorouracil (HR 0.88, 95% CI 0.79-0.97) [23,24]. Furthermore, the subsequent TAX 323 trial found that a three-drug combination that added a taxane to the cisplatin plus fluorouracil regimen significantly improved overall survival compared with cisplatin plus fluorouracil alone, when both were followed by definitive RT [25]. The absence of a survival benefit in some analyses of laryngeal and hypopharyngeal cancer may be due to salvage laryngectomy, and progression-free survival and LFS are more meaningful endpoints. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Induction chemotherapy'.)

The responsiveness of the tumor to induction therapy provides predictive and prognostic information that may be useful in deciding whether functional organ preservation is feasible, whether surgical resection is indicated, or whether more intensive chemoradiation might be given. Three cycles of TPF chemotherapy (table 3) are typically used for induction therapy [25,26].

Sequential chemoradiation — Sequential therapy utilizes induction chemotherapy followed by concurrent chemoradiation. In theory, sequential therapy combines the reduction in distant metastases, improved function, and improved local regional control afforded by induction chemotherapy with more robust improvements in locoregional control achieved with concurrent chemoradiation.

The most extensive data on sequential chemoradiation in squamous head and neck cancer come from the TAX 324 trial, which demonstrated improved effectiveness of induction with TPF (table 3) rather than cisplatin plus fluorouracil alone, with both regimens followed by concurrent chemoradiation using weekly carboplatin [26]. The trial was conducted in a broad spectrum of patients with squamous cell carcinoma of the head and neck. While this study implied a benefit to adding induction chemotherapy to concurrent chemoradiation, nearly all randomized trials to date have not been able to demonstrate that the addition of induction chemotherapy to concomitant chemoradiation alone provides a survival benefit. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Induction chemotherapy'.)

However, some support for TPF induction in patients with locoregionally advanced disease comes from a phase III trial from Italy in which patients were randomly assigned to TPF followed by chemoradiation versus chemoradiation alone [27]. The concurrent chemoradiation regimens involved a secondary randomization between weekly cetuximab and an atypical cisplatin/fluorouracil regimen in weeks 1 and 6. The trial found improved locoregional control, progression-free survival, and overall survival (HR 0.74, 95% CI 0.56-0.97) in patients receiving induction chemotherapy. Interestingly, there was no difference in distant metastasis in the arms. The effect was graphically more robust in nonoropharyngeal carcinoma patients, approximately one-half of whom had a hypopharynx primary, although the statistical test for interaction was negative. Less than 25 percent of the patients in this trial had laryngeal or hypopharyngeal primary cancers, and the subset analysis on these patients was retrospective and preplanned.

Sequential therapy was studied specifically in patients with laryngeal and hypopharyngeal cancers in the phase II TREMPLIN trial [28]. In that study, 153 enrolled patients were treated with induction chemotherapy (three cycles of TPF). Overall, 126 patients (82 percent) responded, and 116 were randomly assigned to RT plus cisplatin or RT plus cetuximab. Local control was superior in the cisplatin arm, but laryngeal preservation, laryngeal function, and overall survival were similar for the two treatment groups (95 versus 93 percent, 87 versus 82 percent, and 92 versus 89 percent) for the cisplatin and cetuximab arms, respectively. The results of this and other trials suggest that the risk of severe toxicity is increased substantially by giving high-dose bolus cisplatin with RT after cisplatin-based induction therapy and should be avoided.

Patients who might benefit the most from sequential therapy are those with large primary tumors (bulky T3 and select T4) and advanced nodal disease who are at high risk for distant metastases. However, randomized trials have yet to confirm a survival benefit for these indications. When a sequential therapy approach is chosen, we generally use TPF induction chemotherapy (table 3), followed by concurrent therapy with carboplatin, as used in the TAX 324 trial [26]. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Induction chemotherapy'.)

