Cancer Treatment Reviews (2006) 32, 504– 515
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/ctrv
ANTI-TUMOUR TREATMENT
Current opinion in diagnosis and treatment of
laryngeal carcinoma
Gino Marioni a,*,c, Rosario Marchese-Ragona
Fortunata Marchese b, Alberto Staffieri a
a,c
, Giuseppe Cartei b,
a
Department of Medical and Surgical Specialties, Section of Otolaryngology, University of Padova,
Via Giustiniani 2, 35100 Padova, Italy
b
UOC Medical Oncology, 1st floor, Istituto Oncologico Veneto, IRCCS, Padova, Italy
Received 3 March 2006; revised 28 June 2006; accepted 3 July 2006
KEYWORDS
Summary Laryngeal carcinoma is the 11th commonest form of cancer in men world-wide,
with 121,000 new cases in 1985. More than 95% of all laryngeal malignancies are squamous cell
carcinomas.
Treatment indications in cancer of the larynx are often controversial, since there are few
comparative studies of different available therapeutic approaches. Surgery and radiotherapy
are both widely used, and the choice between these two procedures is the most common therapeutic decision which has to be taken. Laryngeal function preservation has gained more and
more weight in the last decades and chemotherapy is also a significant component of several
curative approaches. In the last decades, several organ-preserving surgical techniques have
become available and consequently total laryngectomy results less applied. Regardless of the
treatment modality, Tis, T1, T2 laryngeal carcinomas have an 80–90% probability of cure,
whereas for more advanced tumours this is approximately 60%.
The most effective approach to laryngeal cancer remains prevention and early diagnosis
when this cancer is curable with function preserving treatments.
c 2006 Elsevier Ltd. All rights reserved.
Laryngeal carcinoma;
Diagnosis;
Staging;
Treatment;
Follow up
Anatomy
* Corresponding author.
E-mail address: [email protected] (G. Marioni).
c
G.M. and R.M.R. contributed equally to the preparation of this
manuscript.
For clinical and staging purposes, the larynx is currently
divided in supraglottic, glottic and subglottic regions.1
Essential laryngeal anatomy is synthesised by Table 1.
Considering the significant metastatic potential of laryngeal carcinoma to the cervical lymph nodes, concise notes
0305-7372/$ - see front matter c 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctrv.2006.07.002
Current opinion in diagnosis and treatment of laryngeal carcinoma
Table 1
Essential laryngeal anatomy
Regions
Subsites
Supraglottis
suprahyoid epiglottis
aryepiglottic fold
arytenoids
infrahyoid epiglottis
ventricular bands
vocal folds (cords)
anterior commissure
posterior commissure
Glottis
Subglottisa
Remarks: That part of the submucosal space anteriorly to the
epiglottis is called the pre-epiglottic space; lateral to the preepiglottic space are the paired paraglottic spaces. The paraglottic space is a laryngeal space bounded inferiorly by the conus
elasticus, medially by the quadrangular membrane, posteriorly
by the mucosa of the piriform fossa, and antero-laterally by the
thyroid cartilage.
a
The subglottic region conventionally begins 5 mm below the
free edge of the true vocal folds extending to the lower border
of the cricoid cartilage.
of clinical anatomy of cervical lymphatics are mandatory. A
widely accepted level-based system can be synthesized as
follows:
Level I: submental (IA) and submandibular (IB) lymph
nodes;
Levels II (IIA enterior to the vertical plane defined by
spinal accessory nerve; IIB posterior to the vertical plane
defined by spinal accessory nerve), III and IV: upper, middle, and lower jugular lymph nodes, respectively;
Level V: posterior triangle group is composed predominantly by the lymph nodes located along the lower half
of the spinal nerve and the transverse cervical artery;
Level VI: anterior compartment group: pretracheal and
paratracheal nodes, precricoid node, and the perithyroidal nodes including the lymph nodes along the recurrent
laryngeal nerves.2
Epidemiology
Laryngeal carcinoma is the 11th commonest form of cancer
in men world-wide, with 121,000 new cases in 1985.3 It is
one of the most common malignancies in Europe, with about
52,000 new cases per year;4 approximately 9500–11,000
new cases of laryngeal cancer are estimated to occur yearly
in the United States.5,6 The yearly incidence rate for men in
southern and northern Europe is between 18 per 100,000
and 6 per 100,000, respectively. For women, incidence rate
is not higher than 1.5 per 100,000 per year.4
Significant variations in the distribution of carcinoma at
different sites within the larynx have been observed. In
southern Europe, supraglottic carcinoma is more common
than glottic carcinoma, whereas the reverse is true for
north-western Europe.7 Carcinomas of the glottis are predominant in Anglo-Saxon populations; in the Black populations of the United States, the number of glottic and
supraglottic tumours are approximately equal.8
505
Signs and symptoms
The most important functions of the larynx are to provide
airway patency, protect the tracheo-bronchial tree from
aspiration, and allow phonation. Tumours that involve the
larynx may impair these function in a variable degree
depending on location, size and depth of invasion. The presence of hoarseness, sore throat, shortness of breath, dysphagia or ‘‘lump in throat’’ sensation are all symptoms
observed in early or moderately advanced stages of laryngeal cancers. Since lymph node metastases are frequently
the first clinical sign of laryngeal carcinoma, swelling of cervical soft tissues, in the absence of evident signs of infection, should be carefully evaluated.7
Supraglottic cancers present at later stage of disease
typically with sore throat, odynophagia, referred ear
pain, change in voice quality, or enlarged neck nodes.
