How Do We Eliminate Unnecessary Treatment for Prostate Cancer?

Prostate cancer was diagnosed in nearly 200,000 American men in 2009. Approximately 50% to 62% of the men who were diagnosed have low-risk prostate cancer defined as: (1) prostate-specific antigen (PSA) of 10 ng/mL or less; (2) Gleason histologic score of the primary and secondary microscopic patterns each assigned a value of 1 to 5 (an indication of the tumor's potential aggressiveness) and less than a total of 7 (with no patterns of 4 or 5 in biopsies); and (3) no more than 10% to 50% cancer (various opinions) found in no more than 2 of 12 biopsy cores.

Over the past 30 years, nearly 1 million American men have received radiation therapy and/or radical prostatectomy for prostate cancer that would have a very low risk of ever leading to their death. These men, however, have been subjected to the attendant morbidity associated with therapy-morbidity that may have resulted in a decline of their quality of life.1

Willet F. Whitmore, Jr, Chairman of the Urology Service at Memorial Sloan-Kettering Cancer Center for more than 30 years, said of prostate cancer in 1990, "Is cure possible? Is cure necessary? Is cure possible only when it is not necessary?"2 It may be that nothing has fundamentally changed in the past 20 years.

Surgical or radiation treatment for early-stage disease cures 98% of men at 10 years. Those men who receive no treatment for low-risk prostate cancer have a 98% survival rate. What has been accomplished? It is time to rethink our approach to this disease.

Concerning Data

Annually, 30 million men are screened using PSA criteria. But two recent U.S. studies1,3 have thus far not shown any reduction in the death rate from prostate cancer. And European investigators reported4 that only 1 death could be prevented for every 1,400 men screened and 48 treated. Also, studies have shown that for patients with low-risk prostate cancer, a 10-year delay occurs between the time the cancer is detected by PSA and the time there would be physical evidence of the disease.5,6

Radical prostatectomy was performed nearly 60,000 times last year.7 Approximately 80% of surgeons performed fewer than 10 procedures per year, and 25% of men who underwent surgery had a surgeon who performed only a single such procedure in a year. This paucity of experience has been found to translate into poorer outcomes,8 higher complication rates, and a higher risk of postoperative incontinence and impotence. At least 30% of men given curative treatment for prostate cancer experience negative quality-of-life consequences.

In 2009, radiation therapy was used to treat approximately 85,000 patients with prostate cancer (55,000 by external-beam radiation therapy and 30,000 by brachytherapy), the majority with low-risk disease. Radiation therapy and surgery are associated with equivalent 10-year outcome data, but radiotherapy avoids the potential risks associated with anesthesia. Nevertheless, this modality has not produced a significant reduction in the death rate in patients with low-risk prostate cancer.

Relative Treatment Outcomes

Active surveillance or "watchful waiting" offers an option for some men with low-risk prostate cancer,9 in avoiding the potential adverse quality-of-life consequences from treatment. In several large studies of active surveillance, only 2% to 5% of patients had tumor progression and 16% to 25% had a significant rise in PSA.10 This approach has resulted in very few men requiring further therapy, no change in mortality, and of course no complications from surgery or radiation therapy. Thus, no treatment has the same effect on outcome as aggressive therapy.

Yet NCI's Surveillance, Epidemiology and End Results (SEER) data demonstrate that over the past 20 years, marked increases in the use of radiation therapy and radical prostatectomy (compared to no therapy) have been observed. This may be because more men are being screened for elevated PSA. In addition, improvements in both surgical and radiation therapy and over-marketing by the health-care industry have given the public the perception that the treatments today have a greater success rate and fewer complications.

In support of surgical treatment, Holmberg and colleagues reported a randomized Swedish trial designed to determine whether radical prostatectomy reduces the risk of death due to prostate cancer. They observed a statistically significant difference in the risk of death due to prostate cancer after radical prostatectomy, as compared with watchful waiting, but no significant difference between the two groups in the overall survival rate.11

Finding Treatment Criteria

It has been widely reported that prostate cancer deaths have been reduced recently, but this is a reflection of the increased number of men diagnosed because of PSA screening. Actually, it is the proportion of men with prostate cancer who die that has decreased. The percentage of men who die with prostate cancer has declined because the number of men who have been diagnosed through screening has massively increased. In other words, the numerator (deaths) has stayed the same while the denominator (incidence) has risen. In 1975, 1993, and 2005, respectively, approximately 90, 240, and 170 American men per 100,000 were diagnosed with prostate cancer. The number of Americans per 100,000 dying of prostate cancer today is actually higher (~25) than it was in 1930 (~18).12 Wholesale screening results in earlier detection and treatment of a disease that would never cause harm. This is not progress; it is overtreatment13 due to over-screening.

