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Gleason Pattern 5 Prostate Cancer: Further Stratification of Patients With High-Risk Disease and Implications for Future Randomized Trials
Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 5, pp. 1419–1423, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.10.027
CLINICAL INVESTIGATION
Prostate
GLEASON PATTERN 5 PROSTATE CANCER: FURTHER STRATIFICATION OF PATIENTS WITH HIGH-RISK DISEASE AND IMPLICATIONS FOR FUTURE RANDOMIZED TRIALS AKASH NANDA, M.D., PH.D.,* MING-HUI CHEN, PH.D.,y ANDREW A. RENSHAW, M.D.,z x AND ANTHONY V. D’AMICO, M.D., PH.D. * Harvard Radiation Oncology Program, Boston, MA; y Department of Statistics, University of Connecticut, Storrs, CT; z Department of Pathology, Baptist Hospital of Miami, Miami, FL; and x Department of Radiation Oncology, Brigham & Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA Purpose: To compare prostate-specific antigen (PSA) outcomes in a cohort of men with high-risk prostate cancer based on the presence or absence of any Gleason Grade 5 component (primary, secondary, or tertiary). Methods and Materials: Our study cohort consisted of 312 men with T1c–T3N0M0 prostate cancer with Gleason Scores of 7 with tertiary Grade 5, 8, or 9–10 who underwent radical prostatectomy or external beam radiotherapy with or without androgen suppression therapy. Cox regression multivariable analysis was used to assess whether a difference existed in risk of PSA recurrence in men with Gleason Score of 9–10 compared with those with Gleason Score of 8 and 7 with tertiary Grade 5, adjusting for treatment, age, and known prostate cancer prognostic factors. Results: After a median follow-up of 5.7 years, men with a Gleason Score of 8 had a lower risk of PSA recurrence than those with a Gleason Score of 9–10 (hazard ratio, 0.74; 95% confidence interval, 0.52–1.05; p = 0.09). Conversely, men with a Gleason Score of 7 with tertiary Grade 5 had a similar risk of PSA recurrence compared with men with a Gleason Score of 9–10 (hazard ratio, 1.08; 95% confidence interval, 0.60–1.94; p = 0.81). Median times to PSA failure for men with Gleason Scores of 9–10, 7 with tertiary Grade 5, and 8 were 4.5, 5.0, and 5.4 years, respectively. Conclusions: Our results highlight the importance of further substratification of the high-risk Gleason Score category of 8–10 into 8 vs. 9, 10, and 7 with tertiary Grade 5. Ó 2009 Elsevier Inc. Prostate cancer, Prostate-specific antigen (PSA), Gleason score, Tertiary Grade 5, Stratification.
INTRODUCTION Prostate cancer is the most commonly diagnosed solid tumor in men in the United States, with an annual incidence of 186,320 (1). Treatment of patients with prostate cancer is based on the extent of disease (2–4). The Gleason grade represents a major component in stratifying patients for therapy. Although the Gleason scoring system is based solely on architectural features of prostate cancer cells, with inherent limitations, it has a strong track record of predicting outcome and has become the most widely used grading method throughout the world (5, 6). According to the Gleason scoring system, tumor cells initially are examined under low-power magnification and graded from 1 to 5, with 5 the least differentiated. An overall score then is assigned based on the numerical composite of the two most abundant patterns in the tumor specimen (7).
Notwithstanding other important clinical factors, Gleason Scores of 6 or less, 7, and 8 or higher traditionally have represented disease categorized as low, intermediate, and high risk, respectively (8). Although historically, tertiary patterns were not formally incorporated into the overall scoring system, there has been a great deal of interest in addressing the prognostic significance of tertiary Grade 5 disease within the setting of Gleason Score 7 prostate cancer. In 2005, the International Society of Urologic Pathology consensus conference recommended that Gleason Scores of 3 + 4 and 4 + 3 with tertiary Grade 5 disease be reclassified as Gleason Scores 8 and 9, respectively (9). Additionally, recent studies have shown that patients with a Gleason Score of 7 with tertiary Grade 5 disease had a greater risk of prostate-specific antigen (PSA) failure and likelihood of having more advanced pathologic stage than those with Gleason Score of 7 without tertiary Grade 5 disease (10, 11).
