Abstract
Objective
To compare the effects of tumor volume (TV), tumor percentage involvement (TPI) and prostate volume (PV) on PSA recurrence (PSAR) following radical prostatectomy (RP).
Methods
A cohort of 3528 patients receiving RP between 1988 and 2008 was retrieved from the Duke Prostate Center. Patients were stratified by TV (<3cc, 3-6cc, >6cc), TPI (<10%, 10-20%, >20%) and PV (<35cc, 35-45cc, >45cc) and their effects on PSAR evaluated using Kaplan-Meier (KM) analysis. Clinico-pathological variables included in univariate analysis were age at surgery, race, year of surgery, PSA, pathological Gleason score, pathological tumor stage, margin status, extra capsular extension (ECE) and seminal vesicle invasion (SVI). The effects of TV, TPI and PV (as continuous and categorical variables) on PSAR were compared using Cox analysis.
Results
TPI, TV and PV were predictive of PSAR (p <0.05) in KM. In multivariate analysis as continuous variables, TPI and PV were predictive of PSAR (Odds ratio (OR) = 1.16 and OR = 0.65, p <0.05). As categorical variables, TPI > 20% and PV 10-35cc were predictive of PSAR (OR = 1.45 and OR = 1.25, p <0.05). TV was not predictive of PSAR in either analysis. Pathological Gleason score ≥ 7, PSA, positive margins, SVI and tumor stage T3/4 were found to be predictors of PSAR (p <0.05).
Conclusions
TV, TPI and PV were predictive of PSAR in univariate analysis, but only TPI and PV were predictive in multivariate analysis. TPI and PV should be considered when evaluating, assessing and counseling patients about PSAR risk.
Keywords: Prostate cancer, Tumor volume, Tumor percentage involvement, Prostate volume, PSA recurrence
INTRODUCTION
Tumor volume (TV), tumor percentage involvement (TPI) and prostate volume (PV) have all been implicated in PSA recurrence (PSAR), however, contention still exists as to which, if any, factors are clinically useful predictors.
TV has been shown to be an independent predictor of PSAR1,2, positive surgical margins3 and overall survival. 4 Conversely, others 5,6 have shown that TV provides no individual prognostic information when considered with Gleason score and pathological stage and Merrill et al7 showed that tumor volume is only predictive in patients with Gleason greater than or equal to 7.
The percentage of prostate occupied by tumor (TPI) is another variable of interest. It has been shown to be predictive of PSAR in both organ confined disease8,9 and all stages of disease.6,10 On the contrary, Epstein et al11 showed that TPI offered no prognostic information for patients with stage pT2 prostate cancer.
Prostate volume has also been shown to be predictive of PSAR.12,13 Men with smaller prostates have been shown to have higher grade and more advanced disease14 and men with larger prostates have been shown to have lower rates of PSAR.15,16
Currently there is no consensus on the utility of TV, TPI and PV in the prediction of PSAR. The goal of this study was to examine the effects of TV, TPI, and PV on PSAR following radical prostatectomy (RP) in a large patient population. To our knowledge, this was the first paper to examine all three variables in a single population.
MATERIAL AND METHODS
Patient Population
Following institutional review board approval, a cohort of 4562 patients receiving RP between 1988 and 2008 was retrieved from the Duke Prostate Center Database. Patients lacking information on TV, TPI and PV were excluded from the analysis. 3528 patients were included in the final analysis.
Specimen Collection
Prostate specimens were harvested in the operating room, prepared as previously described10 and submitted for microscopic evaluation. Tumor involvement of each slide was estimated by the percent of the slide containing tumor. Estimation of tumor percentage involvement for the entire prostate was completed by summing each individual slide and averaging the results from all slides analyzed.
