Clinical Review

Multidisciplinary Care of
Laryngeal Cancer
Carmen Salvador-Coloma, MD, and Ezra Cohen, MD

University Hospital La Fe, Valencia, Spain;

and UC San Diego Moores Cancer Center,
Abstract
La Jolla, CA
Treatment of larynx cancer has changed dramatically over the past several
years. Novel modalities of treatment have been introduced as organ preservation
has been developed. In addition, new targeted therapies have appeared, and
improvements in radiotherapeutic and surgical techniques have been introduced.
Thus, a large variety of treatment options is increasing local control rates and
overall survival; however, selecting the most appropriate treatment remains a
challenging decision. This article focuses on the multidisciplinary care of early-stage
and locally advanced larynx cancer and attempts to sum up different approaches.
Moreover, it reviews state-of-the-art treatment in larynx preservation, which has
been consolidated in recent years.

EPIDEMIOLOGY AND ETIOLOGY EARLY STAGE (STAGE I AND II)

ASSOCIATED CONTENT
See accompanying commentaries
on pages 725 and 727
DOI: 10.1200/JOP.2016.014225
The incidence of head and neck cancer
is increasing rapidly, accounting for
. 550,000 cases annually worldwide,1 of
which 130,000 are new laryngeal cancer
cases.2 There are geographic differences
in the incidence because of the different
prevalence of risk factors, mainly tobacco
and alcohol, among populations, which also
makes the disease more common in men
because of their greater exposure to those
factors. Tumors can develop in any part of
the larynx; the glottis is the most common
site, followed by the supraglottis and the
subglottis.3 The signs and symptoms, which
include hoarseness, stridor, sore throat,
persistent cough, or a neck mass, depend
on the size and location of the tumor.4
Frequently, glottic tumors are diagnosed
at early stages, because a change in voice
quality is noted relatively early in the course
of the disease. However, supraglottic and
subglottic tumors often present with ad-
vanced disease because their symptoms
are less obvious.
Epidemiology
Approximately 60% of people diagnosed
with larynx cancer have stage I or II cancer
(no evidence of lymph node involvement
or thyroid cartilage invasion).5 With radio-
therapy (RT) or surgery, 10-year disease-
specific survival rates are . 90% and 70%,
respectively, for patients with stage I and II
cancer.6,7 Larynx preservation should be
considered in patients with early-stage can-
cer. Both treatments, RT and surgery, work
well in abolishing early-stage cancer, with no
differences in oncologic outcomes.8-10 How-
ever, RT is usually preferred because of its
functional results.11 Factors such as tumor
characteristics, logistics, and patient pref-
erences should be considered in selecting
the treatment.
Treatment of Early-Stage (Stage I
and II) Disease
Larynx-preserving treatments with RT,
partial laryngectomy, or transoral laser

