1. Done By Ehab Ahmed KAAU

2. Outlines  Epidemiology  Risk factors  Molecular pathway  Pathology  Presentation  Diagnosis  Chemoprevention  Management  Non-urothelial Bladder Cancer

3. Epidemiology  The most common malignancy affecting the Urinary System  80% in patients over 60 years of age  M:F is 3.4:1  In some high incident regions, Bladder Cancer is associated with specific disease status or toxins exposures as in Balkan countries, Urinary Transitional Cell Carcinoma is associated with Balkan nephropathy

4. Risk Factors  Chemical carcinogenesis: o Aromatic Amines or its derivatives as 2- Naphthylamine, Benzidine, Azodyes, and 4-Aminobiphenyl  Occupational : o Aluminum, Dye, Paint, Petroleum, Rubber o 20% Of cases

5.  Environmental : o Smoking :  Increase by 6-10 folds  Related to the extent of exposure, with long term o Analgesic abuse :  Chemical structure similar to Analine dye  Phenactin has been linked to CRD, Cancer of the Bladder, Renal Pelvis, and Ureters

6. o Artificial sweeteners :  Saccharin, and Cyclamates o Coffee consumption :  Week association  Reflect the confounding influence of Smoking o Upper tract cancer (TCC) o Pelvic radiation :  Cervical, Ovarian, and Prostate cancers

7. o Chronic infections :  Cystitis, Schistosomiasis  Mechanisms : 1. Repeated chronic irritations can lead to metaplastic changes, then dysplasia, and finally carcinoma 2. It predispose to obstructive uropathy, bacterial super infection, and production of Nitrosamines in the acidic urine environment 3. Inflammatory cells are rich sources of reactive oxygen species 4. Genetic variations in the genes involved in the inflammatory response alter their expression and function, potentially affecting the risk of developing cancer

8. o Chemotherapy :  Cyclophosphamide have up to 9 fold increase risk of Bladder Cancer o Others :  Black foot disease  Renal transplant recipient (prolong immunosuppressant)

9. Molecular Pathways  Metabolic activation of carcinogens : o arylamines require in vivo activation to acquire carcinogenic potential o Through P45 enzymes  Detoxification of carcinogens : o Acetylation phenotype o Glutathione S transferase

10. Pathology

11.  Pathologic tumor staging : o Lamina Propria Invasion o Muscularis Propria Invasion o Vascular Invasion

12. Non-invasive Urothelial Neoplasm Flat lesions CISDysplasia Papillary lesions Urothelial Papilloma Inverted Papilloma PUNLMPLGPUCHGPUC

16.  Malignant Epithelial Tumors : o Transitional Cell Carcinoma :  90% of Bladder Cancer  75% Papillary and solid o Squamous Cell Carcinoma o Adenocarcinoma o Small Cell Carcinoma o Metastatic :  15% of cases  Usually from Colon, Rectum, Prostate, and Cervix  Less commonly from Melanoma, Stomach, Breast, and Lung

17. Presentation  Hematuria : o Intermittent, gross, painless, and total  Pain : o Usually due to locally advanced or metastatic disease o Flank, Suprapubic, Bone, and Perineal pain  Voiding symptoms : o Functional decrease in the bladder capacity, detrusor overactivity, invasion of the trigone, and obstruction o Irritative (more common), and Obstructive  Constitutional symptoms : o Signs of advanced or metastatic diseases

18. Staging  Histological grade : o Based upon the degree of resemblance to the normal tissue architecture, and degree of nuclear anaplasia o Bladder tumors are now classified as either low or high grade. This replaces the previous system of classification in which tumors were designated as low (G1), intermediate (G2), or high (G3) grade

20.  Clinical staging (TNM) : o Tx – Primary tumor cannot be assessed o T0 – No evidence of primary tumor o Ta – Non-invasive papillary carcinoma o Tis – Carcinoma in situ o T1 – Invade subepetheilial connective tissue o T2 – Invade the muscles o T2a – Superficial muscle (inner half) o T2b – Deep muscle (outer half) o T3 – Invade perivesical tissue o T3a – Microscopically o T3b – Macroscopically (extravesical mass) o T4 – Invade other organs o T4a – Invade Prostate, Uterus, and Vagina o T4b – Invade Pelvic and Abdominal wall

22. o Nx - Regional lymph node cannot be assessed o N0 - No lymph node metastasis o N1 - Single lymph node, 2 cm or less o N2 - Single lymph node 2-5 cm, or multiple lymph nodes less than 5 cm o N3 - Lymph nodes more than 5 cm o Mx - Distant metastasis cannot be assessed o M0 - No distant metastasis o M1 - Distant metastasis

