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Original Contribution |

Biochemical Outcome Following External Beam Radiation Therapy With or Without Androgen Suppression Therapy for Clinically Localized Prostate Cancer FREE

Anthony V. D'Amico, MD, PhD; Delray Schultz, PhD; Marian Loffredo, RN, OCN; Raymond Dugal, MD; Mark Hurwitz, MD; Irving Kaplan, MD; Clair J. Beard, MD; Andrew A. Renshaw, MD; Philip W. Kantoff, MD
[+] Author Affiliations

Author Affiliations: Joint Center for Radiation Therapy, Brigham and Women's Hospital and Dana Farber Cancer Institute (Drs D'Amico, Dugal, and Hurwitz and Ms Loffredo), Beth Israel Deaconess Medical Center Department of Radiation Oncology (Drs Kaplan and Beard), Department of Pathology, Brigham and Women's Hospital (Dr Renshaw), Department of Medical Oncology, Dana Farber Cancer Institute (Dr Kantoff), Boston, Mass; and Department of Mathematics, Millersville University, Millersville, Pa (Dr Schultz).


JAMA. 2000;284(10):1280-1283. doi:10.1001/jama.284.10.1280.
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Context Combined treatment using radiation therapy (RT) and androgen suppression therapy (AST) is used to treat men with clinically localized adenocarcinoma of the prostate, but outcome using this combined therapy compared with RT alone is not known.

Objective To determine the relative efficacy of RT plus AST vs RT alone among men with clinically localized prostate cancer.

Design, Setting, and Patients Retrospective cohort study of 1586 men with prostate cancer who were treated between January 1989 and August 1999 using 3-dimensional conformal RT with (n = 276) or without (n = 1310) 6 months of AST.

Main Outcome Measure Relative risk (RR) of prostate-specific antigen (PSA) failure (defined according to the American Society for Therapeutic Radiology and Oncology consensus statement), by treatment and high-, intermediate-, or low-risk group based on serum PSA level, biopsy Gleason score, and 1992 American Joint Commission on Cancer clinical tumor category.

Results Estimates of 5-year PSA outcome after RT with or without AST were not statistically different among low-risk patients (P = .09), whereas intermediate- and high-risk patients treated with RT plus AST had significantly better outcomes than those treated with RT alone (P<.001 and = .009, respectively). The RR of PSA failure in low-risk patients treated with RT plus AST was 0.5 (95% confidence interval [CI], 0.3-1.1) compared with patients treated with RT alone. The RRs of PSA failure in intermediate-risk and high-risk patients treated with RT plus AST compared with RT alone were 0.2 (95% CI, 0.1-0.3) and 0.4 (95% CI, 0.2-0.8), respectively.

Conclusions Our data suggest a significant benefit in 5-year PSA outcomes for men with clinically localized prostate cancer in intermediate- and high-risk groups treated with RT plus AST vs those treated with RT alone. Results from prospective randomized trials currently under way are needed to validate these findings.

Figures in this Article

Treatment selection for men with clinically localized prostate cancer should be based on the results of carefully designed and well-conducted prospective randomized trials. Two randomized trials, one performed by the Radiation Therapy Oncology Group (RTOG)1 and the other by the European Organization for Research in the Therapy of Cancer (EORTC)2 have documented a benefit in cancer-specific survival for patients with locally advanced (T3, T4) prostate cancer who received a combination of external beam radiation therapy (RT) and short-(4 months) or long-term (3 years) androgen suppression therapy (AST), respectively, compared with RT alone. For men with clinically localized prostate cancer, 2 trials, one performed by the RTOG (RT with or without 4 months of AST) and the other by the Dana Farber Cancer Institute (RT with or without 6 months of AST), are expected to reach their target accruals during 2000.

Currently, however, no data exist regarding the relative efficacy of RT with or without AST for men with clinically localized disease. Therefore, our study was designed to provide early insight regarding the relative efficacy of RT and RT combined with 6 months of AST for men with clinically localized prostate cancer.

Patient Selection

The study population comprised 1586 men treated with 3-dimensional conformal external beam RT with (n = 276) or without (n = 1310) AST at the Joint Center for Radiation Therapy, Boston, Mass, between January 1989 and August 1999 and who had prostate-specific antigen (PSA)–detected or clinically palpable prostate cancer. Selection of patients for administration of AST was determined by physician preference. Patients underwent a staging evaluation as described previously.3

Treatment

Radiation therapy was delivered using a 4-field technique and at least 10 mV photons to a total median dose of 70.2 Gy (range, 70.0-72.4) to the prostate gland after 95% normalization. Androgen suppression therapy was given for 6 months (2 months before, during, and after RT) and consisted of the combination of a luteinizing hormone–releasing hormone agonist and a nonsteroidal antiandrogen.

