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Role of Bladder -Preserving Approach in The Treatment of Muscle Invasive TCC. Introduction. Bladder cancer is a serious threat to life. TCC is the most common bladder tumor. For the yr 2000 (in US): 53,200 new cases 12,200 deaths. Introduction. TCC at the initial presentation.

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introduction
Introduction

Bladder cancer is a serious threat to life.

TCC is the most common bladder tumor.

For the yr 2000 (in US):

53,200 new cases

12,200 deaths

tcc at the initial presentation

Introduction

TCC at the initial presentation.
  • 70% of TCC are superficial
    • Tumor recurrence is 50-70%
      • 10-30% of those will progress to invasive disease.
  • 30% of TCC are muscle invasive
    • More than ½ of them expected to develop metz

= 12,000 death/yr in the US

= 50 –100 / 1,000,000

treatment of invasive tcc

Introduction

Treatment of invasive TCC
  • Aggressive therapy is warranted to control the disease.
  • This shouldn’t obscure the need for reasonable quality of life.
  • In North America, main local management of muscle-invasive TCC remains radical cystectomy with urinary diversion.
slide5

Introduction

  • This approach is undergoing transition.
  • Organ-preserving approaches have been successfully applied to the management of several types of cancer
  • Clearly play an important role in the management of ms invasive TCC.
slide6

Introduction

  • Ideally, trt of invasive TCC aims to:
    • Eliminate the primary tumor.
    • Assure long term survival & quality of life.
    • Maintain normally functioning bladder.
  • In elderly or pts likely to die of other causes local control may be all what is needed.
  • So, reaching those goals & preserving the bladder may appear to be attractive option.
    • In minimal surgery, post op complications can be limited.
cystectomy its price for a gold stander

Introduction

Cystectomy & its Price for a Gold Stander
  • Major operation
  • Complication
    • Acknowledged mortality(although low).
      • 2.3%
    • 10-15% overall complication rate
    • Higher (20-30%) for orthotopic reconstruction.
  • (220 pt Amling, J urol, 1994)
treatment options

Introduction

Treatment Options
  • Radical Cystectomy
  • TURBT or Partial cystectomy alone
  • Radical TUR + Systemic chemo
  • Radiation: Interstitial or External Beam
  • Multimodality therapy
treatment options1
Treatment Options
  • Radical Cystectomy
  • TURBT or Partial cystectomy alone
  • Radical TUR + Systemic chemo
  • Radiation: Interstitial or External Beam
  • Multimodality therapy
turbt alone
TURBT alone
  • The main use today of TURBT alone, in muscle invasion, is mainly in its diagnostic role.
  • It’s use in trt carries the concerns of recurrence & progression.
  • Nevertheless, several studies showed that in selected pts TUR could have therapeutic value.

How this idea came up as a treatment option?

Feneley, Sem in Uro Onco, 2000

turbt alone1
TURBT alone
  • 10-17% of post TURBT cystectomies showed pT0.
  • TCC frequently affect elderly
technique

TURBT alone

Technique
  • Radical TUR
    • Tumor resection to cancer-free margin, requires complete resection of all macroscopic tumor through the bladder wall to extravesical connective tissue.

Feneley, Sem in Uro Onco, 2000

concerns

TURBT alone

Concerns:
  • Feasibility to:
    • Adequately staged
    • Adequately resection of the tu
    • Field changes

Laufer, Sem in Uro Onco, 2000

limitations

TURBT alone

Limitations:
  • In 662 TURs, systematic bx were done from the base, sides & adjacent margins
    • 35% (232) showed residual tu
    • 84% (195) were invasive

Residual noted in solid (76%) > papillary (21.5%)

This can be solved by selection criteria

Kolozsy, Br J Urol, 1991

slide15

TURBT alone

Study

  • 133 pts
    • w invasive TCC bladder
    • treated by radical TUR
    • who had (–ve) bx of the ms layer of the tumor bed.
  • F/U

> 5 years for all subjects

> 10 years 44.4%

Solsona; J urol, 1998

slide16

TURBT alone

  • control gr
    • 76 patients with invasive pathological stage pT2-3a, N0-3
    • treated by cystectomy.

