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IS TUMOR VOLUME AN INDEPENDENT PROGNOSTIC FACTOR IN CLINICALLY LOCALIZED PROSTATE CANCER?
0022-5347/04/1722-0508/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 172, 508 –511, August 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000130481.04082.1a
IS TUMOR VOLUME AN INDEPENDENT PROGNOSTIC FACTOR IN CLINICALLY LOCALIZED PROSTATE CANCER? EIJI KIKUCHI, PETER T. SCARDINO, THOMAS M. WHEELER,* KEVIN M. SLAWIN AND MAKOTO OHORI† From the Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York (EK, PTS, MO), and the Department of Pathology (TMW) and the Scott Department of Urology (KMS), Baylor College of Medicine and The Methodist Hospital, Houston, Texas
ABSTRACT
Purpose: There continues to be debate regarding the prognostic significance of tumor volume (TV) in radical prostatectomy (RP) specimens. We assessed the prognostic significance of TV in a large series of patients followed for a long time to discover whether the effect of TV has changed with earlier detection of smaller tumors. Materials and Methods: TV was measured planimetrically in 1,302 consecutive RP specimens with clinical stage T1–3 prostate cancer from 1983 to 2000. We correlated TV with standard clinical and pathological features, and determined the prostate specific antigen nonprogression rate. Median followup was 46 months (range 1 to 202). Results: TV was weakly associated with other clinical and pathological features. Median TV decreased significantly over time (2.16 cm3 before 1995 vs 1.25 cm3 after 1995, p ⬍0.001) and this decrease was also found within each clinical stage. In univariate analysis TV correlated strongly with the probability of progression. However, in multivariate analysis TV was not a significant independent predictor of prognosis, either in the whole cohort of patients or in those with peripheral zone cancer only. Even in univariate analysis TV had no effect on prognosis for patients in whom cancer was either confined to the prostate or was Gleason score 2 through 6. Conclusions: TV provides no independent prognostic information when considered in multivariate analysis with Gleason score and pathological stage. Measurement of TV before treatment is less likely to characterize prostate cancer accurately than assessment of tumor grade and extent. There seems to be little reason to measure TV routinely in RP specimens. KEY WORDS: neoplasms, prognosis, prostatic neoplasms, prostatectomy
Histopathological analysis of the features of cancer in radical prostatectomy (RP) specimens provides important prognostic information highly predictive of the future course of the disease.1– 4 There is uniform agreement that the pathologist should describe the overall Gleason score of the cancer, the presence of extracapsular extension (ECE) and seminal vesicle invasion (SVI), as well as the status of the surgical margins and, if lymphadenectomy was performed, lymph node involvement. However, there remains controversy about the value of measuring tumor volume. Accurate assessment of tumor volume requires tedious serial sectioning of the specimen and detailed, planimetric measurement of the area of cancer in each section. While tumor volume is clearly associated with Gleason grade and pathological stage, few studies have confirmed the independent prognostic significance in multivariate analysis when the more readily available features of the cancer are considered.5–7 Epstein et al analyzed tumor volume in a series of 185 RP specimens and found no added value once
Gleason score, pathological stage and surgical margin status were determined.6 In contrast, Stamey et al concluded that tumor volume was a primary independent factor predictive of treatment failure and they called for better methods to assess tumor volume preoperatively.8 We had previously analyzed the prognostic significance of tumor volume and had found no independent significance of tumor volume when measured planimetrically in a series of more than 500 patients.5 If tumor volume is an independent prognostic factor, pathologists should measure it routinely. However, few do, reflecting the opinion among urologists and pathologists that tumor volume is not a crucial factor. We reassessed the prognostic significance of tumor volume in a large series of patients evaluated for recurrence during a long period to determine any independent value in measuring total tumor volume. MATERIALS AND METHODS
