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© 2003 American Society for Clinical Oncology Pretreatment Nomogram That Predicts 5-Year Probability of Metastasis Following Three-Dimensional Conformal Radiation Therapy for Localized Prostate Cancer
From the Departments of Urology, Biostatistics, and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, and the Cleveland Clinic, Cleveland, OH. Address reprint requests to Michael W. Kattan, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 27, New York, NY 10021; e-mail: kattanm{at}mskcc.org.
Purpose: There are several nomograms for the patient considering radiation therapy for clinically localized prostate cancer. Because of the questionable clinical implications of prostate-specific antigen (PSA) recurrence, its use as an end point has been criticized in several of these nomograms. The goal of this study was to create and to externally validate a nomogram for predicting the probability that a patient will develop metastasis within 5 years after three-dimensional conformal radiation therapy (CRT). Patients and Methods: We conducted a retrospective, nonrandomized analysis of 1,677 patients treated with three-dimensional CRT at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1988 to 2000. Clinical parameters examined were pretreatment PSA level, clinical stage, and biopsy Gleason sum. Patients were followed until their deaths, and the time at which they developed metastasis was noted. A nomogram for predicting the 5-year probability of developing metastasis was constructed from the MSKCC cohort and validated using the Cleveland Clinic series of 1,626 patients. Results: After three-dimensional CRT, 159 patients developed metastasis. At 5 years, 11% of patients experienced metastasis by cumulative incidence analysis (95% CI, 9% to 13%). A nomogram constructed from the data gathered from these men showed an excellent ability to discriminate among patients in an external validation data set, as shown by a concordance index of 0.81. Conclusion: A nomogram with reasonable accuracy and discrimination has been constructed and validated using an external data set to predict the probability that a patient will experience metastasis within 5 years after three-dimensional CRT.
MANY RISK grouping systems and nomograms have been developed for counseling men with prostate cancer who are considering external beam radiation therapy. Shipley et al1 predicted biochemical recurrence-free probability at 5 years after primary radiation therapy by dividing patients into four risk groups based on pretreatment prostate-specific antigen (PSA) level, clinical stage, and biopsy Gleason grade. An enhanced risk group system was described by Pisansky et al, 2 in whose study patients were stratified into low-, intermediate-, and high-risk groups based on a risk-score equation that incorporated the same predictors. They observed 5-year relapse-free probabilities of 92%, 67%, and 24%, respectively. D’Amico et al3 created a table to predict PSA failure at 2 years, stratified by modality of primary therapy (radical prostatectomy or external beam radiation therapy), pretreatment PSA, biopsy Gleason sum, and clinical stage. Kattan et al4 developed a nomogram to predict 5-year freedom from recurrence, incorporating pretreatment PSA, clinical stage, biopsy Gleason grade, radiation dose, and whether neoadjuvant hormones were administered. Although valuable, these tools have been criticized on two grounds. First, they typically predict biochemical recurrence (BCR), which is a limited end point with uncertain clinical significance. Second, they generally do not reflect the fact that a patient may die before prostate-cancer relapse, as a result of another cause. This approach has limitations because it is hypothetical in nature. In reality, patients can and often do die as a result of other causes before experiencing recurrence of their prostate cancer. The purpose of this study was to develop a nomogram using pretreatment factors to predict the probability that a patient would develop metastasis after receiving primary three-dimensional conformal radiation therapy (CRT). We used statistical methods that recognize that the patient might die as a result of other causes, which prohibits relapse (ie, he is not simply censored at death from another cause, which is the typical approach). We validated this nomogram using an external data set from the Cleveland Clinic (CC) series.
