This document summarizes a study of risk factors for squamous cell carcinoma of the lip. It reviewed literature on lip cancer epidemiology, risk factors like sun exposure and smoking, treatment modalities like surgery and radiotherapy, and risk factors for recurrence and survival. It then presented an analysis of a dataset from Westmead Hospital on lip cancer patients, investigating factors like age, tumor size, grade that affect recurrence and survival through univariate and multivariate survival models. Significant findings from the literature and original analysis were reported.

1. 1
Risk
and
Treatment
Factors
for
Squamous
Cell
Carcinoma
of
the
Lip
A
cohort
study
from
the
Radiation
Oncology
Department,
Westmead
Hospital
Name
of
Student:
Mithilesh
Dronavalli
Supervisor:
Prof.
Val
Gebski
Associate
Supervisor:
A/Prof.
Michael
J.
Veness
Departments:
• National
Health
and
Medical
Research
Council
Clinical
Trial
Centre,
School
of
Public
Health,
Faculty
of
Medicine,
University
of
Sydney
• Radiation
Oncology
Department,
Westmead
Hospital
A
thesis
submitted
in
fulfilment
of
the
requirements
for
the
degree
of
Master
of
Medical
Philosophy
in
the
School
of
Public
Health,
Faculty
of
Medicine
at
The
University
of
Sydney.
August
2011

2. 2
Acknowledgements
I
thank
my
supervisors
for
having
the
patience
and
endurance
to
support
me
throughout
the
candidature.
I
thank
my
parents
and
mentors
for
their
moral
support
throughout
the
candidature.
Declaration
I
declare
that
the
research
presented
here
is
my
own
original
work
and
has
not
been
submitted
to
any
other
institution
for
the
award
of
a
degree.
Signed:
……………………………………………………………………………
Date:
……………………………………………………………………………….

3. 3
Abstract
Patients
with
lip
cancer
who
have
delayed
treatment
or
for
whom
the
cancer
is
more
aggressive,
often
have
worse
outcomes.
The
aim
of
this
investigation
was
to
find
the
risk
and
treatment
factors
for
developing
lip
cancer,
the
recurrence
of
lip
cancer
and
survival.
This
was
investigated
by
a
review
of
the
literature
and
original
analysis
of
data.
A
summary
of
the
outcomes
regarding
survival
and
recurrence
of
patients
undergoing
surgery
or
radiotherapy
(or
combination)
was
conducted
to
compare
these
treatments.
An
original
analysis
of
a
lip
cancer
cohort
dataset
from
the
Department
of
Radiation
Oncology
at
Westmead
Hospital
was
carried
out.
This
included
univariate
analysis
and
multivariate
survival
analysis
investigating
time
to
recurrence
and
survival.
Also
prognostic
risk
models
were
developed
to
classify
patients
into
risk
groups
in
terms
of
recurrence
and
survival.
This
investigation
adds
to
the
literature
as
analysis
was
conducted
from
a
time
to
recurrence
and
survival
perspective
using
survival
analysis,
rather
than
just
by
investigating
the
occurrence
of
the
event.
Here
information
regarding
the
order
in
which
events
occurred
is
used
to
make
inferences.
Also
this
study
gives
insight
on
outcomes
of
patients
with
lip
cancer
who
underwent
surgery
with
adjuvant
radiotherapy,
where
there
is
limited
information
in
the
literature.
It
should
be
noted
that
there
are
biases
involved
in
dealing
with
a
cohort
study,
especially
since
patients
were
not
randomised
to
a
treatment.
In
conclusion
I
have
reported
on
some
significant
findings
regarding
treatment
comparisons
and
risk
factors
for
lip
cancer.

4. 4
Table
of
Contents
Risk
and
Treatment
Factors
for
Squamous
Cell
Carcinoma
of
the
Lip
..............................
1
Tables
....................................................................................................................................
7
Figures
.................................................................................................................................
10
Abbreviations
and
acronyms
................................................................................................
12
Literature
review
..........................................................................................................
15
Introduction
.........................................................................................................................
15
TNM,
staging
and
grading
....................................................................................................
16
Grading
................................................................................................................................
18
Epidemiology
.......................................................................................................................
18
Risk
factors
..........................................................................................................................
20
Sun
exposure
..........................................................................................................................
20
Smoking
as
a
risk
factor
for
developing
disease
.....................................................................
23
Other
risk
factors
for
developing
lip
cancer
...........................................................................
23
Progression
of
disease
.........................................................................................................
24
Treatment
modalities
and
regimens
.....................................................................................
24
Surgery
....................................................................................................................................
25
Radiotherapy
..........................................................................................................................
27
Summary
of
treatment
outcome
..........................................................................................
29
Flowchart
of
articles
...............................................................................................................
30
Recurrence
...........................................................................................................................
35
Age
..........................................................................................................................................
36
Gender
....................................................................................................................................
37
Tumour
size
............................................................................................................................
38
Histological
grade
...................................................................................................................
42
Maximal
tumour
thickness
.....................................................................................................
44
Site
of
lip
cancer
.....................................................................................................................
47
Cellular
and
molecular
factors
................................................................................................
48
Perineural
invasion
.................................................................................................................
52
Other
risk
factors
....................................................................................................................
54
Survival
and
its
risk
factors
...................................................................................................
55
Analysis
of
the
Westmead
lip
cancer
dataset
................................................................
58

5. 5
Materials
and
methods
........................................................................................................
58
Patient
eligibility
..................................................................................................................
58
Inclusion
criteria
.....................................................................................................................
59
Exclusion
criteria
.....................................................................................................................
59
Treatment
............................................................................................................................
59
Methods
..............................................................................................................................
59
Methods
of
univariate
analysis
............................................................................................
60
Methods
for
adjusted
treatment
effect
................................................................................
62
Methods
of
risk
models
........................................................................................................
62
Dataset
description
..............................................................................................................
64
Results
.........................................................................................................................
67
Baseline
demographics
........................................................................................................
67
Dichotomous
variables
used
in
overall
survival
modelling
.....................................................
68
Univariate
models
................................................................................................................
69
Survival
models
from
diagnosis
..............................................................................................
69
Interpretation
of
risk
reduction
..............................................................................................
70
Recurrence
models
from
diagnosis
........................................................................................
74
Multivariate
analysis
............................................................................................................
76
Treatment
comparison:
Patients
treated
with
Sx
vs.
RTx
.......................................................
76
Treatment
comparison:
Patients
treated
with
Sx
or
Sx+RTx
compared
to
RTx
......................
79
Treatment
comparison:
Patients
receiving
Sx+RTx
vs.
Sx.
......................................................
84
Treatment
comparison:
Patients
receiving
Sx+RTx
vs.
RTx
....................................................
87
Risk
modelling
.....................................................................................................................
91
Survival
model
with
treatment
...............................................................................................
93
Survival
model
not
including
treatment
.................................................................................
97
Recurrence
model
with
treatment
.......................................................................................
101
Discussion
..................................................................................................................
105
Tumour
size
.......................................................................................................................
106
Age
at
diagnosis
.................................................................................................................
108
Treatment
comparison:
Sx
vs.
RTx
......................................................................................
109
Treatment
comparison:
Sx
and
Sx+RTx
vs.
RTx
...................................................................
111
Treatment
comparison:
Sx+RTx
vs.
Sx
................................................................................
112
Treatment
comparison:
Sx+RTx
vs.
RTx
..............................................................................
113

6. 6
Risk
models
........................................................................................................................
114
Risk
model:
Survival
with
treatment
.....................................................................................
115
Risk
model:
Survival
without
treatment
...............................................................................
116
Risk
model:
Recurrence
with
treatment
...............................................................................
117
Conclusion
..................................................................................................................
118
Bibliography
...............................................................................................................
120

7. 7
Tables
Table
1
Treatment
outcome
and
treatment
modality
for
each
article
...................................
31
Table
2
Summary
of
results
relating
to
loco-­‐regional
control
................................................
33
Table
3
Summary
of
results
relating
to
overall
survival
..........................................................
33
Table
4
Summary
of
results
relating
to
cause-­‐specific
survival
..............................................
34
Table
5
Summary
of
results
relating
to
disease
free
survival
.................................................
34
Table
6
Summary
of
findings
for
age.
.....................................................................................
36
Table
7
Summary
of
results
for
tumour
size
...........................................................................
38
Table
8
Summary
of
results
for
histological
grade
..................................................................
42
Table
9
Summary
of
results
for
maximal
tumour
thickness
...................................................
44
Table
10
Summary
of
results
for
site
of
lip
cancer
.................................................................
47
Table
11
Summary
of
results
for
cellular
and
molecular
factors
............................................
48
Table
12
Summary
of
results
for
perineural
invasion
.............................................................
52
Table
13
Summary
of
results
for
ulcerated
pattern
and
tumour
area
....................................
54
Table
14
Risk
factors
predicting
survival
in
lip
cancer
in
one
study
........................................
57
Table
15
Treatment
definitions
..............................................................................................
65
Table
16
Patient
and
tumour
predictor
definitions
................................................................
66
Table
17
Summary
measures
on
age
of
patients
by
treatment
groups
..................................
67
Table
18
Baseline
dichotomised
variables
and
all
cause
mortality
.........................................
68
Table
19
Univariate
results
for
overall
survival
......................................................................
69
Table
20
Univariate
results
for
recurrence
modelling
............................................................
74

