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Evidence for Cure of ‘Young’ Men With Prostate Cancer

Evidence for Cure of ‘Young’ Men With Prostate Cancer

ABSTRACT: A study was undertaken to evaluate the question of cure in "young" men with prostate cancer treated by external-beam radiation. Results in young men (£ 65 years) were compared to older men. Biochemical freedom from failure was examined to 10 years’ follow-up, and hazard functions for failure vs time were reported. Results show that prostate cancer patients are cured by external-beam radiation and that there is no difference in results for young or older men. Few failures occur after 5 years’ follow-up and the percentage cured is similar to that with prostatectomy, with much less morbidity. Appropriate dose is necessary to optimize outcome. [ONCOLOGY 15(5):563-574, 2001]

Introduction

With the introduction of prostate-specific antigen (PSA), we have been able to assess which patients are cured of their prostate cancer, the treatment factors that influence cure, and the number of years a patient must live without a rise in his PSA to be cured. Few series—surgical or radiation—exist in the literature with 10-years or more follow-up, and the patterns of referral and practice in the 1980s and 1990s have resulted in few young men receiving external-beam radiation relative to the number treated by prostatectomy.[1-4]

Prior to the PSA era, indications of cure with external-beam radiation (assessed by clinical end points) originated from the Patterns of Care studies and the Radiation Therapy Oncology Group trials. Data from these reports, extending to 10 and 15 years, demonstrated similar survival rates between prostate cancer patients treated with radiation and an age-matched population.[5] A recent literature review for reports of external-beam radiation therapy in young men with prostate cancer produced only one study, by Freedman et al from Fox Chase Cancer Center in 1996.[6]

This article updates our treatment results of young men treated with external-beam radiation. It focuses on evidence of cure, compares results in younger and older men, defines the time beyond which radiation-treated patients with nonrising PSA levels are cured, and emphasizes the low morbidity associated with three-dimensional conformal radiotherapy (3D CRT) for young and older men.

Study Update

MATERIALS AND METHODS

Patient Population: The patient population we selected for analysis was restricted to 411 patients with pretreatment PSA levels < 20 ng/mL, a Gleason score ≤ 7, and palpation stage T1c/T2a disease, who are commonly considered candidates for either prostatectomy or radiation therapy (Table 1).[7] These patients were treated between February 1988 and December 1996. Each patient has been followed for a minimum of 36 months. Of the 411 patients studied, 393 were treated with 3D CRT.

All appropriate candidates for external-beam radiation therapy received radiation if they wished treatment. Patients received a radiation dose ³ 68 Gy to the center of the prostate (median: 73 Gy, range: 68 to 81 Gy). No patient received adjuvant hormonal treatment, except for documented failure. For purposes of this presentation, the 130 men aged ≤ 65 years are called "young men."

Statistics: Freedom from biochemical evidence of disease (bNED) was estimated using the American Society for Therapeutic Radiology and Oncology consensus definition, whereby biochemical failure is defined as three consecutive rises in PSA levels and the date of failure is said to occur midway between the nadir and first rise.[8] A pertinent history, serum PSA levels, and digital rectal examination were performed at 3 months posttreatment, then every 6 months for the next 5 years, and then annually for patients remaining free of disease. All estimates of biochemical failure were made using the Kaplan-Meier methodology. Hazard function estimation was accomplished using life-table methodology with 12-month intervals.[9,10]

Radiation Treatment With 3D CRT: In the subgroup of patients receiving 3D CRT, radiation was delivered with a four-field technique and custom blocks for all treatment portals. Patients with pretreatment PSA levels < 10 ng/mL, a Gleason score 2 to 6, and T1c/T2a disease received irradiation (68 to 77 Gy) to the prostate gland only, with a 1-cm margin. All other patients received irradiation to a small pelvic field that included the proximal lymph nodes treated to 46 Gy, the prostate and seminal vesicles to 56 Gy, and the prostate to 70 to 81 Gy, with a series of cone-down portals. The median dose for all patients was 73 Gy (range: 68 to 81 Gy) to the International Commission on Radiation Units and Measurements reference point near the center of the prostate.[11]

Conventional Radiation: For conventional radiotherapy, a four-field technique was used with corner blocks. The prostate gland alone was treated in patients with pretreatment PSAlevels < 10 ng/mL; the pelvic nodes were treated followed by a prostate boost in patients with higher pretreatment PSA levels or a Gleason score of 7. The median dose for the conventional group was 71 Gy, ranging from 69 to 72 Gy.

