Critical Reviews in Oncology/Hematology 47 (2003) 65 /80

www.elsevier.com/locate/critrevonc

Cancer of the larynx

Lisa Licitra a,*, Jacques Bernier b, Cesare Grandi c, Laura Locati d, Marco Merlano e,
Gemma Gatta d, Jean-Louis Lefebvre f
a
START Project, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
b
Institute of Southern Switzerland, Bellinzona, Switzerland
c
General Hospital Santa Chiara, Trento, Italy
d
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
e
Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
f
Centre Oscar Lambret, Lille, France

Accepted 15 January 2003

Contents
1. General information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
1.1. Epidemiological data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
1.1.1. General data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
1.2. Aetiological and risk factors, and genetic susceptibility . . . . . . . . . . . . . . . . . . 67
1.2.1. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
1.2.2. Genetic susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
1.3. Screening and case finding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
1.3.1. Signs and symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
1.4. Referral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
1.4.1. Suggested referral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
1.5. Selected reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2. Pathology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.1. Biological data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.1.1. Genetic alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.1.2. Molecular epidemiology (HPV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.2. Histological types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.2.1. ICD-O classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.2.2. Anaplastic carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.2.3. Verrucous carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.3. Grading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.4. Accuracy and reliability of pathological diagnosis . . . . . . . . . . . . . . . . . . . . . 69
2.4.1. Histopathological diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.5. Particular histological types considered elsewhere . . . . . . . . . . . . . . . . . . . . . 69
2.5.1. Salivary gland tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.5.2. Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.5.3. Other tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.1. Signs and symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.2. Diagnostic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.2.1. Clinical assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.2.2. Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.2.3. Positron emission tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.2.4. Laryngoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

* Corresponding author. Tel.:
/39-02-23903352; fax:
/39-02-23903353.

E-mail address: start@cancerworld.org (L. Licitra).

1040-8428/03/$ - see front matter # 2003 Published by Elsevier Ireland Ltd.

doi:10.1016/S1040-8428(03)00017-9
66 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80

3.3. Pathological diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

4. Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
4.1. Stage classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
4.1.1. TNM classification [27] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.2. Staging procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.2.1. Clinical staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.2.2. Molecular staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.3. Restaging procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5. Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5.1. Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5.2. Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5.3. Predictive factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
6.1. Local /regional disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
6.1.1. General strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
6.1.2. Dysplasia and carcinoma in situ . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
6.1.3. Supraglottic cancer (T1 /T2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
6.1.4. Glottic and subglottic cancer (T1) . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
6.1.5. Glottic and subglottic cancer (T2) . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6.1.6. Advanced tumours (T3 /T4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6.1.7. *Neck dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
6.2. Recurrent disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
6.2.1. Local /regional relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
6.2.2. Regional relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
6.3. Second head and neck primaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
6.4. Metastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
6.4.1. Treatment aims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
6.4.2. Metastatic diffusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
6.4.3. *Isolated lung metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
6.4.4. Chemotherapy schedules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
6.5. Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
7. Late sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
7.1. Treatment-induced late sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
8. Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
8.1. General principles and objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
8.1.1. Aims of follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
8.2. Suggested protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
8.2.1. Loco-regional and general examinations . . . . . . . . . . . . . . . . . . . . . . . 77
8.2.2. Early diagnosis of second primaries and/or metastasis . . . . . . . . . . . . . . . 77
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

Abstract

In Europe, laryngeal cancer accounts for only 2 /5% of all cancers, the incidence being much higher among males than among
females. Smoke and alcohol represent the major behavioural risk factors. Several carcinogens, occupations and vitamin deficiencies
have been associated with laryngeal cancer. A genetic susceptibility to environmental risk factors and carcinogens is recognized.
Hoarseness is the main symptom for which patients call for medical consultation. Mucosa is the most common histologic site of the
primary lesions considered in the present chapter. Nodal involvement, the site and volume of the primary tumour, and some genes
expression represent the major prognostic factors. A high death rate for not cancer-related events is to be pointed out. The loco-
regional extent of the disease determines the success of cure. Surgery and radiotherapy represent the main therapeutic options. The
choice between these two procedures is often controversial.
# 2003 Published by Elsevier Ireland Ltd.

