Role of bladder preserving approach in the treatment of muscle invasive tcc
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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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Role of Bladder -Preserving Approach in The Treatment of Muscle Invasive TCC

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Role of bladder preserving approach in the treatment of muscle invasive tcc

Role of Bladder-Preserving ApproachinThe Treatment of Muscle Invasive TCC


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.


Role of bladder preserving approach in the treatment of muscle invasive tcc

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.


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

TURBT alone

  • control gr

    • 76 patients with invasive pathological stage pT2-3a, N0-3

    • treated by cystectomy.

Solsona; J urol, 1998


Role of bladder preserving approach in the treatment of muscle invasive tcc

Comparison of results between:

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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)


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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).


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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.


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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.


Single institutional trials

Multimodality therapy

Single-Institutional Trials


Role of bladder preserving approach in the treatment of muscle invasive tcc

  • 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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Role of bladder preserving approach in the treatment of muscle invasive tcc

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


Multi institutional trials

Multimodality therapy

Multi-institutional trials


Role of bladder preserving approach in the treatment of muscle invasive tcc

Multimodality therapy Multi-institutional trials


Role of bladder preserving approach in the treatment of muscle invasive tcc

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.


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