Prostate cancer is a heterogeneous disease with marked variability in its natural progression and response to therapeutic interventions. It is the most commonly diagnosed visceral cancer of men living in western countries, yet it is life-threatening in only a minority of cases. Thus, appropriate patient selection for treatment based on tumor as well as patient characteristics is essential to achieve optimal outcomes. The combination of early cancer detection and technical improvements in local treatment has led to a reduction in disease burden and an increase in cancer survivorship. However, treatment failure remains common among high-risk cases.
Key points
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Prostate cancer is a disease with a spectrum of clinical outcomes in terms of progression and response to therapy.
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Disease progression may be predicted based on risk stratification using stage, grade, and prostate-specific antigen testing.
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High-risk localized prostate cancer often requires multimodal therapy because of local disease extension and the presence of micrometastases.
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Androgen deprivation therapy improves the results of radiation and surgery in select cases.
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Current studies are focused on adjuvant chemotherapy and biologic agents in combination with surgery and radiation.
Introduction
Prostate cancer is the most common visceral cancer and the second most lethal malignancy of men in the western hemisphere. In the United States, there are approximately 240,000 new cases detected each year and 28,000 deaths, which account for 9% of all male cancer deaths. Current estimates indicate that a man’s lifetime risk of prostate cancer death is about 3%. Since the introduction of prostate-specific antigen (PSA) testing over the last 2 decades, lethality rates have steadily declined, resulting in a 44% overall reduction in rate of prostate cancer mortality. During this time period, several technical innovations in local therapies have been introduced that resulted in improved local control with a reduction in treatment morbidity. These initial successes in patient outcomes from PSA testing fueled an enthusiasm for early prostate cancer screening and treatment as a means to reduce the rate of prostate cancer mortality further. However, due to the often indolent nature of prostate cancer, the rates of diagnosis and treatment of clinically insignificant disease (ie, overdiagnosis and overtreatment) during this time period were calculated to be significant. It is estimated that since the introduction of PSA testing, 1.3 million additional men have been diagnosed with prostate cancer, with younger patients experiencing the greatest relative increase compared with the pre-PSA era.
Introduction
Prostate cancer is the most common visceral cancer and the second most lethal malignancy of men in the western hemisphere. In the United States, there are approximately 240,000 new cases detected each year and 28,000 deaths, which account for 9% of all male cancer deaths. Current estimates indicate that a man’s lifetime risk of prostate cancer death is about 3%. Since the introduction of prostate-specific antigen (PSA) testing over the last 2 decades, lethality rates have steadily declined, resulting in a 44% overall reduction in rate of prostate cancer mortality. During this time period, several technical innovations in local therapies have been introduced that resulted in improved local control with a reduction in treatment morbidity. These initial successes in patient outcomes from PSA testing fueled an enthusiasm for early prostate cancer screening and treatment as a means to reduce the rate of prostate cancer mortality further. However, due to the often indolent nature of prostate cancer, the rates of diagnosis and treatment of clinically insignificant disease (ie, overdiagnosis and overtreatment) during this time period were calculated to be significant. It is estimated that since the introduction of PSA testing, 1.3 million additional men have been diagnosed with prostate cancer, with younger patients experiencing the greatest relative increase compared with the pre-PSA era.
Prostate cancer screening and detection
The effectiveness of population-based screening for the detection of prostate cancer has been studied in 2 large randomized trials but remains an area of major controversy. A randomized screening trial in Europe enrolling 182,000 men showed a 21% reduction in the rate of prostate cancer mortality at 11 years, increasing to 29% after adjusting for noncompliance. In contrast, a US-based study of 77,000 men showed no survival benefit to PSA screening in comparison to controls. Important limitations of this study that have been cited include a high rate of cross-contamination with frequent PSA screening in the control group and a follow-up period that was too short to assess rate of mortality. A critical limitation of both of these trials was that, of the prostate cancer cases detected, 60% to 65% were low grade and thus had a reduced biologic potential for the development of clinically significant disease. Based on the interim results from these trials, the US Preventative Services Task Force currently recommends against the use of PSA screening for prostate cancer detection. Other health policy and professional organizations, including the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the American Cancer Society, recommend an informed and shared decision process toward prostate cancer screening. Given the lack of consensus in this area, a personalized approach seems warranted in which the risks and benefits of screening are each carefully weighed with the individual patient’s health concerns in mind.
