Evidence for Cure of ‘Young’ Men With Prostate Cancer

May 1, 2001

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 report by Hanks and colleaguesexamines two controversial issues that are related to the treatment of prostatecancer 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. Thefindings of their study are important not only in addressing these points, butalso because they shed light on another concern often raised by urologists.

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

Outcome of Younger vs Older Men

Screening men for prostate cancer using age-specificprostate-specific antigen (PSA) and the ratio of free over total PSA,[1-3]combined with sextant (or more) transrectal ultrasound-guided prostatebiopsies,[4] has led to a dramatic shift in diagnostic patterns over the past 10years. 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 migrationapparent, there is mounting evidence that younger men are diagnosed earlier andmay actually have a better prognosis than older men.[7]

The number of treatment options has rapidly expanded to includeradical prostatectomy, external-beam radiotherapy, permanent radioactive seedimplant, cryotherapy, and combinations of external-beam radiotherapy andbrachytherapy. It is imperative, therefore, for the outcome of younger men to besystematically contrasted with their older counterparts and for the long-termefficacy of the different modalities to be established. Problems in fairlyassessing relative worth are substantial, considering stage migration, theintroduction of newer treatment approaches, and the improved results that can beachieved using higher radiation doses. Length of follow-up is of overridingimportance, with a median of 4 years or more necessary to draw meaningfulconclusions.

The article by Hanks et al presents the results of 411 patientswith favorable- to intermediate-risk prognostic features and a minimum follow-upof 3 years. The median radiation dose was 73 Gy. They chose an age cutoff pointof 65 years, which by the standards of surgical series, might be consideredhigh. However, very few prostate cancer patients aged 50 years or younger aretreated with radiotherapy. Their patient cohort reflects this trend, with only13 patients in the 50- to 55-year age range. There were 130 patients aged £ 65years and 281 aged > 65 years. Freedom from biochemical failure (bNED) rateswere not statistically different. Although a multivariate analysis was notdescribed, a subset analysis failed to reveal any differences by age for thosewith pretreatment PSA levels < 10 ng/mL or ³ 10ng/mL. More importantly, no failures were recorded over the follow-up range of 6to 10 years. The findings suggest that external-beam radiotherapy is highlycurative, perhaps more so than any other available modality.

The observation of a plateau in the Kaplan-Meier bNED survivalcurves may be extremely misleading. The literature is replete with examples ofthe observance of a plateau with short follow-up that disappears when follow-upis extended. An apparent plateau observed with extended follow-up is morecredible. Likewise, the absence of a plateau suggests that the cure fraction iswell below the fraction of patients remaining free of failure at the time limitof the analysis. The plateau seen in the bNED survival curves displayed by Hankset al is striking, and similar examples are evident in the radiotherapyliterature.[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 10years. In the surgical series, there is no suggestion of a plateau, except invery favorable patients.

Relative Risk of Relapse With Long-Term Follow-up

The group at Fox Chase Cancer Center found the annual hazardrate 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 inaccordance with those of their previous report,[16] in which hazard rates wereat this level beyond 5 years, even for patients with more advanced disease thanwas seen in the current analysis.

A recent report by Amling et al[14] provides correspondingcontemporary surgical data on annual hazard rates. The annual hazard rate at 9to 10 years was 4.0. There was a leveling of hazard function curves between 5and 10 years, with no suggestion that the hazard rate would eventuallydecline. These data corresponded to a drop in bNED from 76% at 5 years to 59% at10 years. For patients with a pretreatment PSA > 10 ng/mL, category pT3disease, or Gleason score > 6, the annual hazard rates between 5 and10 years were in the 5 to 10 range.

Conclusion

In summary, the article by Hanks et al demonstrates that thereis no difference in bNED and hazard rates between young and old men treated withexternal-beam radiotherapy. They also show that higher doses significantlyaffect failure rates for intermediate-risk patients. Thus, the cure fractionwill increase as higher doses are more consistently used. The most provocativeaspect is that the bNED and hazard rates quoted by the authors are superior tothose described in most surgical series, thereby indicating that radiotherapymay be the treatment of choice.

References:

1. Oesterling JE, Jacobsen SJ, Chute CG, et al: Serumprostate-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 thepercentage of free prostate-specific antigen to enhance differentiation ofprostate cancer from benign prostatic disease: A prospective multicenterclinical trial. JAMA 279(19):1542-1547, 1998.

3. Morgan TO, Jacobsen SJ, McCarthy WF, et al: Age-specificreference ranges for prostate-specific antigen in black men. N Engl J Med335:304-310, 1996.

4. Babaian RJ, Toi A, Kamoi K, et al: A comparative analysis ofsextant and an extended 11-core multisite directed biopsy strategy. J Urol163:152-157, 2000.

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

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

7. Smith CV, Bauer JJ, Connelly RR, et al: Prostate cancer inmen age 50 years or younger: A review of the Department of Defense Center forProstate Disease Research multicenter prostate cancer database. J Urol164:1964-1967, 2000.

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

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

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

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

12. Pound CR, Partin AW, Epstein JI, et al: Prostate-specificantigen after anatomic radical retropubic prostatectomy. Urol Clin North Am24:395-406, 1997.

13. Catalona WJ, Smith DS: Cancer recurrence and survival ratesafter anatomic radical retropubic prostatectomy for prostate cancer. J Urol160:2428-2434, 1998.

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

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

16. Hanlon AL, Hanks GE: Failure patterns and hazard rates forfailure suggest the cure of prostate cancer by external beam radiation. Urology55:725-729, 2000.