Statistical Analysis
Patients were stratified by TV (< 3 cc, 3-6 cc, > 6 cc), TPI (< 10%, 10-20%, > 20%) and PV (< 35 cc, 35-45 cc, > 45 cc). Cut off points for the variables TV, TPI and PV were chosen to separate the patient populations, roughly into thirds. TPI was measured by pathologists at our institution as previously described.10 The prostate specimens were assessed and the percentage of tumor contained on each slide averaged. The clinical and pathologic variables age at surgery (<50, 50-60, 60-70, >70), race (African American (AA) or non-AA), year of surgery (pre-2000 or post-2000), PSA at diagnosis, pathological Gleason score (< 7, 7, > 7), pathological tumor stage (pT2 or pT3/4), surgical margin status (positive or negative), extra capsular extension (ECE) (positive or negative) and seminal vesicle invasion (SVI) (positive or negative) were included in univariate analysis. Chi-squared and Kruskal-Wallis tests were used where appropriate. PSA, PV and TPI were log transformed due to non-normal distribution. Individual effects of TV, TPI and PV on PSAR were evaluated using Kaplan-Meier (KM) analysis.
PSAR was defined as any increase in PSA greater than 0.2 ng/ml after the initial four week postoperative period.17 Variables entered into multivariate analysis were TV, TPI, PV, age at surgery, year of surgery, PSA, pathological Gleason score, pathological tumor stage, surgical margin status, ECE and SVI. TV, TPI, PV and PSA all exhibited non-normal distributions and were log transformed for analysis. TV, TPI and PV were all analyzed as both continuous and categorical variables. Significant risk factors for PSAR were determined through Cox proportional hazards analysis using a backwards stepwise logistic regression method.
All statistical analyses were performed using SPSS® 15.0 (Cary, North Carolina).
RESULTS
Patient Demographics
The mean age at surgery for the 3528 patients was 62.3 years (35.0 to 83.1 years). 85.3% of patients were non-AA and 14.7% were AA. The median PSA for all men was 6.3 ng/ml. Statistics including Gleason score, pathologic stage and surgical margin status for all patients are shown in Table 1.
Table 1.
Clinical and pathological characteristics of patients within cohort
| Age at Diagnosis (Years) | n (%) | |
| ≤ 50 | 190 (5.5) | |
| 50.1-60 | 1100 (31.8) | |
| 60.1-70 | 1622 (46.9) | |
| > 70 | 549 (15.9) | |
| Race | ||
| African American | 517 (14.7) | |
| Other | 3004 (85.3) | |
| Body Mass Index | ||
| < 25 | 541 (22.7) | |
| 25-30 | 1192 (50.1) | |
| > 30 | 647 (27.2) | |
| Pathological Gleason | ||
| < 7 | 1621 (45.9) | |
| 7 | 1484 (42.1) | |
| > 7 | 423 (12.0) | |
| Tumor Stage | ||
| T1/T2 | 2115 (60.6) | |
| T3/T4 | 1375 (39.4) | |
| Surgery Year | ||
| Before 2000 | 1817 (51.5) | |
| After 2000 | 1711 (48.5) | |
| TV (cc) | ||
| < 3 | 1059 (34.3) | |
| 3-6 | 957 (31.0) | |
| > 6 | 1074 (34.8) | |
| TPI (%) | ||
| < 10 | 1159 (33.6) | |
| 10-20 | 1461 (42.3) | |
| > 20 | 831 (24.1) | |
| PV (g) | ||
| < 35 | 1267 (40.4) | |
| 35-45 | 843 (26.9) | |
| > 45 | 1024 (32.7) | |
| PSA | Median (IQR) | 6.3 (4.5-10.0) |
| Seminal Vesicle Invasion | 409 (11.6) | |
| Extracapsular Extension | 1219 (34.6) | |
| Positive Margins | 1247 (35.3) | |
| PSA Recurrence | 988 (28.1) |
IQR: Interquartile range
TV
In univariate analysis, age at surgery, race, pathological Gleason score, pathological tumor stage, year of surgery, PSA, SVI, ECE and positive surgical margins were all significantly different with regards to TV groups (p < 0.05). The higher TV, the higher the rate of PSAR was on Kaplan-Meier analysis (p < 0.001, Figure 1A).
Figure 1A.
Increased PSA recurrence associated with increased tumor volume.
