Comment Article COMMENT J.K. MELLON
INTRODUCTION In June 2003, somewhat ahead of schedule, the outcome of the first of two large phase III National Cancer Institute (NCI)-sponsored prostate cancer chemoprevention trials (the Prostate Cancer Prevention Trial, PCPT) was announced [1]. The PCPT reported that the prevalence of prostate cancer in a screened population of men was reduced by 24.8% in men taking finasteride 5 mg/day for 7 years. However, this very positive outcome from the largest urology trial so far conducted was tempered by an apparent increase in the frequency of Gleason 7–10 cancers in the cohort receiving finasteride. The PCPT is undoubtedly a landmark study but because of uncertainty about an increased risk of more aggressive disease, despite an overall reduced risk, further work is now necessary to ensure that prolonged finasteride administration is not a factor in tumour adaptation and the development of higher grade disease. A discussion of the clinical implications of the PCPT has already been published in this journal [2]. Plans for ‘Son of PCPT’ are already at an advanced stage with GlaxoSmithKline’s REDUCE trial, in which the effect of 4 years of dutasteride 0.5 mg (a dual 5a-reductase inhibitor) will be assessed in men with a ‘suspicious’ PSA and a recent negative prostate biopsy. SELECT The second major NCI-sponsored prostate cancer chemoprevention trial is SELECT (SElenium and vitamin E Cancer prevention Trial, details at http://www.crab.org/select/) which is being conducted in 435 sites throughout the USA, Puerto Rico and Canada. This trial started recruitment in August 2001 and hopes to enrol 32 400 participants over a 5-year period. As of August 2003, SELECT had enrolled 24 639 men, or 76% of the target study population. Participants are randomized into four groups, to receive placebo, selenium 200 mg (in the form of selenomethionine),
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CHEMOPREVENTION OF PROSTATE CANCER COMES OF AGE J.K. MELLON – Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester General Hospital, Leicester, UK
vitamin E (400 IU), or a combination of both agents. Recruitment will finish in 2006 but the final study outcome is not anticipated until 2013. The principal endpoint of the trial is the incidence of prostate cancer, assessed by routine clinical care, including an annual DRE and serum PSA measurement. In addition, quality of life will be assessed, and blood and prostate tissue samples stored for analysis of micronutrient levels and certain biological and genetic biomarkers of prostate cancer risk. The incidence of lung and colorectal cancers will also be studied. THE RATIONALE FOR SELECT Both selenium and vitamin E are important intracellular antioxidants. The evidence which initially led to their consideration as chemopreventive agents in prostate cancer arose from studies involving entirely different cancers. In the case of vitamin E, this was the Finnish a-tocopherol, b-carotene (ATBC) study [3] (vitamin E is the general term for all tocopherols and tocotrienols, of which atocopherol makes a significant contribution to the vitamin E content of foods). The ATBC trial was a double-blind, randomized placebocontrolled trial with four study arms, in which patients were randomized to receive two placebo tablets, one placebo and one 50 mg vitamin E tablet, one placebo and one 20 mg b-carotene tablet, or both vitamin E and bcarotene. A total of 29 133 male smokers were recruited and the aim of the study was to assess whether there was a reduction in the incidence of lung cancer after administering these agents. The study concluded that dietary supplementation with a-tocopherol had no effect on the incidence of lung cancer. Paradoxically, the trial showed an increase in lung cancer risk among a subset of men given
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b-carotene supplements who continued to smoke at least 20 cigarettes per day, and who also had a high intake of alcohol recorded. However, secondary analysis of 6-year followup data showed a 32% reduction in the incidence of prostate cancer and a 42% reduction in mortality from this disease among men who received supplementary vitamin E. Similar to the ATBC trial data, the effect of selenium in reducing the risk of prostate cancer was detected by secondary analysis of data from a trial whose primary endpoint focused on another malignancy. In a randomized, placebo-controlled study of 1312 patients with non-melanoma skin cancer, selenium in the form of selenized yeast (200 mg) was found to significantly decrease prostate cancer incidence [4]. In that study investigators retrospectively tested stored blood for PSA before and after treatment, and applied a secondary analysis of the incidence of prostate cancer. Again, there was no effect on the primary endpoint of skin cancer, but the secondary analysis revealed a 63% reduction in the incidence of prostate cancer. Further follow-up of this cohort has, akin to the ATBC trial, identified an increased risk of non-melanoma skin cancer in the population treated with selenium but a maintained reduced risk of prostate cancer, at 52% [5]. The prostate-related findings of the above studies must be treated with some caution, as both studies set out to answer other questions and used highly selected groups. Also it is disappointing to identify an increased risk of cancer associated with agents which had previously shown some promise in reducing this risk. 459
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In addition to SELECT, selenium is also being tested in other prostate cancer-related conditions. Currently, there is an ongoing phase III study of selenium as a chemopreventive agent in patients with highgrade prostatic intraepithelial neoplasia (HG-PIN). This study commenced in July 2000 and is already well on its way to reach its recruitment target of 466 men. Also for men with HG-PIN, selenium is being studied in a phase II trial, in combination with vitamin E and soy protein isolate, as a possible chemopreventive combination regimen.
