Treating prostate cancer
BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e5122 (Published 01 August 2012) Cite this as: BMJ 2012;345:e5122
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The editorial in this journal by Parker1 uses the “best available evidence” from the PIVOT study2 to argue the case for watchful waiting for low risk prostate cancer and questions the need to diagnose the condition at all. Unfortunately the PIVOT trial was marred by a number of flaws that should make us cautious about its conclusions in relation to our own prostate cancer population.
The original design of the PIVOT trial aimed to randomize 2000 patients between surgery and observation. Unfortunately, this goal was not achieved, requiring a modified design to justify a randomization aim of only 740 patients. Median survival was originally assumed to be 15 years and 10 years in the updated design. If one takes the median survival of 12 years in the study’s observation group and assume 7 years for enrollment and an 8 year follow-up, the sample should be 1200 patients to detect a 25% relative reduction in mortality with 90% power and a two-sided alpha level of 0.05. With an actual enrollment of just 731 patients, the study was therefore underpowered to detect this relatively large clinical effect. The wide 95% confidence interval around the hazard ratio for death in the treatment group illustrates this point. A relative increase of 8% to a relative reduction of 29% in the risk of death in the prostatectomy group, as compared with the observation group, cannot be excluded with 95% confidence.
The fact that 50% of men in both groups died by 12 years seems unusual to most treating this disease. Also, only 15% of the deaths were attributed to prostate cancer or its treatment. Although overall mortality has an appeal as an end point, in this context, the majority of end points would be non-informative for the comparison of interest. The expectation of a 25% relative reduction in mortality when 85% of the events are non-informative implies an enormous treatment effect with respect to the informative end points. Furthermore, the finding that around 20% of patients did not adhere to the assigned treatment further reduces the ability of the trial to discern a true treatment effect. Despite this there was a clear trend towards increased survival in the high risk group and overall half the number of metastases in the treatment arm (10.6 to 4.7%).
Prostate cancer is usually a slowly progressive condition, eventually, after many years, resulting in a painful death from metastases in a significant number of patients, unless mortality from other causes supervenes. Radical prostatectomy, now often performed minimally invasively with robotic assistance3, prevents disease progression in >80% of well-selected cases. The intrinsically flawed results of the PIVOT study should not encourage us to turn our backs on a disease that kills more than 10,000 men per annum in the UK and hundreds of thousands more worldwide.
Roger S Kirby
The Prostate Centre, London W1G 8GT. info@theprostatecentre.com
Ben Challacombe, The Prostate Centre and Guy’s Hospital & King’s College London, SE1 9RT
Prokar Dasgupta, The Prostate Centre and Guy's Hospital & King’s College London, SE1 9RT
1. Parker C, Treating prostate cancer. BMJ 2012;345:e5122
2. Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aaronson WJ et al. Radical prostatectomy versus observation for localised prostate cancer. NEJM, 2012; 367: 203-13.
3. Goldstraw MA, Challacombe BJ, Patil K, Overcoming the challenges of robot-assisted radical prostatectomy. Prostate Cancer Prostatic Dis. 2012;15:1-7.
Holmberg study
Competing interests: No competing interests
Chris Parker’s prominent BMJ editorial on prostate specific antigen (PSA) screening for prostate cancer (CaP) is highly misleading. It appears biased against screening by failing even to mention the 3 large, recently published, European studies showing a clear benefit from screening in reducing mortality from CaP. He then comes to a spurious conclusion in proposing that we should do far fewer prostatic biopsies to “cut the annual incidence of prostate biopsies in the UK by more than 10,000 and save time, costs and emotional distress associated with deciding how to treat low risk disease”. By curious coincidence 10,000 is the current UK annual death rate from CaP. This is the real 10,000 we should be concentrating on to reduce the actual time, higher costs, emotional and real physical distress of death from advanced, metastatic CaP.
Over the last 10 years the UK multi disciplinary approach in presenting treatment options to every new case of CaP has done much already to reduce the over treatment more characteristic of the North American practice examined in the PIVOT trial. Furthermore the UK has pioneered Informed Decision Making, the process that provides the information that allows men with early curable CaP to make an informed and reasoned decision on how they wish to be treated.
In the USA where PSA screening is the norm, the American Urological Association recommends that “the PSA test should be offered to well-informed men aged 40 years or older who have a life expectancy of at least 10 years”. By contrast UK men face a lottery and frequent discouragement when seeking CaP screening which can only worsen if GP’s read this unbalanced article - vested with the authority of a prestigious lead editorial - and take away the message that PSA screening is still not advisable. If so, we will continue to fail to detect early enough the dangerous CaPs that cause our unacceptable 10,000 deaths per annum and our death rate will not fall.
Yours sincerely
Chris Booth FRCS
Lead Clinician,
CHAPS Men’s Health Charity
Competing Interest: none
1. Bartsch G et al, Tyrol Prostate Cancer - Demonstration Project BJUI 2008; 101: 809-816
2. Schroder FH et al Screening and Prostate Cancer Mortality in a Randomised European Study NEJM 2009; 360: 1320-1328
3. Hugosson J et al - Mortality from the Goteborg Randomised Population-based Prostate Cancer Screening Trial. Lancet Oncol. 2010; 11 (8): 725-732
4. Wilt TJ et al. The Prostate Cancer Intervention Versus Observation Trial. Con Clin Trials 2009; 30(1): 81-87
Competing interests: No competing interests
Re: Treating prostate cancer
Prostate cancer is slow growing and the patient dies of some other diseases rather than cancer. But in such patients obstructive uropathy can occur, which may cause slow hydronephrosis and chronic renal failure1. Moreover denying treatment is unethical and patients should not be left in the lurch once the diagnosis is made.
In my opinion, there are several energy modalities which are being developed to achieve the trifecta of continence, potency, and oncologic efficiency2. Prostatic tumor ablation can be achieved with different energies: freezing effect for cryotherapy, thermal effect using focalized ultrasound for HIFU, and using thermal effect of light for focal laser ablation (FLA) and activation of a photosensitizer by light for PDT, among others. Radio frequency and microwave therapy have been tested in this field and demonstrated their usefulness. Electroporation is currently being developed on preclinical models. External beam radiation with microboost on neoplastic foci is under evaluation2. HIFU and cryotherapy require the use of sophisticated and expensive machines and, consequently, the procedure is expensive. Laser techniques seem to be less onerous, with the added advantage of size2.
References:
1. Bierer S, Ozgün M, Bode ME, Wülfing C, Piechota HJ.[Obstructive uropathy in adults]. [Article in German] Aktuelle Urol. 2005 Aug;36(4):329-36.
2. Bozzini G, Colin P, Nevoux P, Villers A, Mordon S, Betrouni N. Focal therapy of prostate cancer: energies and procedures. Urol Oncol. 2012 Jul 11. [Epub ahead of print]
Competing interests: No competing interests