25. Stage grouping MN T Stage M0N0TaStage 0a M0N0TisStage 0is M0N0T1Stage 1 M0 N0 Ta Tb Stage 2 M0 N0 NO T3a T3b T4a Stage 3 M0 M1 N0 N1 N2 N3 Any N T4b Any T Ant T Any T Stage 4

26. Diagnosis 1. Urinalysis : o Microscopic, gross examinations, and dipstick chemical test 2. Urine cytology : o 90% is sensitive for Cis o Limited sensitivity for upper tract TCC o Overall false negative rate is 65% o Specificity is 81-100% o Positive cytology considered poor prognostic factor 3. Urine flow cytometry : o Evaluation of abnormal DNA ploidy may be more accurate than cytology for detecting the presence of exfoliated malignant cells

27. 4. Urine immunocytochemistry and proteomocis assaays : o Immunocytochemistry :  More sensitive in detecting Low Grade Tumor than cytology o NMP22 Proteomics assays :  Analysis of protein expression in tissues, serum in order to identify tumors on the basis of unique protein expression pattern

29. 5. Radiographic evaluation :  IVP : o Cystogram phase detect 60-85% of large bladder cancer

30.  Ultrasound : o Can confirm Bladder mass but cannot determine depth of invasion, nodal involvement, and extravesical extension o Useful in evaluating upper tract

31.  CT Scan : o 80% accurate in differentiating locally advanced tumor form less invasive tumor

33. o Advantages :  Demonstrate extravesical extension, nodal involvement, visceral, pulmonary, or osseous metastasis o Disadvantages :  Cannot differentiate depth of Bladder wall invasion, although thickened wall suggest muscle invasive disease  Sensitivity for identification of nodal involvement is relatively low (false negative is 86%, and false positive is 16%)

34. 6. Cystoscopy : o Gold standard o It begins with bimanual examination under anesthesia o Abnormal areas should be sampled o RGP should be done if upper tract cannot be visualized by IVP o Cytology specimen should be taken if not previously done o Should document the following :  Tumor size, number, position, and growth pattern  Mucosa  Lower tract as urethra and prostate

36. 7. Fluorescence cystoscopy : o Intravesical installation of a porphryin such as 5-aminolevulinic acid o More effective than white light endoscope for the detection of multifocal tumors, thereby improving outcomes of TURBT o Sensitivity is 87-97%

37. Purpose Comparison between hexaminolevulinate fluorescence cystoscopy with white light cystoscopy for detecting Ta and T1 papillary lesions in patients with bladder cancer

38. Methods A total of 311 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM HAL for 1 hour. The bladder was inspected using white light cystoscopy, followed by blue light (fluorescence) cystoscopy. Papillary lesions were mapped and resected for histological examination

39. Conclusion HAL fluorescence cystoscopy detected at least 1 more Ta and T1 papillary tumor than white light cystoscopy in approximately a third of the patients with such tumors. Whether this would translate to improved patient outcomes has yet to be determined. University of Texas M.Grossman HB et al, July 2007

40. 8. Metastatic work up : o Chest x-ray :  Non calcified densities o MRI  Sensitive to detect Lymph Node metastasis o Bone Scan  In patients with invasive or locally advanced tumors, and other skeletal symptoms or unexplained elevation in serum Alkaline Phosphatase (ALP)

41. Chemoprevention  Use of various systemic agents to prevent or reverse changes in the urothelium  Two types : 1. Primary chemoprevention : o Block the formation of de novo Bladder Cancer in healthy individuals 2. Secondary chemoprevention : o Avoiding formation of additional tumors in patients who have been treated for bladder cancer

42.  Agents : 1. Retinoids (Vitamin A component) 2. Pyridoxine (Vitamin B6) 3. Vitamin C 4. Alpha tocopherol (Vitamin E) 5. Multivitamins 6. Difluoromethylomithine  Although some of the data supporting these agents is suggestive, NO role has been established for any of these agents in either primary or secondary chemoprevention

43. Management  Prognostic factors : o Stage  Stage Ta, Tis, T1 o Grade o Multicentricity and frequency of recurrence : o Molecular markers

44.  Treatment options : o Endoscopic surgical management o Immunotherapy o Intravesical chemotherapy o Radical cystoectomy o Radiotherapy