8. 8
Table
21
Survival
and
recurrence
models
for
the
treatment
comparison
between
patients
treated
with
Sx
alone
vs.
RTx
alone
........................................................................................
76
Table
22
Survival
and
recurrence
models
for
the
treatment
comparison
between
patients
treated
with
Sx
alone
or
with
adjuvant
RTx
vs.
RTx
alone
......................................................
79
Table
23(a)
Time
dependent
Cox
analysis
at
24
months
........................................................
82
Table
23(b)
Summary
of
patients;
based
on
2
yr
survival.
......................................................
83
Table
24
Adjusted
survival
and
recurrence
models
for
the
treatment
comparison
between
patients
receiving
Sx+RTx
vs.
Sx.
.............................................................................................
84
Table
25
Adjusted
survival
and
recurrence
models
for
the
treatment
comparison
between
patients
receiving
Sx+RTx
vs.
RTx
...........................................................................................
87
Table
26
Time
dependent
Cox
analysis
at
24
months
............................................................
90
Table
27
Proportional
hazards
model
for
the
survival
risk
model
including
treatment
comparison
.............................................................................................................................
93
Table
28
2x2
table
for
risk
grouping
.......................................................................................
94
Table
29
Logrank
test
validating
the
risk
group
cut-­‐off
point
.................................................
95
Table
30
Gronnesby-­‐Borgan
goodness
of
fit
test
...................................................................
95
Table
31
May-­‐Hosmer
goodness
of
fit
test
.............................................................................
97
Table
32
Proportional
hazards
model
for
the
survival
risk
model
excluding
treatment
comparison
.............................................................................................................................
98
Table
33
Chi-­‐squared
test
for
risk
grouping
............................................................................
98
Table
34
Logrank
test
validating
the
risk
group
cut-­‐off
point
.................................................
99
Table
35
Gronnesby-­‐Borgan
goodness
of
fit
test
.................................................................
100
Table
36
May-­‐Hosmer
goodness
of
fit
test
...........................................................................
100

9. 9
Table
37
Proportional
hazards
model
for
the
recurrence
risk
model
including
treatment
comparison
...........................................................................................................................
101
Table
38
Chi-­‐squared
test
for
risk
grouping
..........................................................................
102
Table
39
Logrank
test
for
the
risk
group
cut-­‐off
point.
.........................................................
102
Table
40
Gronnesby-­‐Borgan
goodness
of
fit
test
.................................................................
104

10. 10
Figures
Figure
1
Incidence
rates
in
Asia,
Europe
and
USA
for
lip
cancer.
.......................................
19
Figure
2
Meyer’s
plasty:
steps
involved
to
excise
a
lesion
..................................................
26
Figure
3
Flowchart
of
articles
assessing
treatment
outcomes
for
lip
cancer
......................
30
Figure
4
Cumulative
proportion
experiencing
the
event
for
the
tumour
size
as
a
predictor
of
survival
............................................................................................................................
72
Figure
5
Cumulative
proportion
experiencing
the
event
for
the
variable
of
age
(age≥70
years)
as
a
prognostic
indicator
of
survival
.........................................................................
73
Figure
6
Cumulative
proportion
experiencing
the
event
for
Sx
alone
vs.
RTx
alone
in
predicting
overall
survival
...................................................................................................
77
Figure
7
Cumulative
proportion
experiencing
the
event
for
Sx
alone
vs.
RTx
alone
in
predicting
time
to
recurrence.
............................................................................................
78
Figure
8
Cumulative
proportion
experiencing
the
event
for
Sx
or
Sx+RTx
vs.
RTx
alone
in
predicting
survival
...............................................................................................................
81
Figure
9
Cumulative
proportion
experiencing
the
event
for
Sx
or
Sx+RTx
vs.
RTx
alone
in
predicting
recurrence.
........................................................................................................
83
Figure
10
Cumulative
proportion
experiencing
the
event
for
Sx+RTx
vs.
Sx
alone
in
predicting
survival
...............................................................................................................
85
Figure
11
Cumulative
proportion
experiencing
recurrence
for
Sx+RTx
vs.
Sx
....................
86
Figure
12
Cumulative
proportion
experiencing
the
event
for
Sx+RTx
vs.
RTx
alone
in
predicting
survival
...............................................................................................................
89
Figure
13
Cumulative
proportion
experiencing
the
event
for
Sx+RTx
vs.
RTx
alone
in
predicting
recurrence
.........................................................................................................
90
Figure
14
Risk
model
of
survival
for
patients
who
have
been
treated
...............................
96

11. 11
Figure
15
Risk
model
of
survival
for
patients
diagnosed
and
awaiting
treatment
.............
99
Figure
16
Risk
model
of
time
to
recurrence
.....................................................................
103
Note:
A
P
value
less
than
P
=
0.05
is
considered
significant
in
this
thesis.

12. 12
Abbreviations
and
acronyms
Terms
-­‐
Definitions
2x2
table
–
Two-­‐by-­‐two
table
95%CI
-­‐
95%
Confidence
Interval
ANZ
-­‐
Australia
and
New
Zealand
BT
-­‐
Brachytherapy
Cat.
-­‐
Categorical
cm
-­‐
Centimetres
cont.
-­‐
Continuous
corr.
-­‐
Correlation
CSS
-­‐
Cause
specific
survival
DFS
-­‐
Disease
free
survival
Diff
-­‐
Differentiated
DRR
-­‐
Delayed
regional
recurrence
EBRT
-­‐
External
beam
radiotherapy
FUP
-­‐
Followup
GB-­‐
Gronnesby-­‐Borgan
HDR
-­‐
High
dose
rate
HR
-­‐
Hazard
ratio
KM
-­‐
Kaplan
Meier
LDR
-­‐
Low
dose
rate

13. 13
LR
-­‐
Local
recurrence
LRC
-­‐
Locoregional
control
Mets
-­‐
Metastases
MH
-­‐
May
and
Hosmer
goodness
of
fit
test
mm
-­‐
millimetres
MTT
-­‐
Maximal
tumour
thickness
No.
-­‐
Number
NSW
-­‐
New
South
Wales
OR
-­‐
Odds
ratio
OS
-­‐
Overall
survival
PCNA
-­‐
Proliferating
cell
nuclear
antigen
RCT
-­‐
Randomised
control
trial
RTx
-­‐
Radiotherapy
SA
-­‐
South
Australia
SCC
-­‐
Squamous
cell
carcinoma
SEER
-­‐
Surveillance,
Epidemiology
and
End
Results
Sx
-­‐
Surgery
Sx+RTx
-­‐
Surgery
and
adjuvant
radiotherapy
TNM
-­‐
Tumour,
node
and
metastasis
UICC
-­‐
International
union
against
cancer
USA
–
United
States
of
America

14. 14
UV
–
Ultraviolet
UVB
-­‐
Ultraviolet
B
XP
-­‐
Xeroderma
pigmentosum
yrs
-­‐
Years

15. 15
Risk
and
Treatment
Factors
for
Squamous
Cell
Carcinoma
of
the
Lip
A
cohort
study
from
the
Radiation
Oncology
Department,
Westmead
Hospital
Literature
review
Introduction
Lip
cancer
is
a
malignant
neoplasm
of
the
upper
or
lower
lip,
or
commissure
and
vermillion
border,
or
inner
aspect
of
the
lip
(1)
and
is
classified
according
to
the
International
Classification
of
Disease
as
140.0-­‐140.9
ICD-­‐9.
In
some
studies
lip
cancer
accounts
for
up
to
25%
of
oral
cancers
(2)
although,
at
least
in
Australia,
lip
cancer
is
better
classified
as
a
sun
exposure
induced
cancer
rather
than
a
smoking
related
oral
cancer.
Lip
cancers
account
for
<5%
of
head
and
neck
cancers
after
excluding
other
non-­‐
melanoma
skin
cancer.(2)
Histologically
90%
of
lip
cancers
are
of
squamous
cell
origin,
with
the
remaining
10%
comprising
of
basal
cell
carcinoma
and
adenocarcinoma.
In
this
thesis
I
will
focus
on
squamous
cell
carcinoma
(SCC)
of
the
lip
and
this
is
implied
by
use
of
the
term
lip
cancer
unless
expressed
otherwise.
Lip
cancer
may
follow
an
indolent
time
course
and
have
a
favourable
outcome
if
treated
in
a
timely
and
appropriate
fashion,
however
in
a
subset
of
patients
the
cancer
can
be
aggressive,
with
increased
morbidity
and
mortality
often
associated
with
the
subsequent
development
of
nodal
metastases.(3)
If
these
patients
are
identified
and
treated
early,
the
likelihood
of
cure
is
increased.
It
is
therefore
important
to
identify
the
risk
factors
for
lip
cancer
and
to
investigate
the
effect
of
treatment
options
in
order
to
improve
outcome.
The
objectives
of
this
thesis
are
to
discuss
the
risk
factors
for
lip
cancer
in
terms
of
the
risk
of
developing
disease,
recurrence
and
survival.
Risk
factors
will
be
presented
as
either
patient
or
tumour
factors.
Treatment
factors
for
prognosis
will
also
be
investigated.

