The Early Detection, Diagnostic Evaluation, and Local Treatment of Prostate Cancer

A Paradigm Shift

Background: Approximately 75 000 men receive a diagnosis of prostate cancer in Germany each year. New data on the early detection, diagnostic evaluation, and treatment of prostate cancer provide the basis for a paradigm shift in the management of locally confined prostate cancer.

Methods: This narrative review is based on the systematic literature search that was carried out for the 2025 update of the German clinical practice guideline on prostate cancer.

Results: Risk-adapted early detection is now recommended. This involves the measurement of a baseline PSA value at age 45 whose magnitude determines the interval of follow-up testing: once every 5 years for baseline values below 1.5 ng/mL, and once every two years for baseline values between 1.5 and 3 ng/mL. Patients with PSA levels above 3 ng/mL should undergo a repeat PSA test and, if these levels are confirmed, receive a urological risk assessment including prostatic volume, family history, and past medical history. High risk patients should undergo magnetic resonance imaging (MRI) and, if necessary, prostate biopsy. This new PSA-MRI algorithm increases accuracy in detecting clinically significant prostate cancers, enabling the previously recommended annual testing and digital rectal examination to be avoided. Another novelty is that the indication for an active surveillance strategy for men with low-risk prostate cancer has been expanded to ISUP grade group 1 and 2 cancers with favorable risk.

Conclusion: The need for high-quality diagnostic testing, including MRI, with broad geographic coverage will be a major challenge to the health care system, especially with regard to accessibility. Patients can be expected to benefit greatly from the new PSA-MRI algorithm, as it eliminates unnecessary diagnostic testing and treatment while enabling necessary treatment to be initiated earlier and therefore with fewer side effects.

Cite this as: Albers P, Franiel T, Kötter T, Kristiansen G, Hermann K, Wiegel T: The early detection, diagnostic evaluation, and local treatment of prostate cancer: A paradigm shift. Dtsch Arztebl Int 2025; 122: 420–6. DOI: 10.3238/arztebl.m2025.0099

With approximately 75 000 new cases per year in Germany (2022), prostate cancer is the most common type of cancer in men and the second most common cause of cancer-related deaths, after lung cancer and ahead of colorectal cancer (1). 10–15% of all men will receive a diagnosis of prostate cancer during their lifetime. The 5-year survival rate is approximately 90% (1). Three-quarters of tumors are diagnosed at an early stage (T1 or T2, i.e., confined to the prostate). Prostate cancer is more common in older men (average age at diagnosis in 2021: 71 years) (1). Latent, i.e., undetected and clinically indolent prostate cancer that does not cause any symptoms during the patient‘s lifetime or shorten his life span accounts for half of all diagnosed prostate cancers (2).

In the next 20 years, because of the aging population, the number of new cases worldwide is expected to double, and the number of deaths to rise by 85% (3).

The dilemma is that, with prostate cancer become more common, it is all the more important to distinguish clinically indolent tumors that will not harm a man during his lifetime from those that can metastasize, and to make this distinction as early as possible. The number of overdiagnoses, i.e., detected prostate cancers that will never become clinically manifest or affect longevity, must be kept as low as possible, while, at the same time, potentially dangerous cancers must not be overlooked. At present, for every man who is saved from dying of prostate cancer by early detection, 14 men receive a cancer diagnosis that is unnecessary in every respect, and some of them are treated for cancer as well (4).

Overdiagnosis cannot be completely avoided because no diagnostic procedure is so precise as to detect only cancers that will become life-threatening in the future. However, individualized, highly precise early detection and diagnostic evaluation can at least limit overdiagnosis and subsequent overtreatment. Accordingly, the new S3 guideline on the diagnosis and treatment of prostate cancer (2025) contains major changes in the recommendations for early detection, evaluation, and treatment.

Learning objectives

This article is intended to enable readers to:

• state the current recommendations for the early detection of prostate cancer and be aware of their importance in practice,
• understand new imaging techniques for prostate cancer and their clinical benefits,
• explain the newly altered indications for active treatment (radical prostatectomy, radiation therapy) versus active surveillance and help make appropriate, individualized decisions on treatment jointly with the patient.

