Correspondence to: James A. Talcott, M.D., Center for Outcomes Research, Massachusetts General Hospital, B75 230, 55 Fruit St., Boston, MA 021142696 (e-mail: jtalcott{at}partners.org).
In few diseases are treatment options as distinct, consequences as enduring, and the supporting data as uncertain as for early prostate cancer. The abrupt general acceptance of prostate-specific antigen (PSA) screening a decade ago doubled the number of men diagnosed annually (1,2) and brought the average age at diagnosis forward an estimated 5 years (so-called lead time) (3). The increased incidence, earlier diagnosis, and prostate cancer's usually indolent natural history, further magnified by another effect of screeninglength-biased sampling resulted in an estimated 1.4 million U.S. prostate cancer survivors in 1998 (Surveillance, Epidemiology, and End Results [SEER1] Program data: http://cancercontrol.cancer.gov/ocs/prevalence). Five-year survival rates for all prostate cancer patients rose from 80% in 1986 to 97% in 1993, the most recent patients' cohort with 5-year SEER data. Yet no randomized trial comparing any of the primary treatment modalities for early (nonmetastatic) prostate cancerradical prostatectomy, external-beam radiation therapy, brachytherapy (radioactive seed implants), or observationhas been completed in the past 20 years. Most men develop severe, permanent erectile dysfunction after any local treatment, and enduring urinary incontinence or bowel symptoms, depending on the treatment modality, are common (47). Tens of thousands of men make treatment decisions with very little help from medical research that will ramify for years.
The absence of trial data has not prevented large changes in treatment practice patterns. Two decades ago Walsh and colleagues (8) found that avoiding transection of periprostatic neurovascular bundles lessened the previous certainty of postprostatectomy impotence, and the frequency of this operation increased sixfold from 1984 to 1990 (9). Subsequent attention to patient selection and perhaps a growing appreciation of the risks of urinary incontinence and erectile dysfunction and of the importance of selecting appropriate patients (4,5,10) dampened enthusiasm for surgery, especially for older men. However, dissemination of a new percutaneous technique for delivering radiation to the prostateradioactive seed implantation or brachytherapywas so rapid that a 20% radical prostatectomy decrease in men over 65 between 1993 and 1997 was completely offset by increased brachytherapy (11). And, as the most recent result from the National Cancer Institute's Prostate Cancer Outcomes Study (PCOS) in this issue of the Journal by Potosky et al. (12) confirms, during the last decade physicians began to treat men with asymptomatic early prostate cancer with androgen deprivation therapy (ADT) (13).
The PCOS, a large population-based cohort study, has provided vital new information to clarify men's experience after the diagnosis of prostate cancer (1418). By randomly sampling recently diagnosed patients in six registries of the SEER Program, it obtains much more generalizeable results than the convenience samples studied elsewhere, includes the growing proportion of patients under age 65 invisible in otherwise representative Medicare-based samples and, by oversampling minority populations, provides crucial new information on understudied populations carrying the heaviest disease burden. However, it is not without flaws. Even using Rapid Case Ascertainment, most patients are identified 46 months after diagnosis, when treatment has usually begun and is often complete. To obtain a baseline necessary to identify the deficits due to treatment, the PCOS investigators asked patients to recall their precancer state, allowing time to erode and the experience of treatment to bias their recollected self-assessments, especially if their pretreatment function was abnormal. The PCOS study demonstrates why population-based cohort studies are rare: convenience samples are more convenient to study. Participation in the PCOS surveys was lower (62% of their sample) and the dropout rate higher (18% of men who completed the first 6-month survey did not complete the 12-month survey) than that for other reports, largely because socioeconomically disadvantaged patients are sicker, harder to locate, and less receptive to research.
This report focused on the 701 (23%) of 3073 patients with early (nonmetastatic) cancer who did not undergo surgery, radiation, or cryotherapy for their cancers. Excluding 40 patients for whom the timing and thus the purpose of androgen ablation was unclear, 661 patients did not received any localized, potentially curative initial treatment. The study's first surprising finding was that 245 (37%) of these men underwent ADT alone for their primary therapy, an indication authoritatively endorsed nowhere in the medical literature. The patients' survey responses showed that they paid a price in symptoms. Compared with men who were simply observed, men who underwent ADT were more than fivefold more likely to report breast swelling and hot flashes and, if they reported pretreatment potency, more than twice as likely to become impotent. General measures of health status, less sensitive to short-term change after treatment for early prostate cancer, indicated that ADT patients tended toward reduced physical role functioning and vitality, although these changes decreased after adjustment for potentially confounding demographic and clinical factors.
