ANDROLOGY AUSTRALIA STATEMENT ON PSA TESTING FOR PROSTATE CANCER

ANDROLOGY AUSTRALIA STATEMENT ON PSA TESTING FOR PROSTATE CANCER Population-wide screening for prostate cancer using the current assessment tools of prostate specific antigen (PSA) testing and/or digital rectal examination (DRE) cannot be recommended until the results of randomised controlled trials are complete. It is recognised that de facto screening for prostate cancer is widespread in Australia as evidenced by increasing rates of PSA testing. PSA testing has the potential to benefit some men by diagnosing potentially curable early stage disease but be harmful to others due to the identification of slow growing cancers that may never have been clinically significant and invasive treatment may therefore be unnecessary. Recent changes in prostate cancer mortality rates are not readily explained, but it remains plausible that it may be due in part to testing, early diagnosis and treatment. It is imperative that men requesting prostate cancer testing are appropriately counselled about their prostate cancer risk and the potential benefits, limitations and implications of PSA testing prior to being tested; and in doing so are supported by their practitioner to make an informed decision consistent with their values and personal preferences. If a biopsy result reveals prostate cancer, all treatment options must be discussed. Depending on the man’s age, general health and the volume and grade of the tumour, these may include active surveillance with PSA and periodic biopsies. If invasive treatments are recommended the potential benefits, limitations and side effects must be fully discussed to assist the man to make a treatment decision consistent with his values and personal preferences. • Andrology Australia is a collaborative initiative involving leading health professionals and research organizations from around the country and funded by the Australian Government Department of Health and Ageing to raise the awareness of a range of men’s health disorders, including prostate cancer. Andrology Australia acknowledges the community and professional debate about PSA testing for prostate cancer. Andrology Australia continues to work with other organisations to develop materials for both the community and health professionals that identify the issues associated with testing for prostate cancer; It is clear that, despite the limitations of knowledge about prostate cancer or consensus of the merits of PSA testing, there has been a widespread change in health-seeking behaviour with more men now seeking information about being tested; This statement aims to provide information to the community and medical profession about the current state of knowledge to assist men to make informed decisions about prostate cancer testing and the consequence of that decision. Prostate cancer detection and management involves many complex issues. When considering prostate cancer testing and its consequences, three stages can be considered: Stage 1: Identification of men at risk of having prostate cancer (PSA/DRE): issues of the sensitivity and specificity of testing Stage 2: Establishment that prostate cancer is present (TRUS biopsy) and its likely biological behaviour (Gleason staging): prediction of biological behaviour and risk of cancer related death and morbidity Stage 3: Option for intervention (surgery, radiation etc) or observation: impact of age, co-existing illness, biopsy characteristics and personal factors. Depending upon the results, it is likely an individual man undergoing initial testing may experience each stage in sequence. It is therefore difficult to discuss PSA/DRE testing in isolation without some consideration of the risks and benefits of subsequent biopsy and treatments. This statement therefore provides some background information to all 3 stages. Yet an important perspective is that: ‐ ‐ ‐ most men ‘drop out’ at stage 1 with normal results (albeit with some being falsely reassured); about 1 in 4 men are faced with the assessment burdens of stage 2, and only about 1 in 40 men (ideally of younger age with organ confined disease) are faced with the difficult choices of stage 3 about undergoing invasive treatment and the risk of common and significant side effects. Yet for a significant proportion of men diagnosed with prostate cancer, surveillance (‘watchful waiting’) is appropriate, with delayed intervention if progression occurs. Version: 14/05/2009 May 2009 • • • Page 1 of 6 BACKGROUND: Rates of PSA testing in Australia • Andrology Australia conducted the first comprehensive and representative study of the reproductive health of 6000 Australian men and found that in 2003 approximately 50% of men over the age of 40 years had had at least one PSA/DRE test1. In view of the subsequent promotion of PSA testing in the media, including the personal experience of public figures afflicted by prostate cancer, this rate of testing has almost certainly risen. It is estimated that participation in voluntary PSA testing is similar to the national participation rate for the target group of women in the BreastScreen