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NIH Public AccessAuthor ManuscriptOpen Prost Cancer J. Author manuscript; available in PMC 2013 August 30.NIH-PA Author ManuscriptPublished in final edited form as:Open Prost Cancer J. ; 6: 1–9.Treatment and Mortality in Men with Localized Prostate Cancer:A Population-Based Study in CaliforniaWeiva Sieh, MD, PhD1, Daphne Y. Lichtensztajn, MD, MPH2, David O. Nelson, PhD2, MylesCockburn, PhD3, Dee W. West, PhD1,2, James D. Brooks, MD4,†, and Ellen T. Chang,ScD1,2,†1Division of Epidemiology, Department of Health Research and Policy, Stanford University Schoolof Medicine, Stanford, CA2CancerPrevention Institute of California, Fremont, CA3Departmentof Preventive Medicine, University of Southern California School of Medicine, LosAngeles, CANIH-PA Author Manuscript4Departmentof Urology, Stanford University School of Medicine, Stanford, CAAbstractPurpose—To provide patients and physicians with population-based estimates of mortality fromprostate cancer or other causes depending upon the primary treatment modality, stratified bypatient age, tumor stage and grade.Methods—We conducted a 10-year competing-risk analysis of 45,440 men diagnosed withclinically localized (T1 or T2) prostate cancer in California during 1995–1998. Information onpatient characteristics, primary treatment and cause of death was obtained from the CaliforniaCancer Registry.NIH-PA Author ManuscriptResults—In this population-based cohort, the most common primary treatment was surgery(40.4%), followed by radiotherapy (29.1%), conservative management (20.8%), and androgendeprivation therapy (ADT) monotherapy (9.8%). Prostate cancer mortality differed significantly (p 0.0001) across treatment groups among patients 80 years at diagnosis with moderately orpoorly differentiated disease; the 10-year disease-specific mortality rates were generally highestfor men treated with ADT monotherapy [range: 3.3% (95% CI 0.8–12.5%) to 53.8% (95%CI 34.4–72.2%)], intermediate for men treated with conservative management [range: 1.7% (95%CI 0.7–4.6%) to 30.0% (95% CI 16.2–48.8%] or radiotherapy [range: 3.2% (95% CI 1.8–5.5%)to 18.3% (95% CI 15.1–22.0%)], and lowest for men treated with surgery [range: 1.2% (95%CI 0.8–1.7%) to 11.0% (95% CI 8.4–14.2%)].Conclusion—The cause-specific mortality estimates provided by this observational study canhelp patients and physicians better understand the expected long-term outcomes of localizedprostate cancer given the initial treatment choice and practice patterns in the general population.KeywordsProstate cancer; treatment; mortality; cohort study; California Cancer RegistryCorresponding author: Weiva Sieh, MD, PhD, Assistant Professor of Epidemiology, Department of Health Research and Policy,Stanford University School of Medicine, HRP Redwood Building, Room T254B, 259 Campus Drive, Stanford, CA 94305-5405,Phone: (650) 723-6910, Fax: (650) 725-6951, [email protected]†These authors contributed equally.