Reprint requests to: Akash Nanda, M.D., Ph.D., Harvard Radiation Oncology Program, Brigham & Women’s Hospital, 75 Francis Street, ASB1 L2, Boston, MA 02115. Tel: (617) 732-6310; Fax: (617) 975-0932; E-mail: [email protected] Presented in part at the American Society for Therapeutic Radiol-
ogy and Oncology (ASTRO) 50th Annual Meeting, September 21– 25, 2008, Boston, MA. Conflict of interest: none. Received Aug 21, 2008, and in revised form Sept 26, 2008. Accepted for publication Oct 7, 2008. 1419
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Given such findings, it is reasonable to question whether Gleason Pattern 5 represents a unique biologic entity with important implications for both staging and therapeutic considerations. It is plausible that in patients with high-risk prostate cancer, further stratification based on the presence or absence of Grade 5 disease may optimize outcome prediction and better identify men for entry into clinical trials in which survival after the addition of novel systemic agents to standard management compared with the standard of care could be tested. To this end, in the present study, we compare PSA outcomes in men with high-risk prostate cancer based on the presence or absence of Grade 5 disease. METHODS AND MATERIALS Patient characteristics and treatment The study cohort included 312 men with clinical tumor (T) category T1c–T3 node-negative nonmetastatic adenocarcinoma of the prostate with Gleason Scores of 7 with tertiary Grade 5, 8 (without Grade 5), or 9–10 treated between 1989 and 2005 at Harvard-affiliated institutions (St. Anne’s Hospital, Brigham & Women’s Hospital, and the Dana-Farber Cancer Institute). Cases of Gleason Score of 8 with Grade 5 prostate cancer are exceedingly rare and therefore were excluded from the present study. The incidence of a tertiary Grade 5 component in the setting of Gleason Score 7 disease within our extended database was approximately 3.5%. Patients were treated by using radical prostatectomy (n = 127), radiation therapy (n = 104), or radiation therapy with 2 months each of neoadjuvant, concurrent, and adjuvant androgen suppression therapy (AST; n = 81). Patients were excluded if they had undergone radical prostatectomy and received preoperative or postoperative AST or adjuvant radiation therapy. The study was performed with the approval of the institutional review board of the participating institutions. For our analyses, all Gleason scores were reviewed and assigned by a single pathologist (A.A.R.) who has expertise in grading cancers of the genitourinary tract. In all patients, radical prostatectomy consisted of a radical retropubic prostatectomy with bilateral lymph node sampling. Radiation therapy was delivered by using shaped blocks based on the computed tomography–defined volumes transferred onto pelvic plain films before 1994, and thereafter, computed tomography–based three-dimensional conformal treatment planning was used. A total dose of 70.2 Gy was administered consistently. Adjuvant AST was achieved by using combined blockade with a luteinizing hormone–releasing hormone agonist (leuprolide or goserelin) and a nonsteroidal antiandrogen (bicalutamide or flutamide). Injections of leuprolide (7.5 mg/mo) or goserelin (3.6 mg/mo) were given in either 1- or 3-month formulations. Bicalutamide (50 mg/d) or flutamide (250 mg every 8 hours) were administered orally starting 1–3 days before luteinizing hormone–releasing hormone agonist therapy initiation to block the transient testosterone surge.
Follow-up Median follow-up was 5.7 years (interquartile range [IQR], 2.7– 7.6) with censoring occurring at the time of PSA failure, beginning on the date of radical prostatectomy or initiation of other therapy and concluding on March 8, 2005 (when our database was last updated), or date of death, whichever was earlier. Routine follow-up included serum PSA measurement followed by a digital rectal examination generally every 3 months for 2 years, then every 6 months for an additional 3 years, and annually thereafter. The PSA recurrence after
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radiation therapy (with or without AST) was defined as the date at which PSA levels became 2 ng/ml greater than the nadir according to the 2006 consensus definition of the American Society for Therapeutic Radiology and Oncology (12). The PSA recurrence for surgical patients was defined on the date at which PSA level became greater than 0.2 ng/ml, with a second confirmatory value greater than 0.2 ng/ml (13).
Statistical methods Time to PSA failure analyses. Descriptive statistics were used to define the patient population at baseline. Cox regression univariable and multivariable analyses were performed with the primary end point of time to PSA failure after the end of treatment. Gleason score, tumor category, and treatment modality were analyzed as categorical variables, whereas age and PSA level were considered as continuous variables. For categorical variables, cutoff points were defined before analyzing the data, according to established strata (10, 14). These categories included Gleason Scores 8 (without Grade 5); 7 with tertiary Grade 5; and 9–10; clinical T category T1c, T2, and T3; and treatment with radical prostatectomy, radiation therapy plus AST, or radiation therapy. Baseline groups were Gleason Score of 9–10, clinical T category of T1c, and treatment group radiation therapy plus AST. For all Cox regression analyses, the assumptions of the proportional hazards model were tested and met, and all statistical tests were two sided. Adjusted and unadjusted hazard ratios (HRs) for PSA recurrence with the associated 95% confidence intervals (CIs) were calculated for all covariates (15). Estimates of PSA failure stratified by Gleason score. For the purpose of illustration, estimates of time to PSA recurrence after treatment and stratified by the categorical covariate of Gleason score were displayed, and these estimates were made by using the method of Kaplan and Meier (16). These estimates were compared by using Wilcoxon’s test, which weights time to PSA failure by the number of men at risk (17). Adjustment for multiple comparisons was made with the use of Bonferroni’s correction (18). Given a total of three comparisons, a two-sided p # 0.02 was considered statistically significant. Median time to PSA recurrence was calculated by using the Kaplan-Meier estimator and described. All statistical analyses were performed using SAS, Version 9.1.3 (SAS Institute Inc., Cary, NC).
RESULTS Clinical characteristics of the study cohort As listed in Table 1, median age of the 312 men who comprised the study cohort at the time of initial therapy was 68 years (IQR, 62–73 years). Median PSA level was 8.9 ng/ml (IQR, 5.9–15.5 ng/ml). The distribution of the men by Gleason score was 167 (53.5%) with Gleason Score of 8, 36 (11.5%) with Gleason Score of 7 with tertiary Grade 5, and 109 (35.0%) with Gleason Score of 9–10. Predictors of time to PSA failure As listed in Table 2, after adjusting for treatment received, age, and known prostate cancer prognostic factors, including PSA level and tumor T category, Cox regression multivariable analysis showed that men with Gleason Score 8 disease had a lower risk of PSA recurrence than those with Gleason Score 9–10 disease (HR, 0.74; 95% CI, 0.52–1.05; p = 0.09), which approached statistical significance. Conversely, men with Gleason Score 7 with tertiary Grade 5 disease had
Gleason Pattern 5 prostate cancer d A. NANDA et al.
