Localized Prostate Cancer

Etiology

The most significant risk factors for prostate cancer are not modifiable; these include:

Age

Prostate cancer is rare under the age of 50 (1 in 350); the incidence steeply increases to 1 in 52 by age 59, and at age 65, the incidence is greater than 1 in 2, although many men will not be aware they have the disease. In the modern era of widespread serum prostate-specific antigen (PSA) testing, the majority of men have localized disease at diagnosis with a mean age of 66.[1][9][1]

Race

Worldwide, African-American men are the most likely racial group to develop prostate cancer and are also more likely to develop the disease at a younger age, with high rates evident in Afro-Caribbean men and those of West African origin. Hispanics are at lower risk than Caucasians, as are those from South-East Asia.[1] The reasons for these differences are unclear but appear to reflect genetic predisposition and environmental factors, including diet.

Family History

Although a minority of cases of prostate cancer are truly hereditary, a family history of prostate cancer increases the risk. The relative risk if a first-degree relative is affected is a 2-fold increase, with the risk increased around 8-fold if 2 or more first-degree relatives are affected.[6][10][6]

Other risk factors responsible for a minority of cases include inheritable gene mutations (eg, BRCA2 and HOXB13) and anthropometry; taller men are at a higher risk. No consistent link has been found between the incidence of prostate cancer and dietary factors, although obesity does represent a risk factor for progressive or advanced disease.[11][12]

Epidemiology

Prostate cancer is currently the second most commonly diagnosed cancer in men worldwide. It is an age-related disease, and the incidence is expected to rise alongside global life expectancy. The highest risk group for prostate cancer globally is African Americans living in the United States. The lowest risk group is Asian men living in their native country.[1][13]

Both incidence and mortality of prostate cancer vary vastly across the globe, and, as well as individual risk factors, much of this variation has been attributed to differences in asymptomatic disease screening patterns. For example, in a low-income area such as Western Africa, the age-standardized incidence rate is relatively low at 31.9 per 100,000, but the associated mortality rate is high at 18.6 per 100,000. In contrast, in a high-income area such as North America, the age-standardized incidence is much higher at 73.7 per 100,000, but the associated mortality rate is relatively low at 7.7 per 100,000. High detection rates for localized disease typically occur in high-income countries, likely due to PSA testing detecting earlier diseases with the associated reduction in mortality from treating the lower-risk disease and access to higher diagnostic and treatment capabilities.[13]

There have also been large variations in prostate cancer incidence worldwide over the past 30 years, further supporting the role of PSA screening in driving incidence data. Between 1986 and 1992, prostate cancer incidence doubled in the United States. This coincides with the initiation of widespread PSA screening. This spike was also seen in Europe and Australia. Incidence has started to fall, partially due to the loss of screening popularity due to over-diagnosis. In parallel, prostate cancer mortality, which had been falling over the previous two decades, has recently risen marginally. The recent US Preventative Services Task Force (PSTF) guidelines have clarified the position on PSA screening for men.[14][15]

Pathophysiology

The prostate consists of epithelial acini in a fibromuscular stroma. Almost all adult cases of prostate cancer are adenocarcinoma arising from the acinar epithelium. Rarer variants such as ductal adenocarcinoma, urothelial carcinoma, squamous neoplasms, basal cell carcinomata, and neuroendocrine tumors (World Health Organization [WHO] classification 2016) do occur and generally have a worse prognosis. Rarely, non-epithelial malignant transformation results in lymphomas and sarcomas, more commonly following radiation exposure for previous, eg, rectal cancer.[3]

Histopathology

Histological examination of a prostate needle biopsy currently represents the gold standard in establishing a diagnosis of localized prostate cancer. The diagnosis is most commonly based on microscopic criteria such as glandular architecture (infiltrative growth pattern), perineural invasion, prominent nucleoli, and absence of a defined basal cell layer on hematoxylin and eosin (H&E) stained slides.

Biopsy interpretation can be challenging; immunohistochemistry to specific basal cell proteins in equivocal cases can differentiate benign from malignant tissue. Although these stains (eg, p63, cytokeratin 5/6, keratin 903) can help establish a diagnosis of cancer, there may also be a disrupted basal cell layer in some benign small glands. In these situations, a cancer diagnosis is based on morphology and confirmed by positivity for a-methylacyl-CoA racemase (AMACR) cytoplasmic staining. AMACR is expressed by approximately 80% of prostatic adenocarcinoma on needle biopsy.[5]

Grading is assigned by the Gleason system, which was introduced in 1966 and updated in 2005 and 2014 (see Table. Localized Prostate Cancer Staging Guidelines, Gleason Grade). Gleason grade is based on growth patterns ranging from 1 to 5. In practice, Gleason grades 1 and 2 are not usually described, and grade 3 (infiltrative growth pattern) represents the modern entry criterion for a diagnosis of prostate cancer.