16. 16
The
risk
factors
for
developing
lip
cancer,
recurrence
and
predicting
survival
are
discussed
in
the
first
chapter.
Treatment
comparisons
between
radiotherapy
(RTx),
surgery
(Sx)
and
surgery
and
adjuvant
radiotherapy
(Sx+RTx)
are
also
investigated
and
presented
in
Chapter
1.
In
Chapter
2,
risk
factors
for
recurrence
and
survival
are
examined
via
a
series
of
survival
analyses,
both
univariate
and
multivariate.
Treatment
comparisons
are
assessed
univariately
and
adjusted
for
confounding
variables,
and
risk
models
were
developed
in
order
to
assess
the
risk
of
recurrence
and
survival.
Risk
models
were
constructed
to
classify
patients
into
risk
groups
based
on
baseline
risk
(patient
and
tumour
factors
only)
and
post
treatment
risk
(patient,
tumour
and
treatment
factors).
This
study
aims
to
provide
a
model
that
could
aid
the
understanding
of
the
factors
involved
in
lip
cancer,
and
the
effect
of
different
treatment
options
on
recurrence
and
survival.
However,
this
study
has
inherent
selection
and
referral
bias,
which
will
be
discussed
later,
and
can
therefore
not
be
expected
to
provide
a
high
level
of
evidence.
Note
that
to
my
knowledge
there
have
been
no
published
randomised
control
trials
(RCTs)
on
lip
cancer.
TNM,
staging
and
grading
The
following
is
a
summary
of
the
Tumour,
Node
and
Metastasis
(TNM)
classification
for
lip
cancer
from
the
International
Union
against
Cancer
(UICC).(4)
I.
Codes
describing
the
tumour
TX:
primary
tumour
cannot
be
assessed
T0:
no
evidence
of
primary
tumour
Tis:
carcinoma
in
situ
T1:
tumour
less
than
2
centimetres
(cm)
in
greatest
dimension

17. 17
T2:
tumour
more
than
2
cm
but
not
more
than
4
cm
in
greatest
dimension
T3:
tumour
more
than
4
cm
in
greatest
dimension
T4:
tumour
invades
adjacent
structures
(mandible,
tongue
musculature,
maxillary
sinus,
skin)
II.
Codes
describing
nodal
involvement
NX:
regional
lymph
nodes
cannot
be
assessed
N0:
no
regional
lymph
node
metastasis
N1:
metastasis
in
a
single
ipsilateral
lymph
node,
less
than
3
cm
in
greatest
dimension
N2a:
metastasis
in
a
single
ipsilateral
lymph
node,
more
than
3
cm
but
not
more
than
6
cm
in
greatest
dimension
N2b:
metastasis
in
multiple
ipsilateral
lymph
nodes,
none
more
than
6
cm
in
greatest
dimension
N2c:
metastasis
in
bilateral
or
contralateral
lymph
nodes,
none
more
than
6
cm
in
greatest
dimension
N3:
metastasis
in
a
lymph
node,
more
than
6
cm
in
greatest
dimension
III.
Codes
describing
metastasis
M0:
no
distant
metastasis
M1:
distant
metastasis
IV.
Stage
Grouping
Stage
I:
T1N0M0

18. 18
Stage
II:
T2N0M0
Stage
III:
T3N0M0;
T1
or
T2
or
T3N1M0
Stage
IV:
T4N0
or
N1M0;
Any
T,
N2,
or
N3M0;
Any
T,
any
N,
M1
Grading
The
Broder’s
grading
system
(5)
is
the
main
system
used
in
lip
cancer
studies
to
assess
histological
grading
of
tumour
specimens.
This
system
categorises
tumours
according
to
well,
moderate
and
poor
differentiation.
The
potential
weakness
with
this
system
is
that
the
degree
of
differentiation
may
vary
across
any
surgical
specimen.(6)
However,
some
studies
have
shown
correlation
between
tumour
grading
and
prognosis.
In
contrast,
the
Anneroth
and
Jacobson
system
includes
the
degree
of
keratinisation,
polymorphism,
mitoses,
inflammatory
infiltration
and
mode
of
invasion.
These
5
factors
are
graded
out
of
4
and
total
scores
are
divided
into
grade
I
(0-­‐4),
grade
II
(5-­‐10),
grade
III
(11-­‐15)
and
grade
IV
(16-­‐20).(7)
These
two
systems
are
mentioned
here,
as
when
discussing
later
articles,
histological
grading
will
be
assessed
via
these
two
systems.
Epidemiology
The
epidemiology
of
lip
cancer
is
investigated
here
from
both
an
Australian
and
international
perspective.
In
Australia
one
large
study
in
the
literature
reporting
the
epidemiology
of
lip
cancer
was
undertaken
in
South
Australia
(SA).

19. 19
The
age-­‐standardised
incidence
of
lip
cancer
in
SA
between
1976
-­‐
1996
was
15/100,000
in
males
and
4/100,000
in
females.(8)
The
authors
considered
this
very
high
on
a
global
scale.
Over
the
follow
up
period
there
were
2095
(77.1%)
males
and
621
(22.9%)
females
presenting
with
lip
cancer
(8)
and
as
of
June
2005
there
were
1.54
million
residents
in
SA.(9)
The
average
age
for
diagnosis
was
58.3
yrs
in
males
and
66.0
yrs
in
females.(10)
The
sun
exposed
lower
lip
was
the
most
common
site
(72.5%
lower
lip
vs.
7.7%
upper
lip
vs.
19.8%
remaining).(8)
New
South
Wales
(NSW)
has
a
much
lower
incidence
in
line
with
global
rates
at
3.8/100,000
for
males
and
1.5/100,000
for
females
during
2005.(10)
Figure
1
Incidence
rates
in
Asia,
Europe
and
USA
for
lip
cancer.
Figure
courtesy
of
Yako-­‐Suketomo
et
al,
2008
(11)

20. 20
In
Figure
1
the
contrasting
trends
in
the
incidence
of
lip
cancer
in
Asia,
Europe
and
the
United
States
of
America
(USA)
can
be
seen.
The
incidence
has
been
falling
in
those
countries
with
the
incidence
higher
than
2/100,000
at
1973
in
parts
of
England,
Italy,
and
Denmark
and
in
white
Americans.
Since
the
1970s
there
has
been
a
marked
decrease
in
the
incidence
of
lip
cancer
in
many
countries
as
a
consequence
of
a
better
awareness
of
smoking
and
UV
exposure
as
causes
for
lip
cancer.
The
East
Asian
locations
studied
all
have
a
low
incidence
of
lip
cancer.
Also
black
Americans
have
a
much
lower
incidence
than
white
Americans,
likely
due
to
the
increased
melanin
found
in
dark
skin
that
is
UV
protective.
Risk
factors
The
risk
factors
for
developing
lip
cancer
can
be
defined
as
environmental,
behavioural
or
endogenous.
Environmental
risk
factors
consist
of
ultraviolet
(UV)
sunlight
exposure
and
rural
residence.
Behavioural
risk
factors
include
smoking
(including
pipe
smoking
in
particular),
occupation,
alcohol
consumption,
socioeconomic
status
and
viral
infections
(e.g.
human
papilloma
virus).
Endogenous
factors
include
familial
and
genetic
predisposition,
immunosuppression
and
immunodeficiency.
Race
and
cultural
practices
are
other
risk
factors.
Sun
exposure
Sunlight
exposure
is
a
major
risk
factor
in
developing
lip
cancer
in
Australia,
and
is
a
result
of
a
cumulative
lifetime
exposure
to
sunlight.
UVB
(wavelength
of
290-­‐320nm)
is
the
key
exposure
attributed
to
lip
cancer.
UVB
radiation
induces
mutational
changes
in
the
DNA
that
can
lead
to
cancerous
growth.
In
particular
the
p53
tumour
suppressor
gene
that
would
otherwise
terminate
cancerous
growth
is
mutated
and
rendered
ineffective.(12)
Risk
of
lip
cancer
associated
to
sunlight
exposure
is
influenced
by
outdoor
exposure,
fair
skin
(fair
skin
has
a
lack
of
melanin
which
protects
against
UVB),
increasing
age
(lifetime
sun
exposure),
gender
(males
associated
with
higher
outdoor
exposure),
use
of
sun

