Aktive Überwachung des Prostatakarzinoms

Active surveillance is a valuable treatment option in patients with newly diagnosed low-risk prostate cancer. Studies considering a watchful waiting approach showed favourable cancer-specific survival rates in such patients and it is assumed that patients benefit from a definitive therapy if life expectancy exceeds 10-15 years. Therefore active surveillance is especially valuable in older men and in patients with an elevated comorbidity profile.Precise identification of histologically and clinically insignificant prostate cancers is still not possible today. Active surveillance includes regular PSA measurements combined with follow-up biopsies; however, no standardized protocol exists so far. Histological progression in the follow-up biopsy and PSA elevation are the most important criteria for initiating definitive therapy.Today only a minority of low-risk patients join an active surveillance protocol and a substantial proportion of these men leave such a protocol early without evidence of progression. The psychological burden of living with an untreated cancer seems to be responsible for this. Active surveillance has the potential to lead to undertreatment as there is some evidence that prolonged treatment delay might adversely affect outcome of definitive therapy.     

Insignificant Prostate Cancer and Active Surveillance: From Definition to Clinical Implications

Context

Due to early detection strategies, prostate cancer is diagnosed early in its natural history. It remains unclear whether all patients diagnosed with prostate cancer warrant radical treatment or may benefit from delayed intervention following active surveillance.

Objective

A systematic review of active surveillance protocols to investigate the inclusion criteria for active surveillance and the outcome of treatment.

Evidence acquisition

Medline was searched using the following terms: prostate cancer, active surveillance and expectant management for dates up to October 2008. Further studies were chosen on the basis of manual searches of reference lists and review papers.

Evidence synthesis

Numerous studies on active surveillance were identified. The recent inclusion criteria of the studies are rather similar. Keeping the short follow-up of all studies in mind, the majority of men stay on active surveillance, and the percentage of patients receiving active treatment is as high as 35% of all patients. Once a patients requires active treatment, most patients still present with curable prostate cancer. Furthermore, only few deaths due to prostate cancer have occurred.

Conclusions

Active surveillance is an alternative option to immediate treatment of men with presumed insignificant prostate cancer. It seems that criteria used to identify men with low-risk prostate cancer are rather similar, and immediate treatment of men meeting these criteria may result in an unnecessary number of treatments in these highly selected patients. Data from randomised trials comparing active surveillance and active treatment will provide additional insight into outcome and follow-up strategies.     

Active surveillance as a practical strategy to differentiate lethal and non-lethal prostate cancer subtypes

Differentiation between lethal and non-lethal prostate cancer subtypes has become a very important issue in avoiding excessive treatment in an era when prostate-specific antigen (PSA) screening has reduced the rate of prostate cancer deaths by more than 20%. However, it is difficult to determine the patients who may or may not benefit from immediate treatment interventions at the time of the initial diagnosis. The selection of candidate patients who can postpone immediate treatment and undergo follow-ups with a specific surveillance program, or ‘active surveillance,'' is a practical way to minimize overtreatment. In this review, the benefits and risks of active surveillance are discussed. Future perspectives, including imaging and new biomarkers for improving the outcomes of active surveillance programs, are also discussed.     

Quality of life in active surveillance for early prostate cancer

Recently, the prevalence of the prostate-specific antigen screening test for early-stage prostate cancer has increased, but this has also resulted in an increase in insignificant cancers. The treatment outcome of early-stage prostate cancer is excellent, but such a radical treatment also leaves the patient with undesired adverse consequences. To resolve such problems, attention should be paid to active surveillance as a modern treatment option. This study aimed to systematically review the literature about quality of life in prostate cancer patients undergoing active surveillance. Evidence was acquired from PubMed databases in March 2019 using quality of life, prostate cancer, well-being, anxiety, depression, stress, outcomes, active surveillance, radiation therapy and radical prostatectomy as keywords. Five clinical active surveillance studies measured health-related quality of life and related psychological factors, and seven compared active surveillance with other treatments (radical therapy and hormone therapy). Active surveillance was superior to radical therapy for urinary and sexual function. Furthermore, most patients who opted for active surveillance showed lower anxiety and fear of progression, whereas health-related quality of life was maintained. Although active surveillance has the advantage of being non-invasive, its diagnosis and follow-up protocols are unreliable. Because such uncertainty can affect patients’ quality of life, utilization of imaging modalities, such as magnetic resonance imaging, and the development of new biomarkers are required.     

