Bladder preservation in muscle invasive disease

Nick James

University of Warwick and University Hospitals Birmingham

@Prof_Nick_James

#NJBladderCancer

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Chemoradiation vs radiotherapy alone

Synchronous Chemo-radiotherapy

Numerous phase I/II studies showing feasibility and safetyThree phase III studiesRT vs RT + Cisplatinum (NCIC)RT vs RT + nicotinamide/carbogen (BCON)RT vs RT + 5FU/MMC (BC2001)

BC2001: Trial design

Reduced high

dose volume RT

+ synchronous chemotherapy

Reduced high

dose volume RT

Standard volume RT

+ synchronous chemotherapy

Standard volume RT

Patients with muscle invasive bladder cancer

RANDOMISE

Pragmatic design: Centres could offer double or either single randomisation

CT

No CT

sRT

RHDV RT

Chemotherapy regimen

Target volume tumour + bladder + 1.5-2cm

Chemotherapy via peripherally inserted central

line as outpatient therapy

5FU 500mg/m2/d

MMC 12mg/m2

0 1 2 3 4 5 6 7

Weeks

RT 55 Gy/20 f or

64 Gy/32 f

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Patient demographics

Mean (SD) 70.5 (8.2) yearsMedian (IQR) 71.9 (64.1 - 76.2) yearsOlder than patients in previously published trials including SWOG 87101(median 63 y) and BA062 (median 64 y)

Performance status

Male = 289/360 (80%)

Age at randomisation

Grossman et al NEJM 2003 Volume 349:859-866 Lancet 1999; 354: 533-40

Acute toxicity

Proportions with a grade 3/4 at any time on treatment: 62/179 (34.6%) CT vs. 49/172 (28.5%) No CT (% of pts with data) Stratified Chi-square test p=0.19

Worst grade of on-treatment toxicity by week

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Toxicity: stratified chi-square (grade 0-2 vs. 3-4)

