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Originally published as JCO Early Release 10.1200/JCO.2003.12.037 on August 11 2003 © 2003 American Society for Clinical Oncology The Addition of Interleukin-6 Soluble Receptor and Transforming Growth Factor Beta1 Improves a Preoperative Nomogram for Predicting Biochemical Progression in Patients With Clinically Localized Prostate Cancer
From the Baylor Prostate Center, the Scott Department of Urology, and Department of Pathology, Baylor College of Medicine; the Methodist Hospital, Houston, TX; and the Departments of Urology and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Kevin M. Slawin, MD, Scott Department of Urology, Baylor College of Medicine, 6535 Fannin St, Houston, TX 77030; e-mail: kslawin{at}bcm.tmc.edu.
Purpose: Several preoperative prostate cancer nomograms have been developed that predict risk of progression using pretreatment prostate-specific antigen (PSA) level, clinical stage, and biopsy Gleason grade. We describe the development and performance of a new nomogram. The nomogram adds new markers to the standard clinical predictors that reflect the biologic behavior of prostate cancer: pretreatment plasma levels of interleukin-6 soluble receptor (IL6SR) and transforming growth factor beta1 (TGF-ß1). Patients and Methods: Between November 7, 1994 and December 22, 1997, 714 patients with stage cT1c to cT3a prostate cancer and no prior therapy were treated with radical prostatectomy at the Methodist Hospital, Houston TX. Plasma levels of IL6SR and TGF-ß1 were measured in banked preoperative plasma. With these data, a nomogram was developed to predict the probability of PSA progression within 5 years of surgery. The nomogram was validated with bootstrapping to assess its discrimination and calibration performance. Results: In the multivariable Cox model, PSA (P = .004), IL6SR (P < .001), TGF-ß1 (P < .001), primary Gleason grade (P < .002), and secondary Gleason grade (P = .029) were associated with PSA progression, whereas clinical stage (P = .696) was not. The nomogram seemed to be well calibrated and had a bootstrap-corrected area under the receiver operating characteristic curve (ie, concordance index) of 0.83. For comparison, a nomogram that omitted IL6SR and TGF-ß1 achieved a concordance index of only 0.75. Conclusion: We found that pretreatment plasma levels of IL6SR and TGF-ß1 improved the ability to predict biochemical progression by a prognostically substantial margin. A nomogram including the pretreatment levels of these molecular markers, along with standard clinical markers, has been developed and internally validated.
SEVERAL PREOPERATIVE and postoperative prostate cancer nomograms have been developed to predict prostate cancer stage and risk of disease progression after attempted curative therapy. For surgery, we have developed and validated1 a tool that uses pretreatment prostate-specific antigen (PSA) level, clinical stage, and biopsy Gleason sum to predict the probability of cancer recurrence as experienced by a detectable and rising PSA level within 5 years of treatment, with an area under the receiver operating characteristic curve of 0.74. The addition of other clinical parameters (such as percentage of positive biopsy cores2) to this core group, however, has failed to significantly improve the accuracy of this and other predictive tools.3,4 Recently, there has been a realization that pretreatment PSA levels, the primary predictive parameter in the majority of these tools, may reflect primarily the presence of benign prostatic hyperplasia (BPH) rather than prostate cancer. Stamey et al5,6 recently reported that for patients with a PSA level of  9 ng/mL, PSA poorly reflected the risk of progression after radical prostatectomy but was significantly correlated with the overall volume of the radical prostatectomy specimen, which is a direct reflection of the degree of BPH present. We and others have also failed to detect an incremental predictive value for preoperative PSA for disease progression in several studies that have included patients with clinically localized prostate cancer undergoing radical prostatectomy more recently,7,8 who had lower median PSA levels than patients in most older series. Therefore, there is an imminent need for nomograms that include novel markers that are specifically associated with biologically aggressive prostate cancer for improved prediction of outcome in patients diagnosed with clinically localized prostate cancer. This need is especially apparent in those patients diagnosed with lower PSA levels, to extend and perhaps even preserve the clinical performance of predictive nomograms for future patients. We and others have previously shown that plasma levels of transforming growth factor beta1 (TGF-ß1) and interleukin-6 soluble form of receptor (IL6SR) are markedly elevated in patients with distant prostate cancer metastases.9–13 We recently demonstrated that in patients undergoing radical prostatectomy for clinically localized disease, preoperative plasma TGF-ß1 and IL6SR were associated with eventual prostate cancer progression, after adjustment for the effects of clinical stage, biopsy Gleason sum, and preoperative PSA.9,10 Furthermore, preoperative plasma levels of these markers were associated with aggressive disease progression, suggesting that this association was due to the presence of occult micrometastases already present at the time of surgery. This led us to the present study, in which we have developed and internally validated a prognostic model that adds these two molecular markers to standard clinical predictors to determine whether we could improve on the level of accuracy achieved by our standard, externally validated pretreatment nomogram.