Patient population. A total of 1,389 consecutive patients were treated with RP for clinically localized prostate cancer Accepted for publication February 13, 2004. Supported by the Leon Lowenstein Foundation and a National at Baylor College of Medicine from August 1983 to SeptemCancer Institute SPORE (CA58204). ber 2000 by 2 surgeons (PTS 1,039 patients and KMS 350 Nothing to disclose. patients). We identified a study population of 1,302 consecu* Financial interest and/or other relationship with Pintex Phartive patients who had a complete data set based on the maceuticals. † Correspondence and requests for reprints: Department of Urol- pathological features of the cancer in the RP specimens. ogy, Tokyo Medical University, 6-1-1 Nishi-shinjuku, Shinjuku-ku, Mean patient age was 62.0 years (range 38 to 81). Tokyo 160-8402, Japan (telephone: 011-81-35791-6149; FAX: 011-81Clinical stage was assigned preoperatively with the 1992 33344-4813; e-mail: [email protected]). TNM system. Serum prostate specific antigen (PSA) levels Editor’s Note: This article is the first of 5 published in this were measured by the Hybritech Tandem-R assay (Beckman issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions Coulter, Inc., Brea, California) in ambulatory patients before or at least 3 weeks after prostate biopsy or manipulation. on pages 812 and 813. 508
PROGNOSTIC ROLE OF PROSTATE CANCER VOLUME
Preoperative PSA levels were not available in 64 of the patients, of whom 50 were treated before 1987. The result obtained closest to the time of RP was used for this analysis. Pathology. RP specimens were fixed en bloc in 10% neutral buffered formalin and sectioned transversely at 4 to 5 mm intervals.9 Surgical margins were marked with indelible ink. The location and extent of invasive cancer were identified by a single pathologist (TMW), and precisely mapped in each section. The presence and location of focal or established ECE,9 SVI, positive surgical margins (⫹SM), lymph node metastases (⫹LN) and histological grade were also recorded. Grade was assigned by the Gleason method.10 Cancers with Gleason sum 7 to 10 were considered poorly differentiated. Total tumor volume was computed from cancer maps by a planimetric method using the OPTIMAS (Bioscan, Inc., Edmonds, Washington) image analysis system as previously described.5 If a patient had cancer in a transurethral resection specimen, tumor volume was measured in a manner similar to that of RP specimens and was included in the computation of total tumor volume. Followup. Median followup was 46.4 months (mean 52.3, range 1 to 202). Of these patients 442 (33.9%) were followed for more than 5 years and 93 (7.1%) for more than 10 years. Patients were followed postoperatively with digital rectal examination and serum PSA every 3 months for 1 year, every 6 months until 5 years then annually thereafter. Biochemical recurrence of disease was defined as progressive sustained increase in PSA greater than 0.4 ng/ml (Hybritech, Beckman Coulter, Inc.) in patients who had a persistently increasing PSA on at least 2 occasions. Statistical analysis. Association among clinical and pathological features, and tumor volume were assessed with the chi-square test for trends or Spearman rank correlations. Logarithmic (base 10) transformations of PSA and tumor volume were used to improve the regression analysis. The ordinal and continuous outcomes were compared with the Kruskal-Wallis or Wilcoxon rank sum test. The actuarial probabilities obtained using a Kaplan-Meier analysis were reported as median ⫾ 2 standard errors (95% CI, confidence intervals) and compared using the log rank test. We used the Cox proportional hazards regression analysis to test the association of tumor volume with the other pathological prognostic features. The 36 patients who received adjuvant therapy were included in this study and analyzed as a time dependent covariate. This form of analysis recognizes that a covariate might change with time and incorporates these new values into the model.11 The analyses were performed with the STATA version 7.0 statistical software package (StataCorp LP, College Station, Texas). RESULTS
As clinical stage and biopsy Gleason sum advanced, tumor volume significantly increased (p ⬍0.001 for both), but the level of the correlation was weak (correlation coefficient 0.284 and 0.208, respectively). PSA was also poorly related to tumor volume with R2 0.276 (fig. 1). In a subset of 221 patients with a normal size prostate (less than 25 gm), R2 between tumor volume and PSA (0.441) was strong compared to 0.225 in 263 prostates greater than 50 gm. Therefore, PSA correlates better with tumor volume in men with a small prostate, especially those less than 25 gm. As pathological stage advanced tumor volume increased significantly. However, a wide range and a significant overlap of tumor volumes among pathological stages were appreciated (fig. 2). In fact 12 of 778 (1.5%) patients with cancers confined to the prostate had a tumor volume of 6 cm3 or greater, and 14 of 142 (9.9%) with SVI and 9 of 73 (12.3%) with ⫹LN had a tumor volume of 2 cm3 or less. Tumor volume decreased significantly with time from a median of 2.16 cm3 before 1995 to 1.25 cm3 after 1995
509
FIG. 1. Correlation between PSA and tumor volume. Logarithmic (base 10) transformations of PSA and tumor volume were used. Regression line is log10 PSA ⫽ 0.788 ⫹ 0.352 ⫻ (log10 tumor volume).
FIG. 2. Distribution of tumor volume in each pathological stage. Stages are mutually exclusive and patients are categorized by worst pathological feature.
