Treatment of Early-Stage Larynx Cancer
Early-stage larynx cancer (Stages I and II) can be treated with either surgery or radiation in single-modality therapy. Current recommendations by the American Society of Clinical Oncology are that all patients with T1 or T2 laryngeal cancer, with rare exceptions, should be treated initially with the intent to preserve the larynx. The advantages of surgery compared with radiation are a shorter treatment period (compared with 6–7 weeks for radiation) and the option of saving radiation for recurrence. Specific surgical procedures used in the treatment of early larynx cancer are discussed in the following section. In addition to the risks inherent in any surgical procedure, surgery can result in a poorer voice quality and, for external surgical approaches, a worse cosmetic outcome.
Specific radiation therapy techniques for larynx cancer are discussed under “Nonsurgical Measures.” For early-stage lesions, short-term complications of radiation include odynophagia and laryngeal edema. The long-term complications include a remote possibility of laryngeal fibrosis, radionecrosis, or hypothyroidism. Delayed development of sarcoma (radiation-induced), though possible, is exceedingly rare, with an incidence of 0.03–0.3%.
Treatment of Advanced-Stage Larynx Cancer
Advanced-stage larynx cancer (Stages III and IV) was historically treated by dual-modality therapy with surgery and radiation. For most T3 and T4 tumors, where total laryngectomy is required for the complete removal of the tumor with amply clear margins, organ preservation treatment with combined chemotherapy and radiation therapy is preferred because there is no difference in overall survival and a superior quality of life. Still, extirpative surgery may be used in selected patients, such as those with bone or cartilage destruction in which reasonable organ function is unlikely after conservation therapy. Voice rehabilitation after total laryngectomy is discussed below. For T1, T2, and some T3 lesions, partial laryngectomy procedures with preservation of the voice may be considered (see “Surgical Treatment of Larynx Cancer”). Patient selection is critical with the goal of rendering the patient disease-free with surgery alone because postoperative radiation after partial laryngectomy may result in significant functional impairment. The type of neck dissection chosen is guided by the extent of the neck disease, as discussed below.
Adjuvant radiation should start within 6 weeks of surgery and, on once-daily protocols, lasts 6–7 weeks. The primary site is treated with external-beam irradiation with doses of 55–66 Gy, whereas draining nodal basins typically receive a slightly lower dose, depending on the extent of neck disease. Complications of radiation therapy include those described for radiation given as single-modality treatment for early-stage larynx cancer; however, since the treated area is more extensive, side effects also include mucositis during therapy and chronic xerostomia after treatment. Less common complications include hypothyroidism, radionecrosis, and esophageal stricture.
Organ-preserving protocols have evolved over the past decade. The landmark study of the Veterans Administration Larynx Cancer Study Group randomized 332 patients to receive neoadjuvant chemotherapy followed by radiation, compared with traditional total laryngectomy with postoperative radiation. The study found that two-thirds of patients responded favorably to chemotherapy after just one or two cycles. In two-thirds of these cases, larynges were preserved, and survival was similar to the traditional approach of laryngectomy with postoperative radiation. As a subgroup, patients with larger T4 tumors did not fare as well and, for this reason, organ-preserving protocols sometimes are not offered to patients in this category, particularly if cartilaginous invasion is present. The VA study was followed by a three-arm randomized study comparing induction chemotherapy (cisplatin plus 5-fluorouracil) followed by radiation, concurrent chemoradiation with cisplatin, and once-daily radiation alone in 547 patients. At 2 years, superior organ preservation was achieved with the concurrent chemoradiation group; therefore, this treatment strategy has become the standard of care in most centers. Ongoing studies of combined-modality treatment include radiation with different systemic therapies and systemic therapy with altered radiation schedules, including twice-daily treatment.
Treatment of the Neck in Larynx Cancer
A neck without clinically apparent nodal metastases should be treated in larynx cancer if the risk of nodal metastasis exceeds 15% (see Table 31–2). The treatment of both the ipsilateral and contralateral necks should be considered, therefore, for early-stage, primary cancers of the supraglottis in general and for all advanced laryngeal cancers. Neck disease staged as N0 or N1 can be treated with a single modality—surgery or radiation. The choice of surgery or irradiation for elective treatment of the clinically negative neck depends on the treatment chosen for the primary cancer. An elective neck dissection has the advantage over elective irradiation of the ability to stage the neck pathologically, which provides prognostic information and helps in determining whether adjuvant therapy is required. Neck disease staged as N2 or N3 generally requires a combined-modality treatment.
