# Radiation Oncology/Head & Neck/Larynx/Glottis

Glottic Larynx
* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

## Overview

* Anatomy - true vocal cords, anterior and posterior commissures down to 5 mm below free margin of vocal cords
* Most common laryngeal cancer in USA. Majority occur in anterior 2/3 of vocal cords
* Symptoms - persistent hoarseness, later dyspnea, chronic cough, hemoptysis, stridor
* Staging
** T1 - limited to vocal cords, with normal mobility
*** T1a - limited to one vocal cord
*** T1b - involves both vocal cords
** T2 - extends to supraglottis or subglottis, and/or with impaired vocal cord mobility
** T3 - vocal cord fixation or invades paraglottic space or minor thyroid cartilage erosion
** T4 - invades through other tissues (thyroid cartilage, thyroid, trachea, pharynx, etc)
*** T4a - invades through thyroid cartilage or tissues beyond the larynx
*** T4b - invades prevertebral space, carotid, mediastinum
* Lymphatics - true vocal cords don't have any; lymphatic spread via tumor extension to supraglottis or subglottis
** 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.

## Outcomes

* Florence; 2005 (1970-1999) PMID 16095847 -- "Radical radiotherapy for early glottic cancer: Results in a series of 1087 patients from two Italian radiation oncology centers. I. The case of T1N0 disease." (Cellai E, Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1378-86.)
** Retrospective. 831 T1 glottic patients in 2 institutions. RT: two lateral parallel opposed or slightly angled photon beams with or without wedges or a direct anterior electron field.
** Outcome: 5-year OS (10-year OS): 77% (57%); local control 84% (83%), salvage 95% (93%)
** Predictors of local control: gender, tumor extent, anterior commissure involvement, beam type, dose >65 Gy
** 20-year second tumor probability: 23% (second tumor deaths > laryngeal tumor deaths)
** Conclusion: Use doses >65 Gy and field size 36-49 cm2
* Florence; 2005 (1970-1999) PMID 16115737 -- "Radical radiotherapy for early glottic cancer: Results in a series of 1087 patients from two Italian radiation oncology centers. II. The case of T2N0 disease." (Frata P, Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1387-94.)
** Retrospective. 256 T2 glottic patients in 2 institutions. RT: two lateral parallel opposed or slightly angled photon beams with or without wedges or a direct anterior electron field.
** Outcome: 5-year OS (10-year OS): 59% (37%); local control 73% (70%), salvage 86% (85%)
** Predictors of local control: bulky tumor, impaired cord mobility
** 20-year second tumor probability: 23% (laryngeal tumor deaths > second tumor deaths)
** Conclusion: Consider RT a standard treatment for T2. Late damage infrequent
* Aviano; 2003 PMID 12910521 -- "Radiotherapy for patients with early-stage glottic carcinoma: univariate and multivariate analyses in a group of consecutive, unselected patients." (Franchin G, Cancer. 2003 Aug 15;98(4):765-72.)
** Retrospective. 410 patients with T1-T2 SCC treated 1986-2001
** 10-year OS (5-year): 64% (83%); median time to recurrence 7 months
** Predictors of local control: persistent dysphonia, year of RT
** 22% rate of 2nd primary malignancy -> major cause of death; only 2 died of laryngeal CA
* U Florida; 2001 PMID 11600604 -- "T1-T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy." (Mendenhall WM, J Clin Oncol. 2001 Oct 15;19(20):4029-36.)
** Retrospective. 519 patients with T1-T2
** 5-year local control: T1 93-94%, T2 72-80%; low complications
** Predictors of local control: overall treatment time, T-stage, grade