(p ⬍0.001). Only 15% of patients treated before 1995 had a tumor volume of 0.5 cm3 or less compared to 22.0% of those treated later. Similarly 13% of patients treated before 1995 had a tumor volume of 6 cm3 or greater compared to only 4.9% subsequently. After 1995 the proportion of T1c cancer increased, and T2 and T3 decreased, but tumor volume decreased within each clinical stage (table 1). Furthermore, there was a significant decrease in tumor volume within confined cancers and cancers with ECE alone after 1995. Overall 197 patients (15%) had evidence of recurrence after RP. PSA nonprogression probability at 5 and 10 years was 82.0% ⫾ 1.3% and 77.9% ⫾ 1.7%, respectively. Median tumor volume in patients with progression (3.13 cm3) was significantly greater than in those without progression (1.39 cm3). PSA nonprogression probability at 5 years in patients with tumor volume 12 cm3 or greater was 38.3% ⫾ 9.2% compared to 95.9% ⫾ 1.6% and 86.8% ⫾ 1.8% for patients with tumor volume less than 0.5 and 0.5 to 1.99 cm3, respectively (fig. 3). We analyzed the pattern of treatment failure in patients with or without cancer confined to the prostate in which the recurrence rate was 6% of 778 patients and 30% of 524, respectively. Tumor volume did not affect prognosis in patients with confined cancer. Of 227 men with tumor volume less than 0.5 cm3, 6 had progression compared to only 1 of 12 with
510
PROGNOSTIC ROLE OF PROSTATE CANCER VOLUME TABLE 1. Comparison of median tumor volume before and after 1995 according to clinical stage and pathological features 1983–1994
Clinical stage: T1a,b T1c T2 T3 Pathological features: Confined ECE SVI ⫹LN Gleason score: 2–6 7–10 All pts
Median Cm3 Tumor Vol
1995–2000 p Value
No. (%)
Median Cm3 Tumor Vol
No. (%)
0.87 1.82 2.20 5.62
74 (11.3) 149 (22.8) 392 (59.9) 40 (6.1)
1.55 1.01 1.34 3.25
10 (1.6) 289 (45.7) 306 (48.3) 28 (4.4)
p p p p
⫽ 0.5996 ⬍0.0001 ⬍0.0001 ⫽ 0.0003
1.08 3.67 5.19 4.95
327 (49.9) 312 (47.6) 107 (16.4) 57 (8.7)
0.84 2.70 4.77 3.94
451 (69.7) 194 (30.0) 35 (5.4) 16 (2.5)
p p p p
⫽ ⫽ ⫽ ⫽
1.27 2.81 2.16
297 (45.4) 358 (54.6) 655
0.7 1.83 1.25
324 (50.1) 323 (49.9) 647
p ⬍0.0001 p ⬍0.0001 p ⬍0.0001
0.003 0.002 0.2184 0.1187
FIG. 3. Actuarial PSA nonprogression probability as function of tumor volume for entire population of 1,302 patients
tumor volume 6 cm3 or greater. Tumor volume was also not a significant predictor of PSA progression in patients with Gleason sum 2 to 6 cancer. Univariate analysis revealed that each pathological feature recorded from RP specimens was a significant independent predictor of biochemical recurrence (p ⬍0.001 for all). However, tumor volume failed to provide independent prognostic information when controlling for the other variables in multivariate analysis (table 2). After replacing continuous tumor volume with categorized tumor volume, tumor volume was still not significant (p ⫽ 0.167). In addition, after inclusion of preoperative PSA in the analysis tumor volume was still not an independent predictor (p ⫽ 0.533). DISCUSSION
It has been suggested that the biological aggressiveness of prostate cancer is closely related to cancer volume.12 McNeal TABLE 2. Multivariate analysis of the risk of PSA progression after radical prostatectomy Relative Risk (95% CI) Tumor vol (log10) Gleason score ECE ⫹SM SVI ⫹LN
1.28 (0.87–1.90) 1.88 (1.60–2.23) 2.00 (1.36–2.94) 1.42 (0.98–2.05) 2.19 (1.53–3.14) 2.41 (1.64–3.55)
p Value p p p p p p
⫽ 0.214 ⬍0.001 ⬍0.001 ⫽ 0.062 ⬍0.001 ⬍0.001
et al showed that no patient with a tumor volume of less than 3.0 cm3 had lymph node metastases, whereas 18% of those patients with tumor volume greater than 3.0 cm3 showed spread to the regional lymph nodes.13 In our series 22 of 939 (2%) patients with a tumor volume of less than 3.0 cm3 had lymph node metastases compared to 51 of 363 (14%) patients with tumor volume greater than 3.0 cm3. In a recent study tumor volume was highly related to ECE, SVI or ⫹SM.8 Our data also indicated that increasing tumor volume correlates well with advancing pathological stage, although there are remarkably wide ranges of tumor volume among the different stages. Tumor volume in RP specimens has significantly decreased with time, especially since 1995. Even within T2 or T3 cancers, tumor volume decreased significantly (table 1). Furthermore, tumor volume decreased within each pathological stage and grade. These findings of dramatic change in tumor volume over time strongly suggested the need for reevaluation of its impact on additional prognostic information in patients treated with RP. Tumor volume was an important prognostic factor in univariate analysis in our series (fig. 3). Because of the close association with pathological stage and Gleason grade, tumor volume directly reflects recurrence rates. But tumor volume was not predictive when analyzed among patients with cancer confined to the prostate or among those with a low grade cancer (Gleason grade 2 to 6). In multivariate analysis tumor
PROGNOSTIC ROLE OF PROSTATE CANCER VOLUME