Australia Program (52% of men aged 50-75 years2, compared with 56% of women aged 50-69 years3). Australian data suggests that there has been reduction in the incidence of advanced prostate cancer and prostate cancer mortality4 in association with more widespread PSA testing. One explanation may be that PSA testing results in the detection of potentially life threatening cancers at a stage at which intervention works. However this assertion can only be supported by large randomised controlled trials with participants followed for appropriately long periods of time. Other explanations could explain such observations such as: o widespread PSA testing may detect a higher proportion of low-risk patients who have an excellent long-term prognosis whatever treatment option is chosen o misattribution of the cause of death o Other factors in addition to PSA testing, such as improved treatment regimens, may impact on prostate cancer mortality rates • There is still considerable debate as to whether changes in Australian data warrant changing the current recommendations with regard to population-wide screening for prostate cancer. PSA testing for diagnosis of prostate cancer • Testing levels of prostate-specific antigen (PSA testing) in the blood combined with digital rectal examination (DRE) is considered to be a valid means of identifying men at risk of having prostate cancer. However the use of population-wide PSA testing (PSA screening) is contentious as there is insufficient evidence that such a programme would reliably lead to the identification of tumours that would otherwise have resulted in cancer-related death or disability. Furthermore populationwide PSA screening may lead to unnecessary and harmful interventions in many men with consequences such as infection following prostate biopsy, urinary incontinence and erectile dysfunction following treatments and psychosocial impacts. Even on a case-by-case basis (individual PSA testing) the clinician faces real dilemmas about when and how to use PSA testing in routine clinical practice as these same uncertainties persist. The lack of specificity of PSA testing in discriminating cancer from more common non-cancerous (benign) prostatic problems that raise PSA levels, and limited evidence to support that PSA-based testing helps reduce overall mortality rates from prostate cancer, underlies the current absence of recommendation for population-wide screening for prostate cancer by government and professional societies, including the Urological Society of Australia and New Zealand and Cancer Councils of Australia. However, in the absence of evidence, targeted testing of informed individuals is considered appropriate practice. A Cochrane review published in 2006 reported that no robust evidence from randomised controlled trials is available regarding the impact of screening on quality of life, harmful outcomes associated with screening, or its economic value5. The implication of a cancer diagnosis for an individual man is complicated by the fact that in about 1 in 4 men prostate cancer may behave in an aggressive fashion (e.g. spread to lymph nodes and to bone)6 while in another 1 in 4 men the cancer remains indolent (e.g. remaining localised to the prostate).6, 7 A combination of serum PSA, biopsy findings and clinical staging is used to stratify patients with prostate cancer into low, medium and high-risk disease: high-risk disease shows aggressive behaviour in which the cancer can spread to other parts of the body. Although stratifying is helpful in deciding treatment, it is not perfect. As one cannot reliably predict the behaviour of an individual man’s tumour. In cases where unequivocal features of low or high risk disease are present, the course of action may be clear. However in the majority of cases, one cannot reliably predict the behaviour of an individual man’s tumour. • • • • Page 2 of 6 Version: 14/05/2009 May 2009 • With increasing PSA/DRE testing, about 1 in 4 cancers currently being diagnosed are so-called low risk cancers that they are likely to remain in the prostate and not result in further health problems. For some of these men, invasive treatments may not be the best course of treatment and may result in unnecessary suffering as a consequence of the treatment. Many tumours are indolent and do not lead to poor health outcomes or death: It must be remembered that only 1 man in 8 diagnosed with prostate cancer will die of this disease8 with this percentage varying depending on age and grade of disease at diagnosis, with younger men diagnosed with higher grade disease being more likely to die from the disease (as a result of a lower impact from competing cardiovascular causes of mortality). An increase in PSA levels may reflect a range of benign problems; in contrast PSA levels may be normal in some cases of cancer. An abnormal PSA and DRE may raise the possibility of cancer, but only a biopsy can provide a definitive diagnosis of prostate cancer. Serum free:total PSA ratio has been advocated as providing additional insight in cases with equivocal total levels but the underlying problem with PSA testing