Hypopharyngeal cancer: United Kingdom National [626889]

Hypopharyngeal cancer: United Kingdom National
Multidisciplinary Guidelines
P PRACY1, S LOUGHRAN2, J GOOD3, S PARMAR4, R GORANOVA5
1Department of ENT /Head and Neck Surgery, Queen Elizabeth Hospital Birmingham, Birmingham,2University
Department of Otolaryngology, Manchester Royal Infirmary, Manchester,3Department of Oncology, University
Hospitals Birmingham NHS Foundation Trust, Birmingham,4Department of Oral and Maxillofacial Surgery,
University Hospitals Birmingham NHS Foundation Trust, Birmingham, and5Northern Centre for Cancer Care,
Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK
Abstract
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer
patients in the UK. With an age standardised incidence rate of 0.63 per 100 000 population, hypopharynx
cancers account for a small proportion of the head and neck cancer workload in the UK, and thus suffer fromthe lack of high level evidence. This paper discusses the evidence base pertaining to the management ofhypopharyngeal cancer and provides recommendations on management for this group of patients receivingcancer care.
Recommendations
Cross-sectional imaging with computed tomography of the head, neck and chest is necessary for all patients;
magnetic resonance imaging of the primary site is useful particularly in advanced disease; and computedtomography and positron emission tomography to look for distant disease. (R)
Careful evaluation of the upper and lower extents of the disease is necessary, which may require contrast
swallow or computed tomography and positron emission tomography imaging. (R)
Formal rigid endoscopic assessment under general anaesthetic should be performed. (R)
Nutritional status should be proactively managed. (R)
Full and unbiased discussion of treatment options should take place to allow informed patient choice. (G)
Early stage disease can be treated equally effectively with surgery or radiotherapy. (R)
Endoscopic resection can be considered for early well localised lesions. (R)
Bulky advanced tumours require circumferential or non-circumferential resection with wide margins to account
for submucosal spread. (R)
Offer primary surgical treatment in the setting of a compromised larynx or significant dysphagia. (R)
Midline lesions require bilateral neck dissections. (R)
Consider management of silent nodal areas usually not addressed for other primary sites. (G)
Reconstruction needs to be individualised to the patients ’needs and based on the experience of the unit with
different reconstructive techniques. (G)
Consider tumour bulk reduction with induction chemotherapy prior to definitive radiotherapy. (R)
Consider intensity modulated radiation therapy where possible to limit the consequences of wide field
irradiation to a large volume. (R)
Use concomitant chemotherapy in patients who are fit enough and consider epidermal growth factor receptor
blockers for those who are less fit. (R)
Introduction
The hypopharynx is subdivided into the piriform
sinuses, the posterior pharyngeal wall and the post-cricoid area. The majority of cancers arise in the piri-
form sinuses (65 –85 per cent), 10 –20 per cent arise
from the posterior pharyngeal wall and 5 –15 per cent
from the post-cricoid area. As is the case at othersites in the head and neck, the overwhelming majority
(95 per cent) of cancers are squamous cell carcinomas
(SCCs). Five-year survival is poor with overall survivalat 30 per cent, although for T1 and T2 tumours the sur-
vival is almost 60 per cent. This discrepancy is a reflec-
tion of late presentation, as hypopharynx tumoursremain relatively asymptomatic until they are quiteThe Journal of Laryngology & Otology (2016) ,130(Suppl. S2), S104 –S110 . GUIDELINE
© JLO (1984) Limited, 2016. This is an Open Access article, distributed under the terms of the Creative Commons
Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and
reproduction in any medium, provided the original work is properly cited.
doi:10.1017/S0022215116000529
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advanced. Cases of T1N0 account for only 1 –2 per cent
of all cases seen and 80 per cent of patients are stage IIIor IV at presentation. Half of all patients present
because of cervical nodes and the incidence of distant
metastases at presentation are higher than that for anyother head and neck cancer.
Clinical presentation
The cardinal symptoms of hypopharyngeal cancer are:
Neck mass, with approximately half of patients
presenting such, which reflects the fact that late
presentation is common
Sore throat, particularly if well localised and asso-
ciated with referred ear pain on swallowing
Dysphagia, which is progressive and frequently
results in significant weight loss and malnutrition
Hoarseness, voice change and /or upper airway
obstruction, a late symptom indicating advanceddisease.