The selection of appropriate agents for chemoprevention trials will parallel the increasing understanding of the molecular biology of prostate cancer, particularly in relation to the molecular events associated with HG-PIN and proliferative inflammatory atrophy (PIA, now thought to be the earliest precursor lesion for prostate cancer). An illustration of this is the proposed Merck trial of the selective cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, as a potential chemopreventive agent in prostate cancer, as although there is little evidence of COX-2 expression in prostate cancers or HG-PIN, there is abundant expression of COX-2 in PIA.
FUTURE CHEMOPREVENTIVE STRATEGIES
The PCPT has offered a tantalizing glimpse of what might be achieved by prostate cancer chemoprevention strategies. One estimate before the study outcome being known was that a positive result from the PCPT had the potential for 300 000 prostate cancers to be prevented in the USA over a 10-year period. Currently, the NCI has 13 active prostate cancer chemoprevention trials listed on its website. It is becoming increasingly accepted that over the next 25 years chemoprevention will assume a more major role in the management of men concerned about the development of prostate cancer.
The long period projected for SELECT shows an important issue in the advancement of potential chemopreventive agents from preclinical studies to large-scale clinical trials. In view of the long natural history of prostate carcinogenesis, if the incidence of cancer acts as the only endpoint measured in chemoprevention trials, prolonged periods will be necessary to obtain results. More importantly, during this prolonged period no indication will be available about the potential efficacy of the intervention, nor regarding the risk/benefit ratio for participants. Biomarkers of carcinogenesis, tailored to the agent under investigation, are therefore essential in the clinical development of chemopreventive agents. Examples of such biomarkers are oxidative DNA adduct levels like 8-oxo-dG or M1G, which can be measured in prostate tissue or in white blood cells as a ‘surrogate’ for the prostate, to detect antioxidant changes elicited by dietary supplementation with, e.g. selenium. Clues to the most promising new agents can be relatively rapidly assessed in animal models relevant to prostate cancer. There are not only models of prostate cancer but also of precursor lesions, e.g. the Noble rat, in which HG-PIN is induced in a high proportion of animals by the administration of testosterone and oestradiol. Clearly agents effective in reducing the incidence and progression rates of HG-PIN can then be selected for further study in humans. Nevertheless, despite these animal models, it is difficult to envisage any substitute for large population-based placebo-controlled clinical trials, such as the PCPT and SELECT, before introducing a chemopreventive agent into the general population. 460
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development of prostate cancer. N Engl J Med 2003; 349: 213–22 Marberger M, Adolfsson J, Borkowski A et al. The clinical implications of the Prostate Cancer Prevention Trial. BJU Int 2003; 92: 667–71 The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330: 1029–35 Clark LC, Coombs GF, Turnbull BW et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomised control trial. JAMA 1996; 276: 1957– 63 Duffield–Lillico AJ, Slate EH, Reid ME et al. Nutritional Prevention of Cancer Study Group. Selenium supplementation and secondary prevention of non melanoma skin cancer in a randomised trial. J Natl Cancer Inst 2003; 95: 1477– 81
Correspondence: J.K. Mellon, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester General Hospital, Leicester, LE5 4PW. e-mail:
[email protected] March 2004 934 Comment Article
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comment P. RIMINGTON AND P. DASGUPTA
LAPAROSCOPIC AND ROBOTIC RADICAL CYSTECTOMY P. RIMINGTON and P. DASGUPTA – East Sussex Hospitals, Eastbourne and Guy’s Hospital, London, UK