Potosky and his colleagues (12) also uncovered an apparent rationale for ADT. Men treated with ADT were more likely than those who were not to have palpable tumors, more poorly-differentiated tumors, and baseline PSA values over 10 ng/dL. As a result, using Partin's tables relating clinical parameters to surgical outcome (19), their cancers more likely extended outside the prostate. Less likely either to get cure in trade for the risk of side effects from active treatment or to reassuringly slow PSA rises during observation, the patients receiving ADT and their physicians chose to "do something" over passive observation. They reported a little more often being "pleased" or "delighted" with their treatment (56% versus 45%) and to believe themselves free of cancer (58% versus 46%) than the better-prognosis men who chose watchful waiting. To a small but measurable extent, these men, objectively at greater risk from their cancers, felt less so after choosing castration years earlier in their course than usual.
These men's muted endorsement of ADT echoes growing acceptance elsewhere in the spectrum of prostate cancer. In 1995 Wasson and colleagues (13) surveyed urologists and found that two thirds usually recommend ADT for men whose PSA is newly or persistently elevated following radical prostatectomy, including more than half of urologists who do not believe it prolongs life. Later reports provided some empirical support for earlier ADT (2022). Men who received at least 3 years of adjuvant ADT lived longer after external-beam radiation therapy for locally advanced prostate cancer (20) and, in a small study, after radical prostatectomy when cancer was found in pelvic lymph nodes (21). Early analysis of a Radiation Therapy Oncology Group (RTOG) study found that adjuvant ADT after radiation therapy for unfavorable tumors prolonged survival only among the retrospectively-defined subgroup with poorly-differentiated cancers (Gleason scores 810), but not among men with better-differentiated tumors more likely to be hormone-responsive but whose better survival may delay detecting a mortality benefit (22).
Yet as studies have appeared that suggest a survival benefit from earlier ADT, the toxicity of treatment has also become more evident. Lost libido and impotence are understood consequences of ADT, even if the ramifications for a man's life are not (23), and other studies also document loss of energy and muscle mass, self-image, and bone density (2425). As ADT is used earlier in the natural history of prostate cancer, adverse effects accumulate. As we step back from the bedside, we see that the economic impact on health care is striking. In 1993, before hundreds of thousands of living prostate cancer patients had been diagnosed and indication creep for ADT had just begun, one third of Medicare's expenditure on prostate cancer ($478 million of $1.4 billion) went for luteinizing hormone-releasing hormone (LHRH) agonists for chemical castration (27). Antiandrogens, commonly used with LHRH agonists for combined androgen blockade (CAB), are very expensive agents not covered by Medicare. A recent analysis found that compared with orchiectomy, the cost-effectiveness of CAB is $1 110 000 per quality-adjusted life year (28). For every two men who undergo radical prostatectomy, five are treated with LHRH agonists (29).
Prostate cancer provides an example of a central paradox in medicinethe more a patient appears to require treatment, the less successful treatment is likely to be. The treatment choices in early prostate cancer are less heroic than those faced by critically ill patients, but the diagnosis is chilling, the considerations are complex, and the consequences are enduring. Patients deserve better information from randomized clinical trials to help them make these decisions. Leaving them to ill-informed hunches is chancy medicine and the road to poor, expensive health policy.
NOTES
1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
REFERENCES
1 Giovannucci E, Kantoff P, Spiegelman D, Loughlin KR, Wishnow KI, Corless C, et al. The "epidemic" of early prostate cancer and the medical literature: a causal association? Prostate Cancer and Related Diseases 1998;1:14853.