Solsona; J urol, 1998

slide17

Comparison of results between:

gr 1 (59 pts f/u > 10 yrs) and gr 2 (74 pts f/u > 5 yrs)

slide18

Superficial bl or upper tract

Or prostatic mucosa

Or CIS requiring cystectomy

  • Progression was concentrated in the first 3 years (75.6%).
  • In 3 patients disease progressed at > 5 years (65, 71 & 92 mo)
  • None in f/u of > 10 yrs.

Comparison of results between:

gr 1 (59 pts f/u > 10 yrs) and gr 2 (74 pts f/u > 5 yrs)

slide19

35 (26.3%)

18 (30.5%)

37 (27.8%)

20 (34%)

Followup of entire series

  • In more details
followup

TURBT alone

Followup
  • At 5 & 10 yrs of f/u
    • cause specific survival rates were 80.5 and 74.5%,
    • bl preservation rates were 82.7 and 79.6%,
  • 44.4% alive & free
  • 36% died free from dis
  • 23.7% alive & free
  • 50.8% died free from dis
slide21

No significant difference in cause specific survival, with the control group

Comparison of cause specific survival of all patients (cT2-3a, N0) and controls (pT2-3a, N0-3).

slide22

TURBT alone

Another Study

  • 217 pt
    • 79% not candidate for TUR, but for radical or partial
    • 21% (45 pt) TUR candidate.
      • F/U for median of 5.1 yrs
      • Overall survival = 82% (37/45 pt)
      • 67% (30/45 pt) w functioning Bl
        • 9 free
        • 21 required repeated superficial TUR w or w/o BCG

Herr; urol clinic, 1992

exclusion criteria

TURBT alone

Exclusion Criteria

>T2b

Wide spread CIS

Multiple TCC

>3 cm

+ve TCC at the tumor’s bed on 2nd TUR

Herr; urol clinic, 1992

exclusion criteria1

TURBT alone

Exclusion Criteria

Other studies reported

less favorable outcome

But didn’t follow rigid selection criteria.

>T2b

Wide spread CIS

Multiple TCC

>3 cm

+ve TCC at the tumor’s bed on 2nd TUR

Herr; urol clinic, 1992

final comments

TURBT alone

Final Comments:
  • No randomized trials comparing it w other options like Radical or multi modality.
  • In view of the tolerability of current radiation +/- chemo, the role fro TUR alone diminished.
  • Probably useful in selected case w:

small T2,

+ elderly pt

+ Not candidate for Radiation +/- chemo

Laufer, Sem in Uro Onco, 2000

partial cystectomy
Partial Cystectomy
  • Advantages
    • full-thickness resection
    • adequate margins.
    • LN sampling
    • Resect inaccessible tu through TUR
      • In diverticulum, dome, over ureteral orifice.
  • Drawback
    • Risk of intravesical recurrence
    • Risk of extravesical recurrence
      • decline in more contemporary series to 0%

Laufer, Sem in Uro Onco, 2000

selection criteria

Partial Cystectomy

Selection Criteria
  • Solitary
  • Location (usually upper ½, or 5cm)
    • Amenable to complete resection w free margins
  • Absence of CIS
  • Size
    • Should allow complete resection w/o affecting bl. function.
    • No > 50% should be removed

Dandekar, J Surg Oncol, 1995

outcome

Partial Cystectomy

Outcome

Local recurrence rate: 38-78%

Sweeny, uro clin, 1992

outcome1

Partial Cystectomy

Outcome

Laufer, Sem in Uro Onco, 2000

  • In a review of series from the last 40 yrs:
  • 5 yrs survival:
    • T230- 100%
    • T3a 16- 88%
    • T3b 0 - 45%
  • Dandekar, J Surg Oncol, 1995
  • 20 TCC
    • 5 T2a, 18T2b, 9 T3
  • More to the higher
  • Overall actuarial survial = 80.1% at 5 yrs
  • Barrilero, Actas Urol Esp - 1997
  • 45 pts T2 or higher,
  • f/u = 9-258 mo
  • Partial cystectomy alone.
  • 21 cases showed bladder relapse
  • Survival even better
  • But this is a highly selected gr
slide30

Analysis of 300 cystectomies in the Univ of California LA

The results looks the same

Overall survival (Surv) of patients treated w cystectomy for bladder cancer stratified by pathological stage

Those with N0 stratified by pathological stage.