In multivariate analysis, TV was analyzed as both a categorical and continuous variable. TV was not a significant predictor of PSAR in either analysis (p > 0.05). When TV was analyzed as a continuous variable pathological Gleason score > 7, pathological Gleason score = 7, PSA, positive surgical margins, SVI and pathological tumor stage pT3/4 were significantly predictive of PSAR (p < 0.05). When TV was analyzed as a categorical variable pathological Gleason score > 7, pathological Gleason score = 7, PSA, positive surgical margins, SVI and pathological tumor stage pT3/4 were significantly predictive of PSAR (p < 0.05). Hazard ratios (HR) and p-values are listed in Table 2.
Table 2.
Factors predicting PSA recurrence stratified by continuous and categorical consideration of tumor volume (TV), tumor percent involvement (TPI) and prostate volume (PV)
| Hazard Ratio | 95% Cl | p Value | ||
|---|---|---|---|---|
| Continuous variables considered individually | ||||
| Continous TV | ||||
| Pathological Gleason > 7 | 3.01 | 2.40 | 3.78 | <0.001 |
| Pathological Gleason = 7 | 1.60 | 1.32 | 1.92 | <0.001 |
| PSA | 1.57 | 1.43 | 1.73 | <0.001 |
| Positive Margins | 1.77 | 1.51 | 2.07 | <0.001 |
| Seminal Vesicle Invasion | 1.77 | 1.46 | 2.15 | <0.001 |
| Pathological Tumor Stage T3/T4 | 1.29 | 1.07 | 1.54 | 0.006 |
| TV | 0.99 | 0.90 | 1.09 | 0.805 |
| Continuous TPI | ||||
| Pathological Gleason > 7 | 2.48 | 2.02 | 3.04 | <0.001 |
| Pathological Gleason = 7 | 1.39 | 1.17 | 1.64 | <0.001 |
| PSA | 1.53 | 1.41 | 1.66 | <0.001 |
| Positive Margins | 1.59 | 1.38 | 1.84 | <0.001 |
| Seminal Vesicle Invasion | 1.66 | 1.39 | 1.99 | <0.001 |
| Pathological Tumor Stage T3/T4 | 1.22 | 1.03 | 1.45 | 0.018 |
| TPI | 1.16 | 1.06 | 1.28 | 0.002 |
| Continous PV | ||||
| Pathological Gleason > 7 | 2.90 | 2.33 | 3.60 | <0.001 |
| Pathological Gleason = 7 | 1.52 | 1.27 | 1.82 | <0.001 |
| PSA | 1.67 | 1.53 | 1.83 | <0.001 |
| Positive Margins | 1.66 | 1.42 | 1.93 | <0.001 |
| Seminal Vesicle Invasion | 1.76 | 1.46 | 2.13 | <0.001 |
| Pathological Tumor Stage T3/T4 | 1.27 | 1.06 | 1.51 | 0.008 |
| PV | 0.65 | 0.54 | 0.78 | <0.001 |
|
| ||||
| Categorical variables considered individually | ||||
| Categorical TV | ||||
| Pathological Gleason > 7 | 3.02 | 2.41 | 3.79 | <0.001 |
| Pathological Gleason = 7 | 1.60 | 1.32 | 1.92 | <0.001 |
| PSA | 1.57 | 1.43 | 1.73 | <0.001 |
| Positive Margins | 1.76 | 1.50 | 2.06 | <0.001 |
| Seminal Vesicle Invasion | 1.78 | 1.47 | 2.16 | <0.001 |
| Pathological Tumor Stage T3/T4 | 1.29 | 1.07 | 1.54 | 0.006 |
| TV > 6 cc | 1.07 | 0.86 | 1.33 | 0.533 |
| Categorical TPI | ||||
| Pathological Gleason > 7 | 2.45 | 2.00 | 3.01 | <0.001 |
| Pathological Gleason = 7 | 1.38 | 1.17 | 1.63 | <0.001 |
| PSA | 1.53 | 1.41 | 1.66 | <0.001 |
| Positive Margins | 1.61 | 1.39 | 1.86 | <0.001 |
| Seminal Vesicle Invasion | 1.67 | 1.40 | 2.00 | <0.001 |
| Pathological Tumor Stage T3/T4 | 1.22 | 1.03 | 1.44 | 0.019 |
| TPI > 20% | 1.45 | 1.16 | 1.81 | 0.001 |
| Categorical PV | ||||
| Pathological Gleason > 7 | 2.86 | 2.30 | 3.57 | <0.001 |