RESULTS

Effect of Age on bNED Failure: Figure 1 illustrates the bNED rates to 10 years for all patients, stratified by age at 65 years. This figure includes patients with T1c/T2a disease, a Gleason score ≤ 7, and pretreatment PSA levels < 20 ng/mL. There was no significant difference by age (P = .25), although young patients fared better, and the 5-year rate of bNED control was durable to the last follow-up. The absence of failure after 6 years is consistent with cure. Using standard subdivisions of pretreatment PSA levels (0 to 9.9 ng/mL and 10 to 19.9 ng/mL), there was no difference in bNED control by age.

Hazard Rate for bNED Failure by Age: Hazard rates for bNED failure stratified by age are shown in Figure 2. There was no significant effect of age (P = .25). Again, the hazards for failure of the common PSA subgroups were similar. These bNED and hazard data showed no failure after 6 years, thereby indicating that a nonrising PSA at 6 years is consistent with cure.

Importance of Dose: For young and older patients, bNED control was not statistically different on the basis of age. Because of this, data for all patients were pooled to show the importance of radiation dose in the favorable and less favorable subgroups of patients. Figure 3 shows the fraction of patients in the most favorable subset who were free of failure (T1a/T2c disease, Gleason score 2 to 6, pretreatment PSA levels < 10) divided by dose at 72 Gy. No dose effect on bNED was observed.

Figure 4 shows bNED results for patients with one or more adverse factors (Gleason score 7 or pretreatment PSA levels 10 to 19.9). In this case, the dose was divided at 76 Gy and a significant dose effect was observed (P = .0094). With the appropriate dose, the 5-year bNED increased from 66% to 82% for the group with one or more adverse features. The 82% rate was not different from the subgroup of patients with all favorable pretreatment characteristics (as shown in Figure 3).

Patterns of PSA Failure by Age: Table 2 illustrates patterns of failure divided by patient age. All patients in whom treatment failed (n = 91) experienced a rise in PSA levels. Local failure was based on digital exam, since biopsies were rarely performed. Metastases were determined by clinical examination or imaging. There was no effect of age on patterns of failure.

TREATMENT-RELATED MORBIDITY

Sexual Dysfunction: A total of 45 men, all younger than 65 years old, have completed the Sexual Adjustment Questionnaire to evaluate potency at approximately 3 years. Of the 45 men, 34 completed the questionnaire at approximately 6 years after treatment.[12,13] At the time of the first survey, patients also reported their potency status at the start of treatment (93% were potent). Potency was defined as the ability to achieve an erection sufficient for penetration and intercourse or the resumption of pretreatment sexual activity. Potency preservation (without sildenafil [Viagra]) was 71% at 3 years and 55% at 6 years (Table 3).

Bowel and Bladder Function: Of the 130 young men, 64 assessed bowel and bladder function 3 to 6 years after treatment by completing the Functional Alteration due to Change in Elimination (FACE) questionnaire.[14,15] Key questions are included in Table 4. Stress incontinence requiring one to two pads per day was noted by 2 of 64 patients (3%). No patient evaluated his bowel function as a "big" problem, while 16% noted a "moderate" problem. The pattern of response to bowel and bladder problems is similar to responses in a control population reported by Litwin.[16]

Discussion

The sometimes prolonged natural history of prostate cancer in the pre-PSA era has confused the evaluation of cure with treatment. Gauging of PSA now provides a more accurate end point with which to measure cure. A recent report by Hanlon and Hanks of hazard rates for biochemical failure has presented impressive evidence of cure by radiation treatment in patients with early and advanced disease extent, as well as those with a history of hormonal therapy.[17]

Outcomes for young and older patients with early prostate cancer (T1c/T2a disease, Gleason score ≤ 7, PSA levels < 20) have been examined for evidence of cure by external-beam radiation therapy (97% 3D CRT) to better define the appropriateness of recommending external-beam treatment in young men. Our results have also been examined to see if there is any effect of age on probability of cure or pattern of failure.

Prostate cancer patients are cured by radiation therapy, and there is no difference in the rate of cure or patterns of failure for young vs older men (divided at 65 years). Hazard functions show that the risk of failure is very low after 5 years. Failures occasionally occur 5 years after radiation therapy (as they do after surgery), although we have not seen any after 6 years.[3] No evidence supports a late pattern of increased failure in patients with prostate cancer treated with external-beam radiation in the PSA era.

As noted, the 3D CRT subgroup of this series received a median dose of 73 Gy (range: 68 to 81 Gy). This group was treated with state-of-the-art technology. Technique is important in all patients in order to minimize late morbidity from treatment, which was minimal in our series (as evaluated by patient-completed quality-of-life instruments). Dose is also critical for patients with pretreatment PSA levels of 10 to 20 ng/mL or tumors with a Gleason score of 7, in whom a 15% to 20% increase in 5-year bNED rates was seen with a dose > 76 Gy.