Glottic cancers are usually detected because of hoarseness occurrence, airway obstruction occurs later in disease progression. Cancers arising in the subglottic area
are rare and present with airway obstruction or vocal fold
immobility.
It is recommended that patients with hoarseness persisting longer than 3 weeks or with persisting sore throat,
dysphagia, odynophagia lasting for more than 6 weeks
are referred from a general practitioner to an otolaryngologist.9
Histology
More than 95% of all laryngeal malignancies are squamous
cell carcinomas.10,11 Less common phenotypic expressions
of this malignancy can occur. Verrucous squamous cell carcinoma is a locally aggressive but usually non-metastasizing
highly differentiated variant.
Table 2 summarizes the histologic typing of primary laryngeal malignancies.
Distant metastases to the larynx are extremely uncommon occurrences (60.2%).12 Cutaneous melanomas are the
preponderant primaries metastasizing to the larynx, followed by renal cell carcinomas, and carcinomas of the
breast and lung, respectively.
Risk factors
Tobacco is the predominant risk factor in laryngeal carcinogenesis. Alcohol is generally regarded as the second
major risk factor. In most series, >95% of patients with
squamous cell carcinoma of the larynx have a background
of tobacco and/or alcohol consumption prior to tumour
diagnosis. The appearance of laryngeal cancer has been
related to other factors, such as environmental exposure
(evidence does not support asbestos exposure itself as
increasing the relative risk of laryngeal cancer), gastroesophageal and biliary reflux, viral infection (oncogenic
types of human papilloma virus), dietary factors, radiation
and individual predisposition. When it rarely occurs in
childhood and adolescence, laryngeal carcinoma seems
to be a genetic disease associated with specific chromosomal damage.13
506
G. Marioni et al.
Table 2 Histologic typing of primary laryngeal malignancies according to WHO, 199175
Epithelial tumours
Squamous cell carcinoma
Verrucous squamous cell carcinoma
Spindle cell carcinoma
Adenoid squamous cell carcinoma
Basaloid squamous cell carcinoma
Adenocarcinoma
Acinic cell carcinoma
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Carcinoma in pleomorphic adenoma
Epithelial-myoepithelial carcinoma
Clear cell carcinoma
Adenosquamous carcinoma
Giant cell carcinoma
Salivary duct carcinoma
Carcinoid tumour
Atypical carcinoid tumour
Small cell carcinoma
Lymphoepithelial carcinoma
Soft tissue tumours Fibrosarcoma
Malignant fibrous histiocytoma
Liposarcoma
Leiomyosarcoma
Rhabdomyosarcoma
Angiosarcoma
Kaposi sarcoma
Malignant hemangiopericytoma
Malignant nerve sheath tumour
Alveolar soft part sarcoma
Synovial sarcoma
Ewing sarcoma
Tumours of bone
Chondrosarcoma
and cartilage
Osteosarcoma
Malignant
lymphomas
Miscellaneous
Malignant melanoma
tumours
Malignant germ cell tumours
Secondary tumours
Unclassified tumours
Biologic and clinical behaviour
Primary laryngeal squamous cell carcinoma
development
Pre-invasive lesions (dysplasia and carcinoma in situ) are
characterized by atypical or malignant cytologic features
encompassed within the laryngeal squamous epithelium.
Dysplasia shows cells which have features of malignancy,
but which do not breach the basement membrane to reach
into the adjacent lamina propria. In the natural history of
laryngeal cancer, both dysplasia and carcinoma in situ of
the laryngeal mucosa may subsequently evolve into an invasive neoplasm. It is also a fact that laryngeal cancers may
develop directly as invasive neoplasms and do not pass
through the stage of carcinoma in situ. Squamous cell carcinoma is by its definition invasive.14
Cervical lymph nodes metastases
The supraglottic area is richly supplied with lymphatics, and
invasive carcinomas of the supraglottic region metastasize
in 25–75% of cases when all stages are considered.15 Bilateral metastases are not unusual16 being the supraglottis a
midline structure.
Although early stage glottic carcinoma (T1–T2) is accepted to have a low incidence of lymph node metastasis
(0–10%), the reported incidence with more advanced stage
disease (T3–T4), varies between 10% and 35%.17 The cervical lymph nodes at high risk in advanced (T3 and T4) glottic
cancers include levels II–III–IV and VI.18
Unusual primary subglottic carcinomas spread initially to
the paratracheal and recurrent lymph nodes. The jugular
chain of lymph nodes should be considered as a secondary
site of lymphatic spread for subglottic cancers.