Sieh et al.Page 2INTRODUCTIONNIH-PA Author ManuscriptOver the past two decades, widespread application of prostate specific antigen (PSA) testinghas shifted the clinical landscape of prostate cancer to earlier stages of the disease.[1] In2012, over 241,000 U.S. men were diagnosed with prostate cancer, approximately 80% ofwhom had localized (stage T1 or T2) disease.[2] To date, randomized trials have shownlittle survival benefit with PSA testing, indicating that many indolent tumors are beingoverdetected and overtreated.[3,4] The optimal treatment of localized prostate cancerremains controversial.[5] Standard treatment options include surgery, radiation, andconservative management (active surveillance or watchful waiting).[6] Additionally,primary treatment with androgen deprivation therapy (ADT) is frequent despite lack ofevidence from clinical trials to support its use as monotherapy for localized prostate cancer.[7]NIH-PA Author ManuscriptRandomized controlled trials are currently underway that will ultimately help determinewhether or not treatment reduces mortality in men with localized prostate cancer.Observational studies have suggested that active surveillance of low-risk patients may be asafe alternative to initial treatment and may preserve quality of life.[8] However, recentresults from randomized trials of radical prostatectomy compared with observationdemonstrated that surgery significantly reduced prostate cancer mortality among menyounger than 65 years at diagnosis[9] or high-risk disease,[10] indicating that some patientsubgroups may have a survival benefit from aggressive treatment.The natural history of prostate cancer is heterogeneous, and most men with localizedprostate cancer will die of causes other than their disease.[11] Therefore, knowledge of aman’s absolute risks of dying from prostate cancer versus other causes is critical for makinginformed treatment choices. We assembled a population-based cohort of 45,440 menrepresenting virtually all men diagnosed with clinically localized prostate cancer inCalifornia during 1995–1998. Our aim was to describe the absolute 10-year mortality fromprostate cancer or competing causes of death in patient populations initially treated withsurgery, radiation, ADT monotherapy or conservative management.PATIENTS AND METHODSStudy populationNIH-PA Author ManuscriptWe identified all men diagnosed with a first primary invasive adenocarcinoma of theprostate (International Classification of Diseases for Oncology, 3rd edition [ICD-O-3] sitecode 61.9; morphology code 8140) in California between January 1, 1995 and December31,1998 using data from the California Cancer Registry (CCR; http://www.ccrcal.org/),which captures 99% of cancer diagnoses state-wide. We chose the years 1995–1998 in orderto obtain at least 10 years of follow-up, needed because of low disease-specific mortalityamong men with localized prostate cancer, and to represent the period following theintroduction of PSA testing, when stage migration had largely stabilized.[12] Eligiblepatients were diagnosed with clinical stage T1 or T2 disease (N 55,082). Exclusion criteriaincluded: ambiguous stage (“localized, not otherwise specified”; N 5111); diagnosis onautopsy or death certificate only (N 46); “unknown” or “other” race (N 1799); unknowntumor grade (N 1097); lost to follow-up within 10 years (N 1119); invalid follow-up dates(N 1); and cause of death unavailable or unknown (N 358). We also excluded cases whoreceived chemotherapy (N 111) within 4 months of diagnosis because chemotherapy is notstandard treatment for localized prostate cancer and could reflect more advanced disease.The final study population consisted of 45,440 men. This study was approved by theInstitutional Review Board of the Cancer Prevention Institute of California.Open Prost Cancer J. Author manuscript; available in PMC 2013 August 30.

Sieh et al.Page 3Outcome ascertainmentNIH-PA Author ManuscriptThe CCR regularly updates vital status information through hospital follow-up and linkageswith state and national databases and agencies. Follow-up information was available throughMay 31, 2010; the median follow-up period was 138 months after diagnosis. Cases wereclassified as alive or deceased within 10 years of diagnosis. The cause of death wasclassified as prostate cancer or other competing causes based upon the underlying cause ofdeath on the death certificate, which has been shown to be a reliable means of ascertainingdeath due to prostate cancer.[13,14]Patient characteristicsNIH-PA Author ManuscriptPatient diagnoses and demographic data are routinely collected by the CCR in accordancewith guidelines of the National Cancer Institute (NCI) Surveillance, Epidemiology and EndResults (SEER; http://seer.cancer.gov/) program and the California Department of PublicHealth. For this study, age at diagnosis was categorized in 10-year groups ( 50, 50–59, 60–69, 70–79, 80 ). Tumor stage was categorized as American Joint Committee on Cancer(AJCC) stage T1 (clinically inapparent) or T2 (clinically apparent, confined to prostate)using the SEER clinical extent-of-disease information. Tumor grade was categorized aswell-differentiated (Gleason score 2–4), moderately differentiated (Gleason score 5–7), orpoorly differentiated (Gleason score 8–10) as defined by SEER.