ProtecT Study: an update

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ProtecT Study an update

• Freddie C. Hamdy FMedSci
• Academic Urology Unit
• University of Sheffield
• United Kingdom

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• The way in which Majeed et al set out to
  answer their question is very much the exception
  rather than the rule in surgical research
• The study raises important issues about why
  surgeons do research, how they do it, what
  criteria they use, and how their research
  compares with the rest of the medical community.

Richard Horton, 1996
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Surgical research a myth?

• I should like to shame surgeons out of the
  comic opera performances which they suppose are
  statistics of operation.
• Major Greenwood, 1923
• The limitations on time and intellectual
  resources which are an inevitable consequence of
  the practice of surgery, can lead to poor quality
  work in surgical sciences.
• Hugh Dudley, BMJ 1981

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Surgical Research, Why ?

• Disease is old, and nothing about it has
  changed. It is we who change, as we learn to
  recognize what was formerly imperceptible.
  Jean-Martin Charcot, 1880

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Surgical Research How ?

• In science, one always strives for simplicity,
  which is the elegance of proof Simplex sigillium
  veri.
• Charles Huggins

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Prevalence of Prostate cancer in men with low PSA
levels
Thompson et al, NEJM 2004
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Prostate cancer in the US population
Estimated total with prostate cancer 8,000,000
If all men with a PSA 2.5ng/ml are biopsied, an
estimated 676,780 men with PCa will be diagnosed
(0.5 million additional cancers, and gt15-fold
the number of PCa deaths)
Thompson et al, 2003, Welch et al, 2005 Schröder
et al, 2006
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The dilemmas

• Significant risk of over-detection
• Significant risk of over-treatment
• If 1 million asymptomatic men agreed to receive a
  PSA test, 100,000 will receive biopsies, 20,000
  will have cancer, 10,000 may receive radical
  prostatectomy, 10 will die, 300 will have some
  degree of incontinence, and 4000 will have
  erectile dysfunction
• Frankel et al, Lancet 2002
• Lack of Level 1 evidence that aggressive
  treatment of screen-detected clinically localised
  prostate cancer improves survival and/or quality
  of life

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Does aggressive treatment of screen-detected
disease improve survival and/or quality of life
in men with prostate cancer?
The question
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The ProtecT study (Prostate testing for cancer
and Treatment)
Principal Investigators FC Hamdy (Sheffield) JL
Donovan (Bristol) DE Neal (Cambridge)
2001-2008
Cardiff Edinburgh Leeds
Bristol Birmingham Cambridge
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Leicester Newcastle Sheffield
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ProtecT The story

• 1996 HTA commissioned 2 systematic reviews on
  screening and treatment of prostate cancer
• Recommendations (Selley et al 1997 Melia et al,
  1997)
• Insufficient evidence to suggest benefits of
  screening as public health policy
• Randomised controlled trials of screening and
  treatment are required urgently
• 1997 Call from HTA
• Primary research projects
• Screening for prostate cancer

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ProtecT study design

• Phase I Pilot
• To evaluate the feasibility of a RCT of the major
  treatments for localised prostate cancer
• Is community-based PSA testing possible in the
  UK?
• Would men accept randomisation to surgery,
  radiotherapy and a non-immediate intervention arm
  (or two arms only)
• Could nurses recruit men as effectively as
  urologists?
• Phase II Main Trial
• To conduct a major 3-arm randomised trial to test
  the effectiveness and cost-effectiveness of
  radical prostatectomy, radical conformal
  radiotherapy and active monitoring for localised
  prostate cancer
• Survival at 5, 10 and 15 years
• Disease progression (biochemical and clinical)
• Impact of treatment urinary/bowel symptoms,
  quality of life, sexual function, complications
• Economic evaluation
• Biorepository for basic/translational research
• Qualitative evaluation of recruitment and
  experience

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Recruitment by Feb 2000
Excluded (unfit/refused) 5
Localised prostate cancer 22
Waiting 5
Consent to trial 5 (42)
Preference 7 (58)
2 arm 3
3 arm 2
CM 0
Surgery 1
Radio 2
Surgery 2
Radio 0
Radio 3
Surgery 3
CM 1
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Randomisation rates
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What has made the difference?

• Explaining the trial before the diagnosis
• Challenging patients preference
• Offering randomisation as a solution to a
  difficult problem of decision-making
• Order of treatment description
• Avoiding false re-assurance
• Terminology in the non-intervention arm
  replacing watchful waiting with active
  monitoring
• Equalising treatments in recruiters own mind
• Randomising by end of appointment
• Regular training and monitoring of recruiters
• Reassuring the patient that he comes first, and
  the study comes second
• Perseverance andbelieving.