Methods

This review is based on the literature analyses that were carried out in order to update the S3 guideline on prostate cancer (AWMF registration number 043–022OL) in accordance with the rules laid down by the AWMF. 11 systematic literature searches were conducted for the overall guideline (Medline and Cochrane databases, years 2020–2024). The data were extracted and the evidence was evaluated according to the sign-grading system.

Personalized, risk-adapted early detection

If there is a reason to pursue early detection, e.g., the patient’s desire to do so, the advantages and disadvantages should be openly discussed before any decision is taken (Box). Early detection, if chosen, should begin at age 45 with a baseline measurement of prostate-specific antigen (PSA). This age was also recommended in the past as the starting point for early detection, in the absence of a genetic predisposition, but the reasoning has changed: with a baseline PSA value at this young age, most men can be spared the previously recommended annual early detection tests for at least five years. The less frequent performance of early detection tests will lower both the number of false-positive findings (abnormal PSA level without any further findings on follow-up tests) and the number of overdiagnoses (prostate cancer in fact present, but clinically irrelevant, with no need for treatment). At this age, the detection rate of clinically relevant prostate cancer (histologically defined by a grading group (GG) of 2–5 in the International Society of Urological Pathology (ISUP) classification) is 0.2–0.4% (5, 6). These relatively low prevalence figures for 45– and 50-year-olds are derived from the PROBASE study and from the publication of the first round of the Swedish OPT implementation study, respectively. If early detection is begun ten years later, the detection rate is already 10 times higher (7).

Box

The advantages and disadvantages of PSA-based prostate cancer screening

Prostate-specific antigen

Prostate cells express and secrete prostate-specific antigen (PSA), a serine protease that serves to liquefy the ejaculate. The serum PSA level is elevated whenever prostate cells are damaged, e.g., by prostatitis or trauma (cycling; digital rectal examinations), but also in prostate cancer. When, in men aged 55 to 69, an elevated PSA level is taken as an indication for invasive diagnostic testing (tissue sampling by prostate biopsy), prostate cancer will be found in approximately 25%, with this figure varying depending on the threshold that is set for an “elevated” PSA level. With modern magnetic resonance imaging (MRI)-guided biopsy techniques, the positive predictive value of an elevated PSA level rises to 42%, including 16% of clinically indolent carcinomas in ISUP grading group (GG) 1 (8).

Initial PSA measurement in men aged 45–50 has a further type of predictive value beyond a correlation with current, biopsy-proven prostate cancer: it can also predict the lifelong risk of developing metastatic prostate cancer (9). This predictive potential is highest in men aged 45–50 because they have not yet been affected by age-related benign prostatic enlargement (concept of the baseline PSA level). A major reason for the overdiagnosis and consequent overtreatment of prostate cancer in Germany at present is self-initiated testing at the wrong age. According to data from AOK, a German statutory health-insurance carrier, for the year 2022, most men undergo cancer screening for the first time in their lives when already over 75 years of age, probably in combination with a PSA test. Only 13% do so at the ideal diagnostic age of 45–50 (10).

Digital rectal examination (DRE)

DRE has been part of the annual cancer screening recommended by German statutory health insurance carriers for over 50 years, yet its sensitivity in the early detection of prostate cancer has been shown to be insufficient (5%). DRE is no longer recommended for the early detection of prostate cancer in the updated guidelines.

Risk-adapted early detection and clinical risk factors

Men aged 45–50 who undergo baseline PSA measurement for early detection are divided into three groups according to their PSA level, with different recommendations for further testing in each group (Table). If the PSA level is below 1.5 ng/mL, the patient is considered to be at low risk and no further PSA measurements for early detection are indicated for at least five years. This is the case in 89% of men aged 45 and 82% of men aged 50 (12).

