Japanese Journal of Clinical Oncology 31:74-81 (2001)
© 2001 Foundation for Promotion of Cancer Research
A Study of Pretreatment Nomograms to Predict Pathological Stage and Biochemical Recurrence After Radical Prostatectomy for Clinically Resectable Prostate Cancer in Japanese Men
Departments of 1Urology and 4Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa and Departments of 2Urology and 3Pathology, Kurashiki Central Hospital, Kurashiki, Okayama, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: Accurate pretreatment identification of the risks that prostate cancer has extended beyond the gland and that it will recur would significantly influence practice patterns. Preoperative nomograms to predict such risks have not been developed for the oriental male population.
Methods: Construction of nomograms to predict preoperatively pathological outcome and early biochemical failure following radical prostatectomy in Japanese males was based on logistic regression analysis, with predicted probabilities and 95% confidence intervals for the final model being obtained by repeating the analysis on 1000 bootstrap samples from the original cohort.
Results: Prostate-specific antigen level, clinical stage and biopsy Gleason score contributed significantly to the prediction of pathological stage and of biochemical failure in the univariate analysis (p < 0.001). Combined use of these three variables predicted these treatment outcomes better than any single variable (p < 0.001). Nomograms combining these three variables to predict final pathological findings and early biochemical failure were then developed. The medians and 95% confidence intervals of the predicted probabilities are presented in the nomograms.
Conclusions: This information enables clinicians to use their nomograms when counseling Japanese patients, leading to more informed treatment decisions and helping to identify those with a high risk of early biochemical failure. The nomograms may also be used to assure comparability of different treatment modalities in investigational trials.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Several studies from the urological and oncological literature support the conclusion that the combined use of prostate-specific antigen (PSA), clinical stage and biopsy Gleason score can predict the likelihood of pathological organ confinement, biochemical failure and subsequent metastasis in patients managed with definitive local therapy for prostate cancer (1–6). Preoperative nomograms based on this information have been derived (2–6), but for Western populations and may not be applicable to Japanese males, since practice patterns are different and lower levels of serum PSA are seen in Japanese men than in Western men of the same age (7).
Pathological stage of the tumor is the most influential prognostic factor for progression after radical prostatectomy (8). Patients with early biochemical failure are more likely to harbor occult micrometastases at the time of local therapy (9). Accurate identification of the risks of extraprostatic disease extension and of disease recurrence prior to therapy would thus significantly influence practice patterns and also be useful in clinical trials to assure comparability of treatment (10,11).
This paper reports the development of nomograms to predict pathological outcome and early biochemical failure following radical prostatectomy in Japanese males. To our knowledge, this is the first such study in an oriental male population.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Population
The study population comprised 178 male patients treated with a radical retropubic prostatectomy and bilateral pelvic lymph node dissection at Kitasato University Hospital (n = 110) and Kurashiki Central Hospital (n = 68) between October 1992 and May 1999. Inclusion in this study required: (1) no preoperative hormonal ablation or chemotherapy; (2) no postoperative adjuvant hormonal or radiation therapy until progression; (3) preoperative serum PSA level determined by Dainapack IMx PSA (Dinabot, Tokyo) or Dainapack AxSYM PSA (Dinabot, Tokyo); (4) ultrasound-guided systematic needle biopsy at four or more separate sites; and (5) biopsy and prostatectomy specimens available for review. Results of PSA assays were not interconverted because they were considered virtually the same (12).
Pretreatment Staging and Radical Prostatectomy
All patients with prostate cancer were thoroughly examined for staging, including digital rectal examination, prostatic acid phosphatase, intravenous urography, computed tomography, magnetic resonance imaging and bone scanning supplemented by radiographs of abnormal areas. A clinical stage was assigned by two urologists (S.E. and Y.A.) in accordance with the unified tumor node metastasis (TNM) system (13). Radical prostatectomy was conducted by the retropubic approach by these surgeons or was under their supervision.
Pathological Examination
All biopsy specimens were examined by a single pathologist (S.K.). Tumor grade was determined according to the Gleason grading system. The number of cores showing tumor traces and maximum tumor length in biopsy cores were also recorded. The radical prostatectomy specimens were examined independently by two different pathologists (S.K. and C.T.) using the whole-organ step-section technique. Briefly, specimens were fixed in 10% formalin and sectioned at 5 mm intervals in a plane perpendicular to the long axis of the gland, from the prostatic apex to the tip of the seminal vesicles. Each section was stained with hematoxylin and eosin. Depth of capsular penetration by tumor was determined on the basis of criteria specified previously (7). A search for and assessment of seminal vesicle invasion and lymph node metastasis were made.
Follow-up
After surgery, patients were evaluated at 3–6 month intervals with a PSA measurement and digital rectal examination. Postoperative PSA values were considered elevated (biochemical failure) if values of 
0.1 ng/ml were obtained on two consecutive visits 1 month apart. If PSA never became undetectable postoperatively, then PSA failure was considered to have occurred at time equal to zero.