Comparison of combined chemotherapy and radiation therapy approaches — The most extensive data directly comparing concurrent chemoradiation versus induction chemotherapy followed by RT versus RT alone for organ preservation in patients with stage III or IV laryngeal cancer come from the intergroup RTOG 91-11 trial [22,29]. In this trial, 547 patients (520 evaluable) were randomly assigned to one of three groups:

Induction chemotherapy, using cisplatin (100 mg/m2 on day 1) plus fluorouracil (1000 mg/m2/day by continuous intravenous infusion for five days), for three cycles followed by definitive RT

Concurrent chemoradiation, with definitive RT and concurrent cisplatin (100 mg/m2 on days 1, 22, and 43)

Definitive RT alone

Definitive RT, in all three groups, was given using conventional techniques to a total dose of 70 Gy in 35 fractions. Intensity-modulated RT (IMRT) was not used in this trial.

The primary composite endpoint of the trial was LFS, although as discussed above, these approaches may preserve the organ but not function. Although induction chemotherapy followed by RT and concurrent chemoradiation significantly improved LFS compared with RT alone, the patterns of disease control differed. Key results with a follow-up of almost 11 years included the following [22]:

LFS was significantly improved with both combined modality approaches compared with RT alone (concurrent versus RT alone, five-year LFS 47 versus 34 percent, HR for failure 0.78, 95% CI 0.61-0.98; induction versus RT alone, five-year LFS 44 versus 34 percent, HR for failure 0.75, 95% CI 0.59-0.95).

Locoregional disease control was significantly improved with concurrent chemoradiation compared with induction chemotherapy or RT alone (concurrent versus induction, five-year control rate 68 versus 55 percent, HR for failure 0.66, 95% CI 0.48-0.92; concurrent versus RT alone, five-year control rate 68 versus 51 percent, HR for failure 0.59, 95% CI 0.43-0.82).

Distant control was improved for both concurrent chemoradiation and induction chemotherapy plus RT compared with RT alone (induction versus RT alone, five-year control 85 versus 78 percent, HR for failure 0.63, 95% CI 0.39-1.01; concurrent versus RT alone, 86 versus 78 percent, HR for failure 0.69, 95% CI 0.43-1.11).

The difference in overall survival was not statistically significant among the three approaches, although there was a large trend for concurrent chemoradiation to have a poorer survival than induction chemotherapy with longer follow-up (five-year overall survival rates 55, 58, and 54 percent, respectively, and 10-year survival rates 28, 39, and 32 percent, respectively, for concurrent, induction, and RT alone; HR for death for concurrent versus RT alone 1.08, 95% CI 0.85-1.39; HR for death for induction versus RT alone 0.87, 95% CI 0.68-1.12; HR for death for concurrent versus induction 1.25, 95% CI 0.98-1.61). This trend for a survival decrement with concurrent chemoradiation was in the context of its continued superiority in locoregional control, suggesting that non-cancer causes of death were increased in this arm.

With the exception of the Italian trial mentioned above [27], every other randomized trial to date of sequential therapy compared with concomitant chemoradiation alone has not demonstrated that the addition of induction chemotherapy to concomitant chemoradiation alone provides a survival benefit, although there were significant accrual problems with the other trials [3]. (See 'Induction chemotherapy' above and "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Induction chemotherapy'.)

SURGERY — Although chemoradiation is now widely used in patients with locoregionally advanced disease, surgery retains a role in carefully selected patients as an alternative approach to functional organ preservation. Surgery is also important for the management of patients who are not candidates for chemoradiation.

Larynx preservation surgery — Surgical approaches that preserve the larynx, used in combination with postoperative radiation therapy (RT) or chemoradiation, may provide an alternative treatment option for patients with advanced disease due to neck node burden but with small T-stage primary lesions. In carefully selected cases, such approaches may provide effective local control while maintaining laryngeal function without total laryngectomy and a permanent stoma. Following detailed preoperative evaluation, minimally invasive surgery may be considered.

Preoperative evaluation — Detailed preoperative assessment is critical for patient selection for larynx-preservation surgery:

Preoperative laryngeal examination (typically flexible fiber optic examination and/or videostroboscopy), with careful attention to the mobility of the vocal cord and arytenoid cartilages, is critical. Fixation of the vocal cord is an important negative prognostic finding.