Keywords: Larynx; Surgery; Radiotherapy; Chemotherapy; Evidence-based treatment

 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
1. General information
1.1. Epidemiological data
1.1.1. General data
Cancer of larynx is one of the most common
malignancies in Europe, with about 52,000 new cases
per year, 90% of them occurring in men. The yearly
incidence rate for men in southern and northern Europe
is between 18 per 100,000 and 6 per 100,000, respec-
tively. For women, incidence rate is not higher than 1.5
per 100,000 per year [1].
In southern Europe, supraglottic carcinoma is more
common than carcinoma of the glottic, whereas the
reverse is true for north-western Europe, and this has an
impact on overall survival of laryngeal cancer patients
[2]. Some 95% of all cancers of the larynx are squamous
cell carcinomas [2]. The rates have been broadly stable
for both sexes over the last 15 years, but the pattern by
age suggests a declining risk for the future generation of
men in England and Wales, although the risk has been
increasing in Scotland. Increasing incidence has been
reported from Canada, Italy, Denmark, the United
States, Australia, especially among females. In Finland,
an overall decreasing incidence rate has taken place
among males since early 1970s. This was caused
exclusively by a decrease of supraglottic cancer cases.
This is probably due to the strong decrease in the
prevalence of smoking in Finland [3].
Among the European men population, the incidence
of larynx cancer increases with age, with most carcino-
mas being diagnosed in individuals aged 65 or more
(about 45% of all cases), and a peak incidence in the 6th
and 7th decades with about 50 new cases per 100,000 per
year [1].
Prevalence of larynx, i.e. the number of people living
with a diagnosis of laryngeal cancer, is known for Italy
only [4]. In 1992, the proportion of prevalent people was
142 per 100,000 (271 in men and 22 in women). Most of
them (76%) were long survivors, i.e. individuals living
with a diagnosis made 5 or more years before the index
date. The highest prevalence of larynx cancer was
observed in the region of Veneto (northeast of Italy),
accounting for about 2%.
Relative survival from larynx cancer for adults
diagnosed in Europe [5] during the period 1985 /1989
was 62% at 5 years. An overall progress in prognosis was
seen: during the period 1978 /1989, 5-year survival
increased from 58 to 63% [6].
There are major between-country differences in 5-year
survival for European patients with larynx cancer:
eastern Europe and France were characterized by low
survival (less than 55%). In the Netherlands, Sweden
and Germany, survival was generally higher (more than
70%) [5]. The prognosis of larynx cancer varies con-
siderably according to the anatomical site of origin of
67
the tumour, which affects the early appearance of
symptoms and, therefore, the stage at diagnosis and
the feasibility of surgical radical resection. Geographical
differences in survival may be largely due to a different
case mix of specific sub-sites. Glottic cancer (ICD9
1610) [7] has better prognosis than supraglottic, sub-
glottis, as well as the rare laryngeal cartilage tumours
(ICD9 161.1-3) [7,8]. An association between depriva-
tion and survival has been found for laryngeal cancer
[9]. Survival was lower by 13% for men in deprived
groups than for men in affluent groups.
Stage strong determines of survival. As confirmed by
the survival study of cancer patients in Finland, 5-year
survival is 75, 27 and 13 in male and 69, 31 and 15 in
females for groups of localized cancer, regional metas-
tases and distant metastases, respectively [10]. There is a
continuous decline in relative survival up to at least 10
years after diagnosis. This is largely due to other
smoking-related diseases rather than laryngeal cancer
itself.
The occurrence of multiple primaries (lung and liver)
is frequent and this is a major determinant of prognosis
and a major challenge for treatment [8]. The survival
data reported in these notes derived from information
collected by population-based cancer registries. They
provide the means by which we progress against cancer
can be measured.
1.2. Aetiological and risk factors, and genetic
susceptibility
1.2.1. Risk factors
Cancer of the larynx is mainly caused by tobacco
smoking and alcohol consumption, irrespective of the
type of beverage. The different anatomical parts of the
larynx must be distinguished when considering aetiol-
ogy. Tobacco dominates the risk for cancers of the vocal
cords and glottis, while alcohol is more prominent for
cancer of the supraglottis [11].
According to a large population-based case /control
study in southern Europe, over 90% of the present
incidence of laryngeal cancer could be prevented by
avoiding smoking and alcohol consumption. Most of
the risk is attributable to tobacco, but reducing alcohol
alone could still prevent a quarter of the cases. Tobacco
and alcohol consumption together appear to act syner-
gically [12]. Factors associated to a diet rich in fruit and
vegetables have been found to be protective. Evidence
from many epidemiologic studies suggests that vitamins
such as carotenoids, retinol and vitamin C may decrease
the risk of developing a laryngeal cancer [11].
The relationship between laryngeal cancer and asbes-
tos is controversial. It should be noticed that it is
enhanced by tobacco smoke. A review [13] underlies that
in many cohorts of asbestos-exposed workers, where the
risk for lung cancer was higher than 2, there was also a
68 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
risk for laryngeal cancer: the relative risks were between
1.14 and 3.75 [13]. Other occupational carcinogenic
agents are nickel and mustard gas, the isopropylic
alcohol steam and fumes [14].
The most effective means of preventing laryngeal
cancer is avoiding tobacco smoking. The most effective
dietary means of preventing laryngeal cancer are con-
sumption of vegetables and fruits, and avoidance of
alcohol [11].
1.2.2. Genetic susceptibility
Head and neck cancers occur largely in exposed
individuals who are susceptible to that exposure. Several
factors have to be considered in estimating the true risk
for developing cancer. Any factor influencing carcino-
gen absorption may play a role. Metabolic polymorph-
ism of cytochrome p450, Cyp 1a1 gene, glutathione-S-
transferase and other genes is under investigation.
1.3. Screening and case finding
No whole population screening programme for lar-
yngeal carcinoma has been evaluated, and so screening
cannot therefore be recommended. Narrowing the at-
risk group down to those exposed to known carcino-
gens, such as tobacco or alcohol, is still insufficient to
justify screening from a cost-effectiveness viewpoint,
even in a high-risk sub-population. Preclinical case
finding has not been evaluated and cannot therefore
be recommended either. On the contrary, a diagnostic
goal should be to avoid any medical delay where
suspicious symptoms have been noted. Despite the
high incidence of second primary cancers developing
either in other head and neck sites, or the oesophagus or
the bronchi, screening methods applied after the first
treatment failed to yield a significant reduction in
mortality from these second primaries.
1.3.1. Signs and symptoms
The presence of hoarseness, sore throat, shortness of
breath, dysphagia or of ‘‘a lump in throat’’ are all
symptoms observed in early or moderately advanced
stages of laryngeal cancers. Since lymph node metastases
are frequently the first clinical sign of larynx carcinoma,
swelling of cervical soft tissues, in the absence of evident
signs of infection, should be evaluated carefully. Deep-
ness, firmness and fixity are suspicious signs. The first
symptoms of disease may stem from compression of
adjacent nerves. Unexplained deep pain should prompt
the physician to consider a possible pharyngeal or
laryngeal origin.
1.4. Referral
1.4.1. Suggested referral
Treatment of larynx cancers is complex and in many
cases it requires a multidisciplinary approach. There-
fore, it is recommended that these patients are referred
to experienced institutes, especially when the tumour has
to be treated by combined radio-surgical techniques or if
there is a high risk of acute side effects from treatments
which combine radiation therapy and cytostatic agents.
Such treatment regimens are employed in patients with
locally advanced disease and in controlled clinical trials
investigating high toxicity regimens. Patients should be
referred to specialist institutions even when treatment
looks technically easy. In particular, biopsy and surgery
of the primary lesion, pathological diagnosis, surgery of
the neck adenopathies, and the delivery of chemother-
apy and radiotherapy are critical and require expertise
in treatment of the disease.
1.5. Selected reviews
Forastiere et al., Head and neck cancer, N. Engl. J.
Med. 345 (2001) 1890.
2. Pathology and biology
2.1. Biological data
2.1.1. Genetic alterations
Tumours arise clonally from cells undergoing specific
genetic alterations. A significant proportion of human
tumours from head and neck have been shown to
contain alterations of common oncogenes such as p16,
p53, PTEN, Rb or protoncogenes Cyclin D1, p63 and
EGFR. In particular, in laryngeal cancer Rb, Cyclin D1,
and EGFR may play a role in terms of carcinogenesis
[15]. For example, the loss of p53 function due to a
mutation results in a progression from premalignant to
invasive cancer and increases the probability of further
genetic progression.
Large patient populations will be required to deter-
