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EJSO 35 (2009) 908e915 www.ejso.com

Review
Management of advanced parotid cancer. A systematic review
J.-P. Jeannon*, F. Calman, M. Gleeson, M. McGurk, P. Morgan,
M. O’Connell, E. Odell, R. Simo
Department of Head & Neck Oncology, Guy’s, King’s & St Thomas’ Cancer Centre, Guy’s & St Thomas’ NHS Foundation Trust,
3rd Floor, Thomas Guy House, London SE1 9RT, UK

Accepted 17 October 2008

Available online 21 November 2008

Abstract
Background: Primary adenocarcinomas of the parotid gland are rare and account for less than 5% of all head and neck malignant
neoplasms. There is considerable variation in biological behaviour within this group; low-grade tumours exhibit slow growth rates with
minimal or no local invasion. High-grade tumours, however, show a high incidence of local recurrence and distant metastasis.
Aim: The purpose of this paper is to analyse the important prognostic indicators for this cancer.
Methods: A systematic review was performed involving 19 published studies from 1987 to 2005 which included 4631 patients. T stage,
grade of tumour, N stage and adjuvant radiotherapy on overall (5 year) survival were analysed as prognostic indicators.
Results: T stage ( p ¼ 0.041, hazard ratio 1.8 (confidence interval 1.2e2.9)), N stage ( p ¼ 0.05, hazard ratio 1.1 (0.2e1.8)), and high-grade
( p ¼ 0.001, hazard ratio 2.1 (1.5e2.7)) were associated with a significantly worse survival. The effect of adjuvant radiotherapy was to
improve overall survival: p ¼ 0.002, hazard ratio 2.9 (1.5e4.7). The mean 5 year survival for advanced high-grade parotid cancer was 35%.
Conclusion: High-grade advanced parotid cancers are associated with a poor survival. Adjuvant radiotherapy is indicated in these tumours
and this improves survival.
Ó 2008 Elsevier Ltd. All rights reserved.

Keywords: Parotid carcinoma; High grade; Advanced stage; Adjuvant chemotherapy

Introduction Many published series include a wide range of cancer

Primary adenocarcinomas of the parotid gland are rare
and account for less than 5% of all head and neck malignant
neoplasms. The term ‘parotid cancer’ encompasses a wide
variety of histopathological entities and the terminology
has evolved (Tables 1 and 2). Within this diverse group of
malignant neoplasms, there is a considerable variation in
biological behaviour. Low-grade tumours exhibit slow
growth rates with minimal or no local invasion. These
tumours therefore tend to have an excellent prognosis and
can be managed by surgical excision alone. High-grade
tumours, however, show an aggressive pattern of behaviour
with wide invasion and hence, a high incidence of local
recurrence and distant metastasis leads to a worse prognosis.
* Corresponding author. Tel.: þ44 (0) 20 7188 2213.
E-mail address: jpjeannon@doctors.org.uk (J.-P. Jeannon).
histological types. The majority of cases tend to be early
stage and low grade as these are more common and the
number of advanced T3 and T4 carcinomas tends to be
small. Therefore the reported survival results tend to be
favourable due to the good prognosis of these low-grade
tumours.
When the high-grade advanced parotid carcinomas are
evaluated on their own, the survival results tend to be
universally poor.
The purpose of this paper is to review the published
experience in managing these advanced cancers. By
employing systematic review techniques we are able to
combine several studies each with relatively small numbers
of advanced and high-grade cases in order to analyse the
effect of several prognostic factors on survival, conse-
quently to assess the overall effect of high grade, T stage,
N stage and adjuvant radiotherapy on survival in patients
with primary parotid cancers.

0748-7983/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejso.2008.10.009
 J.-P. Jeannon et al. / EJSO 35 (2009) 908e915 909

Table 1
WHO International histopathological classification of parotid cancers
WHO 1972 WHO 1991 WHO 2005
Mucoepidermoid tumour Acinic cell carcinoma Acinic cell carcinoma
Acinic cell tumour Mucoepidermoid carcinoma Mucoepidermoid carcinoma
Adenoid cystic carcinoma Adenoid cystic carcinoma Adenoid cystic carcinoma
Adenocarcinoma Polymorphous low-grade adenocarcinoma Polymorphous low-grade adenocarcinoma
Epidermoid carcinoma Epithelial myoepithelial carcinoma Epithelial myoepithelial carcinoma
Undifferentiated carcinoma Basal cell adenocarcinoma Clear cell carcinoma
Carcinoma in pleomorphic adenoma Sebaceous carcinoma Basal cell adenocarcinoma
Papillary cystadenocarcinoma Sebaceous carcinoma
Mucinous adenocarcinoma Cystadenocarcinoma
Oncocytic carcinoma Low-grade cribriform cystadenocarcinoma
Salivary duct carcinoma Mucinous adenocarcinoma
Adenocarcinoma Oncocytic carcinoma
Myoepithelial carcinoma Salivary duct carcinoma
Carcinoma ex pleomorphic adenoma Adenocarcinoma NOS
Squamous cell carcinoma Myoepithelial carcinoma
Small cell carcinoma Carcinoma ex pleomorphic adenoma
Undiffererniated carcinoma Carcinosarcoma
Other carcinomas Metastasising pleomorphic adenoma
Squamous cell carcinoma
Small cell carcinoma
Large cell carcinoma
Lymphoepithelial carcinoma
Sialoblastoma