Imaging using computed tomography (CT) or magnetic resonance imaging (MRI) can help assess the degree of cartilage invasion; however, these techniques are limited by low sensitivity [30-33]. Dynamic imaging, such as a modified barium swallow, is also important in evaluating laryngeal function.

Patient selection should consider the patient's ability to actively participate in speech and swallowing rehabilitation. Other treatment options should be considered in patients with significant impairments to rehabilitative potential and in those who will require postoperative RT since functional outcomes after laryngeal conservation surgery and postoperative RT might be significantly worse than after concurrent chemoradiation alone.

Pulmonary reserve, assessed with pulmonary function tests and assessment of exercise tolerance, is an important indicator of how a patient will tolerate postoperative aspiration [31].

Intraoperative assessment, with visualization through a rigid endoscopic examination and palpation of the larynx, aids surgical planning by determining tumor extent and evaluating the uninvolved larynx.

Conservation surgery — In the past, transcervical partial laryngectomy, with or without postoperative RT or chemoradiation, has been used in selected patients as a functional alternative to total laryngectomy or chemoradiation [34,35]. These open approaches are also utilized as salvage treatment for locally recurrent disease following RT.

However, more surgeons are now employing endoscopic transoral methods to address selected patients with T1-T2 laryngeal or hypopharyngeal cancers, with or without postoperative RT/chemoradiation. Vastly improved instrumentation, via suspension laryngoscopy, operating microscope, microsurgical instruments, and coaxial CO2 laser, have facilitated visualization and margin status real-time. Because the laryngeal framework is not disturbed (as is the case in open procedures), routine tracheotomies are typically not required, postoperative swallowing function improves more rapidly, and hospital stays are shortened. These minimally invasive procedures have comparable oncologic results, when compared with open procedures [36-41]. (See "Treatment of early (stage I and II) head and neck cancer: The larynx", section on 'Surgery'.)

Transoral laser surgery (TLS, also called transoral laser microsurgery [TLM]) has also been used for selected advanced T stage (T3 or T4) lesions with planned postoperative treatment [34,40,42-44]. Excellent oncologic outcome and function have been found for this therapeutic option. Five-year locoregional control rates of 69 to 76 percent, recurrence-free survival rates of 60 to 69 percent, and overall survival rates of 47 percent have been reported [36,37,45,46]. One series reported the two-year disease-free and overall survival rates were 68 and 75 percent, respectively. The five-year Kaplan-Meier estimates were local control, 74 percent; locoregional control, 68 percent; disease-free survival, 58 percent; and overall survival, 55 percent [42]. The expertise and experience of the surgeon are important factors to consider if TLS is part of the treatment plan [47].

One of the main limitations of TLS is adequate tumor exposure. A thorough preoperative evaluation by an experienced surgeon is critical. Some controversial limitations include involvement of the posterior paraglottic space, involvement of the inner portion of the thyroid lamina, and extension into the preepiglottic space to the thyrohyoid membrane and hyoid bone. If any of these conditions are present, then the risks and benefits of TLS versus total laryngectomy versus a nonsurgical approach must be discussed with the patient. One study analyzed the factors associated with local relapse in 1119 patients with T1-T3 laryngeal tumors treated with TLM [48]. In this study, the risk of relapse was associated with anterior commissure and paraglottic space involvement. Local relapse also tended to inversely correlate with surgeon experience.

Transoral robotic surgery has been increasingly utilized in advanced cancers of the larynx and hypopharynx when surgery is incorporated into the treatment approach [49]. Minimally invasive robotic ablative procedures include supraglottic laryngectomy, total laryngectomy, vocal cordectomy, and partial pharyngectomy. As in other anatomic areas, this technique provides exceptional views and maneuverability. Oncologic outcomes are not compromised, and better postoperative function compared with open approaches can be achieved [50].

A systematic review that included data from 1921 patients with advanced laryngeal cancer in 21 studies analyzed outcomes after conservative treatment with either transoral or traditional open partial laryngectomy [51]. Pooled disease-free survival was 79 percent, and overall survival was 71 percent, although there was considerable heterogeneity among the studies with respect to the types of surgical procedures and use of adjuvant RT. Neither locoregional control nor functional outcomes were reported.