Table 1. Baseline clinical characteristics of study cohort Characteristic Age (y) Baseline PSA (ng/ml) Gleason Score at biopsy 8 without Grade 5 7 with tertiary Grade 5 9–10 1992 AJCC clinical tumor category T1c T2a T2b T2c T3 Treatment modality Radical prostatectomy External beam radiation External beam radiation + AST
Patients (N = 312) 68 (62–73) 8.9 (5.9–15.5) 167 (53.5) 36 (11.5) 109 (35.0) 112 (35.9) 74 (23.7) 61 (19.6) 38 (12.2) 27 (8.6) 127 (40.7) 104 (33.3) 81 (26.0)
Abbreviations: PSA = prostate-specific antigen; AJCC = American Joint Cancer Committee; AST = androgen suppression therapy. Data presented as median (interquartile range) or number (percent) unless otherwise indicated.
a similar risk of PSA recurrence compared with men with Gleason Score 9–10 disease (HR, 1.08; 95% CI, 0.60–1.94; p = 0.81). This was consistent with univariable analysis, which also showed that compared with men with Gleason Score 9–10 disease, those with Gleason Scores of 8 and 7 with tertiary Grade 5 disease had lower (HR, 0.72; 95% CI, 0.51–1.01; p = 0.06) and similar (HR, 0.96; 95% CI, 0.55– 1.70; p = 0.90) risks of PSA recurrence, respectively. Estimates of PSA failure stratified by Gleason score After a median follow-up of 5.7 years (IQR, 2.7–7.6 years), there were 154 PSA recurrences. As shown in Fig. 1, estimates of PSA recurrence were greater in men with Gleason Score 9–10 disease than in men with Gleason
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Score 8 disease (p = 0.03), but not significantly different from men with Gleason Score 7 with tertiary Grade 5 disease (p = 0.80). Similarly, PSA recurrence was greater in men with Gleason Score 7 with tertiary Grade 5 disease compared with men with Gleason Score 8 disease (p = 0.11), which approached statistical significance. Furthermore, men with Gleason Scores 9–10 and 7 with tertiary Grade 5 disease had median times to PSA failure of 4.5 and 5.0 years, both shorter than the 5.4 years for men with Gleason Score 8 disease, respectively. DISCUSSION Recent data have shown that time to PSA failure after radical prostatectomy or external beam radiation therapy with or without AST in men with Gleason Score 7 with tertiary Grade 5 disease is similar to that in men with Gleason Score 8–10 disease (10). As a result, patients with Gleason Score 7 with tertiary Grade 5 prostate cancer should be classified as having high-risk disease and treated accordingly. In the present study, we individually compared PSA outcomes in patients with high-risk disease to determine whether further stratification was warranted based on the presence or absence of any Grade 5 component. Our results provide evidence to support that men with any component of Gleason Grade 5 disease (i.e., those with Gleason Scores of 9, 10, or 7 with tertiary Grade 5) have a greater risk of PSA recurrence after definitive treatment than those with high-risk disease, but without a Grade 5 component (i.e., those with Gleason Score of 8). This finding, pending validation by others, may have important implications because it shows that high-risk prostate cancers with any component of Gleason Grade 5 disease behave differently than those without Gleason Pattern 5 after definitive treatment. As such, we recommend considering further stratification in high-risk patients by the presence or
Table 2. Unadjusted and adjusted hazard ratios of clinical factors describing the risk of PSA recurrence after definitive therapy Univariable analysis Covariate Gleason Score at biopsy 8 without Grade 5 7 with tertiary Grade 5 9–10 Age at time of treatment (/1-y increase) PSA at diagnosis (/1-ng/ml increase) Tumor stage at diagnosis T1c T2 T3 Type of treatment Radical prostatectomy Radiation therapy Radiation therapy + AST
Hazard ratio (95% confidence interval) 0.72 (0.51–1.01) 0.96 (0.55–1.70) 1 (reference)* 1.01 (0.99–1.03) 1.80 (1.51–2.13) 1 (reference)* 1.17 (0.82–1.67) 1.90 (1.05–3.42) 1.26 (0.78–2.04) 2.70 (1.67–4.36) 1 (reference)*
Multivariable analysis p 0.06 0.90
Hazard ratio (95% confidence interval)
p
0.27 <0.0001
0.74 (0.52–1.05) 1.08 (0.60–1.94) 1 (reference)* 1.00 (0.98–1.02) 1.87 (1.56–2.25)
0.97 <0.0001
0.40 0.03
1 (reference)* 1.20 (0.82–1.73) 1.37 (0.73–2.57)
0.35 0.33
0.35 <0.0001
Abbreviations: PSA = prostate-specific antigen; AST = androgen suppression therapy. * Reference group for the Cox regression analysis.
1.36 (0.79–2.34) 2.80 (1.70–4.62) 1 (reference)*
0.09 0.81
0.27 <0.0001
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Fig. 1. Estimates of prostate-specific antigen (PSA) recurrence stratified by Gleason score after radical prostatectomy or radiation therapy with or without androgen suppression therapy. Pairwise p values: Gleason Score 9–10 vs. 7 with tertiary Grade 5, p = 0.80; Gleason Score 9–10 vs. 8 (without Grade 5), p = 0.03; Gleason Score 7 with tertiary Grade 5 vs. 8 (without Grade 5), p = 0.12. After applying Bonferroni’s correction, p < 0.02 is statistically significant.
