Bladder Cancer

Bladder cancer: Histology

• 90-95% transitional-cell carcinoma

• 3% squamos-cell carcinoma• 2% adenocarcinoma• <1% small-cell carcinoma• Primary Tumor – Superficial or Muscle Invasive

– Superficial• Carcinoma‐in‐situ (CIS) is a flat, intraepithelial carcinoma. It has a

high rate of spread to lymph nodes.• Papillary tumors are superficial, non‐invasive cancers. They are

usually low‐grade tumors.

• Muscle‐invasive tumors are usually high‐grade tumors.

RISK FACTORS• A. Higher in industrialized countries than in developing

countries,• B. Smoking up to 60% of bladder cancers‐• C. Chemicals α & β naphthylamine, 4 Aminobiphenyl, ‐ ‐ ‐ ‐

Benzidine, Chlornaphazine, 4 Chloro otoluidine, o Toluidine, ‐ ‐ ‐4,4’methylene bis (2 chloraniline), methylene dianiline, ‐benzidine derived azo dyes, phenacetin containing compounds. ‐ ‐Workers, usually in the rubber paint and dye industries, exposed to the above chemicals are at increased risk of bladder cancer.

• D. Chronic bladder irritation or infections usually develop ‐squamous cell tumors

SIGNS & SYMPTOMS

• A. 80% of patients present with painless microscopic or gross hematuria.

• B. 20% of patients complain of irritation while voiding (frequency, urgency or dysuria).

• C. Patients with advanced disease may present with symptoms of uremia due to obstruction of one or both kidneys.

Bladder cancer:

Epidemiology

Bladder cancer: Epidemiology

Case• A 66 y/o male presents to his

primary care physician with the chief complaintsn of urinary frequency. During the work-up, a urinalysis reveals microscopic hematuria. Urine cytology demonstrate suspicious cells.

• A cytoscopy found a suspicious lesion that was biopsied. The biopsy showed transitional cell carcinoma that invaded the subepithelial connective tissue (T1 lesion), node(-), M(-)

• What therapy should he receive at the point?

• 75-85%superficial bladder cancerpTa, pTis, pT1 ( carcinoma in-situ, Papillary)

• 10-15%muscle-invasive bladder cancerpT2, pT3, pT4 (high grade)

• 5% metastatic bladder cancerN+, M+

Ta, Tis, T1 :• Non-muscle invasive bladder cancers are divided

into 3 groups: Ta, Tis, and T1– Ta are noninvasive papillary lesions confined to the

urothelium and have not penetrated the basement membrane

– Tis : severe cellular dysplasias usually in the absence of tumor formation

– T1 : tumors that have penetrated into underlying lamina propria but without any involvement of the muscularis propria.

Bladder cancer: Stage and Prognosis

Stage TNM 5-y. Survival

0 Ta/Tis NoMo >85%I T1 NoMo 65-75%

II T2a-b NoMo 57%

III T3a-4a NoMo 31%

IV T4b NoMo 24%each T N+Mo 14%each T M+ med. 6-9 Mo

Superficial Bladder Cancer

• Histological grading is important

G1 G2 G3

Relapse rate 42% 50% 80%

Progression rate 2% 11% 45%

Natural History of bladder cancer

• 70-80% presents with superficial tumors• Grade 3 tumor are most likely to recur • If untreated, 60-70% of CIS will progress • Most common sites of metastatic disease

are lymph nodes, liver, lung, and bone.

TREATMENT BY STAGE

Radical cystectomy/TURBT

Figure 3c.  Orthotopic bladder replacement (neobladder construction).

Catalá V et al. Radiographics 2009;29:461-476

©2009 by Radiological Society of North America

Orthotopic bladder replacement (neobladder construction).