21. 21
protection
and
rural-­‐urban
divide
and
cultural
practices.(12)
In
SA
over
the
period
of
1996-­‐1997
the
incidence
in
rural
areas
was
12.3/100
000,
compared
to
5.9/100
000
in
metropolitan
Adelaide.(13)
This
is
likely
to
be
due
to
increased
outdoor
sun
exposure
for
the
rural
population
living
in
SA.
Lip
cancer
has
a
higher
incidence
in
men
than
in
women,
which
was
seen
in
both
the
SA
and
NSW
studies.(8,
10)
Other
countries,
like
the
USA
(14)
and
Greece
(15)
confirm
a
similar
trend,
which
has
been
attributed
to
higher
exposure
of
men
than
women
to
UVB,
as
well
as
other
carcinogens,
such
as
cigarette
smoke.
For
example,
in
Greece,
the
male:
female
ratio
was
9.2:1
for
lip
cancer,
which
was
attributed
to
women
mostly
staying
in
an
indoor
environment
compared
to
men.
Females
when
working
outdoors
used
a
covering
for
their
face
and
men
generally
did
not.
Also
they
noted
that
the
diagnosis
of
lip
cancer
occurred
on
average,
11.2
yrs
later
in
females
than
males.
At
the
time
of
the
study,
the
incidence
of
smoking
in
females
was
much
lower
than
in
males.
Furthermore,
in
the
897
patients
of
the
study
80%
were
from
a
rural
area.
Rural
residents
doing
agricultural
work
would
have
had
more
sun
exposure
then
their
urban
counterparts.
Recently
the
overall
incidence
of
lip
cancer
has
reduced
in
Greece
with
increased
public
awareness,
decreased
pipe
smoking,
decreased
outdoor
workers
and
the
rural-­‐urban
drift.(15)
In
a
USA
study
of
lip
cancer
African-­‐Americans
comprised
only
7%
of
the
study,
which
suggests
a
low
incidence
of
lip
cancer
in
this
race.(16)
Furthermore
in
Figure
1
from
the
Surveillance,
Epidemiology
and
End
Results
(SEER)
study
the
incidence
was
higher
among
white
Americans
compared
to
African-­‐Americans.
African-­‐Americans
have
significantly
more
melanin
in
their
skin
than
the
white
population
so
they
are
likely
more
protected
against
UV
light
and
developing
skin
cancer.(17)
Among
African-­‐Americans
and
white
Americans
living
in
the
same
area
and
assumedly
receiving
similar
UV
exposure,
African-­‐

22. 22
Americans
have
a
lower
incidence
of
lip
cancer.
Therefore,
this
likely
implies
that
the
protection
by
melanin
from
the
damaging
effects
of
UVB
results
in
a
lower
incidence
of
lip
cancer
among
African-­‐Americans.
There
has
been
a
case
study
of
a
15-­‐year-­‐old
patient
with
xeroderma
pigmentosum
(XP)
diagnosed
with
lip
cancer.(18)
XP
is
a
rare
genetic
disorder
where
there
is
a
deficiency
in
the
ability
to
repair
DNA
mutations
induced
by
UV
light.
This
further
adds
to
the
evidence
that
sun-­‐exposure
is
a
risk
factor
for
the
development
lip
cancer.
This
is
because
if
lip
cancer
is
triggered
by
mutations
induced
by
UV
exposure
then
those
with
XP
due
to
their
deficiency
in
repairing
such
mutations
can
develop
both
skin
cancer
and
also
lip
cancer
at
a
much
younger
age.
Lip
cancer
affects
mainly
older
patients,
with
only
97
of
a
cohort
of
1038
(7%)
patients
aged
under
40
years
old.(19)
Of
these
97
patients,
63
reported
prolonged
sun
exposure
based
in
their
work
environment.
Cumulative
sun
exposure
increases
with
age
and
therefore
patients
under
the
age
of
40
generally
have
a
lower
incidence
of
lip
cancer.
However
these
particular
young
patients
may
have
developed
lip
cancer
in
part
due
to
excessive
sun
exposure
that
they
experienced.
The
mean
age
for
developing
lip
cancer
was
above
58
for
both
sexes
in
one
study
supporting
this
disease
occurring
in
older
patients.(10)
Another
study
also
reported
only
14
patients
out
of
223
below
the
age
of
50
(6.3%).(20)
Lip
cancer
can
therefore
be
considered
a
cancer
of
patients
in
their
60
-­‐
70’s.
Fabbrocini
et
al.,
2000
(21)
noted
that
p53
expression
was
elevated
in
lip
cancer
specimens
compared
to
samples
of
the
lip
from
non-­‐cancer
controls
(Lip
cancer:
50%,
control:
20%).
This
is
an
important
observation
because
p53
expression
increases
in
chronically
UV
exposed
areas
that
develop
lip
cancer.
As
this
is
an
observational
study
(a
snapshot),
we
cannot
say
whether
the
controls
will
go
on
to
develop
lip
cancer
with
time.
This
finding
is
unlikely
to
aid
clinicians
in
treating
lip
cancer
as
diagnosis
is
made
on

23. 23
clinical
presentation
and
histological
findings
and
not
by
p53
expression.
Currently
biopsies
are
not
done
on
at
risk
individuals
as
a
screening
tool
to
assess
p53
expression.
This
study
particularly
did
not
add
support
to
using
p53
as
a
screening
tool
as
it
is
not
a
cohort
study
that
investigates
cause
and
effect
over
time.
Smoking
as
a
risk
factor
for
developing
disease
Lip
cancer
is
strongly
associated
with
smoking
in
some
studies
in
some
countries,
in
particular
pipe
smoking.(2)
This
may
be
due
to
the
local
toxicity
of
smoking.
Smoking
has
also
been
linked
with
lung
cancer
(22)
and
the
rates
of
lung
cancer
are
reported
to
be
higher
in
lip
cancer
patients
than
in
the
general
population.(12)
Therefore,
smoking
has
causality
with
both
lip
cancer
and
lung
cancer.
In
the
previously
mentioned
study
of
patients
below
40
years
of
age,
78
out
of
97
patients
used
tobacco
(80.4%)
a
prevalence
much
higher
than
the
general
population.(19)
This
implies
that
those
aged
below
40
years,
who
had
less
lifetime
sun
exposure,
developed
lip
cancer
possibly
due
to
the
damaging
effect
of
smoking.
Other
risk
factors
for
developing
lip
cancer
The
less
common
risk
factors
of
immunosuppression
or
immunodeficiency
are
important
to
consider
and
are
particularly
relevant
to
the
younger
population.
Many
cases
are
reported
in
young
patients
who
have
had
renal
transplants
and
due
to
the
anti-­‐rejection
medication
are
immunosuppressed.(23)
In
these
patients
the
cancer
is
often
more
biologically
aggressive
due
to
host
susceptibility.
A
study
of
renal
transplant
recipients
identified
age,
time
since
transplant,
current
use
of
azathioprine,
cyclosporine,
male
sex
and
birthplace
outside
Australia
and
New
Zealand

24. 24
(ANZ)
to
be
significantly
associated
with
an
increased
incidence
of
lip
cancer.(23)
The
data
was
obtained
from
the
ANZ
Transplant
Registry
between
1982
and
2003
with
a
sample
size
of
8162
renal
transplant
patients.
The
variables
of
interest
are
the
immunosuppressant
agents
and
time
since
transplant
as
they
reflect
the
degree
of
immunosuppression
in
the
patient.
In
other
studies
increased
alcohol
consumption
was
also
associated
with
lip
cancer
(21)
as
was
low
education
level.(24)
The
hypothesis
being
that
a
low
education
level
could
be
associated
with
heavy
outdoor
work
and
increased
sun-­‐exposure
and
also
an
increased
prevalence
of
smoking.
Progression
of
disease
The
clinical
precursors
to
lip
cancer
predominantly
are
leukoplakia,
hyperkeratosis,
and
actinic
changes
and
are
related
to
sun
exposure.(25,
26)
The
initial
presentation
is
variable
but
may
be
that
of
an
ulcer,
usually
of
the
lower
lip,
that
fails
to
heal
and
gradually
increases
in
size
and
thickness.
Pain
is
often
not
an
issue
with
the
patient.
Only
a
small
proportion
(5-­‐10%)
will
actually
present
with
concomitant
upper
neck
lymphadenopathy
from
metastatic
spread.
Instead
subsequent
nodal
relapse
is
the
most
common
scenario
for
nodal
metastasis.
Treatment
modalities
and
regimens
There
are
various
treatment
options
available
to
a
patient
diagnosed
with
lip
cancer
in
its
different
presentations.
Standard
treatment
recommendation
is
either
RTx
or
Sx.
Post
operative
(or
adjuvant)
RTx
after
Sx
is
also
prescribed,
especially
where
the
margins
of
excision
are
close
or
positive.(27)
There
are
various
operations
utilised
and
these
depend
on
the
size
of
the
tumour
and
its
localisation,
as
well
as
patient,
surgeon
and
institute
preferences.
There
are
also
various
RTx
modalities,
which
include
orthovoltage,
megavoltage
(external
beam
radiotherapy
[EBRT])
and
brachytherapy
(BT).
BT
may
be