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Salvador-Coloma and Cohen
surgery should be the initial approach for patients with early-
stage larynx cancer. However, there are no randomized studies
of RT and conservation surgery that compare local control or
survival for patients with early-stage laryngeal cancer.
Supraglottis
Supraglottic cancers represent approximately one third of
laryngeal cancers. Most studies suggest that RT improves
functional outcomes and is better at preserving voice quality.
RT is effective for stage I larynx cancer in the supraglottic
region. Sykes et al12 showed a local control of 92% with RT
(with surgery after recurrence) for patients with stage I
supraglottic tumors, and regional lymph node control of 91%
with a 5-year survival rate of 83%. Conversely, a retrospective
study comparing radical RT (60 to 66 Gy) versus partial
laryngectomy in patients with T1 to T2 N0 found that surgery is
effective, with results comparable to those of RT.6
Subglottis
Subglottic cancers represent , 2% of laryngeal cancers. Most
cases are diagnosed in patients with advanced disease, so data
on treatment are based on few patients in each study. Early
stages in this location are usually treated with RT. If RT is not
successful, a hemilaryngectomy should be performed.13
Glottis
Cancer of the glottis represents approximately two thirds of
all cases of laryngeal cancer. Patients with early-stage cancer
should be treated using a larynx-preserving approach, with
either RT or transoral laser surgery. Several studies have noted
that transoral laser surgery offers an effective approach to
early-stage glottic cancer. Stoeckli et al8 compared treatment
between laser surgery and RT (68 to 70.2 Gy) involving
140 patients with T1 to T2 glottic cancer. Local control,
progression-free survival, and overall survival were similar
between groups in patients with T1. However, surgery had better
local control for patients with T2 than did RT. Larynx preservation
was superior in the surgery group (T1, 82% for RT v 96% for
surgery; T2, 77% v 89%). In an Italian study with T1a and T1b
glottic cancer, laser surgery resulted in a 90% local control.14
A comparative review of RT, transoral laser surgery, and
partial open laryngectomy in T1 to T2 larynx cancer showed
that patients treated with RT had 5-year local control rates of
85% to 94% and 70% to 80% for T1 and T2, respectively
(Table 1). The overall survival was comparable for all treat-
ments.9 These authors concluded that local control after RT is
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Table 1. Local Control Rates
Control Rates (%)
Treatment T1 T2
Transoral laser resection 80-90 70-85
Open partial laryngectomy 90-95 70-90
Radiotherapy 85-94 70-80
NOTE. Local control rates were assessed from meta-analyses.9
adversely influenced by increasing T stage, male sex, prolonged
overall treatment time, poor histologic differentiation, and
low pretreatment hemoglobin level.9,15,16 Other studies
suggest the same results, showing no differences in local control,
progression-free survival, and overall survival between laser
surgery and RT in patients with T1b glottic cancer.16
In a meta-analysis involving 7,600 patients with early-stage
glottic cancer that compared RT with laser surgery, no dif-
ferences were found in local control. Nevertheless, laser sur-
gery seemed to be superior to RT in improving overall survival
(odds ratio, 1.48; 95% CI, 1.19 to 1.85).17
In a prospective study, Yamazaki et al18 evaluated different
schemes of RT (small tumors [less than two thirds glottis], classic
RT [60 Gy; 2 Gy/fr] v experimental RT [56 Gy; 2.25 Gy/fr];
big tumors [two thirds glottis or more], classic RT [66 Gy;
2 Gy/fr] v experimental RT [63 Gy; 2.25 Gy/fr]). Despite
local control being superior in the experimental arm (92% v
77%, P 5 .004), there were no differences in overall survival.
This technique can decrease the dose to healthy tissues and
increase the dose to tumor with less toxicity; however, patient
selection criteria are critical. Recently, in an analysis of the
National Center Institute’s SEER, a benefit in terms of cancer-
specific survival for intensity-modulated RT (84.1%) versus
other techniques (66%) was observed.19 Moreover, additional
retrospective data support the use of carotid-sparing intensity-
modulated RT over conventional RT in T1 to T2 N0 larynx
cancer, demonstrating no difference in efficacy with sig-
nificantly lower doses to the carotid arteries.20 Whether this
translates into improved long-term vascular outcomes is
still unknown.
Therefore, patients with early-stage disease could be
treated with either RT or transoral laser surgery. Those with a
higher risk (because of involvement of the anterior or pos-
terior commissures or bilateral disease) are usually treated
with RT because of the risk of positive margins.21,22
Copyright © 2016 by American Society of Clinical Oncology