[15] Race/ethnicity wascategorized as non-Hispanic white, non-Hispanic black, Hispanic, or Asian/Pacific Islander.[16] Socioeconomic status (SES) was measured using a neighborhood-level index thatincorporates Census data on education, income, occupation, and housing costs at the censusblock-group level.[17] Each case was assigned to his neighborhood SES quintile based onthe distribution of the composite SES index across California.The CCR collects information on the first course of treatment for prostate cancer that wasadministered or initiated within four months of diagnosis. Primary treatment wascategorized as surgery, radiotherapy, ADT monotherapy, or conservative management (notherapy within four months of diagnosis). Surgery denotes procedures such as prostatectomythat ablate the organ; patients classified as having received surgery included those who alsoreceived adjuvant radiation and/or ADT. Radiotherapy denotes external beam radiation and/or brachytherapy; patients classified as having received radiotherapy included those whoreceived both radiotherapy and ADT. ADT monotherapy denotes initial treatment with onlyhormone therapy or endocrine surgery (orchiectomy).Statistical AnalysisNIH-PA Author ManuscriptCompeting risks of death from prostate cancer or other causes were estimated for each of thefour primary treatment groups, stratified by age, grade, and stage at diagnosis. Cumulativeincidence functions were used to estimate the absolute risk of dying of either prostate canceror other causes, and global tests of the equality of estimated mortality curves acrosstreatment groups were performed using the cmprsk package[18,19] implemented in R (RFoundation for Statistical Computing, Vienna, Austria). 95% confidence intervals (CI) for10-year cumulative mortality estimates were constructed using the delta method and logodds transformation to obtain estimates between 0 and 1.[20] We assessed the sensitivity ofresults to potential misclassification of clinical stage by comparing results in the surgerygroup overall to the subset of 9,665 surgically treated men with pathologically confirmedlocalized disease. All p-values were 2-sided.RESULTSAs of May 31, 2010, 15,143 deaths had occurred among the 45,440 men diagnosed withclinically localized prostate cancer in California during 1995–1998, and 2,720 (18%) ofOpen Prost Cancer J. Author manuscript; available in PMC 2013 August 30.

Sieh et al.Page 4NIH-PA Author Manuscriptthese deaths were attributed to prostate cancer (Table 1). About half of all cases had stageT2 disease at diagnosis and 11.7% of all tumors were well differentiated. The most commonprimary treatment was surgery (40.4%), followed by radiation (29.1%), conservativemanagement (20.8%), and ADT monotherapy (9.8%). Among surgically treated patients,644 (3.5%) received adjuvant radiotherapy only, 2,157 (11.8%) received adjuvant ADTonly, and 250 (1.4%) received both radiotherapy and ADT within four months of diagnosis.A substantially greater proportion of men who underwent primary radiotherapy receivedadjuvant ADT (40.7%) compared with men who underwent surgery (13.1%).Characteristics of patients in the four primary treatment groups are shown in Table 1.Patients who initially received conservative management tended to be older (median age 73years) at diagnosis, and to have well-differentiated and T1 disease. Surgically treatedpatients were youngest (median age 64 years) at diagnosis, and least likely to have welldifferentiated tumors at diagnosis. Patients treated with radiation were intermediate to theother treatment groups with respect to age (median 70 years) at diagnosis and tumor grade,but were the most likely to have T2 disease at diagnosis. Patients who received ADTmonotherapy were the oldest (median age 75 years) at diagnosis, and most likely to havepoorly differentiated tumors.NIH-PA Author ManuscriptTable 2 shows the sample size and proportion of the 45,440 men with clinically localizedprostate cancer that died from their disease or other causes, stratified by age at diagnosis,tumor grade and stage. In general, men with localized prostate cancer were far more likely todie from other causes than from their disease, except for men 60 years diagnosed withpoorly differentiated disease. As expected, the proportion of men who died from prostatecancer generally increased with older age, higher grade, and clinically apparent disease atdiagnosis. The 10-year cumulative mortality rate among all men with localized prostatecancer was 6.5% (95% CI, 6.2–6.7%) for prostate cancer and 27.0% (95% CI, 26.5–27.4%)for competing causes of death. Patients with well, moderately, or poorly differentiateddisease respectively had 10-year cumulative mortality rates of 2.7% (95% CI, 2.3–3.2%),4.3% (95% CI, 4.1–4.5%), and 15.1% (95% CI, 14.3–15.9%) for prostate cancer and 33.5%(95% CI, 32.2–34.8%), 