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Keywords:

  • prostate cancer;
  • hormonal therapy;
  • radical prostatectomy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Study Type – Therapy (retrospective cohort analysis)

Level of Evidence 2b

What's known on the subject? and What does the study add?

Prostate cancer is generally considered to be high risk when the prostate-specific antigen (PSA) concentration is >20 ng/mL, the Gleason score is ≥8 or the American Joint Commission on Cancer (AJCC) tumour (T) category is ≥2c. There is no consensus on the best treatment for men with prostate cancer that includes these high-risk features. Options include external beam radiation therapy (EBRT) with androgen suppression therapy (AST), treatment with a combination of brachytherapy, EBRT and AST termed combined-modality therapy (CMT) or radical prostatectomy (RP) followed by adjuvant RT in cases where there are unfavourable pathological features, e.g. positive surgical margin, extracapsular extension and seminal vesicle invasion. While outcomes for both approaches have been published independently these treatments have not been compared in the setting of a prospective RCT where confounding factors related to patient selection for RP or CMT would be minimised. These factors include age, known prostate cancer prognostic factors and comorbidity. RCTs that compare RP to radiation-based regimens have been attempted but failed to accrue.

OBJECTIVE

  • • 
    To assess the risk of prostate cancer-specific mortality after therapy with radical prostatectomy (RP) or combined-modality therapy (CMT) with brachytherapy, external beam radiation therapy (EBRT) and androgen-suppression therapy (AST) in men with Gleason score 8–10 prostate cancer.

PATIENTS AND METHODS

  • • 
    Men with localised high-risk prostate cancer based on a Gleason score of 8–10 were selected for study from Duke University (285 men), treated between January 1988 and October 2008 with RP or from the Chicago Prostate Cancer Center or within the 21st Century Oncology establishment (372) treated between August 1991 and November 2005 with CMT.
  • • 
    Fine and Gray multivariable regression was used to assess whether the risk of prostate cancer-specific mortality differed after RP as compared with CMT adjusting for age, cardiac comorbidity and year of treatment, and known prostate cancer prognostic factors.

RESULTS

  • • 
    As of January 2009, with a median (interquartile range) follow-up of 4.62 (2.4–8.2) years, there were 21 prostate cancer-specific deaths.
  • • 
    Treatment with RP was not associated with an increased risk of prostate cancer-specific mortality compared with CMT (adjusted hazard ratio [HR] 1.8, 95% confidence interval [CI] 0.6–5.6, P= 0.3).
  • • 
    Factors associated with an increased risk of prostate cancer-specific mortality were a PSA concentration of <4 ng/mL (adjusted HR 6.1, 95% CI 2.3–16, P < 0.001) as compared with ≥4 ng/mL, and clinical category T2b, c (adjusted HR 2.9; 95% CI 1.1–7.2; P= 0.03) as compared with T1c, 2a.

CONCLUSION

  • • 
    Initial treatment with RP as compared with CMT was not associated with an increased risk of prostate cancer-specific mortality in men with Gleason score 8–10 prostate cancer.

