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Laryngeal Cancer Overview

Epidemiology

 * ~10K cases/year in the U.S.
 * ~2% of all cancers; most common upper aerodigestive tract cancer
 * Risk factors: tobacco, extensive use of voice
 * 40% locally advanced

Pathology

 * 95% squamous cell CA; usually well-moderately well differentiated
 * 1-2% verrucous CA; bulky, exophytic, heavily keratinized

Anatomy

 * For clinical staging, larynx consists of three regions: supraglottis, glottis, and subglottis
 * The external structure is formed by hyoid bone, thyroid cartilage and cricoid cartilage
 * Internal structure is formed by the epiglottis and the arytenoid, corniculate, and cuneiform cartilages
 * The epiglottis is joined superiorly to the hyoid bone by the hyoepiglottic ligament and inferiorly to the thyroid cartilage by the thyroepiglottic ligament (just below the thyroid notch and above the anterior commissure)
 * The vocal ligaments and muscles attach to the vocal process of the arytenoid posteriorly and the thyroid cartilage anteriorly. Beneath the epithelium of the free edge of the vocal cord is the lamina propria
 * The intrinsic muscles of the larynx control the movement of the cords; the extrinsic muscles control primarily swallowing. The intrinsic muscles are innervated by the recurrent laryngeal nerve, except for cricothyroid muscle, which is innervated by the superior laryngeal nerve
 * Supraglottis:
 * Sites: Suprahyoid epiglottis (suprahyoid and infrahyoid), aryepiglottic folds, arytenoids, false cords
 * Inferior border: horizontal plane passing through lateral margin of the ventricle
 * Lymphatics: Rich network, pass through thyrohyoid membrane into subdigastric, midjugular, and lower jugular nodes
 * Glottis
 * Sites: true vocal cords, anterior and posterior commissures
 * Vocal cords are 3-5 mm thick
 * Inferior border: 5 mm below free margin of vocal cords
 * Horizontal plane 1 cm in thickness
 * Lymphatics: True vocal cords don't have any; lymphatic spread via tumor extension to supraglottis or subglottis
 * Subglottis
 * Anatomy: 5mm below the free margin of true vocal cords to inferior margin of cricoid cartilage
 * Lymphatics:
 * Larynx is formed from two embryologically defined regions, separate at laryngeal ventricle, with different lymphatic patterns
 * Supraglottis forms from primitive buccopharyngeal anlage and as such as rich lymphatics that drain to upper internal jugular LNs. Supraglottic tumors have therefore much higher incidence of nodal mets at presentation
 * Glottis and subglottis form from tracheobronchial buds and as such have sparse lymphatics that drain to internal jugular and paratracheal LNs. Channels unite to form one anterior and two posterolateral pedicles. Anterior drains through cricothyroid membrane into mid- and lower jugular nodes, or via prelaryngeal node into pretracheal and supraclavicular LNS. Posterior drain through cricotracheal membrane into paratracheal nodes

Treatment Overview

 * Supraglottis
 * LN+ 55% (commonly subdigastric and midjugular), 16% bilateral
 * Supraglottis Page


 * Glottis
 * Glottis Page
 * Most common laryngeal cancer in USA. Majority occur in anterior 2/3 of vocal cords
 * Symptoms - persistent hoarseness, later dyspnea, chronic cough, hemoptysis, stridor
 * LN+ <2% in T1, 5% in T2, 15-20% in T3, 20-30% in T4
 * Treatment:
 * No randomized trials comparing surgery to RT to laser resection
 * For T1-T2: local control, laryngeal preservation, and survival comparable after laser resection, RT, and partial laryngectomy. Voice quality comparable with laser resection and RT in smaller lesions, worse in larger lesions after partial laryngectomy. Therefore recommendation for T1 and T2 with normal cord mobility treated with RT or laser resection for superior voice preservation. Bulky T2 and impaired cord mobility treated with RT or partial laryngectomy
 * Neck dissection in T1-T2 is controversial
 * RT fields:
 * T1 and early T2 - two small opposing lateral fields centering on vocal cords, parallel to trachea. From upper thyroid notch to lower border of the cricoid (at C6). Anterior border 1 cm anterior to the skin surface at the level of vocal cords. Posterior border to include anterior portion of posterior pharyngeal wall. 5 x 5 cm2 field usually good.


 * Subglottis
 * Subglottis Page
 * Primary lesions are rare (<3%); usually extension from glottis. 50-70% are SCC
 * Symptoms - usually asymptomatic, but can present with horseness, dyspnea, stridor
 * Disease often advanced at presentation; thorcacic cavity involved in T3-T4(~50%)
 * LN+ in 20-50%
 * Treatment - no consensus due to small numbers, but Toronto reports good experience with primary RT
 * Stage I-II: RT (include lower neck and mediastinum)
 * Stage III-IV: surgery (include larynx, thyroid, parastomal LNs), post-op RT if LN+ (include lower neck and mediastinum)
 * RT fields - lateral opposed fields inferiorly 2cm below primary tumor, superiorly encompassing upper jugular nodes. Also an anterior low neck and upper mediastinum T-field

Surgery, or post-op RT

 * Overall survival for advanced (Stage III-IV) cancer treated with laryngectomy or laryngectomy + post-op RT was 0-50% at 5-years.
 * Results in functional morbidity: loss of voice, swallowing, permanent tracheostomy.
 * Partial laryngectomy that spares the voice for selected T3N0 pts

