2015 Genitourinary Cancers
Symposium DAILY NEWS
A Snapshot of Change in Prostate Cancer: Innovations in Screening, Detection, Management
Jan 30, 2014
More than 2 million men have been diagnosed with prostate cancer in the past decade. Despite a considerable rise in the age-adjusted incidence of prostate cancer in the United States over the previous two decades, the incidence of prostate cancer has remained stable in this decade, with 180 cases per 100,000 men diagnosed since 2001.1,2 However, the incidence has substantially increased among men younger than age 50, and a majority of tumors are now classified as well- or moderately differentiated (Gleason score ≤ 6) using the National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program data.3 However, the age-adjusted mortality rate in the United States has dramatically decreased by more than 40%. These epidemiologic changes over the past 10 years have been due, in part, to advances in prostate cancer detection and treatment, and these innovations have inspired greater emphasis on individualization of disease management based on risk stratification.
The past decade witnessed the publication of landmark clinical trials on the early detection and prevention of prostate cancer, comparative analyses of treatment for localized disease, and management of high-risk disease. In addition, the development and dissemination of novel prediction tools have been complemented by studies on patient-reported outcomes to improve individualization of disease management. The focus of local therapy has shifted from men with low-grade, organ-confined cancers, now managed conservatively with active surveillance, to aggressive, potentially lethal cancers, which require intensive, sometimes multimodality therapy.
Several large, randomized placebo-controlled trials have reported results of pharmacologic chemoprevention. Lifestyle modifications, including the use of vitamin supplements, have also been studied.
The Prostate Cancer Prevention Trial (PCPT) was designed to evaluate the effectiveness of finasteride in reducing the detection of prostate cancer in men with low risk of disease.4 The results of this trial were unexpected: prostate cancer was detected by biopsy in a remarkable 24.4% of the study participants, and finasteride decreased the overall relative risk of prostate cancer by 25%. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE trial) examined the effects of dutasteride in a higher-risk cohort, with a similar relative risk reduction of 25% and an absolute reduction of 5.1%. In both trials, however, all risk reduction occurred in men with Gleason score of 5 or 6.5 The U.S. Food and Drug Administration Oncologic Drug Advisory Committee refused to issue an indication for the prevention of prostate cancer with either of these 5-alpha reductase inhibitors. This decision was based largely on the premise that low-grade prostate cancers pose little threat to health and should not be treated; therefore, preventing them is of no value. In addition, the Advisory Committee raised concerns that the risk of high-grade cancers (Gleason scores of 8 to 10) may be slightly increased in patients receiving these drugs. Notably, the drugs remain approved for the relief of symptomatic benign prostatic hyperplasia.
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) randomized 35,533 men at low risk for prostate cancer in a double-blind design to regimens of either vitamin or to combinations of these supplements.6 No significant differences were found in rates of prostate cancer across the intervention groups. Based on these results, neither agent is recommended for the prevention of prostate cancer.
Several large, prospective randomized trials addressed the hypothesis that screening using prostate-specific antigen (PSA) values can reduce mortality for prostate cancer. The results remain controversial, and in 2012 the U.S. Preventive Services Task Force recommended against PSA screening on the grounds that there is no net benefit and that the potential harms outweigh the benefits.7 The Task Force’s conclusions have been criticized, however, as premature in a rapidly evolving area of intensive research.8 The U.S.-based Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial found no reduction in prostate cancer-specific mortality associated with screening after a median follow-up of 10 years, but the study was flawed by pretesting with PSA in 40% of the study participants and contamination (by PSA testing) in 70% of the individuals in the “unscreened” control cohort.9 However, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a statistically significant relative reduction of 21% in prostate cancer mortality at 11 years.10 In the longest and largest independent trial, prostate cancer mortality was reduced by 46% at 14 years;11 in a modeling study of the ERSPC trial cancer deaths were reduced by 21%, and five cancers needed to be detected over the lifetime of the screened subjects to prevent one death from prostate cancer.12 In these studies, more than 250,000 men were randomly assigned to screening and followed for prostate cancer death.
During this same era, large case-controlled studies found that PSA levels at mid-life (ages 45 to 60) strongly predicted prostate cancer metastases and death over the next 25 years, suggesting that PSA testing should not be abandoned but should be used more appropriately to risk-adjust screening strategies.13 New panels of biomarkers for detecting prostate cancer, especially high-grade, potentially lethal cancers, offer marked increases in specificity while retaining sensitivity and could substantially reduce unnecessary biopsies and over-detection of low-risk cancers.14,15
With widespread PSA screening for prostate cancer, concerns have arisen about overdetection and overtreatment. In intensely screened populations, 40% to 50% of cancers in the United States have low-risk characteristics and seem to pose little immediate threat to life or health. Large cohorts of men with low-risk cancer have been followed in active surveillance programs with little risk of prostate cancer mortality (at least within 10 years), and those cancers that do appear to progress generally respond to delayed treatment with surgery or radiation.16,17 The feasibility of active surveillance for men with low-risk prostate cancer was initially confirmed in a prospective observational study conducted at the University of Toronto.18 Since that study, multi-institutional reports have been published that describe the safety of active surveillance16 and the substantial improvement in quality of life for men on watchful-waiting protocols, compared with those undergoing radical prostatectomy.16,19 New efforts are needed to standardize the evaluation and follow-up of men on active surveillance, and to define the criteria for eligibility and appropriate triggers for intervention. Molecular profiles and biomarkers in serum (e.g., phi, 4K score) and in urine (e.g., PCA3) are being developed to enhance initial and delayed triage to active surveillance versus active therapy.14,15,20,21
The harms of early diagnosis of prostate cancer are primarily associated with radical treatment, either surgery or radiotherapy. Although these treatments are effective in eradicating most tumors, patients risk post-treatment morbidity and a significant reduction in quality of life through development of side effects such as incontinence, erectile dysfunction, rectal injury, and bowel urgency.22 In the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial, men with nonscreen-detected prostate cancer were randomly assigned to watchful waiting or to radical prostatectomy. Surgery significantly reduced prostate cancer-specific mortality (HR 0.62, 95% CI, 0.44 to 0.87; p=0.01), overall mortality (HR 0.75, 95% CI, 0.61 to 0.92; p=0.007), the risk of metastasis (HR 0.59, 95% CI, 0.45 to 0.79; p<0.001), and of local progression (HR 0.34, 95% CI, 0.26 to 0.45; p<0.001) after a median follow-up of 12.8 years.23 In contrast, the Prostate Cancer Intervention Versus Observation Trial (PIVOT) studied U.S. men randomly assigned to radical prostatectomy versus observation. After 12 years there was an absolute risk reduction in prostate cancer mortality of 3%, which was not statistically significant.24 These discordant results may be explained by the prevalence of screening in men enrolled in PIVOT, in which 50% of the tumors (compared with 12% in SPCG-4) were classified as T1c. When statistical methods were used to adjust for overdiagnosis and lead time due to screening detection, the absolute mortality difference in PIVOT was comparable to that of the SPCG-4 trial.25 These studies confirm that many patients with intermediate- and high-risk cancers benefit from immediate treatment, while active surveillance is more appropriate for most men with low-risk prostate cancer.
