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Evidence for Cure of ‘Young’ Men With Prostate Cancer

Evidence for Cure of ‘Young’ Men With Prostate Cancer

The report by Hanks and colleagues examines two controversial issues that are related to the treatment of prostate cancer with external-beam radiotherapy: (1) the outcome of younger vs older men, and (2) the relative risk of relapse with follow-up beyond 5 years. The findings of their study are important not only in addressing these points, but also because they shed light on another concern often raised by urologists.

The vast majority of urologists strongly advocate radical prostatectomy in younger men based mainly on the premise that, with long-term follow-up, the results gained with this procedure are superior to those of external-beam radiotherapy. This belief has been put forth at national conferences and is transmitted to patients on a routine basis in clinical practice. Such claims, however, are unfounded. There are no conclusive data that there is any difference in outcome between radiotherapy or radical prostatectomy—even with long-term follow-up.

Outcome of Younger vs Older Men

Screening men for prostate cancer using age-specific prostate-specific antigen (PSA) and the ratio of free over total PSA,[1-3] combined with sextant (or more) transrectal ultrasound-guided prostate biopsies,[4] has led to a dramatic shift in diagnostic patterns over the past 10 years. Men are being diagnosed at younger ages, with much earlier disease.[5,6] In the past, results of comparisons of younger and older men have been variable. Age has not been a consistent predictor of relapse. With stage migration apparent, there is mounting evidence that younger men are diagnosed earlier and may actually have a better prognosis than older men.[7]

The number of treatment options has rapidly expanded to include radical prostatectomy, external-beam radiotherapy, permanent radioactive seed implant, cryotherapy, and combinations of external-beam radiotherapy and brachytherapy. It is imperative, therefore, for the outcome of younger men to be systematically contrasted with their older counterparts and for the long-term efficacy of the different modalities to be established. Problems in fairly assessing relative worth are substantial, considering stage migration, the introduction of newer treatment approaches, and the improved results that can be achieved using higher radiation doses. Length of follow-up is of overriding importance, with a median of 4 years or more necessary to draw meaningful conclusions.

The article by Hanks et al presents the results of 411 patients with favorable- to intermediate-risk prognostic features and a minimum follow-up of 3 years. The median radiation dose was 73 Gy. They chose an age cutoff point of 65 years, which by the standards of surgical series, might be considered high. However, very few prostate cancer patients aged 50 years or younger are treated with radiotherapy. Their patient cohort reflects this trend, with only 13 patients in the 50- to 55-year age range. There were 130 patients aged £ 65 years and 281 aged > 65 years. Freedom from biochemical failure (bNED) rates were not statistically different. Although a multivariate analysis was not described, a subset analysis failed to reveal any differences by age for those with pretreatment PSA levels < 10 ng/mL or ³ 10 ng/mL. More importantly, no failures were recorded over the follow-up range of 6 to 10 years. The findings suggest that external-beam radiotherapy is highly curative, perhaps more so than any other available modality.

The observation of a plateau in the Kaplan-Meier bNED survival curves may be extremely misleading. The literature is replete with examples of the observance of a plateau with short follow-up that disappears when follow-up is extended. An apparent plateau observed with extended follow-up is more credible. Likewise, the absence of a plateau suggests that the cure fraction is well below the fraction of patients remaining free of failure at the time limit of the analysis. The plateau seen in the bNED survival curves displayed by Hanks et al is striking, and similar examples are evident in the radiotherapy literature.[8-10]

In contrast, in all of the major prostatectomy series,[11-14] save one,[15] the Kaplan-Meier bNED curves inexorably drop between 5 and 10 years. In the surgical series, there is no suggestion of a plateau, except in very favorable patients.

Relative Risk of Relapse With Long-Term Follow-up

The group at Fox Chase Cancer Center found the annual hazard rate beyond 5 years to be less than 0.5 and no different for young vs older men. No failures occurred beyond 6 years of follow-up. These results are in accordance with those of their previous report,[16] in which hazard rates were at this level beyond 5 years, even for patients with more advanced disease than was seen in the current analysis.