From 1988 to 2001, 1,677 patients received three-dimensional CRT as primary treatment for clinically localized prostate carcinoma at Memorial Sloan-Kettering Cancer Center (MSKCC). This method of treating prostate cancer was previously described by Leibel et al.5 Demographic and clinical characteristics for this cohort can be found in Table 1  . The median age was 69 years (range, 45 to 86 years). Patients were clinically staged by one of three investigators (M.J.Z., Z.F., or S.A.L.) using the 2002 American Joint Committee on Cancer staging classification system.6 The serum PSA level was analyzed using the Tosoh radioimmunoassay (Tosoh Bioscience, Tokyo, Japan). All patients had biopsy proven adenocarcinoma that was classified according to the Gleason grading system.7
Every 3 to 6 months, patients were scheduled to receive follow-up evaluations that included periodic bone scans, computed tomography scans, and magnetic resonance imaging, when indicated, based on biochemical failure. Biochemical failure and the administration of hormonal therapy (HT) were noted but ignored in the statistical analysis. Note that 127 patients in the MSKCC series received salvage HT for biochemical recurrence. No patients in this series received HT in the adjuvant setting after three-dimensional CRT. Patients were followed until metastasis, disease progression, and patient death. The median follow-up time for the cohort was 38 months (maximum, 150 months). The clinical parameters used in the nomogram included pretreatment PSA level, clinical stage, and biopsy Gleason sum. Metastasis was defined radiographically as the definitive onset of visceral metastatic lesions and/or bony osteoblastic lesions, with the date of the first definitive radiographic study listed as the date of metastasis. The nomogram was developed using the MSKCC cohort and constructed from a specialized proportional hazards regression model that provided the probability of metastasis while recognizing that the patient might have died as a result of another cause first.8 The CC series of 1,626 patients who underwent primary radiation therapy for prostate carcinoma from 1986 to 2001 was used to validate the nomogram.4 As with the MSKCC series, the CC series of patients received bone scans, computed tomography scans, or magnetic resonance imaging when indicated. Of the CC patients, 168 received either adjuvant or salvage HT for BCR, without a prior diagnosis of metastasis. Predictive accuracy was assessed in two ways. Discrimination was measured with the concordance index, similar to the area under the receiver operating characteristic curve. Values ranged from 0.5 (no discrimination) to 1.0 (perfect discrimination). Calibration was assessed by plotting the predicted versus the actual probability for quintiles of the predicted probability for metastasis development. All statistical analyses were done using the S-Plus software version 2000 Professional Edition (Insightful, Seattle, WA) with the Design and Hmisc libraries.9
Figure 1A and 1B illustrate the cumulative incidence of metastasis and death resulting from other causes before disease progression to metastasis for the MSKCC and CC series, respectively. At 120 months, 28% of the MSKCC series had developed metastasis, and 7% had died as a result of other causes. In the CC series, 11% had developed metastasis, and 18% had died as a result of other causes at 120 months.
The nomogram predicting 5-year probability of metastasis appears in Figure 2 . It considers that a patient might die as a result of another cause first. Using the external data set from the CC series, we found that the nomogram had an excellent ability to discriminate, as evidenced by a concordance index of 0.81.
Figure 3 plots the mean nomogram predictions against the actual outcome for the patients in the external validation data set. It reveals that the nomogram is generally well calibrated. However, at low levels of predicted probability, the proportion of men developing metastasis was lower, by a few percentage points, than was predicted by the nomogram.
Continuous nomograms have been developed to predict outcomes after external beam radiation therapy. These have been shown to have some advantages in predictive ability, compared with risk-grouping.4 Several previous models predicted BCR as their end point. This limits their clinical usefulness somewhat because of the inherent controversies surrounding, and uncertain clinical significance of, BCR after primary therapy for prostate cancer. Much controversy exists in terms of defining BCR, rate of disease progression in BCR patients, follow-up protocol, treatment options, and timing of treatment for men with BCR. Therefore, we chose to develop a nomogram with the more definite and clinically significant end point of metastatic progression. Researchers have investigated what pretreatment factors predicted development of metastasis in patients who had undergone primary radiation therapy for prostate carcinoma.10–12 Most found that biopsy Gleason grade, clinical T stage, and pretreatment PSA level were strongly associated with eventual metastasis development. Leibel et al10 described that lymph node involvement was highly predictive of metastasis. They concluded that virtually all patients with positive node disease will develop metastasis if followed long enough. Zagars et al11 described a strong association between total serum testosterone and development of metastasis. They discovered that patients with pretreatment testosterone levels of 500 ng/dL or greater had a significantly higher rate of metastasis at 6 years (P = .001). Unfortunately, we did not have testosterone measured in a sufficient number of patients to explore this issue further. Coen et al12 found that local recurrence after radical radiation therapy was the strongest predictor for distant metastasis in a multivariate model (P = .0001). Our focus, however, was the development of a pretreatment model, thus, local recurrence status would not be known. We have developed a nomogram that predicts the probability of progression to metastasis within 5 years after a patient has received primary external beam radiation therapy for prostate cancer. This nomogram was built using a specialized proportional hazards regression model8 and was validated with the CC series. This validation revealed that the nomogram was generally well calibrated and discriminating, based on its concordance index of 0.81. An important feature is its ability to reflect that patients might die of other causes before having a recurrence of their disease and metastasis. This was accomplished by not strictly censoring the patient at death, as is commonly done with Cox regression analysis. Thus, rather than provide a hypothetical probability of metastasis presuming that he cannot die of any other cause first, the nomogram allows us to show the patient his probability of developing metastasis, while recognizing that he might die of another cause.13 We plan to make this nomogram available as free software, as we do with all our nomograms. These are available at http://www.nomograms.org. This nomogram will be useful in counseling patients who are appropriate candidates for external beam radiation before therapy and in selecting patients for prospective clinical trials. Using this nomogram, the physician can give a reasonably accurate prediction of the probability that a patient will develop metastasis within 5 years after receiving primary three-dimensional CRT. This is a more clinically useful end point than biochemical recurrence because a large proportion of BCR patients will not have any further disease progression. It will also be useful in designing prospective clinical trials for neoadjuvant and adjuvant therapies, because these patients are the ones most likely to benefit.
