Research Article: Current Challenges in Prostate Cancer Management and the Rationale behind Targeted Focal Therapy

Date Published: May 10, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Al B. Barqawi, Kevin J. Krughoff, Khadijah Eid.


Among men, prostate cancer has a high prevalence, with relatively lower cancer-specific mortality risk compared to lung and colon cancer. Prostate-specific antigen (PSA) screening has increased prostate cancer awareness since its implementation as a screening tool almost 25 years ago, but, due to the largely indolent course of this disease and the unspecific nature of the PSA test, increased incidence has largely been associated with cancers that would not go on to cause death (clinically insignificant), leading to an overdiagnosis challenge and an ensuing overtreatment consequences. The overtreatment problem is exacerbated by the high risk of side effects that current treatment techniques have, putting patients’ quality of life at risk with little or no survival benefit. The goals of this paper are to evaluate the rise, prevalence, and impact of the overdiagnosis and ensuing overtreatment problems, as well as highlight potential solutions. In this effort, a review of major epidemiological and screening studies, cancer statistics from the advent of prostate-specific antigen screening to the present, and reports on patient concerns and treatment outcomes was conducted to present the dominant factors that underlie current challenges in prostate cancer treatment and illuminate potential solutions.

Partial Text

Accounting for 29% of all cancers in men, prostate cancer is the most common cancer among men behind nonmelanoma skin cancer and is the second highest cause of cancer death among men of all races [1, 2]. Over 2 million men currently alive in the United States have had prostate cancer, and it is estimated that 16.48% of men will be diagnosed with prostate cancer at some point during their lives [3]. Estimates of newly diagnosed prostate cancer cases hover near 240,000 for 2011 [4].

The primary reason for such a high rate of diagnosis for so often a symptomless condition is most likely the result of prostate-specific antigen (PSA) screening practices which came about in the late 1980s following studies which seemed to demonstrate the value of PSA as a biomarker for prostate cancer [6–8]. The 1987 study by Stamey and colleagues was perhaps the most dominant one due to its citation prevalence in Medline [9, 10]. In 2004, however, Stamey and colleagues maintained that PSA was only an accurate reflection of prostate cancer circa 1985 and that it was only demonstrated a relation to benign prostate hyperplasia throughout the five years preceding their newer study [11]. Moreover, Thompson and colleagues demonstrated in 2005 that there was no single PSA cutoff that could yield both high sensitivity and specificity [12].

What may account for this is the fact that, while helping to discover mortal cancers, PSA testing also often led to the discovery of nonmortal cancers, or those which would never have been given notice in the absence of screening [19]. Given that 20–50% of asymptomatic men are found to harbor prostate cancer upon autopsy, it follows that the PSA test, with only a 24.1% positive predictive value, leads to a much greater detection of cancers, both mortal and nonmortal [20–23]. It is also possible that widespread PSA testing and treatment may have slowly weeded out the more dangerous prostate cancers from the population. Whether from increased testing, increased treatment of dangerous cancers, or some combination of the two, more cancers were being found at lower stages from 1986 to 1993, with tumors often being low grade, clinically localized, and/or organ confined. From 1993 to 2003, there was a 75% reduction in the proportion of metastatic diagnoses for prostate cancer [24]. The link between PSA testing and stage migration was documented in Austria during a large-scale PSA testing study and again later in the United States [24–26]. This seems to indicate that as PSA testing continues, prostate cancer will also continue to be diagnosed at clinically insignificant stages.

Given the propensity of PSA testing to detect cancers both mortal and nonmortal, overdiagnosis was a probable outcome. Overdiagnosis due to PSA testing has been documented extensively through epidemiological studies and computerized models, at rates which range from 29% in specific regions to an estimated 80% should all men in the United States be screened [7, 27, 28]. Progress has been made in investigating different biomarkers and variations of PSA testing for early detection of mortal prostate cancer, but, despite its flaws, the PSA test still remains the best screening tool currently available, suggesting continued overdiagnosis [29–31].

