Prostate cancer remains the most common solid organ malignancy diagnosed among men in the United States, with the American Cancer Society estimating that 1 in 6 men will be diagnosed with prostate cancer, and 1 in 35 will die of the disease.
ABSTRACT: The clinical incidence of prostate cancer continues to increase in the patient population, while the actual mortality has remained relatively low. As clinicians, we struggle to identify those patients who require intervention for their disease and to determine which treatment modality is best. Active surveillance, brachytherapy, external-beam radiation therapy, and surgical radical prostatectomy (RP) are the current options for prostate cancer treatment, each with a distinct impact on a patient’s health-related quality of life. We believe that for the majority of patients with organ-confined prostate cancer, RP remains the gold standard with respect to both oncologic success and maximization of quality of life. Herein we discuss the advantages of RP.
Prostate cancer remains the most common solid organ malignancy diagnosed among men in the United States, with the American Cancer Society estimating that 1 in 6 men will be diagnosed with prostate cancer, and 1 in 35 will die of the disease. The advent of prostate-specific antigen (PSA) screening has resulted in an overall downstaging of prostate cancer, such that 82% of newly diagnosed disease will be organ-confined. To date, no prospective randomized trial has shown an overall survival benefit to any of the therapeutic options for organ-confined disease-ie, active surveillance, brachytherapy, external-beam radiation (EBRT), or surgical radical prostatectomy (RP). This poses a perplexing conundrum for both the physician and the patient when evaluating different therapeutic options, each of which has its own distinct profile of benefits and pitfalls.
Clearly, one of the main goals of organ-confined prostate cancer therapy is to eliminate the primary cancer such that there is no recurrence, either local or distant. No study has definitively shown a difference in survival between the active treatment modalities for organ-confined prostate cancer. However, a prospective randomized trial has shown a distinct survival advantage of RP over watchful waiting. For all intents and purposes, watchful waiting is the decision to forgo treatment of prostate cancer.
D'Amico Risk Stratification Groups for Prostate Cancer
Patients with nonmetastatic prostate cancer comprise a very heterogeneous group, and no current discussion of therapy outcomes can be valid or complete without taking into account pretreatment risk-stratification groups. D’Amico and colleagues have stratified patients into low-, intermediate-, and high-risk pretreatment groups using a combination of prostate-specific antigen (PSA), Gleason sum, and clinical stage (Table 1). Using these risk-stratification groups as a context for assessment, survival advantages emerge for RP over brachytherapy or EBRT.
A second goal of prostate cancer treatment is to preserve quality of life with regard to side effects. Although radiation oncologists and surgeons alike tend to minimize the side effects of their treatment plans, the patient’s quality of life following prostate cancer treatment can be seriously affected. Recent development and validation of health-related quality-of-life (HRQOL) tools for treatment of localized prostate cancer have enabled clinicians to provide more accurate data to assist patients in their decision-making process. Here, we compare the results of RP to the other therapeutic options, and show that for the appropriately selected patient, RP remains the gold standard for prostate cancer therapy.
One clear advantage of RP over EBRT, brachytherapy, and active surveillance is accurate pathologic staging. Studies have shown that prostate needle biopsy is not entirely accurate. After RP, 24% to 29% of patients with presumed organ-confined disease are upstaged to pathologic T3 (extraprostatic) disease, and 30% will have a clinically significant upgrade (new diagnosis of Gleason 4 or 5).[6,7] Although extracapsular extension is more commonly found in intermediate- and high-risk patients (35% and 48%, respectively), it is also found in 15% of patients who had been considered low risk. Thus a significant number of patients with presumed low-risk disease will be undertreated with active surveillance or brachytherapy.
Following RP, an oncologist has clear pathologic data with which to ascertain whether the local cancer has been eliminated, and if the disease is organ-confined, can be reassured of a 10-year disease-free survival of 93% to 95%. If the patient’s disease is upstaged to pathologic T3 disease after RP (extracapsular tumor extension, positive surgical margin, or seminal vesicle invasion), the patient can be triaged into adjuvant radiation therapy in a timely fashion, which has been shown to reduce the risk of metastasis and improve overall survival.
Radical prostatectomy also provides the added benefit of a clear and concise interpretation of posttherapy PSA. After successful treatment by RP, PSA becomes undetectable and failure of PSA to fall to undetectable levels generally supports the presence of local or distant disease. PSA recurrence following RP is formally defined as an initial PSA ≥ 0.2 ng/mL, with a second confirmatory level of PSA > 0.2 ng/mL.