26.5% (95% CI, 26.0–26.9%), and 29.0% (95% CI, 28.0–30.0%) forcompeting causes of death.NIH-PA Author ManuscriptFigure 1 shows the estimated mortality curves for prostate cancer or competing causes ofdeath among patients in each of the four primary treatment groups, stratified by age, grade,and stage at diagnosis. Prostate cancer mortality curves differed significantly acrosstreatment groups among men 80 years with moderately or poorly differentiated disease(Table 3). However, no significant differences in prostate cancer mortality were foundacross treatment groups for men 70 years with well-differentiated disease or 80 years withmoderately or poorly differentiated disease (Table 3). The small number of prostate cancerdeaths among men with well-differentiated disease and surgically treated men 80 yearslimited the reliability of mortality estimates in these groups.Prostate cancer mortality was highest among patients who received ADT monotherapy(Figure 1B) across all strata, and was especially high among men 70 years diagnosed withpoorly differentiated disease. Men who received ADT monotherapy or conservativemanagement (Figure 1A) both experienced relatively high mortality from causes other thantheir disease. Prostate cancer mortality was generally similar in men who receivedconservative management or radiotherapy (Figure 1C), although men diagnosed at age 70or with poorly differentiated disease who were treated with radiotherapy tended to havelower mortality rates than those who received conservative management. Surgically treatedmen (Figure 1D) had the lowest mortality from prostate cancer among men 80 years withmoderately or poorly differentiated disease. Sensitivity analyses among men withOpen Prost Cancer J. Author manuscript; available in PMC 2013 August 30.

Sieh et al.Page 5NIH-PA Author Manuscriptpathologically confirmed localized disease following radical prostatectomy with lymph nodedissection showed that prostate cancer mortality was slightly lower but similar to that for allsurgically treated men (data not shown), indicating that misclassification of clinical stage didnot have a substantial impact on the results.DISCUSSIONDetermining the optimal treatment of localized prostate cancer is a great challenge forphysicians and patients, given limited evidence to date regarding the comparativeeffectiveness of treatment alternatives. In this population-based cohort of 45,440 Californiamen with clinically localized prostate cancer, we found that patients who were initiallytreated with surgery, radiotherapy, ADT monotherapy, or conservative management differedsignificantly with respect to their ten-year risk of dying from prostate cancer or competingcauses. To our knowledge, this large observational study is the first to compare mortalityestimates among men with clinically localized prostate cancer treated with surgery,radiation, conservative management, as well as ADT monotherapy. This informationprovides a framework for understanding the expected long-term outcomes of localizedprostate cancer given the initial treatment choice and practice patterns in the generalpopulation.NIH-PA Author ManuscriptNIH-PA Author ManuscriptAlthough ADT monotherapy is not recommended for localized prostate cancer,[6] it wasreceived by 9.8% of the men in this cohort. This proportion was slightly higher than theestimate of 7.6% from a SEER Patterns of Care study (POC) in which treatment data frommedical records was supplemented by forms sent to physicians for men diagnosed withlocalized disease in 1998.[21] We found that combined therapy with ADT was utilized by40.7% and 13.1% of patients treated with radiotherapy and surgery, respectively. Arandomized trial of radiotherapy combined with ADT versus radiotherapy alone forlocalized prostate cancer reported that combined therapy significantly decreased diseasespecific mortality.[22] In contrast, several randomized trials of neoadjuvant ADT beforesurgery have not shown a survival benefit,[23,24,25] which may help explain thesubstantially greater frequency of ADT use among men treated with radiotherapy versussurgery. We found that men treated with ADT monotherapy had the highest disease-specificmortality across all strata of age, grade, and stage at diagnosis, consistent with previousstudies including one randomized trial that did not find a survival benefit with ADTmonotherapy.[7,26,27] It is possible that men treated with ADT monotherapy have higherrisk disease, contributing to poorer outcomes. However, in light of evidence that ADT isadversely associated with osteoporosis,[28] cardiovascular disease and diabetes,[29,30] andthe lack of evidence of a survival benefit from ADT monotherapy, it is especially importantfor patients and physicians to be aware of the long-term outcomes among men in this groupwhen considering treatment options.Approximately 70% of California men with localized prostate cancer underwent attemptedcurative treatment with surgery (40.4%) or radiation (29.1%). We found that men 80 yearswith moderately to poorly differentiated disease treated with surgery had the lowestmortality from prostate cancer. Patients 70 years initially treated with radiotherapy versusconservative managment generally had lower disease-specific mortality, although thedifferences were not significant among men 80 years. These findings are consistent withevidence from randomized trials that treatment with surgery[9] or high-doseradiotherapy[31,32,33,34,35] improves outcomes of localized prostate cancer. In subgroupanalyses from randomized trials, surgery significantly reduced overall and disease-specificmortality only among men 65 years,[9] whereas radiation combined with ADT versusradiation alone significantly reduced disease-specific mortality only among men 70 years.