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Impact of the Percentage of Positive Prostate Cores on Prostate Cancer–Specific Mortality for Patients With Low or Favorable Intermediate-Risk Disease

From the Department of Radiation Oncology and Pathology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA; and Department of Statistics, University of Connecticut, Storrs, CT

Address reprint requests to Anthony V. D'Amico, MD, PhD, Brigham and Women's Hospital, Department of Radiation Oncology, 75 Francis St, L-2 Level, Boston, MA 02215; e-mail: adamico{at}lroc.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: We investigated whether pretreatment factors predicted time to prostate cancer–specific mortality (PCSM) after conventional-dose and conformal radiation therapy (CRT).

PATIENTS AND METHODS: Between 1988 and 2002, 421 patients with low (prostate-specific antigen [PSA] level 10 ng/mL and biopsy Gleason score 6) or favorable intermediate-risk (PSA > 10 to 15 ng/mL or biopsy Gleason score 3 + 4, but not both factors) disease underwent CRT (median dose, 70.4 Gy). Cox regression multivariable analysis was performed to determine whether the PSA level, Gleason score, T category, or the percentage of positive cores (% PC) predicted time to PCSM after CRT. After a median follow-up of 4.5 years, 117 (28%) patients have died.

RESULTS: The % PC was the only significant predictor (Cox P .03). The relative risk of PCSM after CRT for patients with 50% as compared with less than 50% PC was 10.4 (95% CI, 1.2 to 87; Cox P = .03), 6.1 (95% CI, 1.3 to 28.6; Cox P = .02), and 12.5 (95% CI, 1.5 to 107; Cox P = .02) in men with a PSA 10 and Gleason score 6, PSA 10 and Gleason score 7, and PSA 15 and Gleason score 6, respectively. By 5 years after CRT, 5% to 9% compared with less than 1% (log-rank P .01) of these patients experienced PCSM if they had 50% compared with less than 50% PC, respectively.

CONCLUSION: CRT dose-escalation techniques, the addition of hormonal therapy, or both should be considered in the management of patients with low or favorable intermediate-risk disease and 50% PC.

	INTRODUCTION

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Although prostate-specific antigen (PSA) failure occurs after radical prostatectomy (RP) or external-beam radiation therapy (RT) for patients with clinically localized prostate cancer diagnosed during the PSA era, a minority (12% to 20%) of these patients subsequently experience prostate cancer–specific mortality (PCSM).¹ Pretreatment risk groups based on the baseline PSA level, biopsy Gleason score, and clinical T category have been constructed and shown to predict time to PCSM after RP or RT. Specifically, in a prior study² of 7,316 patients treated in the United States at 44 institutions with either RP (n = 4,946) or RT (n = 2,370), evidence was provided to support the prediction of time to PCSM after RP or RT based on pretreatment risk group.

The percentage of positive cores (% PC) has been previously shown to provide additional information to the pretreatment risk group regarding time to PSA failure after RP³ or RT.⁴ However, whether the % PC also adds information to the pretreatment risk group regarding time to PCSM after RT monotherapy is unknown. High-risk (PSA > 20 ng/mL or biopsy Gleason score of 8 to 10) and more advanced intermediate-risk (PSA > 15 to 20 ng/mL and biopsy Gleason score of 7) patients are infrequently considered for RT monotherapy given the survival benefit shown in prior studies of RT plus androgen suppression therapy (AST) as compared with RT for patients with locally advanced prostate cancer.⁵

Therefore, the purpose of this study was to determine whether the % PC provided additional information regarding time to PCSM after RT in patients who would be offered RT as monotherapy controlling for the PSA level, biopsy Gleason score, and clinical T category at diagnosis. Therefore, the study cohort assembled to address this issue were men with low- or favorable intermediate-risk disease.

