PSA—It Just Keeps Getting Better, So Why Should It Stand Alone?


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Anthony V. D’Amico, MD, PhD

If costs for this imaging technology can be moderated, such data hold promise for a future in which a PSA level alone will not be used to determine who to biopsy, but will rather be part of a first-step multimodality screening … to determine if risk of having clinically significant disease is high enough to obtain a multiparametric MRI.

—Anthony V. D’Amico, MD, PhD

The updated results of the European Randomised Study of Screening for Prostate Cancer (ERSPC)—reported in The Lancet by Fritz H. Schröder, MD, of Erasmus University Medical Center, and colleagues1 and reviewed in this issue of The ASCO Post—show a continued decline, as predicted,2 in the number invited to prostate-specific antigen (PSA) screening and the additional number needed to treat to prevent one death from prostate cancer. These estimates have now declined to 781 and 27, respectively. Prostate cancer–specific mortality curves begin to separate 7 years after randomization and continue to diverge at the latest observed time point of 13 years, representing a 21% risk reduction in death from prostate cancer attributable to PSA screening.

Important Considerations

A few important considerations deserve further discussion. First, these results substantiate that PSA screening with further follow-up continues to reduce mortality from prostate cancer by 21% in an average-risk population, with fewer men after 13 vs 9 years of follow-up invited to be screened (1,410 vs 781) and treated (48 vs 27) to avoid one prostate cancer death. Therefore, based on the model2 that predicted these declines in the number needed to screen and number needed to treat, by 25 years of follow-up, the number needed to screen would be expected to be 262, and only 9 additional men would need to be treated to prevent one prostate cancer death. These observed and predicted results have significant lifesaving implications for healthy men in their 50s whose remaining life expectancy exceeds 25 years.

Second, these improved results with longer follow-up speak to the concerns regarding the early reporting at a median follow-up of only 10 years of the Prostate Cancer Intervention vs Observation Trial (PIVOT) study,3 which reported a near significant benefit in reduction in the risk of death from prostate cancer (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.36–1.09, P = .09] for men screened in a Veterans Administration population in the United States.

Further, it should be noted that this hazard ratio is similar to that observed in the Swedish randomized study of radical prostatectomy vs observation4 (HR = 0.56, 95% CI = 0.41–0.77, P = .001)—a trial performed in healthier (by 15 years, 50% vs only 30% of men were alive) and younger (median age, 64.7 vs 67 years at randomization) men with more-advanced disease (T1c = 12% vs 50%; median PSA = 13.0 vs 7.8 ng/mL) that showed a significant reduction in prostate cancer–specific mortality with a number needed to treat of only 8.

Thus, there is considerable evidence to support the concept that treatment of clinically significant prostate cancer in healthy men can save lives and in relatively short order.

Multimodality Screening

Using tools5 that incorporate not only the PSA level but also age, race, and digital rectal examination findings can optimize the diagnosis of prostate cancer that is clinically significant (intermediate- or high-risk). Despite enrolling less healthy men then those of average health in the United States based on Surveillance, Epidemiology, and End Results (SEER)-Medicare data,6 the PIVOT trial3 demonstrated a reduction in the risk of dying from prostate cancer in men with intermediate- or high-risk disease in a postrandomization subgroup analysis.

Moreover, even in the event that prostate cancer of questionable clinical significance is diagnosed (ie, very low- or low-risk disease), active surveillance protocols now exist that evaluate such men with tools such as 3 Tesla multiparametric magnetic resonance imaging (MRI) to identify occult high-grade prostate cancer (ie, Gleason score 7–10) prior to initiating active surveillance and then follow them with annual image-guided targeted transrectal ultrasound–magnetic resonance fusion biopsy of suspicious intraprostatic lesions on multiparametric MRI.7 With this approach, treatment is offered only when a clinically significant prostate cancer is found.

Such an approach coupled with multimodality screening allows men at high risk for developing clinically significant disease to be diagnosed, offered treatment, and educated about potential toxicities, thereby reducing overtreatment and the understandable concerns associated with this issue.

Role of Multiparametric MRI

Based on promising results of a prospective study8 comparing detection of intermediate- and high- vs low-risk prostate cancer using transrectal ultrasound–guided vs MRI-guided biopsy techniques, a new approach as to when to recommend a prostate biopsy may be on the horizon. Specifically, following the determination of elevated risk (perhaps 15%) of having a clinically significant prostate cancer using multimodality screening,5 a patient is referred for a multiparametric MRI and a biopsy is recommended only if clinically significant disease as assessed anatomically (ie, by evidence of extraprostatic or seminal vesicle or neurovascular bundle invasion) and/or diffusion-weighted imaging evidence of restricted diffusion (ie, Gleason score 7 or higher) is present.

In the recent study, the investigators found that by using multiparametric MRI as compared to transrectal ultrasound assessment and guidance for biopsy, the recommendation for biopsy was reduced by 51% and low-risk prostate cancer diagnoses declined by 89.4% while intermediate- and high- risk diagnoses increased by 17.7%.

Looking Ahead

If costs for this imaging technology can be moderated, such data hold promise for a future in which a PSA level alone will not be used to determine who to biopsy, but will rather be part of a first-step multimodality screening using PSA level, age, digital rectal exam findings, race, and family history to determine if risk of having clinically significant disease is high enough (eg, > 15%) to obtain a multiparametric MRI. Then, a prostate biopsy would be recommended only if the index of suspicion for clinically significant disease is high enough based on the multiparametric MRI findings using the scoring system based on the Prostate Imaging and Reporting Archiving Data System (PI-RADS).9 Indeed, promising PI-RADS data regarding the high specificity of this approach to identify clinically significant disease are becoming available.8

By including these additional parameters in the biopsy decision-making process, we can achieve the long-term benefits of PSA screening in reducing death from prostate cancer through early detection while minimizing the diagnosis of disease—at any given point in time—that is unlikely to progress to metastatic disease if left untreated. In this way, overdiagnosis and overtreatment will become significantly less likely. ■

Disclosure: Dr. D’Amico reported no potential conflicts of interest.

References

1. Schröder FH, Hugosson J, Roobol MJ, et al: Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. August 6, 2014 (early release online).

2. Gulati R, Mariotto AB, Chen S, et al: Long-term projections of the harm-benefit trade-off in prostate cancer screening are more favorable than previous short-term estimates. J Clin Epidemiol 64:1412-1417, 2011.

3. Wilt TJ, Brawer MK, Jones KM, et al, the Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367:203-213, 2012.

4. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 370:932-942, 2014.

5. Ankerst DP, Hoefler J, Bock S, et al: Prostate Cancer Prevention Trial risk calculator 2.0 for the prediction of low- vs high-grade prostate cancer. Urology 83:1362-1367, 2014.

6. Aizer AA, Chen MH, Hattangadi J, et al: Initial management of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer. BJU Int 113:43-50, 2014.

7. Verma S, Bhavsar AS, Donovan J: MR imaging-guided prostate biopsy techniques. Magn Reson Imaging Clin N Am 22:135-144, 2014.

8. Pokorny MR, de Rooij M, Duncan E, et al: Prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate biopsies. Eur Urol 66:22-29, 2014.

9. Barentsz JO, Richenberg J, Clements R, et al: European Society of Urogenital Radiology. ESUR prostate MR guidelines 2012. Eur Radiol 22:746-757, 2012.

 

Dr. D’Amico is Department of Radiation Oncology, Harvard Medical School, Chief of Genitourinary Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital.


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