Bladder cancer 12 2012

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Comprehensive overview of urinary bladder cancer: diagnosis and treatment

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Bladder cancer 12 2012

  1. 1. BLADDER CANCERAhmed ZeeneldinAssociate Professor of Medical Oncology
  2. 2. INCIDENCE IN USA¢ 4.5% of cancers¢ M: F: 2.5:1¢ Age: 6th-7th decade
  3. 3. INCIDENCE IN EGYPT¢ NCI males:¢ 1st , 16%
  4. 4. INCIDENCE¢ NCI combined:¢ 4th, 4.4%¢ M: F: 4:1¢ Median age:¢ M: 60¢ F: 58
  5. 5. RISK FACTORS¢ Occupational exposure: — Aniline dyes — Leather, rubber and paint industries¢ Schistosoma haematobium: — Associated with squamous histology — In Africa and middle east¢ Smoking¢ Pelvic irradiation¢ Drugs: cyclophosphamide
  6. 6. HISTOLOGY¢ Urothelial (transitional cell) carcinoma TCC: commonest¢ In situ — Papillary — Flat — With squamous metaplasia — With glandular metaplasia — With squamous and glandular metaplasia¢ Squamous cell carcinoma (SCC)¢ Adenocarcinoma¢ Undifferentiated carcinoma
  7. 7. HISTOLOGY IN EGYPT
  8. 8. HISTOLOGY US EGY ¢ TCC: 90% ¢ TCC: 63% ¢ SCC: 6-8% ¢ SCC: 27% ¢ Adeno: 2% ¢ Adeno: 3% ¢ Small cell: 1% ¢ Undifferentiated: 2%systemic chemotherapy regimens used to treat TCCare ineffective in pure SCC or AdenoIf mixed tumor only TCC responds
  9. 9. STAGES
  10. 10. TNM STAGING 2010 URINARY BLADDER ¢ T0: non-invasive — Ta: Noninvasive papillary carcinoma — Tis: Carcinoma in situ “flat tumor” ¢ T1: mucosa or submucosa ¢ T2: muscle — T2a: inner half — T2b: outer half ¢ T3: outside muscle (adventitia) — T3a: microscopic (histology, no masses — T3b: macroscopic (mass) ¢ T4: surroiundings — T4a: prostate, uterus, vagina — T4b: pelvic or abdominal T T T T4 T4 M1 ¢ N1: regional LN+ 1 2 3 a b — N1: Pelvic LNs (1) — N2 : pelvic LNS (>1) N0 I II III III IV IV — N3: common iliac LN N1- IV IV IV IV IV IV M1: Distant metsSIMPLIFICATION 3 ¢-I: T1 -II: T2-III: T3/T4 a -IV: T4b OR LN+OR M1
  11. 11. STAGINGT0: non-invasive Ta: Noninvasive papillary carcinoma Tis: Carcinoma in situ “flat tumor”T1: sub-epithelial connective tissueT2: Tumor invades muscle T2a: inner half T2b: outer halfT3: Tumor invades perivesical tissue T3a: Microscopically T3b: Macroscopically (extravesical mass)T4: surroundings T4a: prostate, uterus, vagina T4b: pelvic wall, abdominal wallN1: 1 pelvic LNN2: > 1 pelvic LN Tis/0 T1 T2 T3 T4 M1=IVN3: common iliac LN N0 0 I II III T4a: T4b: IVM1: distant mets III IV N1-3 IV
  12. 12. MANAGEMENT OF BLADDER CA¢ Cystoscopy and biopsy: — See lesions — Biopsy and muscle should be included — We will reach to a conclusion: — MUSCLE IS INVADED OR NOT ¢ Not invaded àTURB ¢ Upper UT imaging ¢ CT if sessile or high grade T is suspected ¢ Invaded à CT: ¢ LN small (negative): T2,T3, T4a: cyatectomy ¢ LN large: biopsy: negative — Positive:
  13. 13. NON MUSCLE INVASIVE Grade Cyctectomy TURB IVsT+ CystectomyTis High No Yes BCG Resistent /relapsedTa Low No Yes May (chemo, mito) // Once ? After 6msTa high No Yes BCG > Chemo //T1 Low No Yes BCG* If residual Mito** //T1 high May Yes BCG* if residual Mito** //+ not if extensive TURB or perforation* Whether residual or no residual** chemotherapy only if no residaul
  14. 14. INTRAVESICAL CHMOTHERAPY¢ Drugs — Chemotherapy ¢ Alkylating agents: thiotepa, mitomycin C (40mg in 20 cc st Water), ¢ Anthracyclines: doxorubicin (50 mg in 25 cc St water), epirubicin, valrubicin¢ Value: — Acts by diffusion — Prevent seeding and Reduce recurrence by 6% — No reduction in disease progression or mortality — Within 6 Hrs post TUR, Not if extensive TURB or perforation — Overnight fast, empty bladder before — Keep for .5 hr (post TUR) or 2Hrs, supine and prone (air bubble) — Alkalanize urine with mitomycin