Although surgical techniques are advancing, this retrospective literature is limited by selection bias, very heterogeneous adjuvant management, and poor description of functional outcomes. Since postoperative RT should be delivered in the stage III to IV population, the relative merits of a primary surgical approach (with a potentially lesser dose of radiation) must be weighed against the unknown functional outcomes and established outcomes with definitive RT or chemoradiation, as well as the risk that a patient may ultimately require trimodality therapy.

It is also critical to consider that the clinical presentation of this disease is highly variable, with a spectrum of primary disease bulk versus advanced lymphadenopathy, and thus, the optimal local therapy must be decided on a case-by-case basis by a coordinated multidisciplinary team.

Postoperative radiation therapy — Following larynx preservation surgery, postoperative RT, with or without concurrent chemotherapy, is indicated for all T3 and T4 tumors after surgical excision as well as for patients who have positive resection margins, lymphovascular or perineural invasion, or positive lymph nodes.

The concurrent administration of chemotherapy with postoperative RT is generally preferable to RT alone for high-risk patients, such as those with positive margins or lymph nodes with extracapsular extension. Postoperative RT or chemoradiation should be initiated within six weeks of surgery. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer".)

Total laryngectomy — Total laryngectomy is associated with better survival rates and quality of life for some patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function [3]. In addition, total laryngectomy is frequently needed to treat recurrent disease following chemoradiation.

Potential candidates may include the following:

The older and frail patient, as well as patients with poor compliance or functional status, may have less short- and long-term difficulty with a tracheal stoma than the rigors of prolonged treatment, especially since laryngectomy may obviate the need for chemotherapy. Patients with poor psychosocial support may not tolerate the associated acute and chronic toxicities of nonsurgical therapy, limiting compliance and ultimately locoregional control [52]. However, it is also important to recognize that this population may suffer following total laryngectomy, as postoperative communication challenges can be a significant issue and/or barrier to appropriate care.

Patients with poor baseline swallowing function and/or airway protection, and those with pretreatment destruction of both vocal cords may not recover vocal or airway protective function with larynx-preservation approaches. Such patients typically function better after total laryngectomy.

Total laryngectomy confers protection from aspiration, often results in functionally easier swallowing, and provides the ability to create voice through the patient's mouth (via a tracheoesophageal prosthetic placed in the laryngostome). The main stigma for patients is the presence of the tracheostomy. Postoperative RT or chemoradiation, however, is still required for most of these patients. (See "Alaryngeal speech rehabilitation".)

MANAGEMENT OF THE NECK — The management of the neck is complex. The risk of occult lymph node metastases or residual disease following treatment must be balanced against the potential complications of neck dissection and/or irradiation. Factors that should be considered include the site of the primary tumor as well as the extent of disease, the treatment modality used to treat the primary tumor, and response to therapy [53].

Small glottic tumors infrequently have lymph node metastases, since the glottis has minimal lymphatic drainage. The risk of lymph node involvement increases when glottic tumors extend into supraglottic and subglottic structures, which have more extensive lymphatics.

Supraglottic and subglottic tumors, regardless of tumor size, have a high risk of lymph node involvement.

The hypopharynx also has a rich bilateral lymphatic plexus and, thus, is prone to early occult metastatic disease. Moreover, hypopharyngeal malignancies are more likely to spread to the retropharyngeal and level V lymph nodes (figure 3).

Patients treated with chemoradiation — For patients with head and neck squamous cell carcinomas who have cervical lymph node involvement at presentation and are treated with definitive radiation therapy (RT) or chemoradiation, management of residual abnormalities in the neck can be a particularly difficult issue. For patients with complete regression, as documented clinically and by structural (computed tomography [CT], magnetic resonance imaging [MRI]) and functional (positron emission tomography [PET]) imaging, observation is generally indicated, whereas salvage surgery is indicated in the absence of an adequate response (algorithm 1) [3]. Those with persistent equivocal or positive findings on PET/CT should undergo neck dissection.

The management of the neck, including the extent of surgery, in patients treated with RT or chemoradiation is discussed separately. (See "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma".)