25. 25
delivered
as
either
low
dose
rate
(LDR)
or
high
dose
rate
(HDR)
BT,
which
specifies
the
rate
of
radiation
administered.
All
these
treatment
options
will
be
described
with
a
discussion
of
various
treatment
regimens
currently
utilised.
Surgery
Superficial
lip
cancer
with
maximal
tumour
thickness
(MTT)
less
than
3
millimetres
(mm)
and
also
the
pre-­‐malignant
condition
of
actinic
cheilitis
may
be
indications
for
vermilionectomy.
Actinic
cheilitis
has
a
probability
of
developing
into
lip
cancer
if
left
untreated.(25)
Vermilionectomy
is
the
excision
of
the
vermilion
surface
of
the
lip
and
is
commonly
referred
to
as
a
lip
shave.
For
lesions
measuring
approximately
2
cm
or
less
in
maximum
dimension,
the
most
efficacious
resection
is
a
“V”
shaped
wedge
excision
and
primary
closure.
Here
the
excision
is
in
a
V
shape
around
the
lesion
and
closure
is
performed
on
the
two
edges.
If
the
V
excision
approaches
the
mental
crease,
then
a
“W”
excision
is
performed
using
the
same
principles.
Margins
of
5
to
7
mm
are
recommended,
with
a
total
resection
achievable
of
approximately
one-­‐third
of
the
lower
lip.
There
are
other
more
sophisticated
and
complex
lip
cancer
operations
including
the
Abbe
method
and
the
Estlander
method.
These
operations
are
undertaken
when
the
excision
defect
is
30
to
65%
of
the
lip.
For
defects
larger
than
65%
there
is
the
Bernard-­‐Freeman-­‐
Fries
method.
These
methods
leave
very
little
of
the
lower
lip
remaining
(1.5
cm)
and
therefore,
reconstruction
using
various
flaps
are
utilised,
such
as
the
radial
forearm-­‐
palmaris
longus
tendon
flap.(28)
This
flap
can
be
used
when
the
expected
defect
is
greater
than
80%
of
the
lower
lip.
An
improved
flap
for
this
situation
is
the
anterolateral
thigh
flap,
which
has
an
inconspicuous
scar
compared
to
the
forearm
and
it
is
then
unnecessary
to
sacrifice
one
of
the
two
arteries
of
the
hand.(28)

26. 26
One
consequence
of
many,
but
not
all
operations,
apart
from
poor
cosmesis,
is
microstomia
where
the
oral
opening
is
reduced.
This
is
especially
a
problem
when
a
patient
has
dentures
fitted.(25)
A
further
operation
is
Meyer’s
plasty.
This
operation
can
be
used
for
defects
up
to
80%
and
does
not
require
a
flap
(see
Figure
2).
In
this
method,
cosmesis
was
reported
as
acceptable
in
87%
patients
with
100%
local
control
in
one
small
study.(29)
Figure
2
Meyer’s
plasty:
steps
involved
to
excise
a
lesion
a
Tumour.
b
Tumour
excision.
c
Commissuroplasty:
triangular
cutaneous
excision.
d
Mucosal
flap
incision
and
lower
lip
closure,
blue
arrows.
e
Eversed
mucosal
flap,
yellow
arrows.
f
End
result
with
scars
along
the
white
line
and
labiomental
crease
Figure
courtesy
of
Jaquet
et
al,
2005
(29)

27. 27
Other
operations
include
using
double
free
flaps
(30)
for
increased
mobility.
Some
clinicians
recommend
Sx
as
the
best
option
since
the
margin
status
of
the
excision
can
be
assessed
and
a
detailed
histological
examination
can
be
performed.(31)
However
the
functional
and
cosmetic
outcome
of
any
operation
must
always
be
taken
into
consideration.
Patients
are
often
elderly
and
when
given
the
option
some
patients
may
also
elect
a
non-­‐surgical
treatment.
Patients
may
also
have
medical
co-­‐morbidity
that
precludes
Sx.
Radiotherapy
RTx
offers
a
non-­‐surgical
option
for
treating
patients
with
lip
cancer.
The
mainstay
of
RTx
to
treat
lip
cancer
is
orthovoltage
energy
photons.
RTx
is
a
weekday
out
patient
treatment
taking
10-­‐15
minutes
to
deliver.
Typical
treatments
extend
over
2-­‐6
weeks
(10-­‐
30
treatments).
Shorter
treatments
are
often
considered
in
older
sicker
patients.
Various
dose
schedules
are
also
used
with
one
study
reporting
17
daily
fractions
of
300
centi-­‐Gray
(cGy)
over
4
weeks
of
orthovoltage
as
biologically
equivalent
to
6000cGy
in
30
daily
fractions
of
200
cGy
each,
5
times
per
week,
for
6
weeks
of
megavoltage
therapy.
This
is
also
equivalent
to
an
implant
used
in
BT
of
6000cGy
with
a
LDR
of
40-­‐80
cGy/hr.
This
equivalence
is
in
terms
of
radiobiological
equivalence
of
dose.(32)
BT
is
less
commonly
used
in
Australia
in
treating
patients
non-­‐surgically.
However
when
used,
one
approach
uses
radioactive
iridium-­‐192
wires
with
3
wires
inserted
in
a
triangular
fashion
with
the
dose
rate
pre-­‐calculated
before
treatment.
The
mean
calculated
dose
in
one
study
was
63.54
cGy/hour.(32)
The
total
dose
varied
between
6000-­‐7000
cGy
for
this
study,
with
treatment
completed
in
3
to
7
days.
The
wire
pierces
the
tumour
and
the
surrounding
lip
to
deliver
radiation
directly
to
the
tumour.
The
procedure
is
usually
carried
out
under
local
anaesthetic
with
the
patients
spending
3-­‐5
days
in
a
radio-­‐protective
room
for
LDR
BT.

28. 28
An
accepted
advantage
of
RTx
is
that
it
does
not
require
the
tumour
to
be
excised
and
hence
may
result
in
better
cosmesis
and
functional
outcomes
compared
to
Sx.
This
is
especially
true
in
larger
lesions
where
a
significant
amount
of
the
lip
may
need
to
be
resected.
The
choice
between
EBRT
and
BT
is
based
on
physician
and
patient
preferences
and
what
is
available
at
the
treating
institution,
however,
few
centres
in
Australia
use
BT
for
treating
lip
cancer.
Deeply
infiltrating
tumours
where
surgical
margins
are
ill-­‐defined,
may
make
simple
excision
difficult
and
it
is
these
cases
where
Sx
is
less
ideal.
A
more
extensive
surgical
approach
may
lead
to
less
than
ideal
cosmetic
and
functional
results.
In
such
patients
there
is
a
reasonable
likelihood
that
adjuvant
RTx
will
be
recommended,
as
surgical
margins
are
often
close
or
positive.
For
patients
with
large
tumours
and
for
whom
Sx
is
not
advisable,
or
those
who
would
have
poor
functional
outcome,
RTx
is
often
recommended.
This
often
means
RTx
treated
patients
in
many
observational
studies
have
more
advanced
disease
possibly
leading
to
a
selection
bias
when
reporting
results.(33)
Patients
treated
with
RTx
usually
tolerate
their
treatment
well,
even
older
patients.
When
treating
the
lip,
EBRT
irradiates
a
relatively
small
volume
of
surrounding
normal
tissue,
which
usually
leads
to
symptomatic
local
mucocutaneous
reactions.
However
these
reactions
are
localised
and
usually
resolve
in
4-­‐6
weeks
following
completion
of
treatment.
Systemic
side
effects
are
negligible.
Late
side
effects
are
limited
to
the
irradiated
lip
and
many
include
hypo/hyperpigmentation
of
the
lip
and
skin
with
associated
epithelial
atrophy.
Serious
late
effects
are
rare.