Materials and methods
Literature review
A literature search was used using Medline, Embase and
the Cochrane databases. The following key search words
were used: ‘parotid’, ‘cancer’, ‘advanced’ and ‘survival’.
Study design
This is a systematic review of published cases of pri-
mary adenocarcinomas of the parotid gland. The analysis
involved 19 published studies from 1987 to 2005 which
involved 4631 patients.2e20
Selection criteria
Only primary adenocarcinomas of the parotid gland
were included in the study. All stages and grades of
carcinoma were included. Benign parotid tumours were ex-
cluded. Secondary squamous carcinomas and lymphomas
were excluded. Adenoid cystic carcinomas were also
excluded as these cancers can have a prolonged and unpre-
dictable natural history. Sub-mandibular, sublingual and
minor salivary tumours were also excluded. Data extrac-
tion was performed and only T stage, N stage, effect of
adjuvant radiotherapy and high-grade parotid cancers
were analysed.
As the histopathological categorisation and grading
system has changed over the last two decades, only papers
published in the last 20 years were included. Series report-
ing less than 100 cases were also excluded as the number of
high-grade and advanced cases in such series was too small
for meaningful results.
Statistical analysis
The following factors were extracted from studies and
analysed: T stage, grade of tumour, N stage and adjuvant
radiotherapy on overall (5 year) survival.
Survival for stage T1 and T2 tumours was compared to
T3 and T4. High-grade tumours according to the Word
Health Organisation classification (1991) were compared
to low-grade ones. Survival of node positive (Nþ) were
compared to node negative (N0) patients. Survival of
patients that received radiotherapy was compared to those
that did not. Statistical analysis utilised Stats Direct soft-
ware. 2  2 tables were constructed in order to analyse
Table 2
American Joint Committee on Cancer (AJCC)/UICC staging by TNM
classification1
Primary tumour (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 2 cm or less in greatest dimension without
extraparenchymal extension
T2 Tumour more than 2 cm but not more than 4 cm in
greatest dimension without extraparenchymal extension
T3 Tumour having extraparenchymal extension without
seventh nerve involvement and/or more than 4 cm but
not more than 6 cm in greatest dimension
T4 Tumour invades base of skull, seventh nerve, and/or
exceeds 6 cm in greatest dimension
910 J.-P. Jeannon et al. / EJSO 35 (2009) 908e915

Table 3 odds ratios and 95% confidence intervals (CI). Forest plots
Overall survival (OS; 5 years) for each study (n ¼ 4631, 19 papers) graphs were used to display results. Sensitivity analysis was
Study n 5 year OS undertaken. Bias assessment plots were calculated and tests
Bhattacharyya and Fried, 20053 651 45% of heterogeneity were performed. We used fixed and ran-
Mendenhall et al., 20044 224 44% dom effects models to assess heterogeneity across studies.
Luukkaa et al., 20045 237 23%
Terhaard et al., 20056 498 35%
Spiro et al., 19897 463 25% Results
Renehen et al., 19998 103 45%
Goode et al., 199810 234 37%
Lima et al., 20059 126 36% Initial literature search revealed 379 possible papers.
Pedersen et al., 199211 110 28.5% However, using the selection criteria quoted in the method-
Boahene et al., 200412 128 65% ology, only 19 studies were found to be suitable for analy-
Magnano et al., 199913 126 34% sis. The analysis involved 19 published studies from 1987
Charabi et al., 200014 494 28%
Kirkbride et al., 200115 184 40%
to 2005 which involved 4631 patients (Table 3).2e20
Harbo et al., 200216 152 15%
Pohar et al., 200517 163 24%
Prognostic indicators
Carinci et al., 200218 134 33%
Ball et al., 199519 271 28%
Frankenthaler et al., 199120 178 34% T stage
Dorairajan et al., 200424 155 22% Overall, T stage was seen to be a significant factor in
determining overall survival: p ¼ 0.041, hazard ratio 1.8
(CI 1.2e2.9) (Figure 1).