[22] Thus, evidence from both clinical trials and observational studies suggests that activeOpen Prost Cancer J. Author manuscript; available in PMC 2013 August 30.

Sieh et al.Page 6NIH-PA Author Manuscripttreatment with radiotherapy may be more effective in older men, whereas surgery may bemore effective in younger men.[36] Alternative explanations for the better outcomes amongactively treated men include patient selection based on life expectancy 10 years, absence ofcomorbidities that contraindicate treatment,[6] or other unmeasured factors associated withimproved prostate cancer survival.NIH-PA Author ManuscriptWe found no significant differences in prostate cancer mortality across treatment groupsamong men 70 with well-differentiated disease or 80 years with moderately or poorlydifferentiated disease, suggesting that conservative management is a safe and effectivechoice for these patients. The mortality estimates for California men who underwent initialconservative management was similar to U.S. men diagnosed with localized prostate cancerduring 1992–2002 who were managed without surgery or radiation but may have receivedADT within six months of diagnosis.[37] Studies of SEER treatment data for prostate cancerhave shown that, whereas surgery and radiation are well captured,[38,39] hormonal therapymay be underascertained by medical record abstraction compared to patient self-report.[40]Thus, one potential limitation of the present study is that the conservative managementgroup may include some men who received ADT. However, the similar proportion of menwho received initial ADT monotherapy in this study compared to a SEER POC study in1998 that supplemented registry data with physician surveys[21] suggests that the degree ofADT underascertainment by the CCR may be relatively modest. The high mortality fromnon-prostate cancer causes among men who initially received conservative management orADT monotherapy may reflect high comorbidity contraindicating aggressive treatment.Greater comorbidity has been associated with higher overall mortality as well as lowerprostate-cancer-specific mortality.[41]The main limitation of this observational study was that, without randomization, primarytreatment groups may differ systematically with respect to unmeasured characteristics suchas comorbidities that influence mortality. Thus, the data presented here are intended todescribe mortality given a patient’s initial treatment choice and practice patterns in thegeneral population, and should not be interpreted as a quantification of treatment effects.Additionally, the CCR, like other SEER registries, does not have information on PSA valuesat diagnosis, and Gleason 5–7 tumors were collapsed as moderately differentiated disease,potentially obscuring survival differences in this group. The main strengths of thisobservational cohort study are the large sample size, follow-up for over ten years, andpopulation-based setting, with capture of nearly all prostate cancer cases diagnosed inCalifornia. Thus, the findings are robust and broadly applicable, and are not restricted tospecific clinics or age groups as is often the case for clinical trials or Medicare claims-basedstudies.NIH-PA Author ManuscriptThis study provides population-based estimates of a man’s absolute risk of dying fromprostate cancer or other causes within ten years of his diagnosis with localized prostatecancer depending upon his initial treatment choice and disease characteristics. These datamay help patients and physicians to better understand the expected long-term outcomes ofclinically localized prostate cancer in the context of practice patterns in the generalpopulation. Additional studies will be needed to characterize mortality trends as practicepatterns change over time.AcknowledgmentsWe thank David Johnston and Tammi Nicosia for programming and graphics assistance. This study was supportedby the California State Department of Public Health; National Cancer Institute (NCI) Surveillance Epidemiologyand End Results Program contracts HHSN261201000040C, HHSN261201000035C and HHSN261201000034C;Centers for Disease Control and Prevention, National Program of Cancer Registries U58DP000807; and NCIK07CA143047 (WS). The ideas and opinions expressed herein are those of the authors and endorsement by theOpen Prost Cancer J. Author manuscript; available in PMC 2013 August 30.

