After One Year After I Finish the Radiations the Psa Is Going Yup Again

J Clin Oncol. Author manuscript; bachelor in PMC 2009 Apr 18.

Published in terminal edited form as:

PMCID: PMC2670394

NIHMSID: NIHMS53629

Predicting the Outcome of Salvage Radiation Therapy for Recurrent Prostate Cancer Later Radical Prostatectomy

Andrew J. Stephenson, Peter T. Scardino, Michael West. Kattan, Thomas M. Pisansky, Kevin M. Slawin, Eric A. Klein, Mitchell S. Anscher, Jeff M. Michalski, Howard M. Sandler, Daniel W. Lin, Jeffrey D. Forman, Michael J. Zelefsky, Larry L. Kestin, Claus G. Roehrborn, Charles Northward. Catton, Theodore L. DeWeese, Stanley L. Liauw, Richard K. Valicenti, Deborah A. Kuban, and Alan Pollack

Abstract

Purpose

An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We adult a nomogram to predict the probability of cancer control at half-dozen years after SRT for PSA-defined recurrence.

Patients and Methods

Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional accomplice of 1,540 patients.

Results

The half dozen-yr progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT solitary at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling fourth dimension of 10 months or less or poorly differentiated (Gleason grade 8 to ten) cancer. Meaning variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69.

Conclusion

Near half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the primeval sign of recurrence. The nomogram we adult predicts the outcome of SRT and should prove valuable for medical determination making for patients with a rising PSA level.

INTRODUCTION

An estimated 25% of patients treated with radical prostatectomy (RP) for clinically localized prostate cancer will suffer recurrence of their disease, manifested initially every bit a rising serum prostate-specific antigen (PSA) level with no radiographic evidence of cancer.¹ In the absenteeism of salvage therapy, the median time from PSA recurrence to distant metastasis is 8 years.²

A critical upshot in the management of these patients is determining whether a rising PSA reflects local or distant recurrence, equally the quondam may potentially be cured past salvage radiation therapy (SRT). Androgen-deprivation therapy (ADT) appears only to offer palliation for those patients with recurrent prostate cancer. For the best run a risk of success, SRT to the local tumor bed must exist administered when the cancer burden is lowest; that is, when the serum PSA starting time reaches detectable levels.³ ^– ^xv At these PSA levels, neither imaging studies nor anastomotic biopsy are sufficiently sensitive or specific enough to distinguish those with local recurrence who are suitable for SRT from those with disseminated disease who require systemic therapy.¹⁶ ^– ¹⁹ As a upshot, the reported success rate of SRT after RP has been poor, ranging from 10% to forty%.⁴ ^, ^vii ^, ^eight ^, ¹² ^, ¹³ ^, ^xv ^, ²⁰ ^, ²¹

PSA recurrence associated with a rapidly rising PSA (quantified by a brusk PSA doubling time [PSADT]), poorly differentiated cancer (Gleason course eight to ten), and a short disease-free interval after RP identifies patients at the highest risk for progression to afar metastasis and cancer-specific mortality who are in the greatest need of effective save therapy.ⁱⁱ ^, ²² ^, ²³ PSA recurrence associated with these features is widely believed to stand for occult metastatic disease. Hence, most high-chance patients with a rising PSA are treated with early ADT despite the lack of conclusive testify that that information technology prolongs survival,²⁴ and the potential for long-term toxicity and adverse effects on quality of life.²⁵ ^, ²⁶ Yet, a recent retrospective written report demonstrated that a substantial proportion of recurrent patients with a short PSADT and/or Gleason grade 8 to ten cancer were cancer gratuitous at 4 years after SRT alone,¹³ just this favorable upshot was dependent on several illness parameters.