1% significance level to account for multiple testing

Includes tox blood counts, not liver, bilirubin and creatinine

Chart5111112222233333444445555566666777771111122222333334444455555666667777701234CT No CT% of non-missingRT 64Gy/32F0.19811320750.48113207550.21698113210.103773584900.10377358490.48113207550.30188679250.113207547200.04629629630.51851851850.2870370370.12962962960.01851851850.02777777780.49074074070.33333333330.13888888890.00925925930.01886792450.45283018870.33018867920.18867924530.00943396230.05660377360.40566037740.3207547170.18867924530.02830188680.050.370.360.190.030.31683168320.41584158420.14851485150.0990099010.01980198020.20588235290.42156862750.22549019610.12745098040.01960784310.12621359220.47572815530.26213592230.10679611650.02912621360.10784313730.47058823530.30392156860.08823529410.02941176470.1456310680.39805825240.27184466020.1456310680.03883495150.09803921570.48039215690.23529411760.14705882350.03921568630.17346938780.39795918370.24489795920.14285714290.0408163265OverallPercentweekctrandcount0count1count2count3count4Total non-missingweekctrand012341CT398834161771CT22.0%49.7%19.2%9.0%0.0%2CT168754191762CT9.1%49.4%30.7%10.8%0.0%3CT878692221793CT4.5%43.6%38.5%12.3%1.1%4CT677643111794CT3.4%43.0%35.8%17.3%0.6%5CT248362011075CT1.9%44.9%33.6%18.7%0.9%6CT643342131076CT5.6%40.2%31.8%19.6%2.8%7CT537361931007CT5.0%37.0%36.0%19.0%3.0%1No CT6065251431672No CT3970411821701No CT35.9%38.9%15.0%8.4%1.8%3No CT2475501931712No CT22.9%41.2%24.1%10.6%1.2%4No CT1676561831693No CT14.0%43.9%29.2%11.1%1.8%5No CT1641281541044No CT9.5%45.0%33.1%10.7%1.8%6No CT1149241541035No CT15.4%39.4%26.9%14.4%3.8%7No CT183924144996No CT10.7%47.6%23.3%14.6%3.9%7No CT18.2%39.4%24.2%14.1%4.0%Overall01234CT No CT% of non-missingWorst on-treatment toxicity by week64gy32FPercentweekctrandcount0count1count2count3count4Total non-missingweekctrand012341CT215123111061CT19.8%48.1%21.7%10.4%0.0%2CT115132121062CT10.4%48.1%30.2%11.3%0.0%3CT556311421083CT4.6%51.9%28.7%13.0%1.9%4CT353361511084CT2.8%49.1%33.3%13.9%0.9%5CT248352011065CT1.9%45.3%33.0%18.9%0.9%6CT643342031066CT5.7%40.6%32.1%18.9%2.8%7CT537361931007CT5.0%37.0%36.0%19.0%3.0%1No CT3242151021012No CT2143231321021No CT31.7%41.6%14.9%9.9%2.0%3No CT1349271131032No CT20.6%42.2%22.5%12.7%2.0%4No CT114831931023No CT12.6%47.6%26.2%10.7%2.9%5No CT1541281541034No CT10.8%47.1%30.4%8.8%2.9%6No CT1049241541025No CT14.6%39.8%27.2%14.6%3.9%7No CT173924144986No CT9.8%48.0%23.5%14.7%3.9%7No CT17.3%39.8%24.5%14.3%4.1%64gy32F01234CT No CT% of non-missingRT 64Gy/32F55gy20FPercentweekctrandcount0count1count2count3count4Total non-missingweekctrand012341CT1837115711CT25.4%52.1%15.5%7.0%0.0%2CT536227702CT7.1%51.4%31.4%10.0%0.0%3CT322388713CT4.2%31.0%53.5%11.3%0.0%4CT3242816714CT4.2%33.8%39.4%22.5%0.0%1No CT28231041662No CT1827185681No CT42.4%34.8%15.2%6.1%1.5%3No CT1126238682No CT26.5%39.7%26.5%7.4%0.0%4No CT528259673No CT16.2%38.2%33.8%11.8%0.0%4No CT7.5%41.8%37.3%13.4%0.0%weekctrandcount0count1count2count3count41CT18371152CT5362273CT3223884CT32428161No CT282310412No CT18271853No CT11262384No CT52825955gy20F01234CT No CT% of non-missingRT 55Gy/20F

RTOG 6 month toxicity outcomes

n= 291, 145 RT only, 146 chemo-radiotherapy

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Loco-regional disease free survival in chemotherapy randomisation

Loco-regional control

(invasive and non-invasive)

Invasive loco-regional control

James et al, Radiotherapy with or without chemotherapy for invasive bladder cancer.

NEJM 2012 366, 1477-1488

EGFR

Overexpression correlates with poor prognosisSome evidence RT responses worse in EGFR+ tumoursIn vitro, EGFR targeting radio-sensitises

Cetuximab

IgG1 Mab targeting the EGFRProven role as radiosensistiser in head and neck cancerTargets immune cells to the tumourPossible anti-angiogenic role

TUXEDO

Multi-stage trialPhase I: can we combine Cetximab with chemo-RT?Phase IIa single arm: expanded safety and efficacy with phase I regimenPhase IIb: randomise ChemoRT vs. CRT+ Cetuximab

TUXEDO

Multi-stage trialPhase I: can we combine Cetximab with chemo-RT?Phase IIa single arm: expanded safety and efficacy with phase I regimenPhase IIb: randomise ChemoRT vs. CRT+ Cetuximab

Phase I regimen

Phase 1 patients

No. of patients7Sex7 male, 0 femaleMedian age70 yrs (range 60-75)Tumour stageT2a: 2; T2b: 2; T3b: 3Reduced dosage1 pt had reduced dosage of cetuximab (missed wks 3 and 4 of treatment due to skin toxicity)Withdrawals1 pt withdrew from RT due to relocationDose intensity:CetuximabMitomycin C5-FU99%98.3%100%

Phase 1 toxicity

TUXEDO summary

7/7 phase 1 pts had CR at 3mDelivery of core chemoRT excellentDelivery of cetuximab near 100%Protocol amended to make neoAd chemo optionalDMC approved progression to phase IIa Open to new centres

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