TREATMENT OF LOCOREGIONALLY ADVANCED STAGE
(STAGE III AND IV M0) DISEASE
Until 1990, laryngectomy was the standard treatment of
locoregionally advanced disease. Currently, all patients with
stage III and IV should be evaluated before treatment by
a multidisciplinary tumor board, which can change the
management and thus improve the survival of patients.23
Larynx preservation is considered critical. Functional organ
preservation is recommended and usually involves a com-
bination of chemotherapy and RT. Nevertheless, laryngeal
preservation surgery could be an alternative treatment in
carefully selected patients.10,24 It could be used in combination
with chemoradiotherapy or postoperative RT as an alternative
option for patients with a small T-stage primary tumor but with
advanced disease owing to neck node disease. These kinds of
approaches have not been compared with chemoradiother-
apy; therefore they should be used for carefully selected
patients only.
The locoregionally advanced group has two kinds of
patients: those who are candidates for organ preservation
and those who are not. Currently, the line between them is
not clear and the decision depends on the surgeon and the
institution. Most studies do not clarify resectability cri-
teria. However, some anatomic criteria are unequivocal, as
the following: involvement of the hyoid bone or cricoids
cartilage, extralaryngeal dissemination, involvement of
prevertebral fascia, vascular structure invasion, or complete
resection is not possible. 5 In addition to these criteria,
other aspects of a resectable tumor must be considered,
and these increase the relevance of a multidisciplinary
tumor board.
TREATMENT OF LOCOREGIONALLY ADVANCED
(STAGE III AND IV) DISEASE
In locally advanced laryngeal cancer, the traditional approach
has been laryngectomy followed by adjuvant RT, resulting in a
loss of natural voice production. However, this approach has
important limitations: a suboptimal rate of disease control
(35% to 75%), a 60% chance of locoregional relapse, and a 20%
chanceof metastasisafter5 years.25,26 Because of this, we began
looking for alternatives to surgery.
Treatments for the head and neck have changed dramatically
with the appearance of novel modalities such as combined
therapy. The development of new chemotherapy agents (tax-
anes and cetuximab) and the introduction of new prognosis
factors (margins and extracapsular nodal extension) have
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Laryngeal Cancer
changed the way we treat these patients; these developments
have become an important part of the whole process.
Surgery
The most common treatment of locoregionally advanced dis-
ease is chemoradiotherapy. Nevertheless, surgery is important
for selected patients who are not candidates for or who choose
not to undergo chemoradiotherapy.
Larynx preservation surgery
Larynx preservation surgery is used in combination with
adjuvant RT or chemoradiotherapy. It is an option for patients
with a small primary tumor but who have advanced disease
owing to neck node burden.27
Conservation surgery
Conservation surgery is used as an aggressive treatment of
locally recurrent disease after RT.28,29 In addition, endo-
scopic methods are used for early stages (see Treatment of
Early-Stage [Stage I and II] Disease). In selected T3 or T4
tumors, transoral laser surgery, in combination with post-
operative treatment, may be considered, leading to an ex-
cellent oncologic survival outcome.30
Total laryngectomy
Usually, total laryngectomy is used to treat locally recurrent
disease after chemoradiotherapy. Moreover, it should be used
in older or frail patients.31,32 However, bulky T4 tumors could
be treated with upfront chemoradiotherapy.33
Adjuvant Treatment
After larynx preservation surgery, adjuvant RT is required
for patients with locoregionally advanced disease, with or
without chemotherapy.34
Adjuvant chemotherapy (cisplatin 100 mg/m 2 every
21 days) concurrent with RT has better local control,
progression-free survival, and overall survival than does RT
alone in patients with high-risk locoregionally advanced
disease (the European Organisation for Research and Treat-
ment of Cancer and Radiation Therapy Oncology Group
studies included approximately 22% of patients with larynx
cancer and both trials demonstrated a significant benefit in
disease-free survival and locoregional control).35 Positive
margins and extracapsular nodal extension are the risk factors
that have benefit in overall survival and local control of
concurrent chemoradiotherapy. There are no specific data for
larynx cancer.
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Salvador-Coloma and Cohen