mine more precisely the clinical relevance of the altera-
tions of these genes in head and neck cancers.
2.1.2. Molecular epidemiology (HPV)
All laryngeal papillomas contain human papilloma-
virus (HPV) genomic sequences of types 6 and 11. These
HPV types are also known to cause papillomas of the
oropharynx. Spontaneous malignant conversion of
papillomas is a rare event, by far less frequent than
the risk observed in the genital tract. The cofactors in
these cases are not clearly defined yet: smoking is known
to be one of these cofactors but this feature is also found
in nonsmokers; X-ray therapy, used in the 1930s to treat
 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
laryngeal papillomas caused about one-third of the
larynx carcinomas observed in the follow-up of these
patients. The carcinomas from papilloma patients
harbour the same HPV genomic sequences, of type 6
or 11, found in the papillomas, but the molecules are
shown to have undergone rearrangements that might be
linked the malignant potential of the tumour. Although
up to 15% of the carcinomas of the larynx do contain
HPV DNA, in these cases there is generally a low rate of
p53 mutations as compared with tumours not contain-
ing HPV. This particular feature supports the idea that
squamous cell carcinomas harbouring HPV may repre-
sent a distinct category [16,17].
2.2. Histological types
Precancerous lesions of the larynx can be defined as
lesions associated with an increased risk for later
development into invasive carcinoma. In previous years,
the incidence of keratinization or ‘‘leukoplakia’’ as-
sumed the greatest importance in assessment. More
recently, however, classification relies essentially on the
degree of atypia as this clearly has a bearing on the
prognosis [18]. Current classifications can be summar-
ized as follows:
. I: Squamous cell hyperplasia with or without kera-
tosis, without atypia.
. II: Squamous cell hyperplasia with or without
keratosis, plus atypia or dysplasia.
. III: Carcinoma in situ (ICD-O: M8010/2).
. Carcinoma with microinvasive or superficial stromal
invasion.
. Carcinoma, invasive.
Patients of Groups I, II and III develop invasive
carcinomas in 10, 24 and 58% of cases, respectively.
2.2.1. ICD-O classification
The ICD-O (International Classification of Diseases
for Oncology) morphology code of the histotypes
mentioned in this section is provided in brackets [19].
This chapter will deal with squamous cell carcinoma
(M8070/3) which is by far the most common malignancy
(95%) of the larynx. Well-differentiated carcinomas are
easily recognizable. Epithelial pearls are commonly
observed. The spindle cell variant (M8032/3) is often
confused with sarcoma: these lesions occur on the true
vocal cords in elderly patients. Since there is no
difference in clinical behaviour between these lesions
and squamous cell carcinomas, the same treatment
policy is advocated.
2.2.2. Anaplastic carcinomas
Anaplastic carcinomas are devoid of squamous or
glandular cells: they are characterized by a high
69
biological aggressiveness and have a dismal prognosis
[20].
2.2.3. Verrucous carcinomas
Verrucous carcinomas (M8051/3) are low-grade squa-
mous cell carcinomas usually arising from the oral
cavity mucosa but are also found in the larynx. This
indolent neoplasm may display malignant features such
as basement membrane disruption without true signs of
invasion. Strong associations with HPV of type 16 or 18
have been recently demonstrated for this type of tumour
[21].
2.3. Grading
The histological grading of squamous cell carcinomas
is based on the classification made by WHO for larynx
cancers. It is based on keratinization and overall
resemblance of carcinoma to normal squamous epithe-
lium.
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated or anaplastic
2.4. Accuracy and reliability of pathological diagnosis
2.4.1. Histopathological diagnosis
Diagnosis of squamous cell carcinoma does not raise
particular problems for well-trained pathologists, espe-
cially in patients with well-differentiated carcinomas.
The diagnosis of in situ carcinomas, less differentiated
forms, or rare tumours like spindle cell carcinomas may
be more difficult. It is therefore recommended that slides
should be analyzed by experienced pathology teams who
have a solid background in head and neck oncology.
2.5. Particular histological types considered elsewhere
2.5.1. Salivary gland tumours
Adenocarcinomas */true adenocarcinomas, mucoepi-
dermoid and adenoid cystic carcinomas */originate
from the mucous membranes of the minor salivary
glands. They can be found, among others, in the larynx.
2.5.2. Lymphomas
Cervical lymph nodes and Waldeyer’s ring are the
most frequent sites of head and neck lymphomas. In
Waldeyer’s ring, lymphomas account for 5% of the
tumours found in the tonsils and soft palate and 2% of
the lesions of the base of tongue. The majority of
extranodal lymphomas in these areas of the head and
neck are the non-Hodgkin’s type [22].
70 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
2.5.3. Other tumours
Melanomas and plasmocytomas are other histotypes
found in the oropharynx and the pharyngo-larynx.
Other tumours arising from supportive tissues of the
larynx comprise fibrosarcomas, rhabdomyosarcomas,
paragangliomas, neuromas and lipomas.
3. Diagnosis
3.1. Signs and symptoms
Hoarseness is the main symptom which causes
patients to seek a medical consultation. This is an early
symptom for glottic lesions, but a late one for supra-
glottic tumours. In the latter case dysphagia, the
sensation of a foreign body, and coughing are frequent,
but hoarseness appears only when the glottic plane is
invaded. Subglottic tumours may become manifest only
when the vocal cords are infiltrated.
3.2. Diagnostic strategy
3.2.1. Clinical assessment
A complete ear, nose, and throat examination using
mirror and optical instrument laryngoscopy must be the
first step of the diagnostic work-up for laryngeal cancer.
The flexible fibrolaryngoscope has increased the relia-
bility of laryngoscopy in patients where previously the
larynx was difficult to visualize. Vocal cord mobility and
the precise tumour extension with respect to laryngeal
subsites must be carefully assessed.
3.2.2. Imaging
Computed tomography (CT) and magnetic resonance
imaging (MR) are nowadays the only useful radiological
procedures for staging the disease. Both exams can give
us information about tumour volume (especially in large
lesions), cartilage involvement, invasion of the pre-
epiglottic space, and extension beyond the larynx. At
the same time, additional information about neck nodes
can be obtained.
There is a large variation in the use of CT among
different centers. In general, CT reveals a more ad-
vanced stage disease in approximately 20% of patients
[23].
3.2.3. Positron emission tomography
The evaluation of response after chemotherapy and/
or radiotherapy has become increasingly more relevant
with the increasing popularity of organ preservation
approaches. In these cases, the rate of tumour volume
reduction is generally of great importance in clinical
decision making but oedema and/or fibrosis may con-
found the picture. Both physical examination and
radiologic imaging may be inadequate. Positron emis-
sion tomography (PET) with 2-(F-18)fluoro-2-D-glucose
activity has been shown to be useful in distinguishing
benign from malignant changes after radiotherapy and
for evaluating tumour response but its use should still be
considered investigational or suitable for individual
clinical use [24 /26].
3.2.4. Laryngoscopy
It may be useful to follow-up direct laryngoscopy by
direct microscopical examination, which facilitates pre-
cise definition of the extent of the tumour, even though
the routine use of endoscopic optical devices has tended
to decrease.
3.3. Pathological diagnosis
Pathological confirmation can be achieved both by
direct laryngoscopy or by endoscopy. As direct laryngo-
scopy requires general anaesthesia, it cannot be per-
formed for large stenotic lesions, unless a tracheotomy is
carried out beforehand. However, because a previous
tracheotomy has been demonstrated to increase the risk
of stomal recurrences, the choice between endoscopy
and performing direct laryngoscopy at the same time as
the final surgical procedure must be considered very
carefully.
In cases of small lesions, direct laryngoscopy is
preferred. This can provide optimal definition when
used with a microscope, and also allows the possibility
of performing the therapeutic resection at the same time
of the diagnostic procedure (pre-malignancies).
4. Staging
4.1. Stage classification
The fourth edition (1987) (4.1) of the International
Union against Cancer (UICC) TNM classification
fourth edition (1987) (4.1) was identical to that of the
American Joint Cancer Committee (AJC) [27].
As the TNM system does not systematically require
the use of CT or MR, tumours evaluated with standard
radiological exams may need to be revised [28]. Tumour
volume, which is especially important to predict re-
sponse to radiotherapy, invasion of pre-epiglottic space,
and cartilage erosion, can only be evaluated by CT or
MRI.
Among supraglottic lesions, which represent the
majority of tumours, the T2 category encompasses
different cancers with regard to volume and/or super-
ficial spread. Transglottic lesions may be difficult to
classify, because each tumour has to be attributed to a
specific site (supraglottic, glottic, subglottic).
Small ‘‘marginal’’ tumours may be inappropriately
staged as advanced (T4), even if the prognosis is
 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80 71