	PATIENTS AND METHODS

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Patient Selection and Treatment
Four hundred twenty-one men treated with conformal RT (CRT) between 1988 and 2002 at a Harvard community outreach Hospital (St Anne's Hospital, Fall River, MA) for clinically localized (T1c to T2) and low- (PSA 10 ng/mL and biopsy Gleason score 6) or favorable intermediate-risk (PSA > 10 to 15 ng/mL or biopsy Gleason score of 3 + 4, but not both factors) disease comprised the study cohort. Patients with a PSA level greater than 15 ng/mL, a biopsy Gleason score of 4 + 3 or higher, or evidence of perineural invasion on biopsy were excluded. In addition, patients who had fragmentation of their biopsy specimen (n = 57) were also excluded. A human investigations committee–approved consent form was obtained for each study patient to permit the collection and analysis of de-identified baseline, treatment, and follow-up information. The median age of study cohort at the time of initial therapy was 71.9 years (range, 44.9 to 89.6 years). The pretreatment clinical characteristics of all study patients stratified by the PSA and Gleason score at diagnosis are listed in Table 1.

View this table: [in this window] [in a new window]   Table 1. Percentage Distribution* of the Pretreatment Clinical Characteristics of the 421 Patients Comprising the Study Cohort Stratified by PSA Level and Biopsy Gleason Score at Diagnosis

Staging
In all cases, staging evaluation involved a history and physical examination, including a digital rectal examination (DRE), serum PSA, and a transrectal ultrasound-guided needle biopsy of the prostate, with Gleason score histologic grading⁶ reviewed by a single genitourinary pathologist (A.A.R.). Patients whose cancer was diagnosed during a transurethral resection of the prostate were excluded. The prostate biopsy was performed using an 18-gauge Tru-Cut needle (Travenol Laboratories, Chantilly, VA) via a transrectal approach. The minimum and median number of cores sampled was six, with a range from six to 16 cores. Before 1996, patients generally had a computed tomography scan of the pelvis and bone scan. After 1996, patients with both a pretreatment PSA level less than 10 ng/mL and a biopsy Gleason score 6 did not generally undergo radiologic staging because of the less than 1% chance that these studies would reveal metastatic disease.⁷ The clinical stage was obtained from the DRE findings using the 2002 American Joint Commission on Cancer (AJCC) staging system.⁸ Radiologic and biopsy information were not used to determine clinical stage. All PSA measurements were made using the Hybritech (San Diego, CA), Tosoh (Foster City, CA), or Abbott (Chicago, IL) assays.

Follow-Up
The median time interval between diagnosis and the start of three-dimensional CRT was 2 months (range, 1 to 3 months). The median follow-up for the entire study cohort of 421 patients was 4.5 years (range, 0.4 to 13.0 years) using the last day of three-dimensional CRT as time zero. There were no patients lost to follow-up. Before PSA failure, which was defined using the American Society for Therapeutic Radiology and Oncology consensus criteria,⁹ patients generally had a serum PSA measurement and DRE performed every 3 months for 2 years, then every 6 months for 3 additional years, and then annually thereafter. There were 117 deaths occurring after PSA failure was sustained, 15 of which were from prostate cancer. No patient died of prostate cancer before PSA failure.

Determination of the Cause of Death
To be considered to have died of prostate cancer, the patient needed to have developed documented (ie, positive bone scan) metastatic disease and experienced biochemical disease progression despite having exhausted all known hormonal manipulations and was currently undergoing or had previously received cytotoxic chemotherapy. Patients also needed to have either clinical evidence of prostate cancer progression despite chemotherapy at the time of death or were enrolled in a hospice program for end-stage prostate cancer at the time of death. As a result, no patient was scored as dying of prostate cancer unless he had progressive hormone-refractory metastatic prostate cancer.

