Urological Surgery Trials: the good, the bad and the ugly Mr Grant D - PowerPoint PPT Presentation

Urological Surgery Trials: the good, the bad and the ugly Mr Grant D Stewart BSc, MBChB, FRCSEd (Urol), PhD Chair of Renal Cancer CSG Surgical Subgroup University Lecturer and Consultant in Urological Surgery, Academic Urology Group, University of Cambridge Better Trials Make Better Surgeons – 17 th June 2016

Urological surgery • Changes often happen in leaps (robotics), we need to be well positioned to evaluate • Only one in eight studies published in a major urologic journal provides high-level evidence (1 or 2) • Bulk of our practice is based on limited information from retrospective case series Borawski. J Urol 2007;178:1429–33.

95% of surgical consultants have never randomised a patient into a trial

Professor Richard Shaw Associate Director NIHR Clinical Research Network (Cancer) National Specialty Lead for Surgical Oncology

Molecular biology PhD issue

21% surgical trials are discontinued… • 1 in 5 surgical randomised controlled trials was stopped early and 1 in 3 completed trials did not publish • Commonest reason for discontinuation is poor recruitment (usually identified rapidly after opening) • Futility (i.e. new conclusive data emerges) • Clinically irrelevant questions, comparisons and outcomes • Biases from previous eras (i.e. immunotherapy/CNx in mRCC) Chapman BMJ 2014; 340: g6870

RENAL CSG PORTFOLIO MAP NCRI Renal Cancer Portfolio 3 rd line 2 nd line 1 st line Non- Adjuvant Surgery Neoadjuvant Tumour Type Interventional Metastatic Metastatic Metastatic C P C A C P C A D Photodynamic EORTC 30073 - SURAB NCRN544 therapyT1a ** SURTIME : CSG-developed Physical O A D A activity rehab for Cancer Survivors STAR C P C A EORTC 30073 - SURTIME SCOTRRCC C A O A Genetics of CREATE papillary EORTC 90101 C kidney cancer : CSG-consulted D P A-PREDICT** Clear cell D A DIRECTS O : Other C P PaZ02 * involves multiple tumour types C A ** Involves tissue collection NCRN2888 A : Academically-sponsored C A NCRN396 VE Basket RENAL CANCER P : Academic/Industry Partnership C A SURAB C A O A Physical activity rehab Photodynamic for Cancer therapy T1a ** Survivors O I C A Non-clear cell NCRN2888 SCOTRRCC CLEAR=MULTI-CSG STUDY; DASHED BORDER -IN SET-UP O I NCRN396 VE Basket I : Industry-sponsored PURPLE=IN SET-UP/FUNDED YELLOW=OPEN/RECRUITING Physical O A C A activity rehab for Cancer Survivors ADIUVO Adrenal Version: May 2015 Developed by NCRI CSGs & NIHR CRN Cancer !

RENAL CSG PORTFOLIO MAP The good 3 rd line 2 nd line 1 st line Non- Adjuvant Surgery Neoadjuvant Tumour Type Interventional Metastatic Metastatic Metastatic C P C A C P C A D Photodynamic EORTC 30073 - SURAB NCRN544 therapyT1a ** SURTIME : CSG-developed Physical O A D A activity rehab for Cancer Survivors STAR C P C A EORTC 30073 - SURTIME SCOTRRCC C A O A Genetics of CREATE papillary EORTC 90101 C kidney cancer : CSG-consulted D P A-PREDICT** Clear cell D A DIRECTS O : Other C P PaZ02 * involves multiple tumour types C A ** Involves tissue collection NCRN2888 A : Academically-sponsored C A NCRN396 VE Basket RENAL CANCER P : Academic/Industry Partnership C A SURAB C A O A Physical activity rehab Photodynamic for Cancer therapy T1a ** Survivors O I C A Non-clear cell NCRN2888 SCOTRRCC CLEAR=MULTI-CSG STUDY; DASHED BORDER -IN SET-UP O I NCRN396 VE Basket I : Industry-sponsored PURPLE=IN SET-UP/FUNDED YELLOW=OPEN/RECRUITING Physical O A C A activity rehab for Cancer Survivors ADIUVO Adrenal Version: May 2015 Developed by NCRI CSGs & NIHR CRN Cancer !

RENAL CSG PORTFOLIO MAP The bad 3 rd line 2 nd line 1 st line Non- Adjuvant Surgery Neoadjuvant Tumour Type Interventional Metastatic Metastatic Metastatic C P C A C P C A D Photodynamic EORTC 30073 - SURAB NCRN544 therapyT1a ** SURTIME : CSG-developed Physical O A D A activity rehab for Cancer Survivors STAR C P C A EORTC 30073 - SURTIME SCOTRRCC C A O A Genetics of CREATE papillary EORTC 90101 C kidney cancer : CSG-consulted D P A-PREDICT** Clear cell D A DIRECTS O : Other C P PaZ02 * involves multiple tumour types C A ** Involves tissue collection NCRN2888 A : Academically-sponsored C A NCRN396 VE Basket RENAL CANCER P : Academic/Industry Partnership C A SURAB C A O A Physical activity rehab Photodynamic for Cancer therapy T1a ** Survivors O I C A Non-clear cell NCRN2888 SCOTRRCC CLEAR=MULTI-CSG STUDY; DASHED BORDER -IN SET-UP O I NCRN396 VE Basket I : Industry-sponsored PURPLE=IN SET-UP/FUNDED YELLOW=OPEN/RECRUITING Physical O A C A activity rehab for Cancer Survivors ADIUVO Adrenal Version: May 2015 Developed by NCRI CSGs & NIHR CRN Cancer !