Battacharyya 2005 1.010 (1.010, 1.040)

LuukKaa 2004 2.220 (1.550, 3.300)

Terhaard 2005 3.400 (0.900, 5.400)

Spiro 1989 2.500 (0.300, 4.200)

Renehen 1999 1.900 (1.020, 4.400)

Goode 1998 0.900 (0.030, 2.200)

Lima 2005 1.100 (0.030, 3.300)

Pederson 1992 0.300 (-1.200, 2.000)

Boahene 2004 0.200 (-2.000, 2.000)

Magano 1999 0.300 (0.002, 2.000)

Charabi 2000 1.600 (0.200, 4.200)

Kirkbride 2001 0.010 (-1.000, 1.000)

Harbo 2002 1.900 (0.400, 3.200)

Pohar 2005 1.500 (0.500, 2.400)

Carinci 2002 0.200 (-2.000, 1.000)

Bell 1995 2.100 (1.200, 3.500)

Frankenthaler 1991 1.900 (0.600, 2.400)

Doriarajan 2004 2.200 (1.100, 3.200)

Total 1.8 (1.2-2.9)

effect 0.001 0.01 0.1 0.2 0.5 1 2 5 10
p=0.041
Improved overall survival Worsening overall survival

Heterogeneity Test (fixed) : χ2=0.36 df 4 p=0.49 I2=10%

Figure 1. Forest plot influence of T stage on survival in parotid cancer.

 J.-P. Jeannon et al. / EJSO 35 (2009) 908e915 911

Histological grade hypotheses regarding parotid cancer and supports current

High-grade tumours were consistently associated with
a worse survival compared with low-grade cancers:
p ¼ 0.001, hazard ratio 2.1 (CI 1.5e2.7) (Figure 2).
N status and survival
The majority of studies confirm N status to adversely
effect survival in parotid cancer: p ¼ 0.05, hazard ratio
1.1 (CI 0.2e1.8) (Figure 3).
Effect of adjuvant radiotherapy on survival
Adjuvant radiotherapy was associated with significantly
improved overall survival in the majority of studies p ¼
0.002, hazard ratio 2.9 (CI 1.5e4.7) (Figure 4).
Discussion
This is not a meta-analysis as there were no prospective
randomised controlled studies, rather a systematic review
of 4631 patients from a highly selected group of high-
grade, advanced parotid cancers. It has confirmed several
therapeutic regimens for this subset.
Effect of stage and grade on survival
Advanced stage (T3 and T4) significantly affects overall
survival in the majority of studies. Therefore any published
series must separate advanced from early stage cases when
reporting results. High-grade malignancy is also signifi-
cantly associated with adverse survival compared to low-
grade tumours.
From the histopathological perspective, the study popu-
lation is a technically heterogeneous group. The years at
diagnosis span several decades in which there have been
three WHO classifications of salivary neoplasms. Each
has been modified in use as newer entities have been
described in the literature. Grading systems for specific
entities, such as mucoepidermoid carcinoma, have also
evolved. The majority of carcinomas were classified
according to the 1972 classification but some studies did

Battacharyya 2005 1.48 (1.30, 1.70)

LuukKaa 2004 3.02 (0.90, 8.09)

Terhaard 2005 2.20 (1.10, 4.10)

Spiro 1989 1.80 (0.40, 3.10)

Renehen 1999 3.30 (0.20, 6.20)

Goode 1998 0.40 (0.02, 1.40)

Lima 2005 2.50 (1.10, 5.20)

Pederson 1992 0.10 (-2.10, 1.40)

Boahene 2004 -1.20 (-2.50, 2.60)

Magano 1999 -1.00 (-2.00, 2.00)

Charabi 2000 1.30 (0.30, 3.10)

Kirkbride 2001 -0.20 (-1.00, 0.50)

Harbo 2002 1.82 (0.40, 3.10)

Pohar 2005 -1.00 (-2.30, 0.50)

Carinci 2002 1.50 (0.30, 2.50)

Bell 1995 1.80 (0.30, 2.00)

Frankenthaler 1991 1.40 (0.40, 2.10)

Doriarajan 2004 1.80 (0.30, 2.10)

Total effect HR 2.1 (1.5-2.7)

p=0.001 0.01 0.1 0.2 0.5 1 2 5 10

Improved overall survival Worsening overall survival

Heterogeneity Test (fixed) : χ2=2.62 df 5 p=0.59 I2=29%

Figure 2. Forest plot influence of grade on survival in parotid cancer.

