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Larynx Cancer
101
found microscopic invasion of the thyroid cartilage in as many as 50% of clinically
and radiologically staged T3 tumors of the glottis. Positron emission tomography
using fluorine-labeled deoxyglucose may be useful in detecting recurrent tumor after
primary treatment. In addition, high pretreatment standardized uptake value (SUVs)
has been associated with a poorer prognosis, particularly among patients who are not
surgically treated.
Figure 2. CT and laryngoscopy showing a laryngeal tumor.
References
Allison P, Franco E, Black M, Feine J. The role of professional diagnostic delays in the
prognosis of upper aerodigestive tract carcinoma. Oral Oncol. 1998;34(2):147.
Merritt RM, Williams MF, James TH, Porubsky ES. Detection of cervical metastasis. A
meta-analysis comparing computed tomography with physical examination. Arch
Otolaryngol Head Neck Surg. 1997;123(2):149.
Adams S, Baum RP, Stuckensen T, Bitter K, Hör G. Prospective comparison of 18F-FDG
PET with conventional imaging modalities (CT, MRI, US) in lymph node staging of head
and neck cancer. Eur J Nucl Med. 1998;25(9):1255.
5. Pathology
Squamous cell carcinomas (table-2) comprise 85 to 90% of all laryngeal neoplasms. The
majority of vocal cord carcinomas is well to moderately differentiate and almost always arises
anteriorly from the epithelium of the membranous part of the glottis. Other histologies are
described in table-2.
Reference
World Heath Organization Classification of Tumors: Pathology and Genetics: Head and Neck
Tumors, Barnes L, Everson JW, Reichart P, Sidransky D (Eds), WHO Press, Switzerland
2005.
Gustavo Arruda Viani
102
Type
Description
Squamous cell carcinoma
Up to 90% of laryngeal carcinomas
Verrucous carcinoma
It is a highly differentiated variant of squamous cell carcinoma (SCC)
that constitute about 1 to 4% of laryngeal neoplasms and about 1 to 2%
of vocal cord tumors.
Spindle Cell Carcinoma
Most laryngeal tumors that have been previously classified as laryngeal
sarcomas are now thought to be spindle cell carcinoma.
Mucosal Melanomas
Primary melanoma of the larynx is extremely rare. It is commonly a
tumor of elderly male
Whites, and the majority are found in the supraglottis
Neuroendocrine Tumors
Atypical carcinoid tumor is the most frequent neuroendocrine tumor of
the larynx and has been mistaken for laryngeal paragangliomas.
The vast majority (90%) occurs in the supraglottis, and some are
associated with the carcinoid syndrome.
Primary tumor (T)
Glottis:
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
T1
Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure), with normal
mobility
T1a
Tumor limited to 1 vocal cord
T1b
Tumor involves both vocal cords
T2
Tumor extends to the supraglottis and/or subglottis, and/or with impaired vocal cord mobility
T3
Tumor limited to the larynx with vocal cord fixation and/or invasion of the paraglottic space and/or
inner cortex of the thyroid cartilage
T4a
Moderately advanced, local disease: Tumor invades through the outer cortex of the thyroid cartilage
and/or invades tissues beyond the larynx (eg, trachea, soft tissues of the neck, including deep
extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)
T4b
Very advanced, local disease:Tumor invades prevertebral space, encases carotid artery, or invades
mediastinal structures
Supraglottis:
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
T1
Tumor limited to 1 subsite of the supraglottis, with normal vocal cord mobility
T2
Tumor invades mucosa of more than 1 adjacent subsite of the supraglottis or glottis or region
outside the supraglottis (eg, mucosa of base of the tongue, vallecula, medial wall of piriform sinus),
without fixation of the larynx
T3
Tumor limited to the larynx, with vocal cord fixation, and/or invades any of the following:
postcricoid area, preepiglottic space, paraglottic space, and/or inner cortex of the thyroid cartilage
Table 2. Histological subtypes of laryngeal cancer
7. Staging
The tumor node metastases (TNM) system of the American Joint Committee on Cancer
(AJCC) and the International Union for Cancer Control (UICC) have been used to stage
hypopharyngeal cancers (table-3)
Table 3. TNM staging for laryngeal cancer
Larynx Cancer
103
Primary tumor (T)
T4a
Moderately advanced, local disease: Tumor invades through the thyroid cartilage and/or invades
tissues beyond the larynx (eg, trachea, soft tissues of the neck, including deep extrinsic muscle of
the tongue, strap muscles, thyroid, or esophagus)
T4b
Very advanced local disease: Tumor invades prevertebral space, encases carotid artery, or invades
mediastinal structures
Subglottis:
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
T1
Tumor limited to the subglottis