RENAL CSG PORTFOLIO MAP The ugly 3 rd line 2 nd line 1 st line Non- Adjuvant Surgery Neoadjuvant Tumour Type Interventional Metastatic Metastatic Metastatic C P C A C P C A D Photodynamic EORTC 30073 - SURAB NCRN544 therapyT1a ** SURTIME : CSG-developed Physical O A D A activity rehab for Cancer Survivors STAR C P C A EORTC 30073 - SURTIME SCOTRRCC C A O A Genetics of CREATE papillary EORTC 90101 C kidney cancer : CSG-consulted D P A-PREDICT** Clear cell D A DIRECTS O : Other C P PaZ02 * involves multiple tumour types C A ** Involves tissue collection NCRN2888 A : Academically-sponsored C A NCRN396 VE Basket RENAL CANCER P : Academic/Industry Partnership C A SURAB C A O A Physical activity rehab Photodynamic for Cancer therapy T1a ** Survivors O I C A Non-clear cell NCRN2888 SCOTRRCC CLEAR=MULTI-CSG STUDY; DASHED BORDER -IN SET-UP O I NCRN396 VE Basket I : Industry-sponsored PURPLE=IN SET-UP/FUNDED YELLOW=OPEN/RECRUITING Physical O A C A activity rehab for Cancer Survivors ADIUVO Adrenal Version: May 2015 Developed by NCRI CSGs & NIHR CRN Cancer !

CARMENA case study CA NCER DU REIN METASTATIQUE Metastatic Clear Cell Renal Carcinoma • ‘Unwillingness to recruit due to surgeon/oncology/patient bias’ INCLUSION (Délai<28J) SCREENING Timeframe <28 Days) • ‘many patients not suitable for (vérification des critères d'elligibilité et signature du (verification of eligibility criteria and signature of consent form) consentement) nephrectomy’ • ‘a few patients set on nephrectomy’ J0: RANDOMISATION INFORMATISÉE Day 0: COMPUTERISED RANDOMISATION • ‘competing trials in metastatic disease at the time using other drugs’ NEPH RECTOM IE ANTI-ANGIOGE NIQUE S EUL Arm A Arm B (ds les 28J ap la randomisation) (ds les 21J ap la randomisation) Nephrectomy plus Antiangiogenic Antiangiogenic Alone (Sunitinib) (within 21 days of randomisation) • ‘patients and their families with metastatic disease wanted clear and ANTI-ANGIOGENIQUE ANTIANGIOGENIC quick decision made for a definitive (ds les 3 à 6 sem ap le néphrectomie) (in the 3 to 6wks following nephrectomy) treatment’ • ‘many patients I saw either "obviously" need a nephrectomy or "obviously" need oncology’ FIN DU SUIVI END OF FOLLOW UP (au maximum 24 mois ap l'inclusion du dernier patien t) (a maximum of 24 months after enrolment of last patient)

Serial failures Carmena Surtime CONSERVE Feasibility Study of Partial CA Metastatic Clear Cell Renal Carcinoma NCER DU REIN METASTATIQUE Nephrectomy vs ablation (Radiofrequency INCLUSION (Délai<28J) Ablation/Cryotherapy) for SRMs SCREENING Timeframe <28 Days) (vérification des critères d'elligibilité et signature du (verification of eligibility criteria and signature of consent form) consentement) J0: RANDOMISATION INFORMATISÉE Day 0: COMPUTERISED RANDOMISATION NEPH RECTOM IE ANTI-ANGIOGE NIQUE S EUL Arm A Arm B Nephrectomy plus Antiangiogenic (ds les 28J ap la randomisation) (ds Antiangiogenic Alone (Sunitinib) les 21J ap la randomisation) (within 21 days of randomisation) ANTI-ANGIOGENIQUE ANTIANGIOGENIC (ds les 3 à 6 sem ap le néphrectomie) (in the 3 to 6wks following nephrectomy) ! FIN DU SUIVI END OF FOLLOW UP (au maximum 24 mois ap l'inclusion du dernier patien t) (a maximum of 24 months after enrolment of last patient)

Recovery process

RCC Trial and Urologist Engagement Challenges 1. Lack of surgical renal cancer trials in the portfolio 2. Little knowledge of what renal cancer surgeons in UK want/can deliver trial wise 3. Lack of engagement of UK RCC surgeons (20% renal cancer surgeons engaged) 4. Little/no urology trainee education/involvement in trials (11/150 delegates at Tomorrow’s Leaders course) 5. Only 14% urological cancer patients had trials discussed with them (National Cancer Patient experience)

Non recruiters • 56% no suitable trials • 22% realm of oncologist • 33% no time • 22% no recognition • 22% no infrastructure • ‘perceived hassle, lack of time, many hoops to jump through’ • ‘Centralisation of specialist surgery and significant time constraints due to pressures from emergency and non-renal surgery obligations’

Results of BOXIT: a phase III trial of standard treatment + celecoxib vs. standard treatment + placebo in intermediate and high risk non-muscle invasive bladder cancer. John Kelly on behalf of the BOXIT Trial Management Group CRUK/07/004, ISRCTN84681538 [controlled-trials.com]

51 centres

DETECT I DETECT II