favourable. T1 and T2 categories denote limited lesions T4: Tumour invades through cricoid or thyroid carti-
suitable for a conservative treatment approach (partial lage and/or extends to other tissues beyond the
surgery or radiotherapy). larynx (e.g., trachea, soft tissues of neck, including
thyroid, esophagus)

4.1.1. TNM classification [27]

Regional lymph nodes (N)
Primary tumour (T)
NX: Regional lymph nodes cannot be assessed
TX: Primary tumour cannot be assessed N0: No regional lymph node metastasis
T0: No evidence of primary tumour N1: Metastasis in a single ipsilateral lymph node,
Tis: Carcinoma in situ 3 cm or less in greatest dimension
N2: Metastasis in a single ipsilateral lymph node
more than 3 cm but not more than 6 cm in
Supraglottis greatest dimension, or in multiple ipsilateral
lymph nodes, none more 6 cm in greatest
T1: Tumour limited to one subsite of supraglottis, with dimension, or in bilateral or contralateral lymph
normal vocal cord mobility nodes, none more than 6 cm in greatest dimen-
T2: Tumour invades mucosa of more than one adjacent sion
subsite of supraglottis or glottis, or region outside N2a Metastasis in a single ipsilateral lymph node
the supraglottis (e.g., mucosa of base of tongue, more than 3 cm but not more than 6 cm in
vallecula, medial wall of pyriform sinus) without greatest dimension
fixation of the larynx N2b Metastasis in multiple ipsilateral lymph
T3: Tumour limited to larynx with vocal cord fixation nodes, none more than 6 cm in greatest dimen-
and/or invades any of the following: postcricoid sion
area, pre-epiglottic tissues N2c Metastasis in bilateral or contralateral lymph
T4: Tumour invades through the thyroid cartilage and/ nodes, none more than 6 cm in greatest dimen-
or extends into soft tissues of the neck, thyroid, sion
and/or esophagus N3: Metastasis in a lymph node more than 6 cm in
greatest dimension

