Larynx

Key Points

The larynx is divided into three anatomic sites: supraglottis, glottis, and subglottis.
The majority of tumors present in the glottis, often at an early stage. Subglottic carcinoma is very rare.
The glottis does not have a rich lymphatic supply, so nodal involvement is rare and thus elective treatment of the nodes is not required for Stage I and II disease.
The supraglottic larynx has greater access to the lymphatics, and thus elective nodal irradiation is recommended.
Radiation alone or partial laryngectomy is an effective therapy for early laryngeal cancer. The choice of treatment is generally based on the anticipated voice quality, expertise, and personal preference.
Concurrent radiation and cisplatin is often recommended for patients with intermediate staged disease (bulky T2, T3, or node-positive disease) aiming at preserving the larynx. Some centers prefer induction chemotherapy (docetaxel, cisplatin, and fluorouracil) followed by radiotherapy in patients having at least a partial response.
Patients at risk for aspiration or with advanced disease extending through the cartilage are generally not suited for larynx preservation. These patients are treated with laryngectomy followed by adjuvant radiotherapy and, in the presence of extracapsular nodal extension or positive surgical margins, combined with concurrent cisplatin.
When treated properly, few patients with early or intermediate stage laryngeal carcinoma die of the index cancer. Therefore, in addition to tumor eradication, preservation of the natural speech, swallowing function, and avoidance of permanent tracheostomy are major therapy objectives.

SUPRAGLOTTIS CARCINOMA: EARLY STAGE

Treatment Strategy

Primary radiotherapy is preferred for most T1 tumors. The preferred larynx-preserving therapy for T2 tumors depends on the disease and patient characteristics. For lesions that are nonbulky and exophytic, therapy consists of hyperfractionated or concomitant boost radiotherapy.

For T2 lesions, bulky or infiltrating:

Good pulmonary function and general condition: supraglottic laryngectomy or laser resection with or without postoperative radiotherapy.
Medically unfit or technically not suitable for supraglottic laryngectomy: if medically fit for chemotherapy, radiation with concurrent cisplatin or induction chemotherapy (docetaxel, cisplatin, and fluorouracil) followed by radiation; alternatively, hyperfractionated or concomitant boost radiotherapy.

Primary Radiotherapy

Target Volume

Initial target volume:

T1 and T2 NO: larynx, and nodes at levels II to IV (Case Studies 9-1 and 9-2). Within level II, only the subdigastric nodes need be included.
T1 and T2 N1: larynx and nodes at levels II to IV. Level II nodes are covered to the jugular fossa. Posterior level 1B nodes are also included.

For boost volume: primary tumor and, when present, involved nodes with 1- to 2-cm margins.

Setup and Field Arrangement for Conventional Radiotherapy Technique

The patient is immobilized in a supine position with a thermoplastic mask. Marking of shoulders and, when present, involved nodes facilitates portal design. Lateral parallel-opposed photon fields are used to treat the primary tumor and upper neck nodes.

Case Study 9-1

A 57-year-old woman presented with hoarseness, right otalgia, and odynophagia. A biopsy of a 1-cm tumor confined to the right false vocal cord was positive for squamous cell carcinoma. The vocal cord mobility was normal, and there was no palpable adenopathy. Stage: T1 NO MO. She was treated with primary radiation. Treatment started with parallel-opposed fields covering the levels II and III nodes and the primary tumor. An off-spinal cord reduction was made at 42 Gy and treatment continued to 50 Gy. A boost of 16 Gy was delivered to the primary tumor.

Figure 9.1 shows the three pairs of lateral-opposed portals (Fig. 9.1A) and an isodose distribution through the isocenter (Fig. 9.1B). The beams were modified by the use of 30- and 45-degree wedges.

Figure 9.1A,B

Superior border: approximately 2 cm above the angle of mandible when N0 or approximately 1 cm above the tip of mastoid process when N+.
Anterior border: falloff anteriorly; when there is extension into the oropharynx, a generous part of the base of tongue is encompassed in the field.
Posterior border: behind the spinous processes or more posteriorly in the presence of large nodal mass.
Inferior border: depends on the disease extent—middle or bottom of cricoid cartilage for tumors of the epiglottis or false cord; upper trachea when there is subglottic extension (at least 2 cm below inferior tumor extent).