2 Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995;273:54852.[Abstract]
3 Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 1995;273:28994..[Abstract]
4 Fowler FJ Jr, Barry MJ, Lu-Yao G, Roman A, Wasson J, Wennberg JE. Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 19881990 (updated June 1993). Urology 1993;42:6229.[Medline]
5 Litwin MS, Hays RD, Fink A, Ganz PA, Leake B, Leach GE, et al. Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 1995;273:12935.[Abstract]
6 Fowler FJ Jr, Barry MJ, Lu-Yao G, Wasson JH, Bin L. Outcomes of external-beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three surveillance, epidemiology, and end results areas. J Clin Oncol 1996;14:225865.[Abstract]
7 Talcott JA, Clark JA, Stark PC, Mitchell SP. Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 2001;166:4949.[Medline]
8 Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:4927.[Medline]
9 Lu-Yao GL, McLerran D, Wasson J, Wennberg JE. An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. JAMA 1993;269:26336.[Abstract]
10
Talcott JA, Rieker P, Propert KJ, Clark JA, Wishnow KI, Loughlin KR, et al. Patient-reported impotence and incontinence after nerve-sparing radical prostatectomy. J Natl Cancer Inst 1997;89:111723.
11 Bubolz T, Wasson JH, Lu-Yao G, Barry MJ. Treatments for prostate cancer in older men: 19841997. Urology 2001;58:97782.[Medline]
12
Potosky AL, Reeve BB, Clegg LX, Hoffman RM, Stephenson RA, Albertsen PC, et al. Quality of life following localized prostate cancer treated initially with androgen deprivation therapy or no therapy. J Natl Cancer Inst 2002;94:4307.
13 Wasson JH, Fowler FJ Jr, Barry MJ. Androgen deprivation therapy for asymptomatic advanced prostate cancer in the prostate specific antigen era: a national survey of urologist beliefs and practices. J Urol 1998;159:19936; discussion 19967.[Medline]
14
Stanford JL, Feng Z, Hamilton AS, Gilliland FD, Stephenson RA, Eley JW, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000;283:35460.
15
Potosky AL, Harlan LC, Stanford JL, Gilliland FD, Hamilton AS, Albersen PC, et al. Prostate cancer practice patterns and quality of life: the Prostate Cancer Outcomes Study. J Natl Cancer Inst 1999;91:171924.
16
Potosky AL, Knopf K, Clegg LX, Albertsen PC, Stanford JL, Hamilton AS, et al. Quality-of-life outcomes after primary androgen deprivation therapy: results from the Prostate Cancer Outcomes Study. J Clin Oncol 2001;19:37507.
17
Hamilton AS, Stanford JL, Gilliland FD, Albertsen PC, Stephenson RA, Hoffman RM, et al. Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: results from the Prostate Cancer Outcomes Study. J Clin Oncol 2001;19:251726.
18
Potosky AL, Legler J, Albertsen PC, Stanford JL, Gilliland FD, Hamilton AS, et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000;92:158292.
19 Partin AW, Kattan MW, Subong EN, Walsh, PC, Wojno KJ, Oesterling JE, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. [published erratum appears in JAMA 1997;278:118]. JAMA 1997;277:144551.[Abstract]
20
Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295300.
21
Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999;341:17818.
22 Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 8531. J Clin Oncol 1997;15:101321.[Abstract]
23 Bokhour BG, Clark JA, Inui TS, Silliman RA, Talcott JA. Sexuality after treatment for early prostate cancer: exploring the meanings of "erectile dysfunction." J Gen Intern Med 2001;16:64955.[Medline]
24 Lubeck DP, Grossfeld GD, Carroll PR. The effect of androgen deprivation therapy on health-related quality of life in men with prostate cancer. Urology 2001;58:94100.[Medline]
25
Smith MR, Finkelstein JS, McGovern FJ, Zeitman AL, Fallon MA, Schoenfeld DA, et al. Changes in Body Composition during Androgen Deprivation Therapy for Prostate Cancer. J Clin Endocrinol Metab 2002;87:599603.
26
Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345:94855.
27 Aronson N, Seidenfeld J, Samson DJ, Albertsen PC, Bayoumi AM, Bennett C. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Evidence Report/Technology Assessment No. 4. (Prepared by Blue Cross and Blue Shield Evidence-based Practice Center under Contract No. 290970015). AHCPR Publication No. 99-E012. Rockville (MD): Agency for Health Care Policy and Research, 1999.
28
Bayoumi AM, Brown AD, Garber AM. Cost-effectiveness of androgen suppression therapies in advanced prostate cancer. J Natl Cancer Inst 2000;92:17319.
29 Litwin MS, Pasta DJ, Stoddard ML, Henning JM, Carroll PR. Epidemiological trends and financial outcomes in radical prostatectomy among Medicare beneficiaries, 1991 to 1993. J Urol 1998;160:4458.[Medline]
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |