Refinement and individualization of
target volume delineation in
bladder cancer
By
shokry Hasan
Staging of bladder cancer
Treatment of MIBC
• The curative management of muscle-invasive
bladder cancer (MIBC) involves either radical
cystectomy or radical radiotherapy
• Standard of care = Radical cystectomy with
pelvic lymphadenectomy
Only about 50% of patients with high-grade
invasive disease are cured
Results of radical cystectomy
Stage
T2
T3a
T3b
T4a
Recurrence-Free
5 y.
10y.
NN+
NN+
NN+
NN+
89
50
78
41
62
29
50
33
87
50
76
37
61
29
45
33
Overall Survival
5 y.
10y.
77
52
64
40
49
24
44
26
57
52
44
26
29
12
23
20
Stein et al JCO 2001;19:666
Radical cystectomy
• Radical cystectomy is the removal of the
entire bladder, lymphadenectomy and near by
organs that may contain cancer cells.
– In men , the prostate, the seminal vesicles,
and part of the vas deferens are also
removed.
– In women , the cervix, the uterus, the
ovaries, the fallopian tubes, and part of
the vagina are also removed.
Extent of resection
It carries significant physical, sexual and psychological
morbidity even when neobladder reconstruction is used
CRT as alternative to cystectomy
• The major advantage of this approach is that it
allows 40–60% of patients to retain a functional
bladder at 5 years.
• Patients undergoing bladder conservation report
better overall quality of life and significantly less
sexual morbidity compared with patients having
initial cystectomy
• Local disease control is the primary challenge in
the management of MIBC.
CRT as alternative to cystectomy
The held view that RT inferior to cystectomy is due to:
1. Patients referred for RT are elderly and/or medically
unfit for surgical management.
2. Historically poor RT technique.
3. The discrepancy between pathological staging
(cystectomy series) and clinical staging (RT series).
Clinical staging is more likely to underestimate disease
extent
no RCT exist to support cystectomy over bladder
preservation with radical RT
CRT as alternative to cystectomy
• More recently, there has been increasing
evidence that RT gives comparable survival rates
with those reported in surgical series when using
multimodality protocol with early salvage
cystectomy for residual disease
.
• However, it is important that cautious,
multidisciplinary follow-up is conducted to
ensure that local recurrences are detected and
treated early in order that survival is not
compromised.
Bladder-sparing protocol
Transurthral resection
Induction Therapy: Radiation + chemotherapy
(cisplatin, paclitacel)
Cystoscopy after 1 month
no tumor
Consolidation: RT + CT
tumor
cystectomy
CRT as alternative to cystectomy
• As CRT is slowly becoming more accepted as
an alternative curative treatment option for
MIBC, it seemed desirable to:
(i) highlight factors relating to patient
selection and suitability for this approach;
(ii) make recommendations concerning
optimal RT technique for localized MIBC.
Patient selection
• There are two separate groups of patients in
whom ‘curative’ RT for localized MIBC may be
recommended:
1. patients with who are either medically unfit
and/or surgically inoperable. For these patients,
a radical cystectomy is by definition not an
option.
2. Patients who choose to undergo bladderpreserving treatment, rather than immediate
cystectomy, are by definition medically fit
enough to be potential candidates for surgery.
Selection criteria
• In 2nd group, there are several selection
criteria that need to be considered to ensure
suitability for the organ-conserving approach:
1. Patient factors
2. Tumor factors
3. Treatment factors
Patients factors
• Reasonable life expectancy
• Performance status ECOG 0–2
• Adequate pretreatment bladder function:
patients with a capacity of around 200 mL or less,
and/or those with significant ongoing incontinence,
frequency and dysuria, may be more appropriately
managed by cystectomy.
Tumor factors
1. Tumor stage T2-T4a, N0 M0
2. Multiple invasive tumors-(multifocal):
have worse outcome rates than for solitary lesions(
not an absolute contraindication).
3. Hydronephrosis:
hydronephrosis at diagnosis significantly predict for
a lower CR rate compared with patients with no
hydronephrosis,37% and 68%, respectively.
Tumor factors
4. CIS outside area of invasion
- not an absolute contraindication;
- only one series has reported the effect of CIS on
bladder recurrence following RT; 40 patients only;
authors reported that CIS correlated with higher local
or overall recurrence rate
Treatment factors
• Maximal resection of tumor prior to radiotherapy
- improved CR, local control and freedom from distant
metastases
- Complete TURBT is ideal but not mandatory.
• Hb level >10–12 g/dL (for radiotherapy)
- may improve local response and improve the bladder
preservation rate as well as aiding tolerance to treatment and
reducing anemia-related symptoms (weak evidence)
• Renal function
chemotherapy.
adequate
(for
concurrent
RADIOTHERAPY TECHNIQUE
Anatomical consideration
• The bladder is a depot organ for urine
collection with a capacity of 350–450 mL
• It is under the symphysis pubis when empty.
• The superior portion of the bladder is covered
with peritoneum and is close to the small
intestines by this peritoneum.
