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Keywords:

  • prostate carcinoma;
  • surgery;
  • radiation therapy;
  • prostatic specific antigen

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

BACKGROUND

The optimal management of patients with clinically localized prostate carcinoma remains undefined due in part to the absence of well-designed, prospective, randomized trials. The current study was conducted to compare and contrast outcomes with different forms of therapy for patients with prostate carcinoma who were treated at several institutions using predefined prognostic categories.

METHODS

A retrospective study of 6877 men with prostate carcinoma who were treated between 1989 and 1998 at 7 different institutions with 6 different types of therapy was conducted. Five-year actuarial rates of prostate specific antigen (PSA) failure were calculated based on predefined prognostic categories, which included combinations of pretreatment PSA level, tumor stage, and Gleason score. In addition, outcome was calculated using consistent biochemical failure definitions and a minimum, median length of follow-up.

RESULTS

Substantial differences in outcome were observed for the same type of treatment and at the same institution, depending on the number of prognostic variables used to define treatment groups. However, estimates of 5-year PSA outcomes after all forms of therapy for low-risk and intermediate-risk patient groups were remarkably similar (regardless of the type of treatment) when all three pretreatment variables were used to define prognostic categories. For patients in high-risk groups, the 5-year PSA outcomes were suboptimal, regardless of the treatment technique used.

CONCLUSIONS

The current data suggest that interinstitutional and interspecialty comparisons of treatment outcome for patients with prostate carcinoma are possible but that results must be based on all major prognostic variables to be meaningful. Analyzed in this fashion, 5-year PSA results were similar for patients in low-risk and intermediate-risk groups, regardless of the form of therapy. Findings from prospective, randomized trials using survival (cause specific and overall) as the end point for judging treatment efficacy and longer follow-up will be needed to validate these findings and to identify the most appropriate management option for patients with all stages of disease. Cancer 2002;95:2126–35. © 2002 American Cancer Society.

DOI 10.1002/cncr.10919

Defining the optimal management of patients with localized prostate carcinoma continues to present an elusive goal to clinicians and researchers involved in the treatment of patients with this malignancy. Lacking well-designed, prospective, randomized trials with power sufficient to detect differences in outcome based on disease stage and treatment modality, patients and clinicians alike are forced to choose a particular therapy based on prospective, nonrandomized studies or on retrospective data that may be clouded by potential selection bias and inconsistent data analyses. Fowler et al. recently demonstrated that patients are most likely to receive a recommendation for a particular form of therapy based on the specialty of the oncologist who provides their care.1, 2 This is related directly to the fact that physicians simply are not provided with sufficient, objective, long-term data to guide patients with optimal treatment decisions. Because it is unlikely that a large, prospective, randomized trial comparing various treatment approaches for patients with localized prostate carcinoma will be completed in the immediate future, the only reasonable alternative is to compare outcomes among groups of patients stratified by consistent pretreatment prognostic factors and similar follow-up intervals. Although several groups have attempted to present data in this fashion, patient numbers in these studies generally have been too small and follow-up too short to generate meaningful comparisons.3–26 In addition, due to the fact that pretreatment prostate specific antigen (PSA) level, Gleason score (GS), and tumor stage each can affect results independently, findings from many of those studies may be questionable unless all three prognostic factors were equally distributed in all patient groups. The objective of the current analysis was to compare 5-year actuarial rates of PSA biochemical control (BC) employing various forms of therapy from multiple institutions, using predefined prognostic categories, and with a minimum amount of follow-up.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