An anterior portal is used to treat the lower neck. It may be necessary to use anterior and inferior tilts for patients with a short neck. In this case, the supraclavicular fossa is included in the primary portal.

Case Study 9-2

A 39-year-old man presented with intermittent hoarseness for 6 months. Examination showed a tumor on the left false cord, extending upward to the left aryepiglottic fold and downward to obliterate the left ventricle. There was no evidence of glottic or pyriform sinus involvement. The mobility of both true vocal cords was normal. There was no palpable neck adenopathy. Biopsy showed moderately differentiated squamous cell carcinoma. Stage: T2 N0 M0. This patient was treated with primary radiotherapy using a hyperfractionation schedule.

The primary tumor and upper and middle neck nodes were treated with lateral parallel-opposed fields (Fig. 9.2). Because the tumor was mainly located in the posterior part of the larynx, it was thought that the anterior skin could be excluded from the boost volume. Lower neck nodes were irradiated through an anterior appositional portal. The primary tumor received 76.6 Gy over 7 weeks (55.2 Gy in 46 fractions for 4.6 weeks + 21.6 Gy in 18 fractions for 2 weeks), uninvolved upper neck nodes 55.2 Gy in 46 fractions over 4.6 weeks, and lower neck nodes 50 Gy in 25 fractions for 5 weeks. He had no evidence of disease and worked full time 3 years after therapy.

Figure 9.2

For boost volume, the lateral fields are reduced to 1- to 2-cm margins around the primary tumor and involved nodes. Nodes overlying the spinal cord can usually receive boost dose through oblique-lateral primary boost portals and those in the lower neck through an appositional electron portal or glancing photon fields.

Dose

For T1 N0 tumors: 50 Gy in 25 fractions to the initial target volume followed by 16 Gy in 8 fractions to the primary tumor. For T1 N1 tumors, an addition 4 Gy in two fractions can be delivered to the neck node with either an appositional electron beam or glancing photon beams.

For T2 N0 or T2 N1 tumors: hyperfractionated or concomitant boost regimen. Hyperfractionation delivers 55.2 Gy in 46 fractions to the initial target volume and then 21.6 Gy in 18 fractions (1.2-Gy fractions, twice daily, 6-h interval); the spinal cord dose is limited to 44.4 to 45.6 Gy or less, and uninvolved posterior cervical nodes are supplemented with 2 Gy daily to approximately 55 Gy. Concomitant boost delivers 1.8-Gy fractions to 54 Gy in 30 fractions to the initial target volume and 1.5-Gy fractions to 15 to 18 Gy given as second daily fractions during the last 2 to 2.5 weeks; the spinal cord dose is limited to 45 Gy or less.

Positive nodes receive doses appropriate for the size and the fractionation schedule used, for example, includes 66 to 70 Gy in 2-Gy fractions, 69 to 72 Gy with concomitant boost, or 74.4 to 79.2 Gy with hyperfractionation. The dose to uninvolved lower neck nodes is 50 Gy in 25 fractions (treated once a day).

Intensity-Modulated Radiation Therapy Planning

Most patients are now treated with IMRT to spare parotid function (see Case Study 9-3). The primary tumor is treated with a minimum of 1-cm margin, though, due to laryngeal motion, it is prudent to encompass the majority of the larynx in the high dose target volume (CTV_HD or CTV1). Involved node(s) with 1-cm margin are also encompassed in CTV_HD. The neck compartments outside CTV_HD with a 2-cm (cranial-caudal) margin are delineated as CTV_ID (CTV2). The remaining nodal levels (II, III, IV, and V) are contoured as CTV_ED (CTV3). Level Ib is included in CTV_ED on the side(s) of lymphadenopathy.

For patients with T2 tumors treated with IMRT, we have used the concomitant boost schedule, which requires two separate plans. The first plan delivers 57 Gy in 30 fractions to CTV_HD and CTV_ID and 54 Gy to CTV_ED, and the second plan is for 18 Gy in 10 fractions to CTV_HD. The fractionation regimen is similar to non-IMRT radiotherapy. If the preference is to deliver treatment with one plan, we prescribe 70 Gy to CTV_HD, 60 to 63 Gy to CTV_ID, and 56 to 57 Gy to CTV_ED to be delivered in 35 fractions over 6 weeks, by administering 6 fractions a week for 5 weeks with a 6-hour interfraction interval on the day when 2 fractions are delivered.