These studies highlight the need for improved methods of screening, which preferentially identify potentially lethal prostate cancer. Novel strategies such as these would optimize the efficiency of the screening process and ultimately direct the most suitable patients into evidence-based treatment pathways. Several biopsy prediction tools are currently available that demonstrate the capacity for the prediction of high-grade prostate cancer on biopsy ( Table 1 ). These prediction tools incorporate several readily available clinical biomarkers that can be used to improve risk assessment for the detection of lethal cancer. These strategies help to reduce the number of unnecessary biopsies and reduce the rate of overdiagnosis in men with insignificant cancers. Future studies are likely to incorporate advanced imaging and both serum and urine biomarkers into the risk assessment of patients presenting for prostate cancer screening.
| Reference | Prediction Tool | Population | Predictors | Accuracy | Validation |
|---|---|---|---|---|---|
| Thompson et al, 2006 | Logistic regression | Screening trial | Log PSA, DRE, prior biopsy, age, race | AUC = 70% | External |
| Nam et al, 2007 | Logistic regression | Referral cohort | Age, PSA, %fPSA, DRE | NA | Split sample |
| Ide et al, 2008 | Logistic regression | Referral cohort | PSA, testosterone | AUC = 70% | Split sample |
| Spurgeon et al, 2006 | Classification and regression tree analysis | Referral cohort | PSAD, prostate volume, age | Sensitivity = 92% Specificity = 36% | Split sample |
Risk factors for aggressive prostate cancer
Several clinical and pathologic pretreatment factors are known to predict adverse clinical outcomes in localized prostate cancer. Validated predictors of cancer recurrence and progression that are widely used include Gleason biopsy grade, tumor stage, and level of serum PSA. Tumor stage and level of PSA primarily correlate with extent of tumor burden; however, these are less robust indicators of lethal potential than tumor grade. The effect of tumor grade was clearly demonstrated by Albertsen and colleagues, who showed that the risk of prostate cancer mortality after observation alone was 16-fold higher in men with high-grade cancer compared with those with low-grade cancer. Similarly, in a Swedish trial of observation with a mean follow-up of more than 20 years for localized prostate cancer, tumor grade was highly predictive of cancer metastases and mortality. During the follow-up period, 40% of patients experienced clinical progression and nearly half of these developed metastatic disease. In many cases cancer progression accelerated late in the disease course after a long period of nonprogression (10-15 years). In addition to highlighting the effect of Gleason score on cancer progression, this study also showed the need for continued vigilance and close observation in patients with prostate cancer, particularly among those with expected longevity.
A plethora of tissue markers have been studied as predictive biomarkers in prostate cancer. These tissue biomarkers include oncogenic molecules involved in cell cycle progression, tissue invasion, metastases, cell survival, and angiogenesis. Although these hold great promise for use in patient management, to date none hae proven to be as effective or cost-efficient as current clinical predictive models. Thus, until further data are available, tissue biomarker analyses should remain the subject of ongoing research studies.
To assess and manage the patient with clinically localized prostate cancer accurately, standardized risk stratification groups have been identified that integrate clinical biomarkers used in routine patient care. These risk stratification groups offer several advantages in patient management, including the following: (1) to serve as standard nomenclature for interdisciplinary teams that comanage patients, (2) to determine the need for staging studies, (3) to compare treatments across similar treatment groups, and (4) to codify patient groups for the development of clinical trials with special target populations in mind.
Risk assessment of prostate cancer
There are several clinical factors that are predictive of disease recurrence that aid in the designation of patient risk groups. Although many of these variables have been examined individually, newer predictive models capable of combining several factors have resulted in refined tools that are available for routine clinical use. D’amico and colleagues retrospectively developed a widely used strategy based on clinical data from a single institution cohort undergoing either surgery or radiation with curative intent. This straightforward schema is based on biopsy Gleason score, tumor stage, and level of PSA. Rates of relapse in risk groups were as follows ( Box 1 ): low-risk: less than 25%, intermediate-risk: 25% to 50%, and high-risk: greater than 50%. Risk factors that predicted a greater than 50% chance of cancer recurrence included the following: clinical stage T3–4, a PSA >20, or a Gleason score ≥8. These predictors have been validated in external datasets and incorporated into routine practice guidelines by the National Comprehensive Cancer Network and the European Association of Urology. In addition, tools have been developed that give a more personalized readout in terms of predicting clinical outcomes. Nomograms have been developed that give a numeric value (as opposed to risk grouping) for risk of recurrence. These tools may be of use in informing individual patients of their progression risk in more refined terms than risk groupings provide.