Following radiation therapy, PSA level does not normally fall to an undetectable level, leaving some uncertainty as to the completeness of treatment. The former 1997 American Society for Therapeutic Radiology and Oncology (ASTRO) criteria for PSA recurrence after radiation therapy (three consecutive increases in PSA) have been abandoned in favor of a PSA level of 2 ng/mL or more above the absolute nadir PSA. However, even the new ASTRO definition of PSA recurrence has fallen under scrutiny, with a recent analysis suggesting that the nadir-plus–2 ng/mL definition results in a 5-year delay in diagnosis of cancer recurrence. For the clinician, the ambiguity of PSA levels following radiation therapy in comparison to PSA levels following RP may be frustrating. Is a nadir of 1.9 ng/mL a satisfying indicator of cancer control following radiation therapy? If a patient’s PSA rises from 2.0 to 3.5 ng/mL over the course of 6 months, should this not warrant a concern for recurrence?
To date, no prospective randomized trials have compared RP to active surveillance. However, patients on an active surveillance protocol have a 52% likelihood of treatment initiation within 5 years of diagnosis; in particular, men younger than 65 had an almost 60% likelihood of treatment in 5 years. In the sole prospective randomized trial comparing watchful waiting to RP (note: this was not active surveillance), the patient population younger than 65 who underwent RP showed the greatest reduction in disease-specific mortality. Thus, although we do not have clear evidence for avoiding active surveillance in intermediate- or high-risk patients, current trials examining active surveillance have been reserved for patients over 65 who have low-risk disease.
The only study that has compared oncologic cure rates for RP, EBRT, and brachytherapy in low-risk prostate cancer is a retrospective cohort analysis by D’Amico et al, in which the investigators followed patients up to 8 years after therapy and showed a significant PSA failure-free survival advantage for RP over EBRT (88% vs 78%). However, the EBRT patients in the study received a dose of 70 Gy, so whether these data will transmute into a survival advantage with the more conventional higher radiation dosage is uncertain.
For intermediate- and high-risk prostate cancer, the data are less ambiguous. Currently, brachytherapy alone is not recommended for high-risk patients, as both EBRT and RP have higher cure rates. And although no prospective randomized trials have compared EBRT and RP (Southwest Oncology Group [SWOG] 8890 was cancelled due to poor accrual), empiric evidence suggests that RP may have a survival advantage over EBRT. Several recent studies have shown a benefit of adding androgen-deprivation therapy (ADT) to EBRT for both intermediate- and high-risk prostate cancer.[16-18] No such benefit of adjuvant ADT has been shown for RP, which leads one to hypothesize that RP provides better local cancer control. Additionally, the Prostate Cancer Outcomes Study analyzed patients who had undergone RP or EBRT from year 2 to year 5 posttherapy. Specifically, the researchers quantified the number of patients who were treated with ADT, the addition of which, in this time frame, should reflect use for biochemical recurrence. In the RP group, use of ADT therapy increased by 2% (from 6% to 8%) between year 2 and year 5, whereas use of ADT in the EBRT group had a larger increase of 7% (from 3% to 10%). If prostate cancer recurs, a second goal of the initial treatment modality would be that it not interfere with subsequent therapies. Postprostatectomy EBRT is a well accepted treatment option in the setting of T3 disease or rising PSA. Although side effects of urinary incontinence and erectile function are worse following salvage radiotherapy, the disease-free survival rate is 50% to 78%. Postradiotherapy RP is fraught with complications and seldom performed.
The lack of clear evidence favoring one treatment over another in terms of cancer control causes many patients to base their decision on the minimization of adverse effects on HRQOL. When considering localized prostate cancer treatment, the HRQOL symptom domains that factor into decision-making include sexual dysfunction, urinary dysfunction, and bowel dysfunction. Historically, patients were generally led to believe that radiation therapy had a better outcomes profile than RP with regard to urinary incontinence and erectile function, while RP was associated with less bowel irritation. More recent HRQOL analyses of radiation and surgery have included symptoms of urinary urgency and frequency in addition to urinary incontinence-symptoms that can be quite frustrating for patients after radiation therapy. Additionally, new studies have shown that as patients with prostate cancer are followed for a longer period of time after their initial treatment, the purported advantages of EBRT become vanishingly small.
In attempts to improve HRQOL by minimizing damage to surrounding normal tissues, EBRT for prostate cancer has undergone many changes over the past decade. Development of better cancer-targeting therapies in the form of three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiotherapy (IMRT) theoretically decrease the side effects seen with EBRT. However, during this same time frame, other advances in the field have supported the use of higher doses of radiation for organ-confined disease. Multiple phase III trials have now demonstrated that doses of 78 to 80 Gy are needed to obtain definitive therapy for prostate cancer, which is a great increase from the 70 to 74 Gy that was previously the standard of care.[24-26] With respect to toxicity of EBRT with patients, it is important to note that much of our information is based on studies using lower doses of radiotherapy. The toxicities associated with EBRTside effects are known to be worse at the new higher doses.