Case Study 9-3

A 63-year-old man, long-time smoker, presented to an otolaryngologist for a benign problem and was incidentally found to have a supraglottic tumor (Fig. 9.3A). The lesion was relatively small and involved the suprahyoid epiglottis and left aryepiglottic fold. There was a small lef subdigastric node noted. Biopsy of the primary tumor was positive for squamous cell carcinoma, and the patient was staged as having a T2 N1 carcinoma.

The patient was treated with IMRT using a concomitant boost schedule. Figure 9.3B shows CTV_HD (red) encompassing the primary tumor (T) with generous margin, CTV_ID (blue) the nodal region immediately below the involved node, and CTV_ED (yellow) the remaining uninvolved neck nodes. More superiorly (Fig. 9.3C) CTV_HD covers the involved node with margin and the inferior base of tongue (superior margin on the primary tumor). CTV_ED covers level IV neck nodes bilaterally (Fig. 9.3D). Isodose distributions are shown on axial (Fig. 9.3E), sagittal (Fig. 9.3F), and coronal (Fig. 9.3G) views. He remains free of disease 2 years later and has an asymptomatic left paramedian epiglottis defect (Fig. 9.3H), approximately at the epicenter of the original tumor.

Figure 9.3A-D

Figure 9.3E-H

Background Data

Table 9.1 Squamous Cell Carcinoma of the Supraglottic Larynx: Control of Primary Lesion by Radiotherapy

Site	Stage
	*1954-1963*				*1964-1972*
	T1	T2	T3	T4	T1	T2	T3	T4
Suprahyoid epiglottis	6/6	3/4	9/13	9/15	3/4	7/7	13/15	3/5
Infrahyoid epiglottis	3/5	5/8	0/0	1/4	5/5	11/12	3/4	1/1
Aryepiglottic folds	2/2	9/11	4/7	1/1	5/5	6/7	3/4	3/6
False cords	3/3	5/6	1/1	0/0	2/2	8/10	0/0	1/1
Arytenoids	0/0	2/3	0/1	0/0	2/2	1/1	0/0	0/0
Total	14/16	24/32^a	14/22^a	11/20	17/18	33/37^a	19/23^a	8/13
Note: Approximately 500 rad higher dose in second period.
^aT2 + T3: 1954-1963, 30% failure rate; 1964-1972, 13% failure rate.
χ² = 4.9386; P <0.05.
Data from the M.D. Anderson Cancer Center. Analysis: August 1976.
Modified from Fletcher GH, Goepfert H. Larynx and pyriform sinus. In: Fletcher GH, ed. Textbook of radiotherapy, 3rd ed. Philadelphia, PA: Lea & Febiger, 1980:330-363, with permission.

Table 9.2 Local Control and Complication Rates Following Radical Radiation of T2-T3, N0 N3 Carcinoma of the Supraglottic Larynx

Radiation Schedules	Local Control
Radiation Schedules	*No. of Patients*	*2 yr*	*5 yr*	*Severe Complication^a(%)*
Hyperfractionation^b (1984-1991)	77	87%	80%	2.7
Standard fractionation^b (1970-1981)	98	78%	70%	3.0
Note: Patients treated in 1982 and 1983 were excluded because some received treatment with conventional fractionation and others with hyperfractionation.
^aRequiring tracheotomy or laryngectomy. ^bP = 0.04.
Data from the M.D. Anderson Cancer Center. Analysis, July 1992.

Table 9.3 T2 to T3 Carcinoma of Supraglottic Larynx

Stage	Anatomically Suitable for Supraglottic Laryngectomy			Anatomically Unsuitable
Stage	*Medically Suitable*	*Medically Unsuitable*	*Total*	Anatomically Unsuitable
T2	35/41 (85%)	14/16 (88%)	49/57 (86%)	44/52 (85%)
T3	9/13 (69%)	8/13 (62%)	17/26 (66%)	17/26 (65%)
Total	44/54 (81%)	22/29 (76%)	66/83 (80%)	61/78 (78%)
Note: Local control following radiotherapy according to medical and anatomic suitability for surgery in 83 patients treated at the University of Florida. This excludes patients who died within 2 yr of radiotherapy with primary site continuously disease free.
Modified from Hinerman RW, Mendenhall WM, Amdur RJ, et al. Carcinoma of the supraglottic larynx: treatment results with radiotherapy alone or with planned neck dissection. Head Neck 2002;24:456-467.