Assessment and staging
Clinical examination
Assessment of hypopharyngeal cancer requires a full
symptomatic history, evaluation of associated medicalconditions or comorbidity, determination of weight
loss as well as performance status (Karnofsky or
World Health Organization). The medical history andperformance status are critical in recommending the
extent and intention of treatment. Mortality and mor-
bidity rates are much higher in patients with significantweight loss, comorbidity or poor performance
indicators.
A full head and neck examination, including nasen-
doscopy, is necessary in order to assess the size and
position of the primary tumour, mobility of the vocal
fold and cervical metastases. Clinical examination isalso important in assessment of pre-vertebral fascia
involvement and can be assessed by examining laryn-
gopharyngeal mobility in the lateral direction. This isthen complemented by radiological assessment and
staging endoscopy under general anaesthetic.
Imaging considerations
It is widely agreed that imaging is better performed
prior to biopsy, as this can potentially avoid post-opera-
tive oedema which may overstage the disease on subse-
quent imaging. In addition, it allows assessment of anyadditional abnormalities that have been uncovered by
radiological evaluation such as second primary
tumours.
Cross-sectional imaging is mandatory in the work up
and can take the form of either computed tomography
(CT) or magnetic resonance imaging (MRI). In add-ition to this, the chest should always be imaged due
to the increased incidence of lung metastases in
advanced hypopharyngeal cancer and to look forsynchronous primaries. There is debate about which
modality to use. The critical points in imaging areassessing extent of disease (particularly the lower
limits of the primary cancer) and the presence of
thyroid cartilage invasion. Magnetic resonanceimaging gives better soft tissue definition and has
greater sensitivity (80 per cent) for cartilage invasion,
however, is less specific (74 per cent) than CT, andcan therefore potentially overstage disease. The multi-
planar capabilities of MR can also help in staging the
disease. When compared with histological assessment,CT and MRI produce sensitivities of 66 and 89 per
cent, respectively, and specificities of 94 and 84 per
cent, respectively. The benefit of CT is that the chestcan be imaged at the time of the neck imaging as
well as the reduced potential for motion artefact due
to the speed of the assessment, whereas, if MRI isused the patient needs additional imaging which may
be less convenient for the patient. There is debate
whether or not a simple chest X-ray is sufficient orwhether CT is necessary. There is evidence to
support both arguments, however, as hypopharyngeal
cancer usually presents with stage III or IV diseases,it seems reasonable to recommend chest CT, as there is
a higher incidence of distant metastatic disease in hypo-
pharyngeal cancer.
Currently, the Royal College of Radiologists 2014
guidelines recommends CT or MRI scanning for
imaging the hypopharynx.
1Computed Tomography
should use slice thickness acquired at 0.625 –1.25 mm
and reformatted at no greater than 2.5 mm for viewing.
Scans should be performed during quiet respirationwith arms at the side of the patient. Patients should be
instructed not to swallow during the evaluation.
Magnetic resonance imaging scanning will require acombination of axial, sagittal and coronal T1W and
T2W sequences, often with contrast enhancement with
spectral fat suppression to assess the extent of softtissue involvement and cartilage invasion.
Positron emission tomography (PET) –CT is now
recommended for assessment of advanced hypophar-yngeal primaries, the lower limit of disease in cases
not accessible via endoscopy as well as in imaging
post-treatment patients to assess for residual and/orrecurrent disease.
Examination under anaesthetic and endoscopy
Endoscopy in theatre serves three functions: first, it
allows assessment of the extent of the primarytumour, second, it allows biopsy of the tumour to
confirm pathology and finally it allows assessment of
other potential primary sites. This last indication wasthe rationale of the old fashioned triple endoscopy phil-
osophy which incorporated bronchoscopy as well as
pharyngolaryngoscopy and oesophagoscopy. It is gen-erally recognised that with the advent of good imaging
of the chest the role of formal bronchoscopy has
become virtually obsolete.HYPOPHARYNGEAL CANCER: UK GUIDELINES S105
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At the end of all these assessments then a clinical
stage can be reached using the tumour –node –meta-
stasis (TNM) classification system ( Table I ).