Patients managed with primary surgery — Bilateral prophylactic selective neck dissection, including levels II to IV, is recommended for patients with T3 and T4 tumors with clinically negative cervical nodes (N0) or early nodal disease (N1) (figure 3). RT is an alternative treatment for patients with N0 or N1 lymph nodes, particularly if the primary site requires adjuvant RT.

Patients managed with primary surgery for laryngeal or hypopharyngeal cancers with clinically involved cervical lymph nodes should have a neck dissection [3]. With N2 or N3 disease, we suggest a modified or radical neck dissection if the nodes are invading the jugular vein, accessory nerve, or sternocleidomastoid muscle. If the nodes are mobile and tissue planes preserved, many head and neck surgeons will perform selective neck dissections, if feasible, in order to preserve contour and function, and to minimize the risks of cervicofacial lymphedema.

All patients with pathologically confirmed lymph node involvement should undergo postoperative RT, with the addition of concurrent chemotherapy if adverse pathologic factors are present. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer".)

OLDER AND POOR PERFORMANCE STATUS PATIENTS — Induction chemotherapy and concurrent chemotherapy are often avoided in older adults and those with poor performance status since the use of chemotherapy may delay or prevent the delivery of a course of definitive radiation therapy (RT). In this setting, definitive RT alone remains a treatment option for older patients and those with a poor performance status. This approach decreases the opportunity for functional organ preservation but may reduce the risk of serious treatment-related morbidity and mortality, such as aspiration pneumonia. Given these competing risks, a more conservative locoregional approach may not compromise survival compared with chemoradiation, especially in laryngeal cancer. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Patient selection'.)

Total laryngectomy may also be an option. (See 'Total laryngectomy' above.)

COMPLICATIONS OF TREATMENT — Complications from treatment for advanced laryngeal and hypopharyngeal head and neck cancer include vocal, swallowing, and airway problems; loss of taste and smell; fistula; cranial nerve and spinal accessory nerve injuries; vascular injury and events; fibrosis; chondroradionecrosis; and hypothyroidism [54]. These complications and their management are discussed separately. (See "Management of late complications of head and neck cancer and its treatment".)

POSTTREATMENT EVALUATION AND SURVEILLANCE — For patients treated with concurrent chemoradiation or sequential chemoradiation, assessment to ensure the absence of residual disease is critical. Salvage laryngectomy is indicated when biopsy-proven residual or recurrent cancer is identified pathologically or when highly suspected in a patient with an otherwise dysfunctional larynx. The clinical examination is critical in this evaluation. Imaging studies, particularly computed tomography (CT) and positron emission tomography (PET), augment this evaluation but can be difficult to interpret if they are performed too soon (prior to 12 weeks) after the completion of concurrent chemoradiation [55]. (See "Overview of the diagnosis and staging of head and neck cancer".)

Regular posttreatment follow-up is an essential part of the care of patients after potentially curative treatment of head and neck cancer to detect recurrent disease, to diagnose second malignancies that may develop, and to follow for and manage late complications. Patients should be educated about possible signs and symptoms of tumor recurrence, including hoarseness, pain, dysphagia, bleeding, and enlarged lymph nodes.

In general, the intensity of follow-up is greatest in the first two to four years since approximately 80 to 90 percent of all recurrences after curative intent treatment will occur within this timeframe. Continued follow-up beyond five years is generally recommended because of the risk of late recurrence, second malignancy, and late complications. Posttreatment surveillance of head and neck cancer, including screening for treatment-related complications, is reviewed separately. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

It is particularly important in follow-up to encourage behaviors such as smoking cessation and alcohol abstinence. Such behaviors will support treatment success and minimize cancer recurrence and second malignancies. The approach to smoking and alcohol cessation in this population is discussed separately. (See "Overview of smoking cessation management in adults" and "Treatment of alcohol use and smoking for cancer survivors".)