Patient Selection Criteria

From May 19 to May 22, 2000, the Second Joint International Meeting of the American Brachytherapy Society, the Groupe European de Curietherapia-European Society for Therapeutic Radiology and Oncology, and the Grupo Latino Americano Curietherapia was conducted in Washington, DC. In an attempt to objectively compare and contrast treatment outcome data for patients with prostate carcinoma using various modalities, experts from major academic centers were asked to present their institution's treatment results according to multiple, predetermined prognostic factors. Criteria were agreed upon by all participants to provide as objective and as fair a comparison of treatment results as possible. Recognizing that pretreatment PSA level, clinical tumor stage, and GS all were independent predictors of treatment outcome with all forms of therapy, these three criteria were used to establish primary and secondary prognostic groups. The initial six prognostic groups (primary) included only pretreatment PSA level and GS to provide sufficient patient numbers to generate reasonably meaningful treatment results. An additional nine prognostic groups (secondary) that included tumor stage also were developed to encompass the major categories of patients who are seen in most multidisciplinary prostate carcinoma clinics and to provide additional prognostic information, allowing for more objective comparisons of data. It should be noted that no attempt was made to perform a centralized review of pathologic material. Reporting the GS was at the discretion of each institution and could be based on the findings of one or more pathologist(s).

Statistical Considerations

To reduce the confounding effects (on outcome) of variations in follow-up between patient groups, data were accepted for comparison only if the median follow-up approached 36 months. In addition, a minimum number of patients25–30 were required in each prognostic category to provide a realistic comparison between treatment results. Institutions were asked to provide 5-year actuarial data for BC, disease free survival, and overall survival (if possible). For the initial six primary prognostic groups, the percentage of patients with tumor stage T1–T2 compared with tumor stage T2–T3 were provided to account (partially) for selection bias. Likewise, to provide information to account for additional confounding variables in prognostic subgroups, median values were requested for patient age, PSA, GS, tumor stage (where applicable), and dose (for patients who received radiation therapy [RT]). Patients who received adjuvant androgen-deprivation therapy were reported separately. Patients who were treated with brachytherapy alone were reported separately from patients who were treated with external beam RT (EBRT) as well. Finally, the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel definition of biochemical failure was used to report results for patients who were treated with RT.27 No attempt was made to account for bounces PSA levels in patients who were treated with brachytherapy. Biochemical failure after prostatectomy was defined as any detectable level of PSA.

The specifics of each institution's treatment techniques have been published previously. Table 1 summarizes the major criteria from each of those studies. A total of 6877 patients from 7 institutions using 6 different types of therapy comprised the initial patient population that was used to generate the various prognostic categories. It should be pointed out that not all patients were used in the analysis, because multiple criteria had to be met for inclusion.

Table 1. Patient Cohorts
InstitutionTreatmentNo. of patients
  1. HDR: high dose rate; 3D: three-dimensional; EBRT: external beam radiotherapy.

ArizonaPermanent radioactive seed implant1205
SeattlePermanent radioactive seed implant819
KielTemporary HDR implant172
William Beaumont HospitalTemporary HDR implant142
Fox Chase Cancer Center3D conformal EBRT1500
Wayne State UniversityNeutrons/EBRT324
William Beaumont HospitalEBRT Alone933
BaylorRadical prostatectomy1625
William Beaumont HospitalRadical prostatectomy157
Total6877

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

Tables 2–7 list treatment results based on the six primary prognostic groups. Despite variations between institutions and treatment techniques with respect to the distribution of tumor stage and median values for follow-up, PSA, GS, age, and dose, the 5-year actuarial results were remarkably similar for most prognostic groups. No particular type of treatment or institution reported consistently superior treatment results in any prognostic category listed. However, as shown in Tables 5–7, results from all institutions and with all forms of therapy clearly were less optimal in patients with more advanced stages of disease.

Table 2. Primary Prognostic Group 1: Serum Prostate Specific Antigen Level ≤ 10 ng/mL and Gleason Score ≤ 6
InstitutionNo. of patientsT1c/T2a (%)T2b/T3 (%)MedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; WBH: William Beaumont Hospital; HDR: high-dose rate brachytherapy; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WSU: Wayne State University.

Arizona (seeds)3456733616.07385
Seattle (seeds)431805.556988
Kiel (HDR)573070746.068701.89583
WBH (HDR)262377366.0665630.0100100100
FCCC (3D-EBRT)409871345687383
WSU (neutrons)8084
WBH (EBRT)3728416516.0672667.0717783
Baylor (surgery)7586832445.56621.49497
WBH (surgery)157666.1567848095
Table 3. Primary Prognostic Group 2: Serum Prostate Specific Antigen Level 10–20 ng/mL and Gleason Score ≤ 6
InstitutionNo. of patientsT1c/T2a (%)T2b/T3 (%)MedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WBH: William Beaumont Hospital.