Superficial Bladder Cancer

pTa, pT1, Tis• Standard treatment : complete transurethral

resection of the bladder tumor (TURBT)• Intravesical chemotherapy

– as prophylactic or adjuvant therapy after complete endoscopic resection

• Relapse rate: 70% adjuvant therapy

Superficial Bladder CancerAdjuvant Therapy

• High grade or T1 disease:– TURBT – intravesical bacillus Calmette-Guerin (BCG)

• Intravesical immunotherapy for non-muscle invasive bladder cancer– BCG 81 mg (TheraCys) or 50 mg (TICE) in 50 ml sterile saline

injected into the bladder through a catheter and held for 2h; weekly for 6wk

– Maintenance therapy : at 3, 6, 12, 18, 24, and 36mo after initiation, weekly for 3wk

Patients with non muscle invasive TCC of the ‐ ‐bladder (Stage Tis, Ta, T1) treated with TURBT

• Observation or intravesicular Bacillus Calmette Guerin ‐(BCG)– 10 year Progression free Rate‐ ‐– BCG (n=43) 61.9% : Control (n=43) 37% (p=0.0063)

• Non muscle invasive TCC of the bladder after TURBT ‐ ‐were assigned to intravesicular BCG (40 mg weekly x 6 then at 3, 6, 12, 18, 24 months) or intravesicular doxorubicin

J Clin Oncol 1995;13:1404‐8.

NEJM

1991;325:1205‐9.

Superficial Bladder Cancer

Adjuvant Therapy• Reduces relpase rate by 30-80%

– Doxorubicin weekly 6-8 w. / monthly 6-12

– Mitomycin C weekly 6-8 w. / monthly 6-12

– BCG weekly 6-8 w. /Mo 3 and 6

• BCG Failures– BCG plus interferon :At a median follow up of 24 ‐

months, 45% of patients in the BCG failure groups ‐were disease free with the combination‐

J Clin Oncol 1995;13:1404 8‐

Case

• our patient undergoes a TURBT and then receives intravesicular BCG

Invasive bladder cancer

• 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 Recurrence-Free Overall Survival5 y. 10y. 5 y. 10y.

T2 N- 89 87 77 57N+ 50 50 52 52

T3a N- 78 76 64 44N+ 41 37 40 26

T3b N- 62 61 49 29N+ 29 29 24 12

T4a N- 50 45 44 23N+ 33 33 26 20

Stein et al JCO 2001;19:666

Results of radical cystectomy

Stage Recurrence-Free /Overall Survival5 years

Organ-confined (<pT2pNo) 73% 62%

non-organ-confined (>pT2pNo) 56% 49%

Positiv lymph nodes (pT1-4, pN+) 33% 24%

Madersbacher et al JCO 2003;21:690

Chemotherapy for bladder cancer

• Bladder cancer is a chemosensitive disease• Active single agents.

RR– Cisplatin 30%– Carboplatin 20%– Gemcitabine 20-30%– Ifosfamide 20%

Chemotherapy for bladder cancer

Combination chemotherapy.

RR CR

– MVAC 40-75% <20%– Gemzar / Cisplatin 40-70% 5-15%– Gemzar / Carboplatin 65% 5%– Taxol / Carboplatin 20-40%

Treatment Options for Muscle Invasion (T2 T4, Stage II or above)‐

• TURBT • All muscle invasive tumors : as high-grade urothelial

carcinomas• For organ confined disease, radical cystectomy is the ‐

gold standard.– If surgery is not an option, radiation therapy is

recommended.– 30%– 50% ,5 yr survival rate ( death due to local ‐

relapsed. ) • Neoadjuvant chemotherapy

Neoadjuvant chemotherapy• BA06 trial ( Jco . 2011;29:2171 2177)‐

– 3 cycles of neoadjuvant (cisplatin, vinblastine, methotrexate) vs observation

– 3 year survival : 55.5% vs 50%, p=0.075,‐– 10 year survival : 36% vs 30% (p=0.037)‐

• Intergroup Study N Engl J Med 2003;349:859 66 ‐

– 3 cycles of neoadjuvant M VAC followed by ‐cystectomy or cystectomy alone (control).