Table

The baseline PSA level determines the risk classification and the risk-adapted recommendation for subsequent testing intervals, or for an immediate diagnostic evaluation if indicated

PSA levels between 1.5 and 3.0 ng/mL signify intermediate risk. For these patients, biennial follow-up examinations are recommended. Finally, PSA values of 3.0 ng/mL or above signify high risk, and these patients should undergo further testing, which will reveal prostate cancer in 25–30%. The first steps of further testing are confirmation of the PSA level within three months and a risk assessment. If the confirmed PSA level is still above 3 ng/mL and cannot be explained by an enlarged gland, acute inflammation, or any other known causes, an MRI of the prostate is recommended. These initial diagnostic steps obviate the need for invasive diagnosis by biopsy in half of men with an initially abnormal PSA level. Men with a suggestive family history (one first-degree relative (brother, father) who received a diagnosis of prostate cancer before age 60, or more than one first-degree relative with prostate cancer at any age) are offered the same early-detection strategy.

PSA-based screening is recommended from age 40 onward for men with a genetic predisposition (e.g., pathogenic variants of the BRCA2 gene or the Lynch-syndrome-associated genes MSH2 and MSH6). Smoking is not a risk factor for prostate cancer.

Diagnostic testing

Diagnostic testing for possible prostate cancer that is suspected on clinical/laboratory grounds (elevated PSA level, suspect findings on digital rectal examination, micturition symptoms) is of a different nature from population-based screening. Before non-invasive and/or invasive testing are decided upon, the consequences of a prostate cancer diagnosis must be discussed with the patient. In men with high comorbidity and limited life expectancy, testing should only be performed if prostate cancer would impair their quality of life (11).

The new PSA-MRI diagnostic algorithm

An international consensus now holds that a man of any age whose life expectance is 10 years or more and whose PSA level is 3 ng/mL or higher should undergo diagnostic testing for prostate cancer. The life expectancy can be derived from the physician’s estimate or from the gait speed table of Studenski et al. (mean walking speed over a distance of 6 m [e1]). Such patients should, however, first undergo confirmaton of PSA and risk assessment, taking into account all possible factors that might elevate the PSA level (e.g., earlier diagnostic examinations, prostate size, inflammation, trauma, family history, ethnicity). Online risk calculators are available for objective risk assessment (e.g., ERSPC, Cancer Research UK). If these suggest an increased risk of having prostate cancer (e.g., >10% with the ERSPC No. 2 risk calculator), an MRI of the prostate should be performed next; one should not yet proceed directly to biopsy, as previously recommended. Multiple randomized trials (primarily in prostate screening) of this so-called PSA-MRI diagnostic algorithm (Figure) have revealed that it obviates the need for as many as 70% of prostate biopsies (see systematic review, [8]). Both the technical quality of prostate MRI and the radiologist‘s experience in interpreting it are crucial. For this reason, the new S3 guideline recommends that the MRI should be performed in accordance with the currently applicable quality standards, and that the interpreting radiologist should be one who is specially trained and certified in prostate MRI (Q2 special certificate from the German Society of Radiology). The information available in the images should guide the performance of the biopsy. The new guidelines specify precisely when a biopsy is indicated: A so-called MRI-ultrasound fusion biopsy is indicated only when the suspicion of prostate cancer on MRI is rated at PI-RADS (Prostate Imaging – Reporting and Data System) 4 or 5, or at PI-RADS 3 if the patient is at high individual risk (e.g., when the PSA density – the PSA level in ng/mL, divided by the prostate volume in mL – is greater than 0.15) (Figure 1). This increases the tumor detection rate for clinically relevant prostate cancer in screening studies to nearly 50% (8). The rationale behind these recommendations is to avoid unnecessary biopsies of clinically indolent carcinomas (ISUP GG 1) on the basis of high-level evidence (13, 14, 15, 16). PI-RADS 1–2 lesions should not be biopsied (17, 18).

