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 – 17th 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

NCRI Renal Cancer Portfolio

!

Non- Interventional

3rd line Metastatic 2nd line Metastatic 1st line Metastatic Adjuvant Surgery Neoadjuvant Tumour Type

RENAL CSG PORTFOLIO MAP

Clear cell Non-clear cell

RENAL CANCER

PaZ02 EORTC 30073 - SURTIME A-PREDICT** DIRECTS STAR

Version: May 2015

Developed by NCRI CSGs & NIHR CRN Cancer

EORTC 30073 - SURTIME

Adrenal

ADIUVO Photodynamic therapyT1a ** Photodynamic therapy T1a **

** Involves tissue collection * involves multiple tumour types

NCRN544 NCRN396 VE Basket NCRN2888 NCRN396 VE Basket NCRN2888 Physical activity rehab for Cancer Survivors Physical activity rehab for Cancer Survivors

D O C

: CSG-developed : CSG-consulted : Other

A : Academically-sponsored P : Academic/Industry Partnership I : Industry-sponsored

YELLOW=OPEN/RECRUITING PURPLE=IN SET-UP/FUNDED CLEAR=MULTI-CSG STUDY; DASHED BORDER -IN SET-UP

C A C P D A C P C A C P C A D P D A C P C A C A O A O I O I O A

SCOTRRCC

C A

SURAB

C A

Physical activity rehab for Cancer Survivors

O A

SCOTRRCC

C A

SURAB

C A

CREATE EORTC 90101

C A

Genetics of papillary kidney cancer

O A

The good

!

Non- Interventional

3rd line Metastatic 2nd line Metastatic 1st line Metastatic Adjuvant Surgery Neoadjuvant Tumour Type

RENAL CSG PORTFOLIO MAP

Clear cell Non-clear cell

RENAL CANCER

PaZ02 EORTC 30073 - SURTIME A-PREDICT** DIRECTS STAR

Version: May 2015

Developed by NCRI CSGs & NIHR CRN Cancer

EORTC 30073 - SURTIME

Adrenal

ADIUVO Photodynamic therapyT1a ** Photodynamic therapy T1a **

** Involves tissue collection * involves multiple tumour types

NCRN544 NCRN396 VE Basket NCRN2888 NCRN396 VE Basket NCRN2888 Physical activity rehab for Cancer Survivors Physical activity rehab for Cancer Survivors

D O C

: CSG-developed : CSG-consulted : Other

A : Academically-sponsored P : Academic/Industry Partnership I : Industry-sponsored

YELLOW=OPEN/RECRUITING PURPLE=IN SET-UP/FUNDED CLEAR=MULTI-CSG STUDY; DASHED BORDER -IN SET-UP

C A C P D A C P C A C P C A D P D A C P C A C A O A O I O I O A

SCOTRRCC

C A

SURAB

C A

Physical activity rehab for Cancer Survivors

O A

SCOTRRCC

C A

SURAB

C A

CREATE EORTC 90101

C A

Genetics of papillary kidney cancer

O A

The bad

!

Non- Interventional

3rd line Metastatic 2nd line Metastatic 1st line Metastatic Adjuvant Surgery Neoadjuvant Tumour Type

RENAL CSG PORTFOLIO MAP

Clear cell Non-clear cell

RENAL CANCER

PaZ02 EORTC 30073 - SURTIME A-PREDICT** DIRECTS STAR

Version: May 2015

Developed by NCRI CSGs & NIHR CRN Cancer

EORTC 30073 - SURTIME

Adrenal

ADIUVO Photodynamic therapyT1a ** Photodynamic therapy T1a **

** Involves tissue collection * involves multiple tumour types

NCRN544 NCRN396 VE Basket NCRN2888 NCRN396 VE Basket NCRN2888 Physical activity rehab for Cancer Survivors Physical activity rehab for Cancer Survivors

D O C

: CSG-developed : CSG-consulted : Other

A : Academically-sponsored P : Academic/Industry Partnership I : Industry-sponsored

YELLOW=OPEN/RECRUITING PURPLE=IN SET-UP/FUNDED CLEAR=MULTI-CSG STUDY; DASHED BORDER -IN SET-UP

C A C P D A C P C A C P C A D P D A C P C A C A O A O I O I O A

SCOTRRCC

C A

SURAB

C A

Physical activity rehab for Cancer Survivors

O A

SCOTRRCC

C A

SURAB

C A

CREATE EORTC 90101

C A

Genetics of papillary kidney cancer

O A

The ugly

!