Important limitations do exist with our present nomogram. Although it is well calibrated, it does not predict perfectly. Figure 3
Another limitation is that our nomogram does not take into account the administration of HT. The timing of HT and its effect on progression to metastasis and survival are controversial. In our series, short-term neoadjuvant HT was not associated with time to metastatis (P > .05). While there is evidence to suggest that adjuvant HT may prolong the time to disease progression and metastasis after external beam radiation therapy,14–18 there is no evidence we are aware of revealing that salvage HT for biochemical recurrence does the same. In light of the fact that our patients all received HT in the salvage and not the adjuvant setting, we decided to allow the nomogram to assume that, in the course of the patient’s disease, he might or might not receive HT at the discretion of the treating physician. In addition, as previously mentioned, our nomogram was designed to be a pretreatment predictive tool able to assess a patient’s risk of developing metastasis after initial three-dimensional CRT. It would not be possible to know, in the pretreatment phase, whether a patient will later receive HT. Despite its not making prediction adjustments for hormonal therapy, the nomogram in Figure 2
A third limitation is that our nomogram predicts probability of metastasis only to 5 years. It is possible to develop metastasis after 5 years, as evidenced in Figure 1 A fourth limitation of our nomogram is that not all patients were on strict imaging protocols. Rather, they received imaging as indicated. With strict imaging protocol, the data would have likely yielded a more accurate nomogram and possibly higher rates of metastasis. A fifth limitation of our nomogram is that it does not include a variable for dose. The reason is that dose is a treatment-related variable that is, strictly speaking, not pretreatment. Furthermore, if we were to include dose in the nomogram, the tool might potentially be misused to determine dose rather than simply to predict outcome. Finally, in our data set, dose was not a statistically significant prediction of time to metastasis (P > .05). Given that this tool was developed and validated in centers that typically deliver a relatively high-dose, the tool may or may not be applicable in a lower-dose setting. Despite these limitations, we believe our nomogram will prove to be highly useful in patient counseling, treatment selection, and designing future prospective trials.
The authors indicated no potential conflicts of interest.
Supported in part by a gift from the Leon Lowenstein Foundation.
1. Shipley WU, Thames HD, Sandler HM, et al: Radiation therapy for clinically localized prostate cancer. JAMA 281:1598–1604, 1999 2. Pisansky TM, Kahn MJ, Bostwick DG: An enhanced prognostic system for clinically localized carcinoma of the prostate. Cancer 79:2154–2161, 1997[CrossRef][Medline]
3. D’Amico AV, Whittington RS, 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. 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 5. Leibel SA, Zelefsky MJ, Kutcher GJ, et al: The biologic basis and clinical application of three-dimensional conformal external beam radiation therapy in carcinoma of the prostate. Semin Oncol 21:580–597, 1994[Medline] 6. AJCC Cancer Staging System Manual (ed 6). American Joint Committee on Cancer. Philadelphia, PA, Lippincott-Raven, 2002 7. Gleason DF: Histologic grading and clinical staging of prostatic carcinoma, in Tannenbaum M (ed): Urologic Pathology: The Prostate. Philadelphia, PA, Lea and Febiger, 1977 8. Fine JP, Gray R: A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 446:496–510, 1999 9. Harrell FE: Design: S-Plus function for biostatistical/epidemiologic modeling, testing, estimation, validation, graphics, prediction, and typesetting by storing enhanced model design attributes in the fit. http://hesweb1.med.virginia.edu/biostat/s/design.html 10. Leibel SA, Fuks Z, Zelefsky MJ, et al: The effects of local and regional treatment on the metastatic outcome in prostatic carcinoma with pelvic lymph node involvement. Int J Radiat Oncol Biol Phys 28:7–16, 1994[Medline] 11. Zagars GK, Pollack A, von Eschenbach AC: Serum testosterone: A significant determinant of metastatic relapse for irradiated localized prostate cancer. Urology 49:327–334, 1997[CrossRef][Medline]
12. Coen JJ, Zietman AL, Thakral H, et al: Radical radiation for localized prostate cancer: Local persistence of disease results in a late wave of metastasis. J Clin Oncol 20:3199–3205, 2002 13. Kattan MK, Heller G, Brennan MF: A competing-risks nomogram for sarcoma-specific death following local recurrence. Stat Med 22:3515–3525, 2003[Medline] 14. Walsh PC, DeWeese TL, Eisenberger MA.: A structured debate: Immediate versus deferred androgen suppression in prostate cancer—Evidence for deferred treatment. J Urol 166:508–516, 2001[CrossRef][Medline] 15. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomised trial. Lancet 360:103–106, 2002[CrossRef][Medline] 16. Granfors T, Modig H, Damber JE, et al: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: A prospective randomized study. J Urol 159:2030–2034, 1998[CrossRef][Medline] 17. Lawton CA, Winter K, Murray K, et al: Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 49:937–946, 2001[CrossRef][Medline] 18. Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50:1243–1252, 2001[CrossRef][Medline] Submitted May 7, 2003; accepted October 9, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
