This multicentre prospective study with a high response rate of 89% at 35 days provides generalisable quantitative data about the events occurring in the 35 days after a first prostate biopsy. The findings are based on patient reported outcomes and verifiable criteria, including healthcare resource use. Whereas prostate biopsy was reasonably well tolerated in most men, a few men rated post-biopsy pain and infective/haemorrhagic symptoms as a major/moderate problem—7.3% for pain, 5.5% for fever, 6.2% for haematuria, 2.5% for haematochezia, and 26.6% for haemoejaculate. Immediately after biopsy, 10.9% reported that they would consider further biopsy a major or moderate problem; seven days after biopsy, this proportion had increased to 19.6%. A negative attitude to repeat biopsy was associated with unfavourable experience after the first biopsy, particularly pain at biopsy; differences were evident between centres carrying out the biopsies. Consultation with a healthcare professional (usually their general practitioner) was reported by 10.4%, most commonly for infective symptoms.
Transrectal ultrasound guided biopsy of the prostate is an ambulatory procedure commonly carried out in consulting rooms and outpatient and radiology departments in small and large hospitals. Although accurate figures for the number of procedures carried out in the UK each year are difficult to elicit, approximately 37
000 new cases of prostate cancer are diagnosed annually (http://info.cancerresearchuk.org/cancerstats/types/prostate
), with a cancer detection rate at biopsy of around 35%.17
Assuming that around 100
000 procedures are carried out every year in the UK alone would thus be reasonable.
The results of this study are particularly relevant to screening for prostate cancer rather than the performance of prostate biopsy for confirmation of a diagnosis in clinically evident disease. The cohort is drawn from asymptomatic men, invited for PSA testing in the context of a large randomised controlled trial (ProtecT), with a first biopsy at a PSA concentration of 3.0-19.9 ng/mL, a range commonly held to be appropriate for detection of localised prostate cancer suitable for treatment with curative intent. None of the men had repeat biopsy during the timeframe specified. Particular emphasis was placed on the perception of the man having the biopsy, as well as the identification of adverse events. This emphasis allowed the study to measure how a man perceives the degree of “problem” associated with individual symptoms resulting from a first prostate biopsy. Cross referencing these perceptions with healthcare resource use provided useful triangulation. Maintaining a high response rate of 95% at seven days and 89% at 35 days is a particular strength of the study.
A significant number of men experienced difficulties during or after the biopsy, primarily associated with pain, sepsis, or bleeding. Very few men experienced no symptoms at all (2.1%, grade 0) in the five weeks after biopsy. Of those who did experience one or more symptoms, most considered them to be of little consequence (64.6%, grade 1). The remaining third experienced adverse events that they considered to be a moderate or severe problem. Of interest, the presence of blood in a man’s ejaculate (haemoejaculate) after biopsy is seldom reported in the literature and is often labelled as a “minor” adverse event. In this study, haemoejaculate was perceived as a moderate to severe problem for around one quarter of sexually active men (table 2). Further investigation of the problems generated by this symptom is warranted, and information about its duration and persistence should be given to all men having biopsies.
During initial counselling before PSA testing, men are informed of the possible requirement for repeat biopsies beyond the first procedure, in the event of equivocal results or a benign biopsy with persistent risk factors such as a persistently raised serum PSA concentration. A recent study from the United States reported that 38% of men having a first biopsy will have a repeat procedure within five years of the initial biopsy; the proportion reaches 44% in men under the age of 70 years.23
Several studies have shown that repeat biopsy leads to a detection rate for prostate cancer of 19-59%,24 25 26
so understanding how a first biopsy affects a man’s attitude to additional procedures if needed is essential. In this study, 11% and 20% of men reported an unfavourable attitude to repeat biopsy immediately after biopsy and seven days later; pain experienced at biopsy and infective symptoms in the week after biopsy were strongly associated with this response. Systematic TRUS-Bx was introduced initially without local anaesthetic, although this has been adopted in clinical practice more recently.5 8 9 27
Meta-analyses have described a significant reduction in pain scores with periprostatic nerve blocks28 29
; doubt remains, however, as to whether the reduction in pain scores translates to clinically meaningful changes, particularly as infiltration of local anaesthetic itself has been shown to be associated with pain.30
The association between levels of pain experienced and attitude to having repeat biopsy described in this study is an important observation that supports the mandatory use of periprostatic nerve blockade with local anaesthetic. Even among centres where local anaesthetic was routinely administered, inter-centre variability in its effect existed. This suggests that the technique of administration may need to be standardised to ensure effectiveness of local anaesthesia.
