Bladder cancer

Target audience : Oncology fellows and Oncologists.
Four challenging cases of Bladder cancer and managing decisions including latest management principles are discussed here.

1. Bladder Cancer
Case presentations and discussion
Target Audience: Oncology Fellows, Oncology physicians,
Oncologists
Archer Board Review Courses
www.Ccsworkshop.com

2. Case 1
Chief Complaint:
74 y/o woman with history of
baldder cancer admitted for Partial
Cystectomy

3. HPI
74 y/o woman with history of bladder cancer,
diagnosed in May 2009 – admitted now for partial
cystectomy.
The diagnosis of bladder cancer was made when
she first presented with painless gross hematuria,
cystoscopy revealed a large lesion indwelling the
dome of the bladder. She underwent Trans Urethral
Resection of the Bladder Tumor ( TURBT).
Pathology at that time revealed a poorly
differentiated (grade 3) carcinoma which was
confirmed as primary urothelial carcinoma by
immunohistochemistry ( T1NxMx).

4. HPI
The patient subsequently presented to the ER two
weeks after TURBT with significant hematuria,
required cystoscopy and fulguration of the biopsy
site. Biopsies obtained this time involved only scar
tissue that did not show malignancy ( no bladder
tissue was included in the biopsy material –
uncertain complete resection).
A decision was made to proceed with elective
partial cystectomy for which the patient was
admitted in 8/2009.
No new episodes of hematuria. No dysuria or
urgency. No weightloss/ bone pain

5. History
PMHx/ PSHx : Type 2 DM, Hypertension, CAD s/p
CABG ( 1997), Hysterectomy (fibroids)
Allergies : No known allergies.
Social History : (+) smoking one pack /day x 20
years; quit 15 years ago. Occassional ETOH. No
drug use.
Family history : No history of cancer in the family.
Mother hx of DM.

6. Physical Exam
VS: Afebrile, HR: 82, BP 120/88, RR : 18
HEENT: no palpable lymph nodes, no icterus or
pallor.
CVS: No S3/S4. No murmurs
Lungs: NVBS. Bibasilar creps+
Abd: Soft, NT, ND, BS +, No inguinal adenopathy
Extremities: No LE edema

7. Labs
WBC 8.7
Hb 14.2
Hct 40.8
MCV 92.3
RDW 13.4
Plts 257
PT/PTT WNL

8. Radiology
CT chest/abdomen/ pelvis from 05/20/09
(performed for staging work up) 
–Bilateral pleural effusions ( chronic) with bibasilar
atelectasis and chronic changes.
–No evidence of retroperitoneal lymhadenopathy or mass
lesion .
–Normal liver, spleen and pancreas

9. Hospital Course
Partial cystectomy was performed with out any
complications.
Specimens were sent for pathology.

10. Pathology
Bladder Tumor, Partial Cystectomy
Poorly differentiated infiltrating carcinoma ( 0.4 cm in
greatest dimension), favor primary urothelial carcinoma
with focal glandular differentiation.
No evidence of muscularis propria ( detrusor) invasion
No evidence of lymphovascular invasion
Margins of excision are free of tumor
Pathological stage p-T1NxMx
Clinical – T1N0M0 – Stage I
The carcinoma is histomorphologically similar to that
reported in the previous TURBT specimen ( 5/2009)

11. Final Diagnosis
Bladder cancer, T1N0M0
Stage I

12. Treatment Decisions
No role for radiation or adjuvant chemotherapy in
this setting ( Non muscle invasive Stage I bladder
cancer)
Partial Cystectomy will suffice ( the lesion was
amenable to partial cystectomy because it was in
the dome) . Will need adjuvant intravesical BCG.
Patient will be enrolled in to cystoscopic
surveillance as recommended for high risk
superficial bladder cancer ( high risk of recurrence
because she is grade 3 – poorly differentiated)
–Cystoscopy at 3 months from now
– If no recurrence, Cystoscopy+Cytology every 6 months for 4
years and then every year.
–Upper tract imaging to exclude metachronous lesions of upper
tract every one to two years

13. Case 2
85 y/o woman with history of bladder
cancer and carcinoma in-situ

14. Case Summary
•85 y/o woman who was diagnosed with carcinoma
in-situ ( Tis, Grade 3, right lateral bladder wall) in
August 2008, treated with a course of Intra-vesical
BCG, was then enrolled in to cystoscopic
surveillance with biopsies. Seven months after
initial diagnosis (3/09), the patient was found to
have high grade papillary urothelial carcinoma
( Ta, G3) at a different site ( left bladder neck).