  15. 15. INTRAVESICLA IMMUNOTHERAPY — Immunotherapy ¢ BCG (81 mg for TheraCys and 50 mg for TICE, both in 50 cc physiologic saline) — Value: ¢ Acts by enhancing immune response, drawing lymphocytes and macrophages to the bladder and stimulating a cellular (TH1) immune response ¢ Not immediate (at least 1-2 wks post TUR) ¢ Weekly x 6 w ¢ Maintenance ¢ (3 app x q 3ms) ¢ 3 weekly at 2, 6, 12, 18, 24, 30, 36 ms XXXX? ¢ NOT WITH CIPRO
  16. 16. MUSCLE INVASIVEN Cystectomy Chemotherapy RadiotherapyN- T2* Radical Neoadj or adjuvant No Partial Neoadj or adjuvant May be used instead of CT No CRT CRTN- T3* Radical Neoadj or adjuvant No No CRT CRTN- T4a If possible CRT or chemo CRT or chemo 1st or after (Neoadj or adj) (Neoadj or adj) NeoadjN- T4b If possible CRT or chemo CRT or chemo after Neoadj (Neoadj or adj) (Neoadj or adj)N+ If possible CRT or chemo CRT or chemo after Neoadj (Neoadj or adj) (Neoadj or adj)M1 No Yes may
  17. 17. PROGNOSTIC FACTORS¢ Stage : — depth of invasion¢ Grade: — Low grade: 1-2 — High grade: 3-4
  18. 18. TREATMENTNon-Muscle-invasive Muscle-invasive — Ta ¢ T2 — Tis ¢ T3 — T1 ¢ T4¢ Treatment: — Resection: Repeat TUR ¢ Treat. — +/- intravesical therapy — Resection: cystectomy ¢ Grade ¢ Partial or complete ¢ depth — Chemo: adjuvant/neoadj — RT:
  19. 19. TREATMENT MODALITIES¢ Resection: — TURBT: ONLY FOR non-muscle invasive — Cystectomy: ¢ Partial cystectomy : selected cases of muscle invasion ¢ Radical cystectomy: standard treatment of muscle invasive tumors and as salvage therapy¢ Drug therapy: — Local (intravesical): ONLY FOR non-muscle invasive ¢ Immunotherapy: BCG or INF ¢ Chemotherapy: MMC, Doxorubicin or Valrubicin, thiotepa — Systemic (IV) chemotherapy: ONLY for muscle invasive¢ Radiotherapy: ONLY for muscle invasive
  20. 20. TREATMENT: NON-MUSCLE INVASIVE¢ Includes: Ta, Tis, T1¢ Tx: — Repeated TURB — Post TURB intravesical therapy: ¢ depends on grade and depth of invasion that determines: ¢ Bladder recurrence risk ¢ Progression to muscle invasion risk ¢ Modes: ¢ Adjuvant: to prevent bladder recurrence: MAINLY ¢ Complementary: to eradicate residual disease: RARELY — Cystectomy: rare
  21. 21. TREATMENT: NON-MUSCLE INVASIVE¢ Tis (CIS), always high grade¢ Tx: — TURB — Post TURB intravesical BCG therapy Weekly x 6 — Follow up: cystectoscopy + cytology + imaging of upper Urinary tract q3 m x 24m, then increase intervals — Recurrence: ¢ TURB + ¢ Adjuvant intravesical therapy according to grade and depth of invasion ¢ Follow up: cystectoscopy q3 m
  22. 22. TREATMENT: NON-MUSCLE INVASIVE¢ Ta (papilloma), low grade ¢ Ta (papilloma), high grade¢ Tx: ¢ Tx: — TURB — TURB — Post TURB intravesical therapy: — Post TURB intravesical therapy: ¢ None ¢ None ¢ Adjuvant intravesical ¢ Adjuvant intravesical BCG: chemotherapy (Mitomycin C): ¢ Adjuvant intravesical ¢ Single chemotherapy (Mitomycin C): ¢ Within 24 Hours form TURB ¢ Single — Follow up: cystectoscopy + ¢ Within 24 Hours form TURB cytology q3 m x 12 m, then — Follow up: cystectoscopy + increase intervals cytology + imaging of upper Urinary tract q3 m x 24m, then — Recurrence: increase intervals ¢ TURB + — Recurrence: ¢ Adjuvant intravesical therapy ¢ TURB + according to grade and depth of ¢ Adjuvant intravesical therapy invasion according to grade and depth of ¢ Follow up: cystectoscopy q3 m invasion ¢ Follow up: cystectoscopy q3 m
