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Incidence and Mortality
Estimated new cases and deaths from laryngeal cancer in the United States in 2014:
The larynx is divided into the following three anatomical regions:
The supraglottic area is rich in lymphatic drainage. After penetrating the pre-epiglottic space and thyrohyoid membrane, lymphatic drainage is initially to the jugulodigastric and midjugular nodes. About 25% to 50% of patients present with involved lymph nodes. The precise figure depends on the T stage. The true vocal cords are devoid of lymphatics. As a result, vocal cord cancer confined to the true cords rarely, if ever, presents with involved lymph nodes. Extension above or below the cords may, however, lead to lymph node involvement. Primary subglottic cancers, which are quite rare, drain through the cricothyroid and cricotracheal membranes to the pretracheal, paratracheal, and inferior jugular nodes, and occasionally to mediastinal nodes.
A clear association has been made between smoking, excess alcohol ingestion, and the development of squamous cell cancers of the upper aerodigestive tract. For smokers, the risk of the development of laryngeal cancer decreases after the cessation of smoking but remains elevated even years later when compared to that of nonsmokers. If a patient who has had a single cancer continues to smoke and drink alcoholic beverages, the likelihood of a cure for the initial cancer, by any modality, is diminished, and the risk of second tumor is enhanced. Because of clinical problems related to smoking and alcohol use in this population, many patients succumb to intercurrent illness rather than to the primary cancer. (Refer to the PDQ summary on Smoking in Cancer Care for more information.)
Supraglottic cancers typically present with sore throat, painful swallowing, referred ear pain, change in voice quality, or enlarged neck nodes. Early vocal cord cancers are usually detected because of hoarseness. By the time they are detected, cancers arising in the subglottic area commonly involve the vocal cords; thus, symptoms usually relate to contiguous spread.
The most important adverse prognostic factors for laryngeal cancers include increasing T stage and N stage. Other prognostic factors may include sex, age, performance status, and a variety of pathologic features of the tumor, including grade and depth of invasion.
Prognosis for small laryngeal cancers that have not spread to lymph nodes is very good with cure rates of 75% to 95% depending on the site, tumor bulk, and degree of infiltration. Although most early lesions can be cured by either radiation therapy or surgery, radiation therapy may be reasonable to preserve the voice, leaving surgery for salvage. Patients with a preradiation hemoglobin level higher than 13 g/dL have higher local control and survival rates than patients who are anemic.
Locally advanced lesions are treated with combined modality treatment involving radiation and chemotherapy with or without surgery, the aim of which is laryngeal preservation in appropriately selected candidates. Distant metastases are also common, even if the primary tumor is controlled.
Intermediate lesions have intermediate prognoses, depending on site, T stage, N stage, and performance status. Therapy recommendations for patients with these lesions are based on a variety of complex anatomic, clinical, and social factors, which should be individualized and discussed in multidisciplinary consultation (surgery, radiation therapy, and dental and oral surgery) prior to prescribing therapy.
Follow-up and Survivorship
Second primary tumors, often in the aerodigestive tract, have been reported in as many as 25% of patients whose initial lesion is controlled. A study has shown that daily treatment of these patients with moderate doses of isotretinoin (i.e., 13-cis-retinoic acid) for 1 year can significantly reduce the incidence of second tumors. No survival advantage has been demonstrated, partially because of recurrence and death from the primary malignancy.
Patients treated for laryngeal cancers are at the highest risk of recurrence in the first 2 to 3 years. Recurrences after 5 years are rare and usually represent new primary malignancies. Close, regular follow-up is crucial to maximize the chance for salvage. Careful clinical examination and repetition of any abnormal staging study are included in follow-up, along with attention to any treatment-related toxic effect or complication.
The vast majority of laryngeal cancers are of squamous cell histology. Squamous cell subtypes include keratinizing and nonkeratinizing and well-differentiated to poorly differentiated grade. A variety of nonsquamous cell laryngeal cancers also occur.[1,2] These are not staged using the American Joint Cancer Committee staging system, and their management, which is not discussed here, can differ from that of squamous cell laryngeal cancers. In situ squamous cell carcinoma of the larynx is usually managed by a conservative surgical procedure such as mucosal stripping or superficial laser excision. Radiation therapy may also be appropriate treatment of selected patients with in situ carcinoma of the glottic larynx.