Glottis
Distant metastasis (M)
T1: Tumour limited to the vocal cord(s) (may
involve anterior or posterior commissure) with
MX: Distant metastasis cannot be assessed
normal mobility
M0: No distant metastasis
T1a Tumour limited to one vocal cord
M1: Distant metastasis
T1b Tumour involves both vocal cords
T2: Tumour extends to supraglottis, and/or sub-
glottis, and/or with impaired vocal cord mobility
T3: Tumour limited to the larynx with vocal cord Stage grouping
fixation
T4: Tumour invades through the thyroid cartilage Stage 0 Tis, N0, M0
and/or to other tissues beyond the larynx (e.g., Stage I T1, N0, M0
trachea, soft tissues of neck, including thyroid, Stage II T2, N0, M0
pharynx) Stage III T3, N0, M0
T1, N1, M0
T2, N1, M0
Subglottis T3, N1, M0
Stage IVA T4, N0, M0
T1: Tumour limited to the subglottis T4, N1, M0
T2: Tumour extends to vocal cord(s) with normal or Any T, N2, M0
impaired mobility Stage IVB Any T, N3, M0
T3: Tumour limited to larynx with vocal cord fixation Stage IVC Any T, Any N, M1
72 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
4.2. Staging procedures
4.2.1. Clinical staging
With the exception of small glottic tumours, CT or
MR should always be carried out since these examina-
tions allow visualization of any tumour extension to the
pre-epiglottic and paraglottic spaces and detect cartilage
invasion as well as soft tissue and nodal involvement.
Direct laryngoscopy under general anaesthesia is
indicated when pathological diagnosis cannot be
achieved by endoscopy or when invasion to particular
structures of the larynx has to be investigated (mainly
for surgical decisions).
Pre-treatment bronchoscopy would be justified in
these patients, as the risk of other synchronous or
metachronous respiratory tract tumours is reported to
be as high as 20/30% [29,30]. As the cost /benefit aspect
of this procedure is not well established in the literature,
it should not be considered as a standard option.
4.2.2. Molecular staging
Genetic modifications can be used to detect cancer
cells in tissues with normal histological appearance. The
molecular analysis of free margins of operated head and
neck cancer has been shown to predict local tumor
recurrence [31,32].
4.3. Restaging procedures
Following local regional treatment, evaluation of
response may be difficult, particularly after radiother-
apy. Since local inflammation can confound a correct
evaluation, it is recommended that tumour response
evaluation either by clinical examination or by CT or
MR is not carried out immediately after radiotherapy. It
is recommended that the first tumour evaluation is
performed 40 days after the completion of radiotherapy.
The evaluation should always be based on clinical
examination and in special situations, such as the
presence of post-radiation oedema, supplemented with
CT and or MR.
5. Prognosis
5.1. Natural history
With few exceptions, mucosa is the most common
histologic site of the primary diseases considered in this
chapter. Theoretically, all head and neck sites of this
mucosal blanket are susceptible to carcinogens, account-
ing for the relatively high incidence of synchronous and
metachronous malignancies observed for this clinical
entity.
Early lesions present as erythroplasia (as is the case
for lesions arising from oral pharynx) or leukoplakia (in
larynx and hypopharynx). Muscle invasion is an early
feature of these carcinomas which also show a tendency
to spread along blood vessels, nerves and fascial planes
and through lymphatic vessels. Bone and cartilage are
natural barriers which are destroyed in more advanced
stages of disease [33].
The larynx is composed of three subsites: lateral
epilarynx lesions grow anteriorly from the aryepiglottic
fold to the pharyngo-epiglottic fold or posteriorly to the
posterior cricoid area. Lesions arising from the vocal
cord infiltrate laterally the paraglottic space and super-
iorly, the supraglottic larynx. Lesions arising from the
ventricule may infiltrate, in advanced stages, both the
supraglottis and subglottis areas. Subglottis tumours
can grow superiorly to the glottic area and inferiorly to
the trachea [34].
Except for glottic squamous cell carcinomas, these
tumours spread regionally through the lymphatic vessels
and distally by haematogenous dissemination. Both
regional and distant metastases increase with tumour
volume and biological aggressiveness which can be
reflected by the presence of microvascular invasion.
Usually regional metastases arise ipsilateral to the
primary site. The upper jugular nodes are the most
frequently involved sites of adenopathies in supraglottic
larynx cancer patients.
There is a minority of patients who show delayed
regional relapse (after 2 years) after treatment. The
anatomical primary site is critical in defining the
probability of recurrence: glottic 4%, supraglottic 16%,
subglottic 11%, aryepiglottic fold 22%, while the risk of
distant metastases is 4% for glottic and supraglottic
tumours, 15% for subglottic and aryepiglottic fold [35].
In general, recurrence increases with primary tumour
volume, severity of regional lymphatic spread and
presence of recurrent disease. The common distant sites
are lungs (45%) and bones (25%).
Patients with primary lesions arising from the larynx
are likely to develop subsequent primary lesions. This
risk averages 10% in patients with tumours in supra-
glottic cancers. Two-third of these second primaries are
found in other sites of the head and neck, while the most
common other localizations are the oesophagus and the
bronchi.
5.2. Prognostic factors
Most of the data concerning prognostic factors
relates to patients treated by radiation. The relevant
variables may be different when local /regional control
or survival are considered as the end points of the
analysis. The death rate for non-cancer-related events is
high (15 /20% at 5 years). Alcohol consumption has
been demonstrated to be negatively correlated with
survival [36].
 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
Nodal involvement is the most important prognostic
factor for survival both in radiotherapeutic or surgical
series. The presence of involved lymph nodes halves the
survival rates [37]. Glottic tumours have a more favour-
able prognosis than supraglottic or subglottic ones [38].
Primary tumour volume is strictly correlated with the
local control rate obtained with radiotherapy. The
tumour levels defined by UICC T categories are
generally rather efficient in predicting the probability
of local control. The most relevant variable regarding
local extension is cord mobility [39,40]. Elapsed radio-
therapy time is correlated both with local control and
survival [41].
A pretreatment tracheotomy has been shown to
reduce the survival rates, probably increasing the risk
of a stomal recurrence [42]. The expression of some
genes such as bcl 2, p53 and bax have been studied in
laryngeal cancer, and suggest a possible prognostic role
for bcl 2 [43,44].
5.3. Predictive factors
Response to chemotherapy is an important predictive
factor of response to radiotherapy as has been demon-
strated by the results of organ preservation trials. An Hb
level of
/12.5 g/dl during radiotherapy has been
reported to be an important predictive factor of tumour
response in advanced laryngeal cancer and of outcome
after surgical treatment of patient with glottic cancer
[45,46]. Microvessel density, expressed as the ratio
between total number of microvessels and tumour
area, may predict radiosensitivity thus avoiding ineffec-
tive radiation and complications after surgery in early
laryngeal cancer [47].
6. Treatment
6.1. Local /regional disease
6.1.1. General strategy
The aim of treatment is definite cure. The probability
of being cured depends on loco-regional extension of the