  23. 23. TREATMENT: NON-MUSCLE INVASIVE¢ Persistent or recurrent Ta and Tis — TURB+/- IVTà recurrence/persistence at W12à TURB+IVT à still recurrence or persistence at W 24¢ Tx: — Cystectomy is the first option — TURB and Post TURB intravesical therapy may be considered to avoid cyctectomy ¢ Use different agents ¢ Chemo: MMC, Valrubicin ¢ BCG + INF a ¢ Follow up: cystectoscopy + cytology + imaging of upper Urinary tract q3 m x 24m, then q 6m x 24 m ¢ Recurrence/persistence: cystectomy¢ Another scenario: — TURB+/- IVTà recurrence/persistence at W12à TURB+IVT à CR: — Maintenance BCG — Follow up: cystectoscopy + cytology + imaging of upper Urinary tract q3 m x 24m, then q 6m x 24 m ¢ Recurrence/persistence: TRUB + different IVT or cystectomy
  24. 24. TREATMENT: NON-MUSCLE INVASIVE¢ T1 , low risk ¢ T1, high risk — No high risk features — multifocal lesions, — vascular invasion, — recurrence after BCG¢ Tx: — High grade. — TURB — Post TURB intravesical therapy: ¢ Tx: ¢ Adjuvant intravesical BCG: — TURB ¢ Adjuvant intravesical chemotherapy — Post TURB intravesical therapy: (Mitomycin C): ¢ Adjuvant intravesical BCG: ¢ Single ¢ Adjuvant intravesical chemotherapy ¢ Within 24 Hours form TURB (Mitomycin C): — Follow up: cystectoscopy + cytology ¢ Single q3 m x 12 m, then increase intervals ¢ Within 24 Hours form TURB — Cystectomy — Recurrence: — Follow up: cystectoscopy + cytology ¢ TURB + + imaging of upper Urinary tract q3 ¢ Adjuvant intravesical therapy m x 24m, then increase intervals according to grade and depth of — Persistence after conservative invasion management : ¢ Follow up: cystectoscopy q3 m ¢ Cystectomy
  25. 25. FOLLOW UP¢ Low risk lesion: high risk lesions+ Cystoscopy and cytology Cystoscopy and cytology¢ imaging upper tract¢ q3 m x 12 q3 m x24¢ Then increasing q 6m x 24
  26. 26. TREATMENT: MUSCLE INVASIVE DISEASE¢ Workup: — Lab: CBC, chemistry, Alk phos — Cystoscopy, EAU/TRUBT — Imaging: ¢ Chest Xray ¢ CT/MRI of abdomen and pelvis ¢ +/- Bone scan¢ Aim: Tis/0 T1 T2 T3 T4 M1=IV — Organ confined T2, N0, M0 N0 0 I II III T4a: T4b: IV III IV — Non-organ confined T3, T4, N1, M0 N1-3 IV — Metastatic disease M1
  27. 27. ORGAN CONFINED (T2) DISEASE¢ Surgery (cyctectomy): — Primary Tx — radical : standard particularly in recurrence — Partial (segmental) ¢ More in dome and solitary ¢ Less in neck, trigone and multiple or associated Tis¢ Chemotherapy: — Cisplatin-based ¢ Neoadjuvant: in T3 or T2 or ¢ Adjuvant : pT3 and pT4 and LN+¢ RT: ¢ Adjuvant: pT3 and pT4, LN+, SM+ or high grade¢ Concurrent chemoradiotherapy (CCRT): — Preoperative: in advanced disease — Definitive: in severe comorbidities and poor PS — If CCRT is not tolerable: chemo or radio can be given alone
  28. 28. ORGAN CONFINED (T2 N0)
  29. 29. NON-ORGAN CONFINED (T3, N0)
  30. 30. NON-ORGAN CONFINED (T4 OR N1-3 OR M1)
  31. 31. CYSTECTOMY¢ Radical cystectomy: standard — Male: ¢ removes bladder, prostate, seminal vesicles — Females: ¢ Removes bladder and maybe uterus, ovaries and tubes — Pelvic LND: ¢ decreases recurrence and ¢ increase OS — Urinary diversion or neobladder¢ Partial systectomy: selective — More in dome and solitary — Less in neck, trigone and multiple or associated Tis — Recurrence after partial cystectomy: ¢ Consider as new cancer ¢ Non-M invasive: TURB and IVT ¢ M invasive: as usual but do not consider conservation again
  32. 32. NEOADJUVANT CHEMO¢ Cisplatin-based — MVAC — CMV — Cis-Gem — Cis-adia — Cis-Mtx¢ 3 cycles¢ In T3 (category 1) or T2 (category 2A)
  33. 33. NEOADJUVANT M-VAC CHEMO¢ Grossman et al, N Engl J Med. 2003;349(9):859-66.¢ MVAC x 3 q 28d — Mtx: 30 mg sm d1, 15, 22 — Vinblastine: 3 mg sm d2, 15, 22 — Adrai: 30 mg sm d2 — Cisplatin: 70 mg sm d2¢ T2-T4a¢ Pathological CR: 38%
  34. 34. ADVERSE EVENTS OF MVAC
  35. 35. COMPLICATIONS AFTER SURGERY
  36. 36. Figure 1. Survivalamong PatientsRandomly Assignedto ReceiveMethotrexate,Vinblastine,Doxorubicin, andCisplatin (M-VAC)Followed byCystectomy orCystectomy Alone,According to anIntention-to-TreatAnalysis.