15. Radiology
•CT abdomen performed for staging work up
–No lymphadenopathy
–Unremarkable ureter and urinary bladder

16. Pathology
•Initial diagnosis ( 8/08)
 Right Lateral Wall Bladder Biopsy
Urothelial carcinoma in-situ ( Flat type) ( Tis) in a
background of high-grade dysplasia.
•Surveillance cystoscopy with biopsy (3/09)
Left Bladder Neck Biopsy
Papillary urothelial carcinoma ( Ta), high grade (G3)

17. Treatment Decisions
•Initially, as per recommendations for Tis, she was
treated with a course of intra vesical BCG and
enrolled in cystoscopic surveillance.
•Recurrent cancer in 3/09 – was Ta ( papillary with
out muscle invasion)  TURBT is done. Usually,
no intravesical BCG needed for this type of tumor.
However, this tumor was Grade 3 which is associated with
higher rates of recurrence and progression to muscle invasive
tumor. So, patient was chosen for adjuvant intravesical
immunotherapy with BCG.
Patient will follow with Urology for BCG
No role for chemotherapy in this setting since there is no muscle
invasion or nodal involvement ( Stage 0a disease)

18. Case 3
73 y/o man with initially diagnosed
carcinoma in-situ later presenting
with muscle invasive bladder
cancer.

19. Case Summary
•73 y/o man who was diagnosed with carcinoma
in-situ ( Tis, Grade 3) in April 2004, treated with a
course of Intra-vesical BCG, was then enrolled in
to cystoscopic surveillance with biopsies. One
year after initial diagnosis (4/2005), the patient
was found to have high grade muscle invasive
urothelial carcinoma ( T2, G3).

20. Staging Work up
•Labs were normal except for mildly elevated
alkaline phosphatase ( 152)  bone scan
performed did not reveal metastatic lesions.
•CT Abdomen showed no evidence of
lymphadenopathy or any collection.
•CXR normal

21. Treatment decisions
•Stage II T2N0M0 – Muscle invasive bladder cancer.
•Treatment of choice is Radical cystectomy.
•Not a candidate for bladder preservation strategies
because this is a recurrent cancer.
•Patient was offered cystectomy  however, he refused
and hence given Chemoradiation ( Taxol + carboplatin/
concurrent RT) .
•Cystoscopy performed in 8/05 showed excellent response
so, patient continued on chemoRT.
•Surveillance Cystoscopies (Q6months) since then have
been normal.

22. Case 4
88 y/o man with hx of metastatic
bladder cancer.

23. Case Summary
•88 y/o man with hx of Renal Cell Carcinoma s/p
Right Nephrectomy (2003), developed hematuria
in mid-2008 and cystoscopy revealed bladder
tumor, subsequent TURBT (8/08) demonstrated
Muscle invasive high grade urothelial carcinoma
( G3, T2), treated with Radical cystectomy which
is the standard of care for T2 lesions, however,
was on frozen section, was found to have
metastatic lymphadenopathy ( T2N1M0 – Stage
IV TCC). The patient was started on palliative
chemotherapy with Gemcitabine.

24. Investigations and Treatment decisions
•Alkaline phosphatase was elevated at 174 but bone scan
revealed Paget’s disease with out any bony metastases
( 4/2009).
•Repeat CT scan in 4/2009 revealed increasing
retroperitoneal lymphadenopathy. Chemotherapy was
continued.
•Restaging CT scan performed in 8/2009 revealed sclerotic
bony lesions in the lumbar vertebrae and osteolytic lesion
in right acetabulum, pulmonary nodules, Right groin and
para-aortic lymphadenopathy indicating a diffuse
metastatic disease  recommended orthopedic
stabilization of the hip / hip replacement  patient refused
and hence given Zolendronic acid + palliative RT. Possible
palliativer chemotherapy to be started as well.

25. Bladder Cancer
Polychronotropic
Recurring in time and space any where
along the urothelial tract ( from renal
pelvis to proximal two-thirds of urethra)

26. Epidemiology
•5th male, 9th female cancer
•Incidence ( M:F = 3:1)
•142/100 000 in Men
•33/100 000 in Women
•Pathology usually Transitional Cell Carcinoma
(95%) also
•Squamous cell, adenocarcinoma, small cell, lymphoma,
sarcoma, carcinosarcoma

27. Screening
•Routine screening in all patients for bladder
cancer with either urinalysis or cytology is not
recommended
•Screening for bladder cancer in high risk
individuals ( those exposed to dyes/ leather,
smokers) is controversial  no clear
recommendations.
•Incidentally discovered hematuria should not
be neglected.