Recommendations
Cross-sectional imaging with CT of the head,
neck and chest is necessary for all patients;MRI of the primary site is useful particularly
in advanced disease; and CT –PET to look for
distant disease (R)
Careful evaluation of the upper and lower
extents of the disease is necessary, which mayrequire contrast swallow or CT –PET
imaging (R)
Formal rigid endoscopic assessment under
general anaesthetic should be performed (R)
Management
High importance should be placed on exploring patientpreferences and involving them in treatment decisions.
A clear and unbiased discussion of all options will help
the patients and the medical team make the mostappropriate decisions. Many of these patients present
with dysphagia and significant weight loss and can
be profoundly malnourished. This needs to bemanaged proactively soon after diagnosis and may
require insertion of nasogastric or gastrostomy
feeding tubes prior to any treatment taking place. Afull assessment of the patient ’s performance status
should be carried out to determine their ability to
undergo major surgery or their ability to lie flat forradiotherapy and attend daily for seven weeks.
Although some prospective randomised data exists,
several aspects of the decision making for hypophar-yngeal SCC remain controversial as no treatment has
been shown to be superior in terms of disease
control and survival.
2This section summarises theprinciples of surgical and non-surgical treatment for
these tumours.
Recommendations
Nutritional status should be proactively
managed (R)
Full and unbiased discussion of treatment
options should take place to allow informed
patient choice (G)
Surgical treatment
Based on the extent of the tumour, transoral and open
surgical options exist for hypopharyngeal cancer.3
Transoral approaches have a greater ability to preserve
function suitable for smaller tumours where resections
can be achieved with clear margins. Radiation therapyis favoured over open partial pharyngeal resections
nowadays.
Early stage disease. Early stage (I and II) disease can be
treated with equal effectiveness with surgery or radi-
ation.4,5Early lesions of the hypopharynx can be
treated by transoral resection or open partial laryngo-pharyngectomy with or without reconstruction.
Surgery offers the advantage of providing prognostic
information, such as peri-neural or angioinvasion andlymph node status. This allows the use of post-opera-
tive irradiation for those patients likely to gain the
most benefit, while sparing other patients side effectswithout a significant survival advantage. Occult
nodal disease is present in 30 –40 per cent of patients,
so any treatment plan should include elective treatmentof the cervical nodes.
Late stage disease. Unfortunately, more than 80 per cent
are advanced stages III and IV at presentation (with
locally advanced disease present in the majority).
Submucosal extension is present in more than 60 percent of surgical specimens and is occult in one-third.
6
Local recurrence rates have been reported to occur inequal proportion between patients with negativemargins and those with positive margins, underscoring
the difficulty in clearing disease. Histological studies
have reported submucosal extension ranging from 1to 2 cm, resulting in the recommendation that
minimal resection margins of 1.5 cm superiorly, 3 cm
inferiorly and 2 cm laterally are required in patientstreated surgically. The incidence and extent of sub-
mucosal spread is higher in patients who have under-
gone previous radiotherapy, with macroscopicallyundetected submucosal spread present in 80 per cent.
Bulky advanced tumours will usually require circum-
ferential or non-circumferential resection with freeflap cover.
Recurrent disease. Surgical salvage after failure of
irradiation therapy has a lower success rate forTABLE I
T STAGING FOR HYPOPHARYNGEAL TUMOURS
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumourTis Carcinoma in situT1 Tumour limited to one subsite of the hypopharynx and
2 cm or less in greatest dimension
T2 Tumour invades more than one subsite of the hypopharynx
or an adjacent site, or measures more than 2 cm but 4 cmor less in greatest diameter without fixation of
hemilarynx
T3 Tumour measures more than 4 cm in greatest dimension or
with fixation of hemilarynx
T4a Tumour invades thyroid /cricoid cartilage, hyoid bone,
thyroid gland, oesophagus or central compartment soft
tissue, which includes pre-laryngeal strap muscles andsubcutaneous fat
T4b Tumour invades pre-vertebral fascia, encases carotid artery
or involves mediastinal structuresP PRACY, S LOUGHRAN, J GOOD et al. S106
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hypopharyngeal cancer than at any other site in the
head and neck, and larynx preservation is rarely pos-sible.
7Patients who have undergone previous irradi-
ation require even greater resection margins.