Low risk (<25%):
Clinical T1–T2a
Gleason score 2–6
PSA <10 ng/mL
Intermediate risk (25%–50%):
Clinical T2b–T2c, or
Gleason score 7, or
PSA: 10–20 ng/mL
High risk (>50%):
Clinical T3–T4, or
Gleason score 8–10, or
PSA >20 ng/mL
Imaging in prostate cancer
Patient risk stratification is the primary means of guiding the need and the type of imaging modality in the workup of newly diagnosed prostate cancer. Prostate cancer has a unique tropism for bone whereby it metastasizes in greater than 80% of patients with systemic disease. Lesions involving bone are typically osteoblastic in nature and are a harbinger of tumor progression and death. Radioisotope bone scans are generally reserved for those with high-risk prostate cancer. In lower risk patients bone scans and other imaging modalities are typically omitted. In these cases patients are subject to a higher rate of false-positive results because of the frequency of benign conditions of the skeleton in elderly men. Newer bone imaging agents such as flourine-18 ( 18 F) and 18 F-fluorodeoxyglucose positron emission tomography/computed tomography have shown encouraging preliminary results in terms of improved sensitivity and tumor quantitation; however, these require further study before being incorporated into regular clinical practice. Computerized tomogram scans are of limited utility in discerning the primary tumor extent or location, although these are routinely deployed to assess regional lymph node status, especially in high-risk cases considered to be locally advanced (ie, PSA >20 ng/mL or the presence of T3–T4 cancer or if the predicted chance of lymph node disease exceeds 20%). In the future, the use of magnetic resonance imaging and ferromagnetic nanoparticles are likely to improve local and regional staging, but further study is needed to bring these promising modalities into the sphere of clinical practice. At the authors’ institution, the utility of shutter-speed image analysis for discriminating benign from malignant prostate tissues using shutter-speed modeling is currently being evaluated. This technique has shown encouraging results in early phase testing but requires large-scale prospective testing, which is in the planning stages.
Surgery improves survival in prostate cancer
Radical prostatectomy is considered to be a primary treatment option for appropriate cases of localized prostate cancer. This concept is strongly supported by the results of randomized controlled trials demonstrating significant improvements in oncologic outcomes compared with observation alone. The direct impact of curative therapy on the natural history of prostate cancer was first demonstrated in the Scandinavian Prostate Cancer Group Study 4. In this trial, 695 men with localized prostate cancer were randomized to either observation alone or radical prostatectomy. At baseline, the mean PSA was about 13 ng/mL with half of all patients having PSA values greater than 10 ng/mL. With a median follow-up of 12.8 years, significant improvements in cancer outcomes have been reported for men entered onto the surgical intervention arm of the trial ( Table 2 ). Surgery resulted in a 38% improvement in disease-specific rate of mortality and a 25% improvement in overall survival. Surgical intervention resulted in a 67% reduction in local progression and a 41% reduction in the spread of metastases. More recently, in a study of 731 men diagnosed primarily through PSA testing, surgery was compared with observation alone. In the Prostate Intervention Versus Observation Trial (PIVOT), the mean PSA was lower at 7.8 ng/mL and greater than 70% of patients had low-grade tumors (Gleason 6 or less). With a median follow-up of 10.0 years, there was no benefit to subjects with Gleason 6 cancer or a preoperative PSA ≤10 ng/mL. However, in patients with a PSA >10 ng/mL, surgery resulted in a 21% improvement in overall survival, a 57% improvement in prostate cancer survival, and a 72% improvement in bone metastases-free survival (see Table 2 ). Similar improvements for these metrics were seen in patients with intermediate-risk and high-risk prostate cancer. Thus, based on these and other studies, surgery is considered a mainstay of therapy in men with clinically significant, localized prostate cancer. This benefit seems to be greatest for men with higher levels of PSA and higher grade cancers. Because prostate cancer death is a relatively late occurrence among men with Gleason 6 cancer, the PIVOT trial was poorly designed to capture these late events. Because of this, caution must be taken in making data inferences beyond 10 years in patients with a Gleason 6 or less tumor. Thus the long-term effect (>10 years) of surgery on low-grade PSA-detected prostate cancer remains unknown.
| Outcome | SPCG-4 | PIVOT Study | |
|---|---|---|---|
| PSA ≤10 Ng/mL | PSA >10 ng/mL | ||
| Overall survival | 25% | ns | 21% |
| Prostate cancer survival | 38% | ns | 57% |
| Metastases-free survival | 41% | ns | 72% |
| Local control | 67% | ns | NA |
Surgery for advanced prostate cancer
The rate of cancer recurrence measured by PSA testing after radical prostatectomy is reported to be approximately 30% to 40%. Data from several contemporary surgery series have shown that the increased D’amico/National Comprehensive Cancer Network (NCCN) category is associated with an increased chance of PSA recurrence and risk of prostate cancer death. In a report by Pound and colleagues of patients with Gleason 8 or higher who were observed at the time of PSA recurrence after surgery, metastases-free survival at 7 years was only 29%. In a single-center experience of a cohort of men treated with either surgery or radiation, the risk of metastatic progression was 6.4-fold higher in D’amico/NCCN high-risk versus intermediate-risk or low-risk patients. In addition, in a large retrospective analysis of US population-based data containing nearly 150,000 prostate cancer cases, 33% were found to be at high risk. With a mean follow-up of 60.7 months, the estimated 10-year cancer-specific rate of mortality after radical prostatectomy was 5.8% for patients less than 60 years old, increasing steadily to 21.1% in patients greater than 80 years of age. Thus, prostate cancer is a fatal disease in high-risk prostate cancer and risk of death increases with advancing age.