remains. The key challenge is to identify men with aggressive cancer, and then to intervene early and effectively. Newer and more specific prostate cancer markers are needed before an effective population-wide prostate cancer screening program could be trialled, recommended or implemented. • • • SPECIFIC POINTS 1. The benefits and risks of PSA screening for prostate cancer is being studied in large overseas clinical trails. Such studies are difficult to perform due to the need for large numbers of participants to be followed closely for long periods of time. Without convincing mature evidence from large, randomised prospective controlled studies, whole population screening using PSA/DRE is not justifiable. Two large multicentre studies recently reported on the effectiveness of PSA testing in the population. The first study9 of 162,000 men, conducted in Europe, reported a 27% reduction in prostate cancer death rates but estimated that to prevent one death, 1068 men would need to be screened and an additional 49 men would have to undergo potentially unnecessary treatment. These treatments would also potentially include surveillance rather than active intervention. The second study10,11 of 76,693 men, conducted in the USA, found no significant effect of screening on the death rate from prostate cancer. The studies suggested that screened men are more likely (40-50 fold) to die from other causes compared to prostate cancer, hence the risk of overtreatment is considerable. Both studies had methodological problems including: 1. in the US study, ‘contamination’ of the control group with half of the participants still undergoing PSA testing. In addition, 44% were tested before recruitment into the study therefore reducing prostate cancer diagnoses within the study. in the European study, differences in protocols across sites, both studies had relatively short follow-up times (5 to 9 years) and therefore small numbers of cancers, and neither study could address whether the small but significant decline in prostate cancer death rates seen in recent years is due to improved treatment protocols and/or to the detection of early (curable) stage disease 2. 3. 4. It must be recognised that these studies are not yet complete and their final conclusions must be awaited. Potential outcomes of such studies may be that PSA screening: • • • works well in reducing deaths from prostate cancer, OR may only work well for some aggressive forms of prostate cancer, OR at a population or widespread level is ineffective or even harmful. It is also possible that methodological limitations in these studies may compromise the strength of the final conclusions. Indeed, preliminary findings from the European7 and US8,9 studies highlight the difficulty in conducting controlled clinical trials on prostate cancer screening as the greater awareness of prostate cancer has increased the rates of PSA testing generally in the community. The findings to date suggest that population wide screening for prostate cancer using the PSA test remains equivocal. Page 3 of 6 Version: 14/05/2009 May 2009 2. Men with a strong family history of prostate cancer (such as in first degree relatives) are at much greater risk of cancer. 2.1 Men with an affected father or brother are twice as likely to develop prostate cancer as men with no affected relatives12,13 and should consider being tested after the age of 40 years. However, they should be given verbal and written information about what a positive test result means and the benefits and risks of treatment, to help inform their decision (see below). Hereditary prostate cancer may develop on average 6 years earlier than non-hereditary prostate cancer although the clinical course and the pathological characteristics are the same7,14, 15,16 2.2 A family history of BRCA2 gene positive breast cancer is also important with male carriers of BRCA2 mutations having a 3.5fold increased risk of prostate cancer17 and an earlier onset of this condition18. Furthermore, the minority of patients with prostate cancer and a family history of breast cancer who harbour a BRCA2 mutation has been reported to have poorer survival rates than those without BRCA2 mutations.19, 20, 21 3. Health practitioners must be informed about the current evidence on PSA testing and prostate cancer management. While a PSA test is simple to order, all health practitioners must recognise that the conversation before testing, and that which follows a suspicious value, may have profound effects on the man’s physical and psychosexual health. PSA testing and information provision should be inextricably linked. It is essential that any practitioner ordering and discussing the PSA test is up-to-date with respect to the evidence and ensures that balanced information is provided in a way that is appropriate to the man’s educational level, personal circumstances, language skills and ethnic setting, and that is responsive to the man’s values and personal preferences.. It is not appropriate to order a PSA test as part of a suite of blood tests unless the patient has been adequately informed. 4. 