absence of a Grade 5 component. In other words, men with Gleason Score 8 (without Grade 5) disease would be in a subcategory distinct from those with Gleason Scores 9–10 and 7 with tertiary Grade 5 disease. This becomes especially important in the setting of future randomized trials as interest in testing novel systemic agents to standard management for high-risk patients becomes more widespread (2). Another implication of our findings pertains to the timing of AST for patients with Gleason Score 7 with tertiary Grade 5 disease. Radiation Therapy Oncology Group 92-02 compared short-term vs. long-term hormonal therapy in addition to definitive local radiation therapy in men with locally advanced prostate cancer and showed long-term significant differences in all outcomes (including cause-specific survival) except overall survival. However, subgroup analysis showed a significant survival benefit to long-term AST in men with Gleason Scores of 8–10 (19). Given our findings that Gleason Score 7 with tertiary Grade 5 disease behaves similarly to Gleason Score 9–10 disease and worse than Gleason Score 8 disease, we suggest that consideration be given to also placing this cohort of patients with locally advanced prostate cancer on long-term AST. This, of course, would need to be validated initially within a prospective setting before becoming standard practice. It is curious how a small component of Gleason Grade 5 in a man can lead to worse outcomes compared with others with larger components of Gleason Grade 4, possibly because of differences in biologic characteristics. Given that the vast majority of patients with Gleason Pattern 5 tumors do not
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undergo subsequent resection, evaluation of these tumors is limited to tissue available on routine biopsy. As such, it is possible that some tumors may be sampled inadequately and an important component of the tumor may not be available for evaluation. For example, high-grade neuroendocrine carcinomas (i.e., small-cell carcinomas) commonly occur in the setting of Gleason Pattern 5 disease and may not be sampled by means of routine biopsy alone. In addition, when only a small portion of a high-grade neuroendocrine carcinoma is sampled in a biopsy specimen that has Gleason Pattern 5 disease, it may not be as easy to recognize it as a separate component as it would in a resection specimen (20–25). In either of these settings, our conventional approach to treating these patients may be limited because the current paradigm has been optimized over the years for the treatment of patients with pure adenocarcinomas. Additional studies are required to address this issue more comprehensively. If our present findings of Gleason Pattern 5 as a distinct biologic entity are validated by others, this could provide impetus for a shift in our approach to high-risk patients, particularly when designing new clinical trials incorporating novel systemic agents. The general schema for such a future trial is shown in Fig. 2. Of note, patients would be stratified on the basis of the presence or absence of Gleason Grade 5 to better identify men with high-risk disease who benefit from the testing of novel therapeutic regimens. It is important to note that of patients treated with radiation with or without AST, the prescribed radiation dose was 70.2 Gy. Recent data (26, 27) indicate that radiation dose escalation is likely to have an important role in the combined-modality management of patients with localized, but high-risk, disease, and the relative importance of intensified local therapy needs to be fully explored in clinical trials incorporating novel systemic agents as well. An important limitation of our study is the sample size, which precluded a statistically significant difference in regression analyses between Gleason groups comparing the presence or absence of Grade 5 disease. Based on prior observations (28) and the near statistically significant results
Future Phase III Randomized Trial of Men with High-Risk Prostate Cancer Stratification by +/- Gleason Pattern 5 Disease Gleason Pattern 5 Gleason 8 (without grade 5) Randomize XRT + AST +/- (Docetaxelor novel systemic agent)
•Gleason 7 with tertiary grade 5 •Gleason 9 to 10 Randomize XRT + AST +/- (Docetaxelor novel systemic agent)
Fig. 2. Proposed randomized clinical trial of patients with high-risk prostate cancer with stratification by the presence or absence of Gleason Pattern 5 disease. XRT = external beam radiotherapy; AST = androgen suppression therapy.
Gleason Pattern 5 prostate cancer d A. NANDA et al.
achieved in the comparison of Kaplan-Meier plots between these groups, we are encouraged and look forward to additional studies that assess this finding. We would have liked to include men with Gleason Score of 8 with Grade 5 in our analyses, but these cases are too rare. Comparing PSA recurrence in this cohort of men with that in the present study would be particularly interesting because in many cases, these cancers are deemed Grade 5 because of necrosis rather than loss of architecture. Given such a small sample size, we also were unable to determine whether there was a difference in outcome between men with 3 + 4 = 7 or 4 + 3 = 7 with tertiary Grade 5 disease. We also believe that a longer follow-up period is needed to properly assess the clinically important end points of prostate cancer–specific and all-cause mortality. Future large prospective studies similar to those proposed also are required to ultimately validate our conclusions.
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In summary, in men with high-risk prostate cancer treated with definitive therapy, those with any component of Grade 5 disease had a shorter time to PSA failure than those without Grade 5 disease. These data emphasize the importance of substratifying the standard Gleason Score category of 8–10 into 8 vs. 9, 10, and 7 with tertiary Grade 5 for future randomized studies. They also suggest in conjunction with the recently reported long-term results of Radiation Therapy Oncology Group 92-02 that men with Gleason Score 7 with tertiary Grade 5 and locally advanced disease may benefit from long-term AST in addition to definitive radiation therapy. Our findings warrant further investigation in additional studies and different populations. Pending validation, we recommend that consideration be given to stratifying by the presence or absence of Grade 5 disease for future testing of the most appropriate systemic therapy.
REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96. 2. Mitchell RE, Chang SS. Current controversies in the treatment of high-risk prostate cancer. Curr Opin Urol 2008;18:263–268. 3. Polascik TJ, Mouraviev V. Focal therapy for prostate cancer. Curr Opin Urol 2008;18:269–274. 4. Cox J, Amling CL. Current decision making in prostate cancer therapy. Curr Opin Urol 2008;18:275–278. 5. Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 1974;111:58–64. 6. Bostwick DG. Gleason grading of prostatic needle biopsies. Correlation with grade in 316 matched prostatectomies. Am J Surg Pathol 1994;18:796–803. 7. Gleason DF. Histologic grading of prostate cancer: A perspective. Hum Pathol 1992;23:273–279. 8. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997;277:1445–1451. 9. Epstein JI, Allsbrook WC Jr, Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005;29:1228–1242. 10. Patel AA, Chen M, Renshaw AA, et al. PSA failure following definitive treatment of prostate cancer having biopsy Gleason score 7 with tertiary grade 5. JAMA 2007;298:1533–1538. 11. Whittemore DE, Hicks EJ, Carter MR, et al. Significance of tertiary Gleason pattern 5 in Gleason score 7 radical prostatectomy specimens. J Urol 2008;179:516–522. 12. Roach M III, Hanks G, Thames H Jr., et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965–974. 13. Cookson MS, Aus G, Burnett AL, et al. Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: The American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel Report and Recommendations for a Standard in the Reporting of Surgical Outcomes. J Urol 2007;177:540–545. 14. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation
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therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–974. Klein JP, Moeschberger ML, editors. Survival analysis. New York: Springer-Verlag; 1997. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. Wilcoxon F. Individual comparisons by ranking methods. Biometrics 1945;1:80–83. Shaffer JP. Multiple hypothesis testing. Annu Rev Psychol 1995;46:561–584. Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of Radiation Therapy Oncology Group Protocol 92-02: A phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26: 2498–2504. Epstein JI, Yang XJ. Prostate biopsy interpretation. 3rd ed. Philadelphia: Lippincott, Williams, & Wilkins; 2002. Yao JL, Madeb R, Bourne P, et al. Small cell carcinoma of the prostate: An immunohistochemical study. Am J Surg Pathol 2006;30:705–712. Anker CJ, Dechet C, Isaac J, et al. Small-cell carcinoma of the prostate. J Clin Oncol 2008;26:1168–1171. Slovin SF. Does small-cell phenotype predict the natural history of prostate cancer? A case study in disease behavior. Nat Clin Pract Oncol 2007;4:551–554. Inman BA, DiMarco DS, Slezak JM, et al. Outcomes of Gleason score 10 prostate carcinoma treated by radical prostatectomy. Urology 2006;68:604–608. Wang W, Epstein JI. Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am J Surg Pathol 2008;32:65–71. Stock RG, Cahlon O, Cesaretti JA, et al. Combined modality treatment in the management of high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2004;59:1352–1359. Stone NN, Potters L, Davis BJ, et al. Multicenter analysis of effect of high biologic effective dose on biochemical failure and survival outcomes in patients with Gleason Score 7-10 prostate cancer treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2009;73:341–346. Kattan MW, Zelefsky MJ, Kupelian PA, et al. Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer. J Clin Oncol 2003;21:4568–4571.
doi:10.1016/j.ijrobp.2008.10.027
CLINICAL INVESTIGATION
Prostate
GLEASON PATTERN 5 PROSTATE CANCER: FURTHER STRATIFICATION OF PATIENTS WITH HIGH-RISK DISEASE AND IMPLICATIONS FOR FUTURE RANDOMIZED TRIALS AKASH NANDA, M.D., PH.D.,* MING-HUI CHEN, PH.D.,y ANDREW A. RENSHAW, M.D.,z x AND ANTHONY V. D’AMICO, M.D., PH.D. * Harvard Radiation Oncology Program, Boston, MA; y Department of Statistics, University of Connecticut, Storrs, CT; z Department of Pathology, Baptist Hospital of Miami, Miami, FL; and x Department of Radiation Oncology, Brigham & Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA Purpose: To compare prostate-specific antigen (PSA) outcomes in a cohort of men with high-risk prostate cancer based on the presence or absence of any Gleason Grade 5 component (primary, secondary, or tertiary). Methods and Materials: Our study cohort consisted of 312 men with T1c–T3N0M0 prostate cancer with Gleason Scores of 7 with tertiary Grade 5, 8, or 9–10 who underwent radical prostatectomy or external beam radiotherapy with or without androgen suppression therapy. Cox regression multivariable analysis was used to assess whether a difference existed in risk of PSA recurrence in men with Gleason Score of 9–10 compared with those with Gleason Score of 8 and 7 with tertiary Grade 5, adjusting for treatment, age, and known prostate cancer prognostic factors. Results: After a median follow-up of 5.7 years, men with a Gleason Score of 8 had a lower risk of PSA recurrence than those with a Gleason Score of 9–10 (hazard ratio, 0.74; 95% confidence interval, 0.52–1.05; p = 0.09). Conversely, men with a Gleason Score of 7 with tertiary Grade 5 had a similar risk of PSA recurrence compared with men with a Gleason Score of 9–10 (hazard ratio, 1.08; 95% confidence interval, 0.60–1.94; p = 0.81). Median times to PSA failure for men with Gleason Scores of 9–10, 7 with tertiary Grade 5, and 8 were 4.5, 5.0, and 5.4 years, respectively. Conclusions: Our results highlight the importance of further substratification of the high-risk Gleason Score category of 8–10 into 8 vs. 9, 10, and 7 with tertiary Grade 5. Ó 2009 Elsevier Inc. Prostate cancer, Prostate-specific antigen (PSA), Gleason score, Tertiary Grade 5, Stratification.
INTRODUCTION Prostate cancer is the most commonly diagnosed solid tumor in men in the United States, with an annual incidence of 186,320 (1). Treatment of patients with prostate cancer is based on the extent of disease (2–4). The Gleason grade represents a major component in stratifying patients for therapy. Although the Gleason scoring system is based solely on architectural features of prostate cancer cells, with inherent limitations, it has a strong track record of predicting outcome and has become the most widely used grading method throughout the world (5, 6). According to the Gleason scoring system, tumor cells initially are examined under low-power magnification and graded from 1 to 5, with 5 the least differentiated. An overall score then is assigned based on the numerical composite of the two most abundant patterns in the tumor specimen (7).
Notwithstanding other important clinical factors, Gleason Scores of 6 or less, 7, and 8 or higher traditionally have represented disease categorized as low, intermediate, and high risk, respectively (8). Although historically, tertiary patterns were not formally incorporated into the overall scoring system, there has been a great deal of interest in addressing the prognostic significance of tertiary Grade 5 disease within the setting of Gleason Score 7 prostate cancer. In 2005, the International Society of Urologic Pathology consensus conference recommended that Gleason Scores of 3 + 4 and 4 + 3 with tertiary Grade 5 disease be reclassified as Gleason Scores 8 and 9, respectively (9). Additionally, recent studies have shown that patients with a Gleason Score of 7 with tertiary Grade 5 disease had a greater risk of prostate-specific antigen (PSA) failure and likelihood of having more advanced pathologic stage than those with Gleason Score of 7 without tertiary Grade 5 disease (10, 11).