Neck dissection is tailored to the extent of neck disease. Selective neck dissection (preserving the sternocleidomastoid muscle, internal jugular vein, and spinal accessory nerve) can be performed for clinically N0 necks. For N1 necks, dissection is usually limited to levels II–IV, as metastasis to levels I or V is rare in this condition. Radical or extended radical neck dissection, sacrificing the sternocleidomastoid muscle, the internal jugular vein, and the spinal accessory nerve, and addressing neck levels I–V or more, is performed for extensive neck disease with the involvement of vessels, nerves, muscles, or any combination of these structures. A modified radical neck dissection preserves some of these structures, according to feasibility.
Surgical Treatment of Larynx Cancer
Surgical options for treating larynx cancer include a variety of partial laryngectomy procedures in addition to total laryngectomy. Understanding the lymphatic drainage patterns of the laryngeal subsites permits the surgeon to resect more closely than the 1- to 2-cm margins that typically are recommended at other head and neck sites. This helps preserve functional voice, respiration, and deglutition in partial laryngectomy procedures.
A preoperative consultation with a speech therapist is appropriate if significant voice or swallowing changes are anticipated. These sessions help educate patients about the speech and swallowing functions of the larynx and prepare the patient for postoperative rehabilitation and therapy.
The endoscopic removal of selected larynx cancers can be achieved safely and effectively with use of the operating microscope and microlaryngeal dissection instruments. The carbon dioxide laser, used with direct laryngoscopy and microscope guidance, is also a useful dissection tool, especially for supraglottic lesions. Laser cordectomy has been shown to provide excellent local control and laryngeal preservation of early-stage glottic cancer; it offers low morbidity and excellent retreatment options in case of local failure. Contraindications for endoscopic laser resection include cases in which the entire tumor cannot be visualized, large tumors requiring too much excision of the functional laryngeal unit, thus decreasing airway protection and leading to aspiration, and cartilage invasion. For supraglottic cancer, contraindications also include bilateral arytenoid involvement and direct extension into the neck.
Hemilaryngectomy is the removal of one vertical half of the larynx (or a part thereof; Figure 31–8). Appropriate tumors for this surgery are those with (1) subglottic extension no more than 1 cm below the true vocal cords; (2) a mobile affected cord; (3) unilateral involvement (involvement of the anterior commissure and anterior extent of the contralateral true cord can, in certain cases, also be treated with an extended vertical hemilaryngectomy); (4) no cartilage invasion; and (5) no extralaryngeal soft tissue involvement.
Schematic of the anatomic resection for a vertical hemilaryngectomy. (Modified and reprinted, with permission, from Myers EN, Suen JY. Cancer of the Head and Neck, 3rd ed. WB Saunders, 1996.)
Vocal cord reconstruction is most often done by transposing a flap of strap muscle or microvascular free flap to provide bulk against which the remaining unaffected vocal cord can vibrate (Figure 31–9). Vertical hemilaryngectomy can be done in appropriate surgical candidates who have failed radiation therapy.
Vertical right hemilaryngectomy, postoperative endoscopic view. Note the absence of arytenoid, but the presence of the “pseudocord.”
A supraglottic laryngectomy entails removal of the supraglottis or the upper part of the larynx (or a part thereof). This surgery may be considered when the following conditions are met: (1) for tumors with a T stage of T1, T2, or T3 by preepiglottic space involvement only; (2) the vocal cords are mobile; (3) cartilage is not involved; (4) the anterior commissure is not involved; (5) the patient has good pulmonary status/reserve; (6) the base of the tongue is not involved past the circumvallate papillae; (7) the apex of the pyriform sinus is not involved; and (8) the FEV1 (the forced expiratory volume in the first second) is predicted to be >50%.