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Phase I Feasibility 1999-2001
Qualitative Research
Equipoise
Research Nurses
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ProtecT the milestones

• January 2001
• Invited by HTA to submit full proposal
• February 2001
• Full application submitted
• April 2001
• Positive response from HTA

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House of Commons - March 2003

• We also have a large-scale randomised
  controlled trial of treatments for localised
  prostate cancerthe ProtecT trialevaluating
  different treatments. As the hon. Gentleman said,
  the trial will cost about 13 million and
  consists of three armsactive monitoring, radical
  prostatectomy and radical radiotherapy. The trial
  began on 1 June 2001 and will last for five
  years, so it is fairly lengthy. The lead
  researcher is Professor Freddie Hamdy from
  Sheffield, and the hon. Gentleman could obtain
  further details from him if he wishes.

Hazel Blears, Undersecretary of State for Health
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ProtecT study design

• Phase II Main Trial (2001-2008)
• To conduct a major 3-arm randomised trial to test
  the effectiveness and cost-effectiveness of
  radical prostatectomy, radical conformal
  radiotherapy and active monitoring for localised
  prostate cancer
• Survival at 5, 10 and 15 years
• Disease progression (biochemical and clinical)
• Impact of treatment urinary/bowel symptoms,
  quality of life, sexual function, complications
• Economic evaluation
• Biorepository for basic/translational research
• Qualitative evaluation of recruitment and
  experience

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Why men take part

• Testing perceived to be a good idea
• Better to know early than late
• Easier to treat if caught early
• Need to be young enough to have treatment
• Peace of mind if negative
• To help with research about treatments
• Other motives !...

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ProtecT
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Why men take part
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Case-finding up to June 2007
182,600 Invitations
87,648 (48) Prostate check clinic attenders
8,165 (11.7) Raised PSA
1,913 (81)Localised
264 (11)Advanced
174 (7)Excluded
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Randomisation up to June 2007
1,913 Eligible cases
1,255 (65) Randomised
658 (35) Preference
341 Active monitoring
174 Surgery
74 Radiotherapy (39 brachy)
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PIVOT versus SPCG-4 versus ProtecTBaseline
characteristics
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CAP and ProtecT
General practices (c. 800)
All eligible men flagged
Comparison arm 230,000
ProtecT study 230,000 invited
116,000 PSA tested
116,000 not tested
Standard NHS management
ProtecT study Follow-up
Primary outcome prostate cancer mortality 10 years
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ProtecT research teamPIs Freddie Hamdy, Jenny
Donovan, David NealCo-ordinator Athene Lane