Distant metastases
Distant metastases from laryngeal squamous cell carcinoma
are significantly less frequent than metastases from other
human malignancies. Considering 1667 primary laryngeal
carcinomas, Spector19 reported an overall incidence of distant metastases of 4.4%. In this series, the incidence of distant metastases in supraglottic carcinomas was 3.6% (19/
520 patients). The incidence of distant metastases from
supraglottic carcinomas was not related to primary tumour
stage but to N stage. The incidence of distant metastases in
1119 glottic carcinoma patients was 4.4% (related to T
stage). Primary subglottic SCC had a 14.2% distant metastasis rate (non-TNM stage-related). Incidences of distant
metastasis described in autopsy studies were approximately
three to four times higher than those reported in clinical
studies.20 Lung metastases are the most commonly found,
followed by metastases to bone and liver. Other areas of
metastasis from laryngeal carcinoma included skin, brain,
kidney, adrenal glands, pleura.
Diagnostic strategy and tools
Clinical assessment
The staging for laryngeal cancers is based on laryngeal subsites invasion, vocal cord mobility, and neck involvement.
An outpatient setting examination with flexible and rigid
laryngoscopes with or without local anaesthesia should assess the lesion extension and vocal cord mobility. The flexible fibro-rhinolaryngoscope has increased the reliability of
endoscopy in patients whose larynx was previously difficult
to visualize.
Direct laryngoscopy under general anaesthesia may be
useful to allow precise definition of tumour extension, to explore sub-sites as anterior commissure, laryngeal ventricle,
subglottis, and pyriform sinus, and to perform lesion biopsies.7 In cases of advanced laryngeal carcinomas, a fibroscopic evaluation of the esophagus is mandatory to rule out
a synchronous malignancy of the upper digestive tract.21
Considering laryngeal carcinoma metastatic pattern
involving neck lymph nodes, neck instrumental investigation
is mandatory. The reported false negative rate in assessing
Current opinion in diagnosis and treatment of laryngeal carcinoma
the presence or absence of cervical lymph node metastasis
by palpation is 20–51%.22
Imaging
With the exception of small superficial carcinomas, computerized tomography (CT) and magnetic resonance imaging
(MRI) are nowadays useful radiological procedures for staging primary laryngeal carcinoma. Both exams can offer
information about primary tumour volume (especially in
large lesions), cartilage involvement, invasion of the preepiglottic space, and extension beyond the larynx. Regarding cartilage invasion, MRI is a sensitive method to detect
cartilage alterations having a high negative predictive value. CT results less sensitive than MRI.23 False positive results seem to be inevitable with both methods because
reactive inflammation may lead to overestimation of neoplastic cartilage invasion.24 Positron emission tomography
(PET) is most helpful in differentiating locally recurrent tumour from post-irradiation tissue sequelae after organ preservation approaches.25
Ultrasonography is a sensitive method for detecting neck
metastatic involvement. On the other hand, ultrasound does
not reliably differentiate large reactive lymph nodes from
metastatic ones. Ultrasonography combined with fine needle aspiration cytology is a reasonably accurate technique
for the investigation of cervical lymph node metastases
from laryngeal carcinoma. Reported figures of the accuracy
of fine needle aspiration cytology guided by ultrasonography
range between 89% and 97%.26 Substantial literature supports the value of both CT and MRI scans in clinical staging
of cervical lymph nodes. An 87–93% accuracy of CT scan in
neck staging has been reported.27 MRI evaluation of cervical
nodal metastases is less well documented but available data
suggest comparable sensitivity and specificity.27
Although in literature it has been suggested that routine
work-up to detect distant metastases in patients with head
and neck squamous carcinoma is not feasible, standard staging work-up in several institutions include chest X-rays, liver
ultrasonography, alkaline phosphatase determination. The
guidelines for determining which patients with advanced
laryngeal carcinoma should undergo specific imaging evaluation for distant metastasis are still under debate. De Bree
et al.28 proposed distant metastases screening for patients
with head and neck carcinoma who had three or more neck
lymph node metastases, bilateral lymph node metastases,
lymph nodes of 6 cm or larger, low jugular lymph node
metastasis, locoregional tumour recurrence, or second primary tumours. Interesting techniques for detection of distant metastases (thallium-201 single-photon-emission
computed tomography, fluorine-18-fluorodeoxyglucose positron emission tomography [FDG PET], radioimmunoscintigraphy) have been developed but need further evaluation
for clinical applicability.
507
Conventional light microscopy following hematoxylin and
eosin staining usually allows laryngeal squamous cell carcinoma histological diagnosis. Histopathologically, invasive
squamous cell carcinoma is conventionally graded as follows:
well differentiated (G1);
moderately differentiated (G2);
poorly differentiated (G3).