A supraglottic laryngectomy can be performed endoscopically using a carbon dioxide laser or with a more standard open, external approach. Endoscopic surgery typically removes just the involved portion of the supraglottis. The traditional supraglottic laryngectomy removes the entire supraglottis from the apex of the laryngeal ventricle, including the false cords, the epiglottis, and the preepiglottic space; the arytenoids and part of the thyroid cartilage are preserved (Figure 31–10). Closure in an open supraglottic laryngectomy is done by collapsing the remaining glottic part of the larynx to the base of tongue (Figure 31–11).
Schematic of the anatomic resection for a supraglottic laryngectomy. (Modified and reprinted, with permission, from Myers EN, Suen JY. Cancer of the Head and Neck, 3rd ed. WB Saunders, 1996.)
Supraglottic laryngectomy, postoperative endoscopic view. Note the absence of the epiglottis.
Although the patient's voice is generally normal in quality, some degree of aspiration is an expected side effect of this operation. For this reason, patients with borderline pulmonary function (FEV1 predicted to be <50%) who cannot tolerate chronic aspiration are generally not considered good candidates for supraglottic laryngectomy. Patients must learn a double-swallow technique called the supraglottic swallow to minimize aspiration with oral intake. Regular visits with a speech therapist are critical to properly learn this technique.
This is a newer surgical technique, which expands on the traditional supraglottic laryngectomy procedure to preserve voice for those with cancers located at the anterior glolttis, including the commissure, or those with more extensive preepiglottic space involvement. The true vocal cords, the supraglottis, and thyroid cartilage are taken, preserving the cricoid and arytenoid cartilages (Figure 31–12). Half of the patients remain dependent on their tracheotomy. Pulmonary function and prior radiation candidacy criteria for supraglottic laryngectomy apply for supracricoid laryngectomy as well. Voice results are reported as adequate. Supraglottic swallow techniques must be used.
Schematic of the anatomic resection for a supracricoid laryngectomy. (Modified and reprinted, with permission, from Myers EN, Suen JY. Cancer of the Head and Neck, 3rd ed. WB Saunders, 1996.)
A near-total laryngectomy is a more extended partial laryngectomy procedure in which only one arytenoid is preserved and a tracheoesophageal conduit is constructed for speech (Figure 31–13). Voice is generated by the lungs, but has a more limited range of pitch. Oral intake and swallowing are in the usual fashion, with some aspiration concerns. Patients remain dependent on a tracheotomy for breathing. This procedure is not offered to patients whose radiation treatments have failed, those with poor pulmonary reserve, or those with tumor involvement below the cricoid ring. Candidates are patients with large T3 and T4 lesions with one uninvolved arytenoid, or with unilateral transglottic tumors with cord fixation.
Schematic of the anatomic resection for a near-total laryngectomy. (Modified and reprinted, with permission, from Myers EN, Suen JY. Cancer of the Head and Neck, 3rd ed. WB Saunders, 1996.)
A total laryngectomy entails the removal of the entire larynx, including the thyroid and cricoid cartilages, possibly some upper tracheal rings, and the hyoid bone (Figure 31–14). The proximal tracheal stump is anastomosed to an opening at the root of the neck anteriorly in a permanent tracheostoma; this results in the complete anatomic separation of the respiratory and digestive tracts. Indications for total laryngectomy are (1) T3 and T4 cancers not amenable to the above partial laryngectomy procedures or organ preservation therapy with chemoradiation, (2) extensive involvement of thyroid or cricoid cartilage, (3) the direct invasion of surrounding soft tissues of the neck, (4) tongue base involvement beyond the circumvallate papillae, and (5) salvage therapy for failures of organ preservation strategies. Closure is done by reapproximating the pharyngeal mucosa. If a partial or total pharyngectomy is also required because of the size of the tumor, then free flap or regional flap aids the closure and prevents pharyngoesophageal stricture. The ultimate goal is to maintain for the patient the ability to swallow by mouth.
Schematic of the anatomic resection for a total laryngectomy. (Modified and reprinted, with permission, from Cummings CW, Sessions DG, Weymuller EA, Wood P. Atlas of Laryngeal Surgery. CV Mosby, 1984.)