The staging system for laryngeal cancer is clinical and based on the best possible estimate of the extent of disease before treatment. The assessment of the primary tumor is based on inspection and palpation when possible and by both indirect mirror examination and direct endoscopy when necessary. The tumor must be confirmed histologically, and any other pathological data obtained on biopsy may be included. Head and neck magnetic resonance imaging or computed tomography should be done prior to therapy to supplement inspection and palpation. Additional radiographic studies may be included. The appropriate nodal drainage areas in the neck should be examined by careful palpation.
Definitions of TNM
The American Joint Committee on Cancer has designated staging by TNM classification to define laryngeal cancer.
Small superficial cancers without laryngeal fixation or lymph node involvement are successfully treated by radiation therapy or surgery alone, including laser excision surgery. Radiation therapy may be selected to preserve the voice and to reserve surgery for salvaging failures. The radiation field and dose are determined by the location and size of the primary tumor. A variety of curative surgical procedures are also recommended for laryngeal cancers, some of which preserve vocal function. An appropriate surgical procedure must be considered for each patient, given the anatomic problem, performance status, and clinical expertise of the treatment team. Advanced laryngeal cancers are often treated by combining radiation with concurrent chemotherapy for larynx preservation and total laryngectomy for bulky T4 disease or salvage.[1,2,3,4,5,6]
Evaluation of treatment outcome can be reported in various ways: locoregional control, disease-free survival, determinate survival, and overall survival (OS) at 2 to 5 years. Preservation of voice is an important parameter to evaluate. Outcome should be reported after initial surgery, initial radiation, planned combined treatment, or surgical salvage of radiation failures. Primary source material should be consulted to review these differences.
A review of published clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control when the administration of radiation therapy was prolonged; therefore, lengthening of standard treatment schedules should be avoided whenever possible.[7,8]
Direct comparison of the results of radiation therapy versus endolaryngeal surgery (with or without laser) has not been made for patients with early stage laryngeal cancer. The evidence is insufficient to show a clear difference in the results between treatment options in regard to local control or OS. Retrospective data suggests that in comparison with surgery, radiation therapy might cause less perturbation of voice quality without a significant difference in patient perception.
A direct comparison of chemotherapy followed by radiation therapy versus upfront surgery was made by The Department of Veterans Affairs (VA) Laryngeal Cancer Study Group in a trial in which 332 patients were randomly assigned to three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. After two cycles of chemotherapy, the clinical tumor response was complete in 31% of the patients, and there was a partial response in 54% of the patients. Survival was similar in both arms; however, larynx preservation was possible in 64% of the patients in the chemotherapy-followed-by-radiation therapy arm.
The VA study was followed up in a randomized study, RTOG-91-11 (NCT00002496), in which the laryngeal preservation arm of the VA study was compared with the concomitant chemoradiation and radiation-alone arms, and the primary endpoint was laryngectomy-free survival (LFS). The RTOG 91-11 study evaluated 547 patients with locally advanced laryngeal cancer who were enrolled between August 1992 and May 2000, with a median follow-up for surviving patients of 10.8 years (range, 0.07–17 years). Three regimens were compared, including induction chemotherapy plus radiation therapy, concomitant chemoradiation, and radiation therapy alone. Both chemotherapy regimens improved LFS compared with radiation therapy alone (induction chemotherapy vs. radiation therapy alone, hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.59–0.95; P = .02; concomitant chemotherapy vs. radiation therapy alone, HR, 0.78; 95% CI, 0.78–0.98; P = .03).
Concurrent radiation therapy plus cisplatin resulted in a statistically significantly higher percentage of patients with an intact larynx at 10 years (67.5% for patients who had induction chemotherapy; 81.7% for patients who had concomitant chemotherapy; and 63.8% for patients who received radiation alone); 80% of laryngectomies were performed during the first 2 years (84 laryngectomies during year 1 and 35 laryngectomies during year 2).
Concomitant cisplatin with radiation therapy resulted in a 41% reduction in risk of locoregional failure compared with radiation therapy alone (HR, 0.59; 95% CI, 0.43–0.82; P = .0015) and a 34% reduction in risk compared with induction chemotherapy (HR, 0.66; 95% CI, 0.48–0.92; P = .004). Both chemotherapy regimens had a lower incidence of distant metastases, although this did not reach statistical significance compared with radiation therapy alone.