Sieh et al.Page 7State of California Department of Public Health, NCI, and the Centers for Disease Control and Prevention or theircontractors and subcontractors is not intended nor should be inferred. The authors have no conflicts of interest,including specific financial interests and relationships and affiliations relevant to the subject of this manuscript.NIH-PA Author ManuscriptReferencesNIH-PA Author ManuscriptNIH-PA Author Manuscript1. Cooperberg MR, Broering JM, Litwin MS, Lubeck DP, Mehta SS, et al. The contemporarymanagement of prostate cancer in the United States: lessons from the cancer of the prostate strategicurologic research endeavor (CapSURE), a national disease registry. J Urol. 2004; 171:1393–1401.[PubMed: 15017184]2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012; 62:10–29.[PubMed: 22237781]3. Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, et al. Prostate cancer screening in therandomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after13 years of follow-up. J Natl Cancer Inst. 2012; 104:125–132. [PubMed: 22228146]4. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, et al. Prostate-cancer mortality at 11years of follow-up. N Engl J Med. 2012; 366:981–990. [PubMed: 22417251]5. Smith MR. Effective treatment for early-stage prostate cancer--possible, necessary, or both? N EnglJ Med. 2011; 364:1770–1772. [PubMed: 21542749]6. Mohler J, Bahnson RR, Boston B, Busby JE, D’Amico A, et al. NCCN clinical practice guidelinesin oncology: prostate cancer. J Natl Compr Canc Netw. 2010; 8:162–200. [PubMed: 20141676]7. Wong YN, Freedland SJ, Egleston B, Vapiwala N, Uzzo R, et al. The role of primary androgendeprivation therapy in localized prostate cancer. Eur Urol. 2009; 56:609–616. [PubMed: 19368995]8. Cooperberg MR, Carroll PR, Klotz L. Active Surveillance for Prostate Cancer: Progress andPromise. J Clin Oncol. 20119. Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, et al. Radical prostatectomy versuswatchful waiting in early prostate cancer. N Engl J Med. 2011; 364:1708–1717. [PubMed:21542742]10. Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, et al. Radical prostatectomy versusobservation for localized prostate cancer. N Engl J Med. 2012; 367:203–213. [PubMed:22808955]11. Dall’Era MA, Konety BR. Active surveillance for low-risk prostate cancer: selection of patientsand predictors of progression. Nat Clin Pract Urol. 2008; 5:277–283. [PubMed: 18285752]12. Derweesh IH, Kupelian PA, Zippe C, Levin HS, Brainard J, et al. Continuing trends inpathological stage migration in radical prostatectomy specimens. Urol Oncol. 2004; 22:300–306.[PubMed: 15283887]13. Albertsen PC, Walters S, Hanley JA. A comparison of cause of death determination in menpreviously diagnosed with prostate cancer who died in 1985 or 1995. J Urol. 2000; 163:519–523.[PubMed: 10647669]14. Penson DF, Albertsen PC, Nelson PS, Barry M, Stanford JL. Determining cause of death inprostate cancer: are death certificates valid? J Natl Cancer Inst. 2001; 93:1822–1823. [PubMed:11734600]15. Fritz, A.; Ries, L., editors. SEER Extent of Disease -- 1988 Codes and Coding Instructions. 3.Bethesda, MD: National Cancer Institute; 1998.16. Gomez SL, Le GM, West DW, Satariano WA, O’Connor L. Hospital policy and practice regardingthe collection of data on race, ethnicity, and birthplace. Am J Public Health. 2003; 93:1685–1688.[PubMed: 14534222]17. Yost K, Perkins C, Cohen R, Morris C, Wright W. Socioeconomic status and breast cancerincidence in California for different race/ethnic groups. Cancer Causes Control. 2001; 12:703–711.[PubMed: 11562110]18. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. Journalof the American Statistical Association. 1999; 94:496–509.19. Gray RJ. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a CompetingRisk. Annals of Statistics. 1988; 16:1141–1154.Open Prost Cancer J. Author manuscript; available in PMC 2013 August 30.

