Localized prostate cancer typically causes no symptoms. Any lower urinary tract symptoms (LUTS) are usually due to associated benign prostatic hyperplasia (BPH). Over half of men over the age of 50 will experience LUTS related to BPH. Other causes of symptoms include prostatitis, UTI, urethral stricture, and overactive bladder. This can result in an incidental diagnosis of early-stage cancer with an uncertain impact on long-term mortality. Prostate cancer can present with new-onset erectile dysfunction or rarely with hemoejaculate or initial hematuria.[18]

 Symptoms which might prompt investigation for prostate cancer include:

• Lower urinary tract symptoms (LUTS) such as hesitancy, post-micturition dribbling, and poor stream
• Hematuria
• Hemoejaculate
• New-onset erectile dysfunction

Evaluation for localized prostate cancer most commonly involves a serum PSA level, digital rectal examination (DRE), multiparametric MRI (mpMRI), and needle prostate biopsy. It is relatively rare nowadays for localized prostate cancer to be diagnosed incidentally during treatment for BPH (e.g., transurethral resection chippings) and during an investigation for other symptoms, e.g., as a hot spot in the prostate on PET scanning. Approximately 10% of prostates removed during the course of a cystoprostatectomy for high-grade bladder urothelial cancer will have foci of prostate cancer, that will precipitate further investigation. Prostate-specific antigen (PSA) testing is widely carried out in the context of case-finding for prostate cancer, yet remains highly controversial as a screening modality.

There is strong evidence showing that PSA screening increases the detection of prostate cancer, in particular localized disease, by approximately 30%. Despite this, meta-analyses of the international data have demonstrated no apparent impact on overall survival.[19]

Diagnosis of cases that are unlikely to progress in a man's lifetime to significant clinical illness has been termed 'over-diagnosis.' The rationale is that treatment of the condition will not benefit the man and therefore represents overtreatment of a screen-detected condition. The process of diagnosis (e.g., biopsy) has appreciable morbidity, and indeed mortality and all conventional treatments for prostate cancer have adverse events that have a negative impact on the quality of life.[20][6][21][22][23]

Overall, these risk-benefit considerations have led to recommendations against routine PSA testing in the US and in Europe. The current American Cancer Society Guidelines for targeted prostate cancer screening are as follows:

PSA +/- DRE is offered to the following groups of patients, only after providing information on the risks, benefits, and uncertainties of prostate cancer screening and if they have a life expectancy > 10 years;

• Men aged ≥50
• Men aged ≥45 with a high risk of prostate cancer (African-American or father/brother diagnosed before age 65)
• Men aged ≥40 with significantly higher risk (multiple relatives diagnosed before age 65)

The PSA threshold for further investigation varies between 3.0 (Europe) and 4.0 (US). PSA levels are influenced by sexual activity, prostatic manipulation, UTI, BPH, and vigorous exercise in addition to PSA protein instability and assay characteristics. Men with a borderline PSA result are commonly offered a repeat PSA level a few weeks later with advice to avoid sexual activity and vigorous exercise for 48-72 hrs prior to the repeat test.[6][24][25][26]

Patients are commonly offered DRE alongside PSA testing. A suspicious DRE alone, even in the context of a low PSA, should prompt further investigation as approximately 20% of localized cancers occur without an elevated PSA level.

Currently, following PSA and DRE, multiparametric MRI scanning (mpMRI) or biparametric MRI is offered.  MpMRI combines anatomical and functional information using T1 and T2-weighted sequences, dynamic contrast enhancement (DCE), and diffusion-weighted imaging (DWI). The subsequent images are scored by an experienced urological radiologist using, for example, the Likert or PI-RADS system.

Likert can be used in detection, active-surveillance, post-treatment, and reoccurrence. It utilizes non-pre-specified imaging features and relies on user experience to be interpreted well. PI-RADS can be used in detection only. It utilizes pre-specified imaging features and is less dependent on reader experience. Likert may be more accurate when used by experienced urological radiologists. Both systems produce a score between 1 and 5, with a higher score indicating a higher likelihood of cancer being detected on biopsy. In most centers, a score of ≥3 will prompt a biopsy. In men with more than one risk factor (e.g., strong family history and high PSA density), a systematic biopsy might be recommended with a 'normal' MRI scan. 