Abbreviations
AJCC

American Joint Commission on Cancer

(EB)RT

(external beam) radiation therapy

AST

androgen-suppression therapy

CMT

combined-modality therapy

RP

radical prostatectomy

RCT

randomised controlled trial

IRB

Institutional Review Board

CAD

coronary artery disease

MI

myocardial infarction

CHF

or congestive heart failure

IQR

interquartile range

HR

hazard ratio.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

The optimal management of localised high-risk prostate cancer is controversial. According to the several classification schemes this includes men with a PSA concentration of >20 ng/mL, Gleason score of ≥8 or American Joint Commission on Cancer (AJCC) tumour (T) category ≥2c disease with Gleason score 8–10 having the worst outcome of the three possible inclusion criteria [1,2]. Treatment options for this group of men include external beam radiation therapy (EBRT) with androgen-suppression therapy (AST), treatment with a combination of brachytherapy, EBRT and AST termed combined-modality therapy (CMT) or radical prostatectomy (RP) followed by adjuvant radiation therapy (RT) for high-risk features, e.g. positive surgical margin, extracapsular extension and seminal vesicle invasion given the results of Southwest Oncology Group (SWOG) 8874, which showed an overall survival benefit when adjuvant RT was added to RP in men with these adverse pathological characteristics [3]. However, estimates of prostate cancer-specific mortality after these treatments have not been compared to date in the setting of a prospective randomised controlled trial (RCT), where confounding factors related to patient selection for RP or CMT would be minimised. These factors include age, known prostate cancer prognostic factors and comorbidity. Lacking such a prospective RCT, in the present study we assessed the risk of prostate cancer-specific mortality after initial therapy with RP or CMT in men with Gleason score 8–10 prostate cancer, adjusting for age, cardiac comorbidity, and known prostate cancer prognostic factors. We also limited the study group to men aged <75 years, as RP is rarely performed in men over this age.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Of 14 334 men treated with RT including brachytherapy and EBRT combined with AST between August of 1991 and November of 2005 at the Chicago Prostate Cancer Center or in one of 20 community-based medical centres within the 21st Century Oncology establishment located in Florida, New York, and North Carolina, 372 (2.6%) were aged <75 years, with localised Gleason score 8–10 prostate cancer. In all, 105 men were treated in Chicago and 267 were treated within the 21st Century Oncology practice. Age at the time of treatment, Gleason score, clinical stage, PSA concentration, treatment year and information on cardiac comorobidity, as well as follow-up information including date of last follow-up and cause and date of death, if applicable, were compiled in a database. All men signed an Institutional Review Board (IRB)-approved, informed consent form permitting collection of de-identified patient data at baseline and follow-up.

Of 4036 men aged <75 years who underwent RP with pelvic lymph node dissection at Duke University Medical Center (Durham, NC) between January 1988 and October 2008 for clinical stage T1c–T3, N0 prostate cancer, 285 (7%) men had Gleason score 8–10 prostate cancer. A database was constructed including age and PSA concentration at RP, core needle-biopsy Gleason score, clinical stage, date and cause of death and cardiac comorbidities derived from the past medical history at the time of initial consultation. The study was performed with the approval of the IRB (NCT00978991) at Duke University.

Prostate needle-biopsy specimens underwent review by a pathologist with dedicated expertise in genitourinary pathology at each centre. Cardiac comorbidities included a history of coronary artery disease (CAD), or CAD-induced myocardial infarction (MI) or congestive heart failure (CHF).

RT AND HORMONAL TREATMENT

AST included a LHRH agonist with or without an antiandrogen agent for a median (interquartile range, IQR) of 4.3 (3.6–6.4) months before brachytherapy and concurrent with EBRT. EBRT was delivered using photons to a total dose of 45 Gy in 1.8-Gy fractions to the prostate and seminal vesicles. Treatment plans were designed with the assistance of CT images and radiation plans were either three-dimensional conformal or intensity-modulated. The pelvic lymph nodes were not included in EBRT volumes. Brachytherapy was performed 1–2 weeks after the completion of EBRT using interstitial needles preloaded with permanent 125I, 103Pd, or 131Cs sources according to pre-planned dosimetry. Of the 105 men treated in the Chicago practice, half were treated with 125I, half with 103Pd and <1% with 131Cs. The precise numbers are not available for the Florida group but are probably similar as most practices tend to use a 50/50 mix of iodine and palladium. The prescribed minimum peripheral doses used were 108, 90, and 100 Gy for 125I, 103Pd, and 131Cs, respectively. Implant dosimetry was assessed by CT at 1 month postoperatively. A D90 (the dose that covers 90% of the prostate volume) greater than or equal to the prescription dose was required to be eligible for inclusion in the database given the known association between implant quality and cancer control [4,5].

