Is Death From Prostate Cancer the Right Clinical Endpoint to Guide Screening and Treatment Choices?

Jonathan D. Tward, MD, PhD

Assistant Professor,

Department of Radiation Oncology

Huntsman Cancer Institute at the University of Utah

Salt Lake City, UT

There are few controversies in oncology as divisive as the value of prostate-specific antigen (PSA) screening and subsequent treatment for prostate cancer. Two widely reported and mature prospective trials, the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹ and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial,² found marginal to no benefit for PSA screening with overall survival as the primary endpoint.

This led the US Preventive Services Task Force to recommend against PSA screening.

Specialty societies such as the American Academy of Family Practice, the American Society of Clinical Oncology, and the American Geriatric Society have issued warnings against PSA screening as part of their “Choosing Wisely” initiatives of the American Board of Internal Medicine Foundation.

So if the probable fate of a PSA-screened person is not death from prostate cancer, does the test have any merit? In the ERSPC trial 9.6% of men in the screened group and 6% of men in the control group were diagnosed with prostate cancer. This translates to a number needed to screen (NNS) of 28 persons to diagnose an additional prostate cancer. In the PLCO trial, the NNS was 89 persons. (The actual NNS is almost certainly lower due to contamination in the control groups of men who actually received PSA screening.) Interestingly, in the subgroup of men with minimal to no comorbidities, the NNS to prevent one prostate cancer death was only five persons.³

In order to know if identifying these cancers through screening was worthwhile absent a mortality benefit, we would have to know if screening otherwise maintained or improved quality of life.

Impact of “Conservative” Approach

In 2009, Lu-Yao and colleagues used the SEER-Medicare database⁴ to study the fate of men with localized prostate cancers who were initially put on a “conservative” management approach.

Like the randomized screening trials, prostate cancer deaths were uncommon, with fewer than 6% of these men dying of prostate cancer in the decade following the diagnosis. In PSA screen— diagnosed men aged 66 to 74 years with Gleason sum cancers of 5 to 7, six out of every 10 men were treated with androgen-deprivation therapy (ADT). One in 10 men were treated with palliative radiotherapy, chemotherapy, or spinal surgery. These treatments occurred within the first decade following diagnosis, and ADT was started within the first six months following diagnosis the majority of the time.

Revisiting Radical Treatment Strategy

If we further conclude that, most of the time, the fate of a patient with PSA screening—detected prostate cancer who does not choose a curative- intent treatment upfront leads to ADT—and a concomitant decrease in quality of life and potentially serious health problems—would treating them with a definitive therapy have altered the subsequent use of androgen deprivation and palliative therapy?

The Prostate Cancer Intervention Versus Observation Trial (PIVOT) trial,⁵ which tracks a mostly PSA-screened population randomized to surgery or observation, did report on nonmortality endpoints. Buried in the supplemental appendix to the publication is the finding of an absolute risk reduction of 6% in the prostatectomy group over the watch-and-wait group (number needed to treat of 17) to prevent bone metastasis.

Notable was the fact that this change in development of bone metastases was realized almost exclusively within the first eight years following diagnosis. The PIVOT trial has not reported on hormone therapy—free survival.

In a mostly unscreened population, the Scandinavian Prostate Cancer Study Group Number 4 randomized trial that compared watchful waiting with radical prostatectomy was updated with over 23 years (median 13.4 years) of follow-up in March 2014.⁶ About six of every 10 men in the prostatectomy group never required ADT or developed metastases by 18 years, but only fewer than four of 10 men escaped this fate in the watchful-waiting group. These benefits were even more pronounced when restricting the analysis to men younger than 65 years with low- and intermediate-risk cancers. Moreover, the number needed to treat to prevent one prostate cancer death was only eight persons, and for men under age 65 years at diagnosis, the number was four!

Does Screening and Treatment Protect Quality of Life?

ADT and treatment for bone metastasis is not benign. Some men, and their physicians, would argue that they would rather risk a small chance of urinary bother, bowel bother, and sexual dysfunction with prostatectomy or radiation therapy over the more likely loss of energy, muscle mass, and libido, mood lability, weight gain, and hot flashes that are near certain and indefinite with ADT. When discussing the risks and benefits of PSA screening, limiting the dialogue to death from prostate cancer does a disservice to patients. It is time to include hormone therapy— free survival in results reporting in localized prostate cancer outcome studies.

There are fates other than death.

References

1. Schröder FH, Hugosson J, Roobol MJ, et al. Prostatecancer mortality at 11 years of follow-up. N Engl J Med. 2012;366(11):981-990.
2. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up [published online January 6, 2012]. J Natl Cancer Inst. 2012;104(2):125- 132.
3. Crawford ED, Grubb R 3rd, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial [published online November 1, 2010]. J Clin Oncol. 2011;29(4):355-361.
4. Lu-Yao GL, Albertsen PC, Moore DF, et al. Outcomes of localized prostate cancer following conservative management. JAMA. 2009;302(11):1202-1209.
5. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203-213.
6. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med. 2014;370(10):932-942.