Patients All 814 patients admitted to the Methodist Hospital (Houston, TX) with the intent to treat their clinically localized prostate cancer (cT1c-3a, NX, M0) with radical retropubic prostatectomy by full-time faculty during the period from November 7, 1994 through December 22, 1997 were potential candidates for this analysis. Under an institutional review board–approved protocol investigating clinical markers of prostate cancer, clinical data, serum, and tissue samples were obtained for 800 of these patients after appropriate consent was obtained. Each patient was assigned a clinical stage according to the 1992 tumor-node-metastasis classification system (T1, nonpalpable tumor confined to the prostate; T2, confined tumor palpable or visible by imaging; T3a, palpable or visible tumor extending through the capsule of the prostate unilaterally; NX, regional nodal metastases not assessed clinically; M0, no evidence of distant metastases).14 Pelvic lymph node dissections were performed on all men. Radical prostatectomy was aborted in two of 17 patients who were found to have nodal metastases on frozen section analysis during the operation; these men are not excluded from the analysis, consistent with an intent-to-treat principle. However, 26 men initially treated with definitive radiotherapy (23 men treated with external-beam radiation therapy and three treated with cryotherapy) and 56 who were treated with neoadjuvant hormonal therapy before the radical procedure were excluded from the analysis. The four patients with one or more of the following missing values were excluded (PSA, n = 1; biopsy Gleason grade, n = 3; clinical stage, n = 1). This left 714 men for analysis.
The median age of all patients was 62 years (range, 40 to 81 years) and 86% of the patients were white. Pretreatment PSA was measured by the Hybritech Tandem-R assay (Hybritech Inc, San Diego, CA). The Gleason grade of each tumor was assigned by one pathologist. Percentage of positive cores was calculated by taking the ratio of the positive cores to the total cores removed, and multiplying the value by 100. IL6SR and TGF-ß1 were measured as described previously.9,10 Serum and plasma samples were collected after a preoperative overnight fast on the morning of the day of surgery, at least 4 weeks after transrectal-guided needle biopsy of the prostate. Blood was collected into Vacutainer CPT 8-mL tubes containing 0.1 mL of 1 M sodium citrate (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ) and centrifuged at room temperature for 20 minutes at 1,500 x g. The top layer corresponding to plasma was decanted using sterile transfer pipets and immediately frozen and stored at -80°C in polypropylene cryopreservation vials (Nalgene; Nalge Nunc, Rochester, NY). For quantitative measurements of IL6SR and TGF-ß1 levels, we used quantitative immunoassays (R&D Systems, Minneapolis, MN). For TGF-ß1, before assessment, an additional centrifugation step of the plasma was performed at 10,000 x g for 10 minutes at room temperature for complete platelet removal. Recombinant TGF-ß1 was used as standard. Every sample was run in duplicate, and the mean was used for data analysis. The differences between the two measurements were minimal. The clinical characteristics are listed in Table 1
Biochemical Progression The time of biochemical progression was defined as the earliest date, after the date of surgery, that the serum PSA level was 0.2 ng/mL or higher, or the patient received hormone therapy. No patient experienced clinical failure before biochemical progression. Adjuvant radiation therapy was not considered clinical failure.