4.1 A man considering PSA testing should be informed about the following issues: When considering his first PSA/DRE evaluation, the following should be discussed with his health practitioner. Men should be aware that there are controversies about treatment options in prostate cancer and that there are both potential gains and risks from PSA testing. Refer to Resources listed to help guide discussion. • PSA levels rise with normal ageing as the prostate undergoes benign enlargement. Therefore the normal reference interval for PSA levels must be adjusted for age, usually by decade intervals. Even when the PSA level is within the normal range, a rapid rate of rise (termed PSA velocity) such as a doubling over 12 months requires further assessment. A single PSA level at age 40 years ( cutoff 0.6 ng/ml ) and 50 years ( cutoff 1.5 ng/ml ) may be predictive of increased risk of prostate cancer over the next 10-20 years The inclusion of a DRE has been shown to improve detection rates when combined with PSA but it must be remembered that it is only possible to palpate that part of the prostate immediately in front of the rectum 22,23 A suspicious finding will require evaluation by a specialist urologist to determine whether this is due to a growing cancer or another problem such as prostatitis (inflammation due to infection) or benign prostatic hypertrophy (BPH). The limitations of PSA testing should be discussed. ‐ ‐ A normal PSA test (combined with a negative DRE) reduces the likelihood of prostate cancer being present. However there is no threshold PSA level that provides high sensitivity (the ability to correctly identify cancer in men with the disease) and specificity (the ability to correctly exclude men without the disease) with a continuum of risk for all PSA values24. A PSA <1 ng/ml in an untreated man indicates a very low risk of cancer with recommendations for further testing scheduled for 3 yearly25 intervals • • • • ‐ Page 4 of 6 Version: 14/05/2009 May 2009 4.2 • An abnormal PSA result must be confirmed by re-testing Health practitioners should recognise that a positive PSA test followed by a subsequent biopsy showing low-risk cancer may have the potential to cause anxiety and distress for some men. However, providing information and support by practitioners is likely to assist men to maintain a good quality of life without psychosocial stress despite a cancer diagnosis while continuing active surveillance26. Referral to a specialist urologist is imperative for assessment of an abnormal PSA result including a low free/total PSA ratio, or a rapidly rising PSA. Early referral to a specialist urologist is recommended for consideration of transrectal ultrasound (TRUS)-guided biopsy. The urologist must provide full information about the possible TRUS findings, risks and subsequent management options. Health access and resources Training of the medical workforce and the provision of resources for educational materials are the responsibility of government and the profession in partnership. GPs should provide information both to patients who request it and to those who attend requesting general check-ups. Verbal information can be supported with verified written material or via on line sources PSA testing should not be undertaken without the patient’s knowledge (e.g. as an automatic inclusion in a general health check). Andrology Australia recommends that testing of individual patients occurs only after being appropriately informed of the potential gains and risks of testing and following a shared decision-making discussion with their medical practitioners A man seeking PSA testing should receive written, or have access to web-based, relevant material endorsed by reputable professional bodies which is evidence-based (when this is available) and which is presented in an easily intelligible format. It should not be assumed that patients requesting PSA testing are adequately informed. The diagnosis of prostate cancer can cause significant anxiety and stress. In addition to support from their GP, men should be provided with contact details for the various prostate cancer support groups around the country. Rates of death and disability from prostate cancer are higher in Australian men from regional/rural areas compared with urban centres27. A range of explanations can be offered including later diagnoses due to lower rates of health care seeking and/or poorer health care access and resources. • • 4.3 • • • • • • Useful resources to guide discussion with the patient Resources are freely available from: • • Andrology Australia website http://www.andrologyaustralia.org Fingertip Urology at http://www.bjui.org/FingertipUrology.aspx Article: Whether to test for Prostate Cancer Appendix 2 Pertinent Points in Prostate Cancer: Age-related ranges for Caucasian and Asian men Lions Australian Prostate Cancer website http://www.prostatehealth.org.au/ The Early Detection of Prostate Cancer in General Practice: Supporting Patient Choice. Available from: http://www.andrologyaustralia.org/docs/PSAdecisioncard20041007.pdf • • Page 5 of 6 Version: 14/05/2009 May 2009 References Holden CA, Jolley D, McLachlan RI, Pitts M, Cumming R, Wittert G, Handelsman DJ, de Kretser D (2006). Men in Australia Telephone Survey (MATeS): predictors of men’s help-seeking behaviour for reproductive health disorders. Med J Aust. 185:418-422. 