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Nonsurgical treatment of bladder cancer

By Gregory Reed,2014-04-26 19:44
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Nonsurgical treatment of bladder cancer

    Dr Graham Macdonald

    Nonsurgical Treatment of Bladder Cancer

Risk factors

cigarette smoking, increasing age, aromatic amine exposure, bladder diverticulum, chronic irritation

    (stones, catheter), cyclophosphamide, phenacetin, Schistosomiasis (esp SCC), familial tendency

    (acetylator status)

Pathology

    ; >90% transitional cell carcinoma

    ; 3-6% squamous cell carcinoma

    ; 1-2% adenocarcinoma

Staging investigations

    IVU, cystoscopy (biopsy/TURBT), EUA, CT/MRI, CXR ?bone scan, ?PET

Cystectomy

    ; Outcome of cystectomy for bladder cancer Swiss study (Madersbacher et al, JCO 21:690 2003)

    507 patients operated on 1985-2000

    median age 66 (35-89)

    5 yr survival related to pathological stage

    T2N0 63%

    T3/4N0 49%

    N1 26%

    ; Cystectomy complications

    peri-operative mortality <5%

    1-month mortality - 3% primary cystectomy

    post-op complication rate

    incontinent diversion 13%

    continent diversion 25%

    local pelvic recurrence <10%

Cystectomy v RT

Pro surgery Pro RT

    Better local control Bladder conservation Effective therapy for multifocal and non-Appropriate to elderly, less fit invasive disease, field change Can encompass extravesical disease Certainty of staging May avoid radical surgery in patients destined to

    Avoids radiation damage to normal tissues die of systemic disease Possibilty of continent neobladder Salvage cystectomy

Cochrane review - cystectomy versus radiotherapy

    Only three randomised trials, none contemporary (1977, 1982, 1991)

; 439 patients randomised to receive preoperative radiotherapy plus cystectomy or radiotherapy

    alone

    ; Five-year survival 36% surgery, 20% radiotherapy

    ; Odds ratio for death at 5 years 1.85 (p<0.05)

    ; Limitations of the review acknowledged

    Radiotherapy outcomes (population database)

    ; Ontario experience 1982-94

    o 21,000 new bladder cancers

    o 1372 patients treated with RT (mostly 60Gy/30#)

    o 5ys 28%

    o 5yr CSS 41%

    o 5yr cystectomy-free survival 25%

    Predictive factors for RT failure include

    ; multifocality or presence of Tis

    ; hydronephrosis

    ; increasing T stage

    ; completeness of TURBT

    ; RT dose <60Gy

    ; poor renal function & anaemia

    SPARE study commenced as a feasibility study of cystectomy versus radiotherapy in fit T2/3N0 TCC of

    bladder in patients who had a complete response to 3 x Gem-Cis neoadjuvant chemotherapy

    ; closed in 2010 due to poor accrual

    Chemoradiation vs radiotherapy

    ; NCIC study of chemo-irradiation for bladder cancer (Coppin et al, 1996, JCO 14:2901-7)

    o T2-T4N0M0 disease

    o elected RT only or pre-cystectomy RT

    o whole pelvis RT 40Gy/20#

    o randomised to RT +/- Cisplatin 100mg/m2 d1,15,29

    o then further 20Gy/10# or cystectomy

    Planned for 160 patients stopped at 102 because of slow accrual (4 years)

    o clinical CR 31% RT alone, 47% RT+CP (p=0.16)

    o pathological CR 40% RT alone, 54% RT+CP

    o 3yr survival 33% RT alone, 47% RT+CP (p=0.34, logrank test)

    o pelvic failure less common with RT+CP

    o distant metastases similar in both arms

; BC2001 study of chemoirradiation in bladder cancer (T2-4a bladder cancer (including

    adenocarcinoma and squamous))

    480 patients (120 per arm) in a 2x2 factorial trial design to compare :

    ; synchronous 5-FU/Mitomycin C with radiotherapy versus radiotherapy alone

    o still in follow up

    ; conventional radiotherapy to whole bladder (sRT standard RT) versus radiotherapy

    to reduced volume (rvRT)

    o 55Gy/20# or 64Gy/32# according to local practice

    o sRT used whole bladder as CTV, with 1.5cm expansion to PTV

    o rvRT tumour (GTV) + 1.5cm margin was treated to 100% target dose and

    remaining bladder received 80% target dose

    o results

    ; no difference in loco-regional disease-free survival (HR = 1.06, 95%

    CI: 0.62-1.84) nor overall survival (HR = 0.99, (0.61 - 1.35)) between

    randomised RT groups

    ; 2yr LRDFS is 71% in both RT groups

    ; bladder capacity fell significantly in sRT group (mean reduction at 12

    mths: 59mls, 95%CI: 47-118mls, p = 0.02) but not in rvRT group

    ; Massachusetts General Hospital data (Shipley and Zeitman)