## Carcinoma in situ

RT for treatment of carcinoma in situ of the glottic larynx:
* U.Florida; 2002 (1967-1998) PMID 11933181 -- "Radiotherapy for carcinoma in situ of the true vocal cords." (Garcia-Serra A, Head Neck. 2002 Apr;24(4):390-4.)
** 30 pts; 2/3rd of referred pts had recurrence after at least one stripping procedure.
** 5-yr LC, LC with preservation, ultimate LC (including salvage surgery): 88%, 88%, 100%
** 10% treated pts had local failure with Invasive squamous cell carcinoma (14 mo, 34 mo and 48 months later)
** Conclusion: "RT to approximately 60 Gy at 2.25 Gy per fraction using small (5 x 5 cm) fields produces excellent results with CIS of the TVC."
* U.Florida; 1993 (1964-1990) PMID 8407413 -- "Carcinoma in situ of the glottic larynx: the role of radiotherapy." (Fein DA, Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):379-84.)
** 19 pts; minimum of 2 yrs f/u. Previous procedures: biopsy only in 4, 11 patient with 1 stripping procedure, 4 pts with 2-5 strippings. RT doses 5625 cGy - 6300 cGy (median: 5625 cGy).
** 5-yr LC, ultimate LC, and LC w/ voice preservation: 93%, 100%, 93%.
** Literature review: local control rates after primary treatment with RT, laser resection, and vocal cord stripping were 84%, 68%, and 66%.
** Conclusion: "Primary treatment with radiotherapy should be strongly considered for patients with carcinoma in situ of the true-vocal cord who have a recurrence after vocal cord stripping or who cannot have close follow-up after treatment."

## Fractionation
### Randomized

* Osaka (Japan)(1993-2001) -- RT 2 Gy/fx (60-66 Gy) vs. RT 2.25 Gy/fx (56.25-63 Gy)
** Randomized. 180 patients with glottic T1N0. Arm 1) RT 60/30 (small tumors) or 66/33 (large tumors) @ 2 Gy/fx over ~46 days vs. Arm 2) RT 56.25/25 (small tumors) or 63/28 (large tumors) @ 2.25 Gy/fx over ~39 days. Parallel opposed fields with individualized wedge-filtered technique, majority 5x5 cm
** 5-years; 2006 PMID 16169681 -- "Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time." (Yamazaki H, Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):77-82. Epub 2005 Sep 19.)
*** Outcome: 5-year LC 2 Gy/fx 77% vs. 2.25 Gy/fx 92% (SS); CSS 97% vs. 100% (NS)
*** Late Toxicity: no severe late toxicity, no difference in early/minor late toxicity
*** Conclusion: Use of 2.25 Gy/fx with shorter overall treatment time showed superior local control compared to conventional 2 Gy/fx, without worse toxicity
* RTOG 95-12 / EORTC 22992 -- 70/35 vs. 79.2/66 @ 1.2 Gy BID
** Randomized. 250 patients. T2a-bN0 vocal cord. Modified AJCC staging: T2a - tumor extends to supraglottic and/or subglottic structures without impaired mobility; T2b - tumor causes impaired mobility. Randomized SFX 70 Gy (2 Gy/fx) vs HFX 79.2 Gy (1.2 Gy BID). Boost after 50 Gy (std fx) or 60 Gy (BID). Primary fields: (minimum) 6x6 cm field, centered over mid-thyroid cartilage. Upper border 0.5-1 cm above thyroid notch, posterior border 1 cm behind thyroid cartilage, inferior border at the bottom of the cricoid cartilage, and 1 cm fall off anteriorly. Larger field sizes may be needed to obtain 2 cm margins around the primary. No elective nodal irradiation. Boost includes tumor plus 1 cm margin. Boost may reduce posteriorly off the arytenoids if the posterior 1/3 of the cord is not involved by tumor. Bolus (2-5mm) may be used over the anterior larynx for anterior tumors.
** 2006 ASTRO Abstract "A Randomized Trial of Hyperfractionation vs. Standard Fractionation In T2 Squamous Cell Carcinoma of the Vocal Cord" (Trotti A, IJRBOP Volume 66, Issue 3, Supplement 1, 1 November 2006, Page S15)
*** 5-year outcome: LC HFX 79% vs. SFX 70% (NS); DFS 51% vs. 37% (NS); OS 73% vs. 62% (NS)
*** Toxicity: HFX modestly higher acute skin, mucosal, and laryngeal toxicity; high grade late effects uncommon
*** Conclusion: Local control modestly higher, but with only 58 failures, don't have sufficient power
** Comment: SFX relatively low