In order to deliver these doses safely, 3D CRT technology is necessary. The durability of radiation results after 5 to 6 years is equal or superior to that observed after prostatectomy and superior to one long-term report of implant treatment, where 25% of failures occurred between 5 and 10 years.[1,18] To young men, as well as older men with early prostate cancer, 3D CRT is an increasingly attractive treatment option. Cure rates in this unselected series were excellent and fully competitive with the results obtained by prostatectomy in selected patients.

Our patients’ stress incontinence rates of 3% (2 of 64 patients), along with the absence of total incontinence, were superior to postprostatectomy rates. No patient in our series evaluated his bowel function as a "big problem," and our rates of potency preservation in men ≤ 65 years (71% at 3 years, 55% at 6 years without sildenafil) were also superior to reports of potency preservation after prostatectomy.[19,20] Young men are not sacrificing cure when they select radiation treatment in order to avoid the higher risks of postsurgical incontinence and impotence or a major period of disability that may occur during recovery from prostatectomy.

Lastly, like surgical treatment, radiation treatment is most successful when performed by an experienced practitioner with up-to-date technology and techniques that are practiced in a multidisciplinary setting.

References

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

2. Lerner S, Blute M, Bergstralh E, et al: Analysis of risk factors for progression in patients with pathologically confined prostate cancers after radical retropubic prostatectomy. J Urol 156:137-143, 1996.

3. Shipley W, Thames H, Sandler H, et al: Radiation therapy for clinically localized prostate cancer: A multi-institutional pooled analysis. JAMA 281:1558-1604, 1999.

4. Hanks GE, Hanlon AL, Schultheiss TE, et al: Dose escalation with 3D conformal treatment: Five year outcomes, treatment optimization and future directions. Int J Radiat Oncol Biol Phys 41:501-510, 1998.

5. Hanks GE, Krall JM, Hanlon AL, et al: Patterns of care and RTOG studies in prostate cancer: Long-term survival, hazard rate observations, and possibilities of cure. Int J Radiat Oncol Biol Phys 28:39-46, 1994.

6. Freedman GM, Hanlon AL, Lee WR, et al: Young patients with prostate cancer have an outcome justifying their acceptance for external beam treatment. Int J Radiat Oncol Biol Phys 32:243-250, 1996.

7. Prostate, in Fleming I, Cooper J, Henson D, et al (eds): AJCC Cancer Staging Manual, pp 219-224. Philadelphia, Lippincott-Raven, 1997.

8. Cox J, Grignon D, Kaplan R, et al: Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997.

9. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:447-457, 1958.

10. Lee E: Statistical Methods for Survival Data Analysis, pp 9-74. Belmont, Calif, Lifetime Learning Publications, 1980.

11. International Commission on Radiation Units and Measurement: Prescribing, recording, and reporting photon beam therapy. Washington, DC, ICRU Report 50, 1999.

12. Wurzer J, Nicolaou N, Hanlon A, et al: Long-term durability of potency preservation in younger prostate cancer patients following 3D conformal radiation therapy. Int J Radiat Oncol Biol Phys 45:169, 1999.

13. Bruner D, Scott C, McGowan D, et al: Validation of the sexual adjustment questionnaire (SAQ) in prostate cancer patients enrolled on Radiation Therapy Oncology Group (RTOG) studies 90-20 and 94-08 (abstract 156). Int J Radiat Oncol Biol Phys 42:202, 1998.

14. Hanlon A, Bruner D, Peter R, et al: Long term quality of life study in prostate cancer patients treated with three dimensional conformal radiation therapy: Comparing bowel and bladder quality of life symptoms to that of the normal population. Int J Radiat Oncol Biol Phys. In press.

15. Cella DF, Tulsky DS, Gray G, et al: The Functional Assessment Cancer Therapy scale: Development and validation of the general measure. J Clin Oncol 11:570-579, 1993.

16. Litwin M: Health related quality of life in older men without prostate cancer. J Urol 161:1180-1184, 1999.

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

18. Ragde H, Elgamal A, Snow P, et al: Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma. Cancer 83:989-1001, 1998.

19. Walsh P, Marschke P, Ricker D, et al: Patient-reported urinary continence and sexual function after anatomic radical prostatectomy. Urology 55:58-61, 2000.

20. Walsh P: Radical prostatectomy for localized prostate cancer provides durable cancer control with excellent quality of life: A structured debate. J Urol 163:1802-1807, 2000.

 
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