Follow Up

Median follow-up time for patients stratified by treatment is listed in Table 1. Patients were seen 1 month after the end of RT, then at 3-month intervals for 2 years, every 6 months for 5 years, and annually thereafter. At each follow-up visit, a serum PSA was obtained prior to performing the digital rectal examination. All pretreatment PSA values were obtained within 1 month prior to initiation of therapy. No patients were lost to follow-up. Six men died of causes unrelated to prostate cancer and were censored at the time of their death because all were without evidence of prostate cancer recurrence.

Table Graphic Jump LocationTable 1. Patients Treated With Radiation or Radiation Plus Androgen Suppression Therapy Stratified Annually by Patient Risk Group*
Statistical Analysis

A Cox regression time to PSA failure analysis4 evaluating the ability of the treatment modality (RT with or without AST) to predict time to PSA failure was performed. The assumptions of the Cox model were met. Three risk groups had been previously established3 based on serum PSA level, biopsy Gleason score, and 1992 American Joint Commission on Cancer (AJCC) clinical tumor category. Low-risk patients had a PSA of 10 µg/L or less and Gleason score of 6 or less and 1992 tumor category T1c or T2a. Intermediate-risk patients had a PSA of 10.1 to 20 µg/L or a Gleason score of 7 or 1992 AJCC tumor category T2b. High-risk patients had a PSA of more than 20 µg/L or Gleason score of 8 or 1992 AJCC tumor category T2c. The relative risk (RR) of PSA failure and 95% confidence intervals (CIs) for men treated with RT plus AST vs men treated with only RT were calculated based on the coefficients from the Cox regression model for each risk group.

We defined PSA failure according to the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Statement.5 The definition required 3 consecutive rising PSA values, each obtained at least 3 months apart. Time of PSA failure was defined as the midpoint between the time of the first rise in PSA above the nadir and the PSA nadir. We used this definition while realizing that it may overestimate PSA failure6 in the group of men receiving RT plus AST given the known rebound in PSA following the withdrawal of AST in most men. Time 0 was defined as date of diagnosis.

Pairwise comparisons were made using a log-rank test. Estimates of PSA outcome were calculated using the Kaplan-Meier actuarial method.7 In the low-, intermediate-, and high-risk patient groups, sample size and number of events in the study were sufficient to detect a 10%, 11%, and 13% difference in PSA outcome, respectively, with 80% power at a .05 level of significance. This was calculated for a baseline PSA survival of 84%, 62%, and 43% at 5 years in the low-, intermediate-, and high-risk patients, respectively.

Prognostic Factor Comparison

Table 2 shows pretreatment clinical characteristics for the 1586 study patients stratified by treatment modality and clinical risk group. In the intermediate-risk group, there were more patients with a PSA of 10.1 to 20.0 µg/L (58% vs 47%; P = .03) and biopsy Gleason score of 7 (70% vs 54%; P = .001) in the RT plus AST than in the RT group. This imbalance could bias the results in favor of RT for patients in the intermediate-risk group.

Table Graphic Jump LocationTable 2. Pretreatment Patient Characteristics, Stratified by Treatment and Risk Group (N = 1586)*
Treatment Outcome Assessment

No significant difference between treatment groups was found for patients in the low-risk category (P = .09; relative risk [RR], 0.5; 95% CI, 0.3-1.1). Intermediate-risk and high-risk patients treated with RT plus AST had a 5-fold (RR, 0.2; 95% CI, 0.1-0.3) and 2.5-fold (RR, 0.4; 95% CI, 0.2-0.8) reduction in risk of PSA failure, respectively, compared with patients treated with RT. Estimates of PSA outcome following RT with or without AST are shown in Figure 1 for patients in the low-risk (5-year PSA outcome, 92% vs 84%), intermediate-risk (5-year PSA outcome, 88% vs 62%), and high-risk (5-year PSA outcome, 68% vs 43%) groups.

Figure. Estimates of PSA Failure-Free Survival Outcome Following Radiation Therapy With or Without Androgen Suppression Therapy
Graphic Jump Location
PSA indicates prostate-specific antigen; RT, radiation therapy; and AST, androgen suppression therapy. A, For low-risk patients, Cox regression P value = .09; log-rank P = .13; relative risk (RR) of PSA failure (95% confidence interval [CI]), 0.5 (0.3-1.1). B, For intermediate-risk patients, Cox regression P value <.001; log-rank P = .003; RR of PSA failure (95% CI), 0.2 (0.1-0.3). C, For high-risk patients, Cox regression P value = .009; log-rank P = .02; RR of PSA failure (95% CI), 0.4 (0.2-0.8).