Functional Organ Preservation
The first exploratory study in this area was the landmark trial
conducted by the Department of Veterans Affairs Laryngeal
Cancer Study Group, in which patients were assigned to
receive three cycles of induction chemotherapy (cisplatin
plus fluorouracil) before definitive RT versus surgery (typ-
ically, total laryngectomy) plus adjuvant RT.36 Patients
without at least a partial response were treated with surgery
and adjuvant RT. The larynx was preserved in 64% of the
patients who received chemotherapy followed by RT, and
there were no differences in survival.
The European Cooperative Group trial (EORTC 24891)
showed similar results in patients with hypopharynx cancer, in
which induction chemotherapy (cisplatin plus fluorouracil)
followed by definitive RT was compared with surgery followed
by postoperative RT.37 Patients without a complete response
to chemotherapy underwent salvage surgery and adjuvant RT.
There were no significant differences in survival (Table 2).
Concurrent chemoradiotherapy
Concurrent chemoradiotherapy was developed originally as a
definitive treatment option for inoperable patients; it had
excellent reported local control and survival rates. Concomitant
chemoradiotherapy attempts to take advantage of the radio-
sensitizing properties of chemotherapy. The main problem with
this treatment is an increase in grade 3 and 4 acute toxicities.
Some trials using intensive chemoradiotherapy regimens have
noticed a survival benefit without surgery.40
The standard of treatment changed with the RTOG 91-11
study, and functional organ preservation with concurrent
chemoradiotherapy became a preferred choice in larynx
cancer (Table 2). This treatment approach improves dis-
ease control and laryngeal preservation. Nevertheless, is
less effective than induction chemotherapy followed by
radical RT in decreasing the development of metastasis.
The study randomly assigned patients to investigate three
treatments: induction cisplatin plus fluorouracil followed
by RT, RT with concurrent administration of cisplatin, and
RT alone. The results demonstrated that RT with con-
current administration of cisplatin is superior to the other
treatments for laryngeal preservation and locoregional
control. A trend toward improved overall survival in the
induction group was noted that was not statistically sig-
nificantly different.41
Currently, target therapies such as cetuximab can be
combined with RT as radical treatment in patients with lo-
cally advanced disease. This was investigated in a phase III
trial, which compared RT with RT plus cetuximab as a
radical treatment in patients with locally advanced disease.
The local control was better using the combination

Table 2. Chemoradiotherapy v Other Modalities for Organ Preservation in Locally Advanced Head and Neck Cancer
Tumor Local Acute Toxicity, Survival Larynx Preservation
First Author Trial Location No. Induction CT Therapy High Grade (%) Difference at 2 Years (%)

Forastiere38 Intergroup 91-11 Larynx 510 None CRT (P) 82 No 88*

PF 3 2 RT 81 75

None RT 61 70

VA36 VA 24891 Larynx 332 PF 3 3 RT NA No† 64

None S, RT 64

Lefebvre39 EORTC 24891 Hypopharynx 202 PF 3 3 RT NA Yes (PF arm, 42§k

P 5 .06)‡
None S, RT

NOTE. Data adapted.34,35,37 Statistically significant at P 5 .005. No difference chronic toxicity.

Abbreviations: CRT, chemoradiotherapy: CT, chemotherapy; F, fluorouracil; NA, not available; P, cisplatin; PF, cisplatin 1 fluorouracil; RT, radiotherapy; S, surgery
as local salvage therapy.
*Statistically significant, P 5 .005.
†Induction arm had higher local failure rate and lower distal failure rate.
‡Induction arm had fewer distant failures.
§At 3 years.
║No difference in chronic toxicity.