Immunohistochemical reactions and electron microscope
analysis are not considered necessary to confirm the diagnosis of squamous cell carcinoma in the majority of the cases.
Immunohistochemically, squamous cell carcinoma of the
larynx is usually positive for cytokeratins and epithelial
membrane antigen. The application of electron microscopy
can assist diagnosis of neoplasms considered as undifferentiated at light microscopy evaluation.
Conventional histopathological evaluation after hematoxylin and eosin staining of the neck dissection specimens
allows the definitive diagnosis of cervical lymph nodes
metastases from laryngeal carcinoma. The histological confirmation of extranodal metastatic spreading is extremely
important in adjuvant treatment planning.
Stage information
The staging system estimates the extent of disease before
(cTNM) and after treatment (pTNM). Head and neck CT or
MRI should be done prior to the therapy to supplement
inspection and palpation. The carcinoma presence has to
be confirmed histologically, and any other pathological data
obtained on biopsy may be included. The sixth edition
(2002) of the International Union against Cancer (UICC)
TNM classification30 (Tables 3 and 4) is identical to that of
the American Joint Cancer Committee (AJCC) (sixth edition,
2002)31 (for AJCC stage groupings see Table 5).
Treatment of laryngeal primary carcinoma
Regardless of the treatment modality, Tis, T1, T2 laryngeal
carcinomas 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 controversial, since there are few comparative studies of the
different available therapeutic approaches.7 Surgery and
radiotherapy are both widely used, and the choice between
these two procedures is the most common therapeutic decision which has to be taken. Function preservation has
gained more and more weight in the last decades and, from
this viewpoint, chemotherapy is now also a significant component of several curative approaches.32 In the last decades, several organ-preserving surgical techniques have
become available and consequently total laryngectomy results less applied.
Pathological diagnosis
Supraglottic cancer
Biopsy is mandatory to confirm the diagnosis of laryngeal
squamous cell carcinoma. Biopsy should be deep and reach
necrotic tumour and viable tumour and stroma or muscle to
prove the presence of an invasive squamous cell carcinoma.29
Small superficial cancers without laryngeal fixation or lymph
node metastatic involvement (T1N0 and T2N0) are successfully treated by radiation therapy or surgery alone, including laser excision.
508
Table 3
G. Marioni et al.
TNM definitions (T-stage)
Regions
T-stage
Description
Supraglottis
T1
Tumour limited to one subsite of supraglottis
with normal vocal cord mobility
Tumour invades mucosa of more than one
adjacent subsite of supraglottis or glottis or
region outside the supraglottis (e.g., mucosa
of base of tongue, vallecula, or medial wall
of pyriform sinus) without fixation of the
larynx
Tumour limited to larynx with vocal cord
fixation and/or invades any of the following:
post-cricoid area, pre-epiglottic tissues,
paraglottic space, and/or minor thyroid
cartilage erosion (e.g., inner cortex)
Tumour invades through the thyroid
cartilage, and/or invades tissues beyond the
larynx (e.g., trachea, soft tissues of the neck
including deep extrinsic muscle of the
tongue, strap muscles, thyroid, or
esophagus)
Tumour invades prevertebral space, encases
carotid artery, or invades mediastinal
structures
T2
T3
T4a
T4b
Glottis
T1
T2
T3
T4a
T4b
Subglottis
T1
T2
T3
T4a
T4b
Tumour limited to the vocal cord(s), which
may involve anterior or posterior
commissure, with normal mobility; T1a:
tumour limited to one vocal cord, T1b:
tumour involves both vocal cords
Tumour extends to supraglottis and/or
subglottis, and/or with impaired vocal cord
mobility
Tumour limited to the larynx with vocal cord
fixation and/or invades paraglottic space,
and/or minor thyroid cartilage erosion (e.g.,
inner cortex)
Tumour invades through the thyroid cartilage
and/or invades tissues beyond the larynx
(e.g., trachea, soft tissues of neck, including
deep extrinsic muscle of the tongue, strap
muscles, thyroid, or esophagus)
Tumour invades prevertebral space, encases
carotid artery, or invades mediastinal
structures
Tumour limited to the subglottis
Tumour extends to vocal cord(s) with normal
or impaired mobility
Tumour limited to larynx with vocal cord
fixation
Tumour invades cricoid or thyroid cartilage
and/or invades tissues beyond the larynx
(e.g., trachea, soft tissues of neck, including
deep extrinsic muscles of the tongue, strap
muscles, thyroid, or esophagus)
Tumour invades prevertebral space, encases
carotid artery, or invades mediastinal
structures
Remarks: TX: primary tumour cannot be assessed; T0: no evidence of primary tumour; Tis: carcinoma in situ.
