Radiation Therapy for Cancer of the Larynx and Hypopharynx

Overall Synopsis

Overview

The larynx is central to the uniquely advanced human ability to communicate. Besides directly producing the voice, the larynx is indirectly involved in other critical functions such as swallowing. It follows that larynx cancer is a potentially devastating diagnosis for a patient because it threatens both survival and quality of life. The American Cancer Society reported 12,410 cases of laryngeal cancer in 2019, with 3760 deaths resulting from this disease. Cancer of the hypopharynx is uncommon with approximately 2500 new cases predicted.

Treatment of the larynx and hypopharynx should achieve two major goals: cure of the cancer and whenever possible, preservation of organ function to maintain a high quality of life. For instance, an aggressive surgical approach that would leave the patient with gross deformities and functional impairment is not optimal; on the other hand, advocating “organ-preserving” chemoradiation therapy for a patient with a nonfunctional larynx is also counterproductive. Cure is likely in early-stage larynx and hypopharynx cancers, but the prognosis is poor for patients with advanced-stage disease, with 5-year overall survival (OS) usually ranging from 50% to 60%, although it is even worse for patients with hypopharyngeal cancers (20% to 35%). Unlike other sites in the head and neck, recent survival outcomes in larynx cancer have slightly declined. Possible explanations, including increased use of organ-preservation therapy such as definitive chemoradiation, have been the subject of recent controversy. To optimize patient care and outcomes, the involvement and coordination of a multidisciplinary team including ear, nose, and throat surgeons, radiation oncologists, medical oncologists, and appropriate supportive staff (i.e., nurses, dieticians, social workers, speech and swallowing therapists) is absolutely necessary.

To determine optimal therapy for an individual patient, careful attention should be paid to patient-related factors such as their baseline quality of voice and swallowing function, weight loss, comorbidities, smoking status, duration of symptoms, age, performance status, hemoglobin (Hgb) levels, renal function, preexisting neuropathy or hearing loss, family support system, and the patient's motivation to complete the proposed treatment. Important tumor-related factors include the volume and extent of disease, nodal disease, and tumor grade. Treatment-related factors to incorporate into the selection of therapeutic management include the likelihood of acute/chronic toxicities of the therapy and its impact on the quality of life, and duration of treatment. A holistic patient-centered approach that takes into account these factors is necessary for the optimal individualized selection of each patient's cancer treatment.

In order to achieve succinctness and clarity, this chapter is organized as follows:

• 1

  Review of pertinent anatomy

• 2

  Key points in initial evaluation and workup of patients

• 3

  Overview of treatment options and radiation techniques

• 4

  Innovations and future direction in treatment

Anatomy of the Larynx and Hypopharynx

A fundamental knowledge of laryngeal and hypopharyngeal anatomy is necessary to allow the clinician to understand how (1) a particular cancer affects function to produce signs and symptoms; (2) patterns of local invasion and lymphatic and distant metastases differ for individual cancers of the larynx and hypopharynx; and (3) the extent of tumor within the larynx and hypopharynx determines treatment selection. For the radiation oncologist, anatomy is critical for identifying sites at risk for microscopic disease coverage and for optimal sparing of critical structures.

The hypopharynx extends from the superior aspect of the hyoid bone, which corresponds to the level of the vallecular floor, to the inferior border of the cricoid cartilage. The three subsites of the hypopharynx are (1) the paired pyriform sinuses, (2) the postcricoid area, and (3) the posterior and lateral hypopharyngeal walls.

The larynx is intimately related to the hypopharynx; it is situated anteriorly to the hypopharynx, at approximately the same cervical levels. Anatomically, the larynx extends from the tip of the epiglottis at the level of the lower border of the C3 vertebra to the distal extent of the cricoid cartilage at the level of the C6 vertebra. The larynx is subdivided into three anatomic regions: the supraglottis, the glottis, and subglottis regions. The supraglottic larynx begins superiorly at the suprahyoid epiglottis and inferiorly to where the mucosa of the upper surface of the true vocal cords forms the lateral wall of the ventricle. It includes (1) the suprahyoid and infrahyoid epiglottis, (2) the aryepiglottic folds, (3) the arytenoids, (4) the false vocal cords, and (5) the ventricle. The glottis consists of the true vocal cords and the anterior and posterior commissures. The anterior commissure may approach within 1 cm of the skin surface, an important consideration for radiation treatment planning. The lower boundary of the glottis extends 5 mm below the free margin of the vocal cords, or to the horizontal plane 1 cm below the apex of the ventricle. The vocal cords attach to the thyroid cartilage at what is visualized to be the “figure-of-eight” on a lateral plain film. The subglottis extends from the lower boundary of the glottis to the inferior margin of the cricoid cartilage. These anatomic boundaries are readily visualized on plain lateral x-ray films ( Fig. 110.1 ).

