Treatment of muscle invasive bladder cancer

1. Muscle Invasive, Nonmetastatic
Bladder Cancer

2. Muscle-Invasive Disease
• Upto 30% of total Bladder Ca
•T2, T3, and T4 tumors
• That penetrate the muscularis propria
• Are more aggressive and have a strong
tendency to metastasize

3. Smoking and Bladder Cancer
• Tobacco smoking is the most well-established
risk factor for BC, causing 50-65% of male
cases and 20-30% of female cases(1)
• An immediate decrease in the risk of BC was
observed in those who stopped smoking. The
reduction was about 40% within 1-4 years of
quitting smoking and 60% after 25 years of
cessation(2)
1. Brennan, P., et al. studies. Int J Cancer, 2000. 86: 289.
2. Gandini, S., et al.. Int J Cancer, 2008. 122: 155.

4. Controversy
• Radical cystectomy with pelvic
lymphadenectomy is considered gold standard
• No evidence comparing it with ChemoRT
(bladder preservation)
• New advancements in neoadjuvant ,adjuvant
chemotherapy, radiation therapy and bladder-
preservation protocols should encourage
bladder preservation
• UK SPARE had poor recruitment

7. Neoadjuvant chemotherapy
• Radical cystectomy provides 5-year survival in about 50% .
• To improve these results ,NACT is being used.
• Most common regimens used for neoadjuvant chemotherapy
is three 28-day cycles of MVAC as follows:
Methotrexate (30 mg/m2 on days 1, 15, and 22),
Vinblastine (3 mg/m2 on days 2, 15, and 22),
Doxorubicin (30 mg/m2 on day 2), and
Cisplatin (70 mg/m2 on day 2).
Pathological CR 12-50%
• GC (gemcitabine/cisplatin)
• Pathological CR 12-22%
Stein JP 2006 Aug;24(3):296-304.
David KA Urol 2007 Aug;178(2):451-4.
Grossman, H.B., et al. N Engl J Med, 2003. 349: 859.

8. Advantages
• Improves OS by 5-8%
• Chemotherapy is delivered,
when the burden of
micrometastatic disease is
expected to be low.
• Tolerability of
chemotherapy are expected
to be better pre-cystectomy.
• Favorable pathological
status, by achieving pT0,
pN0 and negative surgical
margins.
Disadvantages
• Delayed cystectomy might
compromise the outcome in
patients not sensitive to. There
are no trials indicating that
delayed surgery, due to NAC,
has a negative impact on
survival.
• Neoadjuvant chemotherapy
does not seem to affect the
outcome of surgical morbidity.
In one randomized trial the
same distribution of grade 3-4
postoperative complications
was seen in both trial arms[1]
Sternberg CN):1644-52[1]

9. European Association of Urology 2016
Recommendations
• Neoadjuvant chemotherapy is recommended
for T2-T4a, cN0M0 bladder cancer and should
always be cisplatin-based combination therapy.
• NACT is not recommended in patients who are
ineligible for cisplatin-based combination
chemotherapy.

10. Pre-operative radiotherapy in muscle-
invasive bladder cancer
Recommendations of European Association of
Urology
1. Pre-operative radiotherapy is not
recommended to improve survival
2. Pre-operative radiotherapy for operable
MIBC can result in tumour down-staging
after 4-6 weeks.
Huncharek M Res 1998 May;18(3b):1931-4.

11. Cystectomy
1. Indications
• MIBC T2-T4a, N0-Nx, M0
• high-risk and recurrent superficial tumours
• BCG-resistant Tis, T1G3
• extensive papillary disease that cannot be
controlled primary therapy
• Salvage cystectomy if bladder preservation fails
• In patients with inoperable locally advanced
tumours (T4b), primary radical cystectomy is a
palliative option.[1]
1. Nagele U World J Urol 2007 Aug;25(4):401-5.