• Birmingham Alan Doherty, Mike Wallace, Alison
  Grant, Pauline Thompson, Chloe Hoult, Rose
  Donohue, Lynn Taylor, Nick James, John Townley,
  Pauline Massey, Marie Tiffany
• Bristol Social Medicine Tim Peters,Michael
  Davis, Kerry Avery, David Jewell, Andrea Wilson,
  Zoe Wilkins, Lynne Smith, Michelle Purdie, Tanya
  Liddiatt, Christine Croker, Nicholas
  Christoforou, Christopher Pawsey, Angela Afonso,
  Tom Steuart-Feilding, Liz Down, Joanna Coast,
  Jane Blazeby, Emma Turner
• Bristol Southmead David Gillatt, Liz Salter,
  Emma Elliott, Hilary Moody, Tricia OSullivan,
  Lynne Bradshaw, Jenny Cloete,, Susan Baker, Janet
  Roxburgh, Elizabeth Bellis-Sheldon, Paula Wilson,
  John Oxley, Raj Persad, Hartwig Schwaibold, Sue
  Yarrow,Helen Appleby
• Cambridge Andrew Doble, Pippa Herbert, Elizabeth
  Wyber, Jenny Wilson, Pippa Tagart, Vicky Jackson,
  Sepideh Modgham, Alison Moore, Vanessa Goss,
  Simon Russell, Susie Hall, Tim Baynes, Anne
  Warren, Donna Routsis, Tony Geater,Helen
  Patterson,Jo Treeby,Richard Benson, John
  McCloughlin
• Cardiff Howard Kynaston, Mandy Jones, Vivienne
  Breen, Sarah Tidball, Sharon Williams, Dennis
  Cochlin, John Staffurth, Murali Varma, Owen
  Hughes, Malcolm Mason, Geraint Lewis, David
  Griffiths, Kevin Pearse, Elliw Richards,Teresa
  Robson, Dean Aston,Lucy Wills,Stephen Slade,Lynda
  Penketh,Claire Heymann
• Edinburgh Prasad Bollina, Norma Lyons, Fiona
  Marshall, Grahame Howard, Duncan McClaren, Ken
  Grigor, Sally Napier, Jan Blaikie, Barbara Mayne,
  Jackie Mutch, Lynda Goddall, Aileen MacLeod,Gill
  Davies
• Leeds Stephen Prescott, Carmel Loughrey, Pat
  Harnden, Mike Collins, Debbie Cooper, Christy
  Walker, Louise Mellen,Colin Woodhouse, Claire
  Daisey, Suzanne Stanley, John Lilley, Neil
  Roberts, Helen Dalton
• Leicester Roger Kocklebergh, Sue Bonnington,
  Jenny Clarke, Mandy Le Butt, Susan Halpin,
  Rachael De La Rue, Penny Ebbs, Sharon Hollings,
  Chris Rippin, Subramaniam Vasanthan, Janet
  Potterton,Tim Terry, Nick Mayer, Steven Bolton,
  Lorraine Williams, Paul Symonds
• Newcastle Philip Powell, Teresa Lennon, Jill
  Ferguson, Julie Needham, Nicola Wilkinson,
  Barbara Hattrick, Hing Leung, Ian Pedley, Mary
  Robinson, Paul Brown, Sue Dark, Marie Mathers,
  Linda Sneddon, Joyce Wilkinson, Alasdair Steele,
  Gill Lawrence, Geoff Lambert, Jane Lambert,
  Michelle Wilkinson, Susan Lamb, Sarah Rushbrook
• Sheffield Joanne Howson, Peter Holding, Sue
  Kilner, Claire Kennedy, Carol Torrington, Carolyn
  Sutton, Irene Sharkey, John Anderson, Catherine
  Ferguson, Peter Kirkbride, John Goepel, Carole
  Stenton, Gill Delaney, Gemma Hayward, Gillian
  Martin,John Conway, Tony Milford-Ward, Carole
  Stenton, Michael Slater
• Collaborators Steven Oliver, Edwin Aird, Rollo
  Moore, Patty Diez, Linda Davies, Lucy Brindle,
  Dan Dedman

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The network effect
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ProtecT Network linked research 99-07
CAP CRUK/DoH Cluster RCT
Recruit. to trials MRC Prog Qual research
ProMPT Collab. of 6 Unis - NCRI Progression,
treatments
Family history Genetics
Prodigal Nested. SW RD Diagnosis, aetiology
Genetic risk factors US DoD
QoL impact CR-UK
Candid/ Nutrition Center MRC/WCRF Diet diaries
P-Mark FP-6 EU Biomarker discovery validation
Lactose intolerance WCRF
Econ/prob modelling CR-UK
Other collaborations Biomarker discovery
(Proteomics/peptidomics) MSKCC (NY) FP-6 P-Mark
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ProtecT - opportunities

• ProtecT Research Resources
• 130,000 men aged 50-69
• Epidemiological and biological data
• Serum, Plasma, DNA
• 3800 prostate cancers
• Clinical data and long-term follow-up
• Tissue, serum, plasma, DNA
• Other Research resources
• Case-mix of patients and controls recruited from
  urological clinics in the collaborative (gt1000
  sets)
• Sequential blood sampling serum, plasma, DNA)
• Robust electronic database
• Funding for biorepository equipment
• Funding obtained from Wolfson Foundation and
  SRIF-3
• State-of-the-art robotic aliquoting and storage

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The Sheffield Biorepository
Three component 1) Dedicated Sample handling
laboratory (robotic aliquoting into straws 2)
-80C freezers (x30) refurbished store 3)
Vapour-phase liquid Nitrogen tank (new build)
1
3
2
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Labman Robotic Specimen Handling
50-300µl
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Processing, storage and Database
SOPs
Cost per sample set plastics only 50 ml 3.8ml
0.60 300 µl 6.80 100 µl 23.30 50 µl 46.60
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ProtecT outcomes when?

• 2008 Median follow-up 3 years
• 2010 Median follow-up 5 years
• First interim analysis
• 2013 Median follow-up 8 years
• First formal analysis
• 2015 Median follow-up 10 years
• Second formal analysis
• 2020 median follow-up 15 years
• Third and final analysis !
• 2023 retirement!...