CHAPTER 112 Radiation Therapy for Cancer of the Larynx and Hypopharynx
Of the millions of species on planet Earth, none has the ability to communicate as effectively as Homo sapiens. Of course, central to this ability to communicate is the larynx. Besides directly assisting the human voice, the larynx is indirectly involved in other critical functions such as swallowing. Hence it is not surprising that cancer of the larynx is a devastating diagnosis for a patient not only because of its potentially life-threatening implications but also due to the numerous implications on the individual’s quality of life. The American Cancer Society estimated that 12,250 cases of laryngeal cancer were diagnosed in 2008 and that 3670 deaths resulted from this disease.1 Cancer of the hypopharynx, though rare with 2500 new cases estimated every year, has similar implications on the individual patient’s well-being and quality of life.
Treatment of the larynx and hypopharynx should achieve two major goals: cure of the cancer and preservation of organ function to maintain quality of life. In one extreme, an aggressive surgical approach that would leave the patient with gross deformities and functional impairment is not optimal; on the other hand, advocating chemoradiation therapy for a patient with a larynx that is not worth preserving is equally futile. Cure can usually be achieved in early-stage larynx and hypopharynx cancers, but the prognosis is still relatively poor for advanced-stage disease, with 5-year overall survival ranging from 15% to 50%. For these reasons, 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 vital to determining the best management for each patient, in order to maximize cure and preserve quality of life.
In determining the most optimal therapy for an individual patient, careful attention should be paid to patient-related factors (e.g., baseline quality of voice and swallowing function, weight loss, comorbidities, duration of symptoms to gauge the “tempo” of the cancer, age, performance status, hemoglobin levels, family support system, patient’s motivation to complete the proposed treatment); tumor-related factors (e.g., volume and extent of disease, nodal disease, tumor grade); and treatment-related factors (e.g., the likely acute/chronic toxicities of the therapy and their impact on the quality of life, duration of treatment). A careful “holistic” approach that takes into account these factors is necessary for the optimal treatment of each patient’s cancer.
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 spread 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, knowing the relation of the laryngeal and hypopharyngeal structures to bony landmarks is critical in radiation treatment planning.
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 region includes (1) the 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. Importantly, the anterior commissure is usually 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. 112-1).
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.
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 portals. Level I nodes are above the hyoid bone, below the mylohyoid muscle and anterior to the back portion of the submandibular gland. 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 by the clavicles 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 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 (Fig. 112-2).
The most common presenting symptoms of carcinoma of the supraglottis are sore throat and odynophagia. Often a neck mass may be the first sign of carcinoma of the supraglottis because of the high incidence of lymph nodal metastases. Unilateral otalgia occurs because of referred pain from the involvement of the vagus nerve and the auricular nerve of Arnold (a branch of cranial nerve X). Hoarseness is usually not an initial symptom, and it occurs with invasion of the vocal cords. Weight loss, dyspnea, foul breath, and aspiration occur with advanced disease.
The most typical presenting symptom of early-stage vocal cord cancer is hoarseness. The symptoms of advanced disease include sore throat, localized pain as a result of cartilage invasion, otalgia, and dyspnea as a result of airway compromise.
Secondary to anatomic location, patients with hypopharyngeal cancers often present at more advanced stages than other head and neck cancers. Typical presenting symptoms include hoarseness, odynophagia and/or dysphagia, a sore throat, otalgia, weight loss (20%), and neck masses. In more advanced stages, patients may also complain of hemoptysis and stridor as the airway becomes involved.