Papel de la resonancia magnética multiparamétrica en la selección y el seguimiento de pacientes en vigilancia activa por cáncer de próstata. Revisión del grupo de Uro-Tecnología (ESUT) de la EAU

IntroductionIn recent years, active surveillance (AS) has gained popularity as a safe and reasonable option for patients with low-risk, clinically localized prostate cancer.ObjectiveTo summarize the latest information regarding the use of mpMRI in the setting of active surveillance (AS) for the management of prostate cancer (PCa).Evidence acquisitionA PubMed-based, English literature search was conducted through February 2020. We selected the most relevant original articles, meta-analyses and systematic reviews that could provide important information.Evidence synthesisThe great importance of mpMRI of the prostate in the setting of PCa diagnosis is its ability to visualize primarily high-grade cancerous lesions potentially missed on systematic biopsies. In several studies, mpMRI has shown an improved performance over clinically based models for identifying candidates which will benefit the most from AS. Although data on prostate mpMRI during follow-up of men under AS is sparse, it holds the probability to improve significantly AS programs by a more precise selection of optimal candidates, a more accurate identification of disease progression and a reduction in number of biopsies. The goal of reassessment of patients undergoing AS is to find the most effective moment to change attitude to active treatment.ConclusionThe value of mpMRI has been recognized due to its high negative predictive value (NPV) for lesion upgrading in low-risk PCa patients. The improvement in imaging detection, and precise diagnosis with mpMRI could reduce misclassifications at initial diagnosis and during follow-up, reducing the number of biopsies.     

Management and survival of screen-detected prostate cancer patients who might have been suitable for active surveillance

OBJECTIVE: Screening practices for prostate cancer have resulted in an increasing incidence of prostate cancers. Our knowledge about which prostate cancers are life threatening and which are not is limited. Thus, for ethical, medical, and economic reasons we need to define which patients can be managed by active surveillance. METHODS: From 1993 through 1999, men from the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC) were screened by two strict protocols, which were based on prostate-specific antigen (PSA), digital rectal examination, and transrectal ultrasound. For this study, men with criteria that reflect current active surveillance studies were selected: those with a biopsy Gleason score < or =3+3 in two or fewer cores, with a PSA density <0.2 and a maximum PSA-level of 15 ng/ml. Clinical stage had to be T1C or T2. RESULTS: Of the 1,014 prostate cancers detected in the prevalence screen, 293 men (28.9%) met the criteria for active surveillance. Their mean age was 65.7 and the mean PSA level was 4.8 ng/ml. Radical prostatectomy was elected by 136 men (46.4%), radiotherapy by 91 (31.1%), and watchful waiting by 64 (21.8%). The mean follow-up was 80.8 months. The eight-year prostate cancer-specific survival was 99.2%; the overall survival was 85.4%. Nineteen men who chose watchful waiting changed to definitive treatment during follow-up. CONCLUSION: Only three men died of prostate cancer, none of whom were on watchful waiting. Our observations provide preliminary validation of the arbitrary selection criteria for active surveillance.     

Formalized prediction of clinically significant prostate cancer: is it possible?

Greater understanding of the biology and epidemiology of prostate cancer in the last several decades have led to significant advances in its management. Prostate cancer is now detected in greater numbers at lower stages of disease and is amenable to multiple forms of efficacious treatment. However, there is a lack of conclusive data demonstrating a definitive mortality benefit from this earlier diagnosis and treatment of prostate cancer. It is likely due to the treatment of a large proportion of indolent cancers that would have had little adverse impact on health or lifespan if left alone. Due to this overtreatment phenomenon, active surveillance with delayed intervention is gaining traction as a viable management approach in contemporary practice. The ability to distinguish clinically insignificant cancers from those with a high risk of progression and/or lethality is critical to the appropriate selection of patients for surveillance protocols versus immediate intervention. This chapter will review the ability of various prediction models, including risk groupings and nomograms, to predict indolent disease and determine their role in the contemporary management of clinically localized prostate cancer.     