In the RP group, we included men who received adjuvant salvage RT (13 men), AST (12) or both (four) although the analysis was also performed excluding those who received salvage treatment. The target volume for salvage RT for PSA failure was the surgical bed and anastomosis using three-dimensional conformal (if before 2006) or intensity-modulated radiotherapy to a total dose of 66.6 Gy in 1.8-Gy fractions over 7 weeks, generally within 1 year after the first measurement of a detectable PSA concentration. Pelvic lymph nodes were not treated. When given alone at the time of initial PSA failure or when administered after salvage RT failure, AST consisted of continuous administration of an LHRH agonist.

FOLLOW-UP AND DEFINING CAUSE OF DEATH

Routine follow-up for both cohorts included history, DRE and serum PSA measurements generally every 3 months for 1 year, every 6 months for an additional 3 years, and annually thereafter. Follow-up began either on the day of RP or the date of completion of brachytherapy and continued until last observation or death, until January 2009. When deaths occurred, the attending oncologist or urologist who regularly followed the patient determined the cause of death. For a death to be considered secondary to prostate cancer, the patient needed to have documented castration-resistant metastatic prostate cancer with a rising PSA concentration at the last follow-up before death as defined previously [6,7].

STATISTICAL METHODS

Descriptive statistics were used to characterise the men at study entry. A Mantel-Haenszel chi-squared test was used to compare distributions of categorical baseline clinical characteristics across treatment methods. For continuous variables, medians and distributions were compared using Wilcoxon two-sample tests [8].

The method of cumulative incidence [9] was used to estimate and characterise prostate cancer-specific mortality stratified by treatment type. Comparisons of these estimates stratified by treatment received were performed by using a k-sample test [10]. A two-sided P < 0.05 was considered to indicate statistical significance.

Fine and Gray regression [11] was used to evaluate for a possible association between clinical covariates and the risk of prostate cancer-specific mortality. Clinical factors examined included treatment method, PSA concentration, Gleason score, AJCC T category, age, presence of cardiovascular comorbidity and year of treatment. PSA concentration was log-transformed to ensure normal distribution and was evaluated as a continuous variable. For categorical variables, thresholds were determined before the analysis based on established clinically relevant strata [12]. Age was treated as a continuous variable and Gleason score, cardiovascular comorbidity, AJCC tumour category and treatment method were considered categorical variables. Baseline groups for categorical variables were defined as treatment with CMT, PSA concentration of ≥4 ng/mL, Gleason score of 8, clinical category T1c or T2a, and no history of CAD, CHF or MI-related comorbidity. Unadjusted and adjusted hazard ratios (HRs) for prostate cancer-specific mortality with associated 95% CIs and P values were calculated for each covariate.

R version 2.1.1 (R Foundation for Statistical Computing, Vienna, Austria) was used for all calculations pertaining to Gray's k-mean test and Fine and Gray regression. SAS version 9.2 (SAS Institute, Cary, North Carolina) was used for all remaining statistical analyses.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

COMPARISON OF BASELINE PATIENT AND TUMOUR CHARACTERISTICS BETWEEN TREATMENT METHODS

As shown in Table 1, men in the CMT group were older than the RP group (P < 0.001) with a median (IQR) age of 70 (66–73) years vs 65 (58–69) years, respectively. A larger proportion of men in the CMT group had a Gleason score of >8 compared with the RP group (P= 0.001). A larger proportion of the RP group had AJCC category T1c or T2a compared with the CMT group (P < 0.001). A higher proportion of men in the CMT group had cardiovascular comorbidities compared with the RP group (P= 0.04). Distributions of PSA concentrations were similar between the RP and CMT groups (P= 0.15). The median follow-up was significantly longer in the RP group compared with the CMT group (7.6 vs 3.6 years, P < 0.001).