Because of the inadequacies of current diagnostic modalities for selecting patients for SRT and the variable outcome depending on patient parameters, models that accurately predict the outcome of SRT on the footing of the overall characteristics of an individual's example rather than a single parameter (eg, PSADT) are needed to select patients for this therapy. We present a predictive model called a nomogram that predicts the 6-year progression-gratis probability after SRT for men with PSA recurrence later on RP.

PATIENTS AND METHODS

For the purpose of developing predictive models for the outcome of SRT, a multi-institutional, retrospective accomplice of 1,603 consecutive patients from 17 North American third referral centers who received SRT after RP for PSA recurrence between 1987 and 2005 was assembled. Earlier SRT, all patients had a PSA level of 0.2 ng/mL or higher at least vi weeks after RP followed by some other higher value, or a single PSA of 0.5 ng/mL or higher.²⁷ Lx-three patients (4%) received adjuvant ADT later on SRT and were excluded from the analysis of PSA-divers end points, leaving ane,540 patients for nomogram development and validation (Table 1). With the exception of a college positive surgical margin rate and lower rates of seminal vesicle invasion and lymph node metastasis, the clinical characteristics of this accomplice were similar to those of consecutive patients with PSA recurrence in RP series.² ^, ²⁸

Table 1

Clinical Characteristics of 1,540 Patients Undergoing Salvage Radiotherapy for PSA Recurrence Afterwards Radical Prostatectomy.

Parameter	No.	%	IQR
Median preprostatectomy age, years	62		58 to 67
Median preprostatectomy PSA, ng/mL	x.5		6.6 to 19
Prostatectomy Gleason grade
4–half dozen	351	26
7	687	52
viii–10	293	22
Extracapsular extension	996	65
Positive surgical margins	787	51
Seminal vesicle invasion	371	24
Positive lymph nodes	48	iii
Median disease-free interval, months	15		5.1 to 34.0
Persistently elevated postprostatectomy PSA, %	449	29
Median PSA level earlier radiotherapy, ng/mL	i.ane		0.6 to 2.ii
Median PSA doubling time, months	half-dozen.9		3.vi to 12.2
Preradiotherapy ADT	214	14
Median radiotherapy dose, Gy	64.8		63 to 66
Median follow-upwards after prostatectomy, months	90		61 to 120
Median follow-up after PSA recurrence, months	64		38 to 95
Median follow-up after radiotherapy, months	53		28 to 81

Because some patients underwent RP at an exterior institution, the method past which the pathologic specimens were processed was non bachelor for all patients. PSADT was calculated using previously described methods based on a minimum of two PSA values at to the lowest degree 6 weeks apart.² Two hundred fourteen patients (fourteen%) received ADT before and/or during SRT for a median duration of 4.i month (range, one to 24 months); 25% of these patients received ADT for longer than 6 months.

After radiation treatment, patients were followed with clinical assessment and serum PSA determinations at regular intervals. The use of diagnostic imaging studies and save ADT was non standardized, and varied over time and past private physician practice. The median follow-upwards after the completion of SRT was 53 months (interquartile range, 28 to 81 months).

The primary terminate point of this report was disease progression afterward SRT, defined equally a serum PSA value of 0.2 ng/mL or more above the postradiotherapy nadir followed by another college value, a continued rise in the serum PSA despite SRT, initiation of systemic therapy after completion of SRT, or clinical progression. Progression-free probability was estimated using the Kaplan-Meier method, and survival was calculated from the completion date of radiotherapy with no dorsum-dating of recurrence. Multivariable Cox proportional hazards regression analysis was the basis for the nomogram. Variables to be used in the nomogram were selected on the footing of knowledge of their prognostic significance from previous reports. All decisions with respect to the categorization of variables were made before modeling. Because of skewed distributions, continuous variables were modeled using restricted cubic splines to accommodate potentially nonlinear furnishings.