28. Etiology
•Smoking ( accounts for 2/3 of bladder cancer cases)
•Other risk factors
•Age, male sex
•Chronic bladder inflammation, schistosomiasis
•External beam radiation
•Previous exposure to cyclophosphamide ( Carcinogenicity
attributed to it’s metabolite “Acrolein”)
•At risk occupations (carcinogens, aniline dyes, diesel)
•Hairdressers, machinists, printers, painters
•Rubber, chemical, textile, metal, leather industries

29. Staging

30. Stage groupingStage grouping
Stage 0aStage 0a TaTa N0N0 M0M0
Stage 0isStage 0is TisTis N0N0 M0M0
Stage IStage I T1T1 N0N0 M0M0
Stage II Stage II
T2aT2a N0N0 M0M0
T2bT2b N0N0 M0M0
Stage IIIStage III
T3aT3a N0N0 M0M0
T3bT3b N0N0 M0M0
T4aT4a N0N0 M0M0
Stage IVStage IV


T4bT4b N0N0 M0M0
Any T Any T N1N1 M0M0
Any TAny T N2N2 M0M0
Any TAny T N3N3 M0M0
Any TAny T Any NAny N M1M1

31. Symptoms
•Hematuria (80%)
• Painless Microscopic Hematuria
•‘Cystitis’ and sterile pyuria
•Bladder irritability
•Anemia
•Urinary tract infection
•Pain (advanced disease)
•Ureteric orifice obstruction
•hydronephrosis, kidney failure

32. Investigations
•Cystoscopy
•EUA ( Examination Under Anesthesia)
•Transurethral Resection of the Bladder Tumors ( TURBT)
•Biopsies
•Ultrasound kidneys/abdomen
•CT scan/MRI scan
•Differential diagnosis
•Staging ( In muscle invasive disease, CT abdomen must
always be performed for staging prior to making treatment
decisions)
•Bone scan if symptomatic or raised alkaline
phosphatase

33. Management
•Non-Muscle Invasive Bladder Cancer
•Muscle-Invasive Bladder Cancer
•T4 Disease
•Metastatic Bladder Cancer

34. Superficial Bladder Cancer
•70%, Ta, T1, Tis {CIS}
•Presence of Tis in the mucosa adjacent to a Ta
or T1 tumor  increases the risk for muscle
invasive disease
•Recurs at primary site or elsewhere in UT.
•22% cause death
•May be lifelong disease
•Diagnose by cystoscopy
•TURBT then adjuvant intravesical therapy for
high risk ( BCG is most commonly used and
superior intravesical agent. Mitomycin C single
shot - (17% decrease in early recurrence rate)
•Further management depending on pathology
and risk stratification ( risk for recurrence or
progression) (see next slide):

35. Grading
•In addition to tumor stage (Tis, Ta, or T1),
histologic grade also influences
–rate of recurrence
–survival
•Grading :
•Grade I : Well differentiated
•Grade II : Moderately differentiated
•Grade III : Poorly differentiated
•In one study, grade was the most significant
tumor variable in superficial bladder cancer
predicting for the development of invasive
carcinoma. (Superficial bladder cancer: the primacy of grade in the development of invasive disease. AU Torti
FM; Lum BL; Aston D; MacKenzie N; Faysel M; Shortliffe LD; Freiha F SO J Clin Oncol 1987 Jan;5(1):125-30)

36. Other Prognostic Variables
•Multicentricity
•Patients with multiple papillary tumors at the time of
presentation have higher rates of recurrence of both
non-muscle invasive and invasive cancer.
•Molecular markers
•May provide an additional way to identify non-muscle
invasive bladder cancers that are likely to progress to
muscle invasive or high-grade disease eg:
abnormalities in p53 may be associated with a less
favorable prognosis where as, the presence of
mutations in fibroblast growth factor receptor 3
(FGFR3) may indicate favorable prognosis

37. Superficial Bladder Cancer

38. Superficial Bladder Cancer

39. Muscle invasive disease
•T2-T3 disease (40-60% 5 year survival)
•Options are
•cystectomy (+/- reconstruction) with neoadjuvant chemotherapy or
•radiotherapy +/- chemotherapy
•Radical cystectomy (2-3% mortality rate)
•Main treatment modality for muscle invasive bladder cancer for
patients who are not candidates for bladder preservation approaches.
•Involves lymph node dissection and removal of bladder and prostate
and seminal vesicles or anterior vaginal wall, uterus, fallopian tubes
and ovaries
•Side effects include loss of native bladder and impotence.
•Bladder preservation strategies
•Elderly, those with significant comorbidities, poor performance status, those who desire
to preserve their bladder.