Several grades often coexist in a single biopsy core or separate biopsy cores. In most cases, the Gleason score (GS) is the sum of the most common (primary) and the second most common (secondary) grade patterns. If a pattern 4 or 5 forms more than 95% of a specimen, any lower grade pattern representing less than 5% is ignored (eg, 97% of pattern 4 and 3% of pattern 3 is Gleason [4 + 4] rather than [4 + 3]). If any amount of pattern 4 or 5 is seen within a specimen, it is included in the GS, even if it forms the tertiary pattern.

For practical purposes, Gleason 6 (3 + 3) is the lowest score usually seen, and patients should be counseled that a grade of 6/10 is considered a low grade. Most recently, the International Society of Urological Pathology (ISUP) has recommended that Gleason scores less than or equal to 6, 3 + 4 = 7, 4 + 3 = 7, 8, and 9-10 be reported as 5 Gleason group grades, ie, ISUP groups 1 to 5 respectively. This system provides additional prognostic benefit by separating Gleason score 7 diseases into 3 + 4 (Group 2) and 4 + 3 (higher risk Group 3).[16][17]

History and Physical

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 that might prompt investigation for prostate cancer include:

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

Evaluation

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 (eg, transurethral resection chippings) and an investigation for other symptoms (eg, as a hot spot in the prostate on PET scanning). Approximately 10% of prostates removed during a cystoprostatectomy for high-grade bladder urothelial cancer will have foci of prostate cancer that will precipitate further investigation. 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 (eg, biopsy) has appreciable morbidity and, indeed, mortality, and all conventional treatments for prostate cancer have adverse events that hurt the quality of life.[6][20][6][21][22][23]

These risk-benefit considerations have led to recommendations against routine PSA testing in the US and 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 greater than 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 to 72 hours before 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.

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). An experienced urological radiologist scores the subsequent images 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 greater than or equal to 3 will prompt a biopsy. In men with more than 1 risk factor (eg, strong family history and high PSA density), a systematic biopsy might be recommended with a "normal" MRI scan. 

Before mpMRI, many men underwent unnecessary biopsies 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.[22][27][28][29][30][22]

For definitive prostate cancer diagnosis, a positive needle biopsy, typically using an 18-G needle, is carried out, most commonly under local anesthetic. Different strategies for biopsy, as well as different targeting modalities, can be used. A targetted biopsy can be obtained using real-time in-bore biopsy during the MRI scan. More commonly, 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. A TRUS-guided 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. Compared with TRUS, there is no difference in the incidence of hematuria, hemoejaculate, or 30-day mortality with TP biopsies. There is a paucity of high-quality evidence for the global adoption of TP sampling in Europe or America.

Systematic sampling, taking a minimum of 10 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 postprocedural hemoejaculate (>90%), hematuria (>80%), and rectal bleeding (>20%), usually lasting for 1 to 2 days, but can be prolonged for 1 to 2 weeks, particularly blood in the semen which can often take many weeks to clear.[6][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 less than 10 ng/ml and stage T1-T2a and grade group 1
• High risk: PSA less than 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.

Treatment / Management

Localized prostate cancer represents a paradox in that when left untreated, 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 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 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. However, the impact on long-term oncological outcomes is uncertain. SDM is a process whereby clinicians help patients reach evidence-informed and value-congruent medical decisions collaboratively. 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 a slow-growing cancer to reduce anxiety. It is important to reassure the patient that discussing the pros and cons of the various approaches is well-spent.[35] (A1)

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 diseases, or selected intermediate-risk diseases 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 of 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 demonstrates significantly improved survival when radiotherapy is added to ADT for patients who previously would have received ADT alone.[36](B2)

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 (National Institute for Health and Care Excellence [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: Six 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](A1)

Recent evidence has demonstrated survival benefits 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 (eg, T3 disease from T2) could trigger 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](A1)

Surgical Management

Radical prostatectomy can be open (ORP), laparoscopic (LRP), or robotic-assisted (RARP). ORP is the traditional method, while LRP and RARP are increasingly popular. 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 75 years 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. However, LRP and RARP will likely lead to shorter hospital stays and fewer blood transfusions.[6][40](A1)

Radiation Therapy

External-beam Radiation Therapy

Intensity-modulated radiation therapy (IMRT) is the preferred method for external-beam radiation therapy (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 (>2 Gy/day) reduces treatment time and improves resource utilization without compromising tumor control, reoccurrence, and side effects when compared to traditional fractions (1.8-2 Gy/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 cardiovascular adverse effects. The impact of these changes on oncological outcomes has not been thoroughly explored.[6][41][42][43][6](A1)

Brachytherapy

This is the implantation of radioactive seeds into the prostate. It is used for primary treatment in 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](B3)

Emergent Focal Therapies 

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 to achieve tumor control while 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 or recurrent cancer on repeat biopsy. At present, as 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](B3)

Differential Diagnosis

Differential diagnoses for localized prostate cancer are mainly conditions that produce LUTS, including:

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

Prognosis

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 considered. 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

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