Organ preservation

 * Historically, total laryngectomy was the standard of care for advanced cancers of the larynx and hypopharynx
 * A landmark VA Larynx Trial showed that induction chemotherapy + RT had equivalent larynx preservation and survival rate as total laryngectomy + postop RT. This concept was confirmed in hypopharynx by EORTC 24891, though a small GETTEC trial that closed early showed survival benefit for laryngectomy + postop RT
 * Concurrent chemo-RT was shown to be superior to induction chemotherapy + RT or RT alone in RTOG 91-11
 * T4 larynx management continues to be based on VA larynx trial. Odds ratio of responding to induction chemotherapy was 5.6 for T1-3 vs T4 (p=0.01), and in the subset of patients who then underwent RT, salvage laryngectomy was required in 56% vs. in 28% of T3 tumors. However, the absolute number of these patients was very small. In clinical practice, patients with T4 larynx are not typically considered candidates for larynx preservation

Prognostic factors
Size:
 * University of Florida, 1997 (1966-94) - PMID 9196155 &mdash; "Definitive radiotherapy for T3 squamous cell carcinoma of the glottic larynx." Mendenhall WM et al. J Clin Oncol. 1997 Jun;15(6):2394-402.
 * Volume measured by CT scan correlated with LC. 87% LC for < 3.5 cm3 vs 29% for > 3.5 cm3.

Radiation alone

 * In selected patients (T3N0) results in 40-70% larynx preservation rate and survival similar to that with surgery
 * In advanced cases, radiation alone (with surgical salvage) results in worse survival

Laryngectomy + postop RT vs. Chemo-RT

 * Singapore (1996-2000) -- Surgery + postop RT vs. concurrent chemo-RT
 * Randomized. Stopped early due to slow accrual. 199 patients, resectable Stage III/IV SCHNC excluding NPC and salivary glands (larynx 32% (supraglottis 23%), oral cavity 27%, oropharynx 21%, hypopharynx 12%). T4 56%. Arm 1) surgery + adjuvant RT 60/30 vs. Arm 2) RT 66/33 + concurrent cisplatin 20 mg/m2 + 5-FU 1000 mg/m2 x2 cycles. 90% received at least 1 cycle of chemo
 * 2005 PMID 16012523 -- "Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison." (Soo KC, Br J Cancer. 2005 Aug 8;93(3):279-86.) Median F/U 6 years
 * Outcome: 3-year DFS: S+RT 50% vs. chemo-RT 40% (NS). Organ preservation (larynx/hypopharynx 68%, oropharynx 55%, oral cavity 21%). Chemo-RT group had poor surgical salvage of 47%, with no long-term survivors (possibly due to larger proportion of T4 and oral cavity cancers)
 * Conclusion: Chemo-RT not superior to surgery+RT, but can be attempted for organ preservation in larynx, hypopharynx, and oropharynx


 * GETTEC (1986-1989) -- total laryngectomy + postop RT vs induction chemo + RT
 * Randomized. Trial stopped prematurely because patients refused laryngectomy. 68 patients. Larynx, T3N0-N2b. Supraglottic larynx or resectable disease not eligible. Arm 1) Total laryngectomy, if N0 then modified neck dissection, if N+ then radical neck dissection followed by post-op RT. Postop RT 50 Gy if SM- and LN-; else 65-70 Gy vs. Arm 2) Induction chemo cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 Q3W x3 cycles, followed by RT 65-70 Gy (36%). If tumor progression on chemo, received total laryngectomy (55%)
 * 1998 PMID 9692058 -- "Randomized trial of induction chemotherapy in larynx carcinoma." (Richard JM, Oral Oncol. 1998 May;34(3):224-8.) Median F/U 8.3 years
 * Outcome: Induction 55% progressed and required laryngectomy. 2-year OS induction 69% vs. laryngectomy 84% (SS)
 * Conclusion: Larynx preservation cannot be considered a standard treatment at the present time

Chemo-RT vs. RT Alone

 * EORTC 24954 (1996-2004) -- Sequential chemo-RT vs. alternating chemo-RT
 * Randomized. 450 patients. Larynx T2-T4 N0-N2 (21% by AJCC staging) or Hypopharynx T2-T4 N0-N2 (79% by AJCC staging), surgical candidates for total laryngectomy not requiring flap closure. Excluded if candidates for partial laryngectomy. Arm 1) Sequential chemo->RT. Induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 x4 cycles followed by RT 70 Gy; if stable/progression on chemo, total laryngectomy vs Arm 2) Alternating chemo->RT. Cisplatin 20 mg/m2 + 5-FU 200 mg/m2 x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week (based on prior Italian randomized data)
 * 6-years; 2009 PMID 19176454 -- "Phase 3 Randomized Trial on Larynx Preservation Comparing Sequential vs Alternating Chemotherapy and Radiotherapy." (Lefebvre JL, J Natl Cancer Inst. 2009 Jan 27. [Epub ahead of print]) Median F/U 6.5 years
 * Outcome: Larynx preservation sequential 1.6 years vs. 2.3 years (NS); 5-year larynx preservation 30% vs. 36% (NS). Median OS sequential 4.4 years vs. alternating 5.1 years (NS); median PFS 3.0 vs 3.1 years (NS). DSS ~50%. Salvage surgery sequential 30% vs. alternating 22%. No difference in patterns of relapse
 * Toxicity: Grade 3-4 mucositis sequential 32% vs. alternating 21%; late fibrosis 16% vs. 11%
 * Conclusion: Both strategies valid for larynx preservation
 * Editorial (PMID 19176460): larynx preservation defined as survival with larynx without tumor, tracheotomy or use of feeding tube, which gives these states equal utility as death; other issues with endpoints used for larynx preservation. Need a common standardized endpoint

Practice Guidelines

 * ASCO; 2006 PMID 16832122 -- "American Society of Clinical Oncology clinical practice guideline for the use of larynx-preservation strategies in the treatment of laryngeal cancer." (ASCO, J Clin Oncol. 2006 Aug 1;24(22):3693-704.)