volume in RP specimens provided no additional prognostic information related to pathological features and Gleason grade. Among others, we had previously reported a similar absence of independent prognostic information that can be gained from measuring tumor volume.5–7 The present study reexamined this issue in a much larger patient population with a much longer followup. Our results differ from those of Stamey et al, who concluded that tumor volume strongly predicted biochemical recurrence after RP in patients with peripheral zone cancers.8 But when we examined our patients with these cancers, 17% of 972 patients experienced recurrence. In univariate analysis tumor volume was a significant predictor of PSA progression (p ⬍0.001) but in multivariate analysis it was no longer significant (p ⫽ 0.274). Possible explanations for these data include differences in the technique of processing the specimen (approximately 2 to 3 mm sections versus 4 to 5 mm in our series), the use of an ultrasensitive PSA assay in their study and their higher recurrence rate (38% versus 17% in our series). In fact the tumor volumes in their patients seem to be larger than those in ours (median 2.9 versus 1.6 cm3 in our series), perhaps reflecting differences in patient selection. While tumor volume is an important feature of prostate cancer, its relevance to the biological potential or clinical behavior of the cancer is limited. For example cancers less than 0.5 cm3 are considered by some to be incidental or clinically insignificant.14 Yet in our series of 239 patients with tumor volume less than 0.5 cm3, 43 tumors were poorly differentiated, 11 had ECE, 6 had ⫹SM and 2 had ⫹LN. Of these patients 7 experienced progression within 5 years. Tumor volume itself inadequately describes the biological potential of prostate cancer. If we consider an indolent or clinically unimportant cancer as one that not only has a tumor volume of less than 0.5 cm3 but also has no poorly differentiated elements and is confined to the prostate,15 then none of our 193 patients had evidence of biochemical recurrence after treatment during the 18-year followup. In our previous analysis of DNA ploidy, 15% of 33 cancer foci 0.01 to 0.1 cm3 in volume and 31% of 48 foci 0.1 to 1 cm3 in volume were nondiploid, suggesting that a certain proportion of small prostate cancer has malignant potential.16 Thus, the clinical significance of prostate cancer cannot be determined solely by tumor volume. CONCLUSIONS
Tumor volume has been decreasing with time, especially since 1995. In univariate analysis tumor volume correlated strongly with prognosis. However, with organ confined or low grade cancer, no relationship has been shown between tumor volume and biochemical recurrence rate. Tumor volume is one of the important factors used to define clinically insignificant cancers. However, in the present study it has not provided additional prognostic information for predicting recurrence when controlled for the effects of other pathological features. Therefore, the time and labor intensive evaluation
511
of tumor volume in RP specimens is not necessary as routine clinical work. REFERENCES
1. Kattan, M. W., Wheeler, T. M. and Scardino, P. T.: Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol, 17: 1499, 1999 2. Hull, G. W., Rabbani, F., Abbas, F., Wheeler, T. M., Kattan, M. W. and Scardino, P. T.: Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol, 167: 528, 2002 3. DeMarzo, A. M., Nelson, W. G., Isaacs, W. B. and Epstein, J. I.: Pathological and molecular aspects of prostate cancer. Lancet, 361: 955, 2003 4. Noguchi, M., Stamey, T. A., McNeal, J. E. and Nolley, R.: Prognostic factors for multifocal prostate cancer in radical prostatectomy specimens: lack of significance of secondary cancers. J Urol, 170: 459, 2003 5. Ohori, M., Wheeler, T. M., Kattan, M. W., Goto, Y. and Scardino, P. T.: Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol, 154: 1818, 1995 6. Epstein, J. I., Carmichael, M., Partin, A. W. and Walsh, P. C.: Is tumor volume an independent predictor of progression following radical prostatectomy? A multivariate analysis of 185 clinical stage B adenocarcinomas of the prostate with 5 years of followup. J Urol, 149: 1478, 1993 7. Salomon, L., Levrel, O., Anastasiadis, A. G., Irani, J., De La Taille, A., Saint, F. et al: Prognostic significance of tumor volume after radical prostatectomy: a multivariate analysis of pathological prognostic factors. Eur Urol, 43: 39, 2003 8. Stamey, T. A., McNeal, J. E., Yemoto, C. M., Sigal, B. M. and Johnstone, I. M.: Biological determinants of cancer progression in men with prostate cancer. JAMA, 281: 1395, 1999 9. Wheeler, T. M., Dillioglugil, O., Kattan, M. W., Arakawa, A., Soh, S., Suyama, K. et al: Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1–2 prostate cancer. Hum Pathol, 29: 856, 1998 10. Gleason, D. F.: Classification of prostatic carcinomas. Cancer Chemother Rep, 50: 125, 1966 11. Therneau, T. M. and Grambsch, P. M.: Modeling Survival Data: Extending the Cox Model. New York: Springer-Verlag, pp. 1–350, 2000 12. McNeal, J. E.: Cancer volume and site of origin of adenocarcinoma in the prostate: relationship to local and distant spread. Hum Pathol, 23: 258, 1992 13. McNeal, J. E., Bostwick, D. G., Kindrachuk, R. A., Redwine, E. A., Freiha, F. S. and Stamey, T. A.: Patterns of progression in prostate cancer. Lancet, 1: 60, 1986 14. Stamey, T. A., Freiha, F. S., McNeal, J. E., Redwine, E. A., Whittemore, A. S. and Schmid, H. P.: Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer, 71: 933, 1993 15. Ohori, M., Wheeler, T. M., Dunn, J. K., Stamey, T. A. and Scardino, P. T.: The pathological features and prognosis of prostate cancer detectable with current diagnostic tests. J Urol, 152: 1714, 1994 16. Greene, D. R., Rogers, E., Wessels, E. C., Wheeler, T. M., Taylor, S. R., Santucci, R. A. et al: Some small prostate cancers are nondiploid by nuclear image analysis: correlation of deoxyribonucleic acid ploidy status and pathological features. J Urol, 151: 1301, 1994