40. Bladder Preservation Strategies
•Tumor characteristics that are optimal for bladder
preservation :
–Solitary, muscle invasive tumor clinically confined to the
bladder.
–No associated CIS
–No evidence of hydronephrosis
–No prostatic urethral involvement
–No prior history of recurrent bladder or upper tract urothelial
tumors.
•Strategies :
–Partial Cystectomy
–Radical Transurethral Resection ( TURBT)
–TURBT followed by chemotherapy alone
–Chemoradiation

41. Chemoradiation
•Combines radical TURBT followed by external-
beam radiation therapy with concurrent cisplatin
as a radiation sensitizing agent ( 5-FU or
Paclitaxal also used)
•The most important predictor of outcome in
patients undergoing chemoradiation is the
completeness of transurethral resection (TUR)
prior to RT.
•Repeat Cystoscopy to evaluate the response
•60 to 75% will achieve a complete response to
chemoradiation and preserve their bladders
• 25 to 40 percent of non-responders will need
immediate salvage cystectomy.

42. Muscle Invasive Bladder Cancer -
Radiotherapy

43. Radiotherapy
•Linear accelerator
•55 Gy in 20 fractions over
4 weeks
•3 or 4 fields
•CT planned treatment
•Verification on set

44. Muscle Invasive
•Side effects of RT include
–Acute - tiredness, cystitis, diarrhea, loss of local hair,
skin reddening
–Late - bladder telangiectasia (5%), fibrosis and
shrinkage, altered bowel habit (<50%), proctitis
(5%), vaginal adhesions/stenosis, impotence
(20-30%) incontinence (1%)

45. Muscle Invasive
•Neo Adjuvant Chemotherapy should be added to
surgery ( cystectomy).
•Improves survival - 5% survival benefit at 5 years
for neoadjuvant chemotherapy
•Preferred regimen – Cisplatin based combination
therapy
• Gemcitabine + Cisplatin preferred regimen due to less
toxicity when compared to MVAC.
•MVAC (methotrexate, vinblastine, doxorubicin, and
cisplatin) with G-CSF support – toxicity limits its use.
•Gemcitabine/ Paclitaxel or Gemcitabine/ Docetaxal are
alternative regimens that are effective but have not been
compared with above standard regimens

46. Muscle Invasive
•Adjuvant Chemotherapy
•No clear consensus.
•Following cystectomy, in patients who did not
receive neoadjuvant chemotherapy, adjuvant
chemotherapy with a cisplatin-based regimen can
be considered for
•patients who have perivesical tumor extension (stage
T3 or higher) or
•regional lymph node involvement.
( Ongoing Phase III trials to provide more insight in to
this.)

47. Stage T4 Disease
•T4a -prostate, uterus, vagina involved
•T4b - pelvic side wall or abdominal wall
•10 % 5 year survival for T4a
- give chemotherapy if patient is fit ( good
performance status) and then radiotherapy to pelvis.
- For those with good PS and adequate renal
function, Cisplatin-based chemotherapy.
Gemcitabine + Cisplatin is the preferred regimen
based upon its decreased toxicity compared to
MVAC
- For those with poor PS and impaired renal
function, carboplatin based therapy
•Palliative treatment for T4b

48. Metastatic Disease
•Chemotherapy is the main treatment option
•Gold standard was MVAC (methotrexate, vinblastine,
adriamycin, cisplatin) but very toxic - needs good PS and
renal function, best for nodal disease only.
•Gemcitabine/cisplatin is as good as MVAC with less
neutropenia and mucositis and is the first line therapy.
•In patients with GFR < 60ml/min, carboplatin must be
substituted for cisplatin in the above regimens
•Newer drugs - Taxol, gemcitabine – combinations of
these agents with lower toxicity profile can be used
based on patient’s performance status, other
comorbidities ( neuropathy etc), compromised liver or
kidney function.

49. Metastatic Disease
•Radiotherapy has role in metastatic disease to
treat bone metastases, brain metastases,
cutaneous metastases, etc.

50. End
Questions?