Statistical Analysis For nomogram validation, we assessed both discrimination and calibration capabilities. Discrimination refers to the ability of the nomogram to rank patients by their risk, such that patients with higher risk of treatment failure should be more likely to experience treatment failure. We assessed discrimination because it is easily quantifiable using the concordance index,16 which is similar to an area under the receiver operating characteristic curve, and applicable time-until-event data. We measured the calibration of the nomogram through visual examination of plots of predicted versus actual probabilities. Bootstrapping was used to obtain more generalizable estimates of expected future performance. All statistical analyses were performed using S-Plus software (PC Version 2000 Professional; Insightful Corp, Redmond, WA) with additional functions (called Design)16 added. All P values resulted from use of two-sided statistical tests.
Of the 714 patients available for analysis, 86 experienced biochemical progression after radical prostatectomy, and seven received hormone therapy in the absence of biochemical progression by our definition. For patients without disease progression, median follow-up was 55 months (maximum, 96.6 months), and 22% had their progression status verified within 1 year of this analysis. There were 243 patients with at least 60 months progression-free follow-up. Overall progression-free probability was 84% (95% CI, 81% to 87%) at 5 years (Fig 1  ). In the multivariable Cox model, PSA (P = .001), IL6SR (P < .001), TGF-ß1 (P < .001), primary Gleason grade (P < .001), and secondary Gleason grade (P = .029) were associated with PSA progression, whereas clinical stage (P = .696) was not. Removal of IL6SR and TGF-ß1 reduced the model fit (likelihood ratio test, P < .001).
A nomogram was constructed on the basis of the Cox model and appears in Figure 2 . The nomogram is used by first locating a patient’s position on each predictor variable scale (PSA through TGF-ß1). Each scale position has corresponding prognostic points (top axis). For example, a PSA of 15 contributes approximately 9 points; this is determined by comparing the location of the 15 value on the PSA axis to the points scale above and drawing a vertical line between the two axes. The point values for all clinical predictor variables are determined in a similar manner and are summed to arrive at a total points value. This value is plotted on the total points axis (second from the bottom). A vertical line drawn from the total points axis straight down to the 60-month PSA progression-free probability axis will indicate the patient’s probability of remaining free from biochemical progression for 5 years, assuming he remains alive.
The nomogram was evaluated for its ability to discriminate among patients’ risk of biochemical progression. This was measured as the area under the receiver operating characteristic curve for censored data (ie, concordance index). This value represents the probability that when two patients are randomly selected (one with progression and one with longer follow-up), the patient who progressed first had the worse prognosis (from the nomogram). This measure can range from 0.5 (no better than chance) to 1.0 (perfect ability to discriminate). To derive an estimate of expected performance of the nomogram against new patients, we performed bootstrapping, a statistical method in which sampling, nomogram building, and nomogram evaluation are repeated a large number of times.17 With the use of bootstrapping, the area under the receiver operating characteristic curve was estimated to be 0.83. For comparison purposes, we bootstrapped a model that omitted IL6SR and TGF-ß1, and this model had a concordance index of 0.75.
Figure 3
Percentage of positive cores was missing in 35 of the 714 patients. When we examined the subset of 679 patients who had values for this variable, we found that the model including percentage of positive cores as a predictor had a concordance index inferior to that of the model that lacked percentage of positive cores (0.81 bootstrap corrected). This apparently was because of the reduced sample size associated with the model that contained percentage of positive cores. Therefore, our final model excludes percentage of positive cores as a predictor.