INTRODUCTION Radical cystectomy has emerged as the most effective treatment for muscle-invasive organ-confined bladder cancer. It has a significant complication rate, including mortality, even in the best hands. The median blood loss is often 1500–1800 mL and many patients need a blood transfusion as a result. The hospital stay and full recovery are not surprisingly quite prolonged. The first laparoscopic cystectomy was performed in 1992 for pyocystis in a retained
bladder. The patient already had an ileal conduit. The first laparoscopic radical cystectomy (LRC) for bladder cancer with an extracorporeal ileal conduit was reported by Sanchez de Badajoz et al. [1]. In the last few years there has been increasing interest in LRC and at the World Congress of Endourology in 2003 an entire session was dedicated to the subject. Published articles and abstracts indicate that >150 LRCs have already been performed. Most were by a 5–6 port transperitoneal technique and 50% chance of surviving 10 years, although it is hard to suggest a value between 50% and 100% that equates to the perception of the likelihood of surviving 10 years. How is life-expectancy assessed? Currently the judgement is subjective, i.e. a personal assessment of the patient’s health based on their medical history and comorbidity, and on basic variables like age, weight and blood pressure. The judgement on patient lifeexpectancy tends not to be based on hard data but rather a feeling generated when meeting the patient and based on personal experience. How accurate is the assessment of lifeexpectancy? Research carried out at our institution and currently unpublished suggests that life-expectancy assessed by clinicians is generally poor, with a wide variation between observers. To try and eliminate this variation, our department is developing a system for use in outpatients and MDT meetings, to more accurately quantify life-expectancy in patients with prostate cancer. Initially we conducted a search of current methods and found that 462
We are constructing a tool using this actuarial model [8], collecting basic data relating to variables such as age, weight, height, blood pressure, lifestyle factors and pre-existing comorbidity. A personalized sum of mortality ratios can be generated for each patient and using actuarial tables [8] a comorbidityattuned age for the patient calculated, i.e. the age a fully-fit patient would be to have the same life-expectancy as the studied patient. For example, a 63-year-old patient with well-controlled diabetes and no diabetic complications may have the same lifeexpectancy as a fully fit 70-year-old man. Using an algorithm that accurately predicts
life-expectancy in patients with little or no comorbidity, a value for the probability of being alive at 10 years can then be generated [9,10]. This value can be computed with a minimal amount of information, although the more comorbidity data collected the more accurate the assessment of life-expectancy. Using this system we are planning to produce a simple computer-based program which will generate a probability of being alive at 10 years for individual patients. This will certainly be more accurate than currently used personal opinion and will eliminate variation among clinicians. With the expansion of the use of Personal Digital Assistants a form of this system could be produced for rapid, portable assessment by clinicians and consequently used in both outpatients and MDT meetings. Although clinical, pathological and radiological variables form the backbone of MDT meetings, most decisions involve some form of life-expectancy assessment, which is currently haphazard and varies significantly among clinicians. If MDT meetings are to prove an acceptable forum for decision making, then areas such as patient lifeexpectancy and patient choice, currently poorly represented, will have to be significantly improved and become formally integrated into the decision-making process.
