Role of Bladder-Preserving Approach in The Treatment of Muscle Invasive TCC

Role of Bladder-Preserving Approach

inThe 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

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

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.

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.

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.

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.

Introduction

•(220 pt Amling, J urol, 1994)

Treatment Options

• Radical Cystectomy

• TURBT or Partial cystectomy alone

• Radical TUR + Systemic chemo

• Radiation: Interstitial or External Beam

• Multimodality therapy

Introduction

Treatment Options






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.

Feneley, Sem in Uro Onco, 2000

How this idea came How this idea came up as a treatment up as a treatment

option?option?

TURBT alone

• 10-17% of post TURBT cystectomies showed pT0.

• TCC frequently affect elderly

Technique

• Radical TUR– Tumor resection to cancer-free margin, requires

complete resection of all macroscopic tumor through the bladder wall to extravesical connective tissue.


TURBT alone

Concerns:

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

Laufer, Sem in Uro Onco, 2000

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%)

Kolozsy, Br J Urol, 1991

TURBT alone

This can be solved by This can be solved by selection criteriaselection criteria

• 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

TURBT aloneStudyStudy

• control gr – 76 patients with invasive pathological stage

pT2-3a, N0-3 – treated by cystectomy.

Solsona; J urol, 1998

TURBT alone

Comparison of results between:

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

Comparison of results between:

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

Superficial bl or upper tractSuperficial bl or upper tractOr prostatic mucosaOr prostatic mucosa

Or CIS requiring Or CIS requiring cystectomycystectomy

•Progression was concentrated in Progression was concentrated in the first 3 years (75.6%). the first 3 years (75.6%).

•In 3 patients disease progressed at In 3 patients disease progressed at > 5 years (65, 71 & 92 mo)> 5 years (65, 71 & 92 mo)

•None in f/u of > 10 yrsNone in f/u of > 10 yrs..

In more detailsIn more details

35 (26.3%)

37 (27.8%)

18 (30.5%)

20 (34%)

Followup of entire seriesFollowup of entire series

FollowupFollowup

• 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 & free44.4% alive & free•36% died free from dis36% died free from dis

•23.7% alive & free23.7% alive & free•50.8% died free from dis50.8% died free from dis

TURBT alone

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

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

• 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

Another StudyAnother Study

TURBT alone

Exclusion Criteria>T2b>T2bWide spread CISWide spread CIS

Multiple TCCMultiple TCC

>3 cm >3 cm

+ve TCC at the tumor’s bed on 2+ve TCC at the tumor’s bed on 2ndnd TUR TUR


TURBT alone

Exclusion Criteria>T2b>T2bWide spread CISWide spread CIS

Multiple TCCMultiple TCC

>3 cm >3 cm

+ve TCC at the tumor’s bed on 2+ve TCC at the tumor’s bed on 2ndnd TUR TUR


TURBT alone

Other studies reported Other studies reported less favorable outcome less favorable outcome But didn’t follow rigid selection criteria.But didn’t follow rigid selection criteria.

Other studies reported Other studies reported less favorable outcome less favorable outcome But didn’t follow rigid selection criteria.But didn’t follow rigid selection criteria.

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


TURBT alone

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%


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

Partial Cystectomy

OutcomeLocal recurrence rate: 38-78%

Partial Cystectomy

Sweeny, uro clin, 1992

Outcome

• In a review of series from the last 40 yrs:

• 5 yrs survival:– T2 30- 100%– T3a 16- 88%– T3b 0 - 45%


Partial Cystectomy


20 TCC20 TCC5 T2a, 18T2b, 9 T35 T2a, 18T2b, 9 T3

More to the higher More to the higher

Overall actuarial survial = 80.1% Overall actuarial survial = 80.1% at 5 yrsat 5 yrs

Barrilero, Actas Urol Esp - 1997•45 45 pts T2 or higher,pts T2 or higher,

•f/u = 9-258 mof/u = 9-258 mo

•Partial cystectomy alone.Partial cystectomy alone.

•21 21 cases showed bladder relapsecases showed bladder relapse

•Survival even betterSurvival even better

•But this is a highly selected gr

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

Analysis of 300 cystectomies in the Univ of California LA

The results looks the sameThe results looks the same

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


Partial Cystectomy

Final Comments

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


• No properly designed study have determine long-term result of partial.

• It should be limited to pt w CI to Radical.

Partial Cystectomy

Treatment Options



• Radical TUR + Systemic chemoRadical TUR + Systemic chemo



Introduction

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.

• 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


StudyStudy

Robert, Clinical Mgt of Bl CA, 1999

• 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



• 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



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



• 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 The results in this selected population selected population

compare favorably w compare favorably w conventional trtconventional trt



• 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



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 Options




• Radiation: Interstitial or External BeamRadiation: Interstitial or External Beam


Introduction

• 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 Therapy

Radiation Therapy

• In Rotterdam:– Initially, Radium needles– Later, cesium-containing needles.

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

Radiation Therapy

IRT

• Almost exclusively in Europe.

• Only 2 small series published in USA.

Radiation Therapy

• Criteria of IRT:– Solitary– <5cm– No LN or distal metz– Pt condition should permit surgery

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

• 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:

• 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%,

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.

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.

EBRT + IRT


• Conditions for good results are:– careful selection of patients w ms invasion, – excellent cooperation between

• urologist

• radiation oncologist

• modern brachytherapy facilities.

In Conclusion:

Treatment Options





• Multimodality therapyMultimodality therapy

Introduction

Multimodality therapy

• 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.

(chemotherapy in conjunction w radiation)

Single-Institutional Trials


Published in 1993 & updated in 1997Published in 1993 & updated in 1997Non random. Non random. T2-4 Nx MoT2-4 Nx MoTUR>NACx2>RT/Cis>repeat cytology, cysto, BxTUR>NACx2>RT/Cis>repeat cytology, cysto, Bx

If –ve continue RT/CTIf –ve continue RT/CTIf +ve Radical cystoIf +ve Radical cysto

•57/76 (75%) had bl free of tu w median f/u of 64 mo.57/76 (75%) had bl free of tu w median f/u of 64 mo.•The 5yr freedom from invasive recurrent among all pts The 5yr freedom from invasive recurrent among all pts was 79%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

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

86%3 metz on each arm3 metz on each arm

No sig diff

• 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

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 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

91 pts T2-4x2 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 Tester, J clin Onco,1996Onco,1996

NCI of Canada (Dr. Coppin in BC)NCI of Canada (Dr. Coppin in BC)99 pts T2- T499 pts T2- T4

Coppin, J clin Onco,1996Coppin, J clin Onco,1996

Multimodality therapy Multi-institutional trials

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%

In 10 trials of CT/RT

Therman, Sem Uro Onc, 2000


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

• 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.

• 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 Summery

General Summery

• With the diversity of opinions in the management, options need to be discussed with patients.

Documents

Role of Bladder-Preserving Approach in The Treatment of Muscle Invasive TCC