disease. Early-stage tumours, such as T1 /T2 tumours,
have an 80 /90% probability of cure, whereas for more
advanced tumours this is approximately 60%. Treatment
indications in cancer of the larynx are often controver-
sial, since there are few comparative studies of different
therapeutic approaches in the literature [48]. Moreover,
pre-selection of the patients may substantially influence
the reported results. In addition, the inadequacy of
TNM classification to identify homogeneous prognostic
categories often reduces the significance of comparisons.
Surgery and radiotherapy are both widely used, and
the choice between these two procedures is most
common therapeutic decision which has to be taken.
73
Function preservation has gained more and more weight
in the last decade and, from this point of view, the use of
chemotherapy has taken on a new relevance [49,50].
When function preservation is not possible a surgical-
voice-restoration programme is strongly recommended
on a type R basis [51].
6.1.2. Dysplasia and carcinoma in situ
CIS of the true cord is equally highly curable by
microexcision, laser vaporization or radiation therapy
[52 /55]. Microexcision is standard treatment on a type
C basis since it provides the pathologist with a sample
that preserves all histological features which may reveal
areas of microinvasion that may be otherwise over-
looked.
6.1.3. Supraglottic cancer (T1 /T2)
Supraglottic cancer may involve different subsites.
Unlike glottic cancer, the probability of nodal involve-
ment, even bilaterally is substantial. Cure probabilities
are approximately 50/70% both with surgery and/or
radiotherapy.
For supraglottic tumours not involving the glottic
plane and the arytenoids, a supraglottic laryngectomy
and bilateral selective neck dissection (excluded level I)
is considered the standard treatment on a type R basis,
considering that a conservative approach, in case of
failure, may not be possible after radiation therapy.
Functional results after this procedure that spares the
vocal cords are fairly good. This operation can also be
safely carried out in cases where there is limited
extension to the valleculae and the base of the tongue.
Postoperative radiation is recommended on a type C
basis in patients with nodal metastases. In these cases,
the remaining larynx should be protected because of the
severe morbidity associated with radiation in these areas
after conservative surgery.
For tumours initially involving the glottic plane,
radiotherapy generally represents the standard treat-
ment on a type R basis, as any surgical option
yields worse functional outcomes. Altered fraction-
ated radiation with concomitant boost is suitable
for individual clinical use on a type 1 level of evidence
[56].
6.1.4. Glottic and subglottic cancer (T1)
For glottic and subglottic cancers, both conservative
surgery, including endoscopic laser surgery, and radio-
therapy give excellent results. Five-year survival is
reported as high as 90 /95% [57]. It has been suggested
that the costs of laser cordotomy are lower than that of
radiotherapy [58]. In a minority of cases, there may
ultimately be a need for salvage total laryngectomy in
cases of a local failure.
The choice between surgery and radiotherapy should
depend on functional considerations. In case of tumours
74 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
of the true vocal cords, unless a limited submucosal
resection is possible, radiation generally obtains better
results. Then, excluding the latter cases, radiotherapy
should be considered the standard treatment on a type R
basis [59]. In tumours staged T1 and in the absence of
bulky neck nodes, conventional fractionation regimens
of radiation therapy, delivering one daily session of 1.8 /
2.0 Gy up to around 66 Gy, is considered the standard
dose on a type C basis. There is no need to treat the
neck. The loco-regional control rates observed after
definitive radiotherapy vary markedly from one anato-
mical site to another. Tumours involving the anterior
commissure are usually considered more radio-resistant,
but this hypothesis, when no sign of cartilage involve-
ment is present, is not clearly documented in the
literature [60,61]. The voice quality after a partial
surgery involving the anterior commissure is, on the
other hand, usually compromised. Based on these
considerations, surgery and radiotherapy are probably
equally effective in curing small tumours involving the
anterior commissure.
Endoscopic laser surgery has nowadays gained in-
creasing popularity. Indications and results are crucially
dependent on the experience of the surgeon. A major
advantage of the procedure is the preservation of the
thyroid cartilage, which can be a barrier in case of
cancer recurrence. Optimal candidates for this approach
are patients with small lesions of the true or false cord.
Extension to the anterior commissure may increase the
technical difficulty but is not considered an absolute
contraindication. Suitability of the patient for direct
laryngoscopy (neck extensibility and adequate mouth
opening) must also be primarily considered. After
endoscopic surgery, radiotherapy may be held in reserve
for further use.
Partial laryngeal resection in laryngofissure is a
surgical alternative for the same lesions: the disadvan-
tage of opening the thyroid cartilage is counterbalanced
by the exposure of the laryngeal structures obtained.
Various larynx ‘‘vertical’’ resections are well described
up to a complete emilaryngectomy. The anterior com-
missure and the upper part of the subglottic region can
also be easily resected.
6.1.5. Glottic and subglottic cancer (T2)
The management of these groups of patient is more
complicated because of heterogeneous characteristics of
the tumours. The probability of cure range from 50 to
85% among different series and may be predicted by
further subgrouping cases by dividing T2 into T2a
(normal cordal mobility) and T2b (impaired cordal
mobility). In T2a patients, radiotherapy is the recom-
mended treatment on a type R basis, as any surgical
option yields worse functional results. Despite differing
opinions reported in literature, local control seems to be
slightly better in surgical series particularly for T2b
lesions. The differences become insignificant when
considering the ultimate results, after eventual salvage
surgery, but in these cases, a total laryngectomy may
often be necessary. As the ultimate results are similar in
terms of cancer control, both options must be consid-
ered acceptable and the choice should be shared with the
patient. When the main aim of the patient is to reduce
the risk of a total laryngectomy, partial surgery is
recommended on an R basis. If the quality of voice is
the primary consideration, the recommended treatment
is radiation on an R basis.
If a total laryngectomy is proposed (tumours invol-
ving both true cords), radiation treatment is the
recommended option on an R basis, at least in patients
in good general condition, in which cases salvage
surgery after radiation does not represent a particular
risk. The radiation plan must be adequately considered:
doses exceeding 60/65 Gy should be avoided as they do
not significantly increase the control rates and make the
eventual salvage surgery critical.
The management of neck disease (Section 6.1.7) is still
controversial. In primarily operated patients, postopera-
tive irradiation is indicated where three or more meta-
static lymph nodes are present. Histopathological
features such as perineural involvement, insufficient or
positive resection margins and extracapsular extension
of metastatic adenopathies are associated with a dismal
prognosis and justify the application of a radiotherapy
in postoperative setting [62].