Table 1.  Comparison of the distribution of patient and tumour characteristics stratified by treatment received for the 657 men in the study cohort
Baseline clinical characteristicsRPCMT P
N285372 
Age, years   
 n (%)   
  <6092 (32)34 (9)<0.001
  60–70138 (48)157 (42) 
  >70–7555 (19)181 (49) 
  Median (IQR)65 (58–69)70 (66–73)<0.001
Baseline PSA concentration, ng/mL   
 n (%)   
  <428 (10)25 (7)0.15
  4–10150 (53)191 (51) 
  >10–2065 (23)93 (25) 
  >2042 (15)63 (17) 
  Median (IQR)7.9 (5.3–12.4)8.5 (6.0–13.6)0.10
Gleason score, n (%)   
 8227 (80)254 (68)0.001
 9–1058 (20)118 (32) 
AJCC tumour (T) category, n (%)   
 T1218 (77)165 (44)<0.001
 T2a41 (14)102 (27) 
 T2b17 (6)75 (20) 
 T2c9 (3)30 (9) 
Comorbidity, n (%)   
 no prior CAD, MI or CHF148 (52)163 (44)0.04
 prior CAD, MI or CHF137 (48)209 (56) 
Median follow-up, years7.63.6<0.001

ESTIMATES OF PROSTATE CANCER-SPECIFIC MORTALITY

As of June of 2009 with a median (IQR) follow-up of 4.6 ( 2.4–8.2) years there were 21 deaths attributed to prostate cancer among the 657 men with Gleason score 8–10 prostate cancer (six in the CMT group and 15 in the RP group). Cumulative incidence estimates for prostate cancer-specific mortality were not statistically different amongst men treated with CMT (P= 0.20). Specifically, 5-year estimates of prostate cancer-specific mortality for men treated with CMT vs RP were 1.5% vs 0% respectively, as shown in Fig. 1.

image

Figure 1. Cumulative incidence estimates of prostate cancer-specific mortality for the 657 men in the study cohort stratified by treatment shows no statistical difference between men treated with RP compared to CMT (k-sample p-value = 0.16).

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PREDICTORS OF PROSTATE CANCER-SPECIFIC MORTALITY

Fine and Gray multivariate regression analysis showed no significant difference in prostate cancer-specific mortality between the two treatments (HR 1.8, 95% CI 0.6–5.5, P= 0.3, Table 2). Factors associated with an increased risk of prostate cancer-specific mortality were a PSA concentration of <4 ng/mL as compared with ≥4 ng/mL (adjusted HR 6.1, 95% CI 2.3–16, P < 0.001), and T2b, c as compared with T1c, 2a (adjusted HR 2.9, 95% CI 1.1–7.2; P= 0.03). Gleason scores 9 or 10 as compared with 8 were not associated with a higher risk of prostate cancer-specific mortality (adjusted HR 1.6, 95% CI 0.6–4.2, P= 0.3) nor were the presence of cardiovascular comorbidities (adjusted HR 0.9, 95% CI 0.9–1.1, P= 1), age (adjusted HR 1.1, 95% CI 1.0–1.1, P= 0.2) or treatment year (adjusted HR 0.8, 95% CI 0.7–1.0, P= 0.1). The analysis was also done excluding the 17 RP patients who received adjuvant salvage treatment and showed similar results for all covariates including no significant difference in prostate cancer-specific mortality for RP compared with CMT (adjusted HR 1.8, 95% CI 0.6–5.7, P= 0.3).