Active surveillance for favorable risk prostate cancer: rationale, risks, and results

Active surveillance for favorable risk prostate cancer has become increasingly popular in populations where prostate cancer screening is widespread, due to evidence that prostate cancer screening results in the detection of disease that is not clinically significant in many patients (i.e., untreated, would not pose a threat to health). This approach is supported by data demonstrating that patients who fall into the category of clinically insignificant disease can be identified with reasonable accuracy, and that patients who are initially classified as low risk who reclassify over time as higher risk and are then treated more aggressively are in most cases still cured. An active surveillance approach means (1) identifying patients who have a low likelihood of disease progression during their lifetime, based on clinical and pathologic features of the disease and patient age and comorbidity; (2) monitoring closely over time, (3) establishing reasonable criteria for intervention, which will both identify more aggressive disease in a timely fashion, and not result in excessive treatment, and (4) meeting the communication challenge to reduce the psychological burden of living with untreated cancer. The results of active surveillance, the criteria for patient selection, and the appropriate triggers for intervention are reviewed.     

Watchful waiting versus active surveillance: Appropriate patient selection

The prostate-specific antigen (PSA) screening era has seen dramatic stage and age migration in patients with newly diagnosed prostate cancer. The average serum PSA level of newly diagnosed patients is about 6 ng/dL, and 60% of patients are diagnosed with clinical stage T1c disease. There is evidence that many low-grade and low-stage prostate cancers have a slow growth rate and protracted clinical course, with a very low threat of metastasis or death over a prolonged interval. Many men are also appropriately concerned about the impact of prostate cancer treatment on sexual and urinary function. Therefore, delaying therapy in favor of careful surveillance, with the expectation of delivering curative treatment upon evidence of progression, is an attractive concept. In this review, we discuss active surveillance, contrast it to watchful waiting, and define common inclusion criteria. We compare follow-up regimens and discuss indications and intervention outcomes after active surveillance. Finally, we support well-designed prospective clinical trials that evaluate active surveillance compared with immediate definitive treatment.     

Aktive Überwachung beim Niedrigrisikoprostatakarzinom

In Europe prostate cancer is one of the most common cancers among men. The diagnostics always include a control of the prostate-specific antigen (PSA) level and examination of a representative tissue sample from the prostate. With these findings it is possible to evaluate the degree of progression of the cancer and its prognosis. Several treatment options for localized prostate cancer are given by national and international guidelines including radical prostatectomy, percutaneous radiation therapy, or brachytherapy and surveillance of the cancer with optional treatment at a later stage. For the latter treatment option, known as active surveillance, strict criteria have to be met. The advantage of active surveillance is that only patients with progressive cancer are subjected to radical therapy. Patients with very slow or non-progressing cancer do not have to undergo therapy and thus do not have to suffer from the side effects. The basic idea behind active surveillance is that some cancers will not progress to a stage that requires treatment within the lifetime of the patient and therefore do not require treatment at all. Unfortunately the criteria for active surveillance are not definitive enough at the current time leading only to a delay in effective treatment for many patients. The surveillance strategy has without doubt a high significance among the treatment options for prostate cancer; however, at the current time it lacks reliable indicators for a certain prognosis. Therefore, patients must be informed in detail about the advantages and disadvantages of active surveillance.     

Active surveillance and focal therapy for low-intermediate risk prostate cancer

Low risk and many cases of low-intermediate risk prostate cancer, are indolent, have little or no metastatic potential, and are not life threatening. Major advances have been made in understanding who these patients are, and in encouraging the use of conservative management in such individuals. Conservative management incorporates the early identification of those ‘low risk’ patients who harbor higher risk disease, and benefit from definitive therapy. Based on the current algorithm of PSA followed by systematic biopsy, this represents about 30% of newly diagnosed low risk patients. A further small proportion of patients with low risk disease demonstrate biological progression to higher grade disease. Men with lower risk disease can defer treatment, usually for life. Men with higher risk disease that can be localized to a relatively small volume of the prostate may be candidates for focal, prostate sparing therapy. The results of active surveillance, embodying conservative management with selective delayed intervention for the subset who are re-classified as higher risk over time based on repeat biopsy, imaging, or biomarker results, have shown that this approach is safe in the intermediate to long term, with a 1-5% cancer specific mortality at 15 years. Further refinement of the surveillance approach is ongoing, incorporating MRI, targeted biopsies, and molecular biomarkers.     