6.1.6. Advanced tumours (T3 /T4)
The probability of cure of advanced supraglottic
cancer is approximately 50% and is frequently asso-
ciated with neck metastasis in 30 /60% of cases. In 32%
of cases, there is a pathologic involvement even in
clinically staged N0 patients. Stage IV tumors are
associated with distant metastases in 30% of cases.
Advanced glottic cancer has a 30 /80% probability of
cure, depending on different prognostic factors includ-
ing the optimal treatment choice. Since there is a high
percentage of occult neck metastasis, neck treatment is
mandatory.
Advanced subglottic tumours tend to present late in
their course with frequent nodal involvement. Cure
probability is approximately 60%.
In every situation laryngeal preservation should be
the goal whenever feasible. Due to the lack of reliable
studies comparing surgery and radiotherapy in T3 /T4
cancer of the larynx, the treatment choice is still
controversial. Selection of patients may play a basic
role in treatment results.
In younger patients, and when at least one arytenoid
cartilage can be preserved and no or minimal subglottis
involvement is present, a subtotal laryngectomy with
crico-hyoido-pexy or crico-hyoido-epiglotto-pexy is sui-
table for individual clinical use [63 /65]. The main
 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
advantage of this procedure is the preservation of the
airway continuity, with the ultimate closure of the
tracheostomy. Disadvantages may arise from postopera-
tive dysphagia and low quality of postoperative voice. In
rare cases, the tracheostomy cannot be removed due to
airway stenosis (postoperative persistent oedema). Sur-
vival results are reported as high as those obtained with
total laryngectomy [66].
A radical or a modified radical neck dissection [67] is
routinely performed. Selective procedures (dissection of
levels II, III and IV) may be considered a standard
option in N0 patients. In every other case, the surgical
treatment implies a total laryngectomy.
In primarily operated patients, postoperative irradia-
tion is indicated in cases of bulky primary tumours,
or/and when three or more metastatic lymph nodes
are present. Histopathological features such as peri-
neural involvement, insufficient or positive resection
margins and extracapsular extension in metastatic
adenopathies are associated with a dismal prognosis
and justify the use of radiotherapy in postoperative
setting [62].
Even if radiation treatment alone is advocated by
many authors, local control rates reported with this
procedure are generally lower than with surgery, parti-
cularly in cases invading the thyroid cartilage: 40/60%
versus 70/80% and salvage surgery may be appropriate
in only 50% of the recurrences.
A well-known large randomized trial [49] demon-
strated that induction chemotherapy, followed by
radiotherapy in responsive patients can preserve the
larynx in more than 60% of surviving patients without
compromising the survival with respect to standard
surgery.
A recently conducted randomized trial showed prob-
ably a further improvement of larynx preservation rate
in patients treated with a concomitant chemoradiation
treatment, but essential data regarding functional status
of the larynx, late morbidity and late salvage surgery are
not yet available [50,68]: as a consequence, this ap-
proach must be considered still investigational or
suitable for individual clinical use. Although neither
concurrent nor neoadjuvant chemotherapy added survi-
val benefit, an organ preservation procedure should be
offered to all patients in good general conditions
candidates for total laryngectomy, with the exception
of patients with large T4 tumours. In consideration of
the data to date available, induction chemotherapy,
followed by radiotherapy in responsive patients repre-
sents the standard treatment on a type 1 level of
evidence. T4 tumors and infiltrative transglottic tu-
mours are still better treated with total laryngectomy.
The management of the neck (Section 6.1.7) is still
controversial.
75
6.1.7. Neck dissection
The optimal management of the node positive neck is
controversial and it depends on the policy of the treating
Institution: some centres routinely perform neck dissec-
tion irrespective of response whereas other advocate
withholding the procedure when a complete response in
the neck is achieved. The low salvage rate of neck
recurrences and the unreliability of clinical examination
suggest a role for planned neck dissection after con-
servative treatment. On the other hand, the presence of
pathological negative specimens at surgery and the
potential increase of surgical morbidity argue for
performing neck dissection only in cases of residual
neck disease [69].
Most studies included a small number of patients
and did not separate different head and neck sites. In a
recent paper, the role of residual disease neck dissection
of supraglottic carcinoma was studied in 121 cases.
The authors concluded that isolated regional relapse
after complete neck response was only 7.5%. Favorable
predictive factors of regional control are female
gender, accelerated fractionation and complete response
[70].
6.2. Recurrent disease
6.2.1. Local /regional relapse
Overall, the majority of loco-regional recurrences are
seen within the first year of treatment. Local recurrences
are generally fewer than regional relapses. The treatment
of choice is generally a total laryngectomy. It has been
reported that after a local and/or a regional recurrence
67% of patients with advanced laryngeal carcinoma
treated with induction chemotherapy and radiotherapy
were candidates for salvage surgery. The probability of
cure is approximately 50% [71]. If the patient has not
received radiotherapy, it may represent a treatment
choice. The concomitant use of chemotherapy is still
investigational.
6.2.2. Regional relapse
If the recurrence is in the untreated neck, the standard
treatment on a type C basis is neck dissection followed
by radiation therapy in selected cases. If neck recurrence
occurs after a properly performed dissection prognosis is
generally dismal and long-term control is probably
achieved in only 5% of cases.
If recurrence occurs in the neck previously treated
with radiotherapy or chemoradiation neck dissection
may afford a good local control if the disease is small
and without extracapsular spread. These conditions
occur infrequently.
76 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
6.3. Second head and neck primaries
When a second primary occurs in a head and neck
site, treatment such as surgery and/or radiotherapy has
to be modulated according to previous treatment. When
cancer appears distant from the previous carcinoma
radiotherapy, if indicated, can be delivered with appro-
priate field arrangements. Chemoprevention is not
currently standard therapy for the secondary prevention
of upper aerodigestive tract tumours [72].
6.4. Metastatic disease
6.4.1. Treatment aims
The treatment endpoints for patients with metastatic
disease are in the majority of cases palliative. Only in
few selected cases can cure be achieved.
6.4.2. Metastatic diffusion
The risk of distant metastases is low at presentation,
but is high as 30% during the follow-up for locally or
regionally advanced tumours.
A cisplatin-based chemotherapy regimen is the stan-
dard option for metastatic disease, on a type C basis. In
these cases, chemotherapy has only a palliative rose, and
the expected response rate does not exceed 40 /70% of
the treated patients, although less than one patient out
of five is expected to reach a complete response. Patients
with less extensive prior radiotherapy and no prior
chemotherapy, with a long disease-free interval and who
are experiencing their first relapse, have the best chance