### Retrospective

* New Zealand; 2006 (1986-1998) PMID 16635034 -- "TN/TN glottic carcinoma: a comparison of two fractionation schedules." (Short S, Australas Radiol. 2006 Apr;50(2):152-7.)
** Retrospective. 145 patients with T1-T2 glottis. RT 6MeV beams, standard fractionation (SFX) 60-66 Gy in 30-33 fx (2 Gy/fx) over 6-6.5 weeks (1986-1992) vs. accelerated/hypofractionated regimen (AHFX) 52.5-55 Gy in 20 fx (2.75 Gy/fx) over 4 weeks. Median F/U 4.9 years
** 5-year OS: 78%, toxicity comparable
** T1N0: loco-regional control AHFX 95% vs. SFX 75% (SS), 5-year laryngectomy-free survival AHFX 95% vs. SFX 75% (SS)
** T2N0: loco-regional control AHFX 81% vs. SFX 80% (NS), 5-year laryngectomy-free survival AHFX 92% vs. SFX 80% (NS)
** Conclusion: Accelerated hypofractionation better for T1, same for T2. Comparable toxicity.
* MD Anderson; 2003 PMID 12527044 -- "Results of radiotherapy for T2N0 glottic carcinoma: does the "2" stand for twice-daily treatment?" (Garden AS, Int J Radiat Oncol Biol Phys. 2003 Feb 1;55(2):322-8.)
** Retrospective. 230 patients with T2, treated 1997-1998. Median f/u 82 months
** RT: 180 patients treated with parallel-opposed fields. 89 patients treated with 2 Gy/fx to 32-75 Gy, 57 patients treated with 2-2.2 Gy to 66-70 Gy, and 81 patients treated with BID fxs to 74-80 Gy
** 5-year local control: 72% (91% after salvage); BID fxs 79% vs. QD fxs 67% (p=0.06)
** Predictors of local control: subglottic extension, daily dose <=2 Gy/fx
** Conclusion: BID to 77 Gy better than QD to 70 in 2 Gy/fx in T2N0
* Poland; 1999 PMID 9989520 -- "Clinical radiobiology of glottic T1 squamous cell carcinoma." (Skladowski K, Int J Radiat Oncol Biol Phys. 1999 Jan 1;43(1):101-6.)
** Retrospective. 235 patients with T1N0 treated by RT alone. RT conventional 5-day schedule, dose 51-70 Gy, dose/fx 1.5-3.0 Gy/fx, on-treatment time 24-79 days. Median f/u 4 years
** Outcome: 5-year LC 84%
** Predictors of control: worse if dose <61 Gy, increase in treatment time 45 to 55 days decreased TCP by 13%. Potential doubling time: 5.5 days. Hemoglobin: drop in 1g/dl resulted in TCP decrease by 6%
** Conclusion: The significant correlation between the total dose, overall treatment time, hemoglobin concentration, and tumor control probability has been found for T1 glottic cancer
* Amsterdam; 1998 (1965-92) PMID 9788401 -- "The impact of treatment time and smoking on local control and complications in T1 glottic cancer." (van der Voet JC, Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):247-55.)
** Retrospective, 383 pts with T1N0 treated with 6 different fractionations. 65 Gy (20 x 3.25 Gy), 62 Gy (20 x 3.1 Gy), 61.6 Gy (22 x 2.8 Gy), 60 Gy (25 x 2.4 Gy), 66 Gy (33 x 2 Gy) and 60 Gy (30 x 2 Gy), all at 5 fx/week.
** 5-yr LRC 89%. Larynx preservation 90% at 10 yrs. Local control decreased with increasing treatment time: 5-year LC 95% for 22-29 days (i.e. 20 fractions) vs 79% for >= 40 days (i.e 28 fractions or more). Larynx preservation by treatment: 20 x 3.25 Gy: 97%; 20 x 3.1 Gy: 96%; 22 x 2.8 Gy: 92%; 25 x 2.4 Gy: 89%; 33 x 2 Gy: 78%; and 30 x 2 Gy: 80%.
** Complications: all grades, 15%, did not vary by treatment factors but did vary by smoking, neck diameter, and tumor extension.
** Conclusion: overall treatment time is a significant factor for local control
* UCSF; 1997 (1956-1995) PMID 9300746 -- "Influence of fraction size, total dose, and overall time on local control of T1-T2 glottic carcinoma." (Le QT, Int J Radiat Oncol Biol Phys. 1997 Aug 1;39(1):115-26.)
** Retrospective. 398 patients with T1-T2 glottic cancer, daily RT. Tumor dose 46.6 - 77.6 Gy (median 63 Gy). Median F/U 9.7 years
** Outcome: 5-year LC T1 85%, T2 70%.
** T1 subset: No impact of size/schedule. Anterior commisure involvement 80% vs. none 88%. If treated in 1981-1995, 91%
** T2 subset: Treatment time <=43 days 100% vs. >43 days 84%; Fraction size <1.8 Gy 44% vs. >=2.25 Gy 100%; Total dose <=65 Gy 60% vs. >65 Gy 78%; normal cord mobility 79% vs. impaired cord mobility 45%; subglottic extension 58% vs. no subglottic extension 77%
** Toxicity: severe 1.8%
** Conclusion: Risk factors evaluated for T1 and T2 glottic cancers
* Robert Wood Johnson; 1988 PMID 3343152 -- "The effect of fraction size on control of early glottic cancer." (Schwaibold F, Int J Radiat Oncol Biol Phys. 1988 Mar;14(3):451-4.)
** Retrospective. 58 pts with Stage I tumors. Of 28 pts treated with 180 cGy fractions (median dose 66.6 Gy, range 63-70.2 Gy), 25% LR in 3 yrs, vs no failures in pts treated with fraction size of 200 cGy or more (median dose 66 Gy).
** Conclusion: suggests fraction size of 200 cGy or higher is a significant factor in the control of glottic cancer