Recommendations
Early stage disease can be treated equally
effectively with surgery or radiotherapy (R)
Endoscopic resection can be considered for
early well localised lesions (R)
Bulky advanced tumours require
circumferential or non-circumferential
resection with wide margins to account for
submucosal spread (R)
Offer primary surgical treatment in the
setting of a compromised larynx or significant
dysphagia (R)
Management of the neck. Midline lesions, those involv-
ing the posterior pharyngeal wall or post-cricoid area,and lesions of the medial wall of the piriform sinus,
require bilateral neck dissection or irradiation,
because of a higher incidence of failure in the contralat-eral neck. In surgically treated patients with a clinically
N0 neck, unilateral or bilateral neck dissection is war-
ranted, depending on the site and size of the primary.In the clinically positive neck, a modified radical
neck dissection or a selective neck dissection on one
or both sides should be considered. Due attentionmust be given to nodal involvement of the ‘silent
nodal areas ’–retropharynx, parapharynx, paratracheal
and mediastinum.
Recommendations
Midline lesions require bilateral neck
dissections (R)
Consider management of silent nodal areas
usually not addressed for other primary sites
(G)
Reconstruction. Reconstruction of pharyngeal defects
and in particular circumferential defects present major
challenges. Modern chemoradiotherapy protocols,
medical comorbidity and poor nutritional statusincrease surgical morbidity. The aims of reconstruction
are to restore swallowing and speech, keeping mortality
and morbidity, in particular fistula and stricture rates, toa minimum.
Partial pharyngeal defects. Partial pharyngeal defects
with more than 3.5 cm of unstretched remaining pha-
ryngeal mucosal width may be closed primarily.Defects with less than 3.5 cm of pharyngeal mucosal
width remaining may be reconstructed using a pedicledflap –usually a pectoralis major flap. Free flaps, such
as the radial forearm flap and the anterolateral thigh
flap may also be used. These reconstructions are alsocalled ‘patch ’grafts. If the pharyngeal mucosal
remnant is very narrow ( <1 cm in width), some sur-
geons would recommend excision of the remnant andundertaking a total circumferential reconstruction.
However, many surgeons preserve this remnant and
reconstruct around it as it may reduce the stricture rate.
Total circumferential pharyngolaryngectomy defects.
Lower anastomosis above the clavicles : Where the
lower anastomosis of a total circumferential pharyngo-
laryngectomy reconstruction would lie above the clav-
icle, several options exist: jejunal free flap (JFF),gastro-omental free flap (GOFF), tubed radial forearm
free flap (RFFF) and a tubed anterolateral thigh free
flap (ALT).
8All the above options carry the risk of
free flap failure, anastomotic leaks, stricturing, donor
site morbidity, failure of voice rehabilitation, swallow-
ing problems and a small peri-operative mortality rate.
Previously untreated cases : jejunal free flaps have
been associated with poorer swallowing thought to be
due to uncoordinated peristalsis and wet soundingspeech. The RFFF is easy to tube but has donor site
issues related to the size of the flap required. Recent lit-
erature has suggested that in previously untreated cases,ALTs tubed over a salivary bypass tube appear to
provide the lowest complication rates –with minimal
donor site morbidity, lower leak rates and lower sten-osis rates.
9Good swallowing and voice rehabilitation
have been reported. However, many authors have not
been able to replicate results in the literature and con-tinue to use the JFF. Use of a salivary bypass tube
appears to reduce the fistula rates in fasciocutaneous
flaps.
Post-chemoradiotherapy (salvage cases) : In general,
reconstructive surgery using free flap surgery post-che-
moradiotherapy carries a higher risk of complicationsdue to the deleterious effects of chemoradiotherapy
on tissue vascularity and wound healing. In such
cases, limited case series suggest that the use of theGOFF may have an advantage due to the availability
and vascularity of the omentum.
10The omentum can
be wrapped around the anastomotic site to decreasethe possibility of leakage and also improve the vascu-
larity of the overlying skin quality. Any of the other
options mentioned previously may also be used in thesalvage cases. In the patients at high risk of breakdown,
a pectoralis major flap may be used to reinforce the
anastomotic suture lines in the pharynx.
Lower anastomosis below the clavicles : If the resec-
tion extends below the clavicles, a gastric pull through
or colonic transposition flap may be used.