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Tiret L, Hatton F, Desmonts JM, Vourc’h G. Prediction of outcome of anaesthesia in patients over 40 years: a multifactorial risk index. Stat Med 1988; 7: 947–54 Farrow SC, Fowkes FG, Lunn JN, Robertson IB, Samuel P. Epidemiology in anaesthesia II. Factors affecting mortality in hospital. Br J Anaesth 1982; 54: 811–7 Fowkes FG, Lunn JN, Farrow SC, Robertson IB, Samuel P. Epidemiology in anaesthesia III. Mortality risk in patients with co-existing physical disease. Br J Anaesth 1982; 54: 819–25 Anonymous. Joint British Societies Coronary Risk Prediction Chart. British National Formulary 43rd edn. London: BMA and Royal Pharmaceutical Society, 2002 Child CG, Turcotte JG. Surgery and portal hypertension. In Child CG ed. The Liver and Portal Hypertension. Major Problems in Clinical Surgery. Vol. I. Chapt.
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1. Philadelphia: WB Saunders Co, 1964: 1– 85 Von Korff M, Wagner EH, Saunders K. A chronic disease score from automated pharmacy data. J Clin Epidemiol 1992; 45: 197–203 http://www.medal.org/index.html Brackenridge RDC, Elder J.W. Medical Selection of Life Risks. Basingstoke: Macmillan Publishers, 1998
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Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chron Dis 1987; 40: 373– 83 10 Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994; 47: 1245–51 March 2004 934 Original Article comment C. CHILTON
PATIENT SAFETY AND SURGERY C. CHILTON – Derby City General Hospital, Derby, UK
INTRODUCTION This comment highlights some of the issues involved in patient safety during their surgical journey. I discuss various aspects of the systems within which clinicians work, and the role of human behaviour, to illustrate how accidents arise. Hopefully it will encourage further thought and debate, to improve surgical systems and safety. PATIENT SAFETY – ‘TOP 10’ ISSUES • Patient safety is paramount and should guide all doctors actions. Primam non nocere – first do no harm. • Patient safety should be part of all doctors early and continuing education and training. A clear understanding of the risks and hazards, together with the mechanisms to prevent accidents, should be a natural, conscious part of all doctors’ daily life. • Patient safety should be a reality and a real concern of all who practice medicine. Clinical Governance sadly has not yet properly involved doctors and is still nurse/ management led. • Patient safety should be the concern of all people involved in patient care, however distant their efforts are from direct patient contact. Teamwork involves all members of staff. • Patient safety should be entrenched in the culture of the organization. Blame should not be the driving force, but there should be a genuine concern for and careful planning of accident avoidance. Pride in patient safety and not fear should be the rule. • Patient safety is not just the responsibility of the doctor. The patient and their carers have a role and duty of care for themselves.
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• Patients safety is the prime duty of those involved in organizing, managing and controlling medical practice. They must provide the environment, staff, equipment and support for all actions doctors have to take on behalf of their patients. • Safety should not be seen as ‘special’ to the NHS. There is much to learn from other organizations and institutions about how to improve patient safety. • Patient safety should be a national effort. Safety should be an active process responding to changes in modern treatments and attitudes. • Patient safety should include all patients. There are some who are more vulnerable and we should take special care of those who cannot take care of themselves.
