Reduced overtreatment and improved quality of life in men with prostate cancer
Group leader: Professor Anna Bill-Axelson
Prostate cancer is the most common cancer in men with approximately 10,000 new cases per year in Sweden. Since the introduction of prostate-specific antigen (PSA) blood testing in the 1990s, the incidence of prostate cancer has greatly increased while mortality has remained unchanged. This is largely because the PSA test means that we find tumors very early where many of the tumors would never lead to death for the patient. According to the national care program, men with low-risk tumors should be offered active surveillance - recurrent follow-ups with PSA tests and prostate biopsies. If the tumor shows signs of progression, the patient is recommended curative treatment with surgery or radiation. Although active surveillance is an attractive approach to reduce overtreatment and avoid side effects of treatment, the optimal design of surveillance programs has not yet been defined. Up to date, there is no randomized evidence to guide clinicians in the decision when radical treatment is likely to be needed and beneficial. In Sweden today, about 75% of men who are diagnosed with low-risk prostate cancer goes to active surveillance, but due to the lack of evidence when curative treatment needs to be initiated, about 30% receives curative treatment within 5 years due to unspecific signs of change such as PSA increase. This means that a large proportion of patients who have very little risk of developing a deadly prostate cancer undergo curative treatment with frequent side effects such as urinary leakage, erectile dysfunction and intestinal disorders as a result. A randomised multicentre trial is the most rigorous and least biased study design to address the question of the safety of standardised triggers in active surveillance. High level evidence from an RTC is needed to inform clinical practice guidelines which currently lack clarity and consistency around specific indicators for initiation of curative treatment. We are therefore currently running the Scandinavian Prostate Cancer Group study number 17 (SPCG-17), in which we compare current practice with standardised triggers for curative treatment in men on active surveillance.
Many men today choose to take a PSA test. However, PSA as a diagnostic marker is nonspecific and an increased PSA value therefore requires further examination of prostate biopsies in order to be able to diagnose prostate cancer. Autopsies have shown that microscopic prostate cancer occurs in 30-70% of men over the age of 60 who have died of causes other than prostate cancer. This high prevalence of the disease results in 25-50% of men taking biopsies being diagnosed with prostate cancer. In Sweden, the National Board of Health and Welfare has said no to population-based screening with the PSA test, but recommends that all men who want to take a PSA test should be informed about the pros and cons of the PSA test before taking the test. PSA is a good marker for monitoring treatment effects after both curative and palliative treatment. But today there is no evidence for which PSA values should trigger curative and palliative treatments, and the use is therefore arbitrary. Knowledge is needed about how PSA is best used and evidence of which PSA values indicate that curative and palliative treatment are beneficial.
In Sweden, nearly 100,000 men live with a prostate cancer diagnosis. What is the patient's experience of living with untreated cancer? How do the men who go into active surveillance experience their quality of life? The lack of knowledge leads to uncertainty and difficulties in following the national guidelines recommending active surveillance.
The overall aim with our research is to strengthen the state of knowledge, to reduce overtreatment and to improve the quality of life for men with prostate cancer. The research group is working on the following projects:
- Quality of life in men with prostate cancer
- PSA database Uppsala-Örebro
1. SPCG-17 – Prostate Cancer Active Surveillance Trigger trial
Although active surveillance might convey substantial benefits compared with routine initial curative treatment of low-risk disease, randomized evidence for when disease progression should trigger treatment with a curative intent is missing. Currently, decisions to re-biopsy and initiate curative treatment are not guided by any set criteria and tend to be at the clinician’s discretion. To address the knowledge gap in relation to safe triggers for treatment in active surveillance for low to intermediate risk prostate cancer we have started a multicentre randomized trial comparing current practice with standardized triggers for initiation of curative treatment. The trial aims to test a set of standardised rules around when to undertake a repeat biopsy and when to initiate curative treatment for men on active surveillance. In all other respects standard care will remain the same. Our hypothesis is that standardized triggers will reduce overtreatment and subsequent side effects, without increasing disease progression and prostate cancer mortality. The trial is a collaboration between hospital sites in Sweden, Finland, Norway, Denmark and the UK, with Anna Bill-Axelson as the coordinating PI. Men from participating sites who are eligible for active surveillance, fulfil the eligibility criteria and give informed consent are randomised to either 1) current practice or 2) an AS protocol of standardised triggers for re-biopsy and initiation of treatment (based on MRI and histopathology findings). Patients in both arms will be followed up with six-monthly PSA tests, an annual clinical examination and two-yearly MRI over the time that they remain on AS. Decisions to re-biopsy or commence curative treatment are only to be made on the basis of per protocol specified triggers. In the comparison arm (current practice) decisions to re-biopsy and to initiate treatment are at the clinician’s discretion or according to local protocols. The primary endpoint to assess safety is progression-free survival. This is defined as cumulative incidence of PSA relapse following curative treatment and cumulative incidence of androgen deprivation therapy in untreated men. Assessment of the primary endpoint will occur one year after the enrolment phase is completed and at three-yearly intervals until the conclusion of the study at the 10-year follow-up point. As of June 2021, just over 1000 out of the proposed 2000 men have been recruited. The SPCG-17 trial is part of Mats Ahlberg’s dissertation work.
2. Quality of life in men with prostate cancer
Quality of life in men with low-risk prostate cancer
Within this project, quality of life in men with low-risk cancer is studied. In a sub-study, all men who were diagnosed with low-risk prostate cancer in 2008 were asked about participation in a study comparing men in active monitoring with men who received curative treatment, with regard to symptoms and quality of life. Results from this research are published in Oskar Bergengren’s doctoral thesis from 2021.