Statistical Methods
A Cox regression multivariable analysis¹⁰ was performed to determine whether the PSA level, biopsy Gleason score, 2002 AJCC clinical T category, or the % PC predicted time to PCSM after CRT for patients with low- or favorable intermediate-risk prostate cancer. Given that prior clinical utility has been shown in predicting time to PSA failure after RP or RT for the % PC using a breakpoint of 50%,^3,4 this breakpoint was used in this study. The PSA level and biopsy Gleason score were evaluated as dichotomous variables, using the cut points of PSA 10 ng/mL versus more than 10 ng/mL to 15 ng/mL and the biopsy Gleason score 6 versus 3 + 4. Therefore, the baseline groups for the dichotomous variables were classic low-risk and were represented by % PC less than 50%, PSA 10 ng/mL, and Gleason score 6. The 2002 AJCC tumor category was evaluated as a categoric variable, where T1c and T2a were the baseline group to which T2c and T2b were compared.

The relative risk of PCSM with its associated 95% CI were derived from the Cox model for each pretreatment clinical predictor and calculated for three patient groups. In addition, an evaluation for interaction effects among the pretreatment predictors, when assessable, was performed. The three patient groups were defined based on the PSA and biopsy Gleason score at diagnosis and were low-risk (PSA 10 ng/mL and Gleason score 6) and two additional groups that also included favorable intermediate-risk (PSA 10 ng/mL and Gleason score 3 + 4, and PSA 15 and Gleason 6 score) patients. These three groups were selected because it is common clinical practice in the United States based on the National Comprehensive Cancer Network¹¹ guidelines to offer low-risk patient and the favorable intermediate-risk patient local-only therapy.

For all analyses, the assumptions of the Cox model were tested and satisfied. Estimates of PCSM were calculated using the cumulative incidence method.¹² Comparisons of PCSM were evaluated using a two-sided log-rank P value. For the purpose of illustration, the relative contributions of PCSM and non-PCSM to all-cause mortality are displayed stratified by the pretreatment factors that were significant predictors of time to PCSM after CRT for each of the three patient groups.

	RESULTS

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Relative Risk of Cancer-Specific Mortality by % PC
At a median follow-up of 4.5 years, 117 (28%) of 421 patients had died, and of the 117 deaths, 15 (13%) were from prostate cancer. The % PC was the only significant predictor (Cox P .03) of time to PCSM after RT. The results of the Cox regression multivariable analyses in which PSA was treated as a categoric variable are listed in Table 2. No significant interaction effects were noted among the pretreatment clinical predictors. The relative risk of PCSM after CRT for patients with 50% as compared with less than 50% PPB was 10.4 (95% CI, 1.2 to 87; Cox P = .03), 6.1 (95% CI, 1.3 to 28.6; Cox P = .02), and 12.5 (95% CI, 1.5 to 107; Cox P = .02) in men with a PSA 10 and Gleason score 6, PSA 10 and Gleason score 3 + 4, and PSA 15 and Gleason 6 score, respectively.

View larger version (24K): [in this window] [in a new window]   Fig 1. Prostate cancer–specific mortality after radiation therapy (RT) and stratified by percentage of positive cores of 50% versus < 50% for patients with a prostate-specific antigen level 10 and Gleason score of 6 at diagnosis. Log-rank P = .008.

View larger version (24K): [in this window] [in a new window]   Fig 3. Prostate cancer–specific mortality after radiation therapy (RT) and stratified by percentage of positive cores of 50% versus < 50% for patients with a prostate-specific antigen level 15 and Gleason score of 6 at diagnosis. Log-rank P = .01.

View larger version (35K): [in this window] [in a new window]   Fig 4. The relative contributions of prostate cancer–specific mortality (PCSM) in blue and non-PCSM in red after radiation therapy (RT) to all-cause mortality stratified by the percentage of positive prostate biopsies and the prostate-specific antigen (PSA) level and biopsy Gleason score at diagnosis. (A) PSA 10 and Gleason 6; (B) PSA 15 and Gleason 6; (C) PSA 10 and Gleason 7.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