Internal validation of the nomogram was performed using two components. First, a concordance index (c-index), which is similar to an expanse nether the receiver operating characteristic curve, was estimated past subjecting the nomogram to bootstrapping with 200 resamples to calculate an unbiased measure of its ability to discriminate among patients.²⁹ ^, ³⁰ The c-index is the probability that, given two randomly drawn patients, the patient who relapses first had a higher probability of recurrence. With this measure, a c-index of 1.0 represents a perfectly discriminating model, and a value of 0.5 is that expected by random chance. The 2nd component of validation compared the predicted probability of disease recurrence versus actual recurrence (ie, nomogram scale) of the 1,540 patients using 200 bootstrap resamples to reduce overfit bias, which would overstate the accuracy of the nomogram.

All statistical analyses were conducted using S-Plus 2000 Professional statistical software (Insightful Corp, Seattle, WA) with the Design library attached.³¹ All P values resulted from the use of two-sided statistical tests, and the level of significance was set at .05. The study was conducted nether Health Insurance Portability and Accountability Act guidelines and received institutional review board approval from all participating institutions.

RESULTS

Overall, 866 patients experienced disease progression after SRT, and the 6-twelvemonth progression-gratis probability was 32% (95% CI, 28% to 35%; Fig 1A). However, an estimated 48% (95% CI, forty% to 56%) who received SRT alone without ADT when the PSA was 0.50 ng/mL or less were disease free at 6 years compared with 40% (95% CI, 34% to 46%), 28% (95% CI, 20% to 35%), and xviii% (95%, xiv% to 22%) of those treated at PSA levels of 0.51 to 1.00, 1.01 to 1.50, and greater than ane.50 ng/mL, respectively (Fig 1B). The 6-year response to SRT among patients treated at PSA levels of 0.fifty ng/mL or less appears to be durable considering only 2 progression events were observed after 6 years amidst 32 patients at adventure at 6 years (median follow-up, 90 months).

An external file that holds a picture, illustration, etc. Object name is nihms53629f1.jpg

(A) Kaplan-Meier approximate of the overall progression-free probability subsequently salve radiotherapy. (B) Progression-free probability after salvage radiotherapy stratified by preradiotherapy prostate-specific antigen 0.50 or less (blue), 0.51 to 1.00 (yellow), 1.01 to ane.50 (gray), and more than 1.50 ng/mL (red).

Sufficient data to evaluate the PSA response to SRT was available for 1,491 patients (97%). A PSA nadir after radiotherapy of 0.x ng/mL or less was achieved in 905 patients (59%), including 726 (55%) of ane,326 patients who did not receive ADT.

We previously reported favorable 4-year response rates subsequently SRT lone in 356 patients with a brusque PSADT and Gleason grade 8 to 10 cancer.¹³ In this larger cohort with longer follow-up, the 4-year progression-gratis probability estimates afterward SRT alone stratified by PSA before SRT (cut point, 2.0 ng/mL), Gleason grade seven or less surgical versus 8 to 10, surgical margins, and PSADT (cut signal, 10 months) were more often than not within ten% of those previously reported, validating the favorable intermediate prognosis in select loftier-risk patients (Fig ii). When SRT was administered at PSA levels of 0.50 ng/mL or less, an estimated 41% (95% CI, 31% to 51%) of patients with a PSADT of 10 months or less or Gleason grade 8 to 10 cancer were disease complimentary at 6 years, including 48% (95% CI, 35% to 62%) who as well had positive surgical margins.

An external file that holds a picture, illustration, etc. Object name is nihms53629f2.jpg

Iv-year progression-free probability afterward salvage radiotherapy for i,326 patients who did non receive androgen-deprivation therapy earlier or during radiation therapy, stratified by preradiotherapy prostate-specific antigen (PSA), Gleason score, surgical margins, and PSA doubling time (PSADT). RT, radiotherapy; PFP, progression-gratis probability; CI, 95% CI.