Arizona (seeds)956436591474589383
Seattle (seeds)137701357083
FCCC (3D-EBRT)203802051707573
WBH (EBRT)156703052136746610596374
Baylor (surgery)1426139441366448797
Table 4. Primary Prognostic Group 3: Serum Prostate Specific Antigen Level ≥ 20 ng/mL and Gleason Score ≤ 6
InstitutionNo. of patientsT1c/T2a (%)T2b/T3 (%)MedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; HDR: high-dose rate brachytherapy; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WBH: William Beaumont Hospital.

Arizona (seeds)5448525437765955
Seattle (seeds)52853057275
Kiel (HDR)3119815633707013688768
FCCC (3D-EBRT)101604065707432
WBH (EBRT)100524872316746622244579
Baylor (surgery)3434665231664195493
Table 5. Primary Prognostic Group 4: Serum Prostate Specific Antigen Level ≤ 10 ng/mL and Gleason Score ≥ 7
InstitutionNo. of patientsT1c/T2a (%)T2b/T3 (%)MedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; WBH: William Beaumont Hospital; HDR: high-dose rate brachytherapy; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WSU: Wayne State University.

Arizona (seeds)515347626.077639170
Seattle (seeds)69656.077080
WBH (HDR)446436307.0769657838185
FCCC (3D-EBRT)1077129377075
WSU (neutrons)6973
WBH (EBRT)1337129496.37756615615470
Baylor (surgery)2495248326.0763117494
Table 6. Primary Prognostic Group 5: Serum Prostate Specific Antigen Level 10–20 ng/mL and Gleason Score ≥ 7
InstitutionNo. of patientsT1c/T2a (%)T2b/T3 (%)MedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; WBH: William Beaumont Hospital; HDR: high-dose rate brachytherapy; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WSU: Wayne State University.

Arizona (seeds)2951496214773382
Seattle (seeds)40631477275
WBH (HDR)315842411576963.538673986
FCCC (3D-EBRT)617525437176.062
WSU (neutrons)3756
WBH (EBRT)856436541377566.020244971
Baylor (surgery)904159301376567391
Table 7. Primary Prognostic Group 6: Serum Prostate Specific Antigen Level > 20 ng/mL and Gleason Score ≥ 7
InstitutionNo. of patientsT1c/T2a (%)T2b/T3 (%)MedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; HDR: high-dose rate brachytherapy; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WSU: Wayne State University; WBH: William Beaumont Hospital.

Kiel (HDR)2914867039707035396662
FCCC (3D-EBRT)60445658687636
WSU (neutrons)5234
WBH (EBRT)87415964378646628252372
Baylor (surgery)3330703729762244085

Tables 8–16 review treatment results based on the nine more restrictive (secondary) prognostic groups. By simply adding tumor stage to the primary prognostic groups, substantial differences in outcome were noted using the same form of treatment at the same institution. For example, a 23% difference in the BC rate (63% vs. 86%) was noted using a permanent seed implant (Arizona experience) when comparing outcome in Primary Prognostic Group 4 (Table 5) (PSA ≤ 10; GS ≥ 7) compared with Secondary Prognostic Group 4 (Table 11) (PSA ≤ 10; GS ≥ 7; T1c/T2a). These differences in outcome were noted for all forms of therapy (although the magnitude of the difference varied substantially depending on the prognostic categories compared and the treatment used).

Table 8. Secondary Prognostic Group 1: Tumor Stage T1c/T2a, Gleason Score ≤ 6, and Serum Prostate Specific Antigen Level ≤ 10 ng/mL
InstitutionNo. of patientsMedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WBH: William Beaumont Hospital.

Arizona (seeds)207626738283
Seattle (seeds)33078656989
FCCC (3D-EBRT)3574666687385
WBH (EBRT)313516673667717785
Baylor (surgery)49134666119797
Table 9. Secondary Prognostic Group 2: Tumor Stage T1c/T2a, Gleason Score ≤ 6, and Serum Prostate Specific Antigen Level > 10 ng/mL and ≤ 20 ng/mL
InstitutionNo. of patientsMedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WBH: William Beaumont Hospital.