Current opinion in diagnosis and treatment of laryngeal carcinoma
Table 4
509
TNM definitions (N-stage)
N-stage
Description
Nx
N0
N1
N2a
N2b
N2c
N3
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Metastasis in a single ipsilateral lymph node, 63 cm in greatest dimension
Metastasis in a single ipsilateral lymph node >3 cm but 66 cm in greatest dimension
Metastasis in multiple ipsilateral lymph nodes, 66 cm in greatest dimension
Metastasis in bilateral or contralateral lymph nodes, 66 cm in greatest dimension
Metastasis in a lymph node >6 cm in greatest dimension
Remarks: Midline nodes are considered homolateral nodes.
Table 5
AJCC Stage groupings
Stage group
TNM staging
0
I
II
III
IVa
Tis N0 M0
T1 N0 M0
T2 N0 M0
T3 N0 M0; T1 N1 M0; T2 N1 M0; T3 N1 M0
T4a N0 M0; T4a N1 M0; T1 N2 M0;
T2 N2 M0; T3 N2 M0; T4a N2 M0
T4b any N M0; any T N3 M0
Any T, any N, M1
IVb
IVc
The major controversies, therefore, surround the selection of treatment for lesions of intermediate size (advanced
T2 and T3). For T2 and T3 supraglottic tumours not involving
the glottic plane and the arytenoids, a horizontal supraglottic laryngectomy is considered the standard treatment. In
supraglottic laryngectomy, the portion of the larynx above
the ventricles (the epiglottis, pre-epiglottic space, false vocal cord, the upper segment of thyroid cartilage, and sometimes hyoid bone) are excised. After this procedure that
spares the vocal cords, functional results are good. This
operation can also be carried out in cases where there is
limited extension to the valleculae and the tongue base.
The resection may also be extended laterally, to encompass
limited tumours of the pyriform sinus, and posteriorly, to include one arytenoid cartilage. Stage for stage, supraglottic
laryngectomy tends to result in better local control rates
than radiotherapy (RT).33 In T3 supraglottic cancers that involve the glottis (also with inner cortex thyroid cartilage
erosion) or the paraglottic space and when at least one arytenoid cartilage can be preserved and no subglottic involvement is present, a partial supracricoid laryngectomy (SCL)
with crico-hyoido-pexy or crico-hyoido-epiglotto-pexy can
be considered. With these procedures, the entire thyroid
cartilage and both vocal cords are removed, the cricoid,
at least one arytenoid with or without the upper half of
the epiglottis are preserved. The advantage of this procedure is the preservation of the airway continuity, with the
aim of normal oral intake, tracheostomy closure and good
oncologic results.34–36 Main postoperative complication
are humble voice quality and dysphagia. Total laryngectomy, exclusive RT, RT-chemotherapy associations have to
be reserved for patients with advanced T3, T4 lesions or
with poor general conditions or unable to tolerate potential
respiratory complications of partial surgery.
Glottic cancer
Radiotherapy, open surgery and endoscopic surgery with
cold steel or laser resection are all accepted modalities of
treatment for early stage glottic cancer (Tis/T1/T2, N0). A
recent review compared the effectiveness of these commonly used treatments of early glottic cancer and found that
there is not enough evidence to show which form of treatment might be better.37 Endoscopic laser surgery has nowadays gained increasing popularity. The major advantages of
the procedure are the preservation of the thyroid cartilage
and significant resource savings (one-day case procedure).
Indications and results are crucially dependent on the experience of the surgeon. Extension to the anterior commissure
may increase the technical difficulty but it is not considered
an absolute contraindication. After endoscopic surgery,
radiotherapy may be held in reserve for further use.7
In the treatment of T1b and T2 glottic cancers recently
several authors proposed SCLs with good oncologic and
functional results. Laccourreye et al.38 reported a 98% actuarial 5-year local control estimate for 62 patients with T1b
or T2 cancer extending to the anterior commissure. Various
vertical partial laryngectomies were also described in the
treatment of these cancers. Considering that SCL allows
more extensive excision of the paraglottic space, several
authors achieved better oncologic results after SCL than
after vertical partial laryngectomies in the treatment of
glottic T2–T3 tumours.39
The classical treatment for T3 glottic carcinoma was total laryngectomy and neck dissection often followed by
radiotherapy. In patients with T3 glottic cancers without
subglottis involvement, when at least one arytenoid cartilage can be preserved, a SCL with crico-hyoido-pexy or crico-hyoido-epiglottopexy may be suitable.36 Chevalier et al.
reported a 5-year actuarial local control rate of 95.4% in 22
patients with T3 cancer treated with SCL. SCL seems to allow a significant increase in local control rate (85–90%) and
ultimate survival when compared with RT alone or other
conservative options.40 Other authors reported good oncological results with this stage tumours with endoscopic laser
resection. Recently promising outcomes were described
after combined treatment modalities (RT/chemotherapy)
that should be reserved to the cases not suitable for partial
laryngectomies.41,42
The treatment of glottic T4a cancers is total laryngectomy with ipsilateral thyroidectomy, ipsilateral comprehensive neck dissection with or without contra-lateral selective
neck dissection.43
510
Subglottis cancer
Primary subglottic cancer is uncommon, representing between 1% and 3.6% of all laryngeal cancers. Consequently,
there is dearth of literature reporting treatment outcomes.