to benefit from the treatment. The average duration of
complete responses is about 7 /8 months, and of partial
responses, 3 /4 months. The hypothesis that tumour
response correlates with increased quality of life has not
been formally tested within appropriate clinical trials. In
these cases, and in patients in good performance status,
a combination treatment is recommended on a type 2
level of evidence [73 /75]. In these studies, polyche-
motherapy offers an improved response rate over
monochemotherapy, although survival is generally not
affected. There is some evidence that chemotherapy may
improve survival of these patients [76].
Patients in poor general conditions may benefit, in
terms of response, from monochemotherapy (Section
6.4.3). Patients with a less than complete response after
front line therapy, or undergoing their second relapse,
have the worse chance of responding to treatment. In
these patients, adequate supportive care is appropriate
and chemotherapy is not recommended. The use of
taxoids as single agents and in combination has not been
proven to be superior to other single agent or combina-
tions.
6.4.3. Isolated lung metastasis
Surgery may play an active role in the treatment of
metastatic disease only where a single distant lesion has
occurred after a long disease-free interval (B/1 year).
There are published data only for lung metastases, with
5-year survival rates after resection ranging around 20/
30% [77,78]. In case of a single pulmonary lesion, it is
possible to differentiate a metastasis from a second lung
primary tumour. In this situation, an aggressive surgical
approach should be considered the recommended op-
tion, on a type R basis.
6.4.4. Chemotherapy schedules
Polychemotherapy. CF: (cisplatin 100 mg/m2 day 1
/
fluorouracil 1000 mg/m2 day 1, 2, 3, 4, 5, as continuous
infusion) q 21 days. Monochemotherapy. Cisplatin: 80/
100 mg/m2 days 1/21; methotrexate: 40 /50 mg/m2
weekly.
6.5. Radiotherapy
The role of radiotherapy in the treatment of recur-
rences at the site of the primary disease is still
investigational or suitable for individual clinical use: it
is limited to the irradiation of recurrences of small
volume within the larynx, preferably well lateralized, in
patients with relatively long relapse interval (
/3 years).
When a second primary occur in a head and neck site
distant from the previous carcinoma, field arrangement
has to be modulated according to the extension of the
portals of the first irradiation in order to avoid overlaps
over radio-sensitive structures such as spinal cord or
laryngeal cartilage.
7. Late sequelae
7.1. Treatment-induced late sequelae
After conservative surgery but also after full doses of
radiation with or without chemotherapy complications
may be aspiration pneumonia, prolonged dysphagia and
dyspnea which can delay decannulation significantly. In
some cases, a feeding tube is needed.
Quality of life evaluated by means of specific and
validated instruments show that laryngectomised pa-
tients have a poorer score in comparison to those
patients who have not undergone demolitive surgery.
These patients also reported more financial problems.
After laryngectomy and/or radiotherapy patients re-
ported fatigue, pain and appetite loss. Typical symptoms
after radiotherapy are dry mouth, sticky saliva and
coughing [79].
An increased risk of ischemic stroke has also been
reported in patients who have been treated with radio-
therapy to the neck [80].
 L. Licitra et al. / Critical Reviews in Oncology/Hematology 47 (2003) 65 /80
8. Follow-up
8.1. General principles and objectives
8.1.1. Aims of follow-up
Follow-up of patients treated for head and neck
cancer aims at early detection of loco-regional relapse
and the detection of second primary cancers, based on
the assumption that early detection of both recurrences
and second tumours are more likely to be cured. Second
malignancies develop in this patient population at a
constant rate of approximately 3 /6% per year.
The physician will have to look mainly for signs of
local and distant relapse; the risk of recurrence will be
the highest throughout the 3 years after completion of
treatment.
The follow-up includes careful clinical observation
both of the primary site, since salvage surgery can be
proposed in a significant number of patients with local
recurrence, and along the neck node chains, since
isolated lymph node recurrences may also be salvaged
by neck dissection. In a general population treated
curatively for head and neck cancer approximately
30% will develop a recurrence. Two-third of them will
recur during the first 2 years and approximately 10%
during the third year of observation. In about 60% of
patients with recurrence relapse is diagnosed through
signs and symptoms; in the rest it is by clinical
examination. Recurrences at the site of the primary
tumour can be salvaged successfully in approximately
40% of patients, particularly in those patients treated
with radiotherapy alone or with limited surgery. Regio-
nal recurrence will occur in approximately 15% of cases;
one-third of them can be cured by salvage neck
dissection.
8.2. Suggested protocols
8.2.1. Loco-regional and general examinations
A first ENT examination should be performed 2/3
months after treatment completion. The next evalua-
tions should be scheduled every 2/3 months in the first 2
years, then every 4/5 months for the third year and on
an annual basis after the third year [81 /84]. Follow-up
should also include radiological investigations (CT,
MR) to assess tumour response to treatment. The role
of PET in follow-up of head and neck cancer patients
has been recently evaluated and it may be superior, as
compared with conventional imaging, in predicting a
recurrent disease, in particular after irradiation [85].
After treatments combining radio- and chemother-
apy, laboratory testing will aim at monitoring bone
marrow, liver and kidney function parameters as well as
thyroid function after neck irradiation.
77
8.2.2. Early diagnosis of second primaries and/or
metastasis
Since the potential of developing a second cancer is
high, even in the absence of any signs or symptoms, a
thorax X-ray is usually performed on a yearly basis,
even if there is no clearly demonstrable benefit from
performing it [86,87]. Other examinations such as
oesophagoscopy are not routinely performed.
Radiological examinations of other possible asympto-
matic sites of metastasis such as liver and bone is
probably not useful for improving survival of the
patient.
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Biographies
Lisa Licitra is Clinical Editor of the START
Programme. She is assistant researcher in the field
of head and neck cancer at Istituto Nazionale Tumori-
Milan, Italy, and Chairperson of the sub-Committee
for Chemotherapy of the EORTC Head and Neck
Group.
Jacques Bernier is Chairman of the Radio-Oncology
Department of the Oncology Institute of Southern
Switzerland-Bellinzona, Switzerland, and Private Doc-
ent at the University of Geneva, Switzerland.
Cesare Grandi is Head of the Otolaryngology Depart-
ment at the General Hospital S. Chiara-Trento, Italy,
and Chairperson of the sub-Committee for Surgery of
the EORTC Head and Neck Group.
Laura D. Locati is Medical Oncologist at Head and
Neck Department at Istituto Nazionale Tumori-Milan,
Italy.
Marco Merlano is Head of the Clinical Oncology
Department, Chief of Medical Oncology Unit, at S.
Croce General Hospital-Cuneo, Italy.
Gemma Gatta is research assistant at the Epidemiol-
ogy Unit, Istituto Nazionale dei Tumori-Milan, Italy.
Jean Louis Lefebvre is Professor of ENT and Head
and Neck Surgery, Chief of the Head and Neck
Department at Centre Oscar Lambret-Lille, France,
and currently Deputy Director of this Centre.