Vol. 172, 508 –511, August 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000130481.04082.1a
IS TUMOR VOLUME AN INDEPENDENT PROGNOSTIC FACTOR IN CLINICALLY LOCALIZED PROSTATE CANCER? EIJI KIKUCHI, PETER T. SCARDINO, THOMAS M. WHEELER,* KEVIN M. SLAWIN AND MAKOTO OHORI† From the Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York (EK, PTS, MO), and the Department of Pathology (TMW) and the Scott Department of Urology (KMS), Baylor College of Medicine and The Methodist Hospital, Houston, Texas
ABSTRACT
Purpose: There continues to be debate regarding the prognostic significance of tumor volume (TV) in radical prostatectomy (RP) specimens. We assessed the prognostic significance of TV in a large series of patients followed for a long time to discover whether the effect of TV has changed with earlier detection of smaller tumors. Materials and Methods: TV was measured planimetrically in 1,302 consecutive RP specimens with clinical stage T1–3 prostate cancer from 1983 to 2000. We correlated TV with standard clinical and pathological features, and determined the prostate specific antigen nonprogression rate. Median followup was 46 months (range 1 to 202). Results: TV was weakly associated with other clinical and pathological features. Median TV decreased significantly over time (2.16 cm3 before 1995 vs 1.25 cm3 after 1995, p ⬍0.001) and this decrease was also found within each clinical stage. In univariate analysis TV correlated strongly with the probability of progression. However, in multivariate analysis TV was not a significant independent predictor of prognosis, either in the whole cohort of patients or in those with peripheral zone cancer only. Even in univariate analysis TV had no effect on prognosis for patients in whom cancer was either confined to the prostate or was Gleason score 2 through 6. Conclusions: TV provides no independent prognostic information when considered in multivariate analysis with Gleason score and pathological stage. Measurement of TV before treatment is less likely to characterize prostate cancer accurately than assessment of tumor grade and extent. There seems to be little reason to measure TV routinely in RP specimens. KEY WORDS: neoplasms, prognosis, prostatic neoplasms, prostatectomy
Histopathological analysis of the features of cancer in radical prostatectomy (RP) specimens provides important prognostic information highly predictive of the future course of the disease.1– 4 There is uniform agreement that the pathologist should describe the overall Gleason score of the cancer, the presence of extracapsular extension (ECE) and seminal vesicle invasion (SVI), as well as the status of the surgical margins and, if lymphadenectomy was performed, lymph node involvement. However, there remains controversy about the value of measuring tumor volume. Accurate assessment of tumor volume requires tedious serial sectioning of the specimen and detailed, planimetric measurement of the area of cancer in each section. While tumor volume is clearly associated with Gleason grade and pathological stage, few studies have confirmed the independent prognostic significance in multivariate analysis when the more readily available features of the cancer are considered.5–7 Epstein et al analyzed tumor volume in a series of 185 RP specimens and found no added value once
Gleason score, pathological stage and surgical margin status were determined.6 In contrast, Stamey et al concluded that tumor volume was a primary independent factor predictive of treatment failure and they called for better methods to assess tumor volume preoperatively.8 We had previously analyzed the prognostic significance of tumor volume and had found no independent significance of tumor volume when measured planimetrically in a series of more than 500 patients.5 If tumor volume is an independent prognostic factor, pathologists should measure it routinely. However, few do, reflecting the opinion among urologists and pathologists that tumor volume is not a crucial factor. We reassessed the prognostic significance of tumor volume in a large series of patients evaluated for recurrence during a long period to determine any independent value in measuring total tumor volume. MATERIALS AND METHODS