Statistical Analysis
Logistic regression analysis with the likelihood ratio test was used to define the correlation between each preoperative variable (clinical stage, biopsy Gleason score and PSA) and each component of pathological stage and biochemical failure. Using these three variables, a logistic model was established to predict the probability of pathologically advanced disease, extracapsular extension, seminal vesicle involvement and early biochemical failure in clinically resectable prostate cancer. The Peason 
2 goodness-of-fit test was used to test the internal validity of these models. Logistic regression analysis gave a score (A) with A = a + b1 x 1 + b2 x 2 + ... as a linear combination of predictors (x1,x2, ...). Probability was determined as P = 1/(1 + e–A).
The nomograms were constructed from predicted probabilities and 95% confidence intervals for the final model, which were obtained by repeating the analysis on 1000 bootstrap samples from the original cohort, as in Partin et al. (4). All these analyses were conducted using a statistics graphic data measurement software program (STATA Computing Resource, Los Angeles, CA; URL, http://www.stata.com; E-mail, stata@stata.com). The calculation of 95% confidence intervals for the final model was made possible by the aid of the STATA technical support center.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Characteristics and Outcome of Surgery
The median age of the 178 patients at radical prostatectomy was 65.0 years (range, 49–80 years; mean, 64.9 years). The median follow-up period after radical surgery was 41.5 months (range, 2.0–82.0 months; mean, 40.9 months).
Median preoperative serum PSA was 7.9 ng/ml (range, 1.2 – 136.0 ng/ml; mean, 13.0 ng/ml). The proportion of patients with PSA in the ranges 
4.0, 4.1–10.0, 10.1–20.0 and 20.1 ng/ml were 14.0, 49.4, 20.2 and 16.3%, respectively (Table 1). The 178 patients were classified clinically as stage T1c (92), T2a (22), T2b (35), T2c (13), T3a (3), T3b (3) and T3c (10). All T3 subgroups were treated as T3 for the purpose of analysis.
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Sextant biopsies were obtained in 54.5% (97/178) of the patients. The remaining patients had <6 (3.4%, 6/178) or >6 (up to 12) biopsies (42.1%, 75/178). Biopsy tumor grade was classified as Gleason score 2–4, 5 and 6 in 21 (11.8%), 24 (13.5%) and 33 (18.5%) patients, respectively. One hundred patients had poorly differentiated tumors, with Gleason scores of 7 in 62 patients (34.8%) and 8–10 in 38 patients (21.3%).
Eighty-one patients (45.5%) had locally advanced disease on final pathological examination; extracapsular extension was seen in 75 patients (42.1%), seminal vesicle involvement in 35 (19.7%) and microscopic nodal involvement in 11 (6.2%). To date, 58 patients have experienced PSA failure at a median of 8.0 months following surgery (range, 0.0–58.0).
Results of Logistic Regression Analysis and Creation of Nomograms for Predicting Final Pathological Stage and Biochemical Failure
Prostate-specific antigen level, clinical stage and biopsy Gleason score contributed significantly to the prediction of pathological stage and biochemical failure in the univariate analysis (p < 0.001). As in our previously reported logistic regression analysis (14,15), combined use of these three variables predicted pathological stage and biochemical failure better than any single variable (p < 0.001). The results of the Peason 2 goodness-of-fit test also indicated that these models fit reasonably well and thus internal validity was confirmed. Tables 2(2A, 2B2b, 2C2c, 2D2d) and 3(3A3a, 3B3b, 3C3c, 3D3d) show nomograms combining these three variables to predict final pathological findings and early biochemical failure, respectively. Data for predicting lymph node involvement were not available owing to the small number of patients with nodal metastasis. Numbers within the nomogram represent the percentage probability of having a given final pathological stage or of biochemical failure, based on all three variables combined. The 95% confidence intervals could not be calculated in several cohorts owing to the small number of cases.
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As an illustration of the use of these nomograms, a patient with T2b disease, a PSA of 15.0 ng/ml (IMx or AxSYM assay equivalent) and a Gleason score of 7 has a 72% chance of having pathologically advanced disease, a 67% chance of extracapsular extension, a 28% of seminal vesicle involvement and a 59% chance of early biochemical failure. Values for this patient obtained from the nomograms of Partin and co-workers (3,4) and D’Amico et al. (5) were 87, 51, 18 and 42% for each event, respectively. There were trends of slightly higher values in the predicted probabilities of pathologically advanced disease and extracapsular extension in the nomogram of Partin and co-workers, but values for seminal vesicle involvement tended to be higher in this study. Values for predicting biochemical failure also tended to be higher in this study than those of D’Amico et al. (5).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Accurate and early identification of men likely ultimately to experience disease progression following definitive therapy for prostate cancer would be particularly useful in discussing treatment options and considering early adjuvant therapy. It would also be helpful in assuring comparability of different treatment modalities in investigational trials. The combined use of PSA, clinical stage and biopsy Gleason score has been advocated as a means for improving preoperative predictability of pathological stages and biochemical failure (1–6).