912 J.-P. Jeannon et al. / EJSO 35 (2009) 908e915

Battacharyya 2005 1.64 (1.32, 2.04)

Mendenhall 2004 1.03 (0.54, 2.01)

LuukKaa 2004 3.65 (1.89, 7.04)

Terhaard 2005 1.91 (1.24, 2.93)

Spiro 1989 0.03 (-1.20, 8.80)

Renehen 1999 1.98 (1.20, 3.10)

Goode 1998 8.32 (2.10, 12.40)

Lima 2005 0.69 (0.10, 2.50)

Pederson 1992 1.94 (0.56, 6.69)

Boahene 2004 1.91 (1.25, 2.99)

Magano 1999 0.10 (-0.20, 0.21)

Charabi 2000 0.40 (0.21, 0.68)

Kirkbride 2001 0.50 (0.23, 1.71)

Harbo 2002 1.19 (0.50, 2.70)

Pohar 2005 1.40 (0.96, 4.30)

Carinci 2002 3.19 (0.98, 6.80)

Bell 1995 1.36 (0.78, 1.90)

Frankenthaler 1991 0.76 (-2.10, 0.20)

Doriarajan 2004 1.99 (1.28, 3.22)

Total effect HR 1.1 (0.2-1.8)

P=0.05 0.01 0.1 0.2 1 2 5 10 100

Improved overall survival Worsening overall survival

Heterogeneity Test (fixed) : χ2=4.41 df 8 p=0.79 I2=36%

Figure 3. Forest plot effect of Nþ status on overall survival in advanced parotid cancer.

not specify standardised diagnostic criteria or categories.
However, a number of factors render the study group
relatively homogeneous. Adenoid cystic carcinoma is ex-
cluded on grounds of its protracted clinical course. This
is the only common high-grade carcinoma with a distinct
growth pattern and its diagnostic criteria have not changed
during the review period. Reclassification from the first to
the second WHO system produced little change in the rel-
ative proportion of high-grade carcinomas. The main con-
sequence of the 1991 classification was to subtype within
the low-grade or high-grade group. A few low-grade le-
sions were moved from benign to malignant or vice versa.
Rare entities, for which diagnosis is likely to be most con-
tentious, were excluded from the largest study.3 For the
purposes of this analysis, high-grade carcinomas can be
considered to have been accurately identified throughout
the study period on the basis of aggressive growth pattern,
cytological pleomorphism, mitotic activity and propensity
for metastasis.21,22
The statistical tests of heterogeneity and the Forest plot
graphs confirm that the studies show relative homogeneity.
Established practice for managing advanced high-grade
parotid cancers involves combined modality treatment.
Wide surgical excision including total conservative paroti-
dectomy is the procedure of choice.
High-grade cancers are more likely to metastasise
locally and relapse with distant metastasis compared to
low-grade tumours.
Loco-regional metastasis to the neck is also associated
with worsening survival and neck dissection is mandatory
for patients with clinically involved nodes.
The role of elective neck dissection for N0 disease
was not formally assessed in this systematic review.
The majority of studies show >20% incidence of occult
cervical lymph node metastasis in high-grade and ad-
vanced parotid cancers. The risk of nodal relapse in
patients with clinically node-negative necks is highest
in patients with locally advanced or high-grade malignan-
cies and is significantly reduced by prophylactic nodal
irradiation.23 Retrospective series comparing elective neck
dissection against observation/therapeutic neck dissection
for N0 parotid cancers does show an increase in
 J.-P. Jeannon et al. / EJSO 35 (2009) 908e915 913

Battacharyya 2005 0.78 (0.61, 0.99)

Mendenhall 2004 3.66 (1.90, 7.05)

LuukKaa 2004 3.32 (2.59, 4.88)

Terhaard 2005 1.41 (0.96, 2.06)

Spiro 1989 5.20 (2.70, 12.10)

Renehen 1999 9.42 (5.23, 16.97)

Goode 1998 0.83 (0.10, 2.11)

Lima 2005 4.82 (0.02, 5.80)

Pederson 1992 5.10 (1.30, 7.30)

Boahene 2004 0.10 (-1.20, 1.20)

Magano 1999 1.37 (0.99, 1.90)

Charabi 2000 1.20 (0.31, 2.97)

Kirkbride 2001 1.36 (0.98, 1.92)

Harbo 2002 0.06 (-1.20, 2.90)

Pohar 2005 1.19 (0.50, 2.90)

Carinci 2002 1.40 (0.96, 2.00)

Bell 1995 0.40 (0.23, 0.77)