Arizona (seeds)586213746985
Seattle (seeds)82711357085
FCCC (3D-EBRT)16349136707574
WBH (EBRT)10951136746610657080
Baylor (surgery)804212664095100
Table 10. Secondary Prognostic Group 3: Tumor Stage T1c/T2a, Gleason Score ≤ 6, and Serum Prostate Specific Antigen Level > 20 ng/mL ≤ 40 ng/mL
InstitutionNo. of patientsMedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WBH: William Beaumont Hospital.

FCCC (3D-EBRT)4356245707543
WBH (EBRT)3966246746615384977
Table 11. Secondary Prognostic Group 4: Tumor Stage T1c/T2a, Gleason Score ≥ 7, and Serum Prostate Specific Antigen Level ≤ 10 ng/mL
InstitutionNo. of patientsMedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy; WBH: William Beaumont Hospital.

Arizona (seeds)26696768672
Seattle (seeds)4362776981
FCCC (3D-EBRT)753867707680
WBH (EBRT)954677756613665871
Baylor (surgery)12131676218094
Table 12. Secondary Prognostic Group 5: Tumor Stage T1c/T2a, Gleason Score ≥ 7, and Serum Prostate Specific Antigen Level > 10 ng/mL and ≤ 40 ng/mL
InstitutionNo. of patientsMedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; WBH: William Beaumont Hospital; FCCC: Fox Chase Cancer Center; 3D-EBRT: three-dimensional external beam radiation therapy.

WBH (HDR)2546168696329786290
FCCC (3D-EBRT)6543157697658
WBH (EBRT)7859167746623244774
Table 13. Secondary Prognostic Group 6: Tumor Stage T2b/T3, Gleason Score ≤ 6, and Serum Prostate Specific Antigen Level ≤ 10 ng/mL
InstitutionNo. of patientsMedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; HDR: high-dose rate brachytherapy; WBH: William Beaumont Hospital; EBRT: external beam radiation therapy.

Arizona (seeds)113586748485
Seattle (seeds)7579656985
Kiel (HDR)3974670703939885
WBH (HDR)25356665630100100100
WBH (EBRT)59546671669697276
Baylor (surgery)21854566419198
Table 14. Secondary Prognostic Group 7: Tumor Stage T2b/T3, Gleason Score ≤ 6, and Serum Prostate Specific Antigen Level < 10 mg/mL ≤ 40 ng/mL
InstitutionNo. of patientsMedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; HDR: high-dose rate brachytherapy; WBH: William Beaumont Hospital; EBRT: external beam radiation therapy.

Arizona (seeds)525618748586
Seattle (seeds)65791857177
Kiel (HDR)387018697016848474
WBH (EBRT)7761186756616364970
Baylor (surgery)62511666447790
Table 15. Secondary Prognostic Group 8: Tumor Stage T2b/T3, Gleason Score ≥ 7, and Serum Prostate Specific Antigen Level ≤ 20 ng/mL
InstitutionNo. of patientsMedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; HDR: high-dose rate brachytherapy; WBH: William Beaumont Hospital; WSU: Wayne State University; EBRT: external beam radiation therapy.

Arizona (seeds)38649777375
Seattle (seeds)46731077267
Kiel (HDR)28648687021757971
WBH (HDR)294087666333644989
WSU (neutrons)12266
WBH (EBRT)695397756816414768
Baylor (surgery)136378763136591
Table 16. Secondary Prognostic Group 9: Tumor Stage T2b/T3, Gleason Score ≥ 7, and Serum Prostate Specific Antigen Level > 20 ng/mL and ≤ 40 ng/mL
InstitutionNo. of patientsMedianFive-year outcome (%)
Follow-up (months)PSA (ng/mL)GSAge (yrs)Dose (Gy)CFBCDFSOS
  1. PSA: prostate specific antigen; GS; Gleason score; Gy: grays; CF: clinical failure; BC; biochemical control; DFS: disease free survival; OS; overall survival; seeds: radioactive seed implant; WBH: William Beaumont Hospital; EBRT: external beam radiation therapy.