| Pathological Gleason = 7 | 1.53 | 1.28 | 1.84 | <0.001 |
| PSA | 1.66 | 1.51 | 1.82 | <0.001 |
| Positive Margins | 1.70 | 1.46 | 1.99 | <0.001 |
| SV Invasion | 1.75 | 1.45 | 2.12 | <0.001 |
| Pathological Tumor Stage T3/T4 | 1.30 | 1.09 | 1.55 | 0.004 |
| PV 10-35 cc | 1.25 | 1.05 | 1.49 | 0.010 |
|
| ||||
| All categorical variables considered together | ||||
| TPI/TV/PV as Categorical Variables | ||||
| Pathological Gleason > 7 | 2.87 | 2.28 | 3.62 | <0.001 |
| Pathological Gleason = 7 | 1.54 | 1.27 | 1.86 | <0.001 |
| PSA | 1.57 | 1.43 | 1.74 | <0.001 |
| Positive Margins | 1.72 | 1.47 | 2.03 | <0.001 |
| SV Invasion | 1.68 | 1.38 | 2.05 | <0.001 |
| Pathological Tumor Stage T3/T4 | 1.20 | 1.00 | 1.45 | 0.05 |
| TV > 6 g | 0.94 | 0.67 | 1.31 | 0.71 |
| TPI > 20% | 1.32 | 1.02 | 1.69 | 0.031 |
| PV 10-35 cc | 1.24 | 1.04 | 1.49 | 0.018 |
TPI
In univariate analysis, age at surgery, race, pathological Gleason score, pathological tumor stage, year of surgery, PSA, SVI, ECE and positive surgical margins were all significantly different in regards to TPI groups (p < 0.05). For prostates with a higher TPI, a higher the rate of PSAR was identified on Kaplan-Meier analysis (p < 0.001, Figure 1B).
Figure 1B.
Increased PSA recurrence associated with increased tumor percent involvement.
In multivariate analysis, TPI was analyzed as both a categorical and continuous variable. As a continuous variable, TPI was found to be a significant predictor (HR = 1.16, p =0.002) of PSAR. Pathological Gleason score > 7, pathological Gleason score = 7, PSA, positive surgical margins, SVI and pathological tumor stage pT3/4 were also found predictive of PSAR (p < 0.05). As a categorical variable, TPI > 20% was found to be a significant predictor of PSAR (HR = 1.45, p = 0.001). Pathological Gleason score > 7, pathological Gleason score = 7, PSA, positive surgical margins, SVI and pathological tumor stage pT3/4 were also found predictive of PSAR (p < 0.05). HR and p-values are shown in Table 2.
PV
In univariate analysis, age at surgery, race, pathological Gleason score, pathological tumor stage, year of surgery, PSA, SVI, ECE and positive surgical margins were all significantly different in regards to PV groups (p < 0.05). The lower the PV the higher the rate of PSAR was on Kaplan-Meier analysis (p = 0.012, Figure 1C).
Figure 1C.
Increased PSA recurrence associated with decreased prostate volume.
On multivariate analysis, PV was analyzed as both a categorical and continuous variable. As a continuous variable, PV was found to be a significant predictor of PSAR (HR = 0.65, p < 0.001). Pathological Gleason score > 7, pathological Gleason score = 7, PSA, positive surgical margins, SVI and pathological tumor stage pT3/4 were also found predictive of PSAR (p < 0.05). As a categorical variable, PV < 35 cc was found to be a significant predictor of PSAR (HR = 1.25, p = 0.015). Pathological Gleason score > 7, pathological Gleason score = 7, PSA, positive surgical margins, SVI and tumor stage T3/4 were also found predictive of PSAR (p < 0.05). HR and p-values are shown in Table 2.