In this study, the prognostic significance of the PSA level, biopsy Gleason score, 2002 AJCC clinical T category, and % PC was investigated in men with low- or favorable intermediate-risk disease whose median age at the time of RT was 71.9 years. Only the % PC was found to be significantly associated with the time to PCSM after CRT (Cox P .03). Moreover, despite the advanced age at the time of treatment and the large contribution to all-cause death from causes other than prostate cancer (102 [87%] of 117 patients) as noted in Figure 4, the relative risk of PCSM was significantly higher (six- to 12-fold) in men with % PC of 50% as compared with less than 50%. This translated into PCSM rates that ranged from 5% to 9% as compared with less than 1% by 8 years after RT for men with % PC of 50% as compared with less than 50%, respectively, as shown in Figures 1 through 3. In addition, this study also found that for patients managed during the PSA era, the 2002 AJCC clinical T category was not significantly associated with the time to PCSM after RT when considered in conjunction with the % PC, PSA level, and biopsy Gleason score, as shown in Table 2.

There are two factors that may explain the increased risk of PCSM in patients with low- or favorable intermediate-risk disease and 50% PC as compared with less than 50% PC. A direct association has been shown between % PC and tumor volume.¹⁴ As a result, in a patient with % PC of 50%, the tumor volume present may not be adequately addressed by the median RT dose administered in this study, being a conventional dose of 70.4 Gy. Therefore, persistent local disease may serve as the nidus for dissemination and eventual PCSM. In addition, given that an increasing % PC has also been shown to be directly correlated with prostatectomy stage¹⁵ and upgrading,¹⁶ a patient with % PC of 50% as compared with 50% or less is more likely to be have occult seminal vesicle invasion or undersampled Gleason score 4 + 4 or higher disease. Both of these adverse factors have been shown to be associated with a shorter time to distant failure after radical prostatectomy,¹⁷ and therefore these patients are at higher risk of harboring occult micrometastatic disease at diagnosis. Therefore, both inadequately addressed local and occult micrometastatic disease may account for the increased risk of PCSM in otherwise low- or favorable intermediate-risk patients with 50% PC as compared with those who have less than 50% PC.

There are several points that require clarification. First, the predictions of PCSM using the % PC in this study are only applicable to patients with clinically localized low- or favorable intermediate-risk prostate cancer undergoing conventional-dose CRT and not RT plus AST. If future studies document a survival benefit for the addition of AST to RT for patients with clinically localized disease, as has been shown for patients with locally advanced prostate cancer,⁵ then the ability of the % PPB to predict the time to PCSM after RT plus AST would need to be evaluated. Perhaps with the addition of AST to RT, the difference in time to PCSM noted in this study may be lost, which could be due to the impact of AST on both local control and occult micrometastatic disease. Second, the impact that % PC has on the time to PCSM after surgery or dose-escalated CRT in the form or external-beam, brachytherapy, or the combination in patients with low- or favorable intermediate-risk disease remains to be studied. It is possible that approaches that improve local control for patients with high biopsy volume and low- or favorable intermediate-risk disease may eliminate or reduce the difference noted in this study in the time to PCSM after treatment when stratified by the % PC. Third, at the time of this analysis, 15 patients had experienced PCSM, and therefore, it is possible that with more events, other predictors may emerge, such as PSA greater than 10 to 15 ng/mL, for which P value was .11 in this study. Fourth, prior studies have shown a significant association with other measures of the tumor extent in the needle cores and either pathologic stage and/or the time to PSA failure after surgery. These measures include the total percentage of needle biopsy tissue involved by carcinoma,¹⁵ the greatest percentage of one core involved by carcinoma,¹⁸ and the total linear millimeters of carcinoma.^18,19 Whether these measures are also associated with the time to PCSM after RT require further study. Finally, whether the specific treatment(s) individual patients received after PSA failure impacted on time to PCSM remains unknown and requires clarification in future studies.