The diagnostic evaluation of a patient who is suspected of having cancer of the larynx should begin with a mandatory history and physical examination. The mainstay of the physical examination is the flexible fiberoptic endoscope, which allows for excellent visualization of the infrahyoid epiglottis and anterior commissure; these regions may be difficult to see with indirect laryngoscopy. Several key clinical pearls should be remembered when performing the examination. In addition to determining the tumor extent, assessment of the mobility of the vocal cords is absolutely critical because this determines staging and is an important factor when deciding between treatment modalities. For lesions in the supraglottis, careful palpation and an examination of the base of tongue should be performed to determine involvement. Because hypopharyngeal carcinomas can often present as skip lesions with disease distant from the primary site, a thorough examination is imperative to localize all areas of disease. The neck should be carefully palpated to determine the size, number, pliability (mobile, partially mobile vs. fixed), and location (ipsilateral, bilateral, or contralateral) of lymph node metastasis. Fixed lymph nodes may warrant preoperative radiation therapy (RT) versus preoperative chemoradiation therapy in order to make surgical resection more feasible.
Routine laboratory tests include a complete blood count and liver function tests. If the liver function tests or serum alkaline phosphatase are abnormal, further studies (e.g., computed tomography [CT] of the abdomen, bone scans) may be indicated.
Imaging studies include a chest radiograph (a CT scan should be considered for patients at high risk of metastasis to the chest) and a CT scan with contrast enhancement of the head and neck region. The CT scan should be performed before the biopsy whenever possible because postbiopsy edema may overestimate tumor extent. CT slices 3-mm thick should be obtained at 3-mm intervals throughout the larynx. The relative usefulness of CT scanning versus magnetic resonance imaging (MRI) remains controversial. MRI is more useful for delineating the soft-tissue extent of the primary tumor and cartilage invasion, whereas CT scanning is better for evaluating early bone invasion and the remainder of the laryngeal anatomy. The disadvantages of MRI are longer scanning time and motion artifact. For patients who are at moderate to high risk for harboring distant metastases, fluorodeoxyglucose positron emission tomography scan is recommended. This is particularly important for patients with hypopharyngeal cancer and for laryngeal cancer associated with bulky (N2-3) nodal disease.
Examination under anesthesia with direct laryngoscopy and biopsy of the tumor is the most important step in the diagnosis of carcinoma of the larynx and hypopharynx. In advanced-stage disease, a panendoscopy (bronchoscopy and esophagoscopy) should be performed to rule out synchronous tumors, if suspected.
If RT is considered, patients should be referred for a thorough dental evaluation and extractions, if necessary, before treatment. This is imperative because xerostomia, which frequently results from radiation, predisposes patients to dental carries, particularly those with poor oral hygiene initially. In addition, if dental work needs to be performed, especially tooth extractions, it should be done before treatment because healing of the mandible is impaired after radiation, leading to increased chances of infection and osteoradionecrosis.
Laryngeal and hypopharyngeal cancers are staged according to the American Joint Commission for Cancer Tumor Node Metastasis system. The sixth and most recent version of the staging system published in 2002 can be found in other chapters. In contrast to staging in other sites, the staging for tumors in the larynx is based on involvement of anatomic structures and not on the size of the lesion. Staging in the hypopharynx is based on size and subsite involvement in early stages. Note that in both the larynx and hypopharynx, fixation of either vocal cord automatically stages the tumor as a T3, regardless of the tumor bulk. T4 disease is the same in all glottic subsites and hypopharynx, reflecting invasion outside of thyroid cartilage or beyond. Nodal staging is the same as that in other head and neck malignancies (with the exception of the nasopharynx). The ability to visualize the stage of the disease from an anatomic framework, rather than memorizing lines of description in text, is useful. Direct laryngoscopy images of early T-stage laryngeal and hypopharyngeal cancers are shown in Figures 112-3A-D.
Treatment Options, Radiotherapy Techniques, Dose-Fractionation Schemes, Outcome, Prognostic Factors, and Complications
Recognizing that management of patients with laryngeal and hypopharyngeal cancers involves a combined modality approach involving the radiation oncologist, the head and neck surgeon, and the medical oncologist, we also recommend consultation with other specialists such as the dentist for clearance before radiotherapy (especially if the mandible is likely to be in the radiation field), dietician, and speech and swallowing therapist to assist the patient’s rehabilitation and recovery from the malignancy and treatment sequelae.