TV, TPI and PV all considered as categorical variables
The final analysis performed included all three categorical variables. Continuous variables were not included in the analysis because TV was calculated using PV and TPI and was therefore linearly dependent. TPI > 20% and PV < 35 cc were found to be predictive of PSAR (HR = 1.32, p = 0.03, HR = 1.25, p = 0.02). TV was not found to be predictive of PSAR. Pathological Gleason score > 7, pathological Gleason score = 7, PSA, positive surgical margins, SVI and pathological tumor stage pT3/4 were also found predictive of PSAR (p < 0.05). HR and p-values are shown in Table 2.
COMMENT
Previous studies have shown TV, TPI and PV to be predictive of PSA recurrence. However, for TV and TPI, conflicting studies exist.1-11 Though all three variables have been analyzed independently in the past, to our knowledge, this is the first study examining the variables within the same population in both univariate and multivariate analysis. Additionally, it is the largest cohort of patients analyzed in such a study.
TV
TV was found to be an independent predictor of PSAR in univariate analysis. However, when included in multivariate analysis it was not found to a significant predictor of PSAR. These findings were in agreement with a number of previous studies.5,6,11
There are two ways to measure TV. One is to use three dimensional reconstruction of radical prostatectomy specimens18 and the other is to use TPI and PV to calculate TV. The method of three dimensional reconstruction is accurate, but only about 12% of urologists have access to such processing and it is typically used for research purposes.19
This study used TPI and PV to calculate the TV. This process, while less exact than the process described previously, uses routinely reported pathologic variables. May et al6, using a similar technique for determining TPI (TV divided by PV) found that TPI > 25% was predictive of PSAR and that TV was not. These findings suggest that TPI and PV are the more important variables for determining PSAR risk and reveal that TV may only appear significant when conditions involving PV are suitable.
TPI
TPI was predictive of PSAR in both univariate and multivariate analysis. Previous studies with fewer patients (ranging from 528 to 2200) and comparable conditions obtained similar conclusions.6,9,8,10 This team and others had previously examined TPI as a categorical variable and found it predictive of PSAR in univariate analysis,8,10 however only a few have considered TPI as a categorical variable in multivariate analysis.
In one such study, Ramos et al9 categorized patients in TPI groups of < 10%, 10- 20% and > 20% (1286, 465 and 99 patients respectively) and found that those with a TPI > 20% has a relative risk (RR) of 2.1 for PSAR. This differed from our finding that patient with TPI > 20% had an HR of 1.45 times for PSAR. This difference is likely due to the higher number of patients and similar number of patients in each group (1159, 1461 and 831) in our cohort.
Our study showed that men with a TPI > 20% were at 1.45 times risk of PSAR relative to the TPI < 10% group, further demonstrating the utility in categorizing TPI. Interestingly, within our model, TPI > 20% was of higher predictive value of PSAR than Gleason = 7 (HR = 1.38) and pathological T3/T4 disease (HR = 1.22) and comparable to PSA (HR = 1.53), all of which are commonly used in nomograms predicting PSAR following treatment.20,21 These results were comparable to those of Ramos who found that men with a TPI > 20% had a relative risk of 2.1 of having PSAR. While further study is needed to confirm the utility, our findings suggest that TPI should be considered, along with other clinically useful variables, by clinicians in determining which patients are at the highest risk for recurrence and may benefit from adjuvant therapies.
PV
PV was shown to be a predictor of PSAR in both univariate and multivariate analysis. Previous studies from this team and others showed that men with small PV had higher risk of PSAR.2,12,14,15 The reason for this remains unknown, however a number of potential explanations exist. It has been suggested that men with smaller prostates may have lower levels of testosterone which has been shown to correlate with more aggressive prostate cancer22. Another explanation is that a tumor within a small prostate has less distance to travel to get outside the prostatic capsule, demonstrated by Yadav et al. who showed that decreased PV is a predictor of ECE23. It is likely that a combination of these factors leads to a greater chance of PSAR following treatment for men with smaller PV.