GLOTTIS CARCINOMA: EARLY STAGE

Treatment Strategy

Primary radiotherapy is preferred for most T1 to T2 tumors.

Primary Radiotherapy

Target Volume

The target volume encompasses the larynx proper (sparing suprahyoid epiglottis) (Case Studies 9-4 and 9-5).

Setup and Field Arrangement for Conventional Radiotherapy Technique

The patient is immobilized in a supine position with a thermoplastic mask. Lateral parallel-opposed photon fields are used. In patients with a short neck, a 5- to 10-degree inferior tilt may be necessary to avoid irradiation through the wider part of the shoulder.

Superior border: top of thyroid cartilage for T1 or higher for T2 tumor with supraglottic extension.
Anterior border: approximate 1 cm falloff.
Posterior border: anterior margin of the vertebral bodies.
Inferior border: lower edge of the cricoid cartilage for T1 or lower for T2 tumor with subglottic extension.

Dose

For microscopic disease (e.g., after “stripping” or excisional biopsy of T1 tumors): 60 Gy in 30 fractions.

Other T1 tumors: Several dose fractionation schedules have been described. The key element is that the dose per fraction should be ≥ 2 Gy. Options are 66 Gy in 33 daily fractions or 63 Gy in 28 daily fractions.

T2 tumors: Altered fractionation schedules are preferred. Hyperfractionation to a dose of 76.6 to 79.2 Gy at 1.2 Gy per fraction delivered twice daily (with at least 6 hours between fractions) is an option. An alternative is 70 Gy in 35 fractions over 6 weeks by treating twice daily once per week (6 fractions per week) for 5 weeks.

Bulky T2 tumors: 70 Gy in 35 fractions over 7 weeks with concurrent cisplatin (see T3 tumors below).

The radiation dose is specified at an isodose line. For patients treated with conventional techniques, treatment is usually given with 15- or 30-degree wedges. Differential loading (2:1 or 3:2) maybe used for unilateral lesions.

Intensity-Modulated Radiation Therapy Planning

IMRT is being investigated for carotid artery sparing (Case Study 9-6). The CTV is the entire larynx excluding the suprahyoid epiglottis. The superior and inferior borders are similar to those used for conventional therapy.

Case Study 9-4

A 66-year-old man presented with a 6-month history of progressive hoarseness. Examina tion showed mild edema and leukoplakia of the anterior commissure and the anterior one third of both true vocal cords. There was no supraglottic or subglottic spread, and vocal cord mobility was normal. No lymph nodes were palpated in the neck.

Biopsies showed microinvasive squamous cell carcinoma on both true vocal cords. Stage: T1 N0 M0. The patient was treated with lateral parallel-opposed fields (Fig. 9.4). A dose of 64 Gy specified in the isocenter was delivered in 2-Gy fractions. After a dose of 50 Gy, the posterior border was moved 1 cm anteriorly to reduce the dose to the arytenoids. A 15-degree wedge was used to produce a slight dose gradient delivering a higher dose to the thickest part of the lesion at the anterior third of the cords. He had no evidence of disease and had good voice quality 4 years after therapy.

Figure 9.4

Case Study 9-5

A 52-year-old woman who smoked cigarettes presented with hoarseness. Examination revealed a tumor involving the entire length of the right true vocal cord. The vocal cord mobility was normal, and the tumor did not extend into the supraglottic or subglottic larynx. A biopsy was positive for invasive squamous cell carcinoma. Stage: T1 N0 M0. She was treated with primary radiation to the larynx only. Parallel-opposed fields were used to deliver a dose of 66 Gy in 33 fractions. Figure 9.5 shows the digitally reconstructed portal radiograph (Fig. 9.5A) and the isodose distribution through the larynx (Fig. 9.5B). A combination of 30- and 45-degree wedges was used to modify the beam, and the dose was delivered preferentially from the right side.

Figure 9.5A,B

Case Study 9-6

This 66-year-old patient was diagnosed with squamous cell carcinoma of the larynx, stage T1 N0, and was treated with IMRT.

Figure 9.6 shows an axial CT slice with the CTV_HD outlined in red (Fig. 9.6A), a sagittal image outlining the superior and inferior borders of the CTV_HD (Fig. 9.6B

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