The corollary of the overdiagnosis problem is an overtreatment problem. While active surveillance (AS) might seem the best course of action for many due to the relatively low mortality rate and exceedingly high 15-year survival rates of prostate cancer, working against that is a lack of consensus on what the inclusion criteria should be for AS, what the optimal follow-up schedule should be, or even how to best define progression [32]. For instance, the Epstein criteria is one common method of establishing whether or not a cancer is clinically insignificant, and this relies on a third or less of biopsy cores being positive, 50% or less involvement of any 1 core, and a PSA density of less than 0.15 ng/mL. However, the D’Amico criteria, also widely used, calls for a Gleason score of six or less, a PSA of less than 10 ng/mL, and a T1 clinical stage. Studies have shown highly favorable results for certain criteria, like the 100% 10-year prostate cancer-specific survival rate documented by researchers who took patients off AS based on PSA doubling time [33]. Other studies suggest that PSA kinetics are not reliable for AS inclusion/exclusion criteria [34]. In yet another study, researchers found that prostate specimens fitting six different inclusion criteria for clinically insignificant disease would have been misclassified 14–27% of the time based on Gleason 8 findings [35]. Research continues to refine AS criteria, but a clear understanding of how to define clinically insignificant disease has not been reached.

The amount of treatment received is certainly disproportional, and studies clearly indicate that a substantial proportion of treatments do not go on to prevent death from prostate cancer. The European Randomized Study for Prostate Cancer (ERSPC) reported, for instance, that 1410 men needed to be screened and 48 treated to prevent 1 cancer death [48]. Results from the Randomized Scandinavian Prostate Cancer Group Study show that an estimated 15 patients needed to be treated to avert one death at 15 years and that, for adjuvant radiation therapy, the number of patients needed to be treated to avert one death at 12.6 years was 9.1 [49]. Perhaps the most favorable results were found in Quebec, where out of an estimated 100 men with screen-detectable prostate cancer, an average of 16 could have their lives extended by surgery (should those men be found by way of extensive screening efforts) [50]. However, the most recent data comes from the Prostate Cancer Intervention versus Observation Trial (PIVOT), which reports that, after 12 years of followup, overall prostate cancer mortality was only 3% lower for men having radical prostatectomy. In fact, men with low-risk prostate cancer were actually shown to have a 2.4% better survival rate with watchful waiting than with surgery. PIVOT reports that, even when looking exclusively at cases of intermediate risk, radical prostatectomy still only achieves a 4.8% better survival rate [51].

Excess treatment brings excess side effects, and, in the case of prostate cancer, they are not uncommon. Overtreated patients run several risks, especially when it comes to radical prostatectomy and/or radiation therapy, the most dominant treatment options. The US Preventative Services Task Forces reviewed the most common side effects of treatment from 1994 to 2002, bringing the problems associated with overtreatment to light. Long-term adverse effects of radical prostatectomy, for instance, were sexual dysfunction (20–70%) and urinary incontinence (15–50%). For electron beam radiation therapy, approximately 45% could expect erectile dysfunction, 2–16% urinary dysfunction, and 6–25% bowel dysfunction. For Androgen Deprivation Therapy (ADT), approximately half of patients who were sexually active beforehand were not sexually active afterward, 5–25% had breast swelling, and 50–60% had hot flashes along with other potential long-term complications like anemia and osteoporosis. For brachytherapy, a majority of men reported having distressing urinary symptoms, 21–36% reported decreased erectile function, 18% diarrhea, and 19% persistent rectal bleeding [52].

The aforementioned statistics indicate that the majority of these treatments will infer no survival benefit in the first place, so the amount of men who go on to suffer such side effects is certainly unwarranted. However, without an established and reliable way to distinguish mortal from nonmortal cancers and the overwhelming preference by both patients and providers to pursue treatment options in the face of such uncertainty, it seems treatment will continue to be the dominant option. Fortunately, focal therapy techniques developing since the 1990s are now showing promise as a method of treatment which is not associated with such arresting rates of side effects. These techniques avoid the costs that other techniques would require in order to reduce side effects to comparable levels while still being effective [59].

While procedural advances and screening efforts continue to report improvements, the PSA test is still the best screening tool currently available, and this suggests a continuing trend of overdiagnosis based on historical data. Early detection of prostate cancer is possible, but early discrimination is not, leading to a great deal of uncertainty as to whether or not a particular patient’s prostate cancer will become aggressive. The psychological burden that comes with this uncertainty more often than not leads to treatment regardless of patients’ understanding of high risks of side effects and low survival benefit rates. Whether or not improved screening or imaging techniques will be able to better distinguish nonmortal from mortal cancers remains to be seen, as well as what role that will play in regards to the psychological distress that comes with being diagnosed with prostate cancer.