T2
Tumor extends to vocal cord(s), with normal or impaired mobility
T3
Tumor limited to the larynx, with vocal cord fixation
T4a
Moderately advanced, local disease: Tumor invades cricoids or thyroid cartilage and/or invades
tissues beyond the larynx (eg, trachea, soft tissues of the neck, including deep extrinsic muscle of
the tongue, strap muscles, thyroid, or esophagus)
T4b
Very advanced, local disease: Tumor invades prevertebral space, encases carotid artery, or invades
mediastinal structures
Regional lymph nodes (N)
NX
Regional nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single ipsilateral lymph node ≤3cm in greatest dimension
N2
Metastasis in a single ipsilateral lymph node >3cm but ≤6cm in greatest dimension; or in multiple
ipsilateral lymph nodes, none >6cm in greatest dimension; or in bilateral or contralateral lymph
nodes, none >6cm in greatest dimension
N2a
Metastasis in a single ipsilateral lymph node >3cm but ≤6cm in greatest dimension
N2b
Metastasis in multiple ipsilateral lymph nodes, none >6cm in greatest dimension
N2c
Metastasis in bilateral or contralateral lymph nodes, none >6cm in greatest dimension
N3
Metastasis in a lymph node >6cm in greatest dimension
Distant metastasis (M)
M0
No distant metastasis
M1
Distant metastasis
Reference
American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton
CC, et al (Eds), Springer, New York 2010.
8. Routes of Spread
The pattern of dissemination of laryngeal cancer basically is related with tumor stage and
origin location. Table 4 describes the incidence of occult metastases according to these
factors.
Reference
Mendenhall WM, Amdur RJ, Morris CG, Hinerman RW. T1-T2N0 squamous cell carcinoma
of the glottic larynx treated with radiation therapy. J Clin Oncol. 2001;19(20):4029.
Gustavo Arruda Viani
104
Supraglotic
carcinoma
The incidence of occult metastasis in supraglottic carcinoma ranges from 20 to 50%
depending on the T stage of the primary.
The primary echelons of nodal drainage are levels II, III, and IV.
Most frequently, in patients with clinically negative neck, micrometastases are found in
40%, with levels II and III most frequently compromised.
Occult metastases at levels I and V were found on pathological examination in only 6
and 1%, respectively.
Glotic
The risk of lymphatic metastases from carcinoma of the true vocal cords is lower than
that for supraglottic carcinoma.
The incidence of occult cervical metastasis has been reported only for surgically
treated higher stage primaries, and ranges from 10% for T 3 to 30 % for T 4 tumors.
The overall rate of metastasis is less than 5% for T 1, 5 to 10% for T 2 , 10 to 20% for
T 3 , and 25 to 40% for T 4 tumors.
The primary echelons of drainage are levels II, III and IV.
Subgloticc
carcinoma
In general, the incidence of cervical lymphatic metastasis from primary subglottic
carcinoma is less than 20%.
The incidence of paratracheal node involvement is, however, much higher than 50%.
Mediastinal nodes can be involved in up to 46% of the cases.
Table 4. Incidence of occult metastases according to tumor stage and location
9. Prognostic Factors
• The clinical stage at diagnosis is the most important prognostic factor for cancer of
the larynx.
• Early stage disease has an excellent prognosis, while locally advanced disease has a
poorer survival.
• Local control is adversely affected by increasing T category, prolonged overall
treatment time, male gender, low pretreatment hemoglobin level, poor histologic
differentiation, and/or failure to stop smoking.
• Patients with advanced lesions submitted to total laryngectomy, do not have a worse
prognosis than patients treated to conserve the larynx. However, inoperable lesions,
beyond organ conservation, have a substantially worse prognosis.
Reference
Mendenhall WM, Amdur RJ, Morris CG, Hinerman RW. T1-T2N0 squamous cell carcinoma
of the glottic larynx treated with radiation therapy. J Clin Oncol. 2001;19(20):4029.
10. Treatment
• Early laryngeal cancer (stage I and stage II), can be treated by definitive radiation
therapy (RT) or larynx-sparing surgery (transoral laser surgery and open partial
laryngectomy). Both treatment modalities generally offer equivalent local tumor
control and survival. The optimal treatment must balance between survival and
functional outcomes, given the importance of maintaining laryngeal function.
Larynx Cancer
105
Trials
Description
Chera et al.
(2004):
Glottic cancer
585 patients with T1N0 to T2N0 invasive SCCA of the glottic larynx treated between
1964 and 2006 with RT alone. All patients had at least 2 years of follow-up, had
histologic diagnosis of invasive SCCA, and received continuous-course RT. None of
these patients received chemotherapy or had elective nodal RT.