Patient population. A total of 1,389 consecutive patients were treated with RP for clinically localized prostate cancer Accepted for publication February 13, 2004. Supported by the Leon Lowenstein Foundation and a National at Baylor College of Medicine from August 1983 to SeptemCancer Institute SPORE (CA58204). ber 2000 by 2 surgeons (PTS 1,039 patients and KMS 350 Nothing to disclose. patients). We identified a study population of 1,302 consecu* Financial interest and/or other relationship with Pintex Phartive patients who had a complete data set based on the maceuticals. † Correspondence and requests for reprints: Department of Urol- pathological features of the cancer in the RP specimens. ogy, Tokyo Medical University, 6-1-1 Nishi-shinjuku, Shinjuku-ku, Mean patient age was 62.0 years (range 38 to 81). Tokyo 160-8402, Japan (telephone: 011-81-35791-6149; FAX: 011-81Clinical stage was assigned preoperatively with the 1992 33344-4813; e-mail: [email protected]). TNM system. Serum prostate specific antigen (PSA) levels Editor’s Note: This article is the first of 5 published in this were measured by the Hybritech Tandem-R assay (Beckman issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions Coulter, Inc., Brea, California) in ambulatory patients before or at least 3 weeks after prostate biopsy or manipulation. on pages 812 and 813. 508
PROGNOSTIC ROLE OF PROSTATE CANCER VOLUME
Preoperative PSA levels were not available in 64 of the patients, of whom 50 were treated before 1987. The result obtained closest to the time of RP was used for this analysis. Pathology. RP specimens were fixed en bloc in 10% neutral buffered formalin and sectioned transversely at 4 to 5 mm intervals.9 Surgical margins were marked with indelible ink. The location and extent of invasive cancer were identified by a single pathologist (TMW), and precisely mapped in each section. The presence and location of focal or established ECE,9 SVI, positive surgical margins (⫹SM), lymph node metastases (⫹LN) and histological grade were also recorded. Grade was assigned by the Gleason method.10 Cancers with Gleason sum 7 to 10 were considered poorly differentiated. Total tumor volume was computed from cancer maps by a planimetric method using the OPTIMAS (Bioscan, Inc., Edmonds, Washington) image analysis system as previously described.5 If a patient had cancer in a transurethral resection specimen, tumor volume was measured in a manner similar to that of RP specimens and was included in the computation of total tumor volume. Followup. Median followup was 46.4 months (mean 52.3, range 1 to 202). Of these patients 442 (33.9%) were followed for more than 5 years and 93 (7.1%) for more than 10 years. Patients were followed postoperatively with digital rectal examination and serum PSA every 3 months for 1 year, every 6 months until 5 years then annually thereafter. Biochemical recurrence of disease was defined as progressive sustained increase in PSA greater than 0.4 ng/ml (Hybritech, Beckman Coulter, Inc.) in patients who had a persistently increasing PSA on at least 2 occasions. Statistical analysis. Association among clinical and pathological features, and tumor volume were assessed with the chi-square test for trends or Spearman rank correlations. Logarithmic (base 10) transformations of PSA and tumor volume were used to improve the regression analysis. The ordinal and continuous outcomes were compared with the Kruskal-Wallis or Wilcoxon rank sum test. The actuarial probabilities obtained using a Kaplan-Meier analysis were reported as median ⫾ 2 standard errors (95% CI, confidence intervals) and compared using the log rank test. We used the Cox proportional hazards regression analysis to test the association of tumor volume with the other pathological prognostic features. The 36 patients who received adjuvant therapy were included in this study and analyzed as a time dependent covariate. This form of analysis recognizes that a covariate might change with time and incorporates these new values into the model.11 The analyses were performed with the STATA version 7.0 statistical software package (StataCorp LP, College Station, Texas). RESULTS
As clinical stage and biopsy Gleason sum advanced, tumor volume significantly increased (p ⬍0.001 for both), but the level of the correlation was weak (correlation coefficient 0.284 and 0.208, respectively). PSA was also poorly related to tumor volume with R2 0.276 (fig. 1). In a subset of 221 patients with a normal size prostate (less than 25 gm), R2 between tumor volume and PSA (0.441) was strong compared to 0.225 in 263 prostates greater than 50 gm. Therefore, PSA correlates better with tumor volume in men with a small prostate, especially those less than 25 gm. As pathological stage advanced tumor volume increased significantly. However, a wide range and a significant overlap of tumor volumes among pathological stages were appreciated (fig. 2). In fact 12 of 778 (1.5%) patients with cancers confined to the prostate had a tumor volume of 6 cm3 or greater, and 14 of 142 (9.9%) with SVI and 9 of 73 (12.3%) with ⫹LN had a tumor volume of 2 cm3 or less. Tumor volume decreased significantly with time from a median of 2.16 cm3 before 1995 to 1.25 cm3 after 1995
509
FIG. 1. Correlation between PSA and tumor volume. Logarithmic (base 10) transformations of PSA and tumor volume were used. Regression line is log10 PSA ⫽ 0.788 ⫹ 0.352 ⫻ (log10 tumor volume).
FIG. 2. Distribution of tumor volume in each pathological stage. Stages are mutually exclusive and patients are categorized by worst pathological feature.