Anatomical consideration in males
•
•
It is positioned next to the seminal vesicles and the
ampulla of the vas deferens posteriorly as well as the
lower tips of the ureters and the rectum.
The base of the bladder is next to the prostate.
Anatomical consideration in females
It is next to the uterus and vagina
Anatomical regions
RT technique
• CT simulation and 3D CRT are mandatory for the
delivery of high-quality RT.
• Rectal/Bladder status
o Single Phase: Bladder empty, rectum empty
o Two Phase: Phase I: Full bladder, rectum neutral
Phase II: Empty bladder, rectum empty
• Patients will be treated supine, without rigid
immobilization
Patient preparation
• One half-hour prior to simulation, the patient
may be given an oral contrast to drink so that
the small bowel can be adequately visualized
during the simulation process.
• When the regional lymph nodes are to be
covered; some recommend that the patient
be treated prone on a belly board, with the
bladder fully distended
Patient preparation
• Foley catheter is inserted into the bladder with a
sterile technique. Pull it down so that you identify
the bladder base.
• A solution of Urographine mixed with saline in a
one to two ratio is then instilled into the bladder.
Generally, 25 cc of this mixture is instilled.
• Approximately 25 cc of air is also injected into the
bladder and the Foley catheter is clamped.
Treatment volumes –GTV• GTV is defined as any gross residual disease
seen at cystoscopy, or by means of imaging
post-TURBT. This includes disease which
extends outside the wall of the bladder.
• Following a complete macroscopic TURBT, for
a tumor that does not extend outside the
bladder wall, there is no definable GTV.
Treatment volumes – CTV
What is the definition of the CTV?
• CTV incorporates the GTV and any microscopic disease
and regions at-risk.
• single phase technique: entire bladder and any
extravesical extension
• Two phase technique:
- 1st phaseentire bladder and any extravesical extension
+ pelvic LN (including common iliac up-to L5-S1 junction,
external iliac and internal iliac and presacral)
- 2nd phaseentire bladder and any extravesical
extension
CTV – single phase or two phases
technique?
Pros of two phases technique:
• Approximately 25% of patients who undergo
curative cystectomy and LN dissection will
have pathological nodal involvement.
• In several surgical series, the extent of the LN
dissection predicts improved loco-regional
control and survival even in those with pN0
disease.
Treatment volumes – CTV
Cons of two phases technique:
• MIBC involving LNs is usually incurable, and the
rationale for treating regional lymphatics as part
of a curative bladder-preservation approach is
less clear.
• There is no evidence to improves outcomes in
trials included the pelvic lymphatic.
• Inclusion of the pelvic nodal regions increases the
amount of normal tissue, especially small bowel,
in the irradiated volume and lead to an increase
in early toxicity as well as late complications.
CTV
• The CTV, is the entire bladder delineated by the outer
surface of the bladder wall, incorporating a 0.5-cm
margin on any regions deemed on clinical or
radiological grounds to have an extra-vesicular
extension.
The basis for inclusion of the whole bladder is twofold.
• Firstly, MIBC commonly presents and/or recurs in a
multifocal manner.
• Secondly, following a TURBT, delineating the
microscopic extent of the lesion on a planning CT is
difficult.
CTV
• Extra-vesical disease extension (EVE) is
sometimes seen on planning CT images.
• Any changes suspicious for EVE that are
consistent with the lesion’s position and
pathological features should be included in the
CTV with a 0.5-cm margin
Larger tumours (>3.5 cm), lymph-vascular invasion and
squamoid differentiation are associated with a greater
extent of extra-vesicular extension but not a higher
frequency.
Should the prostate be included in
the CTV?
• Prostatic urothelial carcinoma is seen in 20–43%
of cystoprostatectomy Specimens
• The method of spread to the prostate is thought
to be either transmural invasion or in situ spread
in an intra-epithelial fashion.
Risk factors for urethral involvement are
 bladder CIS,
 multifocal disease and
 tumor involvement of the trigone and bladder
neck.
Should the prostate be included in
the CTV?
• when one or more of these high-risk factors are
present include the whole prostate gland in
the CTV for RT or phase 1 of a two-phase
course.
• If there is macroscopic involvement of the
prostate and/or urethra, then the prostate
should be included in the CTV for the entire
treatment.
Should the female urethra be
included in the CTV?
• the overall rate of urethral involvement is 7–
46% in female cystectomy series
• In the absence of good data, it would seem
practical to apply the same considerations to
both male and female patients in assessing
higher risk of urethral involvement.
Should anterior vaginal wall be
included in the CTV?
• it is not recommended that the vagina be
routinely included in the CTV
• Anterior vaginal wall invasion seen on imaging
or clinical examination should be included in
the CTV.
• Where the vagina is (partially) included for
macroscopic disease, it is recommended that
the proximal urethra should also be included
in the CTV.
PTV considerations
• PTV incorporates the CTV variation because of
organ motion and other set-up uncertainties to
ensure that the prescribed dose is delivered to
the CTV.