From a radiographic perspective, it is important to note that the thyroid, cricoid, and most of the arytenoid cartilages are composed of hyaline cartilage, which begins to ossify when a person is about 20 years old. The epiglottis, corniculate and cuneiform cartilages, and the apex and vocal process of the arytenoids are made up of elastic cartilage, which does not ossify and therefore is not radiopaque.

Lymphatic Drainage

Knowledge of the lymph node levels in the neck in relation to bony landmarks, as well as surgical landmarks, is important for the radiation oncologist when planning radiation fields. Level I nodes are above the hyoid bone, below the mylohyoid muscle, and anterior to the back portion of the submandibular gland ( Fig. 110.2 ). This corresponds to the submental and submandibular triangles. Level II nodes are located from the skull base to the lower body of the hyoid bone inferiorly, posterior to the back of the submandibular gland, and anterior to the posterior extent of the sternocleidomastoid muscle. The jugular chain lymph nodes, which run from the mandible down to the carotid bifurcation, are included in this level. Level III nodes extend from the lower body of the hyoid to the inferior margin of the cricoid, also anterior to the posterior margin of the sternocleidomastoid muscle, corresponding to the region from the carotid bifurcation to the omohyoid muscle. Level IV lymph nodes are bordered superiorly by the lower border of the cricoid cartilage and inferiorly run to 2 cm superior to the sternoclavicular joint and are anterior to the posterior margin of the sternocleidomastoid muscle, which corresponds to the region from the omohyoid muscle to the clavicle. Level V lymph nodes run from the skull base to the level of the clavicle in the region posterior to the sternocleidomastoid muscle; this area is the posterior triangle bounded by the sternocleidomastoid (SCM) anteriorly, the trapezius posteriorly, and the omohyoid inferiorly. Level VI lymph nodes are between the lower body of the hyoid bone and the suprasternal notch, otherwise known as the anterior compartment between the carotid arteries (see Fig. 110.2 ). The NRG contouring atlas for the N0 neck is a widely used reference available at www.nrgoncology.org .

Glottic Lymphatic Drainage

The glottis has a very sparse lymphatic supply and hence, glottic carcinomas typically present with a very low rate of lymphadenopathy. For a “true” T1 lesion, there should be virtually no lymphadenopathy at diagnosis; for T2 lesions, the incidence of lymphadenopathy is typically 2% to 7%, and approximately 20% for T3 and T4 lesions. Typically, the involved lymphatic nodal stations by glottic cancers include the midjugular (level III) and upper jugular nodes (level IIA).

Supraglottis Lymphatic Drainage

Unlike glottic cancers, supraglottic cancers typically present with lymph nodal metastases at diagnosis, even in early-stage disease. Thus the incidence of lymphadenopathy is 55% at diagnosis with a bilateral rate of approximately 15%. Supraglottic cancers typically drain to nodes along the jugulodigastric chain to mostly upper (level II) and midjugular (level III) lymph nodes.

Subglottis Lymphatic Drainage

Given the rarity of subglottic cancers, data regarding their incidence of lymphadenopathy are sparse. The incidence of lymphadenopathy is quite uncommon in early-stage T1-T2 subglottic cancers. In advanced-stage T3-T4 subglottic cancers, the incidence of lymphadenopathy varies from 10% to 50%.

Biomarkers and Molecular Biology

HPV infection has caused an increase in the incidence of oropharyngeal cancer and is associated with a favorable prognosis. The overall presence of HPV in cancerous lesions of the larynx varies between 3% and 85% with an average of approximately 25% depending on the procedure applied for sample collection and viral DNA detection methodology. The differences depend on primers used for the reaction, genomic localization and the length of the product amplified by PCR, conditions of the reaction, and false-positive results obtained due to the sample contamination with viral particles. Kreimer et al. studied 5046 cases of head and neck cancers from all over the world, 1435 of which were laryngeal cancers tested for the presence of HPV with the use of PCR detection. In 35 publications related to the cancer of larynx, HPV infectivity was found in 24% of cases. In this study, Kreimer et al. paid particular attention to the geographical location of the conducted studies and they confirmed that the prevalence of HPV occurrence in cases of head and neck cancers depends on the region of the world inhabited by the patients. The HPV prevalence in cases of laryngeal infection was the highest in Asia and accounted for 38.2% of squamous cell cancers. Another recent systematic review of the literature found HPV infection in approximately 20% of laryngeal cancer cases but no clear association with treatment outcome.

Epithelial growth factor receptor (EGFR) is a receptor tyrosine kinase frequently overexpressed in HNSCC and it is associated with a worse prognosis. Targeting of the EGFR pathway has proven successful with the monoclonal antibody cetuximab, but use of small-molecule receptor tyrosine kinase inhibitors has been less successful. The EGFR pathway and associated downstream pathways PI3k-AKT-mTOR as well as potential drugs targeting these pathways are represented in the following text ( Figs. 110.3 and 110.4 ).

These pathways involve many potential prognostic markers including AKT, Bcl-xl, NFκB, BAK, p53, Rb, MMP, VEGF, PTEN, cyclin D1, and COX-2.

Clinical Presentation and Evaluation