45.  Risk stratification : High Risk PatientsLow Risk Patients Multiple superficial recurrence within sort time period Initial presentation with superficial tumor >3 cm lesions, sessile, and on a thick stalkLong interval between tumor recurrence Invasion of the lamina propria, poorly differentiated histology 3-4 Lesions, all of which are small (<3 cm) with a papillary appearance and on fine stalk Incomplete resection due to diffuse bladder involvement or unfavorable location No lamina propria invasion, well differentiated histology Presence of diffuse Tis, or Tis in association with papillary tumors

47. Initial Treatment  Transurethral Resection (TURBT) : o Despite complete TURBT, up to 80% of patients with high risk tumors will recur within 12 month. So, adjuvant therapy is widely used

48.  Restaging TURBT : o Patients with high risk bladder cancer who are candidate for Intravesical therapy should undergo a repeat cystoscopy with biopsies of previous areas of involvement prior to therapy. This approach is important to detect previously under diagnosed disease and to reduce the tumor burden prior to therapy

49.  Random biopsies post-TURBT : o Any suspicious areas should be sampled o Not indicated in low-risk pt o 12.4% positive in high risk with normal cystoscopy o Prostatic urethral biopsy may be performed if neobladder creation is anticipated o ?tumor implantation

50. Purpose evaluation of whether restaging transurethral resection (TUR) of superficial bladder cancer improves the early response to bacillus Calmette- Guerin (BCG) therapy

51. Methods A total of 347 patients with high risk superficial bladder cancer (high grade Ta and T1 tumors associated with carcinoma in situ) underwent a single transurethral resection (TUR, 132 patients) or restaging TUR (215 patients) before receiving 6 weekly intravesical BCG treatments The patients were evaluated for response (presence or absence of tumor) at first follow up cystoscopy, at 6 and 12 months after treatment, and evaluated for disease stage progression within 3 years of follow up

52. Result Of the 132 patients who underwent a single TUR before BCG therapy, 75 (57%) had residual or recurrent tumor at the first cystoscopy and 45 (34%) later had progression compared with 62 of 215 patients (29%) who had residual or recurrent tumors and 16 (7%) who had progression after undergoing restaging TUR (p = 0.001)

53. Conclusion Restaging TUR of high risk superficial bladder cancer improves the initial response rate to BCG therapy, reduces the frequency of subsequent tumor recurrence and appears to delay early tumor progression Herr HW, Memorial Sloan- Kettering Cancer Center, Dec 2005

54.  Intravesical therapy : o Permits high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following TURBT and preventing tumor implantation o Indications : 1. Multiple, or large (>3cm) at presentation 2. Recurrence within 1 year 3. High grade Ta 4. Any T1 5. Cis 6. Positive cytology after resection of a visible tumor

55. o Intravesical chemotherapy : ○ Metaanalysis of seven randomized trial has demonstrated that one immediate installation of chemotherapy after TUR decrease the relative risk of recurrence by 40 % ○ Up to 24 hours

56. 1. Intravesical BCG : o Most common o Live attenuated form of Mycobacterium Bovis o The exact mechanism of action is UNKNOWN

57. Antitumor mechanism Mononuclear cell infiltrate (CD4 T, Macrophages) Presence of Interferon gamma in the bladder Cytokines level are increased in the urine following treatment

58. o Dose :  Induction dose as Weekly injection for sex weeks  Each dose consist of a vial of reconstituted theracys (81mg) or one 2 ml ampule of TICE BCG (50mg), plus 50 ml of sterile saline injected into the bladder through a catheter and retained for 2 hours o Maintenance therapy :  Maintenance therapy consisted of intravesical BCG each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy

59. Purpose The role of maintenance therapy, and its long-term effect on recurrence and progression

60. Methods All patients in the study had transitional cell carcinoma of the bladder with carcinoma in situ or an increased risk of recurrence. The criteria for increased risk were 2 or more episodes of tumor within the most recent year, or 3 or more tumors within 6 months. At least 1 week following biopsy of carcinoma in situ and resection of any stage Ta or T1 transitional cell tumors 660 patients were started on a 6-week induction course of intravesical BCG Three months following initiation of BCG induction therapy 550 consenting patients were stratified by purified protein derivative skin test and the presence of carcinoma in situ, and then randomized by central computer to receive BCG maintenance therapy (maintenance arm) or no BCG maintenance therapy (no maintenance arm).