It allows for
• changes during each fraction (intra-fraction),
• changes between fractions (inter-fraction)
• alterations in bladder shape, size and position
over the full treatment course
• daily set-up variations.
Intra-fraction motion.
• The bladder continues to fill during the time
of set up and delivery of RT
• A generalized 1.5-cm margin from CTV to PTV
is appropriate for more than 95% of
treatments in this setting.
Inter-fraction motion
• Changes in bladder volume, shape and
position over a course of RT
• the majority of patients have a consistent or
decreasing bladder volume over time, but a
proportion may have an increase in the
bladder volume from the start to the finish of
the treatment course.
Inter-fraction motion
• Changes in bladder volume and movements of
various regions of the bladder are not
isotropic.
• The largest movement and variability is in the
superior (cranial) and anterior portions of the
bladder.
• Thus, a tumor on the dome of the bladder
will have more variation in location than a
lesion on the trigon, for example
What is a suitable CTV to PTV margin?
• Based on all the available evidence, the
minimum CTV to PTV margin is 1.5 cm in all
directions and 2.0–2.5 cm in the cranial
(superior) direction when using conventional,
non-adaptive RT delivery.
• The inferior expansion may be reduced to 1
cm if the prostate or urethra has been
included.
Dose constraints for OAR
The organs at risk are the rectum and femoral
head/neck, controversy on small bowel.
• Rectum guidelines: contouring of the of the outer
wall of the rectum starts :
 Inferiorly from the lowest level of the ischial
tuberosities.
 ends superiorly before the rectum loses its round
shape in the axial plane and connects anteriorly
with the sigmoid
Rectum
intermediate slice
Distal slice
proximal slice
Femoral feads
• inferiorly from the lowest level of the ischial
tuberosities and superiorly to the top of the
ball of the femur including the trochanters.
Dose/fractionation schedule
• the current recommended dose to the tumor
is 64 Gy in 32 fractions, delivered once daily
• For a two-phase treatment, 50 Gy is delivered
in 25 fractions for phase 1. For phase 2, 14 Gy
in seven fractions is delivered to the reduced
volume.
Hyper-fractionation
• No clear benefit to accelerated and hyperfractionated RT in bladder conservation.
• Given the increased toxicity of this approach
and are logistically more difficult, it is not
considered standard.
Hypo-fractionation
• No randomized trials have compared hypofractionation with conventional fractionation for
MIBC.
• However, several large uncontrolled series show
that 50–57.5 Gy in 16–20 fractions is comparable
with conventional fractionation.
• There
are
limited
data
regarding
hypofractionation with concurrent chemotherapy
 should only be considered as part of a
prospective trial.
Improving Radiotherapy Outcomes
• Rational:
reduce dose to surrounding normal structures, potentially
reducing toxicity and possibly allowing dose escalation.
improved bladder preservation rates.
• Methods:
 Radiotherapy techniques
 IMRT
 VMAT
 Soft-tissue verification techniques:
 IGRT
 ART (Composite volume - A-POLO tech)
 Partial bladder irradiation
IMRT
• IMRT gives better shaping of the dose distribution
around the tumor with larger reductions in normal
tissue toxicity and larger increases in tumor control.
• However, these improvements are documented when
treating the pelvic LN and bladder concurrently. When
treating the bladder alone, less benefit is expected
• Precise target delineation, rigid immobilization and
real-time target verification with online portal imaging
or CBCT are highly desirable
VMAT
• VMAT is a novel type of IMRT in which gantry
speed, MLC leaf position and dose rate are
dynamically varied during rotation of the
gantry yielding a fast and highly conformal
treatment delivery
• as with IMRT, the additional benefit with
VMAT may be small in bladder-only CTV
compared with pelvic CTV
VMAT
Address the disadvantages of IMRT which are:
• increased time required for RT delivery and
the associated risk of bladder filling and
changes in bladder shape and size.
• increased number of monitor units (MU)
needed, which results in a greater integral
body dose, with a probable increased risk of
second malignancies
IGRT
• Given the large day to day variations in
bladder wall and tumor position, bladder
cancer would be an ideal candidate for online
image guidance.
• The combination of CBCT and implanted
fiducial markers (gold seeds or submucosal
lipidol injection) give the way for online
position correction for either gated RT or
adaptive RT
ART
• Composite volume:
use imaging information from the initial treatment
fractions to re optimise the treatment plan.
• Adaptive–predictive organ localization (plan of
the day):
Three bladder plans (small, medium or large) are
generated at 0, 15, and 30 min after voiding and the
most conformal one is chosen before each fraction,
by appropriately trained radiation therapists.
Partial bladder irradiation
• Partial bladder irradiation reduces the volume
and potentially toxicity of treatment in the
curative setting.
• However, treating a partial bladder volume
would require strict bladder instruction,
excellent surgical documentation, high patient
compliance and, ideally, daily image
guidance..
Take home message
• What is the standard of care in the treatment
of bladder cancer
• What is the selection criteria for bladder
preservation protocol
• Pre radiotherapy patient preparation
• What is the CTV in localised MIBC
• What is the PTV – CTV margin
Thank you