T1–T2 lesions can be treated successfully by radiation
therapy alone with preservation of normal voice. Surgery
is reserved for failure of radiation therapy.44 Laryngectomy
plus thyroidectomy and level VI lymph nodes dissection usually followed by postoperative radiation therapy is reserved
for advanced T3–T4 subglottic cancers.45
Advanced laryngeal cancer: surgical approach
Total laryngectomy is still commonly performed in malignancies extending beyond the larynx or after conservative
therapy failures or in patients not otherwise candidates
for organ-preserving strategies. Total laryngectomy implies a permanent tracheostoma and voice loss with permanent separation of the upper respiratory and digestive
tracts. Speech rehabilitation has become an integral part
of these laryngeal cancers treatment. Speech rehabilitation may include electrolaryngeal speech, esophageal
speech, or tracheoesophageal puncture (TEP). The electrolarynx is a vibratory sound wave generator that is usually placed directly on the skin of the submandibular area.
The result is a monotone, electronic-sounding speech.
Some patients are taught to control the release of air
through the upper esophageal sphincter producing an
esophageal speech. TEP is a surgical shunt between the
posterior tracheal wall and the pharynx that may be performed either at the time of laryngectomy or secondarily.
This shunt is fitted with a silicon valve that allows the
passage of air from the trachea to the pharynx preventing
food and liquid penetration into the airway: occluding the
stomal opening, air passes into the pharynx with a fluent
speech production.
Advanced laryngeal cancer: non-surgical
treatments
In 1991 a landmark trial conducted by the Department of
Veterans Affairs Laryngeal Cancer Study Group,46 compared
chemotherapy (cisplatin plus 5-fluorouracil) followed by
radiotherapy vs surgery plus adjuvant radiotherapy. Laryngectomy followed by radiotherapy was performed in patients who did not achieve at least a partial response to
the induction therapy or as salvage approach. Sixty-four
percent of the patients who had received the non-surgical
treatment did not undergo laryngectomy. Two-year survival
rate was 68% in both groups. No significant differences in
survival rates has been reported after more than a 10-year
follow-up period. Less promising results of a French47 study
(2-year survival rates were 69% in the induction chemotherapy group and 84% in the no chemotherapy group) did not
lead clinicians to abandon the idea of laryngeal
preservation.
Current chemotherapy for head and neck carcinoma is
based on 5-fluoruracil and platin (P) combination (PF) in
several varieties according to the day/dose of 5-fluoruracil
(from 750 to 1200 mg/m2/day for 5 to 5 days; from
G. Marioni et al.
continuous infusion to other schedules) and P (from 100 to
65 mg/m2 day) every 21 days. Such a combination results
superior to single agents or other classic combinations. 48–51
Newer combination regimens are based on P (100 mg/m)
with paclitaxel (135–200 mg/m2) every three weeks, with
a Response Rate from 34 to 48%. The median survival after
palliative therapy was 6.5–7.5 months.52,53 Others have
added ifosfamide or docetaxel to PF, gaining a better response rate, with greater toxicity.54,55 Thus, at the moment
there is not a ‘‘reference’’ regimen besides the older PF and
the above quoted chemotherapy types should undergo clinical trials. It is known that chemo-sensitive cancers are
more frequently radiosensitive, and radiotherapy results
may be previewed on the base of the response rate obtained
with chemotherapy.
The currently used chemotherapy is synergistic or at
least additive to radiotherapy in terms of anticancer efficacy. However toxicity is enhanced as well, and the local
toxicity generally stands as the worst. Platin exerts a
peripheral nervous system exquisite toxicity, that is
especially manifest in head neck carcinoma field after
simultaneous radiotherapy. Swallowing dysfunction after
chemo-radiotherapy should be expected. Aspiration pneumonia, prolonged dysphagia and dyspnoea may complicate
conservative surgery after full doses of radiation plus
minus chemotherapy. A first question might be: is a random phase III study worthwhile of the two less toxic carboplatin or oxaliplatin and 5-fluoruracil versus the classic
Platin and 5-fluoruracil? Can be currently used a sparing
peripheral nervous system toxicity, as pyridoxine56 or a
lipoic acid?57 Before instituting chemotherapy, we should
be informed of patient’s specific tolerance of 5-fluoruracil
and P by means of the normal tissue pharmagenomics.
Di-hydropirimidine deidrogenase for the 5-fluoruracil,
metilentetrahydrofolate-reduttase for toxicity of antifolates (metothexate, pemetrexed) and 5-fluoruracil, and
UDP-glucorosil-transferase-A1 for toxicity of the antitopoisomerase irinotecan should be measured in circulating
peripheral nucleated cells. Also red blood cell-folate,
plasma Vit B12 and omocysteine determination can help
as well in knowing some possible metabolic defects, especially in the alcoholists or cirrhotics with laryngeal cancer,
that can be pharmacologically corrected. The risk of
ischemic stroke in patients radiated to the neck should
also be monitored by the study of coagulation, glucose,
lipids and urate metabolisms, and by supraortic-arteries
echo Doppler.