Reprint requests to: Akash Nanda, M.D., Ph.D., Harvard Radiation Oncology Program, Brigham & Women’s Hospital, 75 Francis Street, ASB1 L2, Boston, MA 02115. Tel: (617) 732-6310; Fax: (617) 975-0932; E-mail: [email protected] Presented in part at the American Society for Therapeutic Radiol-
ogy and Oncology (ASTRO) 50th Annual Meeting, September 21– 25, 2008, Boston, MA. Conflict of interest: none. Received Aug 21, 2008, and in revised form Sept 26, 2008. Accepted for publication Oct 7, 2008. 1419
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Given such findings, it is reasonable to question whether Gleason Pattern 5 represents a unique biologic entity with important implications for both staging and therapeutic considerations. It is plausible that in patients with high-risk prostate cancer, further stratification based on the presence or absence of Grade 5 disease may optimize outcome prediction and better identify men for entry into clinical trials in which survival after the addition of novel systemic agents to standard management compared with the standard of care could be tested. To this end, in the present study, we compare PSA outcomes in men with high-risk prostate cancer based on the presence or absence of Grade 5 disease. METHODS AND MATERIALS Patient characteristics and treatment The study cohort included 312 men with clinical tumor (T) category T1c–T3 node-negative nonmetastatic adenocarcinoma of the prostate with Gleason Scores of 7 with tertiary Grade 5, 8 (without Grade 5), or 9–10 treated between 1989 and 2005 at Harvard-affiliated institutions (St. Anne’s Hospital, Brigham & Women’s Hospital, and the Dana-Farber Cancer Institute). Cases of Gleason Score of 8 with Grade 5 prostate cancer are exceedingly rare and therefore were excluded from the present study. The incidence of a tertiary Grade 5 component in the setting of Gleason Score 7 disease within our extended database was approximately 3.5%. Patients were treated by using radical prostatectomy (n = 127), radiation therapy (n = 104), or radiation therapy with 2 months each of neoadjuvant, concurrent, and adjuvant androgen suppression therapy (AST; n = 81). Patients were excluded if they had undergone radical prostatectomy and received preoperative or postoperative AST or adjuvant radiation therapy. The study was performed with the approval of the institutional review board of the participating institutions. For our analyses, all Gleason scores were reviewed and assigned by a single pathologist (A.A.R.) who has expertise in grading cancers of the genitourinary tract. In all patients, radical prostatectomy consisted of a radical retropubic prostatectomy with bilateral lymph node sampling. Radiation therapy was delivered by using shaped blocks based on the computed tomography–defined volumes transferred onto pelvic plain films before 1994, and thereafter, computed tomography–based three-dimensional conformal treatment planning was used. A total dose of 70.2 Gy was administered consistently. Adjuvant AST was achieved by using combined blockade with a luteinizing hormone–releasing hormone agonist (leuprolide or goserelin) and a nonsteroidal antiandrogen (bicalutamide or flutamide). Injections of leuprolide (7.5 mg/mo) or goserelin (3.6 mg/mo) were given in either 1- or 3-month formulations. Bicalutamide (50 mg/d) or flutamide (250 mg every 8 hours) were administered orally starting 1–3 days before luteinizing hormone–releasing hormone agonist therapy initiation to block the transient testosterone surge.
Follow-up Median follow-up was 5.7 years (interquartile range [IQR], 2.7– 7.6) with censoring occurring at the time of PSA failure, beginning on the date of radical prostatectomy or initiation of other therapy and concluding on March 8, 2005 (when our database was last updated), or date of death, whichever was earlier. Routine follow-up included serum PSA measurement followed by a digital rectal examination generally every 3 months for 2 years, then every 6 months for an additional 3 years, and annually thereafter. The PSA recurrence after
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radiation therapy (with or without AST) was defined as the date at which PSA levels became 2 ng/ml greater than the nadir according to the 2006 consensus definition of the American Society for Therapeutic Radiology and Oncology (12). The PSA recurrence for surgical patients was defined on the date at which PSA level became greater than 0.2 ng/ml, with a second confirmatory value greater than 0.2 ng/ml (13).
Statistical methods Time to PSA failure analyses. Descriptive statistics were used to define the patient population at baseline. Cox regression univariable and multivariable analyses were performed with the primary end point of time to PSA failure after the end of treatment. Gleason score, tumor category, and treatment modality were analyzed as categorical variables, whereas age and PSA level were considered as continuous variables. For categorical variables, cutoff points were defined before analyzing the data, according to established strata (10, 14). These categories included Gleason Scores 8 (without Grade 5); 7 with tertiary Grade 5; and 9–10; clinical T category T1c, T2, and T3; and treatment with radical prostatectomy, radiation therapy plus AST, or radiation therapy. Baseline groups were Gleason Score of 9–10, clinical T category of T1c, and treatment group radiation therapy plus AST. For all Cox regression analyses, the assumptions of the proportional hazards model were tested and met, and all statistical tests were two sided. Adjusted and unadjusted hazard ratios (HRs) for PSA recurrence with the associated 95% confidence intervals (CIs) were calculated for all covariates (15). Estimates of PSA failure stratified by Gleason score. For the purpose of illustration, estimates of time to PSA recurrence after treatment and stratified by the categorical covariate of Gleason score were displayed, and these estimates were made by using the method of Kaplan and Meier (16). These estimates were compared by using Wilcoxon’s test, which weights time to PSA failure by the number of men at risk (17). Adjustment for multiple comparisons was made with the use of Bonferroni’s correction (18). Given a total of three comparisons, a two-sided p # 0.02 was considered statistically significant. Median time to PSA recurrence was calculated by using the Kaplan-Meier estimator and described. All statistical analyses were performed using SAS, Version 9.1.3 (SAS Institute Inc., Cary, NC).