A nomogram predicting the half dozen-yr progression-free probability after SRT was constructed from 11 parameters determined earlier handling (Fig 3A). Statistically significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSADT (P < .001), surgical margins (P < .001), ADT administered before or during SRT (P < .001), and lymph node metastasis (P = .019). Statistically insignificant variables were not omitted from the model because of the resultant bias on the remaining predictors and subsequent deleterious effect on predictive accurateness. The predictive accuracy as measured by the c-index was 0.69 in internal validation. The nomogram was well calibrated, and at that place was adept correlation betwixt predicted and observed event beyond the spectrum of predictions (Fig 3B).

An external file that holds a picture, illustration, etc. Object name is nihms53629f3.jpg

(A) Pretreatment nomogram predicting half dozen-yr progression-gratis probability subsequently salve radiotherapy for prostate-specific antigen (PSA) recurrence later on radical prostatectomy. (B) Calibration of the nomogram. Dashed line indicates reference line where an ideal nomogram would lie. Solid line indicates the operation of the electric current nomogram. Dots are quartiles of our information ready. Instructions: Locate the patient's Gleason score on the respective centrality. Depict a straight line upwardly to the Points axis to decide how many points toward illness recurrence that the patient receives for his or her Gleason score. Repeat this process for the other 10 disease and treatment parameters. Sum the points and locate this number on the Total Points axis. Describe a straight line down to find the patient's probability of remaining gratuitous of disease progression at half-dozen years after salve radiotherapy, provided the patient does non die of another cause starting time.

The ability of the nomogram to discriminate among patients for the outcome of SRT was compared with published models (based on PSADT, disease-gratuitous interval, and/or Gleason course) developed to predict the probability of metastases² and of cancer-specific bloodshed²² ^, ²³ for patients with a ascent PSA after RP (Tabular array 2). The predictive accuracy of these models was marginally better than that expected past chance (c-index, 0.56 to 0.60) in our accomplice, and substantially inferior to the nomogram. The c-index of PSA earlier SRT every bit a single parameter was 0.61.

Table 2

Comparing of the Predictive Accurateness of Various Risk Stratification Models for the Rising PSA State for the Upshot of Salvage Radiotherapy

Model	Stop Point	c-Index
Nomogram	6-twelvemonth PFP later on save radiotherapy	0.69^*
PSA doubling time		0.lx
Freedland et al 2005²³	10-twelvemonth cancer-specific survival after PSAR	0.59
Pound et al 1999²	seven-year metastasis-free probability subsequently PSAR	0.56

DISCUSSION

Patients with a rise PSA after RP have a sixty% probability of developing distant metastasis and a xx% probability of dying as a event of prostate cancer within 10 years.¹ ^, ⁱⁱ For those with poorly differentiated cancer and a brusque PSADT, the median metastasis-gratuitous and cancer-specific survival is 3 and 5 years, respectively.² ^, ²³ A disquisitional issue in the management of these patients is determining whether a rising PSA results from local or distant recurrence, because the former may potentially be cured with SRT. Upward to 50% of patients with PSA recurrence may initially have local or regional illness, and thereby benefit from SRT,²⁸ but electric current diagnostic modalities take proven inadequate for selecting patients. To address this issue, we developed a nomogram to predict the half dozen-twelvemonth progression-free probability after SRT. Nomograms predicting the outcome of definitive local therapy for prostate cancer are the near widely used disease-specific prediction tools in oncology.³² ^– ³⁵ This nomogram is the get-go model to predict the consequence of salve therapy for a rising PSA after RP and is anticipated to be useful for medical determination making.