Open radical prostatectomy has been the standard surgical approach in men with localized prostate cancer during most of the past century. Over the past decade, however, the use of robotic-assisted laparoscopic prostatectomy has increased considerably. In 2009, 61% of radical prostatectomy procedures were performed using robotic technology, according to case logs submitted for board recertification.26,27 In the absence of any randomized trials, evidence on outcomes of these procedures is documented in population-based observational studies and single-institution case series.27,28 The rapid growth of robotic-assisted laparoscopic prostatectomy, fueled by direct-to-consumer advertising, has raised concerns about the quality of data that patients with prostate cancer are likely to find on the Internet, as well as about the regulation and credentialing of surgical training conducted prior to adopting novel advanced technologies.29
Whatever the effect of these advances in surgical technology, it is now clear that the skill level of the surgeon, independent of surgical approach, has a major effect on prostate cancer treatment outcomes. The positive association of surgical volume with improved outcomes has been mapped in learning curves charting surgeon experience with cancer-specific and patient-reported functional outcomes.30 Subsequently, innovative web-based tools have been developed to gather patient-reported information and provide individualized real-time feedback to surgeons on the outcomes of their procedures.31,32 Novel prediction tools and nomograms have been further developed and disseminated to assist in shared decision-making by physicians and patients about treatment options for localized prostate cancer.33
Advanced imaging modalities could provide standard, reliable methods for accurately identifying tumor size, location, and extent. In addition to facilitating individualized risk stratification, new imaging techniques could be helpful in directing therapy, assessing treatment effect, and monitoring for disease recurrence or progression. Over the past decade, multiparametric MRI has emerged as the most accurate imaging technique for detecting clinically important prostate cancers.34
Molecular and Genetic Studies
A landmark discovery in the past decade was the identification of a chromosomal rearrangement in an androgen-regulated gene. The fusion between transmembrane protease serine 2 (TMPRSS2) and ERG, an erythroblast transformation-specific (ETS) transcription factor family member, is identified in approximately 50% of primary and metastatic prostate cancer tumors and most often correlated with poor prognosis.35,36 Although the effects of identifying the fusion of these factors on clinical management decisions can be debated, the high prevalence of these fusions provides an important pathway for investigation of new diagnostic and prognostic indications, as well as for potential targets for tailored therapies. A comprehensive, integrated genomic profile of prostate cancer found alterations in key molecular pathways in a surprisingly large number of primary, as well as metastatic tumors, which suggests that the degree of copy number alterations may affect the prognosis of primary tumors treated with surgery.37
Next-generation sequencing technologies have enabled rapid and comprehensive interrogation of genomic data implicated in human diseases. Targeted sequencing of exons located on chromosome 17q21-22, a region previously linked with prostate cancer, has resulted in the identification of a recurrent mutation in HOXB13 among families with a history of prostate cancer.38HOXB13 is the first gene associated with a substantial risk of hereditary prostate cancer and, despite the low prevalence of this mutation in the population, further research on HOXB13 may lead to the identification of pathways found to be abnormal in a greater number of occurrences of sporadic disease.
Progress in the detection, treatment, and understanding of localized prostate cancer has been rapid over the past decade. Major randomized trials were published that examined the role of screening, chemoprevention, and surgical treatment. Tools for assessing patient-reported outcomes and prognosis have been refined. Landmark clinical trials have been complemented by breakthroughs in translational research, improving our understanding of the molecular and genetic factors in prostate cancer. In the near future, we anticipate the use of molecular and genetic tests in the clinic, improvements in the quality of care through reliable metrics of performance and feedback to physicians, and the continuing evolution of surgical technology and advanced imaging.
About the Authors: Dr. Ehdaie is a surgeon at the Sidney Kimmel Center for Prostate and Urologic Cancers. Dr. Scardino is chair of the Department of Surgery and the David H. Koch Chair at Memorial Sloan-Kettering Cancer Center. Dr. Scardino will be presenting his Decade in Review lecture on prostate cancer, “The Urology Perspective,” Thursday, 3:15 PM-4:00 PM.
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