2 Carrière P, Baade P, Newman B, Aitken J & Janda M (2007). Cancer screening in Queensland men. Medical Journal of Australia 186 (8): 404–407. 3 Australian Institute of Health and Welfare (2008). BreastScreen Australia monitoring report 2004–2005. Cancer series no. 42. Cat. no. CAN 37. Canberra: AIHW. 4 Smith D, Supramaniam R, Marshall VR, Armstrong BK (2008) Prostate cancer and prostate-specific antigen testing in New South Wales. MJA 189 (6): 315-318 5 Ilic D, O'Connor D, Green S, Wilt T (2006). Screening for prostate cancer. Cochrane Database Syst Rev. Jul 19; Issue 3:CD004720. 6 Freedland SJ, Presti JC Jr, Amling CL, Kane CJ, Aronson WJ, Dorey F, Terris, MK (2003). SEARCH Database Study Group. Time trends in biochemical recurrence after radical prostatectomy: results of the SEARCH database. Urology 61:736-741 7 Klotz L. Low-risk prostate cancer: the trials and tribulations of active surveillance (2008). World J Urol 26:437-42 8 Hamdy FC, Gardiner RA. Editorial: Low-risk prostate cancer (2008). World J Urol 26: 411-4 9 Schroder FH et al. Screening and Prostate-Cancer Mortality in a Randomized European Study (2009). N Engl J Med. 360 1320-1328 10 Andriole GL et al (2009). Mortality Results from a Randomized Prostate-Cancer Screening Trial. N Engl J Med. 360: 1310-1319 11 Andriole GL, Reding D, Hayes RB, Prorok PC, Gohagan JK; PLCO Steering Committee (2004) The prostate, lung, colon, and ovarian (PLCO) cancer screening trial: Status and promise. Urol Oncol 22: 358-61 12 Melia J, Hewitson P, Austoker J (2005). Review of screening for Prostate cancer. BJU Int 95(Suppl 3):1-3 13 Bratt O (2007). What the Urologist should know about hereditary predisposition to prostate cancer. BJU Int 99:743-747 14 Bastacky SI, Wojno KJ, Walsh PC, Carmichael MJ, Epstein JI (1995). Pathological features of hereditary prostate cancer. J Urol 153:987-92 15 Grönberg H, Damber L, Tavelin B, Damber JE (1998). No difference in survival between sporadic, familial and hereditary prostate cancer. Br J Urol 82:564-7 16 Bratt O, Damber JE, Emanuelsson M, Grönberg H (2002). Hereditary prostate cancer: clinical characteristics and survival. J Urol 167:24232426 17 Willems AJ, Dawson SJ, Samaratunga H, De Luca A, Antill YC, Hopper JL, Thorne HJ; kConFab Investigators (2008). Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation. Clin Cancer Res14:2953-2961 18 Agalliu I, Karlins E, Kwon EM, Iwasaki LM, Diamond A, Ostrander EA, Stanford JL (2007). Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. Br J Cancer. 97:826-831 19 Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, Jonasson JG, Olafsdóttir EJ, Olafsdóttir GH, Rafnar T, Thorlacius S, Jonsson E, Eyfjord JE, Tulinius H (2007). Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 99:929-935 20 Dobson R (2008). Prostate cancer patients with BRCA2 mutation face poor survival. BMJ. Jul 10;337:a705. doi: 10.1136/bmj.a705 21 Narod SA, Neuhausen S, Vichodez G, Armel S, Lynch HT, Ghadirian P, Cummings S, Olopade O, Stoppa-Lyonnet D, Couch F, Wagner T, Warner E, Foulkes WD, Saal H, Weitzel J, Tulman A, Poll A, Nam R, Sun P; Hereditary Breast Cancer Study Group, Danquah J, Domchek S, Tung N, Ainsworth P, Horsman D, Kim-Sing C, Maugard C, Eisen A, Daly M, McKinnon W, Wood M, Isaacs C, Gilchrist D, Karlan B, Nedelcu R, Meschino W, Garber J, Pasini B, Manoukian S, Bellati C (2008) Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer 99:371-374 22 Catalona WJ, Richie _]P, Ahmann FR, Hudson MA,Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, et al (1994). Comparison of digital rectal examination and serum prostate specific antigen in the earl), detection of prostate cancer: results of a mu[ticenter clinical trial of 6,630 men. ] Urol 151: 1283-1290. 23 Lodding P, Aus G, Bergdahl S, Frösing R, Lilja H, Pihl CG, Hugosson J (1998). Characteristics of screening detected prostate cancer in men 50 to 66 years old with 3 to 4 ng/ml Prostate Specific Antigen. J Urol 159:899-903. 24 Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, Parnes HL, Coltman CA Jr (2005). Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA 294: 66-70 25 Aus G, Damber JE, Khatami A, Lilja H, Stranne J, Hugosson J (2005). Individualized screening interval for prostate cancer based on prostatespecific antigen level: results of a prospective, randomized, population-based study. Arch Intern Med 165:1857-1861 26 van den Bergh RC, Essink-Bot M-L, Roobol MJ, Wolters T, Schroder FH, Bangma CH, Steyerberg EW (2009). Anxiety And Distress During Active Surveillance For Early Prostate Cancer: A Longitudinal Analysis (2009). J Urology 181(4): 179. Presented at the 2009 Annual meeting of the American Urological Association. Abstract no: 498 27 Coory MD and Baade PD (2005). Urban-rural differences in prostate cancer mortality, radical prostatectomy and prostate-specific antigen testing in Australia. MJA 182: 112-115 1 Page 6 of 6 Version: 14/05/2009 May 2009