Figure

Algorithm for risk-adapted early detection

Figure 1

Multiparametric magnetic resonance imaging (MRI)

Prostate biopsy technique

In view of the findings of multiple randomized trials, both perineal and transrectal fusion biopsies can be recommended, although transrectal biopsies should only be performed with antibiotic protection (19, 20, 21). Both types of biopsy can be performed under either local or general anesthesia (eFigure).

eFigure

Targeted MRI/ultrasound fusion biopsy system

PSMA-PET-/CT imaging

Initial evidence suggests that positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) as the target molecule can also provide valuable information in primary diagnostic testing, e.g., with respect to the aggressiveness of prostate cancer (ISUP GG). In the new guideline, PSMA-PET/CT is recommended primarily to rule out lymph node and distant metastases in locally advanced prostate cancer (ISUP GG ≥ 3 or cT3/cT4 or PSA > 20 ng/mL) (Figure 2). This method has been found in randomized trials to be significantly superior to conventional imaging (computed tomography [CT] and bone scintigraphy) (22). The accuracy of staging with regard to lymph node metastases was 92% [88; 95] in PSMA-PET-CT examinations versus 65% [60; 69] in conventional staging with CT and bone scintigraphy (p < 0.0001)(22).

Figure 2

PSMA-PET/CT in a 55-year-old man with an initial diagnosis of prostate cancer

The detection of lymph node or distant metastases in prostate cancer has significant therapeutic consequences, because local therapy alone can no longer be performed.

Genetic counseling and testing

Genetic counseling and the offer of germline testing for patients with metastatic prostate cancer are mentioned for the first time in the new S3 guideline. The background to this recommendation is the high prevalence (>10%) of pathogenic variants in DNA repair genes in these patients (23).

The treatment of localized prostate cancer

68% of cases of prostate cancer are localized and non-metastatic, in UICC stages I and II (T1-T2c N0 M0), when initially diagnosed (1). In addition to clinical staging, prostate cancer is classified into different ISUP GG after biopsy. These groups are clinical risk groups, each with its own risk of mortality. The most commonly used and best validated classification is now that of the NCCN (National Comprehensive Cancer Network), but the D‘Amico risk classification is still in use. The new subdivision of the large group of intermediate-risk prostate cancers has important implications for treatment.

The findings of the British ProtecT trial at 15 years were published in 2023 and serve as the most important basis for the new treatment recommendations (24). The classic forms of treatment—radical prostatectomy, radiotherapy, and active monitoring—were compared in a randomized trial; at 15 years, there was no difference in cancer-specific survival (>97% in each case). Patients with localized prostate cancer must therefore be informed neutrally by urologists and radiation oncologists about all three forms of treatment, with due consideration to their comorbidity and life expectancy. This analysis implies that low-risk tumors should be managed with active surveillance, as is recommended in the new S3 guideline.

Active surveillance

Patients in the NCCN low-risk and very-low-risk groups make up approximately half of patients with localized prostate cancer and can be managed with active surveillance. In Germany, a decision was made to define in detail a further group of patients who are at “favorable intermediate risk,” for whom active surveillance is also appropriate.

Large-scale histopathological studies of prostatectomy specimens have revealed a clear correlation between the frequency of Gleason pattern 4 (out of 5) and the PSA recurrence rate after radical prostatectomy. This suggests that patients with ISUP GG 2 prostate cancer and no more than a small amount of Gleason pattern 4 can also be managed primarily with active surveillance. This would correspond in practice to, e.g., less than 25% of Gleason pattern 4 without cribriform or intraductal growth patterns (25).

All patients with low risk (ISUP GG 1) should primarily undergo active surveillance; neither surgery nor radiotherapy is recommended any more for these patients. The active surveillance recommended in the new German S3 guideline is to be carried out more frequently than that described in the ProtecT trial. Active surveillance is recommended only with a prostatic MRI that meets the current quality criteria and an MRI-guided biopsy of the prostate to avoid misclassification. During active surveillance, the PSA level should be checked every 3 months (ISUP GG 2) or every 6 months (ISUP GG 1) for the first two years. In addition, an MRI-guided re-biopsy is recommended at 12–18 months. In the event of histological progression, but not in the event of a PSA increase alone, active surveillance should be discontinued in favor of surgery or radiotherapy. Purely MRI-guided active surveillance without re-biopsy is possible but has not yet been sufficiently evaluated.