Randomized studies1,2 have documented a cancer-specific survival benefit for men with locally advanced prostate cancer (T3, T4) treated with RT plus AST compared with RT; studies evaluating treatments for patients with clinically localized disease (T1, T2) will complete accrual this year. In this retrospective cohort study, which controlled for the established prognostic factors, a significant benefit in 5-year PSA outcome was noted for men with clinically localized disease in the intermediate- and high-risk groups treated with RT plus 6 months of AST vs men treated with RT only.

Several items warrant further discussion. First, patients in the intermediate-risk group had a prognostic factor distribution favoring RT (Table 2). Second, given the known rebound in PSA following the withdrawal of AST and the use of the ASTRO consensus definition to define PSA failure, PSA failure may have been overestimated in patients treated with RT plus AST.6 However, because of a changing practice pattern in the United States beginning around 1996 toward RT plus AST, the median follow-up for patients in the intermediate- and high-risk groups treated with RT was longer by 2 to 6 months vs patients treated using RT plus AST (Table 1). While the difference in median follow-up favors the RT plus AST arm, the prognostic factor distribution and ASTRO definition of PSA failure favor the RT arm.

Next, based on the decreased positive surgical margin rates reported from a randomized trial8 of radical prostatectomy with or without neoadjuvant AST, the benefit in PSA outcome noted in this study may be largely the result of an improvement in local control. That low-risk patients generally have a lower intraprostatic tumor volume and a minimal risk of micrometastatic disease could explain why the difference in PSA outcome for low-risk patients receiving RT plus AST as compared with RT in this study did not reach statistical significance. Whether the improvement in PSA outcome noted from the randomized trial10 of high-dose (78 Gy) vs conventional-dose (70 Gy) 3-dimensional conformal external beam radiation therapy will translate into an additional benefit in PSA outcome for intermediate- and high-risk patients treated with high-dose RT plus AST as compared with high-dose RT needs to be studied.

Shortcomings of this retrospective study and all randomized studies ongoing in clinically localized prostate cancer include the lack of an androgen suppression only control arm. Without such a control arm, it is difficult to ascertain whether any benefit was derived from the addition of RT to hormonal therapy. In addition, a small number of men may have remained castrate following the 6 months of AST, and this could improve PSA outcome in the combined treatment arm. Finally, the current study had a relatively short median follow-up and the median age of the patient population was 70 years, so that a significant risk of dying of other causes existed. Both of these issues may decrease the likelihood of detecting a future difference in cancer-specific survival as a result of the treatment. Realizing these potential limitations, PSA outcome, while not yet proven as a surrogate for cancer-specific survival, was used to assess clinical efficacy in this study.

However, recent studies lend credence to the use of PSA for prediction of cancer-specific survival. Specifically, the time to postoperative10 or postradiation11 PSA failure and a Gleason score of 8 or higher at biopsy for RT-managed patients or at prostatectomy for surgically managed patients were significant predictors of time to distant failure. The surgical study10 also concluded that time to distant failure was a significant predictor for death from prostate cancer. Therefore, given enough time left untreated, PSA failure in a patient who has undergone surgery or RT will lead to death from prostate cancer, and the time interval from PSA failure to death from prostate cancer will be shorter for men with poorly differentiated disease.

It will be several years before the results of the randomized trials evaluating the relative efficacy of RT with or without AST for patients with clinically localized prostate cancer will be available. In the interim, RT plus AST continues to be used to treat men with clinically localized prostate cancer despite the known toxicity12 (anemia, decreased bone density, impotence, decreased libido, mood swings, and decreased muscle mass) and unknown survival benefit compared with RT. Therefore, while no conclusions can be drawn from a nonrandomized retrospective comparison, our data provide physicians with information that may be used to counsel patients with clinically localized disease who have more aggressive prostate cancer (biopsy Gleason score ≥7 or PSA >10 µg/L) than the clinical stage would suggest. The possibility exists that in these select men, the use of RT plus 6 months of AST may result in superior cancer control compared with the use of RT alone.