WBH (EBRT)2652267766622332057
Baylor (surgery)143525762353997

For patients in more favorable prognostic categories (Tables 8–13), again, all forms of therapy appeared to produce remarkably comparable treatment results. However, due to limited numbers of patients in some prognostic categories (and due to subtle but significant differences in the distribution of other confounding variables, such as age), no conclusions on an optimal technique could be reached. In addition, despite requiring a minimum median follow-up, some categories of patients had substantially large differences in median follow-up, creating difficulties for data comparisons. Age at diagnosis and length of follow-up generally were less in patients who underwent surgery.

Again, in patients with more advanced stages of disease (Tables 14–16), all forms of therapy produced less optimal results. However, in patients who were treated with RT, BC appeared to be superior with higher doses of RT (e.g., three-dimensional [3D] conformal RT at Fox Chase Cancer Center compared with previously used lower doses of conventional EBRT at William Beaumont Hospital).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

The current analysis was conducted to provide the most objective possible comparison of multiple treatment options for patients with localized prostate carcinoma, short of a prospective randomized trial. The data presented represent one of the first and largest interinstitutional and interspecialty comparisons of prostate outcome data reported to date. By controlling for multiple pretreatment prognostic factors that each independently predict for outcome with all forms of therapy (and by requiring adequate numbers of patients and a minimum median length of follow-up), these data provide clinicians and patients with a more realistic and objective assessment of treatment options for patients with most stages of disease. Unfortunately, even with this unprecedented approach to data analysis, it is readily apparent that the only truly objective mechanism for comparing and contrasting treatment options is within the confines of a prospective randomized trial. Such a trial will need to stratify patients based on all critical, pretreatment prognostic factors while controlling for length of follow-up and employing common end points for analysis. Until data from such trials are available, these results suggest that, for patients with early-stage disease, most forms of therapy (prostatectomy, 3D conformal EBRT, or brachytherapy) provide reasonably comparable (and good) 5-year BC rates. For patients with more advanced stages of disease, however, no form of therapy that was reviewed appeared to provide acceptable results, suggesting that these patients may require additional, more aggressive, combined treatment approaches (e.g., adjuvant androgen deprivation and/or systemic chemotherapy).

The introduction of the serum PSA level into the clinic in the late 1980s provided clinicians with a powerful, new prognostic factor that could be used both to stratify patients into well-defined prognostic categories and to accurately monitor patients after treatment. Unfortunately, it has recently become apparent that additional prognostic factors (e.g., GS, tumor stage, perineural invasion, percentage of positive cores at biopsy, etc.) also are necessary to separate objectively patients into distinct prognostic categories so that accurate comparisons of treatment efficacy can be made. Because so many different, independent prognostic factors are necessary to segregate patients into unique groups, it has been difficult for any single institution to generate sufficient patient numbers in any one prognostic category to assess the efficacy of various treatment approaches. This point was exemplified recently by D'Amico et al. in a comparison of PSA outcome between two forms of RT (interstitial brachytherapy plus EBRT vs. 3D conformal EBRT).20 The authors clearly demonstrated that the combination of prognostic factors (PSA, GS, and tumor stage) in a patient cohort can have a significant impact on PSA outcome. Consequently, they recommended controlling for all established prognostic factors when comparing PSA outcomes. This point is illustrated clearly in the current analysis. Different rates of 5-year BC were observed for the same form of treatment (at the same institution), depending on the number of prognostic factors used (two factors vs. three factors) to define a specific prognostic group.

An additional issue that is not raised frequently in most analyses of prostate carcinoma outcome data is the importance of the follow-up interval on the results observed. In both the surgical literature and the radiotherapy literature, studies that have addressed this issue clearly demonstrate that objective interpretations of treatment efficacy can be achieved only with adequate and comparable follow-up intervals. The magnitude of the effect of differences in follow-up, in many situations, can lead to serious misinterpretations of treatment efficacy. Vicini et al. and Lu recently demonstrated that reporting data prematurely can produce erroneous interpretations of BC rates (treatment efficacy), sometimes as great as 15–30%.28, 29 In the current analysis, large differences in median follow-up (beyond 36 months) probably accounted for a substantial part of the differences in outcome observed between treatment techniques. Clearly, follow-up should be considered as an equal and important parameter compared with all other prognostic factors.