Prior to mpMRI, many men underwent unnecessary biopsy as they had a clinically insignificant disease. The introduction of mpMRI as an initial investigation can potentially avoid biopsy in 25% of men with an elevated PSA at the risk of missing approximately 3% to 5% of cases. [27][28][29][30][22]

For definitive prostate cancer diagnosis, a positive needle biopsy typically using an 18G needle is carried out, most commonly under local anesthetic. Different strategies to biopsy, as well as different targetting modalities, can be used. A targetted biopsy can be obtained using real-time in-bore biopsy during the MRI scan. More commonly, either cognitive or fusion targetting using the saved MRI image with the real-time transrectal ultrasound image is employed, with the needle deployed either transrectally or transperineally. Transrectal Ultrasound-Guided (TRUS) biopsy remains the most common technique, but Transperineal (TP) biopsy is growing in popularity, with usage varying across centers. The advantages of TP biopsy include a lower post-biopsy sepsis rate and the ability to sample tissue within the anterior of the prostate gland, which is often missed by TRUS biopsy. The disadvantages include increased discomfort and analgesic requirements, increased urinary retention rates, and a higher risk of post-biopsy erectile dysfunction. When compared with TRUS,  there is no difference in the incidence of hematuria, hemoejaculate, or 30-day mortality with TP biopsies, and currently a paucity of high-quality evidence for global adoption of TP sampling in Europe or America.

Systematic sampling taking a minimum of ten cores (usually 10-12) from representative areas of the peripheral zones of the prostate, in addition to targetted sampling, results in a higher yield of significant prostate cancer. There is, however, a higher risk of detecting incidental non-clinically significant disease. Patients undergoing biopsy should receive prophylactic antibiotics. It is important for patients to be warned about the risks above, including the most usual post-procedural hemoejaculate (>90%), hematuria (>80%), and rectal bleeding (>20%), usually lasting for 1-2 days, but can be prolonged for a week or two, particularly blood in the semen which can often take many weeks to clear.[31][32][6]

Following the biopsy, prostate cancer is risk-stratified to determine the necessity for further investigations and decide on initial management. This includes PSA, grade group (table 2), and stage :

• Low risk - PSA < 10ng/ml and stage T1-T2a and grade group 1.
• High risk - PSA > 20 or grade group 4-5.
• Intermediate risk constitutes a variety of combinations falling between low and high risk.

All patients with high-risk cancer should complete staging examinations looking for metastatic disease with a bone scan and cross-sectional abdominopelvic imaging.[6][33][34] The routine use of such imaging in intermediate-risk is controversial.

Localized prostate cancer represents a paradox in that when left untreated, and it is generally associated with a good prognosis. However, because prostate cancer is a common cause of cancer-related mortality, there is usually significant patient anxiety once the diagnosis is confirmed. All standard treatments carry risks of adverse events that might negatively impact on short, medium, or long-term quality of life. As such, the clinical approach to managing localized prostate cancer must take into account not only the disease features, such as stage, grade, and volume of cancer detected, but also patient co-morbidities, life-expectancy, and priorities.

The optimal management of localized prostate cancer starts with discussion by a multidisciplinary team (MDT) consisting of radiation oncologists, medical oncologists, urologists, histopathologists, radiologists, and specialist nurses. Each brings their own expertise and knowledge of the patient to help determine which treatment options are appropriate for an individual.

There is evidence that a shared decision-making (SDM) environment leads to better self-perceived quality of life and less treatment regret for patients with prostate cancer, although the impact on long-term oncological outcomes is uncertain. SDM is a process whereby clinicians collaboratively help patients to reach evidence-informed and value-congruent medical decisions. SDM takes time and relies on physician empathy and excellent communication skills. The role of the physician is to draw attention to the natural history of prostate cancer as slow-growing cancer to reduce anxiety. It is important to reassure the patient that time spent discussing the pros and cons of the various approaches is time well-spent.[35]

The standard approaches to localized prostate cancer include a monitoring strategy, radical surgery, radiation therapy (brachytherapy or external beam), and emergent focal therapies.[6]

Monitoring

Natural history studies suggest that the majority of men, particularly elderly men, diagnosed with localized prostate cancer, die with their disease rather than of it, reflecting competing hazards associated with aging. Although many cases do not progress, there does appear to be a true progression rate over the years of follow-up. Both grade and volume of the disease are predictive of progression to locally advanced and metastatic disease. As such, monitoring strategies are most suited to elderly men, low-risk disease, or to selected intermediate-risk disease with careful counseling and close follow-up. Two broad approaches to monitoring are generally described.

