SPCG-4: a needed START to PIVOTal data to promote and protect evidence-based prostate cancer care.

JNCI | Editorials 1123 Surgical removal of the prostate for cancer therapy was fi rst performed in 1866 ( 1 ), although Young ( 2 ) is credited with the fi rst radical surgical procedure in 1904. Prostate cancer deaths were rarely reported in the 1800s, but the relatively high frequency of asymptomatic disease was recognized as early as 1898 ( 3 ). Radical prostatectomy has been widely advocated as an effective treatment for localized prostate cancer. However, the only prior randomized trial comparing surgery to watchful waiting ( 4 ), begun 40 years ago, failed to demonstrate a survival difference even at 23 years of follow-up. Twenty years ago Whitmore ( 5 ) asked these questions regarding the natural history and treatment of prostate cancer: “Is cure necessary in those for whom it is possible and is cure possible in those for whom it is necessary? ” Recent systematic reviews have been unable to address Dr Whitmore’s questions, concluding there was little high-quality evidence on comparative treatment effectiveness and harms ( 6 , 7 ). Uncertainty surrounding early treatment of localized prostate cancer has taken on greater importance today. Life expectancy for men exceeds 75 years and has increased by 20 years since the 1930s. The average life expectancy for a man aged 65 is 17 years ( 8 ). Prostate cancer is now the most common visceral malignancy and second leading cause of male cancer mortality ( 9 ). Widespread use of the prostate-specifi c antigen (PSA) blood test to detect prostate cancer is common even among men with very limited life expectancy ( 10 ). Physicians are diagnosing prostate cancer earlier and more often. Thresholds of PSA values that label an individual abnormal have been lowered ( 11 ). The number of tissue specimens obtained at biopsy and the frequency of repeating biopsies among men with initially negative biopsies have increased. Twice as many men are diagnosed with prostate cancer today, many with very low volume tumors, than in the pre – PSA era. Grade infl ation, the tendency of pathologists to assign a higher grade now than in the past, has led to an upward shift in the percentage of tumors assigned an aggressive histologic score ( 12 ). Surgical and radiation techniques have been refi ned and new therapies developed and marketed. These factors have contributed to a markedly increased use of potentially effective but unproven early intervention options. In the United States, Medicare expenditures related to prostate cancer are $8 billion annually, and urologists perform 60 000 radical prostatectomy procedures ( 13 ). Radical prostatectomy is performed in approximately 60% of men with prostate cancer who are younger than age 75 ( 14 ). A report in this issue of the Journal ( 15 ) helps answer some of the late Dr Whitmore’s questions. Bill-Axelson et al. ( 15 , 16 ) provide long-term follow-up of a randomized trial comparing radical prostatectomy with watchful waiting in 695 men with clinically localized prostate cancer. The SPCG-4 study was of high methodological quality. It was large, long-term, and designed to assess prespecifi ed clinically relevant outcomes. Investigators maximized treatment adherence, minimized loss to follow-up, and used intention-to-treat analyses. They rigorously assessed prostate cancer death and nonmortality outcomes. Their primary fi ndings indicated that radical prostatectomy reduced death from prostate cancer and distant metastases compared to watchful waiting by 5.4% and 6.7%, respectively, at 12 years (numbers needed to treat = 18 [95% confi dence interval = 9 to 500] and 15 [95% confi dence interval = 8 to 500]). Differences remained stable after 10 years. Nonmortality outcomes, including local recurrence and/or progression, institution of hormonal therapy, and use of other palliative therapies, also favored radical prostatectomy. Overall mortality was not statistically signifi cantly different between groups ( P = .09) but favored surgery (13.5% vs 19.5%). The authors assessed whether tumor and patient factors modifi ed treatment outcomes. The presence of extracapsular tumor extension strongly increased the risk of prostate cancer death among men undergoing surgery, and only two prostate deaths occurred among 151 men whose prostatectomy specimens indicated no extracapsular disease. The effect of radical prostatectomy was surprisingly not modifi ed by baseline PSA level or Gleason score. However, it was highly dependent on age ( P for interaction on overall mortality = .015). Surgery improved overall mortality, disease-specifi c mortality, and distant SPCG-4: A Needed START to PIVOTal Data to Promote and ProtecT Evidence-Based Prostate Cancer Care