  37. 37. OS in pT0 vs RD
  38. 38. NEOADJ CIS-ADRIA OR CIS-MTX¢ Sherif et al, Eur Urol 2004;45:297–303.¢ Combined analysis of 2 trials¢ Regimens: — Cis 70 mg/sm & A 30 mg/sm q 3w x2 + RT — Cis 100mg/m & Mtx 250mg/sm q3w x 3 NO RT¢ OS HR 0.80 (95% CI 0.64–0.99) in favor of neoadjuvant treatment.¢ 5 Y OS was 56% for neoadjuvant and 48% in the control group,¢ 8% reduction in risk of death.
  39. 39. OS
  40. 40. NEOADJ CMV¢ 967 pts¢ 16% reduction in mortality with NACT
  41. 41. NEOADJUVANT CHEMOTHERAPY FOR TRANSITIONAL CELL CARCINOMA OF THE BLADDER: A SYSTEMATIC REVIEW AND META-ANALYSIS.¢ Winquist et al, J Urol. 2004 Feb;171(2 Pt 1):561-9.¢ 11 trials (2,605 patients)¢ Conducted between 1984 and 2002¢ TCC stages II and III (T2-T4, Nx-N3, M0)¢ Pooled HR of death was 0.90 (95% CI 0.82 to 0.99, p = 0.02).¢ Absolute OS benefit of 6.5% (95% CI 2 to 11%) from 50% to 56.5%¢ PFS benefit consistent with OS benefit¢ CR rates: 14-38%, Major Pathological response: 43%¢ Major pathological response was associated with improved OS in 4 trials
  42. 42. REGIMENS
  43. 43. NEOADJUVANT CHEMO
  44. 44. CONCURRENT CHEMORADIOTHERAPY ¢ Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group.¢ Coppin et al, J Clin Oncol. 1996 Nov;14(11):2901-7.¢ RCT in 99 patients¢ T2 to T4b TCC¢ Randomized to CCRT or RT — (cisplatin 100 mg/m2 at 2-week intervals x 3 cycles concurrent with pelvic radiation), or RT (radiation without chemotherapy)
  45. 45. DESIGN
  46. 46. CCRT VS RT IN TCC OF BLADDER¢ Pelvis relapse significantly lower in CCRT¢ Distant relapse were similar¢ PFS better with CCRT (P 0.08)¢ 3 y OS rates 47% in CCRT and 33% in RT (P0.34)
  47. 47. OS & PFS
  48. 48. ADJUVANT CHEMOTHERAPY¢ Non-urothelial CA — No data in any stage¢ Urothelial CA — Conflicting data — Many trials showing benefit are not randomized — Metaanalysis of 6 trails ¢ 25% mortality reduction ¢ But many limitations ¢ Regimens ¢ GC ¢ MVAC, MVEC ¢ CAP ¢ No. of cycles: at least 3
  49. 49. ADJUVANT CHEMOTERAPY FOR TCC OFBLADDER
  50. 50. CHEMOTHERAPY IN METASTATIC TCC
  51. 51. ADJ RT¢ Dat are scarce¢ Possible role in T3a, T3b, T4a — Due to High recurrence (30% that increase to 60% if SM+)¢ May be given with concurrent cisplatin¢ Adj chemotherapy is also indicated in these cases¢ Adj RT and Adj CT are not give together
  52. 52. BLADDER PRESERVATION¢ Partial cystectomy alone¢ Chemotherapy then partial cystectomy¢ TUR alone¢ TUR followed by — Chemotherapy and radiotherapy (BEST) ¢ Cisplatin w1, 4 +/-8 — Chemo only — Radio only¢ Indications — Urothelial ca — Unfit pts — Refusing pts

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