Conservative Palliative Strategy

Often termed ‘watchful waiting,’ this modality is most commonly offered to elderly, frail, asymptomatic men.  It is anticipated that disease progression in the remaining lifetime of the man is unlikely to cause a clinically significant problem. In addition, the morbidity/ mortality associated with radical treatment does not justify the anticipated benefits in longevity. Treatment in the form of primary androgen-deprivation therapy (ADT) may be offered to control symptoms as and when they occur or if there is evidence of metastatic disease. The aim is remission, which occurs in around 80% of cases, rather than ‘cure.’ This approach has been called into question due to improvements in life-expectancy, treatments, and imaging modalities. Additionally, evidence now demonstrates significantly improved survival when radiotherapy is added to ADT for patients who previously would have received ADT alone.[36]

Deferred Curative Strategy

Often termed ‘active surveillance’ this approach is aimed at reducing overtreatment for prostate cancer that is unlikely to progress in the man’s lifetime. Regular follow up using a combination of biomarker repeat assessment (typically serum PSA), imaging findings (interval and mp-MRI), clinical evaluation (symptoms/ DRE), and repeat biopsy are offered. A commonly used protocol (NICE guidance, UK) is:

• First-year - PSA test every 3 to 4 months
• At 6 and 12 months – clinical review, DRE
• 12 months- interval mpMRI
• Subsequently - 6 monthly PSA with yearly DRE in subsequent years

Repeat biopsy is utilized where there are discordant findings between biomarkers and imaging. Radical treatment is offered if evidence of disease progression is present, or if the patient requests it.  Large randomized controlled trials, such as the ProtecT trial, have demonstrated no detriment to 10-year survival from offering active surveillance over primary radical treatment. The trade-off for the patient is an increased risk of disease progression against the adverse effects of radical treatment.[6][37][38]

Recent evidence has demonstrated survival benefit from radiotherapy plus ADT in men who would have been traditionally assigned to watchful waiting when they progress to locally advanced disease. This calls into question the distinction between active surveillance and watchful waiting.  For instance, although the risk-benefit analysis at initial presentation with the localized disease might be considered unfavorable in an asymptomatic man with co-morbidities, progression to a more advanced stage (e.g., T3 disease from T2) could act as a trigger for a more radical approach. This is in line with deferred curative treatment. As such, the key to successful monitoring of localized prostate cancer rests on thorough clinical evaluation and an honest appraisal, with the patient, of goals and priorities.[39]

Surgical Management – Radical Prostatectomy

Radical prostatectomy can be open (ORP), laparoscopic (LRP), or robotic-assisted (RARP). ORP is the traditional method, whilst LRP and RARP are increasing in popularity. As RARP becomes more available, conventional LRP has been overtaken. Patients with high-risk cancer should also undergo extended pelvic lymph node dissection. Nerve-sparing RP reduces the risk of subsequent urinary and sexual dysfunction. The risk of post RP incontinence increases with age, with 75yrs being the most common cut-off in most centers. There is currently a lack of evidence demonstrating the superiority of any specific method of RP for mortality, cancer recurrence, or postoperative complications, although LRP and RARP are likely to lead to shorter hospital stays and fewer blood transfusions.[6][40]

Radiation Therapy

External-beam Radiation Therapy (EBRT)

Intensity-modulated radiation therapy (IMRT) is the preferred method for EBRT delivery as it allows targeted radiation delivery to the prostate gland with less toxicity to surrounding organs. Side effects of radiotherapy are gastrointestinal toxicity, genitourinary toxicity, and secondary malignancy. Acute proctitis and cystitis commonly resolve following treatment completion.

Hypofractionation (>2Gy/day) reduces treatment time and improves resource utilization without compromising tumor control, reoccurrence, and side effects when compared to traditional fractions (1.8-2Gy/day). Hypofractionated IMRT is commonly 60Gy delivered in 20 fractions.

Androgen-deprivation therapy is commonly used as an adjunct to EBRT in intermediate and high-risk prostate cancer. In localized prostate cancer, this is generally short term (6 months). In high-risk patients, particularly where there might be early T3 extension, ADT might be prolonged for up to 3 years. The safety of such neoadjuvant use of ADT has recently been questioned as there is evidence of significant cardiovascular side effects. The current trend is to aim to reduce the duration of exposure to ADT to as short a period as possible and indeed avoid it altogether in men at particularly high risk of CV adverse effects. The impact of these changes on oncological outcomes has not been thoroughly explored.[41][42][43][6]

Brachytherapy

This is the implantation of radioactive seeds into the prostate. It is used for primary treatment in a low risk and low volume intermediate-risk localized prostate cancer. It can also be used as an adjuvant to EBRT in high volume intermediate-risk and high-risk cancer.

Brachytherapy can be divided into low dose rate (LDR) and high dose rate (HDR). In LDR brachytherapy, radioactive seeds release their radiation over a few months and remain in the prostate permanently. In HDR, a radioactive source is delivered into the prostate during a single visit to the hospital and then removed; this is then most commonly combined with a subsequent course of external beam radiotherapy (brachytherapy boost).