The median follow-up for survivors was 12 years. Five-year LC rates were as follows:
T1A, 94%; T1B, 93%; T2A, 80%; and T2B, 70%.
LC with laryngeal preservation were: T1A, 95%; T1B, 94%, T2A, 81%; and T2B,
74%. Twenty-four (4%) of 585 patients failed in the neck; only 7 neck failures (1%)
were isolated.
Mendenhall et
al. (2001):
Glottic cancer
519 patients were treated with radiation therapy and had follow-up for>or= 2 years.
Local control rates at 5 years after radiation therapy were as follows: T1A, 94%; T1B,
93%; T2A, 80%; and T2B, 72%.
Cause-specific survival rates at 5 years were as follows: T1A and T1B, 98%; T2A,
95%; andT2B, 90%.
Hinerman et
al. (2002)
Supraglotic
cancer
Continuous-course radiotherapy alone or combined with a planned neck dissection
was used to treat 274 patients with squamous cell carcinoma of the supraglottic larynx
between 1964 and 1998. All patients had follow-up for a minimum of 2 years, and
250 (91%) had follow-up for 5 years or more.
At 5 years, the actuarial probability of local control after radiotherapy according to T
stage was as follows: T1, 100%; T2, 86%; T3, 62%; and T4, 62%. The probability of
cause-specific survival at 5 years by AJCC stage was as follows: stage I, 100%; II,
93%; III, 81% IVA, 50%; and IVB, 13%. The risk of severe late complications was
4%. Of 57 patients undergoing planned postradiotherapy neck dissection, 7%
experienced a severe complication.
• Patients with early stage cancers of the supraglottic and glottic larynx, should be
treated by RT rather than surgery because of the better functional outcomes.
• Patients with higher risk tumors (bilateral disease and/or extensive involvement of
the anterior or posterior commissures) should be treated with RT, because of the risk
of positive margins and/or suboptimal voice quality after transoral laser surgery or
open vertical hemilaryngectomy (table-5).
Table 5. Clinical evidence for radiotherapy in early laryngeal cancer
References
Mendenhall WM, Amdur RJ, Morris CG, Hinerman RW. T1-T2N0 squamous cell carcinoma
of the glottic larynx treated with radiation therapy. J Clin Oncol. 2001;19(20):4029.
Hinerman RW, Mendenhall WM, Amdur RJ, Stringer SP, Villaret DB, Robbins KT.
Carcinoma of the supraglottic larynx: treatment results with radiotherapy alone or with
planned neck dissection. Head Neck. 2002;24(5):456.
• Patients with locally advanced laryngeal cancer (stage III or IV), an organ
preservation treatment rather than surgical resection should be recommended.
Although organ-sparing treatment may permit larynx preservation this strategy does
not provide a survival advantage compared with total laryngectomy.
• For organ preservation both concurrent chemoradiotherapy and sequential
chemoradiotherapy are used. Chemoradiotherapy is a better option for patients with
Gustavo Arruda Viani
106
Study
Description
VA Larynx Trial
(1991):
332 patients with III/IV larynx (T1N1 excluded), randomized to surgery and
post-op RT (50– 74 Gy) vs. induction cisplatin/5-FU × 2c (with a third cycle if
PR/CR) Æ RT (66–76 Gy). No routine neck dissection for N+ patients. Chemo
allowed 64% larynx preservation at 2 years.
There was no difference in 2-year OS (68%). Chemo-RT decreased distant
recurrences, but had higher LF (12 vs. 2%).
Organ preservation improved quality of life. Salvage laryngectomy was
required for 56% of T4 patients.
EORTC 24891
(Lefebvre et al.
1996):
202 patients with operable pyriform sinus tumors randomized to surgery Æ
post-op RT (50–70 Gy) vs. induction cisplatin/5- FU × 2c (with a third cycle if
PR/CR) followed by RT (70 Gy).
Nonresponders to chemo underwent surgery and RT. Fifty-one to fifty-four
percent of patients had a CR after chemo. There was no difference in LRF, and
chemo decreased DM (36 vs 25%).
The 3/5-year functional intact larynx rates were 42/35% with chemo. On
update, no difference in 5- or 10-year OS and PFS.
RTOG 91–11
(Forastiere et al.
2003):
547 patients with stage III/IV larynx randomized to one of three arms: RT
alone, chemo Æ RT, or concurrent chemo-RT. RT was 2/70 Gy in all arms.
Induction chemo was cisplatin/5-FU × 2c Æ reassessment.