Active surveillance for low-risk prostate cancer: selection of patients and predictors of progression

The natural history of prostate cancer is often of long duration, and the disease is incompletely understood. Whether all men with prostate cancer require immediate treatment or whether men with tumors of low malignant potential are being overtreated with potentially harmful therapies is a subject of much debate. Results from a randomized trial that compared watchful waiting and active therapy showed all-cause and disease-specific survival advantages with radical therapy, but the study group was mixed in terms of disease risk; the optimum treatment strategy for men with low risk features remains unclear. Multiple centers are gaining experience with active surveillance and delayed intervention with curative intent for men with prostate tumors of potentially low clinical risk. This Review describes the background studies behind the rationale for active surveillance, thoughts on selection criteria for candidates and some early reported outcomes for active surveillance cohorts. The psychosocial impact of active surveillance on patients is discussed as well as contemporary methods for disease monitoring.     

Active surveillance criteria for prostate cancer: Can they be applied to Japanese patients?

Prostate-specific antigen screening has significantly increased the percentage of men who are diagnosed with low-risk prostate cancer. All men undergoing retropubic radical prostatectomy for primary treatment of prostate cancer from April 2004 to September 2010 in our hospital were examined in order to determine whether active surveillance criteria could be applied to Japanese men. From pathological data of prostate biopsies, whether these men met five published criteria for active surveillance (Johns Hopkins Medical Institution, Prostate Cancer Research International: Active Surveillance Study, University of California, San Francisco, Toronto and Kakehi criteria) was evaluated. Men who met any of the criteria had a statistically significant lower extracapsular extension rate and organ-confinement rate. From the view of the possibility of Gleason upgrading and organ-confinement rate, the Johns Hopkins Medical Institution and Prostate Cancer Research International: Active Surveillance Study criteria showed to be appropriate for Japanese patients. However, the present study had limitations of selection bias and a limited number of cases.     

Aktive Überwachung beim Niedrig-Risiko-Prostatakarzinom

Autopsy studies have confirmed the high prevalence of latent prostate cancer; however, only a certain portion of patients require definite treatment. Active surveillance is one of the treatment options which, according to national and international guidelines, should be offered to patients with newly diagnosed low-risk prostate cancer. Prostate cancer-specific survival is high in these patients; therefore, curative treatment, such as radical prostatectomy, external beam radiotherapy and brachytherapy may be initially deferred in order to avoid therapy-related side effects. In order to qualify for active surveillance, strict inclusion criteria have to be met; nevertheless, the reliable identification of low-risk prostate cancer patients is not always possible. Patients under active surveillance are followed up regularly with prostate-specific antigen (PSA) testing, digital rectal examination (DRE) and repeat prostate biopsies. Due to the heterogeneity of primary prostate tumors precise molecular diagnostic techniques could allow individualized treatment strategies in the future.     

Active surveillance for prostate cancer: trials and tribulations

INTRODUCTION: Prostate specific antigen (PSA) screening results in the detection of prostate cancer in many men who are not destined to die from the disease. This often results in overtreatment. One approach to reducing the overtreatment effect is to treat selectively by observing patients with favorable risk disease, and treating only the subsets who are reclassified as higher risk over time, based on biochemical or pathologic progression of disease. METHODS: The data supporting the active surveillance concept is reviewed, including the results of several large-scale Phase 2 studies. A number needed to treat analysis was performed based on these studies and a large randomized trial of radical prostatectomy versus watchful waiting. The arguments in favor of, and opposed to, active surveillance are presented. RESULTS: The largest, most mature Phase 2 study of active surveillance has reported an 85% overall survival and 99% disease-specific survival with a median follow-up of 8 years (range 2-11 years). The number needed to treat analysis suggests that between 80 and 100 radical prostatectomies would be required for each prostate cancer death avoided in a favorable risk, screen detected population. CONCLUSION: Active surveillance appears to be safe for favorable risk prostate cancer and represents an appealing alternative to radical treatment for all newly diagnosed men. Further follow-up and a randomized study design are required to conclusively demonstrate the safety of this approach over the 15- to 20-year time frame. A large-scale randomized trial has recently been initiated internationally to address this question.     

Prostate Cancer: To Treat or Not to Treat?

ContextTo treat or not to treat is one of the most difficult dilemmas facing prostate cancer patients, especially elderly men with early prostate cancer or small cancer that is contained within the prostate.ObjectiveThe primary objective of this review is to analyse the treatment options for patients with localised prostate cancer. This information can be considered alongside other important factors like natural history of disease and diagnostic tests.Evidence acquisitionSeveral randomised and nonrandomised clinical trials published in the literature investigating the natural history of the disease, diagnostic tests, and treatment options for localised prostate cancer have been reviewed for this paper.Evidence synthesisAnalysis of prostate-specific antigen (PSA) kinetics should play a major role in the management of localised prostate cancer. Trials investigating long-term outcomes of active surveillance are under way.ConclusionTaking all these factors into consideration, the data support active surveillance as an appropriate choice for patients with well-differentiated or moderately differentiated, low-volume prostate cancer who have a life expectancy of <10 yr. Men with higher grade tumours and longer life expectancy may be at excess risk of death from prostate cancer if managed with active surveillance.     