The PSA level before SRT was a highly significant predictor of illness progression, with more favorable outcomes observed at low PSA levels. An estimated 48% of patients who received SRT alone at PSA levels of 0.50 ng/mL or less were free of progression at half-dozen years, compared with 26% for those treated at higher PSA levels. The power to provide successful salvage treatment for approximately 50% of patients with "early" SRT is similar to the 52% to 57% relative risk reduction in the charge per unit of PSA progression amid high-risk patients randomly assigned to adjuvant radiotherapy versus observation later on RP in 2 recent randomized trials.³⁶ ^, ³⁷ An important ascertainment in our report is that the 6-yr responses for those treated at PSA levels less than 0.l ng/mL appeared to be durable. This evidence suggests that approximately 50% of patients with recurrent prostate cancer afterward RP may derive long-term benefit from SRT when it is administered at the earliest signs of recurrence.

The favorable outcome associated with SRT at lower PSA levels suggests that intervention when the cancer burden is lowest and near amenable to therapy, and before systemic dissemination, leads to improved effect. Alternatively, this favorable issue may be explained by the indolent natural history of PSA recurrence in some patients with a single PSA elevation between 0.two and 0.39 ng/mL.²⁷ ^, ³⁸ However, nosotros included in our analysis simply patients who experienced two or more PSA rises at levels of 0.two ng/mL or higher or a unmarried PSA level of 0.5 ng/mL or higher, which are associated with a risk of subsequent PSA progression that is greater than 90%.²⁷ The PSA level before SRT was also a highly significant predictor of progression in our multivariable analysis after decision-making for all other important parameters.

SRT is nigh frequently recommended to patients judged to be at depression-hazard for occult metastases,³⁹ because cancer command rates in such patients range up to 77%.¹³ Our study demonstrates that select patients with a short PSADT or Gleason grade 8 to x cancer may besides benefit from SRT, validating previously published results.¹³ The 41% affliction-free estimate at 6 years in patients with a PSADT of 10 months or less or Gleason grade eight to x cancer treated at depression PSA levels is potentially clinically significant considering that these patients have a 60% to 70% probability of developing metastatic illness inside the same time period in the absence of save therapy.² This suggests that SRT may prevent or delay the appearance of metastatic disease in a substantial proportion of patients.

The potential for morbidity resulting from radiation therapy argues against its indiscriminate use in the salve setting. Mild to moderate acute rectal and genitourinary toxicity is seen in the majority of patients, but the reported incidence of acute grade 3 to four complications is less than 4%.⁴ ^, ^six ^, ⁹ ^, ¹⁴ ^, ²¹ ^, ³⁶ Late grade 1 to 2 rectal and genitourinary toxicity are reported in 5% to xx% of patients, and late course iii toxicity is less than four%.³ ^, ⁴ ^, ⁶ ^, ^viii ^, ¹¹ ^, ²¹ Although rare, pelvic radiation therapy for prostate cancer is associated with an increased risk of secondary pelvic malignancies.⁴⁰ Postprostatectomy radiotherapy does not announced to significantly increase the risk of urinary incontinence,³ ^, ⁴ ^, ⁶ ^, ¹⁴ ^, ²¹ ^, ⁴¹ just we must presume that it has some adverse result on erectile office on the basis of the data from principal radiation therapy series. The nomogram tin be used to restrict SRT to those patients virtually likely to benefit and avoid treatment-related morbidity in those predicted to take a low probability of a long-term benefit.

The present written report has several limitations worth noting. The c-index of the model (0.69) indicates that its predictive accurateness is slightly worse than midway between a perfect model (1.0) and a coin flip (0.v); previous prostate cancer nomograms for RP and external-beam radiotherapy had c-indices near 0.75.³² ^, ³³ ^, ⁴² ^, ⁴³ As a retrospective, multi-institutional cohort of patients whose disease was managed over an eighteen-year time menstruation, this may be attributable to variations amidst institutions (and over fourth dimension) in pathologic staging, clinical staging before SRT, radiations therapy techniques and the use and duration of ADT, and surveillance protocols regarding the frequency of PSA testing. Despite this limitation, we believe that the nomogram performs better than whatsoever other model or imaging modality for predicting the effect of SRT.

