Hind Rafei, MD
Brian F. Chapin, MD
THE MANAGEMENT of localized prostate cancer remains controversial. Although the widespread use of prostate-specific antigen (PSA) testing has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer, many men do not benefit from intervention because the disease is either indolent or disseminated at diagnosis. Moreover, interventions may have adverse effects on sexual, urinary, or bowel function.
The role of intervention in early localized prostate cancer has been a clinical dilemma in question in a number of recently reported clinical trials including ProtecT (Prostate Testing for Cancer and Treatment), PIVOT (Prostate Cancer Intervention Versus Observation Trial), and SPCG-4 (Scandinavian Prostate Cancer Group study 4). These three studies compared survival in early localized prostate cancer among patients who underwent prostatectomy as opposed to those who were on a watchful waiting or active surveillance program. The ProtecT trial additionally included patients who underwent radiotherapy.
In December 2018, updated data were reported from the Scandinavian trial (SPCG-4), as reviewed in this issue of The ASCO Post. The data showed that after a median follow-up of 23.6 years, radical prostatectomy led to a 2.9-year survival benefit compared with watchful waiting in patients with clinically detected, localized prostate cancer and a long life expectancy.1 This study presents unique evidence of the beneficial role of surgery in early localized prostate cancer in contrast to the results of the other two aforementioned clinical trials.
In the most recent update from the ProtecT study,2 after a median follow-up of 10 years, the mortality in PSA-screened localized prostate cancer was low in the surgery, radiotherapy, and active monitoring groups. Similarly, the PIVOT trial3 showed that radical prostatectomy and observation did not differ for all-cause mortality or prostate cancer mortality, after a median follow-up of 12.7 years. Although the results from these studies seem to be contradictory on the surface, an in-depth analysis shows they are in fact complementary, and application in the clinic requires clinicians to individualize treatment.
Study Population in the Scandanavian Trial
THE SCANDINAVIAN TRIAL included 695 men with localized prostate cancer from 14 centers in Sweden, Finland, and Iceland who were enrolled between 1989 and February 1999. In both the radical prostatectomy and watchful waiting groups, the most common stage was T2, and the majority had a Gleason score of 5/6 or 7. It is important to note that the most common method of detection was based on the presence of symptoms at presentation (43.8% in the radical prostatectomy group and 39.7% in the watchful waiting group), which constitutes the first and most meaningful test that intervention is needed. These clinical characteristics confer a higher-risk phenotype compared with a PSA screen–detected population.
“The results from [the Scandinavian trial] are informative but not generalizable to the contemporary PSA-screened population.”— Hind Rafei, MD, and Brian F. Chapin, MD
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Not only are there differences in how prostate cancers are detected now, compared with in 1989 to 1999, but also in how they are treated. Although this could be viewed as a limitation to the study’s impact on current clinical practice, in a way, it supports what we believe to be true: higher-risk patients with clinically detected prostate cancer benefit from early local therapy. Nonetheless, the inclusion of newly diagnosed patients with prostate cancer who have presenting signs and symptoms creates an ascertainment bias that should be critically considered when determining management of early prostate cancer in individual patients. The results from SPCG-4 are informative but not generalizable to the contemporary PSA-screened population.
Statistical Consideration
FROM A STATISTICAL standpoint, the article presented the per-protocol analysis of the relative risks according to the treatment given within the first year. The relative risk for overall mortality was significantly different between the two groups in the overall population but only in younger men (< 65 years old) when stratifying by age. Again, this observation supports what we practice on a regular basis under the assumption that older men are less likely to benefit from aggressive local treatment. It is important to note that the per-protocol analysis results in a major bias by selecting out patients presumed not to derive benefit from the intervention, such as the elderly population. In the intention-to-treat analysis (available in the supplementary material), death from causes other than prostate cancer occurred similarly in patients in the radical prostatectomy group and in the watchful waiting group (190 vs 182 patients, P value not available).
Differences in Management Approaches
IN ADDITION TO the methods of detection, the methods of diagnosis, surgical techniques, follow-up monitoring, and treatment of prostate cancer have evolved. As prostate cancer mortality has declined, the quality of cancer survivorship, as measured by patient-reported outcomes, has become an important element in treatment decision-making.
In 2008, the investigators from the Scandinavian study reported health-related data from its randomized trial. At a mean follow-up of 12.4 years, the prevalence of erectile dysfunction was the same with radical prostatectomy (84%) and watchful waiting (80%), but urinary incontinence was much more common in the surgery group (41%) than in the watchful waiting group (11%).4 Currently available surgical techniques and nerve-sparing strategies aim to mitigate the classic side effects of surgery, including erectile dysfunction and urinary incontinence, but remain to prove their benefit.
“We should avoid radical treatment in men with indolent disease while providing curative therapy to men with more aggressive findings at diagnosis or identified by monitoring during active surveillance.”— Hind Rafei, MD, and Brian F. Chapin, MD
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Approaches to Surveillance
IT IS IMPORTANT to note that patients in the watchful waiting arm of Scandinavian study did not eventually receive a curative approach (not active surveillance). With the advent of newer biopsy techniques such as fusion biopsies and prostate magnetic resonance imaging (MRI), today’s modern practices are considered active surveillance rather than watchful waiting. Surveillance can entail monitoring patients with frequent PSA measurements, sequential digital rectal exams, serial MRI, and repeat biopsies, with the goal of identifying disease progression and offering a curative treatment if deemed necessary.
Closing Thoughts
THE SCANDINAVIAN TRIAL provides valuable information with regard to the role of surgery in a subset of patients who are younger and have features of a clinically aggressive disease. After consideration of the difference in baseline patient characteristics and the methods of detection/screening of prostate cancer, an in-depth analysis of data from the Scandinavian trial actually demonstrated an alignment with the findings from the ProtecT and PIVOT studies—we should avoid radical treatment of men with indolent disease while providing curative therapy to men with more-aggressive findings at diagnosis or identified by monitoring during active surveillance. It is crucial for clinicians to engage in an honest discussion with patients with regard to the findings from these different studies, especially pertaining to implications of interventions, the roles of active surveillance and watchful waiting, and the individualized patient and tumor characteristics that assist in informing the treating team and patients regarding the potential benefit (or harm) of treatment with curative intent. ■
Dr. Rafei is a hematology and medical oncology fellow at MD Anderson Cancer Center, Houston. Dr. Chapin is Associate Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center.
DISCLOSURE: Dr. Rafei reported no conflicts of interest. Dr. Chapin is a consultant/advisor with Blue Earth Diagnostics and Janssen and has received research funding from Janssen.
REFERENCES
1. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in prostate cancer—29-year follow-up. N Engl J Med 379:2319-2329, 2018.
2. Hamdy FC, Donovan JL, Lane JA, et al: 10- Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 375:1415-1424, 2016.
3. Wilt TJ, Jones KM, Barry MJ, et al: Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med 377:132-142, 2017.
4. Sanda MG, Dunn RL, Michalski J, et al: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 358:1250-1261, 2008.