61. Result No toxicities above grade 3 were noted in the 243 maintenance arm patients. The policy of withholding maintenance BCG from patients with increased side effects may have diminished the opportunity to observe severe toxicity. Estimated median recurrence-free survival was 35.7 months in the no maintenance and 76.8 months in the maintenance arm (p<0.0001). Overall 5-year survival was 78% in the no maintenance compared to 83% in the maintenance arm

62. Conclusion Compared to standard induction therapy maintenance BCG immunotherapy was beneficial in patients with carcinoma in situ and select patients with Ta, T1 bladder cancer. Median recurrence-free survival time was twice as long in the 3-week maintenance arm compared to the no maintenance arm, and patients had significantly longer worsening-free survival Lamm Dlet al, West Virginia University Medical Center,April 2000

63. o Efficacy :  Delay tumor progression, decrease the need for subsequent cystectomy, and improve overall survival rate o Long term outcome :  Studies showed that the survival rate at 4-5 years (70-86%) following BCG is similar to that achieved after Cystectomy

64. o Complications :  Cleavland Clinic approach for toxicity management Moderate symptoms less than 48 hours Grade 1 Mild to moderate irritative symptoms, mild hematuria, and fever <38.5 Presentation Urine culture to rule out UTI Assessment Anticholinergic, Antispasmodic, NSAID, Analgesia Management

65. Severe symptoms and\or more than 48 hours Grade 2 Severe irritative symptoms, hematuria, or symptoms lasting more than 48 hours Presentation Urine culture, chest radiograph, and liver function Assessment Infectious consultation, treat culture result as appropriate Antimicrobial agents: INH 300 mg\day PO and Rifampin 600 mg\day PO Management

66. Serious complications (hemodynamic instability, persistent high grade fever Grade 3 Allergic reaction (joint pain, rash) Presentation Urine culture, chest radiograph, and liver function Assessment INH 300 mg\day PO and Rifampin 600 mg\day PO for 3-6 month depend on the response Consider Prednisone 40 mg\day, when response is inadequate for septic shock (NEVER given without effective antibacterial therapy) Management

67. o Contraindications : Relative ContraindicationsAbsolute Contraindications UTIImmunosuppressed patients Liver diseasePersonal history of BCG sepsis TBGross hematuria Poor overall performance statusTraumatic catheterization Advanced ageTotal incontinence Immediately after TURBT, risk of intravasation

68. o BCG Failure :  Predictors of BCG Response  skin testing and granuloma formation  some studies have suggested that p53 status might provide a useful predictor for BCG response  Llopis et fli showed that p53 expression analyzed at a cutoff of 20% positivity is a significant predictor of progression  Sub classified to  BCG Refractory  BCG-Resistant  BCG-Relapsing

69. o Recommendations for the use of BCG :  BCG is superior to chemotherapy for preventing recurrence  Patients with intermediate risk and high risk tumors are suitable for BCG therapy  BCG delay, prevent progression to muscle invasive disease  Maintenance therapy is necessary for optimal therapy, but the optimal schedule and does have not yet been defined  At least 1 year maintenance therapy is advised EUA 2007

70. 2. Mitomycin C : o Alkylating agent that is minimally absorbed from the bladder circulation into the systemic circulation o 20-60 mg o Weekly for 6-8 weeks o Side effects include chemical cystitis and skin reactions 3. Anthracyclines : o Epirubicin, Doxorubicin, and Valrubicin o Approved for use in patients who have failed BCG, and in whom immediate cystectomy is either refused or contraindicated

71. 4. Interferon : o 10-100 million units o Weekly for sex weeks o Side effects include Flu-like symptoms o Still under trial 5. Thiopeta : o Seldom used o High incidence of irritative voiding symptoms, myelosupression, and secondary leukemia

72.  Cystectomy : o Indications : 1. Muscle invasive disease 2. Failure to control symptoms (hemorrhage) with other parameters 3. Multiple tumors with unfavorable locations 4. Recurrent within short period of time despite use of Intravesical therapy 5. Superficial tumor of the prostatic urethra particularly if complete resection cannot be accomplished

73. Adjuvent Treatment Papillary or solid Any Cis

74. Papillary or Solid Ta,low grade chemotherapy into the bladder within 24 h of surgery Cystoscopy Q 3 m Ta, high grade or T1, low grade BCG Cystoscopy, cytology Q3 month for 2 years, then Q6 month for 2 years, the each year UT Q1-2 year T1, high grade

75.  T1, high grade : o Cystectomy and intravesical BCG therapy are both acceptable primary therapies For high-grade Tl disease and both options should be discussed o The ideal candidate for conservative treatment of Tl bladder cancer is ○ a patient with a solitary or at least completely resectable tumor, ○ a negative upper tract evaluation, and ○ no evidence of invasive disease in the prostatic urethra