Brachytherapy commonly causes urinary side effects such as urinary retention, incontinence, and the requirement for transurethral resection of the prostate (TURP). It also causes erectile dysfunction in up to 40% of patients.[6][44][45]

Emergent Focal Therapies 

The radical treatment for prostate cancer is associated with significant detriment to the quality of life, for example, incontinence, reduced sexual function, and radiation toxicity. Increased sophistication of prostate imaging has allowed for the rapid emergence of focal therapies such as focal laser ablation, high-intensity focal ultrasound (HIFU), irreversible electroporation (IRE), photodynamic therapy (VTP), and focal cryotherapy. These are used to ablate the dominant tumor in the prostate with a view to achieving tumor control whilst reducing the adverse events of treatment. Of these, cryotherapy and HIFU are probably the most available.

As yet, studies for these treatments are confined to short and intermediate-term follow-up. They appear to have a vastly lower rate of high-grade complications. However, the long-term oncological results are uncertain, particularly given a relatively high-rate of residual/ recurrent cancer on repeat biopsy. At present, promising as the results appear from the perspective of preserving the quality of life, they should only be offered as part of a clinical trial.[46]

Differential diagnoses for localized prostate cancer are mainly conditions which produce LUTS, as discussed earlier:

• BPH
• Prostatitis
• Urethral stricture
• UTI
• Overactive bladder
• Bladder cancer
• Advanced prostate cancer

Despite being common, prostate cancer has the highest 5-year survival of all cancers at 98%. As previously discussed, localized prostate cancer is frequently indolent and has an excellent prognosis even if left untreated. By definition, patients with high-grade, high-volume cancer are more likely to progress to locally advanced and metastatic disease, but risks can be mitigated by early detection and treatment.

Evidence demonstrates similar outcomes for patients treated with active surveillance, surgery, and radiotherapy, although patient wishes and side effect profiles should be taken into account. Patients choosing monitoring strategies should be aware of a small increase in the risk of progression and that subsequent radical treatment will be required in around 50% of cases, as often for patient anxiety as for biochemical, clinical, or imaging evidence of disease progression.[22][47]

Complications of localized prostate cancer mainly consist of side effects of treatment. For surgical treatment, this is nerve damage resulting in incontinence and/or erectile dysfunction. There are also risks associated with surgery, such as anesthetic risk and blood loss. Radiotherapy risks include GI, GU, and local toxicity and risk of future secondary malignancies.

The majority of risk factors for prostate cancer are not modifiable. As such, patients should be educated about inherent risk factors such as age, ethnicity, and family history to ensure the correct groups present for PSA testing. It is important to educate patients requesting PSA screening about the risks of over-diagnosis and to reassure those who do not meet the criteria for testing.

Lifestyle factors do not affect the risk of developing prostate cancer but may influence the risk of progression. Patients already diagnosed with prostate cancer should be encouraged to lead a healthy lifestyle, including diet and exercise, to reduce the risk of developing advanced disease. Obesity is a risk factor for prostate cancer progression and advanced disease.

Localized prostate cancer is commonly an indolent disease. Patients exhibit few to no symptoms, and if symptoms are present are often caused by co-existing BPH. It is important to be aware of the criteria for offering a PSA test and also to be prepared to discuss the pros and cons of such testing with patients. The steps involved in assessing a patient with localized prostate cancer are key to selecting the best treatment strategy for that patient, be it active or passive.

The initial evaluation of lower urinary tract symptoms and any request for PSA testing usually rests with the family physician or general practitioner. It is at this point that a careful evaluation of the symptoms, a search for other conditions that might mimic BPH (e.g. bladder cancer), and patient counseling around the pros and cons of PSA testing is carried out.

The urologist is usually the primary specialist involved in making the diagnosis and therefore the first line of providing care for men with localized prostate cancer. Given the many treatment options involved and the difficulties associated with the interpretation of needle biopsy and MRI scans of the prostate, the involvement of other multidisciplinary team members is essential prior to a definitive treatment discussion. Initial referral is commonly from the general practitioner. Diagnosis involves histology and radiology, whilst treatment may involve a radiation oncologist or a full surgical team, including recovery and ward teams.

Clinical nurse specialists are invaluable in supporting patients diagnosed with cancer, and input from psychologists or support groups might prove valuable. Trained clinical exercise specialists can be helpful in achieving lifestyle changes including exercise training and dietary modification.

When considering treatment, large randomized controlled trials have demonstrated equivalent overall and disease-specific mortality of active surveillance, radical radiotherapy, and radical surgery at 10 years of follow-up. Thus, it is important to assess each patient individually to establish his co-morbidities and priorities whereby to optimize treatment and minimize side effects (for example, not offering radiotherapy to a patient with pre-existing colitis).

With prompt and effective diagnosis and treatment, localized prostate cancer has a favorable prognosis for patients. It is vital that members of the multidisciplinary team come together to support patients and optimize both oncological and non-oncological outcomes.