As well as resulting in a negative attitude to re-biopsy, infective complications were the most common reason for seeking medical advice or primary care intervention (10.4%). Most symptoms were evident within seven days of biopsy, with a small proportion of men continuing to report symptoms for up to five weeks after biopsy (box). This information is particularly valuable for general practitioners when counselling patients before PSA testing. The American Urological Association’s best practice policy statement recommends administration of a fluoroquinolone as uniform antimicrobial prophylaxis in all men having TRUS-Bx.31
Current practice, however, has been influenced predominantly by randomised controlled trials indicating the efficacy of a single dose of ciprofloxacin in reducing the incidence of infective complications after TRUS-Bx32 33
; subsequent studies have suggested that prolonging treatment to three days results in superior clinical effectiveness.34
A recent report has identified an increasing rate of sepsis related admission to hospital after prostate biopsy in the decade between 1996 (0.6%) and 2005 (3.6%).35
This may be related to a general reduction in peri-biopsy antibiotic use,36
but the development of quinolone resistance may also be implicated.37 38 39 40
Against this backdrop, antibiotic prophylaxis for TRUS-Bx is universally used, but without consensus on best practice.41
We have shown some evidence of differences in infective complications between centres, but our study was not specifically designed to evaluate the effectiveness of antibiotic prophylaxis; this warrants further prospective investigation.
The classification of adverse events described in this study is similar to that described after systemic chemotherapy. It is based on a combination of reported events and their effect from a patient’s perspective. Its wider use needs further validation and is likely to show the need to standardise and refine the technique of prostate biopsy to minimise its adverse events. No fatal events occurred in our cohort. This is not surprising, as our participants were relatively healthy with an upper age limit of 69 years and no symptoms. Mortality after prostate biopsy has been reported as ranging between 0.09% and 1.3% at 120 days,35 42
and it is associated with older, less healthy men.
In contrast with a large retrospective Canadian study referred to earlier,35
we found no difference in our prospective study in hospital admission rate (grade 3 adverse event) between participants with cancer and those without (1.7% v
1.1%). The findings of the Canadian study may result from the investigation of a population at different risk or, as acknowledged by the authors, from inaccuracy in coding associated with its retrospective nature.
Limitations of study
The ProBE study cohort included asymptomatic men aged between 50 and 69 years presenting for a first prostate biopsy after a PSA test, received through the ProtecT study during the period February 2006 to May 2008. The ProBE study was carried out over this limited period, sampling approximately 11% of the ProtecT participants. The cohort did not include men seen in routine UK clinical practice with urinary symptoms or clinically suspected prostate cancer. Of the men eligible for inclusion, 65% were recruited and thus are likely to be representative of the men who attended for PSA testing within the ProtecT study. Embedding the ProBE study in the ProtecT trial was beneficial, providing a standardised biopsy template and recruitment from a wide range of practices across the UK and improving compliance with follow-up. However, participants had responded to a single written invitation to attend for PSA testing sent out via general practices, so non-responders may not be represented in this study. The observations are likely to remain valid in the context of men seeking PSA testing for detection of prostate cancer.
