In 2013, over 238,000 men were diagnosed with prostate cancer in the United States. Each of these patients and their physicians has undoubtedly been faced with a vexing series of decisions: What should I do next? Will the treatment help, or will the cure be worse than the disease? The publication of the 18-year follow-up of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) in this week’s NEJM attempts to provide some guidance to those diagnosed with and those treating localized prostate cancer.
While the lifetime risk of being diagnosed with prostate cancer is around 17%, the risk of mortality from prostate cancer is substantially lower. Historically, this discrepancy has spawned debates between those who believe localized prostate cancer represents a low risk for morbidity or mortality and should therefore only be monitored, and those who believe that surgical intervention represents a unique option to cure this potentially fatal disease as well as to prevent future complications.
The body of literature that guides this debate has been limited by study design and the indolent course of prostate cancer progression. Most relevant trials have been retrospective cohorts criticized for their susceptibility to potential bias. Those few randomized controlled trials examining management of localized prostate cancer are designed to detect outcomes over extended periods of time, introducing a significant lag time between intervention and recognition of meaningful results.
It should not be surprising then that SPCG-4 began enrolling patients in the distant past: 1989. Between then and 1999, SPCG-4 randomized 695 men in Sweden, Finland and Iceland to either radical prostatectomy or watchful waiting. All patients were subsequently followed at regular intervals. The primary outcomes were all-cause mortality, prostate cancer specific mortality, and identification of disease metastatic to bone or outside of the pelvic area.
By December 31st, 2012, 294 of the 347 men randomized to receive radical prostatectomy underwent the procedure, and 294 of the 348 men randomized to watchful waiting had not undergone curative treatment. The radical prostatectomy group had an overall mortality rate of 56.1% versus 68.9% in the watchful waiting group (RR 0.71, p<0.001). There was a similar significant difference in favor of radical prostatectomy with respect to prostate cancer-specific mortality (17.7% versus 28.7%, RR 0.56, p=0.001), and detection of distant metastases (26.1% versus 38.3%, RR 0.57, p<0.001). In the subgroup analysis, an overall mortality benefit was restricted to men younger than 65 years at time of diagnosis as well as those with low or intermediate risk cancer at the time of study enrollment. These results are consistent with the SPCG-4 twelve-year results, also published in NEJM.
These results, while impressive, also highlight a potential shortcoming of SPCG-4. Between the time of the SPCG-4 patient enrollment and current day practice, prostate cancer diagnosis was revolutionized by the PSA test, which was first approved by the FDA in 1994 for use with digital rectal exams in screening for prostate cancer. The ubiquity of the PSA screening test is especially apparent when one discovers that only 5.2% of SPCG-4 patients were diagnosed via use of the PSA test, compared to modern day, where a majority of cases are diagnosed via the PSA test. It is possible that the PSA test, by allowing earlier detection of prostate cancer, places most of today’s newly diagnosed males in an even lower risk category than those studied by SPCG-4.
What to do with these lower risk patients is the focus of ongoing trials, including ProtecT (Prostate Testing for Cancer and Treatment trial) and PIVOT (Prostate Cancer Intervention versus Observation Trial), each begun during the era of PSA screening. Of note, the 12-year follow-up of PIVOT, published in NEJM in 2012, did not show a significant mortality benefit for radical prostatectomy versus watchful waiting—additional data from longer periods of follow-up are being collected.
The 18-year follow-up of SPCG-4 is far from the final answer in the debate over management of localized prostate cancer. In the meantime, SPCG-4 highlights an important lesson: for those clinicians and patients faced with decisions regarding newly diagnosed prostate cancer, treatment plans should always be considered within the context of the patient’s characteristics and disease severity. As NEJM Deputy Editor Dan L. Longo notes, “The challenge facing the field is clear: more sophisticated measures are needed to distinguish potentially fatal from non-fatal disease early in the course.”
For clinicians and patients who favor watchful waiting in localized prostate cancer: does SPCG-4 make you more or less likely to consider radical prostatectomy? For clinicians and patients who favor radical prostatectomy in localized prostate cancer: does SPCG-4 make you more or less likely to consider watchful waiting?