Pilepich MV, Winter K, Roach M.  et al.  Phase III Radiation Therapy Oncology Group (RTOG) trial 86-10 of androgen deprivation before and during radiotherapy in locally advanced carcinoma of the prostate. From: 42nd Annual Meeting of the American Society of Therapeutic Radiology and Oncology; October 22, 2000; Boston, Mass.
Bolla M, Gonsalez D, Warde P.  et al.  Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin.  N Engl J Med.1997;337:295-300.
D'Amico AV, Whittington R, Malkowicz SB.  et al.  Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer.  JAMA.1998;280:969-974.
Cox DR. Regression models and life tables.  J R Stat Soc B.1972;34:187-189.
Cox JD.for the American Society for Therapeutic Radiology and Oncology Consensus Panel.  Guidelines for PSA following radiation therapy.  Int J Radiat Oncol Biol Phys.1997;37:1035-1041.
Slivjak AM, Pinovwe WH, Hanlon AL.  et al.  The ASTRO consensus definition of bNED failure is an inappropriate endpoint for prostate cancer patient treated receiving conformal radiation therapy and androgen deprivation therapy (CRT + AD) [abstract].  Int J Radiat Oncol Biol Phys.1998;42:176.
Kaplan EL, Meier P. Non-parametric estimation from incomplete observations.  J Am Stat Assoc.1958;53:457-500.
Soloway MS, Sharifi R, Wajsman Z.  et al.  Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer.  J Urol.1995;154:424-428.
Pollack A, Zagars GK, Smith LG.  et al.  Preliminary results of randomized dose escalation study comparing 70 Gy to 78 Gy for the treatment of prostate cancer.  Int J Radiat Oncol Biol Phys.1999;45:146-147.
Pound CR, Partin AW, Eisenberger MA.  et al.  Natural history of progression after PSA elevation following radical prostatectomy.  JAMA.1999;281:1591-1597.
Smith LG, Pollack A, Zagars GK. Predictors of distant metastasis 7 years after a rising PSA in prostate cancer patients treated with external beam radiation therapy.  Int J Radiat Oncol Biol Phys.1999;45:218-219.
Crawford ED, Eisenberger MA, McLeod D.  et al.  A controlled trial of leuprolide with and without flutamide in prostatic carcinoma.  N Engl J Med.1989;321:419-425.

Figures

Figure. Estimates of PSA Failure-Free Survival Outcome Following Radiation Therapy With or Without Androgen Suppression Therapy
Graphic Jump Location
PSA indicates prostate-specific antigen; RT, radiation therapy; and AST, androgen suppression therapy. A, For low-risk patients, Cox regression P value = .09; log-rank P = .13; relative risk (RR) of PSA failure (95% confidence interval [CI]), 0.5 (0.3-1.1). B, For intermediate-risk patients, Cox regression P value <.001; log-rank P = .003; RR of PSA failure (95% CI), 0.2 (0.1-0.3). C, For high-risk patients, Cox regression P value = .009; log-rank P = .02; RR of PSA failure (95% CI), 0.4 (0.2-0.8).

Tables

Table Graphic Jump LocationTable 1. Patients Treated With Radiation or Radiation Plus Androgen Suppression Therapy Stratified Annually by Patient Risk Group*
Table Graphic Jump LocationTable 2. Pretreatment Patient Characteristics, Stratified by Treatment and Risk Group (N = 1586)*

References

Pilepich MV, Winter K, Roach M.  et al.  Phase III Radiation Therapy Oncology Group (RTOG) trial 86-10 of androgen deprivation before and during radiotherapy in locally advanced carcinoma of the prostate. From: 42nd Annual Meeting of the American Society of Therapeutic Radiology and Oncology; October 22, 2000; Boston, Mass.
Bolla M, Gonsalez D, Warde P.  et al.  Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin.  N Engl J Med.1997;337:295-300.
D'Amico AV, Whittington R, Malkowicz SB.  et al.  Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer.  JAMA.1998;280:969-974.
Cox DR. Regression models and life tables.  J R Stat Soc B.1972;34:187-189.
Cox JD.for the American Society for Therapeutic Radiology and Oncology Consensus Panel.  Guidelines for PSA following radiation therapy.  Int J Radiat Oncol Biol Phys.1997;37:1035-1041.
Slivjak AM, Pinovwe WH, Hanlon AL.  et al.  The ASTRO consensus definition of bNED failure is an inappropriate endpoint for prostate cancer patient treated receiving conformal radiation therapy and androgen deprivation therapy (CRT + AD) [abstract].  Int J Radiat Oncol Biol Phys.1998;42:176.
Kaplan EL, Meier P. Non-parametric estimation from incomplete observations.  J Am Stat Assoc.1958;53:457-500.
Soloway MS, Sharifi R, Wajsman Z.  et al.  Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer.  J Urol.1995;154:424-428.
Pollack A, Zagars GK, Smith LG.  et al.  Preliminary results of randomized dose escalation study comparing 70 Gy to 78 Gy for the treatment of prostate cancer.  Int J Radiat Oncol Biol Phys.1999;45:146-147.
Pound CR, Partin AW, Eisenberger MA.  et al.  Natural history of progression after PSA elevation following radical prostatectomy.  JAMA.1999;281:1591-1597.
Smith LG, Pollack A, Zagars GK. Predictors of distant metastasis 7 years after a rising PSA in prostate cancer patients treated with external beam radiation therapy.  Int J Radiat Oncol Biol Phys.1999;45:218-219.
Crawford ED, Eisenberger MA, McLeod D.  et al.  A controlled trial of leuprolide with and without flutamide in prostatic carcinoma.  N Engl J Med.1989;321:419-425.
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