In the absence of nationally agreed, evidence based patient information leaflets, each centre delivered its own information about the biopsy process, which may have influenced men’s views. Recall bias may also have occurred for recording the duration of symptoms, as men were asked to summarise their experience over the previous four weeks in the 35 day questionnaire. For the main analyses, we required data with evaluable responses from both the seven day and 35 day questionnaire assessments. This reduced the numbers and may have led to some degree of underestimation of the prevalence of adverse events. Although relevant to the overall outcome, some of the reported symptoms (such as fever/shivers) may not have been related to the biopsy itself and may have inadvertently influenced a negative attitude to repeat biopsy.
Administration of local anaesthesia is important in determining pain experienced, but other factors, such as environment, training, education, and nursing care, will clearly affect anxiety and pain. We have explored some of these factors in a linked qualitative study (data not included). Similarly, although we have sought men’s initial and early views on the acceptability of repeat biopsy, attitudes may change with time; we shall therefore follow up this cohort carefully to analyse the re-biopsy rate and assess patients’ subsequent views.
While healthcare providers await further evidence to decide whether screening for prostate cancer should become public health policy, primary care physicians need to be well informed of the risks and adverse events related to TRUS-Bx as well as PSA before testing. The findings of this study contribute further generalisable quantitative data about the potential harms associated with making a diagnosis of prostate cancer in asymptomatic men.
The ProBE study investigated a large cohort of men aged between 50 and 69 years who had TRUS-Bx for the first time as a result of a PSA concentration between 3.0 and 20 ng/mL. The cohort comprised 65% of eligible men biopsied within a trial population. The results are likely to be generalisable to all asymptomatic men in this age group who seek diagnosis of prostate cancer through PSA testing and in the context of screening. They may, however, not be applicable to younger or older men, those with clinical evidence of prostate cancer, or men who have previously had prostate biopsy.
After prostate biopsy, one third of men having first time TRUS-Bx for a high PSA reported moderate to severe biopsy related symptoms. Immediately after TRUS-Bx, one in 10 men had an unfavourable attitude to repeat biopsy, rising to one in five later. This was associated with adverse events in the seven days after biopsy and seemed to affect younger men more; as these men are most likely to benefit from early diagnosis of prostate cancer as well as require re-biopsy, this requires further investigation. Within 35 days of biopsy, 1.3% of men required admission to hospital and a further 119 (10.4%) men initiated a biopsy related consultation with their general practitioner (n=92), urology department nurse (n=14), or other source of medical advice (n=13) such as NHS Direct, most commonly for infective symptoms. The adverse event classification scheme described may help to show variation in rates of adverse events across centres that arise from differences in information and biopsy technique. Training, protocols, and consistent reporting methods should be considered to achieve excellence in practice. Information for patients about biopsy should be standardised and include the findings of this study, so that men and physicians are fully informed about the risks and benefits of the diagnostic process before they embark on prostate cancer detection.
What is already known on this topic
- Prostate biopsy is essential for diagnosis of prostate cancer, but its acceptability and effects have rarely been investigated prospectively
- Prostate biopsy is thought to be well tolerated, but little is known about the effect of adverse events on men, their attitude to re-biopsy, or their subsequent use of healthcare resources
- Prostate biopsy can be associated with considerable morbidity, including sepsis, pain, bleeding, and even mortality, but at unknown rates owing to variable reporting
What this study adds
- At seven days after biopsy, 39% of men had pain, 12% had fever, 64% had haematuria, 33% had rectal bleeding, and 94% of those who were sexually active had haemoejaculate; all symptoms were less prevalent at 35 days
- Men rated only a small proportion of these events as serious, with the exception of haemoejaculate in those who were sexually active, with one in four describing this as a moderate/major problem
- Immediately after a first biopsy, one in 10 men had an unfavourable attitude to a repeat procedure, increasing to one in five at seven days
- After a first biopsy, one in 10 men sought help from primary care, and one in 100 needed hospital admission within 35 days of the procedure