Table 2.  HR of prostate cancer-specific mortality for patient and tumour characteristics from univariate and multivariate Fine and Gray regression analysis
CovariateNo. of menNo. of eventsUnivariate analysisMultivariate analysis
HR (95% CI) P HR (95% CI) P
Treatment group:      
 CMT37261 [Reference] 1 [Reference] 
 RP285151.0 (0.4–2.3)1.01.8 (0.6–5.5)0.3
PSA concentration, ng/mL:      
 <45356.2 (2.3–17)<0.0016.1 (2.3–16)<0.001
 4–20588161 [Reference] 1 [Reference] 
Gleason score:      
 8469121 [Reference] 1 [Reference] 
 9–1017692.0 (0.9–4.7)0.11.6 (0.6–4.2)0.3
AJCC tumour (T) category:      
 T1c–T2a526141 [Reference] 1 [Reference] 
 T2bc13172.7 (1.1–6.6)0.032.9 (1.1–7.2)0.03
Comorbidity:      
 no prior CAD, MI or CHF311121 [Reference] 1 [Reference] 
 prior CAD, MI or CHF33790.9 (0.4–2.1)0.90.9 (0.9–1.1)1.0
Age at treatment, years  1.0 (0.9–1.1)1.01.1 (1.0–1.1)0.2
Treatment year  1.0 (0.9–1.1)0.70.8 (0.7–1.0)0.1

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

These data do not provide evidence to support a significant difference in prostate cancer-specific mortality amongst men with Gleason score 8–10 prostate cancer treated with CMT vs RP after controlling for known prostate cancer prognostic factors, age and cardiovascular comorbidities. Although the adjusted HR was >1.0 for treatment with RP as compared with CMT, suggesting a worse outcome for men treated with RP, it was not significant (P= 0.3). In addition, the shorter median follow-up for the CMT as compared with the RP group could bias results in favour of RP, as less time would be available to observe events in the men treated with CMT.

Conversely, for RP there should be a measurable PSA from residual prostatic tissue, so that PSA failure is detected more readily after RP and therefore can be treated with salvage RT sooner than after CMT where a PSA rebound first occurs from testosterone rebound after the discontinuation of AST [13]. As the PSA rebound delays recognition of biochemical failure in CMT-managed patients as was recently demonstrated [14], the use of salvage AST is often significantly delayed and may lead to a higher risk of prostate cancer-specific mortality. This effect, which can lead to an increased risk of prostate cancer-specific mortality, can counterbalance to some extent the longer follow-up of men treated with RP. Additionally, the average duration of AST in CMT patients was 4.3 months, much shorter than typical modern courses, which have been shown to provide a survival benefit in men with high-risk prostate cancer. Perhaps with a longer duration of AST in the CMT group a survival advantage may have emerged.

The proportional difference of men who met the inclusion criteria for the present study in the CMT group (2.6%) vs the RP group (7%) can be explained based on the difference in the median age of the men in the two groups and the historical context. Men included in the present study treated with CMT were older and some of the men in the overall CMT sample were excluded from analysis by imposing an age limit of 75 years. Additionally, the proportion of men treated with definitive RT who met the CMT inclusion criteria was probably further depressed because CMT was not generally accepted as the standard of care when many of these men were treated. Indeed, EBRT or brachymonotherapy were more common until practice patterns began to change in the late 1990s after a survival benefit with the addition of hormonal therapy was reported [1].

A few points deserve further discussion. First, known prognostic factors that were not available for all men in the present study, e.g. perineural invasion [15–17], percentage of cores positive [18,19], and PSA kinetics [20–23] may also have an impact on outcomes. Second, consistent with previous observations a PSA concentration of ≥4 ng/mL in this high-risk population of men with Gleason score 8–10 prostate cancer corresponds to a decreased risk of prostate cancer-specific mortality probably because PSA concentrations of <4 ng/mL correspond to differentiated cancer, which is generally more aggressive and unresponsive to initial and salvage hormonal therapy [24].

Finally, the study is limited in power to measure a difference by the few prostate cancer-specific mortality events. A larger prospective and randomised study is needed to definitively answer this question. Despite these considerations, initial treatment with RP as compared with CMT was not associated with an increase in the risk of prostate cancer-specific mortality. Prospective validation of this association is needed in the setting of a randomised controlled trial.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES
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