29. 29
Summary
of
treatment
outcome
Various
studies
have
reported
treatment
outcomes
following
Sx
or
RTx
for
patients
with
lip
cancer.
The
outcome
measures
from
these
studies
include
loco-­‐regional
control
(LRC),
overall
survival
(OS),
cause
specific
survival
(CSS)
and
disease
free
survival
(DFS).
LRC
is
defined
as
the
percentage
of
lip
cancer
patients
that
did
not
relapse
either
locally
in
the
lip
or
regionally
to
the
nodes.
DFS
refers
to
the
percentage
of
the
cohort
that
did
not
relapse
locally,
regionally,
distantly
or
develop
a
second
primary.
DFS
and
LRC
differ
in
that
a
metastasis
to
a
distant
site
is
counted
in
DFS
where
it
is
not
counted
in
LRC.
OS
is
the
percentage
of
the
cohort
surviving,
i.e.
not
dying
of
any
cause.
CSS
or
determinate
survival
is
calculated
using
various
methods
but
refers
to
the
percentage
of
the
cohort
who
have
not
died
due
to
the
disease.
This
section
of
the
thesis
aims
to
summarise
treatment
results
and
make
comparisons
between
different
treatments.
There
are
various
weaknesses
in
many
retrospective
studies
noting
that
as
most
studies
do
not
have
two
treatment
groups
for
direct
comparison
but
often
just
describe
the
outcome
of
either
Sx
or
RTx
as
a
single
modality
treatment.
Following
a
literature
review
articles
were
selected
from
the
main
medical
databases
(PubMed,
Science
Direct
and
Embase,
etc.).
The
search
criteria
was
as
follows:
Lip
AND
(Carcinomas
or
Cancer
or
SCC
or
Neoplasm)
AND
(survival
or
patients
or
cases).
All
abstracts
were
deidentified
and
had
the
results
removed
by
an
external
researcher.
I
excluded
all
non-­‐related
articles
and
sent
this
list
to
my
supervisor
who
checked
if
any
of
them
should
be
re-­‐included.
From
this
selection
process
76
articles
remained.
The
flowchart
of
included
articles
is
presented
in
Figure
3.

30. 30
76
articles
Identified
56
articles
remaining
49
articles
remaining
35
articles
remaining
24
articles
on
Sx
15
articles
on
RTx
6
articles
on
Sx+RTx
7
articles
on
BT
20
articles
excluded
(see
below
*)
7
articles
had
no
data
in
required
format
(i.e.
LRC,
OS,
CSS,
DFS)
8
articles
had
only
non-­‐
treatment
specific
data
41
articles
remaining
6
articles
had
no
5-­‐year
data
available
Outcome
LRC
–
10
OS
-­‐
15
CSS
–
10
DFS
-­‐
6
Outcome
LRC
–
6
OS
-­‐
10
CSS
–
3
DFS
-­‐
4
Outcome
LRC
–
4
OS
-­‐
2
CSS
–
0
DFS
-­‐
0
Outcome
LRC
–
7
OS
-­‐
5
CSS
–
2
DFS
-­‐
4
Flowchart
of
articles
Figure
3
Flowchart
of
articles
assessing
treatment
outcomes
for
lip
cancer
*4
had
no
lip
specific
data
(only
oral),
2
epidemiological
studies
without
usable
data,
1
basal
cell
carcinoma,
6
advanced
disease
but
not
at
primary
presentation,
1
review
article
without
original
data,
1
site
other
than
lip,
2
duplicate
or
obsolete
studies,
1
chemotherapy
only,
2
abstracts
with
no
data
(of
which
1
article
was
in
foreign
language
with
an
English
abstract)
(total
20).
Sx:
Surgery;
RTx:
Radiotherapy;
Sx+RTx:
Surgery
and
adjuvant
radiotherapy;
BT:
Brachytherapy;
LRC:
Locoregional
Control;
OS:
Overall
Survival;
CSS:
Cause
Specific
Survival;
DFS:
Disease
Free
Survival
Of
the
35
articles
remaining
in
Figure
3
many
reported
more
than
one
outcome
and
some
articles
reported
on
more
than
one
treatment
also.
In
Table
1
the
outcomes
reported
and
treatments
used
are
listed
with
the
years
of
study.

31. 31
Table
1
Treatment
outcome
and
treatment
modality
for
each
article
Title
Reference
Years
of
Study
n
OS
DFS
CSS
LRC
Brachy-­‐
therapy
Sx
RTx
Sx+RTx
A
comparison
of
results
after
radiotherapy
and
surgery
for
stage
I
squamous
cell
carcinoma
of
the
lower
lip
de
Visscher
et
al,
1999
(34)
1980-­‐1994
256
Yes
Yes
No
No
No
Yes
Yes
No
A
study
of
squamous
cell
carcinoma
of
the
lip
at
West
Virginia
University
Hospitals
from
1980-­‐2000
Wilson
et
al,
2005
(35)
1980-­‐2000
52
No
No
No
Yes
No
Yes
No
Yes
Brachytherapy
for
lower
lip
epidermoid
cancer
tumoral
and
treatment
factors
influencing
recurrences
and
complications
Beauvois
et
al,
1994
(36)
1972-­‐1991
237
Yes
No
Yes
Yes
Yes
No
No
No
Brachytherapy
for
squamous
cell
carcinoma
of
the
lip
Tombolini
et
al,
1998
(37)
1970-­‐1992
57
Yes
Yes
No
Yes
Yes
No
No
No
Cancer
of
the
lips
Results
of
the
treatment
of
299
patients
Cowen
et
al,
1990
(38)
1970-­‐1985
299
No
No
No
Yes
Yes
No
No
No
Carcinoma
of
the
lip
Heller
et
al,
1979
(39)
1955-­‐1969
171
Yes
No
Yes
Yes
No
Yes
No
No
Carcinoma
of
the
lip
Petrovich
et
al,
1979
(40)
1945-­‐1975
250
Yes
No
No
Yes
No
No
Yes
No
Choice
of
the
treatment
for
lip
carcinoma–an
analysis
on
74
cases
Wu
et
al,
1985
(41)
1958-­‐1974
74
Yes
No
No
No
No
Yes
Yes
No
Critical
review
of
121
squamous
cell
epitheliomas
of
the
lip
Giuliani
et
al,
1989
(42)
1974-­‐1986
121
Yes
Yes
No
Yes
No
Yes
No
No
Curative
radiotherapy
for
early
cancers
of
the
lip,
buccal
mucosa,
and
nose–a
simple
interstitial
brachytherapy
Ngan
et
al,
2005
(43)
1996-­‐2004
13
Yes
Yes
Yes
Yes
Yes
No
No
No
Effectiveness
of
brachytherapy
in
the
treatment
of
lip
cancer
a
retro
at
the
Istanbul
university
oncology
institute
Aslay
et
al,
2005
(44)
1988-­‐2003
41
Yes
Yes
No
Yes
Yes
No
No
No
Interstitial
brachytherapy
for
carcinomas
of
the
lower
lip
Results
of
treatment
Orecchia
et
al,
1991
(45)
1973-­‐1988
47
Yes
Yes
No
Yes
Yes
No
No
No
Lip
cancer
experience
in
Mexico.
An
11-­‐year
retrospective
study
Luna-­‐Ortiz
et
al,
2004
(46)
1990-­‐2000
113
Yes
No
No
No
No
Yes
Yes
No
Long
term
results
in
treating
squamous
cell
carcinoma
of
the
lip,
oral
cavity
and
orophar
Hemprich
et
al,
1989
(47)
15
years
352
Yes
No
No
No
No
No
Yes
No
Lymph-­‐node
metastasis
in
squamous
cell
carcinoma
of
the
lip
Califano
et
al,
1994
(48)
1975-­‐1987
105
Yes
No
Yes
No
No
Yes
No
No
Management
of
lower
lip
cancer
a
retrospective
analysis
of
118
patients
and
review
of
the
literature
Bilkay
et
al,
2003
(18)
1983-­‐1999
118
Yes
No
Yes
Yes
No
Yes
No
No
n:
number
of
patients
in
study,
OS:
Overall
survival,
DFS:
Disease
free
survival,
CSS:
Cause
specific
Survival,
LRC:
Loco-­‐regional
control,
Sx+RTx:
Surgery
and
adjuvant
radiotherapy

