Laryngeal Cancer

Anh Q. Truong
MS-4
University of Washington, SOM
Anatomy
Vaezi, MF . Nature Clinical Practice Gastroenterology & Hepatology (2005) 2, 595-603
Anatomy cont

Anatomy subdivision
Source: AJ CC Cancer Staging Manual, 6
th
Ed (2002)
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%
Epidemiology
American Cancer Society: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008.
Tobacco smoking, bidi smoking,
alcohol.
MJ smoking correlation
HPV, GERD implicated
Possibly perchloroethylene

Risk Factors
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
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.
Supraglottis
Tis: CA in-situ
T1: limited to subsite of
supraglots w/normal cord
mobility
T2: invade mucosa of >1 subsite
of supraglottis, glottis, or outside
of supraglottis w/out fixation of
the larynx
T3: limited to larynx w/vocal cord
fixation and/or invades
postcricoid area, pre-epiglottic
tissues, paraglottic space, and/or
minor thyroid cartilage erosion
T4a: invades thyroid cartilage
and/or tissues beyond larynx
T4b: invades prevertebral space,
encases carotid artery, or
invades mediastinal structures
Glottis
Tis: CA in-situ
T1: limited to cord;
T1a: one cord; T1b: two cords
T2: extends to supraglottis,
and/or subglottis, and/or
w/impaired cord mobility
T3: limited to larynx w/vocal cord
fixation and/or invades
paraglottic space, and/or minor
thyroid cartilage erosion
T4a: invades thyroid cartilage
and/or tissues beyond larynx
T4b: invades prevertebral
space, encases carotid artery, or
invades mediastinal structures
Subglottis
Tis: CA in-situ
T1: limited to subglottis
T2: extends to vocal cord with
normal or impaired mobility
T3: limited to larynx w/vocal cord
fixation
T4a: invades cricoid or thyroid
cartilage, and/or invades tissues
beyond the larynx
T4b: invades prevertebral
space, encases carotid artery, or
invades mediastinal structures
Staging
Source: AJ CC Cancer Staging Manual, 6
th
Ed (2002)
Subglottis
Tis: CA in-situ
T1: limited to subglottis
T2: extends to vocal cord with
normal or impaired mobility
T3: limited to larynx w/vocal cord
fixation
T4a: invades cricoid or thyroid
cartilage, and/or invades tissues
beyond the larynx
T4b: invades prevertebral
space, encases carotid artery, or
invades mediastinal structures
Staging
Nodes
N0: no regional node mets
N1: single ipsilateral node, 3
cm
N2a: single ipsilateral node, >3
cm, 6 cm
N2b: multiple ipsilateral nodes,
6 cm
N2c: bilateral or contralateral
nodes, 6 cm
N3: node >6 cm

Mets
Mx: unknown
M0: no distant mets
M1: distant mets
Source: AJ CC Cancer Staging Manual, 6
th
Ed (2002)
Stage Grouping
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III
T3 N0 M0
T1-3 N1 M0
Stage IVA
T4a N0-1 M0
T1-4a N2 M0
Stage IVB
T4b any N M0
any T N3 M0
Stage IVC any T any N M1
Early
stage
Advanced
stage
Surgery
Microlaryngeal surgery
Hemilargyngectomy
Supraglottic laryngectomy
Near-total laryngectomy
Total laryngectomy
Photodynamic Therapy
Radiation
Chemothrapy
Cisplatin + 5-fluorouracil
Treatments Options
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


Treatment Early Stage (I/II)
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

1
Yu E. et al., Int J Radiat Oncol Biol Phys. 1997 Feb 1;37(3):587-91.
2
www.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 J an 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 3
rd
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
Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90.
Overall Survival
Surg + XRT
Chemo + XRT
2 yr OS =68% in both groups, P =0.9846
Surg + XRT
Chemo + XRT
Chem + XRT shorter disease free
interval, but dif not significant
Disease Free Survival
Treatment Advanced Stage
(III/IV) VA Study cont
Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90.
Site of
recurrence
Surgery
(N = 166)
Chemotherapy
(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%)
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 3
rd
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 3
rd
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

2 yr 3.8 yr 5 yr update
A

- induction chemo XRT: 75% 72% 70.5%
- concurrent chemoXRT : 88%* 84%* 83.6%
- XRT alone : 70% 67% 65.7%
Laryngeal Preservation
Forastiere AA et al, N Engl J Med 2003;349:2091-8.
A
Forastiere AA et al, Journal of Clinical Oncology, Vol 24, No. 18S(J une 20 Supplement),2006:5517.
Treatment Advanced Stage
(III/IV) RTOG 91-11 Study
2 yrs 5 yr update
A

- induction chemo XRT: 64% 54.9%
- concurrent chemoXRT : 80% 68.8%
- XRT alone : 58% 51%
Locoregional Control
Forastiere AA et al, N Engl J Med 2003;349:2091-8.
A
Forastiere AA et al, Journal of Clinical Oncology, Vol 24, No. 18S(J une 20 Supplement),2006:5517.
Treatment Advanced Stage
(III/IV) RTOG 91-11 Study
Concurrent
chemoXRT
Induction chemo
XRT
XRT alone
2 yrs 5 yrs 2 yrs 5 yrs 2 yrs 5 yrs
Dz Free
Survival
A

61% 36% 52% 38% 44% 27%
Overall
Survival
B

74% 54% 76% 55% 75% 56%
Distant
mets
C

8% 12% 9% 15% 16% 22%
A
Chemo therapy significant decreased in dz free survival compared to XRT
alone (P =0.02 compared w/induction, P = 0.06 compared w/conccurent Tx)
B
No significant difference
C
Difference 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.
Hypothyroidism
Mucositis
Dermatitis
Xerostomia
Fibrosis
Fistulas
Dysgeusia
Anticipated Toxicities
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
Dont 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?