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 Laryngeal Cancer

treatment (24.4 months v 14.9 months, P 5 .005), as was
overall survival (45.6% v 36.4%; hazard ratio, 0.73). It
should be noted that the trial was not designed for
platinum-ineligible patients; the objective was to evaluate
cetuximab in a broad population of patients with locally
advanced disease.42
Trials are underway in unresectable disease, but until
further data become available, the treatment selection will
depend on toxicity and patient fragility.
This approach seems to be effective for locoregional
control, but some trials revealed a worse control in distant
disease, especially in patients with an advanced nodal stage.
For that reason, induction chemotherapy was developed (see
Induction chemotherapy).
Induction chemotherapy
Induction chemotherapy is an option for functional larynx
preservation in locoregionally advanced disease. Usually, the
scheme is induction chemotherapy followed by definitive RT;
however, this treatment is less effective than concomitant
chemoradiotherapy treatment in terms of locoregional con-
trol.43 Induction chemotherapy has shown a survival benefit
effect. That has been tested in several trials (Paccagnella et al44;
Domenge et al45; Pignon et al34,46,47), which have shown a
consistent survival benefit and increased cure rates in a
subset of nonoperable patients. In the Pignon et al34 meta-
analysis, the researchers noted a 5% increase in survival,
reaching statistical significance (P 5 .05), in trials using a
cisplatin-plus-fluorouracil regimen only.
Cisplatin plus fluorouracil. In the earlier results of the
Meta-Analysis of Chemotherapy in Head and Neck Cancer,
there was no survival benefit for induction chemotherapy
because of the heterogeneity of the studies and the platin
absence in some of them. Nevertheless, the latest reports
showed a significant benefit of 5% in overall survival for
induction chemotherapy using cisplatin plus fluorouracil.34
In addition, other studies in the hypopharynx and oro-
pharynx have shown good results in organ preservation
(Table 3).
Taxanes. The incorporation of taxanes into induction
treatment has improved larynx preservation and response
rates. Therefore, induction chemotherapy that is based on
taxanes and local treatment has become the new standard
treatment.
In the TAX 323 trial, it was noted that the combination
regimen of taxane, cisplatin, and fluorouracil improved overall
survival compared with cisplatin plus fluorouracil, when both
were followed by radical RT. The induction response has a
prognostic and predictive value in deciding the following
treatment, chemoradiotherapy or surgery.50
The TAX 324 trial showed the effectiveness of induction
with docetaxel, cisplatin, and fluorouracil followed by
concomitant chemoradiotherapy using weekly carboplatin.
In a subset of nonoperable patients, the overall survival was
40 months for patients treated with taxanes versus 21 months
for the group treated with cisplatin plus fluorouracil.51 The
GORTEC 2000-01 study had 213 patients with stage III to
IV larynx or hypopharynx tumors who were candidates for

Table 3. Studies in Hypopharynx and Oropharynx Showing Good Results in Organ Preservation With Induction Cisplatin
Plus Fluorouracil
First Author Trial Trial Characteristics Patient Treatment Results

Lefebvre37,48 EORTC 24891 Phase III 202 Exp. arm: Induction CT (PF) No difference in overall
Randomized → RT (if CR) or surgery 1 RT survival
Patients: resectable hypopharynx (if not CR)
tumor with locoregional advance
disease Control arm: Surgery→ adjuvant RT

Worden49 UMCC 9921 Patients: resectable oropharynx 66 Induction CT (PF or CBDCA + FU): 7-year larynx-preservation
tumors rate, 73.4%
→ If CR or PR → CT 1 RT

→ If less than PR→ Surgery 1 RT

Abbreviations: CBDCA, carboplatin; CR, complete response; CT, chemotherapy; EORTC, European Organization for Research and Treatment of Cancer; Exp arm,
experimental arm; FU, fluorouracil; PF, cisplatin 1 FU; PR, partial response; RT, radiotherapy.

