Abstract & Commentary
Synopsis: Among patients with early, localized prostate cancer, the mortality rate accelerated after 15 years.
Source: Johansson JE, et al. JAMA. 2004;291:2713-2719.
These researchers from Sweden report their latest findings from their population-based cohort study of men with early, localized, prostate cancer. In previously published updates, they demonstrated that tumor grade at diagnosis is an excellent predictor of local and distant progression (1989);1 that the 10-year, disease-specific survival rate was 87% (1992);2 and that the corrected 15-year survival rate of 81% was similar in patients with deferred treatment and in those who received initial treatment (1997).3 The current update extends the follow-up to an average 21 years with only 9% of the original cohort still living.
The subjects were recruited from 1977 to 1984. The world in which this study was conceived, commenced, and conducted is different than the one in which we find ourselves today. There was no prostate-specific antigen (PSA) testing or mass screening for prostate cancer. Cancer was diagnosed by digital rectal exam (DRE) or serendipitously discovered after transurethral resection (TURP) for suspected benign prostatic hypertrophy. Standard of care was to treat tumors confined to the prostate with no distant metastases with watchful waiting. During the first 2 years of the study only patients with highly differentiated tumors were included in the no treatment group. After that, patients younger than 75 years old with moderately or poorly differentiated tumors were randomized to no treatment or local treatment. A total of 654 Swedish males with newly diagnosed prostate cancer began the study; 233 were in the untreated group. They were an average of 72 years old (range, 41-92). Almost half (48%) of the diagnoses were made at TURP. The tumors were predominantly highly differentiated (65%); only 9% were poorly differentiated. The tumors were either T0 or T1-2.
All patients were followed until death or September 1, 2001. At periodic follow-up visits, clinical examinations, blood work, and bone scans were performed. If their cancers become symptomatic, they were treated with exogenous estrogen or orchidectomy. Patients were offered fine-needle biopsy every 2 years during the first 6 years of follow-up. There were biopsy specimens from 178 (80%) of patients. Over the course of the study, 21 (of 178) patients had their tumors downgraded from high to moderate, 7 from moderate to low, and 3 from high to low differentiation.
After an average of 21 years of follow-up, 89 (40%) of subjects had tumor growth through the prostate capsule; 39 (17%) developed distant metastases; and, 35 (16%) had a cancer-related death. Patients who were = 70 years at diagnosis had a greater degree of death from cancer (22/101, 22%). There was no difference in mortality between patients who were identified at TURP and those by DRE; however, poor differentiation was highly predictive (56%). During the first 15 years of follow-up, the prostate mortality rate held steady at 15 per 1000 person-years; during this follow-up period, it shot to 44 per 1000. Degree of differentiation was associated with rate of mortality (10 per 1000 for highly differentiated tumors, 194 per 1000 for poorly differentiated). After multivariate analysis, tumor grade, but not age at diagnosis or tumor stage, was significantly associated with prostate cancer mortality. On the other hand, the rate of local progression did not increase over time.
Comment by Allan J. Wilke, MD
This has been a time of surprises in prostate cancer research. The main surprise in this study was the increased rate of death after 15 years of follow-up. What explains this? Johansson offer several hypotheses, including tumor de-differentiation. Editorialists suggest that the introduction of new technology since to onset of the study has allowed for more complete recognition of prostate cancer recurrence. Other explanations are the development of a different clone of prostate cancer or cardiovascular disease secondary to estrogen therapy among those patients who developed symptomatic prostate cancer. A couple of weeks before this article was published in JAMA, the New England Journal of Medicine published4 (and Internal Medicine Alert reviewed5) an article that looked at the incidence of prostate cancer among men with PSA = 4.0 ng/mL (15%), the level that is commonly assumed to be the upper end of normal. We had high hopes when PSA testing was first introduced that it would identify those men who would benefit from prostate cancer treatment. Free PSA determination was supposed to improve this. I don’t think we’re there yet, but we may be getting closer. The current iteration is PSA velocity; men with PSA levels that double6 or increase greater than 2.0 ng/mL/yr7 have shorter times to death from prostate cancer.
Before applying these findings to your patients, remember the study’s limitations. All of the subjects were northern Europeans. None of the cancers were discovered though PSA testing. To make this information really useful, we need to know what the lead-time is between cancer detectable by PSA and by DRE or TURP. An important observation that the authors make incorporates the findings of another recent prostate study. In that study,8 radical prostatectomy reduced death from prostate cancer by half. If that finding were applied to the 35 subjects in this study who died of prostate cancer, 18 patients would have benefited; the other 205 would not have.
Dr. Wilke, Assistant Professor of Family Medicine, Medical College of Ohio, Toledo, OH, is Associate Editor of Internal Medicine Alert.
1. Johansson JE, et al. Lancet. 1989;1(8642):799-803.
2. Johansson JE, et al. JAMA. 1992;267:2191-2196.
3. Johansson JE, et al. JAMA. 1997;277:467-471.
4. Thompson IM, et al. N Engl J Med. 2004;350: 2239-2246.
5. Scherger JE. Internal Medicine Alert. 2004;26(12): 91-92.
6. Albertsen PC, et al. J Urol. 2004;171:2221-2225.
7. D’Amico AV, et al. N Engl J Med. 2004;351:125-135.
8. Holmberg L, et al. N Engl J Med. 2002;347:781-789.