A recent report by Amling et al[14] provides corresponding contemporary surgical data on annual hazard rates. The annual hazard rate at 9 to 10 years was 4.0. There was a leveling of hazard function curves between 5 and 10 years, with no suggestion that the hazard rate would eventually decline. These data corresponded to a drop in bNED from 76% at 5 years to 59% at 10 years. For patients with a pretreatment PSA > 10 ng/mL, category pT3 disease, or Gleason score > 6, the annual hazard rates between 5 and 10 years were in the 5 to 10 range.

Conclusion

In summary, the article by Hanks et al demonstrates that there is no difference in bNED and hazard rates between young and old men treated with external-beam radiotherapy. They also show that higher doses significantly affect failure rates for intermediate-risk patients. Thus, the cure fraction will increase as higher doses are more consistently used. The most provocative aspect is that the bNED and hazard rates quoted by the authors are superior to those described in most surgical series, thereby indicating that radiotherapy may be the treatment of choice.

References

1. Oesterling JE, Jacobsen SJ, Chute CG, et al: Serum prostate-specific antigen in a community-based population of healthy men: Establishment of age-specific reference ranges. JAMA 270:860-864, 1993.

2. Catalona WJ, Partin AW, Slawin KM, et al: Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: A prospective multicenter clinical trial. JAMA 279(19):1542-1547, 1998.

3. Morgan TO, Jacobsen SJ, McCarthy WF, et al: Age-specific reference ranges for prostate-specific antigen in black men. N Engl J Med 335:304-310, 1996.

4. Babaian RJ, Toi A, Kamoi K, et al: A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy. J Urol 163:152-157, 2000.

5. Amling CL, Blute ML, Lerner SE, et al: Influence of prostate-specific antigen testing on the spectrum of patients with prostate cancer undergoing radical prostatectomy at a large referral practice. Mayo Clin Proc 73:401-406, 1998.

6. Stephenson RA, Stanford JL: Population-based prostate cancer trends in the United States: Patterns of change in the era of prostate-specific antigen. World J Urol 15:331-335, 1997.

7. Smith CV, Bauer JJ, Connelly RR, et al: Prostate cancer in men age 50 years or younger: A review of the Department of Defense Center for Prostate Disease Research multicenter prostate cancer database. J Urol 164:1964-1967, 2000.

8. Pollack A, Smith LG, von Eschenbach AC: External beam radiotherapy dose-response characteristics of 1127 men with prostate cancer treated in the PSA era. Int J Radiat Oncol Biol Phys 48:507-512, 2000.

9. Zelefsky MJ, Leibel SA, Baudin PB, et al: Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 41:491-500, 1998.

10. Kupelian PA, Mohan DS, Lyons J, et al: Higher than standard radiation doses (³ 72 Gy) with or without androgen deprivation in the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys 46:567-574, 2000.

11. Trapasso JG, deKernion JB, Smith RB, et al: The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 152:1821-1825, 1994.

12. Pound CR, Partin AW, Epstein JI, et al: Prostate-specific antigen after anatomic radical retropubic prostatectomy. Urol Clin North Am 24:395-406, 1997.

13. Catalona WJ, Smith DS: Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer. J Urol 160:2428-2434, 1998.

14. Amling CL, Blute ML, Bergstralh EJ, et al: Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: Continued risk of biochemical failure after 5 years. J Urol 164:101-105, 2000.

15. Dillioglugil O, Leibman BD, Kattan MW, et al: Hazard rates for progression after radical prostatectomy for clinically localized prostate cancer. Urology 50:93-99, 1997.

16. Hanlon AL, Hanks GE: Failure patterns and hazard rates for failure suggest the cure of prostate cancer by external beam radiation. Urology 55:725-729, 2000.

 
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