32. 32
Title
Reference
Years
of
Study
n
OS
DFS
CSS
LRC
Brachy-­‐
therapy
Sx
RTx
Sx+RTx
Meyer’s
surgical
procedure
for
the
treatment
of
lip
carcinoma
Jaquet
et
al,
2005
(29)
1983-­‐2001
24
Yes
No
Yes
Yes
No
Yes
No
No
Oncologic
aspects
of
the
vermilionectomy
in
squamous
cell
carcinoma
of
the
lower
lip
abstract
van
der
Wal
et
al,
1996
(49)
1985-­‐1992
14
No
No
No
Yes
No
Yes
No
No
Outcome
analysis
for
lip
carcinoma
Zitsch
et
al,
1995
(2)
1940-­‐1987
1252
Yes
No
Yes
No
No
Yes
Yes
No
Prognostic
factors
in
squamous
cell
carcinoma
of
the
oral
cavity.
Beltrami
et
al,
1992
(50)
80
Yes
No
Yes
No
No
Yes
No
No
Radiotherapy
for
cancer
of
the
lip
Gooris
et
al,
1998
(32)
1974-­‐1994
85
No
Yes
No
Yes
Yes
No
Yes
Yes
Results
of
radiation
therapy
of
cancer
of
the
lip
Miltenyi
et
al,
1980
(51)
170
Yes
No
Yes
No
No
No
Yes
No
Results
of
radiotherapy
for
scc
lower
lip.
A
retrospective
analysis
of
108
patients
de
Visscher
et
al,
1996
(52)
1980-­‐1992
108
Yes
Yes
No
No
No
No
Yes
No
Squamous
carcinoma
of
the
lower
lip
in
patients
under
40
years
of
age
Boddie
et
al,
1977
(19)
1943-­‐1974
1308
Yes
No
Yes
No
No
Yes
Yes
No
Squamous
cell
carcinoma
of
the
lip:
a
retrospective
review
of
the
Peter
MacCallum
Cancer
Institute
experience
1979-­‐88
McCombe
et
al,
2000
(33)
1979-­‐1988
323
No
No
No
Yes
No
Yes
Yes
No
Squamous
cell
carcinoma
of
the
lip
analysis
of
the
Princess
Margaret
Hospital
experience
Cerezo
et
al,
1993
(53)
1971-­‐1976
117
No
No
No
Yes
No
Yes
Yes
Yes
Squamous
cell
carcinoma
of
the
lip:
is
there
a
role
for
adjuvant
radiotherapy
in
improving
local
control
following
incomplete
or
inadequate
excision?
Babington
et
al,
2003
(27)
1980-­‐2000
130
Yes
Yes
No
Yes
No
Yes
Yes
Yes
Squamous
cell
carcinoma
of
the
lip
treated
with
Mohs
Holmkvist
et
al,
1998
(54)
1986-­‐1999
50
No
Yes
No
Yes
No
Yes
No
No
Squamous
cell
carcinoma
of
the
lip
Cruse
et
al,
1987
(55)
1962-­‐1982
117
Yes
No
Yes
No
No
Yes
No
No
Squamous
cell
carcinoma
of
the
lips
in
a
northern
Greek
population.
5yr
Surv
rate
Antoniades
et
al,
1995
(15)
1979-­‐1989
906
Yes
No
No
No
No
Yes
Yes
Yes
Squamous
cell
carcinoma
of
the
lower
lip
and
supra-­‐
omohyoid
neck
dissection
Kutluhan
et
al,
2003
(26)
1994-­‐2000
31
Yes
No
Yes
Yes
No
Yes
No
No
Squamous-­‐cell
carcinoma
of
the
lower
lip
a
retrospective
study
of
58
patients
dos
Santos
et
al,
1996
(56)
1980-­‐1999
58
Yes
Yes
No
Yes
No
Yes
No
No
Surgical
treatment
of
squamous
cell
carcinoma
of
the
lower
lip
de
Visscher
et
al,
1998
(57)
1979-­‐1992
184
Yes
Yes
No
Yes
No
Yes
No
No
Survival
analysis
of
5595
head
and
neck
cancers
Rao
et
al,
1998
(58)
1987-­‐1989
62
Yes
No
No
No
No
Yes
Yes
Yes
The
step
technique
for
the
reconstruction
of
lower
lip
defects
after
cancer
resection
Blomgren
et
al,
1988
(59)
25
years
165
Yes
No
Yes
Yes
No
Yes
No
No
n:
number
of
patients
in
study,
OS:
Overall
survival,
DFS:
Disease
free
survival,
CSS:
Cause
specific
survival,
LRC:
Loco-­‐regional
control,
Sx+RTx:
Surgery
and
adjuvant
radiotherapy,

33. 33
Table
2
Summary
of
results
relating
to
loco-­‐regional
control
Treatment
5yr
LRC
95%CI
No.
of
studies
No.
maintaining
LRC
Sample
size
Crude
ratio
Sx
89.8%
(87.9
–
91.6%)
10
785
947
82.9%
EBRT
85.3%
(82.2
–
88.3%)
5
414
504
82.1%
Sx+RTx
95.3%
(88.3
–
100%)
4
43
47
91.5%
BT
94.6%
(92.8
–
96.4%)
6
579
617
93.8%
95%CI:
95%
Confidence
interval,
No.:
Number
Treatment
results
were
pooled
together
with
results
weighted
according
to
the
inverse
variance.
That
is
larger
studies
contributed
more
to
the
pooled
results
than
smaller
studies,
because
they
have
a
decreased
variance
due
to
the
larger
sample
size.
Where
the
5yr
LRC
rate
was
either
100%
or
0%
the
Wilson
interval
was
used
to
calculate
the
variance.(60)
In
Table
2
the
results
for
LRC
are
summarised.
The
results
suggest
that
patients
undergoing
BT
may
have
a
slightly
better
outcome
than
patients
undergoing
either
Sx
or
RTx.
Sx
may
result
in
better
LRC
than
RTx
noting
that
the
95%
CIs
do
not
overlap.
The
combination
of
Sx+RTx
may
also
be
better
than
RTx
with
CIs
touching.
Note
that
the
crude
ratio
is
the
number
of
patients
with
an
outcome
(e.g.
maintaining
LRC)
divided
by
the
total
number
of
patients
in
the
sample
(the
sample
size).
Table
3
Summary
of
results
relating
to
overall
survival
Treatment
5yr
OS
95%CI
No.
of
studies
No.
alive
Sample
size
Crude
ratio
Sx
81.9%
(80.1
–
83.7%)
15
1146
1550
73.9%
EBRT
79.9%
(77.4
–
82.4%)
10
729
943
77.3%
Sx+RTx
72.0%
(56.2
–
87.8%)
2
11
18
61.1%
BT
85.3%
(81.8
–
88.8%)
4.00
280
357
78.4%
95%CI:
95%
Confidence
interval,
No.:
Number

34. 34
Table
3
details
the
results
for
OS.
Patients
having
BT
had
the
best
outcome,
followed
by
Sx
then
RTx
and
lastly
Sx+RTx
but
note
all
CIs
were
overlapping
indicating
no
statistically
significant
difference
in
OS
between
the
4
treatments.
Table
4
Summary
of
results
relating
to
cause-­‐specific
survival
Treatment
5yr
CSS
95%CI
No.
of
studies
No.
not
dead
of
disease
Sample
size
Crude
ratio
Sx
94.9%
(93.7
–
96.1%)
10
1114
1219
91.4%
EBRT
96.0%
(94.3
–
97.8%)
3
401
439
91.3%
Sx+RTx
0
0
0
BT
91.1%
(87.5
–
94.8%)
1.00
216
237
91.1%
95%CI:
95%
Confidence
interval,
No.:
Number
Table
4
details
the
results
for
CSS.
Patients
receiving
RTx
achieved
the
best
CSS,
followed
by
Sx
and
BT.
No
studies
with
Sx+RTx
were
available.
Here
also
the
CIs
overlapped
for
all
treatments
suggesting
no
significant
difference
in
CSS
between
treatments.
Table
5
Summary
of
results
relating
to
disease
free
survival
Treatment
5yr
DFS
95%CI
No.
of
studies
No.
disease
free
Sample
size
Crude
ratio
Sx
85.0%
(82.4
–
87.6%)
6
486
630
77.1%
EBRT
81.7%
(77.5
–
85.9%)
4
247
314
78.7%
BT
90.2%
(84.9
–
95.4%)
3
105
120
87.5%
95%CI:
95%
Confidence
interval,
No.:
Number