The 10-year cumulative rates of late toxicity (grades 3–5) were 30.6% for induction chemotherapy, 33.3% for concomitant chemotherapy, and 38% for radiation alone, and were not significantly different between the arms.
OS was not significantly different between the groups, although there was possibly a worse outcome in the concomitant groups compared with the induction chemotherapy group (HR, 1.25; 95% CI, 0.98–1.61; P = .08). The OS rates were 58% (5 year) and 39% (10 year) for induction chemotherapy, 55% (5 year) and 28% (10 year) for concomitant chemoradiation, and 54% (5 year) and 32% (10 year) for radiation alone. The number of deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% vs. 20.8% with induction chemotherapy and 16.9% with radiation alone), because after approximately 4.5 years, the survival curves began to separate and favor induction, although the difference was not statistically significant.
The risk of lymph node metastases in patients with stage I glottic cancer ranges from 0% to 2%, and for more advanced disease, such as stage II and stage III glottic, the incidence is only 10% and 15%, respectively. Thus, there is no need to treat glottic cancer cervical lymph nodes electively in patients with stage I tumors and small stage II tumors. Consideration should be given to using elective neck radiation for larger or supraglottic tumors.
For patients with cancer of the subglottis, combined modality therapy is generally preferred for the uncommon small lesions (i.e., stage I or stage II); however, radiation therapy alone may be used.
Patients who smoke during radiation therapy appear to have lower response rates and shorter survival durations than those who do not; therefore, patients should be counseled to stop smoking before beginning radiation therapy.
Accumulating evidence has demonstrated a high incidence (i.e., >30%–40%) of hypothyroidism in patients who have received external-beam radiation to the entire thyroid gland or to the pituitary gland. Thyroid-junction testing of patients should be considered prior to therapy and as part of posttreatment follow-up.[13,14]
Standard treatment options:
Radiation should be preferred because of the good results, preservation of the voice, and the possibility of surgical salvage in patients whose disease recurs locally.
Standard treatment options:
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I laryngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Radiation should be preferred because of the good results, preservation of the voice, and the possibility of surgical salvage in patients whose disease recurs locally.
Treatment options under clinical evaluation:
Treatment options under clinical evaluation:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II laryngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
A meta-analysis of three trials of patients with locally advanced laryngeal carcinomas compared patients who received standard radical surgery plus radiation therapy with patients who received neoadjuvant cisplatin and fluorouracil (5-FU), followed by radiation therapy alone in responders or radical surgery plus radiation therapy in nonresponders. The meta-analysis demonstrated a nonsignificant trend in favor of the control group who received standard radical surgery plus radiation therapy with an absolute negative effect in the chemotherapy arm that reduced survival at 5 years by 6%. The possibility of a slightly decreased survival must be balanced by the retention of the larynx in those patients whose disease was controlled.
A meta-analysis of three trials of patients with locally advanced laryngeal carcinomas compared patients who received standard radical surgery plus radiation therapy with patients who received neoadjuvant cisplatin and fluorouracil, followed by radiation therapy alone in responders or radical surgery plus radiation therapy in nonresponders. The meta-analysis demonstrated a nonsignificant trend in favor of the control group who received standard radical surgery plus radiation therapy with an absolute negative effect in the chemotherapy arm that reduced survival at 5 years by 6%. The possibility of a slightly decreased survival must be balanced by the retention of the larynx in those patients whose disease was controlled.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III laryngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
A meta-analysis of three trials of patients with locally advanced laryngeal carcinomas compared patients who received standard radical surgery plus radiation therapy with patients who received neoadjuvant cisplatin and fluorouracil, followed by radiation therapy alone in responders or radical surgery plus radiation therapy in nonresponders. The meta-analysis demonstrated a nonsignificant trend in favor of the control group, who received standard radical surgery plus radiation therapy with an absolute negative effect in the chemotherapy arm that reduced survival at 5 years by 6%. The possibility of a slightly decreased survival must be balanced by the retention of the larynx in those patients whose disease was controlled.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV laryngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Treatment of recurrent supraglottic, glottic, and subglottic cancer includes further surgery or clinical trials.[1,2,3,4]
Salvage after previous combined total laryngectomy and radiation therapy is poor.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent laryngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of laryngeal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Laryngeal Cancer Treatment are:
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National Cancer Institute: PDQ® Laryngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/head-and-neck/hp/laryngeal-treatment-pdq. Accessed <MM/DD/YYYY>.
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