Figure 4
Building on previous work in this area, we have constructed a prognostic nomogram that adds two novel molecular markers, IL6SR and TGF-ß1, to a core group of clinical variables. The new nomogram better predicts the risk of biochemical progression 5 years after radical prostatectomy for clinically localized prostate cancer. The addition of these two predictors to our previously published nomogram resulted in a substantial improvement in discriminatory ability, increasing the bootstrap-corrected concordance index from 0.75 to 0.83. IL6SR and TGF-ß1 were chosen because of their robust, distinctive, and complementary association with features of prostate cancer aggressiveness and metastases at the earliest disease stages before more obvious clinical evidence of metastases (Shariat et al, submitted for publication).9,10 We have performed a comprehensive evaluation of the performance of a host of potential biomarkers for prostate cancer invasion, progression, and metastasis, including insulin-like growth factor-1 and its binding proteins type 2 and 3,8 vascular endothelial growth factor and soluble vascular cell adhesion marker type 1 (manuscript in preparation), and IL-6.9 Although preoperative circulating levels of some markers were associated with features of biologically aggressive prostate cancer or progression and metastasis, when evaluated in preoperative multivariable models that adjusted for standard features, IL6SR and TGF-ß1 were the only biomarkers associated with prostate cancer progression after surgery (data not shown). To further test the association of these two markers with prostate cancer, we measured pre- and postoperative levels of TGF-ß1 and IL6SR in a consecutive cohort of 302 patients who underwent radical prostatectomy (Shariat et al, submitted for publication). We confirmed the strong association of preoperative plasma levels of TGF-ß1 and IL6SR with established features of aggressive primary prostate cancer, with clinically evident and occult metastases present at the time of primary treatment, and with eventual disease progression. Although both of these markers were associated with frank metastatic disease to lymph nodes, we identified definite distinctions in the associations of these markers with other clinical and pathologic parameters of the local tumor. For example, preoperative plasma levels of TGF-ß1 were associated with features of locally invasive disease, such as extraprostatic extension and seminal vesicle invasion, but not the histologic grade of disease. Conversely, preoperative plasma levels of IL6SR were associated with pathologic grade of disease (ie, Gleason sum), but not extraprostatic extension or seminal vesicle invasion. Furthermore, preoperative levels of IL6SR were positively correlated with local tumor volume, whereas TGF-ß1 levels were not. In addition, we found that in patients who experienced disease progression, the postoperative TGF-ß1 levels decreased only minimally (9%) and were not significantly different from preoperative TGF-ß1 levels. Conversely, after prostate removal, plasma IL6SR levels decreased significantly both in patients who experienced disease progression and in those who did not. In aggregate, these data suggest that circulating levels of IL-6 and its soluble receptor seem to be associated with the potential of prostate cancer to metastasize, but not with the metastases themselves. In contrast, it seems that circulating levels of TGF-ß1 are more closely associated with the metastatic process, either because of direct release from foci of metastatic tumor or as a result of the host’s response to cancer invasion and dissemination.
Others have demonstrated the value of using predictive parameters to stratify patients with regard to their risk of progression after primary therapy for prostate cancer. These approaches have primarily focused on using clinical parameters (such as pretreatment PSA level or biopsy Gleason sum) to categorize patients into low-, intermediate-, and high-risk groups. Although superficially this approach may seem less cumbersome, the reduction of continuous-risk variables, maintained in nomograms, into defined risk categories diminishes the level of predictive accuracy substantially. For example, using data from our patient cohort, classifying patients as low or high risk2 results in a concordance index of only 0.69—considerably less discriminating than the nomogram’s concordance index of 0.83. In clinical terms, this reduction in the concordance index translates into profoundly different anticipated outcomes for patients faced with this disease. For example, Figure 4 We found that the concordance index, which is based on standard clinical factors alone, was 0.75. This finding is consistent with earlier work with nomograms for surgery,18 external-beam radiation therapy,19 and brachytherapy,20 such that standard clinical factors alone cannot seem to achieve concordance indices above approximately 0.75. The addition of molecular markers seems to have resulted in a substantial increase in predictive accuracy, allowing us to achieve a concordance index of 0.83. Improving our ability to predict treatment outcomes for clinically localized prostate cancer is critical. In this disease, treatment choices need to be tailored to the preferences of the individual patient,21 who is forced to make a decision on the basis of predictions of treatment outcomes. The risks of complications must be weighed against the risks of progression for untreated cancer and the predicted ability of aggressive therapy to delay or prevent progression. Partin et al4,22,23 were among the first to provide a nomogram for use in this context by predicting final pathologic stage. We have extended their work by predicting biochemical progression, an end point more definitive than final pathologic stage.24 Although treatment decision making is substantially more complicated than choosing the therapeutic strategy that seems to minimize the likelihood of biochemical progression, prediction of this end point is a valuable component of decision making for this disease.