Rehabilitation of voice and swallowing function following treatment are discussed separately. (See "Alaryngeal speech rehabilitation" and "Speech and swallowing rehabilitation of the patient with head and neck cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Laryngeal cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

Prior to treatment, all patients with advanced (stage III and IV) cancer of the larynx or hypopharynx should be seen by a multidisciplinary team with experience in the treatment of head and neck cancer. Selection of a treatment approach depends on tumor extent and location, patient-specific factors (eg, age, performance status, comorbidity, psychosocial support), clinician expertise, and availability of rehabilitation services. (See 'Overview of management' above.)

For most good performance status patients with locally advanced (stage III or IV) laryngeal or hypopharyngeal cancer, we recommend a functional organ-preservation strategy rather than surgical resection (Grade 1B). Organ-sparing approaches may permit larynx preservation but do not provide a survival advantage compared with total laryngectomy. (See 'Overview of management' above.)

Concurrent chemoradiation, induction chemotherapy followed by radiation therapy (RT) alone, and sequential therapy (ie, induction chemotherapy followed by concurrent chemoradiation) are all used as functional organ-preservation techniques. (See 'Combined modality therapy' above.)

Concurrent chemoradiation may be preferable for medically fit patients, and induction therapy may offer advantages for patients with a relatively high risk of distant metastases, such as those with advanced nodal disease. Three cycles of TPF chemotherapy (table 3) are typically used for induction therapy. (See 'Concurrent chemoradiation' above and 'Induction chemotherapy' above.)

Sequential therapy may be particularly useful in patients with both large primary tumors (bulky T3 and select T4) and advanced nodal disease who are at high risk for distant metastases. (See 'Sequential chemoradiation' above.)

Partial laryngectomy and minimally invasive surgery may be options for carefully selected patients, especially those with relatively small primary tumors combined with more extensive neck disease. Postoperative RT is generally required in these cases. (See 'Surgery' above and 'Postoperative radiation therapy' above.)

Patients who may not be candidates for an organ-preservation approach include patients with resectable tumors that have destroyed both vocal cords, older adult patients for whom the toxicity associated with chemoradiation or full-dose RT alone is problematic, and those with extensive cartilage destruction from the primary tumor. (See 'Overview of management' above and 'Total laryngectomy' above and 'Older and poor performance status patients' above.)

Management of the neck is complex and depends on disease extent, the treatment modality used to treat the primary tumor, and response to therapy. (See 'Management of the neck' above and "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma".)

For patients who are not candidates for a functional organ-preserving approach, total laryngectomy is a potential alternative. Definitive RT alone may be used as a functional organ-preserving approach for laryngeal cancer patients who are not felt to be candidates for chemotherapy, although there is a higher risk of recurrence and, thus, a need for salvage laryngectomy. (See 'Total laryngectomy' above and 'Older and poor performance status patients' above.)

For active smokers, the importance of smoking cessation must be continuously emphasized to support treatment success and to reduce the subsequent likelihood of second malignancies. Counseling services should be offered, if available. (See "Overview of smoking cessation management in adults" and "Treatment of alcohol use and smoking for cancer survivors".)

Adequate posttreatment surveillance and long-term follow-up are crucial to ensure adequate voice and swallowing rehabilitation and to monitor for disease recurrence or a second primary malignancy. Lifelong follow-up is also necessary to ensure that late complications of treatment are addressed to mitigate the risk of non-cancer causes of mortality. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