Sieh et al.Page 8NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript20. Oehlert GW. A Note on the Delta Method. American Statistician. 1992; 46:27–29.21. Hamilton AS, Albertsen PC, Johnson TK, Hoffman R, Morrell D, et al. Trends in the treatment oflocalized prostate cancer using supplemented cancer registry data. BJU Int. 2011; 107:576–584.[PubMed: 20735387]22. Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, et al. Radiotherapy and short-termandrogen deprivation for localized prostate cancer. N Engl J Med. 2011; 365:107–118. [PubMed:21751904]23. Yee DS, Lowrance WT, Eastham JA, Maschino AC, Cronin AM, et al. Long-term follow-up of 3month neoadjuvant hormone therapy before radical prostatectomy in a randomized trial. BJU Int.2010; 105:185–190. [PubMed: 19594741]24. Soloway MS, Pareek K, Sharifi R, Wajsman Z, McLeod D, et al. Neoadjuvant androgen ablationbefore radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol. 2002; 167:112–116. [PubMed: 11743286]25. Debruyne FM, Witjes WP. Neoadjuvant hormonal therapy prior to radical prostatectomy: theEuropean experience. Mol Urol. 2000; 4:251–256. discussion 257. [PubMed: 11062381]26. Lu-Yao GL, Albertsen PC, Moore DF, Shih W, Lin Y, et al. Survival following primary androgendeprivation therapy among men with localized prostate cancer. JAMA. 2008; 300:173–181.[PubMed: 18612114]27. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, et al. Bicalutamide 150 mg plus standardcare vs standard care alone for early prostate cancer. BJU Int. 2006; 97:247–254. [PubMed:16430622]28. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation forprostate cancer. N Engl J Med. 2005; 352:154–164. [PubMed: 15647578]29. Saylor PJ, Smith MR. Adverse effects of androgen deprivation therapy: defining the problem andpromoting health among men with prostate cancer. J Natl Compr Canc Netw. 2010; 8:211–223.[PubMed: 20141678]30. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgendeprivation therapy for prostate cancer. J Clin Oncol. 2006; 24:4448–4456. [PubMed: 16983113]31. Beckendorf V, Guerif S, Le Prise E, Cosset JM, Bougnoux A, et al. 70 Gy versus 80 Gy inlocalized prostate cancer: 5-year results of GETUG 06 randomized trial. Int J Radiat Oncol BiolPhys. 2011; 80:1056–1063. [PubMed: 21147514]32. Zietman AL, Bae K, Slater JD, Shipley WU, Efstathiou JA, et al. Randomized trial comparingconventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma ofthe prostate: long-term results from proton r

Sieh et al. Page 3 Open Prost Cancer J. Author manuscript; available in PMC 2013 August 30. NIH-PA Author Manuscript. these deaths were attributed to prostate cancer (Table 1). About half of all cases had stage T2 disease at diagnosis and 11.7% of all tumors were well differentiated. The most common