Radical prostatectomy

Radical prostatectomy (RP) is recommended for patients with localized prostate cancer and an ISUP grading group above 2, or 2 with an unfavorable risk profile. A German randomized trial comparing laparoscopic and robot-assisted surgical techniques revealed a significant difference in early continence at 3 months, in favor of robotics (26). The 3-month continence rate after robot-assisted radical prostatectomy was 54%, compared to 46% after open surgery (p = 0.027). A systematic review of randomized trials of open surgery vs. robot-assisted techniques did not reveal any significant difference in oncological outcomes or long-term side effects (27). Patients with a high-risk profile and/or locally advanced tumors (pT3/pT4 and ISUP 4–5) should be offered adjuvant radiotherapy. This can be performed in patients with multifocal positive margins (28). The alternative for patients with a high-risk profile is delayed percutaneous salvage radiotherapy, if biochemical recurrence (BCR) from the nadir (PSA below the detection limit) is detected after surgery (29). In patients with BCR and a favorable risk profile (PSA doubling time > 12 months, ISUP GG < 4), watchful waiting is an acceptable approach (30). PSMA-PET/CT examinations may be useful if PSA levels rise above >0.2 ng/mL to localize the recurrence and assist in treatment planning (31).

Primary curative radiation therapy

Intensity-modulated percutaneous radiotherapy (IMRT) of localized prostate cancer should be carried out with image guidance (IGRT). The standard dose is at least 74 Gy to 80 Gy in normofractionated form. For localized intermediate-risk and localized high-risk prostate cancer, either moderate hypofractionation (e.g., over four weeks instead of eight) or normofractionated radiotherapy is indicated (32, 33). In patients with an intermediate-risk profile, this should be accompanied by hormone ablation therapy for four to six months. For high- to very- high-risk profiles according to the NCCN, hormone ablation therapy should be given for 24 to 36 months. Proton therapy has no greater clinical benefit than IMRT and IGRT (34). In patients with an intermediate-risk profile, extreme hypofractionation (5–7 fractions over one or two weeks of radiotherapy) can also be performed under certain conditions (35). A so-called focal boost has also been added to the recommendations: this consists of a local dose increase above 78 Gy up to a total dose of approximately 90 Gy, with the boost covering the major portion of the carcinoma that is visible in multiparametric MRI. A focal boost can be used for locally confined tumors with a high risk profile (36). In patients with a very-high-risk profile and stage cN0 (PSMA-PET/CT negative), supplementary radiotherapy of the pelvic lymphatic drainage areas can be performed as adjuvant treatment (37).

As implied by new data from the randomized STAMPEDE trial, patients with pelvic lymph node metastases (cN1 in conventional CT staging) should be given not only radiotherapy of the prostate and pelvic lymphatic drainage areas, but also extended systemic treatment with abiraterone for two years in addition to androgen deprivation therapy (ADT) (38).

Low-dose-rate (LDR) brachytherapy

On the basis of findings from a randomized trial, LDR mono-brachytherapy has been reevaluated and can now be considered a standard treatment option for patients with a favorable intermediate risk profile (39). Brachytherapy is generally supplemented with androgen-deprivation treatment for the same length of time as percutaneous radiotherapy (4–6 months or 24–36 months).

The treatment of patients with lymph node metastases (cN1)

The increasing use of PSMA-PET/CT staging has led to an increasing number of diagnoses at stage cN+. It remains unclear which form of treatment should be recommended for these patients. False-positive PSMA PET findings are very rare in conjunction with an unfavorable NCCN risk profile (40). In all cases, treatment of the primary tumor with surgery or radiotherapy is recommended. The STAMPEDE trial with conventional staging provides strong evidence for combined radiotherapy of the prostate and its lymphatic drainage pathways (38).

eBox

Collaborators of the S3 guideline on prostate cancer

Conflict of interest statement
The authors state that they have no conflict of interest.

Manuscript submitted: on 6 February 2025, revised version accepted on 26 May 2025.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Peter Albers

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