– Median Survival : Neoadjuvant 77 months vs Control 46 months (p=0.06)

Neoadjuvant chemotherapy• A meta analysis of 11 randomized trials‐

– platinum based combination chemotherapy‐• Reduce 14% relative risk of death • Improvement in 5 year survival, 45% -> ‐ 50% (P = .003)• No survival benefit with single agent cisplatin.‐

• To preserve bladder function and avoid a radical cystectomy ( are combining bladder preserving surgery (TURBT), irradiation and chemotherapy.– None has been compared to radical cystectomy. (NEJM

1993;329:1377 82.‐ )

Metaanalysis collaboration. Eur Urol. 2005;48:202‐205.

Neoadjuvant chemotherapy

• Meta-analysis of ten randomised trials (2688 patients)

13% reduction in risk of death5% absolute benefit at 5 yearsOS increased from 45% to 50%

ABC Meta-analysis Collaboration. Lancet 2003;361:1927

Adjuvant chemotherapy

• Randomized trials have not shown a survival advantage.

• T3 tumors may receive 3 cycles of adjuvant (chemotherapy or radiation) therapy to delay recurrence

Ann Oncol 2006;17 Suppl 5:v118‐22

Case

• Two years later, he returns to the clinic complaining of abdominal & pelvic pain. A CT scan of the chest and abdomen demonstrate multiple pulmonary nodules & an abdominal mass. Based upon this information,

• what therapy should he now receive?

Treatment options for Advanced Disease (Stage IV) – rarely curable

• Cisplatin/chemotherapy better than single agent therapy.• Cisplatin alone (70 mg/m2) vs M VAC (methotrexate 30 mg/m2 ‐

IV on days 1, 15, 22; vinblastine 3 mg/m2 IV on days 2, 15, 22; doxorubicin 30 mg/m2 IV on day 2; cisplatin 70 mg/m2 IV on day 2) q 28 days. 19

• Response rate Overall Survival (Cisplatin 12% 8.2 months vs M‐VAC 39% (p<0.001) 12.5 months (p=0.002) – M VAC therapy : greater incidence of neutropenia, febrile ‐

neutropenia, mucositis, and nausea/vomiting.– Long term survival benefit for M VAC. ‐ ‐ J Clin Oncol 1997;15:2564‐69

First-line chemotherapy for muscle invasive bladder cancer

• Gemcitabine and cisplatin : Gemcitabine 1000 mg/m2 on days 1, 8, and 15 plus cisplatin 70 mg/m2 IV on day 1; repeat cycle every 28d for a total of 4 cycles or

• MTX, vinblastine, doxorubicin, and cisplatin (MVAC): Methotrexate 30 mg/m2 IV on days 1, 15, and 22 plus vinblastine 3 mg/m2 IV on days 2, 15, and 22 plus doxorubicin 30 mg/m2 IV on day 2 plus cisplatin 70 mg/m2 IV on day 2; repeat cycle every 28d for a total of 3 cycles.

Gemcitabine/Cisplatin vs. M‐VAC phase III study. J Clin Oncol 2000;17:3068 3077‐

Intravenous Carboplatin/Paclitaxel 23 26‐

3 phase II and 1 phase III trial with advanced bladder cancerLimited data for carboplatin substitutionConsider in patients “unfit” for cisplatin (PS > 2; CrCl < 60ml/min)

23. J Clin Oncol 1998;16:1844‐48., 24. Br J Cancer 1997;78:370‐4.25. J Clin Oncol 1998;16:1844‐8. 26. EORTC study 30986. J Clin Oncol. 2012;30:191‐199.

Non Platinum Regimens: Paclitaxel & Gemcitabine ‐Phase Ⅱ

a. 54 pts with advanced unresectable bladder cancer ; the 65% of patients had no prior therapy.b. Paclitaxel 200mg/m2 on day 1 & gemcitabine 1000 mg/m2 IV on days 1, 8, & 15. repeated q 21 days.