12. • In men, standard RC includes removal of the bladder,
prostate, seminal vesicles, distal ureters, and regional
lymph nodes. Prostate-sparing cystectomy is an
option in a subset of carefully selected patients with
without involvement of the prostatic urethra and
without prostate cancer. This procedure is
oncologically safe [1]
• In women, standard RC includes removal of the
bladder, entire urethra and adjacent vagina, uterus,
distal ureters, and regional lymph nodes [2].
• Orthotopic bladder cannot be offered for N2
disease[3]
1. Mertens, J Urol, 2014. 191: 1250.
2. Stenzl, A., et al. Series, 2005. 3: 138
3. Lebret, T., et al. Eur Urol, 2002. 42: 344.

13. European Association of Urology 2016
Recommendations
• Offer sexual-preserving techniques to Male/
female patients motivated to preserve their sexual
function since the majority will benefit.
And Select patients based on:
1. Organ-confined disease;
2. Absence of tumor in bladder neck or urethra.
3. Do not offer pelvic organ-preserving radical
cystectomy for Male /female patients as standard
therapy for MIBC.

14. Lymph node dissection
• The extent of LND has not been
established to date. Standard
lymphadenectomy in BC patients
involves removal of nodal tissue cranially
up to the common iliac bifurcation, with
the ureter being the medial border, and
including the internal iliac, presacral,
obturator fossa and external iliac nodes
[1](Extended LN dissection)
• No difference in outcome was reported
between extended and super-extended
LND in the two high-volume-centre
studies identified [2]
1.Simone, G., et al. J Urol, 2013. 20: 390.
2. Liu JJ J Urol 2011 May;185

15. Trimodality bladder-preserving
treatment
• Combines TURBT f/b chemoradiation.
• A standard radiation schedule includes external-
beam RT to the bladder and limited pelvic lymph
nodes to an initial dose of 40 Gy, with a boost to
the whole bladder to 54 Gy and a further tumour
boost to a total dose of 64-65 Gy.
• Radiosensitising chemotherapy, cisplatin [1] or
mitomycin C plus 5-fluorouracil can be used [2]
1. Milosevic, M., et al. 2007. 69: 80.
2.James, N.D., et al N Engl J Med. 2012. 366: 1477
3 Hoskin, P.J., et al. J Clin Oncol, 2010. 28: 4912.
4. Kaufman, D.S., et al. Urology, 2009. 73: 833.

17. Mortality and Morbidity of
Cystectomy
• Mortality ranging from 0.8% to 8.3% (1)
• Renal and pouch stones – 10%
• Incision hernia (4.5%)
• Uretero enteric anastomotic stricture
• Recurrent UTI (23%),
• Uremia and dialysis in 9.2%
• Nocturnal, stress and urge incontinence 51.5%
• Erectile dysfunction developed post-operatively
in 35 cases (80.5%).
A. Shelbaia1, J urology 89–93

19. Contra-indications to TMT
• Extensive Carcinoma in situ
• Poor bladder function
• Not eligible for Cisplatin based chemotherapy
• Absence of hydronephrosis
• Absence of malignant lymphadenopathy on
imaging

20. Results of Tri- Modality Treatment
• 5-yr cancer-specific survival 50% to 82%
• Overall survival rates range from 36% to74%,
• Salvage cystectomy rates of 25-30%.
• The best cancers eligible for bladder preservation
are those with low-volume T2 disease without
hydronephrosis or extensive carcinoma in situ.
Ploussard G et al Eur Urol. 2014 Jul;66(1):120-37

21. Adjuvant chemotherapy
Adjuvant cisplatin-based combination
chemotherapy to patients with pT3/4 and/or pN+
disease if no neoadjuvant chemotherapy has been
given[1,2,3]
1.Cohen, S.M., et al..Oncologist, 2006. 11: 630
2. Sylvester, R., et al. Ann Oncol, 2000. 11: 851.
3. David, K.A., et al.. J Urol, 2007. 178: 451.