Novel Tools to Improve Patient Selection and Monitoring on Active Surveillance for Low-risk Prostate Cancer: A Systematic Review

Context

Active surveillance (AS) is an alternative to initial radical treatment of low-risk prostate cancer (PCa). Current criteria for selection and follow-up incorrectly exclude some patients eligible for AS and misclassify some who actually harbour significant disease. Better prediction of cancer behaviour at diagnosis would allow less strict monitoring and may improve acceptance of AS.

Objective

To review and critically analyse the literature on the value of novel clinical tools for patient selection and monitoring on AS.

Evidence acquisition

A comprehensive search of the PubMed database until July 10, 2013, was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement guidelines. Studies assessing novel markers and diagnostics for patient selection for AS and follow-up during AS were included. Studies analysing only classic clinical parameters used in current protocols (prostate-specific antigen, prostate volume, number of (positive) prostate biopsies, percentage malignant tissue, Gleason score) were excluded. This review focuses only on the AS setting and not on predicting insignificant disease in general.

Evidence synthesis

Of 787 studies on AS, 30 were included in this review: 14 on magnetic resonance imaging (MRI), 5 on serum markers, 5 on urinary markers, 4 on histopathology markers, and 2 on germline genetic markers. Several of these markers improve the prediction of tumour volume, tumour grade, or time to active treatment. MRI has a high specificity for low-risk PCa; new serum markers are associated with unfavourable disease. In none of the studies was the new marker used as the primary decision tool. Long-term outcome measures such as mortality were not assessed. The definition of indolent PCa is disputable.

Conclusions

Imaging and serum markers may improve future patient selection for AS and follow-up during AS. Prospective studies should aim to further evaluate the clinical utility of these new markers with respect to longer term outcomes of AS.

Patient summary

We searched the literature for articles reporting new ways to safely monitor low-risk prostate cancer for patients who have not had radical treatment. We found 30 articles. The most promising tools appear to be magnetic resonance imaging scans and various new blood markers. These may be used in the future within active surveillance regimens.     

Does active surveillance for men with localized prostate cancer carry psychological morbidity?

OBJECTIVES: To investigate, in a cross-sectional study, the prevalence of anxiety and depression in patients with localised prostate cancer managed by active surveillance, compared with those receiving immediate treatment, as active surveillance is a relatively new approach to managing this disease, designed to avoid 'unnecessary' treatment, but it is unclear whether the approach contributes to psychological distress, given that men are living with untreated cancer. PATIENTS AND METHODS: A consecutive series of 764 patients with prostate cancer were approached in outpatient clinics. Of these, 329 men with localized disease (cT1/2, N0/NX, M0/MX) meeting the study entry criteria, completed the Hospital Anxiety and Depression Scale (HADS); 100 were on active surveillance, 81 were currently receiving radical treatment (radiotherapy + neoadjuvant hormone therapy) and 148 had previously received radical radiotherapy. RESULTS: Overall, 16% (51/329) of patients met the HADS criteria for anxiety and 6% (20/329) for depression. Analyses indicated that higher anxiety scores were significantly associated with younger age (P < 0.01) and a longer interval since diagnosis (P < 0.01), but not with management by active surveillance (P = 0.38). Higher depression scores were significantly associated with a longer interval since diagnosis (P < 0.05), but not with management by active surveillance (P = 0.83). CONCLUSION: Active surveillance for managing localized prostate cancer was not associated with greater psychological distress than more immediate treatment for prostate cancer.     

Limitations of a contemporary prostate biopsy: The blind march forward

In an attempt to reduce morbidity, focal targeted therapies and active surveillance have become increasingly popular treatment choices for localized prostate cancer. However, these modalities rely heavily on accurate and reliable tumor localization information provided by a prostate biopsy. Evidence that our contemporary biopsy techniques can do little more than detect some prostate cancers is notably lacking. What is meant by the accuracy and reliability of a prostate biopsy and why they are such important concepts to focal therapy and active surveillance are discussed.