Is Surgery Still Necessary for Prostate Cancer?

Stage migration: increased incidence of localized prostate cancer

In the prostate-specific antigen (PSA)-based early detection era, approximately 81% of men with prostate cancer (PCa) have disease considered confined to the prostate gland (clinically localized PCa), and only 4% present with distant disease. Survival has improved and disease-specific mortality has declined with overall 5-year survival rates now at 99%. With better understanding of the biological behavior of PCa, most clinically localized tumors are now understood to be indolent, with a relatively benign course even without treatment, whereas a minority is more aggressive and potentially lethal. This subset still account for more cancer deaths among US men than any malignancy except lung cancer.

Standard management options include observation/conservative strategies, including watchful waiting (WW) and active surveillance (AS), while active treatment options include radical prostatectomy (RP) (open, laparoscopic (LRP) or robotic assisted (RARP) approaches), and radiation therapies (RT) (various forms of external beam radiation therapy (EBRT) and brachytherapy (BT)). Primary androgen deprivation therapy (PADT), while not a standard option for localized PCa, is still adopted by some urologists for patients not fit for or refusing RP and RT. Other less common treatments include cryotherapy, and outside the United States, high-intensity focused ultrasound (HIFU) therapy.

Treatment should be tailored to each patient, taking in consideration the patient’s overall health, life expectancy, and the disease risk, including the PSA, tumor extent, and Gleason grade. Other factors that should further bear on the decision include the clinician’s skill and experience, and the patients’ preference to trade off potential benefits, side-effects, and complications (such as urinary leakage, sexual, and bowel dysfunction). In an era of tightly constrained healthcare resources, costs must also be considered at the societal level, if not necessarily in the setting of individual patient discussions. In this chapter, we sought to discuss the role of surgery, and its comparative effectiveness with other strategies in the treatment of PCa.

Comparative effectiveness research (CER) among different approaches

Comparative effectiveness research (CER) and related cost effectiveness studies are critical to help guide patients and physicians regarding the most appropriate modality and timing for each individual case. In fact, the relative effectiveness of the management strategies for localized PCa was considered among the highest initial national priorities for CER by the Institute of Medicine (IOM) in 2009. Several related factors must be addressed when comparing different treatments: oncological efficacy, measured in terms of recurrence, cancer specific, and/or overall survival rates; short- and long-term side effects and their effects on health-related quality of life (HRQOL); and the cost of the initial and subsequent treatments and their sequelae.

Challenges to CER among treatments for localized PCa

CER among treatments for localized PCa is not an easy task given several factors, including a notable paucity of randomized controlled trials (RCTs) comparing the outcomes of different treatments. However, recently the use of observational cohorts from large disease registries accruing long-term follow-up has allowed for the comparison of different therapeutic strategies, in some cases based on data on “real-world” outcomes. The long natural history of PCa creates further challenges in comparing long-term outcomes, and increases the cost and complexity of adequate follow-up. Addressing the effects of different treatments on HRQOL – reported by the patients – is of utmost importance; it should be emphasized that physician-reported HRQOL assessments generally underestimate the adverse impacts of treatments when compared to patients’ reports, and HRQOL outcomes derived from administrative (billing/coding) data are entirely unreliable.

The various treatments have notably different effects on PSA and PSA kinetics, which severely complicate comparison among different treatment modalities for localized PCa based on biochemical recurrence rates. The definition of biochemical recurrence varies from one treatment to another, and measured within-modality disease progression rates may vary up to 35% depending on the definition used. For RP, the most widely accepted definition for biochemical recurrence is that of the American Urological Association (AUA), which is defined as serum PSA ≥0.2 ng/mL following surgery, with confirmation by a repeat test. For patients who undergo RT, the Phoenix consensus criteria were adopted by the American Society for Radiation Oncology (ASTRO), specifying that a PSA rise of ≥2 ng/mL above the nadir PSA is considered as biochemical failure after RT, regardless of whether or not a patient receives ADT.

These definitions diverge in their express intent: the RP definition is intended to identify persistent or recurrent disease early, whereas the Phoenix definition is intended to predict long-term clinical outcomes. For this reason – and given fundamental differences in the time course of tumor ablation via surgery versus radiation – biochemical recurrence is wholly invalid as a means of comparing the oncological efficacy of surgery versus radiation therapy. A useful illustrative example was provided by Nielsen et al., who found that compared to the standard surgical definition, applying the Phoenix definition to cohort of RP patients caused overestimation of the biochemical recurrence-free survival, even after stratifying patients into the standard prognostic risk groups. Among those patients recurring, the apparent time to biochemical recurrence would be shifted forward more than 5 years , from 2.8 years to 7.9 years. Unfortunately, papers continue to be published claiming oncological superiority of radiation over surgery based on biochemical outcomes. Without exception, such analyses will be biased artifactually and irrecoverably in favor of radiation and against surgery. Thus, while biochemical recurrence might be used to compare external-beam with interstitial radiation, for example, only clinical endpoints (metastasis, cancer-specific mortality, overall mortality) can be used legitimately for comparison studies between surgery and radiation.