(p ⬍0.001). Only 15% of patients treated before 1995 had a tumor volume of 0.5 cm3 or less compared to 22.0% of those treated later. Similarly 13% of patients treated before 1995 had a tumor volume of 6 cm3 or greater compared to only 4.9% subsequently. After 1995 the proportion of T1c cancer increased, and T2 and T3 decreased, but tumor volume decreased within each clinical stage (table 1). Furthermore, there was a significant decrease in tumor volume within confined cancers and cancers with ECE alone after 1995. Overall 197 patients (15%) had evidence of recurrence after RP. PSA nonprogression probability at 5 and 10 years was 82.0% ⫾ 1.3% and 77.9% ⫾ 1.7%, respectively. Median tumor volume in patients with progression (3.13 cm3) was significantly greater than in those without progression (1.39 cm3). PSA nonprogression probability at 5 years in patients with tumor volume 12 cm3 or greater was 38.3% ⫾ 9.2% compared to 95.9% ⫾ 1.6% and 86.8% ⫾ 1.8% for patients with tumor volume less than 0.5 and 0.5 to 1.99 cm3, respectively (fig. 3). We analyzed the pattern of treatment failure in patients with or without cancer confined to the prostate in which the recurrence rate was 6% of 778 patients and 30% of 524, respectively. Tumor volume did not affect prognosis in patients with confined cancer. Of 227 men with tumor volume less than 0.5 cm3, 6 had progression compared to only 1 of 12 with
510
PROGNOSTIC ROLE OF PROSTATE CANCER VOLUME TABLE 1. Comparison of median tumor volume before and after 1995 according to clinical stage and pathological features 1983–1994
Clinical stage: T1a,b T1c T2 T3 Pathological features: Confined ECE SVI ⫹LN Gleason score: 2–6 7–10 All pts
Median Cm3 Tumor Vol
1995–2000 p Value
No. (%)
Median Cm3 Tumor Vol
No. (%)
0.87 1.82 2.20 5.62
74 (11.3) 149 (22.8) 392 (59.9) 40 (6.1)
1.55 1.01 1.34 3.25
10 (1.6) 289 (45.7) 306 (48.3) 28 (4.4)
p p p p
⫽ 0.5996 ⬍0.0001 ⬍0.0001 ⫽ 0.0003
1.08 3.67 5.19 4.95
327 (49.9) 312 (47.6) 107 (16.4) 57 (8.7)
0.84 2.70 4.77 3.94
451 (69.7) 194 (30.0) 35 (5.4) 16 (2.5)
p p p p
⫽ ⫽ ⫽ ⫽
1.27 2.81 2.16
297 (45.4) 358 (54.6) 655
0.7 1.83 1.25
324 (50.1) 323 (49.9) 647
p ⬍0.0001 p ⬍0.0001 p ⬍0.0001
0.003 0.002 0.2184 0.1187
FIG. 3. Actuarial PSA nonprogression probability as function of tumor volume for entire population of 1,302 patients
tumor volume 6 cm3 or greater. Tumor volume was also not a significant predictor of PSA progression in patients with Gleason sum 2 to 6 cancer. Univariate analysis revealed that each pathological feature recorded from RP specimens was a significant independent predictor of biochemical recurrence (p ⬍0.001 for all). However, tumor volume failed to provide independent prognostic information when controlling for the other variables in multivariate analysis (table 2). After replacing continuous tumor volume with categorized tumor volume, tumor volume was still not significant (p ⫽ 0.167). In addition, after inclusion of preoperative PSA in the analysis tumor volume was still not an independent predictor (p ⫽ 0.533). DISCUSSION
It has been suggested that the biological aggressiveness of prostate cancer is closely related to cancer volume.12 McNeal TABLE 2. Multivariate analysis of the risk of PSA progression after radical prostatectomy Relative Risk (95% CI) Tumor vol (log10) Gleason score ECE ⫹SM SVI ⫹LN
1.28 (0.87–1.90) 1.88 (1.60–2.23) 2.00 (1.36–2.94) 1.42 (0.98–2.05) 2.19 (1.53–3.14) 2.41 (1.64–3.55)
p Value p p p p p p
⫽ 0.214 ⬍0.001 ⬍0.001 ⫽ 0.062 ⬍0.001 ⬍0.001
et al showed that no patient with a tumor volume of less than 3.0 cm3 had lymph node metastases, whereas 18% of those patients with tumor volume greater than 3.0 cm3 showed spread to the regional lymph nodes.13 In our series 22 of 939 (2%) patients with a tumor volume of less than 3.0 cm3 had lymph node metastases compared to 51 of 363 (14%) patients with tumor volume greater than 3.0 cm3. In a recent study tumor volume was highly related to ECE, SVI or ⫹SM.8 Our data also indicated that increasing tumor volume correlates well with advancing pathological stage, although there are remarkably wide ranges of tumor volume among the different stages. Tumor volume in RP specimens has significantly decreased with time, especially since 1995. Even within T2 or T3 cancers, tumor volume decreased significantly (table 1). Furthermore, tumor volume decreased within each pathological stage and grade. These findings of dramatic change in tumor volume over time strongly suggested the need for reevaluation of its impact on additional prognostic information in patients treated with RP. Tumor volume was an important prognostic factor in univariate analysis in our series (fig. 3). Because of the close association with pathological stage and Gleason grade, tumor volume directly reflects recurrence rates. But tumor volume was not predictive when analyzed among patients with cancer confined to the prostate or among those with a low grade cancer (Gleason grade 2 to 6). In multivariate analysis tumor
PROGNOSTIC ROLE OF PROSTATE CANCER VOLUME