Another limitation of the model is the fact that it predicts the probability of being free of recurrence at 6 years, and some patients may even so feel progressive illness more than than 6 years after SRT. The nomogram also does not provide data on the probability of developing metastatic illness or dying as a result of prostate cancer afterwards SRT. The favorable 6-twelvemonth biochemical affliction-gratuitous rates observed among patients with a short PSADT and/or poorly differentiated cancer who received SRT at low PSA levels suggests it may delay or prevent the emergence of metastatic affliction, just we exercise not know how these patients would have fared without local salve treatment. A randomized clinical trial is needed to determine whether SRT prevents clinical progression or improves the survival of patients with a ascension PSA afterward RP. A randomized trial of adjuvant radiotherapy versus observation afterwards RP for pathologic stage T3 prostate cancer showed a 25% relative take a chance reduction in the rate of distant metastasis at 10 years, but this upshot was not statistically pregnant.³⁷

Recently, risk groups predicting the development of metastatic illness and cancer-specific mortality take been adult for the post-RP PSA recurrence population.² ^, ²² ^, ²³ These tools are nigh helpful to guess the risk a rising PSA poses to a homo's longevity, just they do non provide information virtually which treatment should be considered. Physicians may be influenced by these tools to select patients for SRT despite the fact that they were non designed to place local versus distant affliction or the characteristics of patients who will answer favorably to SRT. The nomogram was substantially amend at predicting the issue of SRT than were these models, which performed marginally better than that expected by random gamble.

A rising PSA alone is not justification for initiating salvage therapy because patients with PSA recurrence are as likely to die every bit a outcome of competing causes as they are of prostate cancer.¹ To determine the need for relieve therapy, we suggest using one of several existing tools to estimate the probability of developing metastatic disease or cancer-specific mortality.ⁱⁱ ^, ²² ^, ²³ Patients at loftier risk of progression to these clinically significant events and/or a long life expectancy should be assessed for SRT using our nomogram. We have avoided specifying a minimum prediction at which SRT should not be considered. We believe this determination should be fabricated after a discussion betwixt the patient and his medico focusing on the probabilities of treatment success, toxicity, and the risk of clinical illness progression if observation is chosen. Therapeutic options for patients with a low probability of a durable response to SRT include immediate or deferred ADT or entry onto clinical trials.

In the setting of principal radiotherapy, dose escalation and combined therapy with ADT have been proven to increment local control, disease-free survival, and/or overall survival.⁴⁴ ^– ⁴⁶ No prospective study has evaluated the impact of ADT in the salvage setting. ADT administered earlier and/or during SRT was associated with improved PSA control in our study, although this may potentially be explained by the effects of prolonged ADT (up to 24 months in some patients) on masking PSA recurrence. ADT may improve the efficacy of SRT, simply a randomized trial is required to test this hypothesis. Nosotros did not identify an association betwixt radiation dose and the outcome of SRT, although the range of doses administered was relatively narrow, and few patients received doses greater than 70 Gy. Combined therapy with ADT, radiations dose escalation, and improved target localization using modalities such as endorectal coil magnetic resonance imaging may better the efficacy of SRT.⁴⁷

In summary, the outcome of SRT is influenced past several disease-and treatment-related parameters and provides long-term control of disease in approximately i 3rd of patients with PSA recurrence after RP. Improved results are observed when SRT is administered at low PSA levels, and a substantial proportion of patients with poorly differentiated cancer and a curt PSADT are observed to benefit. The nomogram represents the all-time tool available to predict the effect of SRT and is anticipated to exist useful for medical decision making for patients with a ascent PSA.

Acknowledgments

Supported in part by National Cancer Institute Prostate Cancer SPORE grants (P50-CA92629, P50-CA97186, P50-CA58236), David Koch Fund, Leon Lowenstein Foundation. A.J.S. is supported in role by the American Foundation for Urologic Disease and National Institutes of Health T32-82088.

Footnotes

Presented in office at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June ii–six, 2006.