76. o Primary intravesical therapy should comprise induction BCG immunotherapy with 6 weekly instillations beginning no sooner than 2 weeks after tumor resection. o Cystoscopy with urinary cytology and possible biopsy should be done at 3 months to confirm the absence of recurrence or progression. o Maintenance therapy should be given. although comparison studies have not been done, the SWOG regimen of 3 weekly instillations at 3, 6, and every 6 months for 3 years is recommended

77. o For patients with initial induction BCG therapy failure Who are unfit, refuse cystectomy, or have low- or.intermediate- grade disease >>> an additional course of a BCG- containing intravesical therapy is the preferred option o Cystectomy is indicated if salvage therapy fails, and it should be performed in a timely

78. o Early cystectomy is recommended in diffuse high grade tumor who fail to response to Intravesical therapy

79. Patients undergoing delayed cystectomy ( > 2 years) have a poorer prognosis than those undergoing more immediate cystectomy.

80. Any Cis BCG Installation Cystoscopy Q 3month for 2 years, then Q6 monthe for 2 years, the each year Upper tract imaging Q1- 2 year Urinary biomarkers is optional

81. Post Treatment Follow Up  Recurrent disease can develop any where in the genitourinary epithelium including Renal pelvis, Ureters, Urethra, and the Bladder 1. Cystoscopy 2. Urinary biomarkers 3. Urethra (prostatic)

82. 4. Upper urinary tract : o 3-20%, median time to discover of such tumors are 3-7 years o IVP, CT Urography, RGP, and MRI Urogram o Factors that may increase the risk of developing upper tract tumors are: 1. Urethral involvement 2. VUR 3. Occupational exposure 4. Multiple tumor, Tis

83. o Patients with negative cytology after TURBT, imaging of the upper tract every 1-2 years is recommended and should continued for 5 years in patients with low risk disease and for life in patients with high risk disease o Patients with positive cytology and NO obvious intravesical tumor, carful periodic evaluation of the upper tract is important by CT Urography

87. Treatment of Recurrent, Persistent Disease  Cancer present on follow up cystoscopy: o TURBT o Adjuvant treatment according to the type and grade of the tumor o Follow up Q3 month for 2 years then Q6 month for 2 years then each year

88.  Positive cytology with Negative cystoscopy : Random biopsies of the bladder and prostate (in men) NO Cancer found Follow up, or BCG into the bladder Cancer found

89. BCG Complete response Maintenance BCG, Follow uo Incomplete response Different drug trial Persist Cystectomy

90. Recurrent post 2 cycle of BCG, Mitomycin C treatment Complete response Maintenance BCG Recurrent as Tis, Ta Cystectomy or different drug into the bladder Recurrent as T1, high grade Cystectomy

91. Non-urothelial Bladder Cancer  The development of METAPLASIA and the presence of CHRONIC INFECTIONS are believed to be important factors in tumorgenesis  Non-Schistosomal SCC  Adenocarcinoma  Schistosomal Bladder Cancer  Non-epethilial Bladder Cancer

92.  Non-Schistosomal SCC : o 3-5% in North America and Europe, 75% in areas where Schistosoma Haematobium is endemic o Risk factors include chronic UTI, bladder stones, pelvic radiation, cyclophosphamide exposure, and smoking o Hematuria and irritative symptoms are present o Tumors are commonly bulky and locally invasive at diagnosis, but distant metastases are present in only 8 to 10 percent of cases at diagnosis o Treatment :  Surgery  Chemoresistant

93.  Adenocarcinoma : o 0.5-2%, 10% Urachal Adenocarcinoma o Non-urachal Adenocarcinoma :  Low grade  Treatment :  Radical Cystectomy and lymph node dissection  Chemotherapy for unrespectable tumor  RT have been utilized by some centers with mixed results o Urachal Adenocarcinoma :  Treated with surgical resection and resection of the Urachal ligament and Umbilicus  No role for Chemotherapy or Radiotherapy

94.  Schistosomal Bladder Cancer : o 70% SCC, 20% TCC, and 5% Adenocarcinoma o Tumors are usually low- to moderate-grade. At diagnosis, lymph node metastases are present in about 20%, and distant metastases in 3%, possibly due to mural fibrosis causing delayed spread of the tumor o Treatment :  Non-metastatic tumor treated with Radical Cystectomy and Lymph Node dissection  Adjuvant Radiotherapy improve survival rate  Neoadjuvent Chemotherapy improve survival rate ( 74% vs. 38% with cytectomy alone)

95.  Non-epithelial Bladder Cancer : o Sarcoma o Paraganglioma o Melanoma o Lymphoma o Lymphepithelioma-like carcinoma o Metastatic tumor

96. Thank You