11Both these
techniques carry increased morbidity and mortality due
to the need to enter multiple visceral cavities. Gastric
pull through carries a mortality rate of 5 –15 per cent,HYPOPHARYNGEAL CANCER: UK GUIDELINES S107
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morbidity of 31 –55 per cent and reported fistula rates
of 3 –23 per cent. Colonic transposition carries
similar risks, and appears to be less commonly used.
It can however provide a higher cranial reach than
gastric pull through, and is therefore useful fortumours that extend up high into the oropharynx.
Swallowing after reconstruction with fasciocut-
aneous flaps (RFFF and ALT) and GOFF is reportedto be superior to that after JFF reconstruction. There
is little literature on the outcome of speech rehabilita-
tion following free flap reconstruction of total pharyn-geal defects. However, speech rehabilitation is thought
to be best when fasciocutaneous flaps are used to
reconstruct the pharynx. There is a question as to theadvisability of primary tracheoesophageal puncture in
these cases. It has been argued that the presence of a
puncture site and valve or catheter can increase thechance of infection and flap failure, and for this
reason, many surgeons would recommend secondary
puncture once the patient has healed and receivedtheir post-operative radiotherapy as indicated. Some
centres perform a puncture if there is a reasonable
distance between the lower anastomosis and the siteof the puncture. As there is no evidence to support
either position, it is best to decide on an individual
case basis and depending on the experience of theteam.
Recommendation
Reconstruction needs to be individualised to
the patients ’needs and based on the
experience of the unit with different
reconstructive techniques (G)
Non-surgical management
Definitive radiotherapy is a potentially organ-sparing
alternative to surgery in the treatment of early SCC ofthe hypopharynx. In combination with systemic
therapy, it also has a role in the curative management
of locally advanced cancers, although typically notthose in which the cartilage is extensively involved or
the function of both vocal cords significantly impaired.
Post-operative radiation or chemoradiation improveslocoregional disease control and overall survival in
the presence of well-established high-risk features
such as a positive margin or extra-capsular nodal exten-sion of disease.
12
There has been no randomised side-by-side compari-
son of surgery and radiotherapy in T1 and 2 N0 hypo-pharyngeal cancer. In advanced cancers, prospective
trials have shown equivalent rates of local control and
survival when surgery and adjuvant treatment wascompared with primary non-surgical therapy.
13Given
that the risk of local or locoregional failure is greater
than that of distant metastases, cancers that proveradiation resistant are sometimes surgically salvage-
able. The choice of initial therapy is often driven bypragmatic clinical factors such as age, performance
status, medical comorbidity and patient wishes as
well as more subjective considerations such astumour accessibility, local expertise or predicted func-
tional outcome after radiotherapy. A multidisciplinary
approach involving surgical and radiation oncologists,speech and language therapists and clinical nurse spe-
cialists is required.
The lymphatic drainage of the hypopharynx and the
resulting significant risk of occult nodal disease at pres-
entation typically mandate extensive irradiation of at-
risk nodal groups as well as treatment of the primarytumour site and clinically apparent nodes. Intensity
modulated radiation therapy (IMRT) is now well estab-
lished in UK radiotherapy centres. This technique, incombination with adherence to consensus guidelines
regarding target volume delineation and sophisticated
imaging of patient position and anatomical changesduring radiotherapy, allows much more precise and
accurate targeting of tumouricidal radiation dose to
the target. Intensity modulated radiation therapy alsoreduces radiation dose to organs at risk, such as the
parotid, resulting in reduced medium term toxicity.
There is also some evidence that patients treated withIMRT rather than three-dimensional conformal radio-
therapy achieve higher rates of local control and
better functional outcomes. Intensity modulated radi-ation therapy should therefore be considered the stand-
ard of care.
The predominantly loco-regional pattern of treat-
ment failure in hypopharyngeal cancer has generated
interest in treatment intensification, particularly in the
setting of locally advanced disease. Intensity modu-lated radiation therapy has facilitated attempts at escal-
ation of radiation dose. The addition of concomitant
systemic therapy in the form of cisplatin (or cetuximabin patients with contraindications such as impaired
renal function) confers a modest improvement overall
survival at the expense of increased acute toxicity.All but the least fit patients under the age of 71 with
stage III or selected stage IV disease should therefore
be considered for combination treatment. Patientsaged 71 or more were shown in the meta-analysis of
chemotherapy in head and neck cancer to be unlikely
to benefit from the addition of systemic therapy.