J Clin Oncol 2001;19:3018‐24.

Combined Radio- and Chemotherapy

CR 5y.OS

• Radiotherapy 57% 47%

• RT and cisplatin 85% 69%

• RT and carboplatin 70%57%

Birkenhake et al. Strahlenther Onkol 1998;174:121

Bladder-sparing therapy for invasive bladder cancer

• High probability of subsequent distant metastasis after cystectomy or radiotherapy alone (50% within 2 years)

• Radiotherapy im comparison with cystectomy has inferior results (local control 40%)

• Muscle-invasive bladder cancer is often a systemic disease

combined modality therapy

Bladder-sparing protocol

Transurthral resection

Induction Therapy: Radiation + chemotherapy

(cisplatin, paclitacel)

Cystoscopy after 1 month

no tumor tumor

Consolidation: RT + CT cystectomy

Bladder-sparing protocol

Shiply et al. Urology 2002;60:62

T2: 5y / 10y OS: 74% / 66%

T3-T4a: 5y / 10y OS: 53% / 52%

Results of bladder-sparing therapy and cystectomy

Bladder-sparing n Pat. 5y. OS 5y. Survivaltherapy % with Bladder %

Houssett 1997 120 63 NASauer 1998 162 55 44Shipley 1998 123 49 38Shipley 2002 190 54 45Rodel 2002 415 50 42

Cystectomy

Dalbagni 2001 181 36 NAStein 2001 633 48 NA

Combined-modality treatment and organ preservation in invasive

bladder cancer

Rödel et al. JCO 2002;20:3061

415 patients with T1 high-risk, T1-4, No-1

Treatment: 1. Transurethral resection

2. RT (n=126), RCT (n=289) RT median 54 Gy, CT cisplatin week 1, 5

3. Restaging-TUR

Combined-modality treatment and organ preservation in invasive

bladder cancer

• Rödel et al. JCO 2002;20:3061

• Complete remission 72%• Local control after CR 64% (10 y.)

• distant metastasis 35% (10 y.)

• Disease-specific survival 42% (10 y.)

• Preservation of bladder >80%

Local control Distant metastasis

Rödel et al. JCO 2002;20:3061

Disease-specific survival for patients after salvage cystectomy

50%45%

21% 18%

Rödel et al. JCO 2002;20:3061

TUR and adjuvant Radio-Chemotherapy

• 5 year Survival 50-65%

• Preservation of Bladder38-43%

Conclusion

• Superficial tumors have a 5 year survival rate of > 50%.‐• With muscle invasive carcinoma have a 5 year survival ‐

rate of 20 50%‐• Regional lymph nodes are involved the 5 year survival ‐

drops to 0 20% ‐• The treatment of advanced metastatic bladder cancer is

palliative.– M VAC or gemcitabine + cisplatin survival is just over ‐

one year.

A 65 year old male presents with painful urination. Upon work‐ ‐up microscopic hematuria is detected and a cystoscopy is performed. He is found to have a stage III bladder cancer with muscle invasion. The best treatment option for this patient after cystectomy would be:

• A. Observation.

• B. Intravesicular bcg vaccine.

• C. Three cycles of neoadjuvant single‐agent cisplatin.

• D. Three cycles of neoadjuvant m‐vac followed by radical cystectomy.

2. JM is a 62 year old female diagnosed with stage IV bladder ‐ ‐cancer. Her laboratory values are largely unremarkable except for long standing chronic renal disease that has resulted in a baseline ‐serum creatinine of 1.9mg/dL. Which of the following is the best treatment option for JM?

• A. M VAC chemotherapy repeated every 28 days ‐with a reduced dose of cisplatin.

• B. Dose dense M VAC repeated every 14 days‐ ‐• C. Cisplatin on day 2 + Gemcitabine on days 1, 8,

and 15 repeated every 28 days• D. Paclitaxel on day 1 + Gemcitabine on days 1, 8,

and 15 repeated every 21 days