Over the past 10–15 years, numerous other investigators have attempted to compare retrospective treatment results in patients with localized prostate carcinoma to define an optimal therapeutic technique. Similar to the current analysis, these comparisons demonstrate reasonably comparable 5-year PSA outcomes for in low-risk patients and intermediate-risk patients using either EBRT, brachytherapy, or radical prostatectomy. Unfortunately (and, again, similar to our findings), inconsistent and contradictory results were obtained for patients with more advanced stages of disease. This suggests that higher risk patients may require treatment for subclinical disease outside of the local field and/or more aggressive forms of local therapy. Recent data employing adjuvant androgen-deprivation therapy with RT clearly demonstrate this concept. Published randomized studies by the Radiation Therapy Oncology Group (studies 8531, 8610, and 9202) and the European Organization for Research and Treatment of Cancer all have shown improvements in survival in high-risk patients given prolonged (2–3 years) androgen suppression with RT, suggesting the need to provide some form of systemic therapy in these high-risk patients.30–32

An additional, significant problem that is encountered when analyzing results with different forms of therapy is whether the end points chosen for analysis are truly comparable. Although the ASTRO Consensus Panel definition of biochemical failure was used to analyze all RT results, it is not clear whether PSA outcomes between surgery and various forms of RT can be compared objectively and to what extent subtle differences in follow-up will affect results. This issue is clouded further by the effect of androgen-deprivation therapy on short-term serum PSA interpretations. Ideally, disease specific survival and overall survival should be employed as the most appropriate end points to compare different or new forms of therapy. However, given the protracted natural history of prostate carcinoma, the use of serum PSA results as a surrogate and/or early marker for treatment efficacy most likely will remain as the most common method for analyzing results. It is hoped that future studies will be directed toward identifying the most appropriate method for comparing PSA results (i.e., biochemical cure and/or biochemical failure definitions) between different forms of treatment.

Although our analysis represents one of the largest attempts at comparing data from multiple institutions (and different forms of therapy) using several predefined prognostic factors, it is readily evident that even larger patient numbers (and more extended follow-up) will be required before truly objective comparisons of techniques can be performed. This is exemplified by the fact that, if a Phase III trial were designed to detect differences in outcome between two different local therapies of as much as 10%, then at least 330 patients would be required in each treatment arm (using an α of 0.05 and a power of 90% and assuming a 75% rate of BC for patients with intermediate stage disease). Whether or not such a large Phase III trial ever could be completed is uncertain. Nonetheless, these statistical estimates clearly demonstrate the need for extremely large patient numbers if objective differences in outcome are to be detected (particularly with retrospective, pooled data).

Finally, although it may not be possible to use our data to define with accuracy the most optimal treatment alternative for patients with each stage of the disease, it is readily apparent that advances in local therapy do translate into improvements in outcome. For example, in patients who are treated with RT, the ability to safely escalate doses using 3D conformal techniques has produced greater BC rates and reductions in acute and chronic toxicity. This is demonstrated by comparing the lower BC rates with conventional EBRT from older data from William Beaumont Hospital using only 66 grays. Using higher doses of RT delivered with 3D conformal EBRT at the Fox Chase Cancer Center, substantially better results were obtained by patients in virtually all prognostic categories. A dose response relation has now been demonstrated in multiple other published studies.33–35 Likewise, refinements in surgical techniques also have produced improvements in both BC and morbidity.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

These data suggest that interinstitutional and interspecialty comparisons of treatment outcome for patients with prostate carcinoma are possible and that 5-year PSA results are remarkably similar for low-risk patients and intermediate-risk patients, regardless of the form of therapy used. Results from prospective randomized trials will be needed to validate these findings and to identify the most appropriate management option for patients with all stages of disease.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

The authors thank Ms. Chris Mitchell, R.N., for assistance in data analysis and Ms. Vicky Dykes for her assistance in the preparation of this article.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
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