Partin and co-workers popularized the use of a pretreatment nomogram based on PSA, clinical stage and biopsy Gleason score to predict the pathological stage of localized prostate cancer (3,4). Multi-institutional modeling and validation of the clinical utility enabled clinicians to use their nomograms when counseling individual patients, leading to more informed treatment decisions based on the probabilities of different pathological stages. Indeed, probability estimates are easier to understand and more familiar to patients than other ways of presenting their situations. D’Amico et al. developed a pretreatment nomogram for predicting biochemical failure after radical prostatectomy or external beam radiation therapy for clinically localized prostate cancer (5). They could successfully identify those with a high risk (>50%) of early (2 years) biochemical failure, who are thus at risk of subsequent distant failure. The nomograms were also considered useful for selecting high-risk patients for trials evaluating adjuvant systemic and improved local therapies. Hence they may be used to assure comparability of different treatment modalities in investigational trials.
While a nomogram might be applicable to the patient population in which it was developed, extrapolation of the results to other populations may be of limited usefulness or validity (16). This is particularly true when applying nomograms developed in a Western population to oriental males. Since the serum PSA for a Japanese male is generally lower than that of a Caucasian of the same age, primarily because the Japanese man’s prostate gland is smaller and his 5
-reductase activity lower, the clinical significance of a given serum PSA value may be different in the two populations (7). Differences in practice patterns between countries, such as prevalence of PSA-based screening programs leading to differences in tumor volumes, may also affect overall pathologic tumor stages (16,17). All these considerations may in part account for slight differences in the predicted probabilities of each event between studies (3–5). Race-specific nomograms therefore need to be established.
We have previously reported that the use of the number of cores with cancer and maximum cancer length in conjunction with the three variables (PSA, clinical stage and biopsy Gleason score) significantly improved predictability of final pathological findings in clinically resectable prostate cancer (14). This finding was reproduced in the present study. However, the improvement quantitated by the areas under receiver operating characteristic curves was modest, an increase of ~8% (0.7935 versus 0.8628, p = 0.01). Similar findings were obtained for predicting biochemical failure: an increase of ~2% (0.8107 versus 0.8291, p < 0.01), but such levels of improvement may not be clinically significant. D’Amico et al. suggested that a significant amount of the variation in biochemical outcome following definitive therapy needed to be explained by other clinical, pathologic and/or molecular factors (5). Improvement in PSA outcome prediction may therefore need further identification of other predictors.
The use of two different sets of patient information from different hospitals in this study may have advantages in minimizing institutional bias. However, the assessment of clinical stage and method of ultrasound-guided biopsy are operator dependent and may possibly be inconsistent. Although serum PSA was measured using the same assay, inter-laboratory variations in PSA levels are not uncommon. There may also have been differences in the classification of extraprostatic cancer by the respective pathologists. The relatively short observation period of 41.5 months is also problematic. In one study, 23% of the men who ultimately demonstrated biochemical failure had an undetectable PSA for at least 5 years after radical prostatectomy (18). It is highly likely that more patients will develop biochemical failure in longer follow-up. Our nomogram for biochemical failure was therefore only for predicting early events following surgery.
The present model may not necessarily be applicable to different populations. Although the bootstrap procedure was applied to yield estimates of the medians and 95% confidence intervals of the predicted probabilities, our study is limited by the absence of validation analysis. A wide range and lack of 95% confidence intervals in some cohorts were also due to the small number of patients.
In this study, an individual patient was provided with separate predictors for each aspect of pathologically advanced disease (e.g. for extracapsular extension regardless of seminal vesicle or lymph node involvement or for seminal vesicle involvement regardless of extracapsular extension or lymph node involvement). This is similar to what was originally done by Partin et al. (3). In their more recent work, they assigned the worst, mutually exclusive category of pathological findings to a patient, since they view this as more practical (4). Hence the interpretation and comparison of data sets need caution and careful consideration.
Overestimation of the risk may be more deleterious to a patient who has a good chance of cure by appropriate treatment. More data from a greater number of patients and validation in different populations are essential before recommending this model. Further work is warranted.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported in part by grants from the Ministry of Health and Welfare of Japan (11–10) and the Foundation for Promotion of Cancer Research in Japan. We thank Dr W. A. Thomasson for expert editorial assistance.
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FOOTNOTES |
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+ For reprints and all correspondence: Shin Egawa, Department of Urology, Kitasato University School of Medicine, 1–15–1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan. E-mail: s-egpro@sa2.so-net.ne.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received July 27, 2000; accepted December 4, 2000.
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