## Field Size

* Osaka (Japan)(1982-1992) -- RT 5x5 cm vs. RT 6x6 cm
** Randomized. 273 patients with T1N0 glottic cancer, treated with RT 4 MV bilateral portals. Arm 1) field size 5x5 cm vs. Arm 2) field size 6x6 cm. Dose 60/30
** 5-years; 1996 PMID 8721266 -- "Radiation therapy for early glottic carcinoma (T1N0M0). The final results of prospective randomized study concerning radiation field." (Chatani M, Strahlenther Onkol. 1996 Mar;172(3):169-72.)
*** Outcome: 5-year RFS 5x5 88% vs 6x6 88% (NS)
*** Toxicity: acute toxicity same (NS); late toxicity 5x5 17% vs. 6x6 23% (SS)
*** Conclusion: Small field (5x5 cm) is recommended

## Specific Situations

Anterior commissure extension
* 2004 Lausanne PMID 14762660 -- Decreased local control following radiation therapy alone in early-stage glottic carcinoma with anterior commissure extension. (Zouhair A, Strahlenther Onkol. 2004 Feb;180(2):84-90.)
** Retrospective. 122 patients with T1-T2N0 treated 1983-2000; median f/u 85 months
** RT: 3D-CRT in 40%, median dose 70 Gy in 2Gy/fx over 46 days
** 5-year OS: 80%, DFS 70%; median time to recurrence 13 months. Only 6 died of laryngeal CA
** Poor predictors of local control: anterior commissure extension, arytenoid protection, male gender
Subglottic extension
* 1997 Louisiana State PMID 9192435 -- Glottic cancer with subglottic extension. (Ampil FL, Radiat Med. 1997 Mar-Apr;15(2):103-7.)
** Retrospective. 27 patients over 13 years. Surgery + RT (60%), RT alone (40%)
** Locoregional failure: 18% in surgery + RT, 40% in RT alone (NS)
** 2-year OS: 53% surgery + RT, 42% RT alone (NS)
** Recommend: surgery + RT
Quality-of-life
* PMID 15936548 -- A screening questionnaire for voice problems after treatment of early glottic cancer. (van Gogh CD, Int J Radiat Oncol Biol Phys. 2005)
** Conclusion: "The questionnaire proved to be a reliable, valid, and feasible method to detect voice impairment in daily life. The questionnaire is easy to fill in, and interpretation is straightforward. It is useful for both radiation oncologists and otorhinolaryngologists in their follow-up of patients treated for early glottic cancer."
Set-Up
* T1 larynx is typically a clinical verification set up, unless OBI available
* Isocenter should line up 1cm below and 1cm posterior to the thyroid notch on visual field inspection
Review
* 2004 PMID 15112257 -- Management of T1-T2 glottic carcinomas. (Mendenhall WM, Cancer. 2004 May 1;100(9):1786-92.)
Keywords: radiation, radiotherapy