Study of quality of life within the SPCG-17 trial
Within SPCG-17, a quality of life study is conducted, in which the men who have given consent for participation completes a web-based quality-of-life questionnaire every two years during the follow-up in the trial. The questionnaire contains both study-specific questions and EPIC-26. Responsible for the study are Anna Bill-Axelson and Eva Johansson.
Eva Johansson also prospectively studies how the quality of life is affected during active surveillance within the Study of Active Monitoring in Sweden (SAMS).
Study of quality of life within the SPCG-4 trial
Within SPCG-4 (see below), a quality of life study is also conducted. The men participating in the study have filled in forms with questions about urinary tract and sexual dysfunction, as well as questions about quality of life and anxiety. The first results were published in the New England Journal of Medicine in 2002. The results of long-term follow-up on symptoms and quality of life after radical prostatectomy compared to expectancy were published in Lancet Oncology in 2011 and further sub-studies are ongoing. Eva Johansson's published thesis from 2011 is based on results from the study.
This project collects data from all men who have taken PSA tests in the Uppsala-Örebro region between the years 2005-2015. To this cohort, we then link data from the National Prostate Cancer Registry (NPCR) for information on tumour characteristics and treatments in those diagnosed with prostate cancer, the LISA database for education and socioeconomic data, the Cause of Death Register, the National Patient Register for co-morbidity information, the Total Population Register, as well as the Medicines Register for information on hormonal therapy. The project studies, among other things, patterns for diagnostic tests as well as for curative and palliative treatment.
In Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), we compared radical prostatectomy with watchful waiting among men with localized prostate cancer. Enrolment, which began in 1989, predominantly included men with clinically detected tumours. The first analysis was done in 2002 and analyses have thereafter been performed every third year with publications in New England Journal of Medicine and Journal of the National Cancer Institute. In the follow-up study conducted 29 years after the start of the trial, at a point at which 80% of the men enrolled had died, we analysed whether the survival benefit after radical prostatectomy continued, whether the benefit differed according to age at diagnosis, whether protocol violations had biased the results, and how many years of life, on average, had been saved for each man after radical prostatectomy. We also investigated whether histopathological variables predicted a long-term prognosis in the radical-prostatectomy group.
After 29 years of follow-up, lower overall mortality, lower mortality due to prostate cancer, and a lower risk of metastasis prevailed in the radical-prostatectomy group. The findings from a per-protocol analysis with adjustment for nonadherence to the assigned treatment did not differ from the main findings from the intention-to-treat analysis. At 23 years of follow-up, radical prostatectomy resulted in a mean of 2.9 years of life gained. Extracapsular extension and a Gleason score of 8 or 9 in the radical-prostatectomy group were strong predictors of death from prostate cancer.
We are collaborating with the British study ProtecT, which is investigating PSA as a marker for intervention, as well as with Harvard Medical School of Public Health in a project investigating biomarkers.
PcBaSe is a database for clinical epidemiological research on prostate cancer that is based on interactions between the National Prostate Cancer Registry (NPCR), which is a national population-based quality registry, and other national registers. PcBaSe enables us to study unusual but important consequences of a prostate cancer diagnosis. Anna Bill-Axelson, together with the PcBaSe chief investigator Professor Pär Stattin, has studied the risk of suicide after diagnosis. Magdalena Lycken have studied patterns of palliative care and possible socio-economic or regional differences, three years before death in prostate cancer. She also published results from studies on the risk of hormone therapy after curative treatment. Eva Johansson investigates consequences correlated to the use of prescribed drugs for erectile dysfunction, as well as sick leave following radical prostatectomy. Furthermore, we have also studied the incidence of infections following prostate biopsies, in collaboration with Karl-Johan Lundström from Östersund Hospital, as well as the risk of bowel obstruction and abdominal pain after robotic-assisted laparoscopic radical prostatectomy compared with open radical prostatectomy.
Uppsala University Psychosocial Care Programme (U-CARE) is an initiative where cancer patients who show signs of depression (according to the self-assessment form HAD) are randomized between standard treatment and internet-based cognitive behavioural therapy.
Prostatacancerpodden – a prostate cancer podcast
In the urologist’s work day there is often limited time to inform patients, while there is a lot of information a man who has been diagnosed with prostate cancer should have access to in order to decide about treatment. In support of patients, professor and urologist Anna Bill-Axelson has started the podcast Prostatacancerpodden, which is a source of information for anyone who wants to know more about prostate cancer, whether you are a patient, a relative, or just interested. In each episode, Anna interviews and talks with other colleagues about what prostate cancer is, about screening and the pros and cons of the PSA test, about different treatment options, etc. In another episode, we hear a story about the experience of being both a prostate cancer patient and a doctor. The podcast also addresses mental wellness and depression in cancer.
The fact that patients are not used to receiving information about prostate cancer via radio is known to us from a study in which several thousand men answered how they sought and received information. The hope is that a radio podcast about prostate cancer will be able to change this and we will therefore in a few years do a new study where we will among other things ask the men from where they received information about the disease. The purpose of this study is to see if podcasts are a good way to disseminate information.
Members of the research group 2021
Anna Bill-Axelson MD, Professor
Eva Johansson MD, PhD
Oskar Bergengren MD, PhD
Mats Ahlberg MD, PhD student
Hans Garmo, Associate Professor, Statistician
Ulrika Åberg PhD, Research Coordinator
Organisations that support our research
Swedish Research Council (VR)
Nordic Cancer Union
Swedish Cancer Society (Cancerfonden)
Percy Falk Foundation (Percy Falks stiftelse)
Swedish Prostate Cancer Federation (Prostatacancerförbundet)
Region Uppsala (ALF)