We do not devote much consideration to the management of the neck in this chapter because it is covered extensively elsewhere in this textbook. As a matter of principle, nonbulky nodal disease (i.e., ≤3 cm) can be generally managed with either RT alone or chemoradiation therapy with surgery reserved for salvage therapy. However, bulky nodal disease (i.e., >3 cm) generally requires a combined-modality approach involving either preoperative or postoperative RT, or definitive chemoradiation or radiotherapy alone followed by a planned (generally limited) neck dissection, especially if the patient still has palpable lymphadenopathy after full doses of irradiation. Hence when we speak of “early-” versus “advanced-” stage disease, we are usually referring to the “T-stage” versus “N-stage” disease.
Early-stage laryngeal cancer can often be cured with either RT or surgery. No randomized trials have directly compared surgery with RT, but published series report similar local-regional control rates for both treatment approaches. Selection of a treatment modality for an individual patient depends on a number of factors including number of prior surgical procedures (e.g., “surgical stripping,” laser excisions), quality of voice, and location of the lesion. For example, laser excision of a lesion in the region of the anterior commissure can result in permanent hoarseness as a sequela of surgery. On the other hand, the same laser excision of a mid-vocal-cord lesion often leaves patients with excellent quality of voice without the need for 6 to 7 weeks of daily radiotherapy treatments. Conversely, a patient who has already failed a number of prior surgical interventions (e.g., “surgical strippings,” laser excisions) is unlikely to achieve the “same old” natural quality of voice when treated with definitive RT. Generally, the advantages of RT include the following:
Multiple-dose fractionation schemes have been used to treat patients with T1 and T2 glottic carcinoma, with total dose equaling 66 to 70 Gy at 2.0 Gy/fraction (fx) per day, 63 Gy at 2.1 Gy/fx per day, or 60.75 Gy to 65.25 Gy at 2.25 Gy/fx per day, 5 days per week.2–4 At the Department of Radiation Oncology, University of Southern California (USC) Keck School of Medicine (KSOM), patients with Tcis, T1 (including verrucous carcinoma), and small T2 lesions are treated to 66.0 Gy at 2.0 Gy/fx. Patients with T2 lesions are treated to a total dose of 70 Gy at 2.0 Gy/fx. These dose-fractionation schemes are used at USC because of the ease of tolerability (i.e., rarity of treatment related interruptions) in our experience and excellent local control rates. Doses less than 2.0 Gy/fx should not be used to treat early-stage glottic tumors because of the extended interval of RT, which enhances tumor repopulation rates, leading to inferior local control rates.5,6 Although altered-dose fractionation schemes (i.e., hyperfractionated or accelerated radiotherapy) can be used to treat patients with unfavorable early-stage glottic cancers (e.g., bulky T2 lesion), the treating radiation oncologist should only embark on this path if he or she has experience in using these alternative-dose fractionation schemes.
At USC, a three-dimensional conformal RT (3-D CRT) approach is used to treat patients with early-stage laryngeal carcinoma. A planning CT scan is done with the patients in a supine treatment position, with the head hyperextended and immobilized with an individually made face mask. For T1 and very early T2 lesions, two small opposing lateral fields, usually measuring 5 × 5 cm2 to 6 × 6 cm2, are used (Fig. 112-4). The fields typically extend from the upper thyroid notch superiorly to the lower border of the C6 vertebral body inferiorly. The anterior border of the field should flash at least 1 cm in front of the skin surface at the level of the vocal cords (approximately C4). The posterior border of the field should include the anterior portion of the vertebral bodies. During fluoroscopic simulation (if possible) of the fields, the patients should be asked to swallow to monitor the superior extension of the glottis to ensure that it is still within the radiotherapy field because sometimes a patient may actually swallow during the radiation treatment. During treatment planning, radiation dose homogeneity, especially in the anterior commissure region, using wedges should be achieved to prevent overdosing or underdosing (Fig. 112-5). The lymph nodes are not treated in patients with Tcis and T1 disease because of the virtually nonexistent incidence of lymphatic nodal metastases. The incidence of lymphatic nodal involvement varies from 5% to 15% with T2 disease. Generally, for T2 lesions, we recommend treatment of at least the first-echelon lymph nodes (subdigastric and midjugular, or lower levels II and III), especially in a patient with bulky disease.