  1. Global Cancer Observatory. International Agency for Research on Cancer. World Health Organization. Available at: https://gco.iarc.fr/ (Accessed on June 06, 2021).
  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022; 72:7.
  3. Forastiere AA, Ismaila N, Wolf GT. Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update Summary. J Oncol Pract 2018; 14:123.
  4. Patel SG, Lydiatt WM, Glastonbury CM, et al. Larynx. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), Springer, New York 2017. p.149.
  5. Lydiatt WM, Ridge JA, Patel SG, et al. Oropharynx (p16-) and hypopharynx. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), Springer, New York 2017. p.123.
  6. Kelly SL, Jackson JE, Hickey BE, et al. Multidisciplinary clinic care improves adherence to best practice in head and neck cancer. Am J Otolaryngol 2013; 34:57.
  7. Wheless SA, McKinney KA, Zanation AM. A prospective study of the clinical impact of a multidisciplinary head and neck tumor board. Otolaryngol Head Neck Surg 2010; 143:650.
  8. Wuthrick EJ, Zhang Q, Machtay M, et al. Institutional clinical trial accrual volume and survival of patients with head and neck cancer. J Clin Oncol 2015; 33:156.
  9. Gourin CG, Conger BT, Sheils WC, et al. The effect of treatment on survival in patients with advanced laryngeal carcinoma. Laryngoscope 2009; 119:1312.
  10. American Society of Clinical Oncology, Pfister DG, Laurie SA, et al. American Society of Clinical Oncology clinical practice guideline for the use of larynx-preservation strategies in the treatment of laryngeal cancer. J Clin Oncol 2006; 24:3693.
  11. Forastiere AA, Ismaila N, Lewin JS, et al. Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2018; 36:1143.
  12. Lefebvre JL, Ang KK, Larynx Preservation Consensus Panel. Larynx preservation clinical trial design: key issues and recommendations--a consensus panel summary. Head Neck 2009; 31:429.
  13. Lefebvre JL, Ang KK, Larynx Preservation Consensus Panel. Larynx preservation clinical trial design: key issues and recommendations-a consensus panel summary. Int J Radiat Oncol Biol Phys 2009; 73:1293.
  14. Browman GP, Wong G, Hodson I, et al. Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 1993; 328:159.
  15. Browman GP, Mohide EA, Willan A, et al. Association between smoking during radiotherapy and prognosis in head and neck cancer: a follow-up study. Head Neck 2002; 24:1031.
  16. Silver CE, Beitler JJ, Shaha AR, et al. Current trends in initial management of laryngeal cancer: the declining use of open surgery. Eur Arch Otorhinolaryngol 2009; 266:1333.
  17. Forastiere AA, Weber RS, Trotti A. Organ Preservation for Advanced Larynx Cancer: Issues and Outcomes. J Clin Oncol 2015; 33:3262.
  18. Department of Veterans Affairs Laryngeal Cancer Study Group, Wolf GT, Fisher SG, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991; 324:1685.
  19. Hong WK, Lippman SM, Wolf GT. Recent advances in head and neck cancer--larynx preservation and cancer chemoprevention: the Seventeenth Annual Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 1993; 53:5113.
  20. Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996; 88:890.
  21. Lefebvre JL, Andry G, Chevalier D, et al. Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 2012; 23:2708.
  22. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013; 31:845.
  23. Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol 2011; 100:33.
  24. Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355:949.
  25. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007; 357:1695.
  26. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007; 357:1705.
  27. Ghi MG, Paccagnella A, Ferrari D, et al. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial. Ann Oncol 2017; 28:2206.
  28. Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol 2013; 31:853.
  29. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003; 349:2091.
  30. Holsinger FC, Nussenbaum B, Nakayama M, et al. Current concepts and new horizons in conservation laryngeal surgery: an important part of multidisciplinary care. Head Neck 2010; 32:656.
  31. Chu EA, Kim YJ. Laryngeal cancer: diagnosis and preoperative work-up. Otolaryngol Clin North Am 2008; 41:673.
  32. Barbera L, Groome PA, Mackillop WJ, et al. The role of computed tomography in the T classification of laryngeal carcinoma. Cancer 2001; 91:394.