Voice rehabilitation after a total laryngectomy is best accomplished with tracheoesophageal speech, using a tracheostomal device that is a one-way valve directing air into the neopharynx during exhalation when the tracheostoma is occluded (Figure 31–15). The individual accomplishes this with digital occlusion, but foam buttons and hands-free techniques also exist. There are several models of the electrolarynx, which achieves its sound by external vibration. Learning to use the device to optimize comprehensibility is a challenge to most patients; those listening to an individual using an electrolarynx must also be familiar with the sound to understand the speech. Some patients learn pure esophageal speech by forcing air into the esophagus and releasing the air while using the tongue, teeth, cheeks, and lips to produce speech. A speech therapist familiar with postlaryngectomy voice rehabilitation is an essential member of the patient care team for patients undergoing a partial or total laryngectomy.
Tracheoesophageal speech requires a prosthesis and a tracheostoma occlusion. (Reprinted, with permission, from InHealth Technologies, Carpinteria, CA.)
More recently, minimally invasive robotic surgery was introduced and currently has increasing applications in the treatment of laryngeal cancer. In many ways, it addresses the shortcomings of both endolaryngeal surgery and open surgical approach. In comparison to transoral laser surgery, the robotic approach allows for en bloc tumor resection as opposed to piecemeal excision with the laser. It can also allow for procedures that are commonly done with an open approach, such as excision of supraglottic or base of tongue lesion through an endoscope. The latter would decrease morbidity associated with an open procedure, thus precluding the need for a tracheostomy.
Photodynamic therapy is an emerging modality of treating early larynx cancer, as well as cancer arising from other primary mucosal sites of the head and neck. A photosensitizing agent (a chemical preferentially taken up by tumor tissue and sensitive to specific wavelengths of light) is administered intravenously. A laser is then used to activate the photosensitizing agent and induce the destruction of tumor tissue. This treatment has been shown to be effective in treating cancers as deep as 5 mm, with local control and survival rates similar to traditional treatment modalities. The side effects of photodynamic therapy include light sensitivity that can linger for several weeks after the administration of the photosensitizing agent. For this reason, patients must wear sun-protective clothing during this period of time and avoid being outside during the hours of maximal sun intensity.
Radiation Treatment Techniques for Larynx Cancer
Radiation given as the primary treatment for larynx cancer or as an adjuvant treatment after surgery is most often done using an external-beam technique; a dose of 6000–7000 cGy is administered to the primary site. When the risk of locoregional nodal metastasis in a clinically negative neck exceeds 15–20%, 5000 cGy is delivered prophylactically to the neck as well. The indications for postoperative adjuvant radiation include advanced-stage disease, close or positive margins, extracapsular spread of tumor in a lymph node, perineural or angiolymphatic spread, subglottic extension, and the involvement of nodes in multiple neck levels (in particular, levels IV or V, or the mediastinum). Although conventional adjuvant radiation treatment consisted of radiation alone, two recent randomized trials have shown improved local control with concurrent radiation and cisplatin for certain risk factors. Patient selection for such treatment continues to be debated, but patients with good performance status and adverse tumor features should be seriously considered for postoperative adjuvant concurrent chemoradiation. As noted previously, newer protocols are using various combinations of radiation with systemic therapies for tumor sensitization and eradication of micrometastatic disease. Altered radiation schedules are also being studied—both with and without systemic agents. Advances in treatment delivery with intensity-modulated radiation therapy have allowed for more accurate tumor dose delivery with greater sparing of normal tissue, including salivary gland preservation with reduced xerostomia. Before undergoing radiation, patients should have a thorough dental examination. When the field will encompass the oral cavity, carious teeth are extracted before starting radiation owing to the radiation-induced dental decay and increased risk of osteoradionecrosis.
Short-term side effects of radiation, lasting up to 6 weeks after the conclusion of therapy, include mucositis, odynophagia, dysphagia, skin and erythema, altered taste, and edema. Common long-term side effects include varying degrees of xerostomia, fibrosis, and edema. Uncommon side effects include hypothyroidism, chondroradionecrosis, and osteoradionecrosis. As noted previously, an exceedingly rare complication is radiation-induced sarcoma.