Frankenthaler 1991 0.41 (0.24, 0.69)

Doriarajan 2004 0.10 (-1.20, 2.20)

Total effect HR 2.9 (1.5-4.7)

P=0.002
0.01 0.1 0.2 0.5 1 5 10 100

Worsening overall survival Improved overall

Heterogeneity Test (fixed) : χ2=8.21 df 10 p=0.95 I2=16%

Figure 4. Forest plot effect of adjuvant radiotherapy on overall survival for parotid cancer.

loco-regional failure rates in the observational therapeutic
groups.24,25
Therefore elective treatment of the neck in terms of neck
dissection or radiotherapy is indicated. The evidence
regarding the superiority of type of neck dissection was
not assessed; however, modified radical neck dissection is
reported as the most frequently used.
Effect of adjuvant radiotherapy on survival
This study confirms that adjuvant radiotherapy for
parotid malignancy improves overall survival. Patients
with lymph node involvement, positive margins, T3eT4
tumours or any high-grade malignancy all have a significant
risk of local relapse following surgical excision and this is
reduced by adjuvant radiotherapy.6,26,27 Improved local
control has been demonstrated with increasing doses of ra-
diation, particularly in patients with positive margins28 and
doses of 60e66 Gy are recommended. The treatment of sal-
ivary tumours with high doses is challenging owing to the
proximity of critical structures and the irregularity of the
planning target volume, and optimal radiotherapy treatment
requires either 3-D conformal radiotherapy planning (CRT)
or intensity-modulated radiotherapy (IMRT). Although
high-grade cancers are more likely to metastasise locally
and relapse with distant metastasis compared to low-grade
tumours, local control remains a significant problem and
reduced local control leads to decreased rates of survival,
particularly in patients without nodal involvement.23
The role of facial nerve sacrifice was not assessed in this
paper as the individual data from studies was not clear.
Surgical management for advanced cases where the facial
nerve is functioning involves total conservative parotidec-
tomy (nerve sparing) with modified radical neck dissection.
If the facial nerve is involved pre-operatively, total radical
parotidectomy with nerve resectionereconstruction and
neck dissection is undertaken.28
Advances in surgical reconstructive techniques have
made wider resections of adjacent structures such as skin,
mandible and temporal bone possible. Even with an
914 J.-P. Jeannon et al. / EJSO 35 (2009) 908e915
aggressive surgical resection policy, close or positive mar-
gins often result due to proximity of the facial nerve, inter-
nal carotid artery and jugular foramen.
Despite the advances in reconstruction making wider re-
section possible, the survival results for high-grade advanced
primary parotid tumours has remained depressingly poor.
We accept the limitations of this study in that 5 year
overall survival may not be an appropriate measure of
outcome in some low-grade salivary gland malignancies
that have a long natural history. However, this study has
established that the 5 year survival for advanced and
high-grade salivary gland tumours is universally poor.
This analysis shows that the overall survival for advanced
high-grade parotid cancer remains on the order of 35%. These
poor survival results for advanced high-grade tumours sug-
gest that we should consider novel methods to treat these ag-
gressive cancers. Treatment with high-energy neutrons gives
better local control in both randomised and non-randomised
series but because of the high incidence of distant metastases
in these patients, no long-term survival advantage has been
demonstrated with neutron therapy. In addition the incidence
of serious late morbidity is higher with neutron therapy29,30
than in photon therapy, suggesting that the biologically equiv-
alent dose used in neutron studies may have been higher thus
leading to an advantage over photons; also, the lack of wider
access to neutron therapy makes this approach impractical.
In the palliative setting, chemotherapy using platinum-
based combinations may bring about response rates of up
to 30% in patients with high-grade carcinomas.31e33 Con-
comitant chemo-radiotherapy treatment in high-grade
carcinomas may give improved local control and requires
further investigation. Recent clinico-pathological studies
have demonstrated over-expression of molecular markers
such as EGFR, c-erb-B2 and the HER2 oncoprotein,34
suggesting possible avenues for new treatment approaches
with biological agents such as cetuximab.
Conclusion
This is a systematic analysis of 4631 patients with
parotid cancer from 19 published studies, each consisting
of at least 100 patients. High histological grade, advanced
T stage and N stage are significantly associated with poor
prognosis. Adjuvant radiotherapy is associated with
improved overall survival.
The overall survival for advanced and high-grade cases
is on the order of 35%. This subset of parotid malignancy
has a very poor prognosis despite current aggressive thera-
peutic options.
Conflict of interest
The authors declare that they do not have any financial
and personal relationships with other people or organisa-
tions that could inappropriately influence (bias) their work.
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