  33. Beitler JJ, Muller S, Grist WJ, et al. Prognostic accuracy of computed tomography findings for patients with laryngeal cancer undergoing laryngectomy. J Clin Oncol 2010; 28:2318.
  34. Peretti G, Piazza C, Penco S, et al. Transoral laser microsurgery as primary treatment for selected T3 glottic and supraglottic cancers. Head Neck 2016; 38:1107.
  35. Campo F, Mazzola F, Bianchi G, et al. Partial laryngectomy for naïve pT3N0 laryngeal cancer: Systematic review on oncological outcomes. Head Neck 2023; 45:243.
  36. Steiner W, Ambrosch P, Hess CF, Kron M. Organ preservation by transoral laser microsurgery in piriform sinus carcinoma. Otolaryngol Head Neck Surg 2001; 124:58.
  37. Vilaseca I, Blanch JL, Bernal-Sprekelsen M, Moragas M. CO2 laser surgery: a larynx preservation alternative for selected hypopharyngeal carcinomas. Head Neck 2004; 26:953.
  38. Suárez C, Rodrigo JP. Transoral microsurgery for treatment of laryngeal and pharyngeal cancers. Curr Oncol Rep 2013; 15:134.
  39. Leong SC, Kathan C, Mortimore S. Early outcomes after transoral CO2 laser resection of laryngeal and hypopharyngeal squamous cell carcinoma: one centre's experience. J Laryngol Otol 2010; 124:185.
  40. Kutter J, Lang F, Monnier P, Pasche P. Transoral laser surgery for pharyngeal and pharyngolaryngeal carcinomas. Arch Otolaryngol Head Neck Surg 2007; 133:139.
  41. Cabanillas R, Rodrigo JP, Llorente JL, Suárez C. Oncologic outcomes of transoral laser surgery of supraglottic carcinoma compared with a transcervical approach. Head Neck 2008; 30:750.
  42. Hinni ML, Salassa JR, Grant DG, et al. Transoral laser microsurgery for advanced laryngeal cancer. Arch Otolaryngol Head Neck Surg 2007; 133:1198.
  43. Blanch JL, Vilaseca I, Caballero M, et al. Outcome of transoral laser microsurgery for T2-T3 tumors growing in the laryngeal anterior commissure. Head Neck 2011; 33:1252.
  44. Preuss SF, Cramer K, Klussmann JP, et al. Transoral laser surgery for laryngeal cancer: outcome, complications and prognostic factors in 275 patients. Eur J Surg Oncol 2009; 35:235.
  45. Olthoff A, Ewen A, Wolff HA, et al. Organ function and quality of life after transoral laser microsurgery and adjuvant radiotherapy for locally advanced laryngeal cancer. Strahlenther Onkol 2009; 185:303.
  46. Remacle M, Lawson G, Hantzakos A, Jamart J. Endoscopic partial supraglottic laryngectomies: techniques and results. Otolaryngol Head Neck Surg 2009; 141:374.
  47. Bernal-Sprekelsen M, Blanch JL, Caballero-Borrego M, Vilaseca I. The learning curve in transoral laser microsurgery for malignant tumors of the larynx and hypopharynx: parameters for a levelled surgical approach. Eur Arch Otorhinolaryngol 2013; 270:623.
  48. Vilaseca I, Nogués-Sabaté A, Avilés-Jurado FX, et al. Factors of local recurrence and organ preservation with transoral laser microsurgery in laryngeal carcinomas; CHAID decision-tree analysis. Head Neck 2019; 41:756.
  49. Dziegielewski PT, Kang SY, Ozer E. Transoral robotic surgery (TORS) for laryngeal and hypopharyngeal cancers. J Surg Oncol 2015; 112:702.
  50. Karabulut B, Deveci I, Sürmeli M, et al. Comparison of functional and oncological treatment outcomes after transoral robotic surgery and open surgery for supraglottic laryngeal cancer. J Laryngol Otol 2018; 132:832.
  51. Mannelli G, Lazio MS, Luparello P, Gallo O. Conservative treatment for advanced T3-T4 laryngeal cancer: meta-analysis of key oncological outcomes. Eur Arch Otorhinolaryngol 2018; 275:27.
  52. O'Neill CB, O'Neill JP, Atoria CL, et al. Treatment complications and survival in advanced laryngeal cancer: a population-based analysis. Laryngoscope 2014; 124:2707.
  53. Layland MK, Sessions DG, Lenox J. The influence of lymph node metastasis in the treatment of squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx: N0 versus N+. Laryngoscope 2005; 115:629.
  54. Levendag PC, Teguh DN, Voet P, et al. Dysphagia disorders in patients with cancer of the oropharynx are significantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a dose-effect relationship. Radiother Oncol 2007; 85:64.
  55. Ljumanovic R, Langendijk JA, Hoekstra OS, et al. Pre- and post-radiotherapy MRI results as a predictive model for response in laryngeal carcinoma. Eur Radiol 2008; 18:2231.
Topic 3402 Version 47.0

References