Chemotherapy for Larynx Cancer
Chemotherapy had not traditionally been part of larynx cancer primary treatment protocols. Starting in the 1980s, organ-preserving protocols using chemotherapy in conjunction with radiation for advanced-stage laryngeal cancer have been compared with standard surgery and radiation treatment. Comparable survival rates have been shown with differing treatment morbidities. In general, lowered rates of distant metastasis are seen, although questionably higher rates of local recurrence are also cited in comparison with surgery and locoregional radiation protocols.
Cisplatin and 5-fluorouracil are the two agents found to be the most effective against larynx cancer. Recently, paclitaxel (Taxol) and docetaxel (Taxotere) have demonstrated activity without the side effects of cisplatin, which include neurotoxicity, ototoxicity, and renal toxicity. Chemotherapy has been given in the neoadjuvant (induction) setting concurrent with radiation and also in the adjuvant setting. Even though successes have been reported for all three approaches, concurrent chemoradiation has generally been deemed the most successful. Trials with neoadjuvant and concurrent intra-arterial chemotherapy have shown excellent local tumor response in selected cases, but with enhanced local toxicity. Cisplatin is the most commonly used agent in concurrent protocols. Agents, such as amifostine, are being used to mitigate side effects and preserve salivary function in the setting of radiation. Chemotherapy may also be used for the palliation of advanced larynx cancer. Once again, cisplatin is the preferred agent, but methotrexate was historically used with some benefit. Chemotherapy is not considered a first-line treatment or standard of care for early-stage (Stages I and II) larynx cancer.
Molecular Targeted Therapy
Recent discoveries in the molecular biology of laryngeal cancer have provided insight into the understanding of the molecular basis of these cancers, which have led to the development of targeted therapeutic strategies aimed at improving clinical outcomes and possibly survival for these patients. Clinical trials are exploring the use of p53-engineered recombinant adenoviruses to restore wild-type gene function and the use of epidermal growth factor receptor pathway antagonists. Other molecular-targeted therapies such as antiangiogenic drugs and vaccine-based therapies are also being developed and evaluated for the treatment of laryngeal cancer.
Complications of Treatment
The complications of larynx cancer reflect the treatment modality (or modalities) used.
Hoarseness may complicate any treatment of larynx cancer, even the smallest larynx cancer. Voice changes can be as subtle as the loss of vocal range, vocal fatigue, and lowered threshold for bouts of laryngitis. Deepening of the voice or a raspy, rough quality of the voice is common. Failure to achieve tracheoesophageal speech after a total laryngectomy can be due to hypertonicity or stricture of the neopharyng\eal segment, an inappropriately positioned voice prosthesis, problems with digital occlusion of the stoma, or other neurologic impairment.
After partial laryngectomy procedures, aspiration risk is significant. This can be due to surgical removal or to denervation, in whole or in part, of the protective mechanisms of the larynx. Acute side effects of radiation include mucositis, thick secretions, odynophagia, and edema, which all contribute to swallowing difficulties in the immediate periradiation period. Xerostomia is a long-term side effect of radiation that also contributes to dysphagia. Stricture, stenosis, or fibrosis of the pharyngoesophageal segment as a result of surgical scarring or as a residual effect of radiation can lead to intolerance of solid foods or an inability to take adequate nutrition by mouth.
Radiation can permanently damage taste buds, although this side effect is often transient. After total laryngectomy, anatomic changes result in a lack of airflow through the nose and mouth. This severely changes the patient's sense of smell and, therefore, the sense of taste.
A fistula, or connection between the pharynx and skin of the neck, reflects the failure of the pharyngeal surgical closure to seal after laryngectomy. This results in the leakage of saliva and pharyngeal contents (including food) into the neck. When this initial fluid collection ruptures, leakage of mucoid and fluid material occurs onto the skin. Fistulas are more prone to occur in patients who have undergone previous radiation (up to 35% more likely) or surgery, and in those in whom the pharyngeal closure is tight. A fistula is more likely to occur if the nutritional status of the patient is poor (common) and may reflect a residual underlying cancer. Most fistulas close by secondary intention with conservative management, including feeding through a nasogastric or gastrostomy tube. Occasionally, surgical closure with a flap is advisable for vascular protection, for control of infection, or for facilitation of the delivery of indicated postoperative adjuvant therapy.