14,15
The optimal use of induction chemotherapy in hypo-
pharyngeal cancer, as in other anatomical subsites,
remains a topic of discussion. Two large trials havedemonstrated its utility in an organ preservation
approach with comparable survival to surgery in laryn-
geal cancer. Induction therapy reduces the incidence ofdistant metastases but does not have a consistent effect
on overall survival, although individual studies com-
paring induction schedules with and without a taxanehave shown a significant benefit for triple-agent
chemotherapy.
16One pragmatic approach is to offerP PRACY, S LOUGHRAN, J GOOD et al. S108
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induction chemotherapy prior to chemoradiation to fit
patients with bulky T3 or early T4 disease,13with lar-
yngectomy for those who do not respond to chemother-
apy, and to patients at high risk of distant relapse such
as those with N2b or c or N3 disease.
Recommendations
Consider tumour bulk reduction with
induction chemotherapy prior to definitive
radiotherapy (R)
Consider IMRT where possible to limit the
consequences of wide field irradiation to a
large volume (R)
Use concomitant chemotherapy in patients
who are fit enough and consider EGFR
blockers for those who are less fit (R)
Palliative care
It has been estimated that up to 25 per cent of patients
are not suitable for curative treatment at presentationbecause of age, the extent of locoregional disease,
distant metastases, comorbidity or refusal of surgery.
Following treatment, 50 –60 per cent of patients
develop a recurrence in less than 12 months, and
most mortality in the first two years following diagno-
sis is due to locoregional recurrence. The overall five-year disease specific survival rate is approximately
30–35 per cent with five-year survival rates of 14 –22
per cent for stage IV disease. Volume of disease andlaryngeal involvement adversely impact survival.
Combination chemotherapy has been shown to
improve overall survival.
17
Patients with hypopharyngeal cancer may suffer
from severe symptoms; including pain, swallowing dif-
ficulties, aspiration, chest infections, anorexia andweight loss. In many cases, symptoms will have been
aggravated by previous treatments; surgery, radiation
and chemotherapy (mucositis, hypopharyngeal sten-osis, infections, pharyngocutaneous fistula, psycho-
logical distress and cachexia). All of these require
attention and some may be relieved by surgical inter-ventions such as tracheostomy and the insertion of a
gastrostomy to relieve breathing and restore hydration
and nutrition.
Some patients, with minimal local symptoms are
suitable for targeted agents in recurrent local and /or
metastatic disease. These are highly selected patientsand palliative treatments should be discussed and
offered to patients through the multidisciplinary team
(MDT). Patients with symptomatic lung metastasesare often those who benefit most from palliative
chemotherapy. Palliative radiotherapy may be used
for patients, unsuitable for curative treatment, whopresent with bleeding or uncontrolled pain from the
hypopharynx and can be excellent for cutaneous metas-
tases, painful lymph nodes or bony disease.Key points.
The majority of cancers arise in the piriform
sinuses (65 –85 per cent), 10 –20 per cent arise
from the posterior pharyngeal wall and 5 –15 per
cent from the post-cricoid area
Patient choice and involvement in treatment deci-
sions is of high importance and a clear and
unbiased discussion of their options will help
them and their medical team make the most appro-priate treatment decisions
Primary non-surgical treatment is recommended
for most locally advanced tumours unless thelaryngeal function is compromised or significant
dysphagia exists
Early stage (I and II) disease can be treated with
equal effectiveness with surgery or radiation
Bulky advanced tumours will usually require cir-
cumferential or non-circumferential resectionwith free flap cover
Five-year survival is poor with overall survival at
30 per cent, although for T1 and T2 tumours thesurvival is almost 60 per cent
Up to 25 per cent of patients are not suitable for
curative treatment at presentation because of age,the extent of locoregional disease, distant metasta-
ses, comorbidity or refusal of surgery.
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Address for correspondence:
Paul Pracy,Department of ENT Head and Neck Surgery,Queen Elizabeth Hospital Birmingham,
Birmingham, UK
E-mail: paul.pracy@uhb.nhs.ukP PRACY, S LOUGHRAN, J GOOD et al. S110
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