In conclusion, there was a significant increase in relative risk (six- to 12-fold) of PCSM after CRT delivered to a median dose of 70.4 Gy for patients in this study who had 50% as compared with less than 50% PC. Therefore, CRT dose-escalation techniques or the addition of hormonal therapy should be considered in the management of patients with low- or favorable intermediate-risk disease and 50% PC.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

View larger version (25K): [in this window] [in a new window]   Fig 2. Prostate cancer–specific mortality after radiation therapy (RT) and stratified by percentage of positive cores of 50% versus < 50% for patients with a prostate-specific antigen level 10 and Gleason score of 3 + 4 at diagnosis. Log-rank P = .008.

	NOTES

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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2. D'Amico AV, Moul J, Carroll P, et al: Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol 21:2163-2172, 2003[Abstract/Free Full Text]

3. D'Amico AV, Whittington R, Malkowicz SB, et al: The clinical utility of the percentage of positive prostate biopsies in defining biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer. J Clin Oncol 18:1164-1172, 2000[Abstract/Free Full Text]

4. D'Amico AV, Schultz D, Silver B, et al: The clinical utility of the percent of positive prostate biopsies in predicting biochemical outcome following external beam radiation therapy for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 49:679-684, 2001[CrossRef][Medline]

5. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomised trial. Lancet 360:103-106, 2002[CrossRef][Medline]

6. Gleason DF: Histologic grading and staging of prostatic carcinoma, in Tannenbaum M (ed): Urologic Pathology. Philadelphia, PA, Lea & Febiger, 1977, pp 171-187

7. Lee CT, Oesterling JE: Using prostate-specific antigen to eliminate the staging radionuclide bone scan. Urol Clin North Am 24:389-394, 1997[CrossRef][Medline]

8. Greene FL, Page DL, Fleming ID, et al: American Joint Committee on Cancer: Manual for Staging Cancer (ed 6). New York, NY, Springer-Verlag, 2002, pp 337-346

9. Cox JD: Consensus statement: Guidelines for PSA following radiation therapy—American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997[CrossRef][Medline]

10. Klein JP, Moeschberger ML (eds): Survival Analysis. New York, NY, Springer-Verlag, 1997, pp 229-263

11. Bahnson RR, Hanks GE, Huben RP, et al: NCCN practice guidelines for prostate cancer. Oncology (Huntingt) 14:111-119, 2000

12. Gaynor JJ, Feur EJ, Tan CC, et al: On the use of cause-specific failure and conditional failure probabilities: Examples from clinical oncology data. J Am Stat Assoc 88:400-409, 1993[CrossRef]

13. Crawford ED: Epidemiology of prostate cancer. Urology 62:3-12, 2003 (suppl 1)[Medline]

14. Stamey TA, McNeal JE, Yemoto CM, et al: Biological determinants of cancer progression in men with prostate cancer. JAMA 281:1395-1400, 1999[Abstract/Free Full Text]

15. Freedland SJ, Aronson WJ, Terris MK, et al: Percent of prostate needle biopsy cores with cancer is significant independent predictor of prostate-specific antigen recurrence following radical prostatectomy: Results from SEARCH database. J Urol 169:2136-2141, 2003[Medline]

16. Grossfeld GD, Chang JJ, Broering JM, et al: Under staging and under grading in a contemporary series of patients undergoing radical prostatectomy: Results from the Cancer of the Prostate Strategic Urologic Research Endeavor database. J Urol 165:851-856, 2001[CrossRef][Medline]

17. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591-1596, 1999[Abstract/Free Full Text]

18. Bismar TA, Lewis JS Jr, Vollmer RT, et al: Multiple measures of carcinoma extent versus perineural invasion in prostate needle biopsy tissue in prediction of pathologic stage in a screening population. Am J Surg Pathol 27:432-440, 2003[CrossRef][Medline]

19. Naya Y, Slaton JW, Troncoso P, et al: Tumor length and location of cancer on biopsy predict for side specific extraprostatic extension. J Urol 171:1093-1097, 2004[Medline]

Submitted January 26, 2004; accepted June 10, 2004.

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