When chemotherapy is neoadjuvant, or adjuvant after
surgery and radiotherapy, could we plan newer chemotherapy regimens based on antitopoisomerases drugs associated
with the platin salts? In our experience the Topoisomerases
I, IIa and IIb rise much and steepy after a DNA-antiblastic
damage. In these patients the administration of antitopoisomerases drugs blocks almost completely the topoisomerase rise.58 The antitopoisomerases drugs could be added
to platin after a pharmacological demonstration of utility
in the single patient.
Severe late complication following concurrent chemoradiotherapy are common. A recent analyses of the RTOG
(Radiation Therapy Oncology Group, Philadelphia) experience concerning 226 evaluable patients allows to consider
independent risk factors the following: older age, advanced
Current opinion in diagnosis and treatment of laryngeal carcinoma
T-stage and larynx-hypopharynge primary site. Also, neck
dissection after concurrent chemo-radiotherapy plays a risk
role.59 The meta-analysis of radiotherapy in head and neck
carcinomas by Bourhis et al60 shows that the treatments
benefit decreases with increasing age.
The recommendations by Gilbert and Forastiere61 about
chemotherapy, either neoadjuvant or concomitant or adjuvant for organ preservation, indicate the state of art at the
beginning of 2004. That by Lefebvre and Calais62 highlights
the ‘‘ètat de la question’’ at the 2005. Both recommendations should be kept in mind.
In laryngeal oncology as in other oncological fields, the
place of newer drugs as taxanes has to be explored.
According to a French multicenter experience in advanced
laryngeal cancer the combination of platin, 5-fluoruracil
and Docetaxel (T) (PFT) leads to a significantly superior
overall response rate compared to the PF regimen.63
Toxicity was reduced because of lesser doses of P and
5-fluoruracil. The postoperative concurrent PF and radiotherapy versus radiotherapy alone has been randomly
studied in a phase III trial in Germany, in 440 patients
with high risk head and neck carcinoma. The combination
that improved both locoregional control and progression
free survival (by 10% after 5 years)64 had an ‘‘acceptable’’ toxicity.
Increased expression of Epidermal Grow Factor Receptor
(EGFR) in head and neck carcinoma has been correlated
with poor prognosis. Neoadjuvant Erlotinib (EGFR Tyrosine-Kinase inhibitor) is well tolerated.65 This drug will be
included in promising controlled trials.
Previously reserved for palliation, chemotherapy is now
also a central component of several curative approaches
to the management of patients with advanced-stage head
and neck cancer.
Table 6
Recurrent laryngeal cancer
Small superficial recurrent cancers without laryngeal fixation or lymph node involvement are successfully treated
by radiation therapy or surgery alone, including endoscopic
laser excision surgery.66
On the other hand more than 80% of the recurrent tumours are staged as rT3 or rT4. Total laryngectomy is considered the treatment of choice in the majority of these
cases of laryngeal carcinoma relapse after partial laryngeal
surgery or radiotherapy. Selected recurrent laryngeal cancers may be candidated for partial laryngectomy also after
high-dose radiation therapy failure.67,68 The identification
of chemotherapy agents active in head and neck cancer first
occurred in patients with recurrent disease who were being
treated with palliative intent. Historically, the most active
single agent is cisplatin, with phase II response rates of up
to 30% and median survivals of about 6 months. Methotrexate, carboplatin, fluorouracil, and ifosfamide are also active
in this disease, with phase II response rates of less than 30%.
Among the newer generation of drugs, the taxanes, docetaxel and paclitaxel, have significant activity in head and
neck cancer recurrence.32
Treatment of cervical lymph node metastases
Concise notes regarding surgical classification of neck dissection types are synthesized in Table 6.
Treatment of clinically positive neck
The comprehensive neck dissection is performed in patients
with clinical evidence of lymph nodes metastasis.
Neck dissections classification2
Comprehensive neck dissection
Radical neck dissection
Modified radical neck
dissection
Selective neck dissection (SND)a
SND (I–III)
SND (II–V)
SND (II–IV)
SND (VI)
Extended neck dissection
a
511
Removal of all the lymph node levels I–V and
sacrifices the spinal accessory nerve, the
internal jugular vein, and the
sternocleidomastoid muscle
Removal of all the lymph node levels I–V and
preservation of one or more non-lymphatic
structures. In type I, only the spinal
accessory nerve is preserved; in type II, both
the spinal accessory nerve and the internal
jugular vein are spared; in type III, all the
three above mentioned non-lymphatic
structures
Removal of levels I, II, III
Removal of the nodes in levels II–V and the
suboccipital and retroauricular nodes
Removal of levels II, III and IV
Removal of level VI, surrounding the visceral
structures of the anterior compartment of
the neck are removed
Additional lymph node groups and/or nonlymphatic structures not encompassed by the
radical neck dissection are removed
Selective neck dissection refers to a cervical lymphadenectomy in which there is a preservation of 1 or more of the lymph node groups
that are removed in radical neck dissection.