22. MVAC vs GC
• Response rates were 46% and 49% for MVAC
and GC.
• The long-term survival results have confirmed
the anticipated equivalence of the two
regimens
• The lower toxicity of GC has resulted in it
becoming a new standard regimen
1.von der Maase, H., et al. cancer. J Clin Oncol, 2005. 23: 4602

23. Surveillence
• .

24. Additional Surveillance in Bladder
preservation
• Additionally, patients should undergo an intial
restaging TUR at 3 months following
completion of therapy. Surveillance
cystoscopy should then be performed at 3-
month intervals for the first year, then every 6
months until 5 years, and annually thereafter

25. Treatment of Metastatic Bladder
Cancer
• First-line treatment for fit patients: Use cisplatin-containing
combination chemotherapy with GC, PCG, MVAC, preferably with
G-CSF, or HD-MVAC with G-CSF.
1. Do not use carboplatin and non-platinum combination
chemotherapy. (1,2)
• First-line treatment in patients ineligible (unfit) for cisplatin:
1. Use carboplatin combination chemotherapy or single agents.
preferably with gemcitabine/carboplatin.
2. Second-line treatment: Offer vinflunine to patients progressing
after platinum-based combination chemotherapy for metastatic
disease.
3. Offer zoledronic acid or denosumab to treat bone metastases.
4. A retrospective study of post-chemotherapy surgery after a partial
or complete response has indicated that surgery may improve DFS
in selected patients(3)
1. von der Maase, H., et al. J Clin Oncol, 2005. 23: 4602
2. Sternberg, C.N., et al. Eur J Cancer, 2006. 42: 50.
3. Herr, H.W., et al. J Urol, 2001. 165: 811.

26. Radiation techniques in Bladder
Cancer
• Definitive RT
1. Conventional Technique
2. 3D-CRT
3. IMRT
• Palliative RT
• Altered Fractionation
• Brachytherapy

27. External Beam Irradiation
• The standard protocol for combined modality
therapy conventional technique .
• It uses a four field iso-centric technique for
both initial and boost field.
• It consists of shaped anterior , posterior , right
and left lateral fields
• Induction and boost treatment fields will be
discussed further

28. Simulation
1. Instruct patient to void urine
2. Insert Foley's catheter
3. Measure post void residual urine and replace with
equal volume of bladder contrast + Additional
25mL contrast + 15mL of air.
• Contrast defines the inner walls of bladder
• Air aids visualization of anterior bladder on lateral
simulation film
• Contrast amount should not be less than post void
residue
4. AP/PA and Lateral radiographs are taken or CT
simulation is done

30. Induction Field
1. During first phase of treatment, bladder is treated
along with 2 cm margin.
2. If using radiograph , contrast lines only inner
wall hence another 5-10mm is added.
3. In men prostate is included and in women
proximal 2 cm of urethra is included .
4. Limit the amount of small bowel irradiated.

31. Break to evaluate
1. After induction treatment or after a dose of 39-
42Gy, repeat cystoscopy is done .
2. If CR/Ta/Tis then they are advised to continue
boost.
3. If the stage is more than T1 ,then advise
cystectomy.

32. Boost Field
1. Tumor alone with 2 cm margin .
2. Tumor is delineated using information from
bladder map during TURBT/Cystoscopy and
CT/MRI
3. Another alternate is to treat the whole bladder and
exclude the nodal volume
4. If tumor is in trigone or PL walls of bladder only
lateral fields can be used for boost

33. Dose
1. Total dose of 65Gy(1.8-2Gy fractions, 5 days
per week) together with chemo and max
TURBT.
2. 40-45Gy is Induction dose
3. The tumor is then boost to full dose (15-20Gy)
4. In invasive cancer ,if there is complete
response then local recurrence is limited to 15-
18% implying that dose is adequate in
responders

34. Partial bladder treatment
1. Rationale – High dose (upto 80 Gy) can be given if
1/3 of bladder is spared .
2. Indications
• <5cm in size
• Unifocal disease
• Without extensive Tis
• No significant difference between arms
Arms Dose/# 5 yr Local
control
Partial bladder
irradiation
57.5/20 58%
Whole bladder
irradiation
52.5/20 59%

35. Treatment margins in Conformal
radiotherapy
1. CTV to PTV margin , an isotropic 2 cm margin in
all 3 dimensions.
2. As the greatest degree of bladder wall positional
change occurred in cranial direction and least in
antero-inferior direction , limited by pubic
symphysis.
3. Anisotropic margin of 1.6cm anteriorly and
posteriorly , 1.4cm laterally , 3cm superiorly , 1.4cm
inferiorly has been recommended by Graham
4. Daily imaging
5. Fuducial based matching