RESULTS Clinical characteristics of the study cohort As listed in Table 1, median age of the 312 men who comprised the study cohort at the time of initial therapy was 68 years (IQR, 62–73 years). Median PSA level was 8.9 ng/ml (IQR, 5.9–15.5 ng/ml). The distribution of the men by Gleason score was 167 (53.5%) with Gleason Score of 8, 36 (11.5%) with Gleason Score of 7 with tertiary Grade 5, and 109 (35.0%) with Gleason Score of 9–10. Predictors of time to PSA failure As listed in Table 2, after adjusting for treatment received, age, and known prostate cancer prognostic factors, including PSA level and tumor T category, Cox regression multivariable analysis showed that men with Gleason Score 8 disease had a lower risk of PSA recurrence than those with Gleason Score 9–10 disease (HR, 0.74; 95% CI, 0.52–1.05; p = 0.09), which approached statistical significance. Conversely, men with Gleason Score 7 with tertiary Grade 5 disease had
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Table 1. Baseline clinical characteristics of study cohort Characteristic Age (y) Baseline PSA (ng/ml) Gleason Score at biopsy 8 without Grade 5 7 with tertiary Grade 5 9–10 1992 AJCC clinical tumor category T1c T2a T2b T2c T3 Treatment modality Radical prostatectomy External beam radiation External beam radiation + AST
Patients (N = 312) 68 (62–73) 8.9 (5.9–15.5) 167 (53.5) 36 (11.5) 109 (35.0) 112 (35.9) 74 (23.7) 61 (19.6) 38 (12.2) 27 (8.6) 127 (40.7) 104 (33.3) 81 (26.0)
Abbreviations: PSA = prostate-specific antigen; AJCC = American Joint Cancer Committee; AST = androgen suppression therapy. Data presented as median (interquartile range) or number (percent) unless otherwise indicated.
a similar risk of PSA recurrence compared with men with Gleason Score 9–10 disease (HR, 1.08; 95% CI, 0.60–1.94; p = 0.81). This was consistent with univariable analysis, which also showed that compared with men with Gleason Score 9–10 disease, those with Gleason Scores of 8 and 7 with tertiary Grade 5 disease had lower (HR, 0.72; 95% CI, 0.51–1.01; p = 0.06) and similar (HR, 0.96; 95% CI, 0.55– 1.70; p = 0.90) risks of PSA recurrence, respectively. Estimates of PSA failure stratified by Gleason score After a median follow-up of 5.7 years (IQR, 2.7–7.6 years), there were 154 PSA recurrences. As shown in Fig. 1, estimates of PSA recurrence were greater in men with Gleason Score 9–10 disease than in men with Gleason
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Score 8 disease (p = 0.03), but not significantly different from men with Gleason Score 7 with tertiary Grade 5 disease (p = 0.80). Similarly, PSA recurrence was greater in men with Gleason Score 7 with tertiary Grade 5 disease compared with men with Gleason Score 8 disease (p = 0.11), which approached statistical significance. Furthermore, men with Gleason Scores 9–10 and 7 with tertiary Grade 5 disease had median times to PSA failure of 4.5 and 5.0 years, both shorter than the 5.4 years for men with Gleason Score 8 disease, respectively. DISCUSSION Recent data have shown that time to PSA failure after radical prostatectomy or external beam radiation therapy with or without AST in men with Gleason Score 7 with tertiary Grade 5 disease is similar to that in men with Gleason Score 8–10 disease (10). As a result, patients with Gleason Score 7 with tertiary Grade 5 prostate cancer should be classified as having high-risk disease and treated accordingly. In the present study, we individually compared PSA outcomes in patients with high-risk disease to determine whether further stratification was warranted based on the presence or absence of any Grade 5 component. Our results provide evidence to support that men with any component of Gleason Grade 5 disease (i.e., those with Gleason Scores of 9, 10, or 7 with tertiary Grade 5) have a greater risk of PSA recurrence after definitive treatment than those with high-risk disease, but without a Grade 5 component (i.e., those with Gleason Score of 8). This finding, pending validation by others, may have important implications because it shows that high-risk prostate cancers with any component of Gleason Grade 5 disease behave differently than those without Gleason Pattern 5 after definitive treatment. As such, we recommend considering further stratification in high-risk patients by the presence or
Table 2. Unadjusted and adjusted hazard ratios of clinical factors describing the risk of PSA recurrence after definitive therapy Univariable analysis Covariate Gleason Score at biopsy 8 without Grade 5 7 with tertiary Grade 5 9–10 Age at time of treatment (/1-y increase) PSA at diagnosis (/1-ng/ml increase) Tumor stage at diagnosis T1c T2 T3 Type of treatment Radical prostatectomy Radiation therapy Radiation therapy + AST
Hazard ratio (95% confidence interval) 0.72 (0.51–1.01) 0.96 (0.55–1.70) 1 (reference)* 1.01 (0.99–1.03) 1.80 (1.51–2.13) 1 (reference)* 1.17 (0.82–1.67) 1.90 (1.05–3.42) 1.26 (0.78–2.04) 2.70 (1.67–4.36) 1 (reference)*
Multivariable analysis p 0.06 0.90
Hazard ratio (95% confidence interval)
p
0.27 <0.0001
0.74 (0.52–1.05) 1.08 (0.60–1.94) 1 (reference)* 1.00 (0.98–1.02) 1.87 (1.56–2.25)
0.97 <0.0001
0.40 0.03
1 (reference)* 1.20 (0.82–1.73) 1.37 (0.73–2.57)
0.35 0.33
0.35 <0.0001
Abbreviations: PSA = prostate-specific antigen; AST = androgen suppression therapy. * Reference group for the Cox regression analysis.