DALBAGNI, J OF UROL, 2001

final comments1

Partial Cystectomy

Final Comments
  • It should be noted that
    • Rigid pt selection  good long-term result w partial cystectomy alone,
    • Only suitable for 10% of the pt

Dandekar, J Surg Oncol, 1995

final comments2
No randomized trials comparing partial w Radical or multimodal bladder-preserving options.

Partial Cystectomy

Final Comments

Laufer, Sem in Uro Onco, 2000

  • No properly designed study have determine long-term result of partial.
  • It should be limited to pt w CI to Radical.
treatment options2

Introduction

Treatment Options
  • Radical Cystectomy
  • TURBT or Partial cystectomy alone
  • Radical TUR + Systemic chemo
  • Radiation: Interstitial or External Beam
  • Multimodality therapy
radical tur systemic chemo
Radical TUR + Systemic Chemo
  • Rationale
    • Experience with systemic chemo indicate some improvement of the local control.
  • In 1982,
    • Socquet reported a favorable result in 25 pt using Methotrexate w folinic a. post partial cystec. for T3a.
slide35

Radical TUR + Systemic Chemo

Study

  • Collaborative N. of England gr.
  • treated 61 pts w T2/3 but used:
    • Radical TUR
    • X4 chemo (Methotrexate)
    • Repeated cysto/ TUR
    • If tu persist  conventional trt

Robert, Clinical Mgt of Bl CA, 1999

slide36

Radical TUR + Systemic Chemo

  • Of the 61 pts:
    • 17 (28%) had persistent tu
    • 15 (25%) developed recurrent invasive tu
      • at median of 18 mo
      • Treated by radical cysto or radiation
    • 15 (25%) recurrent superficial tu
  • Overall 29/61 (48%) remain free of invasive tu

Robert, Clinical Mgt of Bl CA, 1999

slide37

Radical TUR + Systemic Chemo

  • This same gr (Collaborative N. of England gr) added cisplatin to methotrexate (55 pts) and the whole population of 116 pt published recently:
  • Median f/u 11.6 yrs (4-15yrs)
    • 13 yrs for the old gr of methotrexate + folinic a
    • 8 yrs for the combination gr

Robert, Clinical Mgt of Bl CA, 1999

slide38

Radical TUR + Systemic Chemo

  • Most tu were < 5 cm
  • Only 13% were T2 (the rest were higher)
  • Random bx were not taken
    • ?CIS status is not known
    • 17 pt in the combination gr had adjacent CIS
  • Most pts in this series had G3 (78.4%)

With all these potential –ve factors, what was the outcome?

Robert, Clinical Mgt of Bl CA, 1999

slide39

Radical TUR + Systemic Chemo

  • The actuarial disease-specific survival
  • For the 1st gr
    • 2, 5, 10 yrs
    • 69%, 39%, 33%
  • For the 2nd gr
    • 82%, 70%, 61%
  • Only 28% of pts w combination trt required cystectomy or radiotherapy

The results in this selected population compare favorably w conventional trt

Robert, Clinical Mgt of Bl CA, 1999

slide40

Radical TUR + Systemic Chemo

  • Similarly good results reproduced in other centers in Europe
    • Many published in BJU from 1991-1997
    • They also used MVAC, CMV, 5FU,
  • In the MSKCC tried neoadj MVAC in 32 pt w 75% preserving their bladder in a median f/u of 19 months

Feneley, Sem in Uro Onco, 2000

in conclusion

Radical TUR + Systemic Chemo

In conclusion
  • The results discussed of the combination chemo + conservative surgery suggest that the approach should be tested in a randomized comparison w more conventional approaches
treatment options3

Introduction

Treatment Options
  • Radical Cystectomy
  • TURBT or Partial cystectomy alone
  • Radical TUR + Systemic chemo
  • Radiation: Interstitial or External Beam
  • Multimodality therapy
radiation therapy
Radiation Therapy
  • In several European centers, the combination of external beam and interstitial radiotherapy is standard trt in a selected group w muscle-infiltrating TCC.