36. 3D-CRT and IMRT
Patient position and immobilization
• The patient should be planned and treated in the same position; supine with
arms on their chest. Knee and ankle immobilization should be used to
ensure patient positioning is reproducible.
• The rectum should be empty of flatus and faeces. The use of daily micro-
enemas may be considered.
• Patients will be asked to empty their bladder 15 minutes prior to scan.
• Whilst breathing normally, the patient should have a CT scan performed
with 3–5-mm slice spacing.
• Upper Extent -3 cm above the dome of the bladder or bottom of L5
(whichever is higher)
• Lower Extent –ischial tuberosities
• Reference radio-opaque tattoos should be made at the base of the abdomen
and over each hip.

37. Volume Delineation
• The GTV should integrate information from
the staging CT or MRI as well as the
diagnostic TURBT . MRI/CT fusion may be
helpful, where available.
• CTV constitutes the entire bladder.
• Most significant bladder movement is in the
cranial and AP directions

38. • Most significant bladder movement is in the
cranial and AP directions.
• Patients with significant residual volumes post
voiding should be considered for planning and
treatment with a catheter in situ , although this
is likely to increase urinary toxicity.
• CTV to PTV by 1.5 cm if no extravesical
involvement
• CTV to PTV by 2 cm if extravesical
involvement
• CTV to PTV by 3cm if tumor lying in cranial
part of bladder

39. • OAR should be outlined including rectum,
femoral heads and small bowel.
• Recommended dose constraints are:
1. Rectum V50 <60 per cent, V60 <50 per cent;
2. Femoral heads V50< 50 per cent
3. Small bowel V45 <250 cm3.

41. Conformal Planning
• Forward planning is used to
optimise a 3D conformal plan,
usually with 10–15MV
photon beams, such as an
anterior and two-wedged
lateral or posterior oblique
beams.
• The angle between the
posterior oblique beams
should be chosen to minimise
dose to the rectum

42. Dose distribution

43. IMRT
• Reduce the dose to normal tissues, allow the
delivery of a synchronous boost needed for
partial bladder irradiation and
• Permit dose escalation to the tumour.
• However, IMRT for this tumour site requires
excellent immobilisation, with IGRT to locate
• Without IGRT isotropic margin of 3cm
• With IGRT 1.2cm

44. Verification
• The current standard is EPI comparing bony
anatomy with the AP and lateral DRRs daily
for the first 3–5 days, and then once weekly for
correcting for systematic errors.

45. Altered Fractionation
• In T2-T4 tumors unsuited for cystectomy
Numb
er of
patien
ts
Dose Survival
at 5 yrs
Local
control
Clinical
complete
response
Hyperfractio
nation
84 1 Gy three times a
day to a dose of
84Gy
27% 12% 59%
Conventiona
l
84 2Gy everyday to a
dose of 64Gy
18% 7% 36%

46. Palliative Radiotherapy
• Palliative bladder irradiation is used in the
treatment of bleeding from a primary tumor or
a metastatic lesion to the bladder that cannot
be controlled cystoscopically.
• Symptomatic improvement can be achieved in
60-70% of patients
• Schedules used: 30 Gy in 10 fractions
21 Gy in 3 fractions

47. Brachytherapy
• Indications:
- A solitary transitional cell carcinoma
- Diameter less than 5 cm
- Muscle invasion but with no extension through
the bladder wall
• Contraindications: tumor extending to
perivesical fat and adjacent structures,
multifocal, lymph node involvement.

48. • Initially preoperative EBRT of 3 x 3.5 Gy
fractions for T1 tumors and 20 x 2 Gy for T2
tumors is delivered
• Partial Cystectomy with routine iliac
lymphadenectomy is performed.
• Hollow Nylon tubes are placed
intraoperatively for afterloading with Iridium
sources

52. • Acute postoperative complications like
thromboses, infections, delayed wound healing
and fistula formation were seen in 19.5-30% of
the cases.
• Late complications: 25-39% were reported
In the first year hematuria, stone formation, chronic
cystitis were observed
Symptomatic ulceration or fistula formation needing
treatment or ureter stenosis with hydronephrosis
is rare (1-6%)
Chronic radiocystitis (0.6%)

53. Thank You!!