Laryngeal Cancer

Anh Q. Truong
MS-4
University of Washington, SOM
Anatomy
Anatomy – cont’

Vaezi, MF . Nature Clinical Practice Gastroenterology & Hepatology (2005) 2, 595-603

Anatomy – subdivision

Source: AJCC Cancer Staging Manual, 6th Ed (2002)

Epidemiology
 Most common head and neck CA (excluding skin)
 12,250 new cases/yr
 Male : Female = 4 : 1
 > 90% squamous cell cancer
 Glottic CA more common in Caucasian (in US)
 Glottic CA = supraglottic in African American (in US)
 Variation of ratio around world

Incidence by Site
Supraglottic 40%
Glottic 59%
Subglottic 1%

American Cancer Society: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008.
Risk Factors
 Tobacco smoking, bidi smoking,
alcohol.
 MJ smoking correlation
 HPV, GERD implicated
 Possibly perchloroethylene
Clinical Presentation
 Signs and symptoms
 Mass effect: hoarseness, dysphagia, hemoptysis, neck
mass, airway compromise (difficulty breathing), aspiration
 Throat pain, ear pain (referred through CN X branch)
 Suggests advanced stage
 Hoarseness = allow for early detection of glottic cancer
 Supraglottic CA = tend to present later
 Usually present w/bulkier tumors before Si/Sx present
 More likely to present w/node mets d/t richer lymphatics
 Weight loss
Clinical Presentation – cont’
 Physical Exam
 Complete head and neck exam
 Palpation for nodes; restricted laryngeal crepitus.
 Quality of voice
 Breathy voice = cord paralysis
 Muffled voice = supraglottic lesion
 Laryngoscopy
 Laryngeal mirror
 Fiberoptic exam (lack depth perception)
 Note: contour, color, vibration, cord mobility, lesions.
 Stroboscopic video laryngoscopy
 Highlights subtle irregularities: vibration, periodicity, cord closure
Differential Diagnosis
 Infectious
 Inflammatory
 Granulomatous disease (TB, sarcoidosis)
 Papillomatosis
 Lymphoma
Imaging
 CT or MRI
 Evaluate pre-epiglottic or paraglottic space
 Laryngeal cartilage erosion
 Cervical node mets

 PET
 Role under investigation, currently not standard of care
 Specific application
 Identifying occult nodal mets
 Distinguish recurrence vs radionecrosis or other prior tx sequalae

 Ultrasound
 In Europe: used to identify cervical mets and laryngeal abn.
Biopsy and Histology
 Direct laryngoscopy with biopsy
 Histologic subtypes
 Squamous cell carcinoma
 > 90% of causes

 Characterized by nl  hyperplasia  dysplasia  CIS 

invasive CA
 Invasive CA characterized by: well, moderately, or poorly
differentiated
 Nest of malig epi cells, desmoplastic & inflammatory stroma,
keratin pearls (in well and mod dif CA).
 Linked to tobacco and excessive alcohol
 Variance: verrucous, spindle cell carcinoma, & basaloid.
Biopsy and Histology – cont’
 Histologic subtypes - cont’
 Salivary gland
 Adenoid cystic carcinoma
 Mucoepidermoid carcinoma
 Surgery is preferred w/guidelines for adjuvant XRT

 Sarcomas (mainly chondrosarcoma)

 Most commonly from cricoid cartilage
 Nonaggressive, preferably tx with partial laryngeal surgery
 XRT viewed as ineffective

 Others: carcinoid tumors, lymphoma, mets.

Staging
Supraglottis
• Subglottis
Glottis
– Tis:
Tis: CA
CA in-situ
in-situ

– T1:
T1:limited
limitedto tosubsite
cord;
subglottisof
supraglots w/normal cord
– T1a:
T2: extends
mobility one cord; to vocal
T1b: two
cordcords
with
–
normal
T2:
T2: extends
invade or impaired mobility
to supraglottis,
mucosa of > 1 subsite
– T3:
of limited
and/or
supraglottis, to larynx
subglottis, w/vocal
and/or
glottis, cord
or outside
of supraglottis
w/impaired
fixation cordw/out fixation of
mobility
– the
T3:
T4a:larynx
limited
invades to cricoid
larynx w/vocal
or thyroidcord
 T3: limited
fixation
cartilage, to larynx
and/or
and/or w/vocal
invades
invades cord
tissues
fixation
beyondand/or
paraglottic thespace,invades
larynx and/or minor
postcricoid
thyroid area,
cartilage pre-epiglottic
erosion
– T4b: invades
tissues, prevertebral
paraglottic space, and/or
– minor thyroid cartilagecartilage
T4a:
space, invades
encases thyroid
carotid artery, or
erosion
 and/or
invades
T4a: tissues
invades mediastinal
beyond
thyroid structures
larynx
cartilage
– and/or tissues prevertebral
T4b: invades beyond larynx
 space,
T4b: encases
invades carotid artery,
prevertebral or
space,
encases carotid artery,
invades mediastinal or
structures
invades mediastinal structures