In addition to serving as a prognostic tool, the nomogram in Figure 2 The nomogram developed here has certain limitations. First, we developed the nomogram in a population of patients treated with radical prostatectomy, so it is only applicable for patients who otherwise seem to be candidates for surgery, rather than all patients diagnosed with prostate cancer. Because a patient and his physician may exert selection bias for a particular treatment (in this case, radical prostatectomy) on the basis of the characteristics of the cancer, it would be most appropriate to apply the nomogram as a last step in the decision-making process after the patient has decided on radical prostatectomy as his treatment choice. The nomogram is not necessarily applicable for changing the mind of the patient who has decided against radical prostatectomy because we do not know his progression probability; rather, it is to be used for revisiting the choice of surgery. Future research should examine whether these two novel serum assays are prognostic in other treatment modalities, such as external-beam and interstitial radiation therapy. Second, the nomogram predicts biochemical progression as an end point. All patients who progress biochemically do not die as a result of their disease or even progress to metastasis. Biochemical progression is an early warning sign that treatment has not necessarily been effective. Although this is a potential weakness of this and all models that predict biochemical progression, this end point is nonetheless important. No patient would select, nor would any clinician recommend, an aggressive therapy that is destined to lead to biochemical progression (ie, 100% chance of failing biochemically), despite the potentially loose association with metastasis and additional disease sequelae. Thus, it is a matter of risk-benefit where one draws the line when selecting a therapy. Furthermore, patients who progress biochemically, despite having no disease-related symptoms, have reduced quality of life.25 We are currently developing nomograms that predict progressive disease with aggressive features that would be more likely to progress to clinical metastases. These nomograms are likely to include molecular markers, such as IL6SR and TGF-ß1, because of their association with micrometastatic disease rather than with locally recurrent prostate cancer. Third, our nomogram predicts only to the 5-year point, beyond which progression is indeed possible. In the future, we hope that we and others produce data containing these markers with more mature follow-up. Nonetheless, we are not aware of other preoperative nomograms developed in the PSA era that predict probabilities longer than 5 years. Fourth, all data are from the same institution, and we have no outside validation data set. All Gleason grading was performed by one expert pathologist. The accuracy of the nomogram in the wider medical community assumes comparable grading accuracy by other pathologists. Despite lack of validation, the factors driving the nomogram are objectively measured, unlike clinical staging or histologic grading. In this regard, we would expect the nomogram to validate well given the good external validation1,26 of the prior nomogram that relied more heavily on subjective predictors. Fifth, the nomogram is a little cumbersome to use because it involves drawing lines and summing points. For this reason, we plan to offer computer implementation of the model on our Web sites (http://www.nomograms.org and http://www.drslawin.com), where we offer several other free cancer prediction tools. In conclusion, we developed a nomogram that allows one to predict the probability of biochemical progression after radical prostatectomy for localized prostate cancer (clinical stage T1c-T3a, NX, M0) from the clinical stage, Gleason grade, serum PSA level, and plasma levels of IL-6SR and of TGF-ß1. The nomogram may assist the physician and patient in deciding whether radical prostatectomy is an acceptable treatment option. It may also be useful in identifying patients at high risk of biochemical progression who may benefit from neoadjuvant treatment protocols.
The authors indicated no potential conflicts of interest.
Supported in part by grants from the Austrian Science Fund, the Frost Foundation, Inc, and the National Cancer Institute Specialized Program of Research Excellence (SPORE CA58203).
