# Radiation Oncology/Head & Neck/Larynx/Overview

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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 has 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
* Indications for post-op RT:
** NCCN (2010)
*** pT4
*** N2-N3
*** PNI+
*** LVI+
** Perez (5th ed, p982)
*** Close or positive margins
*** Significant subglottic extension (1 cm or more)
*** Cartilage invasion
*** Perineural invasion
*** Endothelial-lined space invasion
*** Extension of the primary tumor into the soft tissues of the neck
*** Multiple positive neck nodes
*** Extracapsular extension
*** Control of subclinical disease in the opposite neck

## Larynx 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 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. Larynx preservation rate was superior with RTCT (Veterans 91)
* 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 — "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. 119 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. Glottic larynx, T3N0-N2b, fixed vocal cords. Supraglottic larynx or resectable disease not eligible (different population than VA Larynx trial). 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
* VA Larynx Trial (1985-1989) - Total laryngectomy + postop RT vs. induction chemo + RT
** Randomized. 332 patients. Stage III or IV (excluding T1N1) cancer of the glottic or supraglottic larynx (63% supraglottic). Arm 1) Classic wide-field total laryngectomy, regional LND + postop RT vs. Arm 2) Induction chemo (cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 Q3W x3 cycles) + radical RT. If not at least a PR to chemo after 2nd cycle, underwent surgery and post-op RT. Primary RT 66-76 Gy and neck 50-75 Gy depending on nodal size. Assessed 12 weeks after RT and had salvage laryngectomy if residual disease in larynx or neck dissection for residual nodal disease. Postop RT 50 Gy to microscopic disease, 60 Gy to high risk areas, and 65-74 Gy to residual disease.
** 2-years; 1991 PMID 2034244 — "Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer." (The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med. 1991 Jun 13;324(24):1685-90.) Median F/U 2.7 years
*** Outcome: 2-year OS chemo-RT 68% vs surgery+RT 68% (NS); DFS (NS) but but pattern of recurrence differed, with more recurrence at the primary site (12% vs 2%) in chemo/RT group vs more distant mets in surgery group (17% vs 11%).
*** Larynx preservation: Overall 64%. Laryngectomy 18% after induction alone, 11% after induction + RT for persistent tumor, 7% for recurrent tumor (majority within 1st year). Salvage laryngectomy T3 29% vs. T4 56% (SS), Stage III 29% vs. Stage IV 44% (SS)
*** Conclusion: Induction chemotherapy and radiation can be effective in preserving larynx, without compromising survival
** 3-years; 1993 PMID 8221647 -- "Recent advances in head and neck cancer--larynx preservation and cancer chemoprevention: the Seventeenth Annual Richard and Hinda Rosenthal Foundation Award Lecture." (Hong WK, Cancer Res. 1993 Nov 1;53(21):5113-20.)
*** Nice overview of larynx preservation history. 3-year outcome induction chemo 56% vs. surgery-RT 53% (NS). Survival for patients who failed induction chemo and underwent laryngectomy (18%) comparable. Larynx preservation 62%, improved swallowing.
** No difference in survival at 10 years of follow-up. (later paper)