    ; 190 patients from sequential RTOG trials

    ; agressive TURBT

    ; 40Gy (1.8Gy#) to pelvis with cisplatin

    ; ‘checkpoint’ with cystoscopy and biopsy

    ; CR completion of bladder conserving therapy with further 20-25Gy

    ; cystectomy

    o results

    ; 5yr OS 54%

    o T2 62% (cf 63% in Swiss surgical series)

    o T3/4 47% (cf 49% in Swiss surgical series)

    ; 5yr DFS 63%

    ; 5yr cystectomy free survival 46%

    ; cystectomy rate 34%

    ; pelvic relapse 8.4%

    Complications and functional outcomes after bladder conservation

    ; local recurrences - Zeitman (MGH)

    o 26% had superficial relapse in conserved bladder at a median 2 years follow up o 84% of these managed conservatively

    o (generally <20% relapses are >T1)

    o superficial relapsers had same survival as non relapsers, but reduced cystectomy-free

    survival (61 vs 34%)

    ; RT toxicity

    o Erlangen data - 1.6% cystectomy rate for contracted bladder o Yorkshire data - severe bladder toxicity 6%

     - severe bowel toxicity 2%

    ; Urodynamic outcomes

    ; 24/32 had normal urodynamic study

    ; 7 had reduced compliance

    ; QoL outcomes

    ; 6% flow symptoms

    ; 15% urgency

    ; 19% control problems

    ; >50% of males retained potency

    ; global QoL high (above US age-matched mean)

Neoadjuvant chemotherapy

    ; Grossman et al (NEJM 349, 2003) - trial of cystectomy +/- MVAC neoadjuvantly

    ; 5ys 43% vs 57%

    ; median survival 77 vs 46 months (p=0.06)

    ; pT0 rate of 38%

    ; ABC meta-analysis (Eur Urol, 2005)

    ; 11 RCTs, 3005 patients

    ; HR for death 0.86 (p=0.003) in favour of platinum-combination chemo

    ; 5% absolute survival benefit at 5 years

Adjuvant chemotherapy post-cystectomy

    ; ABC meta-analysis (Eur Urol 2005)

    ; 491 patients, 6 trials, T2-4A

    ; all used cisplatin-based chemo, 5 in combination

    ; collected individual patient data

    ; HR for OS 0.75 (0.60-0.96, p=0.019)

    ; equivalent to 9% improvement in 3ys

    ; with number of patients, only 15% difference could reliably be detected with 80% power

    at 5% level

; EORTC 30994 - the definitive adjuvant study?

    ; 1344 patients, post cystectomy, T3-4 N0 or any T N1-3, M0, TCC

    ; randomised to 4 cycles of adjuvant chemotherapy or chemotherapy on relapse

    ; either MVAC or HD-MVAC or GemCis

Metastatic disease

    MVAC vs GemCis in advanced or metastatic bladder cancer (von der Masse et al)

    Classical MVAC vs GC

    ; 405 patients with T4b or N2-3 or M1 TCC

    ; KPS at least 70%

    ; Response rate 46% vs 49%

    ; Response duration 11.0 vs 9.6 months

    ; Median survival 14.8 vs 13.8 months

    ; Toxic deaths 3% vs 1%; Neutropenia fever 14% vs 2%

LaMB study is a current NCRN study randomising patients to placebo or lapatinib in Her1 or Her2+ve

    TCC after at least 4 cycles of palliative chemotherapy with no evidence of progression

Palliative RT for bladder cancer

    ; MRC Trial BA09

    o 500 patients with muscle-invasive bladder Ca unsuitable for radical therapy (too frail 321,

    too advanced 179)

    o 21Gy/3#/1w v 35Gy/10#/2w

    o symptom improvement in 64% v 71% (no difference)

    o median time to symptom progression 9 months; Survival equivalent in the 2 arms

    o median 7.5 months, 35% 1 year, 19% 2 years

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