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2. D’Amico AV, Whittington R, Malkowicz SB, et al: Clinical utility of the percentage of positive prostate biopsies in defining biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer. J Clin Oncol 18:1164–1172, 2000
3. D’Amico AV, Whittington R, Malkowicz SB, et al: Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol 17:168–172, 1999 4. Partin AW, Mangold LA, Lamm DM, et al: Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 58:843–848, 2001[CrossRef][Medline] 5. Noguchi M, Stamey TA, McNeal JE, et al: Preoperative serum prostate specific antigen does not reflect biochemical failure rates after radical prostatectomy in men with large volume cancers. J Urol 164:1596–1600, 2000[CrossRef][Medline]
6. Stamey TA: Preoperative serum prostate-specific antigen (PSA) below 10 microg/l predicts neither the presence of prostate cancer nor the rate of postoperative PSA failure. Clin Chem 47:631–634, 2001
7. Shariat SF, Gottenger E, Nguyen C, et al: Preoperative blood reverse transcriptase-PCR assays for prostate-specific antigen and human glandular kallikrein for prediction of prostate cancer progression after radical prostatectomy. Cancer Res 62:5974–5979, 2002
8. Shariat SF, Lamb DJ, Kattan MW, et al: Association of preoperative plasma levels of insulin-like growth factor I and insulin-like growth factor binding proteins-2 and -3 with prostate cancer invasion, progression, and metastasis. J Clin Oncol 20:833–841, 2002 9. Shariat SF, Andrews B, Kattan MW, et al: Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis. Urology 58:1008–1015, 2001[CrossRef][Medline]
10. Shariat SF, Shalev M, Menesses-Diaz A, et al: Preoperative plasma levels of transforming growth factor beta1 strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol 19:2856–2864, 2001 11. Adler HL, McCurdy MA, Kattan MW, et al: Elevated levels of circulating interleukin-6 and transforming growth factor-B1 in patients with metastatic prostatic carcinoma. J Urol 161:182–187, 1999[CrossRef][Medline] 12. Kakehi Y, Oka H, Mitsumori K, et al: Elevation of serum transforming growth factor beta 1 level in patients with metastatic prostate cancer. Urol Oncol 2:131–135, 1996
13. Nakashima J, Tachibana M, Horiguchi Y, et al: Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res 6:2702–2706, 2000 14. Ohori M, Wheeler TM, Scardino PT: The New American Joint Committee on Cancer and International Union Against Cancer TNM classification of prostate cancer: Clinicopathologic correlations. Cancer 74:104–114, 1994[CrossRef][Medline] 15. Harrell FE Jr, Lee KL, Mark DB: Multivariable prognostic models: Issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 15:361–387, 1996[CrossRef][Medline] 16. Harrell FE Jr, Califf RM, Pryor DB, et al: Evaluating the yield of medical tests. JAMA 247:2543–2546, 1982[Abstract] 17. Efron B, Tibshirani RJ: An Introduction to the Bootstrap. New York, NY, Chapman & Hall, 1993
18. Kattan MW, Eastham JA, Stapleton AMF, et al: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 90:766–771, 1998
19. Kattan MW, Zelefsky MJ, Kupelian PA, et al: Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. J Clin Oncol 18:3352–3359, 2000 20. Kattan MW, Potters L, Blasko JC, et al: Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer. Urology 58:393–399, 2001[CrossRef][Medline]
21. Cowen ME, Miles BJ, Cahill DF, et al: The danger of applying group-level utilities in decision analyses of the treatment of localized prostate cancer in individual patients. Med Decis Making 18:376–380, 1998 22. Partin AW, Yoo J, Carter HB, et al: The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 150:110–114, 1993[Medline] 23. Partin AW, Kattan MW, Subong EN, et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer: A multi-institutional update. JAMA 277:1445–1451, 1997 (Published erratum appears in JAMA 278:118, 1997)[Abstract] 24. Kattan MW, Stapleton AM, Wheeler TM, et al: Evaluation of a nomogram used to predict the pathologic stage of clinically localized prostate carcinoma. Cancer 79:528–537, 1997[CrossRef][Medline]
25. Wei JT, Dunn RL, Sandler H, et al: Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol 20:557–566, 2002 26. Graefen M, Karakiewicz P, Cagiannos I, et al: A validation of two preoperative nomograms predicting recurrence following radical prostatectomy in a cohort of European men. Urol Oncol 7:141–146, 2002[CrossRef][Medline] Submitted December 6, 2002; accepted May 8, 2003. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