PATIENT SAFETY – ‘TOP 10’ AREAS FOR IMPROVEMENT RECRUITMENT More attention needs to be given to recruitment into medicine. Surgery needs special skills which include communication, clinical aptitude, attitude and manual dexterity. Where the evidence exists, physical skills and psychometric testing should be included to select surgeons and guide them into appropriate surgical specialities. HUMAN ERROR Human personality, behaviour and interpersonal relationships affect all events and their outcomes. The personal relationship and bond of trust between the surgeon and
the patient is vital. The contract between the surgeon and the patient is the key to achieving agreed outcomes. Risks sometimes have to be taken but a clear understanding, a sound contract and good teamwork can often reduce these to acceptable and predictable levels. Most human errors are complex, multifactorial and are caused or enhanced by deficiencies in the organization. The role of human error in medical accidents needs to be explored much more carefully. Proper training should be introduced to prevent such events and modify personal behaviour for the best. Patients must come first. There is no such thing as a brave surgeon – only a brave patient. RESOURCES Surgery has become safer but is still dangerous. High-technology surgery needs many skilled people, beds, investigations and equipment to make it work. For surgeons to have to embark on a programme of care or surgery without proper resources is bad practice, potentially dangerous and unacceptable. MANAGEMENT Management need to be properly informed about the resources needed to ensure that patients are treated with care and safety. Management need to support surgical teams and not only recognize and reward successes but also understand and handle the inevitable failures objectively. Management needs to be lean, supportive, understanding and in tune with hospital practices and processes. Management needs to understand central directives but be free to modify practices to fit in with local needs and imperatives. SYSTEMS Systems of checks and balances need to be in place to reduce risk and ensure the patient’s safety. Some of these systems are timeless, logical, practical and work. Some are outdated and inappropriate, and must be changed. These systems need to be open, transparent and regularly audited. At each critical stage, key components needs to be in place before the next stage can take place – a safety net to reduce risk. 463
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Where accidents happen the procedures to examine the causes, implement change or take action must be clear, precise, speedy, effective and not judgmental. Where an accident has happened and the patient is unhappy the complaints procedure to address patients’ worries and questions and prevent further accidents must be transparent, open and relevant. EQUIPMENT Working with old, outdated, poorly functioning, unreliable and inappropriate equipment is the everyday experience of all doctors in the NHS. This is unacceptable. Proper funding for new equipment and replacement programmes for old equipment are essential. TRAINING, APPRAISAL AND ASSESSMENT There is a woeful lack of training at all levels in the culture of teams, teamworking and safety in the NHS. Doctors should be directly involved in safety issues and accident prevention. This training has to be relevant, practical and achievable, and not cumbersome and overloaded with paperwork, but fun, relevant and related to promotion and reward.
Unless surgeons know what is being done and to what effect to their patients they cannot make the changes necessary to improve the efficiencies and safety of the service. All surgical services should be exposed to the same process of Audit and Clinical Governance. This is accepted in the NHS and private practice, and should also apply to the new Diagnostic and Therapeutic Centres run by imported teams of surgeons. Patients’ long-term safety must not be compromised by short-term expediency. EXTERNAL FACTORS New European legislation, Department of Health targets and NHS reconfigurations are examples of external factors that can make operations become a chore rather than a fulfilling exercise to help patients and teach a new generation of surgeons. It is time to give up the use of the word ‘theatre’ and to adopt the American term ‘Operating Room’. Surgery is not theatre, drama or play-acting; it is real, serious and dangerous. It demands a duty of respect and care and that surgeons do their best for their patients at all times.
CONCLUSIONS It is evident that the surgical patient’s journey is littered with potential hazards; it is the surgeon’s job to recognize these possible problems and set systems and training in place to minimize them to acceptable levels. Audit allows these processes to be revisited and revised, to continually improve patient safety – our key role together.
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AUDIT The NHS has not been and is still not prepared to properly fund information technology and audit systems. These systems should be staffed by audit/data clerks, and clinical time released for audit to take place effectively.
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Despite all the best laid plans accidents have, do and will continue to happen; that is the nature of human existence. However, with care and attention these can be reduced to levels that are almost acceptable. Safety is no accident.
Brennan TA, Leape LL, Laird NM et al. Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. NEJM 1991; 324: 370–6 Leape LL, Brennan TA, Laird N et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. NEJM 1991; 324: 377– 84 Vincent C, Neale G, Woloshynowych M. Adverse events in British hospitals; preliminary retrospective record review. Br Med J 2001; 322: 517–9 Bryan Sexton J, Thomas E, Helmreich R. Error, stress, and teamwork in medicine and aviation: cross sectional surveys. Br Med J 2000; 320: 745–9 Reason J. Managing the Risks of Organisational Accident. Ashgate. Aldershot (1997). From ‘An Organisation with a Memory; Report of an expert group on learning from adverse events in the NHS’. London: DOH, Stationary Office, 2000
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