The PROTECT trial provides the first real level 1 evidence comparing treatments and may offer important data for such men to determine the net risks and benefits for their initial treatment choice over about a 10-year follow-up.— Andrew J. Armstrong, MD, ScM, FACP, W. Robert Lee, MD, and Judd Moul, MD, FACS
The ProtecT trial showing similar 10-year survival with active monitoring, surgery, or radiotherapy for prostate-specific antigen (PSA)-detected localized prostate cancer but a greater risk of disease progression/metastasis with monitoring was recently reported by Hamdy and colleagues and is summarized in this issue of The ASCO Post.1,2
The initial treatment of men with low- and intermediate-risk localized prostate cancer is complicated by heterogeneity, notably related to differences between men in their underlying health and life expectancy, differences in the biologic aggressiveness and heterogeneity of their cancers, and, of course, the preferences of men and their families. This is captured well by comparing the outcomes in the ProtecT trial for a 66-year-old sexually active man with low-volume/stage Gleason 6 disease and a PSA level under 10 ng/mL and a 62-year-old man with a positive digital rectal exam (T2 disease) and a Gleason sum of 4+3=7 who has preexisting erectile dysfunction.
In the first low-risk case, the ProtecT trial clearly suggests initial surveillance is appropriate, given the low 10-year prostate cancer–specific mortality to minimize immediate harms. However, in the second higher-risk case, ProtecT leaves great uncertainty, given the higher risk of clinical disease progression and metastasis over time with initial surveillance.
Andrew J. Armstrong, MD, ScM, FACP
The ProtecT trial provides the first real level 1 evidence comparing treatments and may offer important data for such men to determine the net risks and benefits for their initial treatment choice over about a 10-year follow-up. Although 10 years is not sufficient for prostate cancer mortality, as exemplified by the lower-than-expected prostate cancer mortality rates observed (< 1% observed vs 10% expected), the present data, including patient-reported outcomes and side effects, are helpful in shared decision-making with patients.
Growing Popularity of Active Surveillance
The initial use of active surveillance has become increasingly popular in the United States as a result of several trials, such as the SPCG-4 and PIVOT trials,3,4 in which men over the age of 65 and men with lower-risk prostate cancer were not shown to have a survival benefit from initial surgery, and the results of several key longitudinal studies of men on active surveillance with low-risk prostate cancer, who experienced no increase in mortality over the general population. However, men in the ProtecT trial who were randomized to receive active surveillance had an increase in clinical disease progression rates, which started around years 2 to 4. In this study, disease progression was defined as evidence of metastases, diagnosis of clinical T3 or T4 disease, long-term androgen-deprivation therapy, ureteric obstruction, rectal fistula, or the need for a urinary catheter owing to local tumor growth. In each of these scenarios, the window for cure is diminished, and these progression events are medically significant, resulting in a more urgent need for treatment and often lifelong hormonal therapy and expensive medical care.
In the ProtecT trial, this risk of disease progression was nearly twice that with surveillance as compared with radical surgery or radiation (112 events vs 46 events), and the absolute risk appeared to be around 20% by 10 years. Over half of the men followed on active surveillance moved to radical therapy within 10 years. Metastatic disease developed in twice the number of men assigned to initial surveillance (33 vs 13 and 16). The bottom line is that although initial active surveillance may be associated with a similar 10-year survival as initial radical therapy, the risk of clinical disease progression and metastasis is real, particularly among Gleason 7 cancers, and men need to be followed closely with repeat biopsies, imaging, and laboratory and physical monitoring of the disease.
W. Robert Lee, MD
An emerging approach at our multidisciplinary program and nationally is multiparametric prostate magnetic resonance imaging, which is being incorporated into a risk-based surveillance strategy along with repeat tissue sampling of target lesions and nontargeted biopsies to determine the need for treatment, along with PSA and digital rectal exam monitoring and ongoing counseling. The use of molecular risk assessments is also emerging to aid in this risk stratification.
Selecting the Optimal Initial Therapy
When a man needs treatment, which treatment is optimal? The ProtecT trial clearly confirmed that urinary incontinence was a greater risk with prostatectomy as compared with radiation, and all treatments had more side effects initially than did initial surveillance. Radiation had greater preservation of sexual function as compared with surgery, even despite the near-universal use of 6 months of concurrent androgen-deprivation therapy. Radiation, however, slightly increased the risk of bowel toxicity. Over 10 years, most men had a significant decline in sexual function, even among those assigned to initial surveillance.
Given the similar efficacy of surgery and radiation therapy, the differences in toxicity profiles over time become the key decision points in selecting the optimal initial therapy for men. Only over longer-term follow-up of efficacy in reducing metastasis and prostate cancer–specific mortality over years 10 to 20 will we develop a clearer picture of the relative merits of radiation vs surgery in reducing these outcomes.
Vital Data for Shared Decision-Making
The ProtecT trial may be among the most important controlled trials in prostate cancer to date, as it assessed a screening strategy, a diagnosis and risk-stratification strategy, and a comparison of surveillance with two active forms of definitive treatment. The good news is that initial surveillance for men at low risk and perhaps even low-intermediate risk prostate cancer may afford preservation of quality of life and minimize the risks of therapy without a reduction in the risk of dying of prostate cancer over 10 years. Thus, initial active surveillance is quite reasonable for a man with a life expectancy of less than 10 years with less aggressive localized prostate cancer. But active surveillance requires a proactive monitoring approach, and given the higher risk of clinical and metastatic disease progression over 5 to 10 years, repeat and regular assessments are needed over time, including repeat biopsies and imaging and examinations with PSA testing.
Judd Moul, MD, FACS
Although active surveillance may also be reasonable for men with longer life expectancies or even Gleason 7 disease, the risk of progression to metastasis and the impact of delayed therapy on possible prostate cancer morbidity and mortality in years 10 to 20 are concerning, and the ProtecT trial provides valuable data on comparative patient-reported outcomes and efficacy of surgery vs radiation for such men. Although the ProtecT trial did not sufficiently evaluate brachytherapy, and advances in both surgical techniques and intensity-modulated radiation therapy dose escalation and hypofractionation have improved care delivery through smaller scars and less blood loss or shorter periods of radiation, these data will likely stand as vital to shared decision-making.
At Duke, we have had a robust multidisciplinary prostate cancer clinic for over 12 years, and we work as a team to try to counsel men through shared decision-making, reflecting the current evidence-based approaches.5 However, our patient population is approximately 25% African American, and the ProtecT trial may not best inform our care of this higher-risk patient population, given the limited number of men of African descent enrolled in this study (< 1%). Thus, further study is needed in disproportionately affected and high-risk men on optimal initial treatment choices.
Returning to these two scenarios, our 66-year-old male with low-risk prostate cancer and good erectile function could be counseled that initial active surveillance is recommended, with close follow-up over subsequent years using serial imaging and biopsies to determine whether treatment becomes necessary, given the risk of tumor evolution, particularly over 5 to 10 years. For the 62-year-old male with erectile dysfunction and intermediate-risk disease, initial surveillance over even just 2 to 3 years remains concerning, given the higher risk of clinical/metastatic disease progression during this time, and the ProtecT trial offers him valuable patient-reported outcomes to help select between radiation/androgen-deprivation therapy and surgery to match these treatments with his preferences. ■
Disclosure: Drs. Armstrong, Lee, and Moul reported no potential conflicts of interest.