Wijnmaalen, Sem in Uro Onco, 2000

radiation therapy1
Radiation Therapy
  • In Rotterdam:
    • Initially, Radium needles
    • Later, cesium-containing needles.
interstitial radiation

Radiation Therapy

Interstitial radiation
  • Advantages:
    • High local dose to the tu in short time.
    • Less toxicity to the surrounding tissue.
  • Never became widely used due to:
    • Modern technique of Ex Beam RT.
    • Advancement of anesthesia & surgery time.
  • But in several European ctrs IRT
    • further developed &
    • remain the standerd for selected pts

Wijnmaalen, Sem in Uro Onco, 2000

slide46

Radiation Therapy

IRT
  • Almost exclusively in Europe.
  • Only 2 small series published in USA.
  • Criteria of IRT:
    • Solitary
    • <5cm
    • No LN or distal metz
    • Pt condition should permit surgery
radiation therapy2
Radiation Therapy

Afterload:

  • The afterload technique 1st reported in 1969.
  • Adopted in 1989 in France
  • Radio active material is introduced post op
  • Less exposure to the personnel
steps of the combination ebrt irt
Steps of the combination EBRT + IRT
  • TUR or partial
  • Low EBRT (11 Gy) + high IRT (50 Gy)
  • Or high EBRT (30-40 Gy) + high IRT (30 Gy)

Wijnmaalen, Sem Uro Onc, 2000

results

EBRT + IRT

Results:
  • Summery of six published studies;
  • 5 yrs of:
    • Local control= 64- 88%
      • Relapse rate 11-36%
    • Distant metz 14-24%
    • Actuarial overall survival= 47-66%
    • Disease-free survival= 62%-81%,

Wijnmaalen, Sem Uro Onc, 2000

results1

EBRT + IRT

Results
  • MR= 1.5-3%
  • Wound complication were not uncommon
    • Generally resolved by conservative mgt.
  • Necrosis at the area of the tu in 14-20%
    • Causes no complaints in most pts
    • Transient.
  • Ureteral stenosis was reported by some.

Wijnmaalen, Sem Uro Onc, 2000

in conclusion1

EBRT + IRT

In Conclusion:
  • The approach of combining EBRT + IRT is successful in preserving the normal bladder.
  • The risk of bladder relapse appears to be higher in pt started the RT after recurrent disease.

Wijnmaalen, Sem Uro Onc, 2000

in conclusion2
In Conclusion:
  • Conditions for good results are:
    • careful selection of patients w ms invasion,
    • excellent cooperation between
      • urologist
      • radiation oncologist
      • modern brachytherapy facilities.
treatment options4

Introduction

Treatment Options
  • Radical Cystectomy
  • TURBT or Partial cystectomy alone
  • Radical TUR + Systemic chemo
  • Radiation: Interstitial or External Beam
  • Multimodality therapy
multimodality therapy
Multimodality therapy

(chemotherapy in conjunction w radiation)

  • Since the 1980s, several single and multi-institutional trials were done on the combined modality organ-preserving approach.
  • Limitation of these series:
    • Not consistently use the same dose of chemo/RT
    • Not the same sequence of RT/CT
    • However, they do argue strongly for further Ix.
slide57

Published in 1993 & updated in 1997

  • Non random.
  • T2-4 Nx Mo
  • TUR>NACx2>RT/Cis>repeat cytology, cysto, Bx
    • If –ve continue RT/CT
    • If +ve Radical cysto
  • 57/76 (75%) had bl free of tu w median f/u of 64 mo.
  • The 5yr freedom from invasive recurrent among all pts was 79%
  • Few important points:
    • Combination TUR/RT/CT even when unsuccessful didn’t compromise overall survival
    • T2 : better outcome
    • Complete TUR > incomplete: Hydro did < w/o
slide58