Some patients undergoing partial laryngectomy procedures are left with either an inadequate laryngeal airway or significant aspiration; for these reasons, they remain dependent on tracheotomy tubes. Excessive laryngeal edema can also happen as a sequela of radiation treatment alone. For patients who undergo a total laryngectomy, excessive secretions and crusting mucus can occlude the tracheostoma. Patients who undergo total laryngectomy often have an increased air temperature sensitivity, which manifests by cough; the lack of airway protection may also result in increased risk of aspiration and drowning.
During the surgical dissection for a partial or total laryngectomy with neck dissection, cranial nerves VII (the marginal mandibular branch), IX, X, XI, and XII are encountered and are therefore at risk for potential injury. Injury can be temporary or permanent. Preoperatively, patients need to be counseled about the following potential postoperative complications: asymmetric smile and mouth closure, swallowing difficulties, hoarseness and aspiration, shoulder drop and range-of-motion limitation, and the impairment of tongue mobility. Similarly, patients with aggressive larynx tumors with neck extension or locoregional metastases may present with, or develop, these cranial nerve deficits because of tumor involvement of the nerve.
Vascular Injuries and Events
Stroke is a risk of laryngectomy and neck dissection, but occurs surprisingly infrequently. A long-term sequela of radiation to the neck is acceleration of carotid atherosclerosis, and patients who have undergone radiation to the neck have a greater risk for stroke because of this.
In advanced tumors with necrosis and the resulting exposure of the carotid artery or the internal jugular vein, rupture (a carotid or jugular “blowout”) is a risk. In cases of sentinel bleeds, angiographic embolization or stenting can prevent or stave off further bleeding. Flap coverage with vascularized tissue, when feasible, can protect against further bleeding. For patients who do experience a carotid blowout, the incidence of major debilitating stroke is >50% in attempts at surgical salvage. Surgical salvage consists of ligating the carotid artery or more rarely attempting bypass. Major vessel rupture is otherwise a commonly fatal event.
Injury to the spinal accessory nerve during neck dissection results in a loss of trapezius muscle function, an inability to abduct the arm past 90°, and downward and inward rotation of the shoulder. These limitations can also occur as a result of primary tumor or neck metastases involving the spinal accessory nerve. Patients complain of a loss of shoulder function and pain. With intensive physical therapy, these deficits and pain can be overcome by increasing the strength of the other muscles of the shoulder girdle.
Because of radiation and surgery, which are augmented by the loss of the function of cranial nerve XI (when it occurs), larynx cancer patients often experience significant fibrosis of neck tissues. This manifests by stiffening, loss of range of motion, and pain. Fibrosis of the larynx and ankylosis of the cricoarytenoid joint have also been observed as a result of radiation treatment, leading to bilateral vocal cord immobility many years after the treatment.
A loss of thyroid function can occur as a result of radiation to the lower anterior neck from a thyroidectomy done as part of laryngectomy, devascularization, or as a combined result of both. Hypothyroidism may not become apparent clinically or by serum tests until 6–12 months (or longer) after the completion of treatment for larynx cancer. Severe hypofunction may be responsible for poor healing of flaps and fistulas. For this reason, thyroid function tests should be performed periodically. Replacing the thyroid hormone with appropriately titrated doses of enteral thyroxin is curative, but requires periodic monitoring.
Other risks of laryngectomy include hematoma and infection.
Long-Term Clinical Follow-Up
Patients with larynx cancer should be followed up clinically in the same manner in which patients with cancer of the head and neck are generally followed up. After treatment is completed, routine office visits are scheduled at 4-to 6-week intervals. During these visits, a complete head and neck examination is performed, focusing on the primary site for signs of recurrence, but also screening for metachronous primary malignant lesions. So-called “second” primary lesions have an annual incidence of 4–7%. After the first year, visits can extend to every 2 months during the second year, every 3 months during the third and fourth years, and every 6–12 months thereafter. Most recurrences of head and neck cancer occur within the first 2 years after treatment. Individuals are considered to be cured of their index primary after 5 years of disease-free status. The signs and symptoms of recurrence are the same as those of the initial presentation, including hoarseness, dysphagia, otalgia, hemorrhage, cervical adenopathy, and pain. The findings of the physical examination, the evaluation for metastases, and the diagnostic tests are the same for recurrences as they were for the original occurrence.
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