512
Table 7
G. Marioni et al.
Indications to elective neck dissection according to laryngeal primary site and T stage
Site/T
Ipsilateral neck levels
Contralateral neck levels
Glottic/T2 with impaired mobility of the vocal cord, T3, T4
Supraglottic/T2, T3, T4
Subglottic/T3–T4
II–III–IV
II–III–IV (strictly lateral lesion)
II–IV, VI
–
II–III–IV
VI
The overall prevalence of lymph node metastases in laryngeal cancers proportionally increased with T category
from 10% in pT1, 29% in pT2, 38% in pT3 to 57% in pT4.69
Cervical node involvement is the most significant prognostic
factor in squamous cell carcinoma of the larynx.70 The surgical procedure of choice for N+ necks should be a comprehensive neck dissection.71
Treatment of clinically negative neck
The options for N0 neck treatment include neck dissection,
irradiation, observation with subsequent salvage neck dissection (the ‘wait and see’ policy). Elective neck dissection
refers to the dissection of cervical lymphatics in the absence of clinical evidence of metastatic disease. An elective
treatment of the neck is considered as necessary when
there is a risk of occult lymph node metastasis higher than
20%.72 Elective neck dissection is a comprehensive term
used for different types of neck dissection. The procedure
of choice for elective surgery was radical modified neck dissection. Nowadays this operation has been considered an
unnecessarily extensive procedure for treatment of the clinically negative neck: the dissection of level I and level V in
the absence of clinically evident neck metastases is considered an over-treatment.73 Selective neck dissection [SND
(II–IV)] has been indicated for the elective treatment of
the clinically negative neck in patients with laryngeal carcinoma. An intraoperative evidence of positive neck node
should require a comprehensive neck dissection. Recently,
the Brazilian Head and Neck Cancer Study Group74 prospectively compared selective lateral neck dissection vs type III
radical modified neck dissection as part of elective treatment for patients with laryngeal carcinoma. After a mean
follow-up of 42 months, the authors found no difference
in the oncological outcome between patients treated with
either modality.
Considering occult neck nodes metastases incidence
data, in patients with T1 or T2 glottic carcinoma with normal mobility of the cord or with T1 supraglottic carcinoma
there is no indication for elective neck treatment because
of the very low metastatic risk. Table 7 summarizes the
indications to elective neck dissections according to site
and T stage of primary laryngeal lesion. T3–T4 subglottic
carcinomas may also involve the thyroid gland: total or
sub-total thyroidectomy has to be considered.
Elective neck irradiation, using a dose of 50 Gy, is also
indicated in reducing the incidence of recurrence in the
clinically negative neck. The choice of elective neck dissection or elective neck irradiation in patients with a clinically
negative neck depends on the treatment chosen for the primary cancer.
Post-operative radiation therapy
Post-operative radiation with or without chemotherapy is
indicated when one or more of this adverse features is
found: close/positive surgical margins; pT4 disease; perineural/lymphatic/vascular invasion; multiple positive nodes
(three or more metastatic lymph nodes); extracapsular
spread or perineural involvement; N3 nodes; subglottic
extension of primary carcinoma.
Follow up controls
Follow-up controls are scheduled on an individual basis
determined by the risk of recurrence, to survey for the
development of second primary tumours, to deal with morbidity from treatment (i.e. speech and swallowing problems
as well as wound care), to provide social and psychological
support, and to deal with co-morbidity not directly related
to the cancer itself and to oversee the abstention of these
patients from alcohol and smoke or others risk factor.
Periodic examinations by the head and neck surgeon may
be necessary during radiation therapy in patients experiencing difficulty with nutritional intake, airway or pain
control.
After all treatment is completed, a general formula
which may be modified according to the individual
patient’s characteristics is:
1st year post treatment: 1–3 months
2nd year post treatment: 2–4 months
3rd year post treatment: 3–6 months
4th and 5th years: 4–6 months
After 5 years: Every 12 months
Chest X-rays, yearly.
Liver enzymes in advanced stages, yearly.
Periodic examinations by the radiation oncologist and, if
appropriate, a dentist in patients that received radiation
therapy;
Thyroid function tests should be monitored if the patient
received radiation to the lower neck.43
Conclusions
Although in the management of laryngeal cancer significant
clinical improvements have been allowed by new surgical
procedures that have extended the indications to partial
laryngectomies and by combination therapies (induction
chemotherapy, concurrent administration of chemotherapy
and radiotherapy, and adjuvant chemotherapy administered
after the patient has been rendered free of disease), the
most effective approach to laryngeal cancer remains
Current opinion in diagnosis and treatment of laryngeal carcinoma
prevention and early diagnosis when this cancer is curable
with function preserving treatments.
21.
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