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Salvador-Coloma and Cohen

laryngectomy. They were randomly assigned to three cycles
of induction chemotherapy (with or without taxane) fol-
lowed by RT or surgery, depending on the response to
chemotherapy. It was noted that there was a higher larynx
preservation rate in the group receiving the taxane, cis-
platin, and fluorouracil regimen than in the group receiving
the cisplatin and fluorouracil regimen (70% v 57%). Overall
survival was 60% for both chemotherapy regimens.52
A phase II trial by Gruppo di Studio sui Tumori della Testa e
del Collo showed a benefit in locoregional control (50% v
21.2%, P 5 .04), overall survival, and progression-free sur-
vival53 in the induction arm. Moreover, the phase III pre-
liminary results were presented in 2014; they showed a benefit
in progression-free survival (29.7 months v 18.5 months) and
3-year overall survival (53.7 months v 30.3 months) for the
induction arm.
Thus, the triple combination of taxane, cisplatin, and
fluorouracil is an effective treatment for reducing metastasis
incidence and increasing local control. However, the main
problem for these patients remains the locoregional re-
currence, so evaluating the treatment after the induction
seems to be important.
Cetuximab. Target therapies that decrease treatment
toxicity have been studied. The TREMPLIN study is a phase II
trial that analyzed induction chemotherapy (three cycles of
taxane, cisplatin, and fluorouracil regimen) followed by RT
Table 4. Recommendations for the Treatment of
Early-Stage Laryngeal Cancer
Location Recommendation
Supraglottis Radical radiotherapy (60-66 Gy) or surgery (T1-T2 N0)
Subglottis Radiotherapy; if radiation therapy is not successful,
a hemilaryngectomy should be performed
Glottis Patients with early-stage laryngeal cancer should be
treated using a larynx-preserving approach, with
either RT or transoral laser surgery.
Abbreviation: RT, radiotherapy.
cancer, especially those with locally advanced disease, should
be evaluated by a multidisciplinary tumor board.
For the majority of patients with locally advanced (stage
III or IV) laryngeal cancer, a functional organ preservation
approach with chemoradiotherapy is recommended. How-
ever, surgery may be an option for selected patients and for
those who are not candidates for larynx preservation. Targeted
therapies play a role in chemoradiotherapy, but further
comparative trials must be performed. Great advances have
been made in larynx cancer treatment, but we must continue
Locoregionally
advanced stage

plus cisplatin or plus cetuximab in patients with laryngeal and

hypopharyngeal tumors. There were no differences in on- Resectable
cologic outcomes (3-month larynx preservation, overall
survival, 18-month functional larynx preservation) with the NO YES
exception of local control, which was superior in the cisplatin
group.54 Target therapies such as cetuximab showed evi-
PS Evaluation of PS and
dence of a benefit in resectable disease in the TREMPLIN organ preservation
trial; however, adequate evidence for patients with unre-
sectable disease is not available currently. Until further data POOR GOOD

become available, the treatment selection will depend on

toxicity and patient fragility. - Cetuximab+RT CT+RT SURGERY
- RT
Induction chemotherapy followed by sequential - Palliative treatment
chemoradiotherapy. Several trials have evaluated differ- High-risk
ent combinations of induction chemotherapy followed by pathology

concomitant chemoradiotherapy. Most of the studies were

negative, and this approach remains controversial. Adjuvant
Follow-up
In conclusion, the treatment of larynx cancer has changed treatment

dramatically over the past 3 decades. The most important

modification is the use of the multidisciplinary approach FIG 1. Recommendations for the treatment of advanced-stage laryngeal
(Table 4; Fig 1). Before treatment, all patients with larynx cancer. CT, chemotherapy; PS, performance status; RT, radiotherapy.

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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

improving our knowledge and quality standards to benefit as
many patients as possible.
Authors’ Disclosures of Potential Conflicts of Interest
Disclosures provided by the authors are available with this article at
jop.ascopubs.org.
Author Contributions
Conception and design: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
Corresponding author: Ezra Cohen, MD, Division of Hematology/Oncology,
Department of Medicine, UC San Diego Moores Cancer Center, 3855 Health
Sciences Drive, #0658, La Jolla, CA 92093; e-mail: ecohen@ucsd.edu.
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 Laryngeal Cancer

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Multidisciplinary Care of Laryngeal Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For
more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml.

Carmen Salvador-Coloma Ezra Cohen

No relationship to disclose Consulting or Advisory Role: Merck, Bristol-Myers Squibb, AstraZeneca,
Human Longevity, Pfizer

Copyright © 2016 by American Society of Clinical Oncology Volume 12 / Issue 8 / August 2016 n jop.ascopubs.org
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.