86%

3 metz on each arm

  • 1988-1991, 54 pts T2-4
  • Altered CT/RT dose/fraction to increase tu kill w/o inc in SE
    • Intermittent CT 1,2,3,15,16 & 17
    • BID RT(3 Gy) 1,3,15 & 17
  • At 6 wks repeat cyst & Bx
  • If CR :either Cystectomy or RT/CT x 2 wks
  • If PR : cystectomy

No sig diff

slide59

Multimodality therapy: Single-Institutional Trials

  • RTOG gr
    • Following the same protocol
    • 34 pt T2-T4a
    • 26 visible complete TUR
    • 65% (22pts)= no tu detected on repeated cysto
    • 35% (11pts)= detected tu

6pts cystec+5 RT

Shipley, Int J Rad Onc Bio Phys, 1999

rtog gr

Multimodality therapy: Single-Institutional Trials

RTOG gr
  • 11/27 ( w conserved bl) had local relapse
  • 3/11 required cystectomy for invasive
  • At 2 yrs
    • 71% alive w intact bl
    • Actuarial over all survival 87%
  • Encouraging, but require longer f/u.

Shipley, Int J Rad Onc Bio Phys, 1999

in conclusion3

Multimodality therapy: Single-Institutional Trials

In conclusion
  • Other studies w longer f/u data support the role of bl preserving therapy.
  • Alternate regimen can provide results= standard
  • Important Q:
    • Which chemo most appropriate?
      • Taxol: signif activity as single & in combination.
      • Gemcitabine: reasonable activity & radiosensitizing.

Thurman, Sem Uro Onc, 2000

slide64

Multimodality therapy Multi-institutional trials

  • NCI of Canada (Dr. Coppin in BC)
  • 99 pts T2- T4
  • Coppin, J clin Onco,1996
  • 91 pts T2-4
  • x2 MCV regimen>RT 40 Gy/cis>85 underwent complete urologic evaluation
  • 68 (75%) CR
  • 14 operable patients with residual tumor underwent immediate cystectomy.
  • Of 70 patients treated with consolidation cis/RT:
    • 23 invasive had salvage cystectomy /36 bladder recurrences,
    • = total of 37 of 91 patients (40%) required cystectomy.
  • The 4-year:
  • cumulative risk of invasive local failure was 43%
  • actuarial risk of distant metastasis was 22%
  • actuarial survival rate of the entire group was 62%
  • actuarial rate of survival with bladder intact was 44%
          • Tester, J clin Onco,1996
side effects

Multimodality therapy

In 10 trials of CT/RT

Side Effects
  • Acute:
    • 40-70% N/V/D, neutropenia, fatigue
  • MR 1.1% (9/807)
  • 1% required cystectomy for sever bl pain or dysfunction
  • GU symptoms: 0-15%

Therman, Sem Uro Onc, 2000

in summery
In Summery
  • Multimodality consistently confers equivalent overall survival, in selected patients, compared with survival following radical cystectomy.
  • These trials are very encouraging and allow organ preservation to be considered an appropriate therapeutic option for selected patients with muscle-invasive bladder cancer.
general summery
General Summery
  • The role of neoadjuvant chemo is not clear.
    • Requires further study
  • It is not clear which drug or combination of drugs is the most efficacious?
  • The results hypofractionation of RT/CT are provocative. ? long f/u
  • Molecular & cellular biomarkers may in the future improve the Dx & the delivery of individualized therapies.
general summery1
General Summery
  • Bladder-preserving strategies have been shown to be feasible w encourging results in selected pts w muscle invasive, organ-confined bladder CA.
  • With careful f/u cystectomy is not delayed in pt w truly local failures.
general summery2
General Summery
  • With the diversity of opinions in the management, options need to be discussed with patients.
ad