For Tcis and T1 lesions, local tumor control rates vary between approximately 85% and 95% at 5 years (Table 112-1). With surgical salvage, ultimate local control rates between 95% and 99% at 5 years can be achieved. For T1 verrucous carcinoma, similar high local control rates have been reported with definitive RT. For T2 glottic lesions, initial local control rates vary between 70% and 90% at 5 years with RT alone (Table 112-2). Following surgical salvage of radiotherapy failures, ultimate local control rates between 80% and 96% at 5 years can be achieved for T2 lesions.
Anterior commissure involvement has been shown in older studies to be associated with lower tumor local control rates. However, in the era of 3-D CRT with computer treatment planning, which can detect and thus limit underdosing of the anterior commissure region, this prognostic factor is no longer significant. Fraction sizes of less than 2.0 Gy result in inferior local control rates and therefore should not be used. Studies have also shown that extending treatment times beyond approximately 42 days results in inferior outcomes secondary to accelerated repopulation by tumor cells.8 In a study of 91 patients with T1N0 squamous cell carcinoma of the glottis treated with definitive radiotherapy, both overall treatment time (i.e., ≤42 days vs. > 42 days) and dose per fraction (i.e., <200 cGy vs. ≥200 cGy) predicted for local control. Typically, a loss of approximately 1.4% (0.4% to 2.5%) in local control occurs for every day of a treatment break or overall extension of treatment time. Multiple studies have shown an adverse effect of low pretreatment and/or post-treatment hemoglobin levels (Hgb) on outcome in early- and advanced-stage laryngeal cancer.9 For example, in a study from Fox Chase Cancer Center that analyzed 109 patients with T1 or T2 glottic cancers treated with definitive RT, pretreatment Hgb levels less than or equal to 13 g/dL adversely affected both 2-year local control rates and overall survival (66% vs. 95% and 46% vs. 88%, respectively) on multivariate analysis.
Because the treatment fields for early-stage glottic cancer are small, patients typically experience few side effects from RT. Common side effects include skin erythema and/or hyperpigmentation, desquamation, hoarseness, sore throat, and resultant dysphagia. These effects are self-limiting, manifesting approximately 2 to 4 weeks into therapy and usually resolving within 6 to 8 weeks after the completion of treatment. Hypothyroidism is also a possible consequence of radiation, and therefore patients should have thyroid function testing before treatment and every 6 to 12 months. Hypothyroidism rates as high as 30% to 40% have been reported in the literature after radiation.13 Hormonal replacement can be given to replete thyroid hormone levels. More serious though rarer late sequelae from RT include laryngeal arytenoid edema and laryngeal arytenoid necrosis. In patients who have been irradiated for carcinoma of the glottis, the incidence of mild to moderate laryngeal edema persisting for more than 3 months after RT is about 15.4% to 25%.14 The incidence of severe laryngeal edema is about 1.5% to 4.6%,15–18 and this increases with greater total dose, field size, dose per fraction, and T stage of the lesion.16,18,19 Initially these patients should be managed conservatively with voice rest, abstinence from alcohol and cigarettes, and careful, close follow-up examinations. Antibiotics and low-dose steroids (i.e., 2 mg po bid) may be used when there is suspicion of infection or when the edema is severe enough to significantly compromise the airway. However, if the edema is progressive and unresponsive to conservative measures and recurrent disease is strongly suspected, biopsies should be carried out to rule out malignancy as the underlying cause. Salvage surgery is performed if biopsies are positive. Late laryngeal arytenoid necrosis after RT is rare, with a reported incidence of about 0.5% to 1.8% for glottic cancer.15,20,21