volume in RP specimens provided no additional prognostic information related to pathological features and Gleason grade. Among others, we had previously reported a similar absence of independent prognostic information that can be gained from measuring tumor volume.5–7 The present study reexamined this issue in a much larger patient population with a much longer followup. Our results differ from those of Stamey et al, who concluded that tumor volume strongly predicted biochemical recurrence after RP in patients with peripheral zone cancers.8 But when we examined our patients with these cancers, 17% of 972 patients experienced recurrence. In univariate analysis tumor volume was a significant predictor of PSA progression (p ⬍0.001) but in multivariate analysis it was no longer significant (p ⫽ 0.274). Possible explanations for these data include differences in the technique of processing the specimen (approximately 2 to 3 mm sections versus 4 to 5 mm in our series), the use of an ultrasensitive PSA assay in their study and their higher recurrence rate (38% versus 17% in our series). In fact the tumor volumes in their patients seem to be larger than those in ours (median 2.9 versus 1.6 cm3 in our series), perhaps reflecting differences in patient selection. While tumor volume is an important feature of prostate cancer, its relevance to the biological potential or clinical behavior of the cancer is limited. For example cancers less than 0.5 cm3 are considered by some to be incidental or clinically insignificant.14 Yet in our series of 239 patients with tumor volume less than 0.5 cm3, 43 tumors were poorly differentiated, 11 had ECE, 6 had ⫹SM and 2 had ⫹LN. Of these patients 7 experienced progression within 5 years. Tumor volume itself inadequately describes the biological potential of prostate cancer. If we consider an indolent or clinically unimportant cancer as one that not only has a tumor volume of less than 0.5 cm3 but also has no poorly differentiated elements and is confined to the prostate,15 then none of our 193 patients had evidence of biochemical recurrence after treatment during the 18-year followup. In our previous analysis of DNA ploidy, 15% of 33 cancer foci 0.01 to 0.1 cm3 in volume and 31% of 48 foci 0.1 to 1 cm3 in volume were nondiploid, suggesting that a certain proportion of small prostate cancer has malignant potential.16 Thus, the clinical significance of prostate cancer cannot be determined solely by tumor volume. CONCLUSIONS
Tumor volume has been decreasing with time, especially since 1995. In univariate analysis tumor volume correlated strongly with prognosis. However, with organ confined or low grade cancer, no relationship has been shown between tumor volume and biochemical recurrence rate. Tumor volume is one of the important factors used to define clinically insignificant cancers. However, in the present study it has not provided additional prognostic information for predicting recurrence when controlled for the effects of other pathological features. Therefore, the time and labor intensive evaluation
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of tumor volume in RP specimens is not necessary as routine clinical work. REFERENCES
1. Kattan, M. W., Wheeler, T. M. and Scardino, P. T.: Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol, 17: 1499, 1999 2. Hull, G. W., Rabbani, F., Abbas, F., Wheeler, T. M., Kattan, M. W. and Scardino, P. T.: Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol, 167: 528, 2002 3. DeMarzo, A. M., Nelson, W. G., Isaacs, W. B. and Epstein, J. I.: Pathological and molecular aspects of prostate cancer. Lancet, 361: 955, 2003 4. Noguchi, M., Stamey, T. A., McNeal, J. E. and Nolley, R.: Prognostic factors for multifocal prostate cancer in radical prostatectomy specimens: lack of significance of secondary cancers. J Urol, 170: 459, 2003 5. Ohori, M., Wheeler, T. M., Kattan, M. W., Goto, Y. and Scardino, P. T.: Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol, 154: 1818, 1995 6. Epstein, J. I., Carmichael, M., Partin, A. W. and Walsh, P. C.: Is tumor volume an independent predictor of progression following radical prostatectomy? A multivariate analysis of 185 clinical stage B adenocarcinomas of the prostate with 5 years of followup. J Urol, 149: 1478, 1993 7. Salomon, L., Levrel, O., Anastasiadis, A. G., Irani, J., De La Taille, A., Saint, F. et al: Prognostic significance of tumor volume after radical prostatectomy: a multivariate analysis of pathological prognostic factors. Eur Urol, 43: 39, 2003 8. Stamey, T. A., McNeal, J. E., Yemoto, C. M., Sigal, B. M. and Johnstone, I. M.: Biological determinants of cancer progression in men with prostate cancer. JAMA, 281: 1395, 1999 9. Wheeler, T. M., Dillioglugil, O., Kattan, M. W., Arakawa, A., Soh, S., Suyama, K. et al: Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1–2 prostate cancer. Hum Pathol, 29: 856, 1998 10. Gleason, D. F.: Classification of prostatic carcinomas. Cancer Chemother Rep, 50: 125, 1966 11. Therneau, T. M. and Grambsch, P. M.: Modeling Survival Data: Extending the Cox Model. New York: Springer-Verlag, pp. 1–350, 2000 12. McNeal, J. E.: Cancer volume and site of origin of adenocarcinoma in the prostate: relationship to local and distant spread. Hum Pathol, 23: 258, 1992 13. McNeal, J. E., Bostwick, D. G., Kindrachuk, R. A., Redwine, E. A., Freiha, F. S. and Stamey, T. A.: Patterns of progression in prostate cancer. Lancet, 1: 60, 1986 14. Stamey, T. A., Freiha, F. S., McNeal, J. E., Redwine, E. A., Whittemore, A. S. and Schmid, H. P.: Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer, 71: 933, 1993 15. Ohori, M., Wheeler, T. M., Dunn, J. K., Stamey, T. A. and Scardino, P. T.: The pathological features and prognosis of prostate cancer detectable with current diagnostic tests. J Urol, 152: 1714, 1994 16. Greene, D. R., Rogers, E., Wessels, E. C., Wheeler, T. M., Taylor, S. R., Santucci, R. A. et al: Some small prostate cancers are nondiploid by nuclear image analysis: correlation of deoxyribonucleic acid ploidy status and pathological features. J Urol, 151: 1301, 1994