Some of the most immediately applicable and important findings in our study came from the analysis of PV. As a categorical variable, our stratification and analysis of PV in sub-groups of < 35, 35-45, and > 45 cc, is one of only a few studies to analyze prostate volumes in a range that has immediate clinical relevance and, to our knowledge, included the largest cohort of patients. Our study showed that a prostate volume < 35 cc was a risk factor for PSAR compared to men with prostates > 45 cc. Many previous studies have analyzed prostate volume and while results were significant, they often focused on results from prostates in the 50-100 cm3 range.15,16,24 However, these larger prostate volumes are not consistently seen in routine practice. The size of a normal prostate is 20-30 cc 25, 26 and reported medians in the literature set the median for diseased prostate volume around 35-45 cc.2, 12,13,15,24 In our study the median prostate volume was 38.4 cc, with only 25% of men having prostates larger than 50 cc and 10% larger than 64 cc. As a result, our finding that men with prostate volumes less than 35 cc have a 25% increased risk for PSAR compared to men with larger volume prostates provides clinicians with a clinically relevant value by which to assess patients risk for PSAR following RP. Additionally, the prognostic value was comparable to that of T3/T4 disease, a variable often considered when predicting risk for PSAR.27,28
As a continuous variable, PSAR was significantly associated with PV (HR = 0.65, p < 0.001). The reduction in PSAR risk may initially seem unimpressive, however when considered in context with other variables, it becomes more significant. The prognostic value of PSA in this model was HR = 1.67, however, when the inverse is taken, an HR of 0.60 is found. Taking the reciprocal of PSA shows, as expected, that a decrease in PSA is predictive of decreased PSAR risk; interestingly, the predictive value is similar to that of PV. PSA is a major factor in the stratification of risk for PSAR20,21 and death29,30 for patients with prostate cancer. PV may offer additional information that should be considered when counseling patients about their risk of PSAR following RP.
TV, TPI and PV all considered as categorical variables
When TV, TPI and PV were all included in multivariate analysis as categorical variables, TPI > 20% and PV < 35 cc were found to be predictive of PSAR. Previous studies have examined the effects of two of the variables in a single population such as TPI and TV6, 9, 11 or TPI and PV10. To our knowledge, this is the first study to include TV, TPI and PV in multivariate analysis within a single population. The findings add strength to the argument that PV and TPI are of greater importance than TV with regards to PSAR risk.
PV and TPI are easily calculated pathological variables that give clinicians additional information regarding patient risk of PSAR following RP. While neither PV between 10-35 cc nor TPI > 20% was found to be as predictive as variables such as a Gleason score > 7, their prognostic abilities (HR = 1.24 and HR = 1.32 respectively) were comparable to that of a T3/T4 pathological stage (HR = 1.20), which is included in predictive nomograms28 as well as considered when making decisions regarding treatment. The results of this study suggest that PV and TPI should be taken into consideration when counseling patients on their risk for PSAR following RP.
Limitations
Limitations of our study include potential population bias as Duke is a high volume and tertiary care center. This potentially limits the generalizability of the findings of the study. Additionally, this study was retrospective. Next, only 77% of our total patient population was included in the analysis due to missing data. While this represents a significant portion of the cohort, the excluded men were not found to be significantly different with respect to rates of PSAR than men included in the analysis. It should also be noted that as prostates get larger it may be more difficult to accurately characterize some pathological characteristics due to the increased work involved. Finally, within our analysis, TV was found by multiplying the TPI and PV rather than using the three dimensional reconstruction of radical prostatectomy specimens.
CONCLUSION
TV, TPI and PV were predictive of PSAR in univariate analysis, but only TPI and PV were predictive in multivariate analysis. Previous studies that considered only one or two of these variables may have failed to recognize important information related to PSAR risk. Considered individually, TPI > 20% and PV had PSAR predictive values comparable to or better than a pathological stage of T3/T4, Gleason score = 7 and PSA. When all variables were considered, patients with a PV less than 35 cc and patients with a TPI of greater than 20% were found to be at an increased risk of PSAR. TPI and PV should be considered when evaluating, assessing and counseling patients about the risks of PSAR.
Acknowledgments
NIH Grant TL1 RR 024126
Footnotes
CONFLICTS OF INTEREST None.
References
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