This nomogram has been adapted for use on personal digital assistants and personal computers and is available in the public domain for costless download at http://www.nomograms.org.

Authors' disclosures of potential conflicts of interest and author contributions are plant at the finish of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF Involvement

Although all authors completed the disclosure declaration, the following authors or their immediate family unit members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Northward/A Leadership: Kevin M. Slawin, Oncovance Technologies Consultant: Peter T. Scardino, Oncovance Technologies; Michael W. Kattan, Oncovance Technologies Stock: Northward/A Honoraria: N/A Inquiry Funds: N/A Testimony: Due north/A Other: North/A

Author CONTRIBUTIONS

Conception and blueprint: Andrew J. Stephenson, Peter T. Scardino, Michael West. Kattan, Kevin Thou. Slawin, Michael J. Zelefsky, Alan Pollack

Financial back up: Peter T. Scardino, Alan Pollack

Administrative support: Andrew J. Stephenson, Peter T. Scardino, Michael Due west. Kattan, Thomas Chiliad. Pisansky, Kevin M. Slawin, Eric A. Klein, Mitchell Due south. Anscher, Jeff M. Michalski, Howard Grand. Sandler, Daniel W. Lin, Michael J. Zelefsky, Jeffrey D. Forman, Larry 50. Kestin, Claus Yard. Roehrborn, Charles N. Catton, Theodore L. DeWeese, Stanley L. Liauw, Richard K. Valicenti, Deborah A. Kuban, Alan Pollack

Provision of written report materials or patients: Peter T. Scardino, Thomas M. Pisansky, Kevin M. Slawin, Eric A. Klein, Mitchell Southward. Anscher, Jeff Thou. Michalski, Howard G. Sandler, Daniel W. Lin, Michael J. Zelefsky, Jeffrey D. Forman, Larry L. Kestin, Claus G. Roehrborn, Charles N. Catton, Theodore L. DeWeese, Stanley L. Liauw, Richard Thousand. Valicenti, Deborah A. Kuban, Alan Pollack

Drove and assembly of data: Andrew J. Stephenson, Peter T. Scardino, Thomas M. Pisansky, Kevin M. Slawin, Eric A. Klein, Mitchell S. Anscher, Jeff Thousand. Michalski, Howard M. Sandler, Daniel W. Lin, Michael J. Zelefsky, Jeffrey D. Forman, Larry Fifty. Kestin, Claus M. Roehrborn, Charles North. Catton, Theodore Fifty. DeWeese, Stanley Fifty. Liauw, Richard K. Valicenti, Deborah A. Kuban, Alan Pollack

Data analysis and estimation: Andrew J. Stephenson, Peter T. Scardino, Michael W. Kattan, Thomas M. Pisansky, Kevin M. Slawin, Eric A. Klein, Mitchell South. Anscher, Jeff M. Michalski, Howard One thousand. Sandler, Daniel Westward. Lin, Michael J. Zelefsky, Jeffrey D. Forman, Larry Fifty. Kestin, Claus One thousand. Roehrborn, Charles N. Catton, Theodore L. DeWeese, Stanley L. Liauw, Richard G. Valicenti, Deborah A. Kuban, Alan Pollack

Manuscript writing: Andrew J. Stephenson, Peter T. Scardino, Alan Pollack

Final approval of manuscript: Andrew J. Stephenson, Peter T. Scardino, Michael W. Kattan, Thomas M. Pisansky, Kevin K. Slawin, Eric A. Klein, Mitchell S. Anscher, Jeff One thousand. Michalski, Howard M. Sandler, Daniel West. Lin, Michael J. Zelefsky, Jeffrey D. Forman, Larry L. Kestin, Claus G. Roehrborn, Charles Due north. Catton, Theodore L. DeWeese, Stanley Fifty. Liauw, Richard K. Valicenti, Deborah A. Kuban, Alan Pollack

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670394/