35. 35
Table
5
details
the
results
for
DFS.
Patients
undergoing
BT
had
the
best
outcome,
followed
by
Sx
and
then
RTx.
Once
again
all
CIs
overlapped.
It
is
important
to
note
that
these
results
do
not
conclusively
favour
one
particular
treatment
over
the
other
across
the
outcomes
of
LRC,
OS,
CSS
and
DFS.
Most
patients
did
not
die
from
their
lip
cancer
so
OS
may
not
necessarily
be
an
accurate
outcome
to
investigate
in
this
disease.
Similarly
CSS
is
calculated
using
deaths
due
to
lip
cancer.
This
outcome
may
be
biased
if
people
die
due
to
a
secondary
cause
unrelated
to
lip
cancer
(e.g.
heart
attack),
before
they
may
have
relapsed
and
potentially
die
from
their
lip
cancer.
An
alternative
way
is
to
analyse
this
problem
is
to
use
competing
risk
survival
analysis,
where
the
probability
of
dying
due
to
lip
cancer
is
adjusted
for
by
the
presence
of
competing
co-­‐morbid
events
that
precede
death
due
to
lip
cancer
such
as
other
causes
of
mortality.
However
no
studies
we
reviewed
have
used
this
statistical
methodology.
Recurrence
Following
treatment
patients
may
experience
recurrence
at
either
the
primary
site
(local
recurrence)
or
regionally
(nodal
recurrence).
Alternatively,
but
much
less
likely,
lip
cancer
may
metastasise
to
distant
sites
such
as
the
lung
or
liver.
Delayed
regional
recurrence
(DRR)
implies
that
regional
metastases
were
not
clinically
present
at
the
time
of
diagnosis
but
occurred
later.
If
recurrence
does
occur,
95%
of
such
cases
usually
occur
within
5
years
of
treatment.(18)
The
peak
incidence
of
recurrence
usually
occurs
in
the
first
and
second
years.
For
example
in
one
study
from
1996,
12
out
of
108
patients
developed
local
or
regional
recurrences
and
of
these
8
occurred
within
the
first
2
years
following
treatment.(52)
The
predictors
of
recurrence
as
documented
in
the
literature
include:
tumour
size,
histological
grade,
MTT,
extent
of
surgical
margins
(positive/close
vs.
clear
margins),

36. 36
perineural
and
muscle
invasion,
age
and
various
cellular
and
molecular
factors.
These
predictors
will
be
investigated
using
the
data
published
by
other
researchers
and
analysing
a
database
of
patients
from
Westmead
Hospital,
Sydney,
Australia.
Predictors
of
recurrence
and
survival
can
be
divided
into
patient,
tumour
and
treatment
factors.
Patient
factors
include
age,
gender,
smoking
and
UVB
exposure
from
sunlight.
Tumour
factors
include
tumour
size,
histological
grade,
MTT,
perineural
invasion,
muscle
invasion,
cellular
and
molecular
factors
and
status
of
surgical
margins.
Treatment
factors
include
treatment
comparisons
(Sx
or
RTx).
Age
Table
6
Summary
of
findings
for
age
Study
Outcome
Cut-­‐off
point
N
Effect
size
95%CI
P
value
FUP
Event
rate
Fernandez
et
al,
2003
(61)*
Mets.
Cat.
251
1.013
OR
(0.97-­‐1.06)
0.05
5
yrs
6.40%
Zitsch
et
al,
1999
(5)
DRR
40yrs
1001
-­‐
-­‐
0.99
5
yrs
4%
n:
Sample
size,
95%CI,
95%
Confidence
interval
FUP:
Minimum
follow
up,
Mets:
Metastases,
DRR:
Delayed
regional
recurrence,
Cat.
:
Categorical,
*:
multivariate
model
There
are
various
hypotheses
as
to
why
age
may
be
associated
with
recurrence.
One
is
that
cancer
is
likely
to
recur
in
older
people
due
to
the
increased
rate
of
accumulated
somatic
genetic
mutation
with
increasing
age.
Alternatively
lip
cancer
is
more
biologically
aggressive
in
the
young
and
hence
more
likely
to
recur
despite
treatment.
Fernandez
et
al,
2003
(61)
as
detailed
in
Table
6
analysed
age
in
a
multivariate
model
along
with
site
and
tumour
area
and
reported
a
non-­‐significant
odds
ratio
(OR)
with
no
P
value
given.
However
the
CI
for
the
OR
included
1
and
this
usually
implies
that
the
result

37. 37
is
statistically
non-­‐significant.
In
this
study
there
were
251
patients
with
a
minimum
follow
up
of
5
yrs
and
an
event
rate
of
6.4%
throughout
the
study
period.
Zitsch
et
al,
1999
(5)
also
reported
a
statistically
non-­‐significant
association
between
age
and
DRR
using
age
as
a
binary
variable
with
the
cut-­‐off
point
at
40
years.
This
study
had
1001
patients
and
was
one
of
the
larger
studies
dealing
with
lip
cancer.
An
OR
was
not
reported.
Both
these
large
studies
suggest
that
age
alone
is
not
a
strong
predictor
of
DRR
or
worse
outcome.
Gender
The
effect
of
gender
on
DRR
was
investigated
in
2
studies.
These
both
found
no
association
between
gender
and
DRR.(5,
62)
Of
these
studies,
Zitsch
et
al,
1999
(5)
had
1001
patients
with
a
minimum
follow
up
of
5
yrs
and
reported
the
association
between
gender
and
DRR
as
statistically
non-­‐significant
(P=0.34).
The
other
study
of
Vukadinovic
et
al,
2007
(20)
had
223
patients
with
a
median
follow
up
of
56
months
and
also
found
no
statistically
significant
association
between
gender
and
DRR.
The
study
did
not
mention
an
OR
or
P
value.
A
previously
described
study
found
no
association
between
gender
and
the
tumour
size
of
the
primary
tumour
which
is
itself
an
indicator
of
DRR.(20)
Also
gender
did
not
impact
on
the
risk
of
CSS
from
lip
cancer
(i.e.
proportion
dying
of
disease).(2)

38. 38
Tumour
size
Table
7
Summary
of
results
for
tumour
size
Study
Outcome
Cut-­‐off
point
n
Effect
size
95%CI
P
value
FUP
Event
rate
Zitsch
et
al,
1999
(5)
DRR
3
cm
1001
-­‐
-­‐
0.034
5
yrs
4%
Hosal
et
al,
1992
(3)
DRR+LR
-­‐
-­‐
-­‐
no
corr.
-­‐
-­‐
de
Visscher
et
al,
2002*
(57)
LR
Cat.
184
-­‐
-­‐
<0.01
2
yrs
6%
de
Visscher
et
al,
2002*
(57)
DRR
Cat.
184
-­‐
-­‐
>0.05
2
yrs
5%
McGregor
et
al,
1992
(63)
DRR
-­‐
108
-­‐
-­‐
<0.05
2
yrs
18%
Heller
et
al,
1979
(39)
LR
-­‐
171
1.01
OR
-­‐
0.99
-­‐
8%
Rodolico
et
al,
2005
(7)
DRR
T2&T3
vs.
T1
97
15.21
HR
(2.25-­‐94.1)
0.033
5
yrs
-­‐
Rodolico
et
al,
2005
(7)
DRR
cont.
97
1.09
HR
(1.05-­‐1.13)
<0.0001
5
yrs
-­‐
Rodolico
et
al,
2005*
(7)
DRR
T2&T3
vs.
T1
97
13.5
HR
(2.19-­‐83)
0.005
5
yrs
-­‐
Rodolico
et
al,
2005*
(7)
DRR
cont.
97
1.04
HR
(0.99-­‐1.09)
0.042
5
yrs
-­‐
Rodolico
et
al,
2004
(64)
DRR
2
cm
97
-­‐
-­‐
0.05
5
yrs
-­‐
n:
Sample
size,
95%CI:
95%
Confidence
interval,
FUP:
Minimum
follow
up,
DRR:
Delayed
regional
recurrence,
LR
Local
recurrence
Cat.
:
Categorical,
*:
multivariate
model,
cont.:
continuous,
cat:
categorical,
corr.:
correlation
Tumour
size
is
recorded
as
the
maximum
lesion
size
and
is
the
largest
diameter
of
the
tumour.
Tumour
size
is
reported
in
the
TNM
classification
at
cut-­‐offs
of
2
cm
(T1),
2-­‐4
cm
(T2)
and
>4
cm
(T3).
Various
studies,
as
presented
in
Table
7,
have
investigated
tumour
size
as
a
predictor
of
regional
recurrence.
These
studies
incorporate
both
the
event
of
recurrence
and
time
to
event,
in
survival
models.
Tumour
size
has
an
impact
on
prognosis
and
also
on
selection
of
the
appropriate
treatment.
Zitsch
et
al,
1999
(5)
with
39
patients
developing
DRR
found
tumour
size
to
be
a
statistically
significant
predictor
of
DRR
(P
=
0.034).
Tumour
size
was
dichotomised
into
above
or
below
3
cm.
Despite
the
larger
size
of
this
study,
the
power
to
detect
a
50%
difference
in
prevalence
of
risk
factors
between
the
two
tumour
size
categories
was
only
very
low.
This
was
because
the
overall
event
rate
was
low
and
also
due
to
the
small
number
of
patients
with
tumour
size
above
3cm,
who
composed
only
14%
of
the
total
sample.