If progression or <PR, treated with laryngectomy and post-op RT. If PR/CR Æ
third cycle chemo Æ RT. Concurrent chemo was cisplatin × 3c. All patients
with cN2 had neck dissection within 8 weeks after RT.
On update, concurrent chemo-RT improved 5-year larynx preservation (84%)
vs. induction chemo (71%) and RT alone (66%), and LRC (69%) vs. induction
chemo (55%) and RT alone (51%). Chemo reduced the rate of DM (13%
concurrent, 14% induction vs. 22% RT alone) and improved DFS (39% with
chemo vs. 27% with RT alone).
GORTEC 2000–01
(Pointreau et al.
2009):
220 patients with locally-advanced larynx or hypopharynx cancer that required
total laryngectomy randomized to 3c of TPF (docetaxel, cisplatin, 5-FU) vs. PF
(cisplatin, 5-FU) chemo.
If CR, PR, and larynx mobility, patients received RT with or without additional
chemo; if no response, patients had surgery and post-op RT with or without
additional chemo.
TPF improved overall response (80 vs. 59%) and 3-year larynx preservation
rate (70 vs. 58%), but had more neutropenia.
Cetuximab (Bonner
et al. 2006):
424 patients with locoregionally advanced resectable or unresectable stage III–
IV SCC of oropharynx, larynx, or hypopharynx randomized to RT or RT +
cetuximab given 1 week before RT and weekly during RT. RT options included
2/70 Gy, 1.2 b.i.d./72–76.8 Gy, or CB 72 Gy.
Cetuximab increased 3-year LRC (34 vs 47%) and OS (45 vs 55%). With the
exception of acneiform rash and infusion reactions with cetuximab, toxicity
was similar.
EORTC 24954
(Lefebvre et al.
2009):
450 patients with resectable T3–T4 larynx or T2–T4 hypopharynx, N0–N2
randomized to sequential arm (2c cisplatin/5-FU and if >50% tumor reduction,
2 more cycles cisplatin/5-FU with RT 70 Gy) vs. alternating arm (4 c
cisplatin/5-FU in weeks 1, 4, 7, and 10 alternating with 20 Gy RT during 2week interval to 60 Gy total).
No difference in larynx preservation, PFS, OS, or acute and late toxicity.
N0 and N1/N2 tumors. On the other hand, sequential therapy is more apropriated for
patients with a relatively high risk of distant metastases (N3), as decribed in table-6.
Table 6. Clinical evidence for chemoradiation in locally advanced larynx cancer
Larynx Cancer
107
References
Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer:
preliminary results of a European Organization for Research and Treatment of Cancer
phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst
1996;88:890-899.
Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for
organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-2098.
Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with
cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl
Cancer Inst 2009;101(7):498-506.
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell
carcinoma of the head and neck. N Engl J Med 2006; 354: 567-578.
Lefebvre JL, Rolland F, Tesselaar M et al. Phase 3 randomized trial on larynx preservation
comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst.
2009;101(3):142-52.
• Patients with both vocal cords destroyed by the tumor, patients without clinical
performance to chemoradiotherapy, and patients with extensive cartilage destruction
aren`t candidates for organ preservation. For these patients a total laryngectomy is a
potential alternative (figure – 3).
Figure 3. Schematic of the anatomic resection for a total laryngectomy.
• Management of the neck is controversial and depends on tumor extent, treatment
modality used, and response to therapy.
Gustavo Arruda Viani
108
Study
Decription
EORTC 22931
(Bernier et al.
2004)
334 patients with operable stage III/IV oral cavity, oropharynx, larynx, and
hypopharnx cancer randomized to post-op RT (2/66 Gy) vs. post-op chemo- RT
(2/66 Gy and cisplatin 100 mg/m2 on days 1, 22, 43).
All patients received 54 Gy to the low-risk neck. Eligible stages included pT3–
4N0/+, T1–2N2–3, and T1–2N0–1with extra capsular extension, +margin,or
perineural invasion.
Chemo-RT improved 5-year DFS (59 vs 47%), 5-year OS (65 and 53%), and 5-
year LRC (82%), but increased grade 3–4 toxicity (21 and 41%).
RTOG 95–01
(Cooper et al.
2004)
459 patients with operable cancer of the oral cavity, oropharynx, larynx, or
hypopharynx who had 2 or more involved lymph nodes, nodal extracapsular
extension, or a + margin were randomized to post-op RT (2/60–66 Gy) vs. postop chemo-RT (2/60–66 Gy and cisplatin ×3 c).