In addition to improved survival with escalated doses of radiotherapy, there is also now clear evidence that patients with intermediate- and high-risk prostate cancer have better survival with the addition of ADT. The addition of ADT to EBRT or brachytherapy is associated with worse HRQOL outcomes for both sexual and urinary domains. In addition, the adverse physiologic effects of ADT, including loss of libido, hot flashes, and osteoporosis, are not trivial and need to be factored into the choice of radiation therapy. Newer data suggest that ADT also increases the risk of coronary artery disease, diabetes mellitus, and myocardial infarction. For radiotherapy, the additional risks of ADT need to be factored into the decision-making process.
RP, EBRT, and brachytherapy all negatively impact a patient’s sexual function to varying degrees. A potential bias may exist when comparing sexual side effects between RP and radiation, in that patients undergoing RP tend to be younger, and therefore may be more cognizant of sexual dysfunction. Additionally, when EBRT and RP patient populations are followed for a longer period of time, the differences in sexual side effects dissipate. Miller et al showed that when individuals undergoing RP, EBRT, and brachytherapy were age-matched, there was no statistically significant difference with regard to sexual dysfunction outcomes in the three treatment groups-however, sexual HRQOL continued to deteriorate in the EBRT group throughout the 6 years of follow-up, whereas the sexual side effects in the RP group remained stable.
The Prostate Cancer Outcomes study analyzed both overall sexual function and erectile dysfunction. Though RP was associated with a greater incidence of erectile dysfunction at 5 years than EBRT (79% vs 63%), there was a continual decline in erectile function for the EBRT group from years 2 to 5, which was reflected in overall sexual function ultimately falling to the same level by year 5. Brachytherapy has a smaller negative effect than RP on sexual function; however, the negative impact of brachytherapy on sexual activity can be quite significant if such therapy is given in conjunction with EBRT.
The reported incidence of urinary incontinence following RP has been reported as 14% to 18%, although the definition of extent of leakage differs among studies. For patients undergoing EBRT, the incidence of urinary incontinence is ~4%. The difficulty in comparing urinary outcomes in patients undergoing brachytherapy or EBRT is that most prostate cancer HRQOLs do not measure irritative symptoms. Brachytherapy is associated with irritative symptoms that improve but are still significantly worse than what patients experience after RP. Irritative symptoms associated with EBRT have been reported in as many as 54% of patients. And although urinary incontinence remains stable following RP, urinary incontinence HRQOL worsens for both brachytherapy and EBRT with time, which may reflect worsening irritative symptoms. When including both irritative symptoms and incontinence into an “overall urinary HRQOL,” Sanda et al showed a clear advantage to RP; with 18% of brachytherapy patients, 11% of EBRT patients, and only 7% of RP patients reporting moderate to severe distress at 1 year posttherapy.
RP offers a clear benefit to HRQOL in prostate cancer patients with regard to bowel dysfunction, which appears limited to those undergoing EBRT (29% of patients undergoing EBRT vs 19% of patients undergoing RP). As discussed earlier, current data support better oncologic cure rates with EBRT using higher radiation doses, and thus, we may begin to see even more cases of bowel toxicity in this patient population. In one study, grade 2/3 rectal complications at 78 Gy were more than double that seen with the traditional 70 Gy (12% vs 26%). Ultimately, QOL takes into account not only objectively defined side effects, but a patient’s subjective sense of well-being. A recent study from the Scandinavian Prostate Cancer Group (SPCG-4) compared 376 men randomly assigned to either watchful waiting or RP, with regard to QOL. The QOL data used in the assessment included symptoms, symptom-induced stress, sense of well-being, and self-assessed QOL. After a follow-up of 6 to 8 years, a statistically significant decrease in QOL was seen in the active surveillance group. Both groups had physical symptoms relating to either their treatment or their disease, but interestingly, as the number of physical symptoms increased, all psychological variables worsened in the active surveillance group.
Athough we still struggle to identify patients who truly require intervention for their prostate cancer, surgical prostatectomy is the gold standard for patients who seek treatment of their disease. Over the past half-decade, laparoscopic prostatectomy (with or without the robot) has garnered much attention in the prostate cancer world. Advantages of the laparoscopic approach include decreased operative blood loss and a shorter hospital stay,[35,36] which for some patients can be a concern. However, most high-volume surgical centers in the United States report similar short hospital stays and low blood loss for both open and laparoscopic RP.[37,38] Regardless of approach, RP has stood the test of time for the treatment of prostate cancer, which is reflected in current choices for prostate cancer intervention: 51% of patients undergo RP, 6% EBRT, and 13% observation. Prostate cancer is a slowly progressive disease, and for that reason, patients need to be followed at least 7 to 10 years before a survival advantage between treatment modalities is apparent. With recent changes in treatment modalities for EBRT (including adjuvant ADT and higher-Gy treatments), RP is likely to remain the gold standard for the foreseeable future.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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