Historically, resectable locally advanced carcinoma of the glottic larynx (i.e., T3 and T4 and/or N2 and N3 disease) has been generally treated with combined surgery and postoperative RT. However, a primary surgical approach requiring a total laryngectomy has the disadvantage of loss of organ function such as voice and swallowing. Hence during the past several decades, various primary nonsurgical approaches have been explored to achieve cure of locally advanced disease and preserve the larynx so as to maintain organ function. These therapeutic approaches have consisted of radiotherapy alone or a combination of chemoradiation therapy. Currently, concurrent chemoradiation therapy has evolved to become the “standard of treatment” for patients with locally advanced laryngeal cancer who otherwise would require a total laryngectomy. For patients whose primary lesion is amenable to conservation laryngeal surgery, the choice is between chemoradiation and the former. The authors advise against the use of such a “generic” reflexive chemoradiation approach that does not individualize therapy for each patient. For example, a patient presenting with a large-volume laryngeal glottic carcinoma with significant epiglottic destruction and poor voice quality is unlikely to have reversal of these symptoms let alone eradication of local disease; hence a primary surgical approach consisting of a total laryngectomy followed by postoperative RT with or without chemotherapy would be more optimal for the patient in this setting.
At USC, we prefer to use postoperative versus preoperative radiotherapy in the setting of a primary surgical approach based on results of the Radiation Therapy Oncology Group (RTOG) 7303 and the “inherent” advantages of adjuvant treatment.22 RTOG 7303 was a randomized trial comparing preoperative (50 Gy) versus postoperative (60 Gy) RT in advanced-stage, operable supraglottic larynx and hypopharynx cancers. The 10-year locoregional control was significantly improved in the postoperative versus the preoperative group (70% vs. 58%, respectively). Additionally, the rate of complications was much higher in the patients undergoing preoperative RT (9%) versus the postoperative group (5%). On the basis of the results of this RTOG study and the inherent advantage of having pathologic information after surgery, postoperative RT is preferred over preoperative RT. At USC, the role of preoperative RT is limited to shrinking locally advanced disease considered to be unresectable.
Although locoregional tumor control rates with total laryngectomy followed by postoperative RT are relatively high, some patients with high-risk disease features still do poorly with adjuvant radiotherapy alone. Hence several randomized trials have evaluated the role of adding concurrent chemotherapy to adjuvant RT following surgery for locally advanced head and neck cancer including primary laryngeal tumors. These studies include RTOG 9501, European Organization for the Research and Treatment of Cancer (EORTC) 22931, and the German ARO 96-3 study (Table 112-3).23–26 All three of these randomized trials showed that adjuvant concurrent chemoradiation therapy is better than radiotherapy alone for local control and disease-free survival in patients with high-risk disease following surgery. In the RTOG 9501 trial, 459 patients with high-risk locally advanced head and neck cancer defined as any T-stage disease with two or more involved lymph nodes, positive extracapsular extension (ECE), and/or positive mucosal margins of resection were randomized to either RT alone (60 to 66 Gy at 2.0 Gy/fx) or the same RT with concurrent cisplatin (100 mg/m2 on days 1, 22, and 43). At 2 years, local control rates (82% vs. 72%, p = 0.01, respectively) and disease-free survival (35% vs. 25%, p = 0.04, respectively) were significantly better among those who underwent adjuvant chemoradiation therapy versus radiotherapy alone, respectively. However, there was no statistical difference in overall survival between the two arms (45% vs. 35%, p = 0.19, respectively). In the EORTC 22931 trial, high-risk disease was defined as any patient with a pT3 or pT4 tumor with any nodal stage, or a pT1/pT2 tumor with N2 or N3 disease, or pT1/pT2 and N0 or N1 disease with involved mucosal margins, positive ECE, perineural invasion, and/or vascular emboli. In the EORTC trial, 334 patients were randomized to RT alone (66 Gy at 2.0 Gy/fx) or the same RT with cisplatin (100 mg/m2