Disease recurrence after radical prostatectomy may occur locally in the surgical site or at distant sites such as the axial bones. Imaging is of limited use in locating the anatomic source of PSA recurrences when the levels are low. However, recent clinical trial reports show that most of these early recurrences are local within the surgical bed (ie, prostatic fossa). This finding clearly highlights the need for technical improvements in the surgical procedure along with the need for effective combination therapy when indicated.
Improvements in our comprehension of prostatic anatomy and its surrounding structures as well as the pathways of disease extension have resulted in technical advancements in the surgical procedure. Surgery may be performed through a standard open technique or by robotic-assisted laparoscopy. These procedural modifications must include a precise and thorough apical dissection along with the wide local excision of the neurovascular bundles in advanced disease. Currently it is unclear which of these 2 methods is superior, because limited comparative data are available for high-risk cases.
Further improvements in the tumor staging and clinical outcomes result from the performance of an extended pelvic lymph node dissection versus a more limited pelvic dissection. Long-term PSA-free survival is possible in 10% to 20% of patients with positive lymph nodes treated with an extended (vs limited) pelvic lymph node dissection. Extended pelvic lymph node dissection should be performed in all patients with intermediate-risk or high-risk prostate cancer. In low-risk patients a lymph node dissection is generally omitted but should be considered on a case-by-case basis, particularly if other adverse features are present. Long-term cancer control in these node-positive cases is achievable but may require the addition adjuvant and salvage therapies.
Contemporary modifications to standard treatment have resulted in improved cancer-free rates in patients undergoing either surgery or radiation. These contemporary modifications are considered effective treatment options for low-risk to intermediate–risk prostate cancer; however, satisfactory therapeutic approaches have yet to be developed for patients with clinically localized, high-risk disease.
Adjuvant and salvage radiation therapy
Disease recurrence after radical prostatectomy or radiation therapy may occur locally in the surgical site or at distant sites. Existing or suspected subclinical, microscopic disease is below the threshold of detection of any imaging modality and may forever be. However, recent scientific data support the concept that, despite technically adequate dissections, residual disease in the surgical bed can progress to metastases and death unless eradicated.
The benefit of maximizing local control in high-risk prostate cancer is strongly supported by controlled prospective trials of adjuvant radiotherapy after prostatectomy ( Table 3 ). In a phase III trial of adjuvant pelvic radiation versus observation after surgery for high-risk disease, postoperative radiation resulted in improved disease control. The European Organization for Research and Treatment of Cancer (EORTC) reported the results of 1005 men who were randomized to receive postoperative radiation if they had 1 of 3 well-known prognostic factors for disease recurrence after radical prostatectomy: positive margins, extracapsular extension, or seminal vesicle invasion. After a median follow-up of 5.0 years, the group treated with adjuvant radiotherapy after prostatectomy had a 52% reduction (74% vs 53%) in either biochemical or clinical progression compared with control subjects. In this study, follow-up is ongoing to assess the effects on cancer-specific and overall survival.
| Study | No. Subjects (Follow-up, Years) | Main Entry Criteria | Primary Endpoint | Treatment | Main Results |
|---|---|---|---|---|---|
| Thompson et al, 2006 | 431 (10.6) | Extracapsular extension, positive surgical margin, or seminal vesicle invasion | Metastases-free survival | 60–64 Gy to prostate fossa | Metastases or death improved in RT group (HR 0.75, 95% CI, 0.55–1.02; P = .06). Improved PSA-free survival. |
| Bolla et al, | 1005 (5.0) | Extracapsular extension, positive surgical margin, or seminal vesicle invasion | PSA recurrence-free survival | 60 Gy treatment within 16 wk of surgery to prostate fossa | RT reduced PSA recurrence by 52% (HR 0.48, 98% CI 0.37–0.62; P <.0001). Improved locoregional control but no difference in metastases or overall survival |
| Wiegel et al, | 307 (4.5) | Pathologic T3–T4, N0 Undetectable PSA | PSA recurrence-free survival | 60 Gy treatment within 6–12 wk of surgery to prostate fossa | RT reduced PSA recurrence (HR = 0.53; 95% CI, 0.37 to 0.79; P = .0015). No difference in metastases or overall survival |
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