Chemo-RT improved 2-year DFS (43 vs 54%), LRC (72 vs 82%), and had a
trend for improved OS (57 and 63%), with increased grade 3–4 toxicity (34 and
77%).
Pooled
RTOG/EORTC
analysis (Bernier
2005)
Chemo-RT improved OS, DFS, and LRC for ECE and/or + margins, but
provided only trend for improvements (p > 0.06) for stage III–IV, PNI, LVSI,
and/or enlarged LN in levels IV–V.
• For early stage cancer of the subglottic larynx, a total laryngectomy in conjunction
with thyroidectomy and bilateral paratracheal node dissection should be
recommended.
• Bilateral elective neck treatment, extending from levels II to IV, is recommended for
early stage supraglottic cancer (with a clinically negative neck).
• Early stage glottic cancers staged clinically and without positive lymph nodes,
observation rather than elective neck treatment is suggested.
• Patients submitted to primary surgery, postoperative RT is indicated for those with
positive resection margins, lymphovascular or perineural invasion, or pathologically
positive lymph nodes. Postoperative chemoradiotherapy is recommended for positive
margins or positive lymph node with extracapsular extension (table-7).
Table 7. Clinical evidence for adjuvant chemoradiotherapy in locally advanced
larynx cancer
References
Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck
cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy
trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27(10):843-50.
Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and
chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med
2004;350:1937-1944.
Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without
concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med
2004;350:1945-1952.
Larynx Cancer
109
11. Radiotherapy Techniques
All patients with hypopharyngeal cancer should be planned with CT images due to the
complex volume shape and position. If opposing lateral beams are planned to be used, the
borders can be defined in the simulator on a lateral radiograph.
Patients lie supine on a headrest to keep the spine straight, with a custom-made shell
fixed to the couch top in at least five places to reduce movement (figure – 4).
Figure 4. Thermoplastic mask fixed to the couch top in five places to reduce movement.
The treated volume will usually extend inferior to the level of the shoulders which should
be as low as possible to facilitate beam entry.
CT images with 3 mm thick are obtained from the skull base to the carina. The inferior
border is at the carina to facilitate planning with lateral beams angled inferiorly. Intravenous
contrast is to help in the definition of lymph node volumes but is unlikely to add more
information than contrast-enhanced diagnostic imaging which must be available at the time of
target volume definition.
There is as yet no proven role for image fusion with MRI or PET in defining tumour
volumes. The role of PET for target volume definition is evolving and may facilitate dose
escalation by identifying a smaller target volume within the GTV.
The primary tumor site, all nodal beds at risk of containing subclinical disease, and the
entire operative bed should be included in the CTVs. Both ipsilateral and contralateral
posterior nodes should be included in the treatment portals. Areas of initial gross disease,
should receive 70 Gy in 2-Gy-daily, while any area that has a high-risk feature, and any area
that has been dissected should receive 60–66 Gy in 2-Gy-daily increments. Areas that are not
dissected and considered at relatively low risk can receive 44- 54 Gy. The CTVs suggested
for laryngeal tumors is described in table 8.
For early glottis cancer a bilateral field sizes as small as 5x5 cm, covering from the
thyroid notch to the bottom of the cricoid cartilage and flashing skin to the anterior 1/3 of the
vertebral body can be used (figure 5). For designing the CTV 70 only tumor and microscopic
disease extension are delineated on CT planning. PTV is growing with 1 cm of margin (figure
5)
Gustavo Arruda Viani
110
Glottis
CTV44 nodal levels
CTV70 nodal levels
T1N0
None
None
T2N0
Level III nodes immediately adjacent to tumour
None
T3/4 N0/1
Bilateral low level II, levels adjacent to tumour
III–IV. Level VI for subglottic tumor.
Involved nodal levels + level III
nodes immediately adjacent to
tumor
T3/4 N2/3
Bilateral level II–IV. Level V
if _1 node involved in that
side of the neck. Level VI
for subglottic tumours
Involved nodal levels _ level III
nodes immediately adjacent to
tumour
Supraglottis
T1/2 N0
Bilateral level II, III
Level II, III nodes immediately
adjacent to tumour
Positive node
Bilateral levels II–IV Consider Ib, V depending
on site of primary and of involved nodes.
Involved nodal levels _ level III
nodes immediately adjacent to
tumour
Table 8. CTVs recommended for laryngeal cancer
Figure 5. Radiotherapy field and isodoseline distribution for early laryngeal cancer.
T1 lesions of the glottic larynx need to be treated with at least 2 Gy per fraction per day
[e.g., to a total dose of 66 Gy at 2 Gy per day (in 33 daily fractions)]. Some authors suggest