Source: AJCC Cancer Staging Manual, 6th Ed (2002)

Staging
• Subglottis • Nodes
– Tis: CA in-situ – N0: no regional node mets
– T1: limited to subglottis – N1: single ipsilateral node, ≤ 3
– T2: extends to vocal cord with cm
normal or impaired mobility – N2a: single ipsilateral node, > 3
– T3: limited to larynx w/vocal cord cm, ≤ 6 cm
fixation – N2b: multiple ipsilateral nodes, ≤
– T4a: invades cricoid or thyroid 6 cm
cartilage, and/or invades tissues – N2c: bilateral or contralateral
beyond the larynx nodes, ≤ 6 cm
– T4b: invades prevertebral – N3: node > 6 cm
space, encases carotid artery, or
invades mediastinal structures
• Mets
– Mx: unknown
– M0: no distant mets
– M1: distant mets

Source: AJCC Cancer Staging Manual, 6th Ed (2002)

Stage Grouping
Stage 0 Tis N0 M0
Early
Stage I T1 N0 M0
stage
Stage II T2 N0 M0
T3 N0 M0
Stage III
T1-3 N1 M0
T4a N0-1 M0
Stage IVA
T1-4a N2 M0 Advanced
stage
T4b any N M0
Stage IVB
any T N3 M0
Stage IVC any T any N M1
Treatments – Options
 Surgery
 Microlaryngeal surgery
 Hemilargyngectomy
 Supraglottic laryngectomy
 Near-total laryngectomy
 Total laryngectomy
 Photodynamic Therapy
 Radiation
 Chemothrapy
 Cisplatin + 5-fluorouracil
Treatment – Early Stage (I/II)
 Current therapeutic options
 Laser microsurgery (transoral)
 Open partial laryngectomy
 Radiation therapy
 No RCT to compare surgery w/XRT
 Rate of local control similar between surgery and
radiation
 Current recommendations, XRT with surgery reserved
for salvage therapy with local recurrence

Mendenhall WM et al., Cancer. 2004 May 1;100(9)

Dose Fractionation
 Yu et al., 1997 [1]
 Retrospective study – 5 yr local ctr rate of XRT on T1 glottic CA
 Daily fx > 2 Gy (50 Gy/2.5Gy QD & 65.25Gy/2.25 Gy QD) had 5
yr local ctr rate of 84%
 Daily fx = 2 Gy had 5 yr local ctr 65.6%

 Andy Trotti, RTOG 95-12 – closed [2]

 Randomized pts with T2 glottic cancer to 70Gy/2Gy QD vs 79.2
Gy/1.2 Gy BID

1Yu E. et al., Int J Radiat Oncol Biol Phys. 1997 Feb 1;37(3):587-91.
2www.rtog.org/members/protocols/95-12/95-12.pdf
Dose Fractionation
 Yamazaki et al., 2006
 RTC – 5 yr local ctr rate of XRT on T1 glottic CA
 2 Gy/fx (60Gy/30 fx or 66Gy/33fx): 5 yr local ctr rate = 77%
 2.25 Gy/fx (56.25Gy/25fx or 63 Gy/28fx): 5 yr local ctr rate = 92%

Yamazaki H et al., Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):77-82
Treatment – Advanced Stage
(III/IV) – VA Study
 Dept of VA Laryngeal CA Study Group, 1991
 RCT: Induction chemo  XRT vs laryngectomy  post-op
XRT
 Chemo arm = cisplatin + 5-FU x 2c  if partial/complete
response  3rd cycle  XRT*, else  salvage surgery

 Surgery arm = total laryngectomy (partial if poss)  XRT*

 *XRT = definitive: 66 Gy – 76 Gy; post-op: 50.4Gy (+10Gy if

high risk of local recurrence)

Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90.
Treatment – Advanced Stage
(III/IV) – VA Study cont’

Disease
Overall Free Survival
Survival

Surg + XRT
Surg + XRT

Chemo + XRT
Chemo + XRT
2 yr OS = 68% in both groups, P = 0.9846
Chem + XRT shorter disease free
interval, but dif not significant

Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90.
Treatment – Advanced Stage
(III/IV) – VA Study cont’
Site of Surgery Chemotherapy
recurrence (N = 166) (N=166)
Primary 4 (2%) 20 (12%)
Regional 9 (5%) 14 (8%)
Distant 29 (17%) 18 (11%)
All 42 (25%) 52 (31%)

No difference in rate of recurrence, significant difference in

site of recurrence, significant difference in development of
a 2nd primary CA (surg 6%, chemo 2%)

Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90.
Treatment – Advanced Stage
(III/IV) – VA Study cont’

Of the 166 pts in the chemo arms

- 107 (64%) patients had preserved larynx
- 30 patients (18%)  laryngectomy before
definitive XRT
- 29 patients (18%)  laryngectomy after
definitive XRT

Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90.
Treatment – Advanced Stage
(III/IV) – RTOG 91-11 Study
 Forastiere et al, (RTOG 91-11), 2003
 RCT: XRT alone vs induction chemo  XRT vs concurrent
chemoXRT, primary endpoint = larynx perservation

 XRT: 70Gy/35fx in all arms

 Induction – cisplatin + 5 FU x 2c  if complete or partial

response, w/out neck progression  3rd cycle  XRT; else 
laryngectomy  XRT

 Concurrent – cisplatin x 3c + XRT

Forastiere AA et al, N Engl J Med 2003;349:2091-8.

Treatment – Advanced Stage
(III/IV) – RTOG 91-11 Study
 Induction Chemotherapy
 173 assigned  168 completed chemo x 2c  144 complete or
partial response  134  completed 3rd chemo cycle
 84% of pts received ≥ 67 Gy

 Concurrent Chemoradiation
 172 assigned  120 (70%) completed cisplatin x 3 cycle, 40
(23%) completed cisplatin x 2 cycles.
 91% of pts received ≥ 67 Gy

 Radiation alone
 95% of pts received ≥ 67 Gy

Forastiere AA et al, N Engl J Med 2003;349:2091-8.

Treatment – Advanced Stage
(III/IV) – RTOG 91-11 Study
Laryngeal Preservation

2 yr 3.8 yr 5 yr updateA
- induction chemo  XRT: 75% 72% 70.5%
- concurrent chemoXRT : 88%* 84%* 83.6%
- XRT alone : 70% 67% 65.7%

Forastiere AA et al, N Engl J Med 2003;349:2091-8.

AForastiere AA et al, Journal of Clinical Oncology, Vol 24, No. 18S(June 20 Supplement),2006:5517.
Treatment – Advanced Stage
(III/IV) – RTOG 91-11 Study
Locoregional Control

2 yrs 5 yr updateA
- induction chemo  XRT: 64% 54.9%
- concurrent chemoXRT : 80% 68.8%
- XRT alone : 58% 51%

Forastiere AA et al, N Engl J Med 2003;349:2091-8.

AForastiere AA et al, Journal of Clinical Oncology, Vol 24, No. 18S(June 20 Supplement),2006:5517.
Treatment – Advanced Stage
(III/IV) – RTOG 91-11 Study
Concurrent Induction chemo XRT alone
chemoXRT  XRT
2 yrs 5 yrs 2 yrs 5 yrs 2 yrs 5 yrs
Dz Free 61% 36% 52% 38% 44% 27%
SurvivalA
Overall 74% 54% 76% 55% 75% 56%
SurvivalB
Distant 8% 12% 9% 15% 16% 22%
metsC

AChemo therapy  significant decreased in dz free survival compared to XRT

alone (P =0.02 compared w/induction, P = 0.06 compared w/conccurent Tx)
BNo significant difference
CDifference only significant comparing concurrent chemoXRT vs XRT alone.

Forastiere AA et al, N Engl J Med 2003;349:2091-8.

Treatment – Advanced Stage
(III/IV) – cont’

Forastiere AA et al, N Engl J Med 2003;349:2091-8.

Anticipated Toxicities
 Hypothyroidism
 Mucositis
 Dermatitis
 Xerostomia
 Fibrosis
 Fistulas
 Dysgeusia
Take Home Points
 Most laryngeal CA are SCC
 Low stage can be tx by different modalities
 Fraction size ≥ 2.25 Gy/fx may increase local ctr
 OS similar b/w surgery + XRT vs chemo +
XRT in advanced stage, but organ
preservation better with chemo + XRT
 Organ preservation: concurrent XRT >
chemo  XRT = XRT alone
 Don’t smoke or drink too much alcohol
 An Actual Picture of a
Laryngeal Cancer

(L) Source: http://www.medscape.com/content/2002/00/44/25/442595/442595_fig.html

(R) Source: http://www.som.tulane.edu/classware/pathology/medical_pathology/New_for_98/Lung_Review/Lung-62.html
Questions?