Non- Interventional

3rd line Metastatic 2nd line Metastatic 1st line Metastatic Adjuvant Surgery Neoadjuvant Tumour Type

RENAL CSG PORTFOLIO MAP

Clear cell Non-clear cell

RENAL CANCER

PaZ02 EORTC 30073 - SURTIME A-PREDICT** DIRECTS STAR

Version: May 2015

Developed by NCRI CSGs & NIHR CRN Cancer

EORTC 30073 - SURTIME

Adrenal

ADIUVO Photodynamic therapyT1a ** Photodynamic therapy T1a **

** Involves tissue collection * involves multiple tumour types

NCRN544 NCRN396 VE Basket NCRN2888 NCRN396 VE Basket NCRN2888 Physical activity rehab for Cancer Survivors Physical activity rehab for Cancer Survivors

D O C

: CSG-developed : CSG-consulted : Other

A : Academically-sponsored P : Academic/Industry Partnership I : Industry-sponsored

YELLOW=OPEN/RECRUITING PURPLE=IN SET-UP/FUNDED CLEAR=MULTI-CSG STUDY; DASHED BORDER -IN SET-UP

C A C P D A C P C A C P C A D P D A C P C A C A O A O I O I O A

SCOTRRCC

C A

SURAB

C A

Physical activity rehab for Cancer Survivors

O A

SCOTRRCC

C A

SURAB

C A

CREATE EORTC 90101

C A

Genetics of papillary kidney cancer

O A

CARMENA case study

ANTI-ANGIOGENIQUE t) NEPH IE ANTI-ANGIOGE EUL (ds consentement) CA (ds les 3 à 6 sem ap le néphrectomie) FIN DU SUIVI (au maximum 24 mois ap l'inclusion du dernier patien J0: RANDOMISATION INFORMATISÉE RECTOM (ds les 28J ap la randomisation) NIQUE S les 21J ap la randomisation) INCLUSION (Délai<28J) (vérification des critères d'elligibilité et signature du NCER DU REIN METASTATIQUE ANTIANGIOGENIC (in the 3 to 6wks following nephrectomy) END OF FOLLOW UP (a maximum of 24 months after enrolment of last patient) Arm B Antiangiogenic Alone (Sunitinib) (within 21 days of randomisation) Arm A Nephrectomy plus Antiangiogenic Day 0: COMPUTERISED RANDOMISATION

Metastatic Clear Cell Renal Carcinoma

SCREENING Timeframe <28 Days) (verification of eligibility criteria and signature of consent form)

• ‘Unwillingness to recruit due to

surgeon/oncology/patient bias’

• ‘many patients not suitable for

nephrectomy’

• ‘a few patients set on nephrectomy’
• ‘competing trials in metastatic

disease at the time using other drugs’

• ‘patients and their families with

metastatic disease wanted clear and quick decision made for a definitive treatment’

• ‘many patients I saw either

"obviously" need a nephrectomy or "obviously" need oncology’

Serial failures

ANTI-ANGIOGENIQUE t) NEPH IE ANTI-ANGIOGE EUL (ds consentement) CA (ds les 3 à 6 sem ap le néphrectomie) FIN DU SUIVI (au maximum 24 mois ap l'inclusion du dernier patien J0: RANDOMISATION INFORMATISÉE RECTOM (ds les 28J ap la randomisation) NIQUE S les 21J ap la randomisation) INCLUSION (Délai<28J) (vérification des critères d'elligibilité et signature du NCER DU REIN METASTATIQUE ANTIANGIOGENIC (in the 3 to 6wks following nephrectomy) END OF FOLLOW UP (a maximum of 24 months after enrolment of last patient) Arm B Antiangiogenic Alone (Sunitinib) (within 21 days of randomisation) Arm A Nephrectomy plus Antiangiogenic Day 0: COMPUTERISED RANDOMISATION

Metastatic Clear Cell Renal Carcinoma

SCREENING Timeframe <28 Days) (verification of eligibility criteria and signature of consent form)

Carmena Surtime

!

CONSERVE

Feasibility Study of Partial Nephrectomy vs ablation (Radiofrequency Ablation/Cryotherapy) for SRMs

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’

CRUK/07/004, ISRCTN84681538 [controlled-trials.com]

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

51 centres

DETECT I DETECT II

Trials supported/suggested

• Window studies – 90%
• SRM study of treatment modality – 93%
• New cytoreductive Nx study – 100%

Working with and learning from wider surgical community

New trials for the new era

• Age ≥ 18
• Biopsy proven clear

cell RCC

• Resectable Tumor
• cT3a (RV Ix), cT3b,

cT3c

• N0, N1, Nx
• M0, M1
• Stratification by Neves

classification

Axitinib 5mg tw/d, up to 10mg tw/d ** /2months*

Radical nephrectomy with thrombectomy****

*Imaging at baseline, 2 weeks, 8 weeks **in the absence of axitinib related toxicity > grade 2 for a continuous 2-week period and in the absence of hypertension (defined as two blood pressure [BP] measurements of 150/90 mmHg taken in the clinic or in the community) *** Neves et al., BJU Int, 1987, 59 (5) 390 **** 36 hours after stopping axitinib

Main Objective:% patients with decrease in Neves*** classification Secondary objectives:

• % change in surgical approach
• Response rate (RECIST)
• Evaluation of morbidity
• Prog/pred response imaging+biomarker identification

PHASE II NEOADJUVANT STUDY OF AXITINIB FOR REDUCING EXTENT OF VENOUS TUMOUR THROMBUS IN CLEAR CELL RENAL CELL CANCER WITH VENOUS INVASION (NAXIVA)

Conclusions

• Translation begets trials & trials beget translation
• Trials need to be deliverable by your colleagues
• Pilot/feasibility studies are ideal starting points
• Become one of the 5% and you can change surgical treatment

paradigms