Histologic Grade Determines Treatment

The histologic grade should determine whether the patient is treated. A Gleason grade totaling 6 or less for the primary and secondary areas commonly indicates that the disease will not cause the patient's death. However, when the pattern results in a score of 7 or greater, the cancer has a much more aggressive course. For every one-level increase in histologic grade of either the primary or secondary pattern, there is a reduction in survival of 20% to 50% in every age range over 5, 10, and 15 years. These data are substantially true regardless of treatment.14

Does this imply that the patient's survival is determined at the time of the diagnosis? Should patients who are diagnosed with a Gleason score of 7 to 10 be treated but have a higher expectation of prostate cancer leading to their death, and those with Gleason 6 or less be left untreated? Perhaps. What is absolutely certain is that there are tens of thousands of men who are needlessly or inappropriately treated (any treatment, wrong treatment, or treatment by an inexperienced doctor), either because they have low-risk prostate cancer, an expected survival of less than 10 years, or advanced disease.

Need for Research

Billions of dollars are expended annually in overscreening, overdiagnosis, and treatment of tens of thousands of American men,15 resulting in loss of quality of life. Only a tiny fraction of desperately needed money is focused on research.

Recent studies in genetics at the University of Michigan,16 Memorial Sloan-Kettering,17 Texas Southwestern,18 and Harvard19 have identified DNA signatures that are more prevalent in aggressive tumors. This type of critical basic research could lead to an understanding of which patients should be observed and which should be offered curative therapy.

Basic research must be expanded to determine which patients need treatment; medical decision-making must be based upon evidence and outcomes; and men should be treated by experienced doctors only if there is the likelihood that prostate cancer may cause their death. ■

References

1. Welch HG, Albertsen PC: Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986-2005. J Natl Cancer Inst 101:1325-1329, 2009.

2. Whitmore WF Jr: Natural history of low-stage prostate cancer and impact of early detection. Urol Clin North Am 17:689-697, 1990.

3. Andriole GL, Crawford ED, Grubb RL 3rd, et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 360:1310-1319, 2009.

4. Schröder F, Hugosson J, Roobol SJ, et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 360:1320-1328, 2009.

5. Draisma G, Boer R, Otto SJ, et al: Lead times and over detection due to PSA screening: Estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst 95:868-878, 2003.

6. Tornblom M, Eriksson H, Franzen S, et al: Lead time associated screening for prostate cancer. Int J Cancer 108:122-129, 2004.

7. Blum RH, Scholz M: Invasion of the Prostate Snatchers. New York, Other Press, 2010.

8. Savage CJ, Vickers A: Low annual caseloads in US surgeons conducting radical prostatectomy. J Urol 182:2677-2679, 2009.

9. Klotz L: Active surveillance for favorable risk prostate cancer: What are the results, and how safe is it? Los Angeles, Prostate Cancer Research Institute. Available at http://www.prostate-cancer.org/education/localdis/klotz_activesurveillance.html.

10. NCI Cancer Bulletin, January 12, 2010. Available at http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2010/011210/page2. Accessed October 4, 2010.

11. Holmberg L, Bill-Axelson A, Helgesen F, et al: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 347:781-789, 2002.

12. Jemal A, Siegel R, Jiaquan Xu, et al: Cancer statistics, 2010. CA Cancer J Clin 60:277-300, 2010.

13. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate cancer. V.3.2010. Available at www.nccn.org. Accessed October 4, 2010.

14. Albertsen PC, Hanley JA, Gleason DF, et al: Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 280:975-980, 1998.

15. Saigal CS, Litwin MS: The economic costs of early stage prostate cancer. Pharmacoeconomics 20:869-878, 2002.

16. Palanisamy N, Ateeq B, Kalyana-Suldaram S, et al: Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 16:793-798, 2010.

17. Taylor BS, Schultz N, Hieronymous H, et al: Integrative genomic profiling of human prostate cancer. Cancer Cell 18:11-22, 2010.

18. Kong Z, Xie D, Boike T, et al: Downregulation of human DAB2IP gene expression in prostate cancer cells results in resistance to ionizing radiation. Cancer Res 70:2829-2839, 2010.

19. Min J, Zaslavsky A, Fedele G, et al: An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-κB. Nat Med 16:286-294, 2010.