### 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
* RTOG 91-11 / Intergroup (1992-2000) -- Sequential chemo -> RT vs. concurrent chemo-RT vs. RT alone
** Randomized, 3 arms. 518/547 patients. Stage III or IV cancers of the glottic or supraglottic larynx, which would require total laryngectomy. Excluded T1 and large volume T4 (penetrating through cartilage or >1cm into BOT). Arm 1) Induction cisplatin 100 mg/m2 + 5-FU C.I. 1000 mg/m2 Q3W x3 cycles, followed by RT (if CR or PR) or laryngectomy if poor response (this Arm based on results of the VA Larynx trial) vs. Arm 2) Concurrent cisplatin 100 mg/m2 Q3W + RT vs. Arm 3) RT alone. RT dose was 70/35, elective neck and SCV 50/25. Patient in the first arm who had salvage surgery for poor response to chemo received adjuvant RT to 50-70 Gy depending on surgical margin status. Planned lymph node dissection was performed for LN > 3cm or multiple lymph nodes at original staging. In induction group, 83% continued to RT and most of others received more chemotherapy or RT but not surgery. End point was preservation of larynx
** ASTRO; 2002 Webcast: Moshe Maor Discussion: Louis Harrison
** 4-years; 2003 - PMID 14645636 — "Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer." (Forastiere AA et al. N Engl J Med. 2003 Nov 27;349(22):2091-8.) Median F/U 3.8 years
*** Larynx preservation: induction 72% (SS) vs. concurrent 84% vs. RT alone 67% (SS). No benefit to induction chemo over RT alone. Laryngectomy-free survival at 2-years and 5-years was 59%/43% (induction), 66%/45% (concurrent), and 53%/38% (RT alone), with no S.S. difference between the two chemo groups but a S.S. difference between concurrent and RT alone. There was no difference in LFS between the two chemo arms due to an increase in intercurrent deaths for the concomitant group.
*** Speech & swallow: 2-year moderate+ impediment induction 3% vs. concurrent 6% vs. RT alone 8% (NS)
*** Outcome: 2-year OS induction 76% vs. concurrent 74% vs. RT alone 75% (NS). 5-year OS 55% vs. 54% vs. 56% (NS). LC 64% (SS) vs. 80% vs. 56% (SS), no benefit for induction over RT alone. DM induction 9% vs. chemo-RT 8% vs. RT alone 16% (SS)
*** Toxicity: Grade 3-4 induction chemo 24% vs. concurrent chemo 30% vs. RT alone 36% (NS); treatment-related deaths 3% vs. 5% vs. 3%
*** Conclusion: Larynx preservation best with concurrent chemo; distant mets reduced by chemotherapy.
** Salvage Laryngectomy; 2003 PMID 12525193 — "Outcome of salvage total laryngectomy following organ preservation therapy: the Radiation Therapy Oncology Group trial 91-11." (Weber et al. Arch Otolaryngol Head Neck Surg. 2003 Jan;129(1):44-9.)
*** Outcome: Total laryngectomy induction 28% vs. concurrent 16% vs. RT alone 31% (SS). Complication rate 52-59% (NS), pharyngocutaneous fistula 15-30%. LRC 74% vs. 74% vs. 90%. 2-year OS 69% vs. 71% vs. 76% (NS)
*** Conclusion: Laryngectomy following organ preservation treatment has acceptable morbidity. Survival not influenced by initial organ preservation strategy
** 5-years; 2006 ASCO Abstract -- "Long-term results of Intergroup RTOG 91-11: A phase III trial to preserve the larynx--Induction cisplatin/5-FU and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy." (Forastiere AA, Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 5517)
*** Outcome: 5-year laryngectomy-free survival I+RT 45% vs CRT 47% vs. RT 34% (SS). Laryngeal preservation 70% vs. 84% vs 66% (SS). LRC 55% vs 69% vs 51% (SS). CRT significantly better than I+RT or R. DM low 14% vs. 13% vs 22% (NS). OS 59% vs. 55% vs. 53% (NS)
*** Conclusion: Concurrent chemo-RT superior treatment in terms of larynx preservation and locoregional control, but no difference in 5-year overall survival
** 10-years; 2012 PMID 23182993 -- "Long-Term Results of RTOG 91-11: A Comparison of Three Nonsurgical Treatment Strategies to Preserve the Larynx in Patients With Locally Advanced Larynx Cancer." (Forastiere AA, J Clin Oncol. 2013 Mar 1;31(7):845-52)
*** Median f/u 10.8 yr. Both chemo/RT regimens improved LFS compared with RT alone (HR 0.75 induction, 0.78 concomitant). No significant difference in OS. Concomitant chemo/RT improved larynx preservation rate over induction chemo/RT (HR 0.58) and RT alone; induction chemo/RT was not better than RT alone.
*** No difference in late effects, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemo/RT (30.8% vs 20.8% induction vs 16.9% RT alone).
*** Conclusion: "induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS. Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone. New strategies that improve organ preservation and function with less morbidity are needed."

### Re-Examination of Larynx Preservation

* Editorial; 2010 PMID 19953627 -- "Reexamining the treatment of advanced laryngeal cancer." (Olsen KD, Head Neck. 2010 Jan;32(1):1-7.)
** Larynx preservation inappropriate in many patients, survival worsening
** Reply; 2010 PMID 19953621 -- "Reexamining the treatment of advanced laryngeal cancer: the VA laryngeal cancer study revisited." (Wolf GT, Head Neck. 2010 Jan;32(1):7-14.)
** Reply; 2010 PMID 19953631 -- "Larynx preservation and survival trends: should there be concern?" (Forastiere AA, Head Neck. 2010 Jan;32(1):14-7.)

### 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.)

## Other Resources

* ARRO Case - Supraglottic Larynx