1.36 (0.79–2.34) 2.80 (1.70–4.62) 1 (reference)*
0.09 0.81
0.27 <0.0001
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Fig. 1. Estimates of prostate-specific antigen (PSA) recurrence stratified by Gleason score after radical prostatectomy or radiation therapy with or without androgen suppression therapy. Pairwise p values: Gleason Score 9–10 vs. 7 with tertiary Grade 5, p = 0.80; Gleason Score 9–10 vs. 8 (without Grade 5), p = 0.03; Gleason Score 7 with tertiary Grade 5 vs. 8 (without Grade 5), p = 0.12. After applying Bonferroni’s correction, p < 0.02 is statistically significant.
absence of a Grade 5 component. In other words, men with Gleason Score 8 (without Grade 5) disease would be in a subcategory distinct from those with Gleason Scores 9–10 and 7 with tertiary Grade 5 disease. This becomes especially important in the setting of future randomized trials as interest in testing novel systemic agents to standard management for high-risk patients becomes more widespread (2). Another implication of our findings pertains to the timing of AST for patients with Gleason Score 7 with tertiary Grade 5 disease. Radiation Therapy Oncology Group 92-02 compared short-term vs. long-term hormonal therapy in addition to definitive local radiation therapy in men with locally advanced prostate cancer and showed long-term significant differences in all outcomes (including cause-specific survival) except overall survival. However, subgroup analysis showed a significant survival benefit to long-term AST in men with Gleason Scores of 8–10 (19). Given our findings that Gleason Score 7 with tertiary Grade 5 disease behaves similarly to Gleason Score 9–10 disease and worse than Gleason Score 8 disease, we suggest that consideration be given to also placing this cohort of patients with locally advanced prostate cancer on long-term AST. This, of course, would need to be validated initially within a prospective setting before becoming standard practice. It is curious how a small component of Gleason Grade 5 in a man can lead to worse outcomes compared with others with larger components of Gleason Grade 4, possibly because of differences in biologic characteristics. Given that the vast majority of patients with Gleason Pattern 5 tumors do not
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undergo subsequent resection, evaluation of these tumors is limited to tissue available on routine biopsy. As such, it is possible that some tumors may be sampled inadequately and an important component of the tumor may not be available for evaluation. For example, high-grade neuroendocrine carcinomas (i.e., small-cell carcinomas) commonly occur in the setting of Gleason Pattern 5 disease and may not be sampled by means of routine biopsy alone. In addition, when only a small portion of a high-grade neuroendocrine carcinoma is sampled in a biopsy specimen that has Gleason Pattern 5 disease, it may not be as easy to recognize it as a separate component as it would in a resection specimen (20–25). In either of these settings, our conventional approach to treating these patients may be limited because the current paradigm has been optimized over the years for the treatment of patients with pure adenocarcinomas. Additional studies are required to address this issue more comprehensively. If our present findings of Gleason Pattern 5 as a distinct biologic entity are validated by others, this could provide impetus for a shift in our approach to high-risk patients, particularly when designing new clinical trials incorporating novel systemic agents. The general schema for such a future trial is shown in Fig. 2. Of note, patients would be stratified on the basis of the presence or absence of Gleason Grade 5 to better identify men with high-risk disease who benefit from the testing of novel therapeutic regimens. It is important to note that of patients treated with radiation with or without AST, the prescribed radiation dose was 70.2 Gy. Recent data (26, 27) indicate that radiation dose escalation is likely to have an important role in the combined-modality management of patients with localized, but high-risk, disease, and the relative importance of intensified local therapy needs to be fully explored in clinical trials incorporating novel systemic agents as well. An important limitation of our study is the sample size, which precluded a statistically significant difference in regression analyses between Gleason groups comparing the presence or absence of Grade 5 disease. Based on prior observations (28) and the near statistically significant results
Future Phase III Randomized Trial of Men with High-Risk Prostate Cancer Stratification by +/- Gleason Pattern 5 Disease Gleason Pattern 5 Gleason 8 (without grade 5) Randomize XRT + AST +/- (Docetaxelor novel systemic agent)
•Gleason 7 with tertiary grade 5 •Gleason 9 to 10 Randomize XRT + AST +/- (Docetaxelor novel systemic agent)
Fig. 2. Proposed randomized clinical trial of patients with high-risk prostate cancer with stratification by the presence or absence of Gleason Pattern 5 disease. XRT = external beam radiotherapy; AST = androgen suppression therapy.
Gleason Pattern 5 prostate cancer d A. NANDA et al.
achieved in the comparison of Kaplan-Meier plots between these groups, we are encouraged and look forward to additional studies that assess this finding. We would have liked to include men with Gleason Score of 8 with Grade 5 in our analyses, but these cases are too rare. Comparing PSA recurrence in this cohort of men with that in the present study would be particularly interesting because in many cases, these cancers are deemed Grade 5 because of necrosis rather than loss of architecture. Given such a small sample size, we also were unable to determine whether there was a difference in outcome between men with 3 + 4 = 7 or 4 + 3 = 7 with tertiary Grade 5 disease. We also believe that a longer follow-up period is needed to properly assess the clinically important end points of prostate cancer–specific and all-cause mortality. Future large prospective studies similar to those proposed also are required to ultimately validate our conclusions.
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In summary, in men with high-risk prostate cancer treated with definitive therapy, those with any component of Grade 5 disease had a shorter time to PSA failure than those without Grade 5 disease. These data emphasize the importance of substratifying the standard Gleason Score category of 8–10 into 8 vs. 9, 10, and 7 with tertiary Grade 5 for future randomized studies. They also suggest in conjunction with the recently reported long-term results of Radiation Therapy Oncology Group 92-02 that men with Gleason Score 7 with tertiary Grade 5 and locally advanced disease may benefit from long-term AST in addition to definitive radiation therapy. Our findings warrant further investigation in additional studies and different populations. Pending validation, we recommend that consideration be given to stratifying by the presence or absence of Grade 5 disease for future testing of the most appropriate systemic therapy.
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