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Surgery versus radiotherapy for localised

PRASANNA SOORIAKUMARAN

Even though there have Study sHR (95% CI) sHR (95% CI) been no controlled trials Risk group 1 All 1.91 (1.16–3.14) comparing the effectiveness Age <64 1.92 (0.96–3.82) of radical prostatectomy and Age ≥65 1.87 (0.94–3.69) Charlson comorbidity index score 0 1.67 (0.93–2.99) radiotherapy for treatment of Charlson comorbidity index score ≥1 2.91 (0.88–9.59) localised prostate cancer, there Risk group 2 is substantial observational All 1.77 (1.37–2.29) Age <64 1.95 (1.31–2.91) evidence in favour of surgery. Age ≥65 1.61 (1.16–2.25) Charlson comorbidity index score 0 1.91 (1.42–2.57) Charlson comorbidity index score ≥1 1.36 (0.81–2.30) rostate cancer is the commonest non- dermatological cancer and the second Risk group 3 P All 1.50 (1.19–1.88) leading cause of cancer death in western Age <64 1.78 (1.26–2.51) 1 men. The overwhelming majority of new Age ≥65 1.24 (0.92–1.68) cases are clinically localised, and the most Charlson comorbidity index score 0 1.59 (1.21–2.07) frequent methods of treatment are with Charlson comorbidity index score ≥1 1.30 (0.83–2.03) 2 radical or radiotherapy. Non-metastatic (risk groups 1–3) 1.76 (1.49–2.08) Risk group 4 TRIAL EVIDENCE LACKING All 0.76 (0.49–1.19) Despite millions of men having undergone Age <64 1.08 (0.57–2.03) Age ≥65 0.58 (0.33–1.01) these prostate cancer treatments, no Charlson comorbidity index score 0 0.81 (0.46–1.43) randomised controlled trial evidence Charlson comorbidity index score ≥1 0.65 (0.31–1.35) currently exists to compare their effectiveness. The only such trial underway, 0.25 0.5 124 the ProtecT study, will not report until 2016 Favours radical and may have limited generalisability due to Favours radiotherapy prostatectom y differences in the randomised population and the prostate cancer population at large. 3 Figure 1. Forest plot showing propensity score-adjusted subdistribution hazard ratios for Also, only a small number of the entire radiotherapy versus radical prostatectomy for prostate cancer mortality stratified by risk study cohort has undergone randomisation group (1 = low risk; 2 = intermediate risk; 3 = high risk; 4 = advanced prostate cancer) and (500 cases per treatment arm), and around substratified by age and Charlson score 11 85% of the cases are low or intermediate risk; hence, follow-up to 10 years may not treatment options, and thus is more likely be long enough to find survival differences to show up any comparative effectiveness Prasanna Sooriakumaran, MD, PhD, in this study. differences, but unfortunately will not FRCS(Urol), FEBU, Senior Clinical mature for the next 10 years (O. Akre, Researcher, University of Oxford; A soon-to-be-set-up study, the Scandinavian personal communication). Hence, as prostate Honorary Consultant Urological Surgeon, Prostate Cancer Group (SPCG)-15 trial, is cancer clinicians, we are left with only Oxford University Hospitals NHS Trust randomising high-risk men to different observational data currently to guide us

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when we counsel patients with localised A similar, but larger, study using the same Charlson comorbidity index, and cancer- prostate cancer. primary dataset, on 67 087 men with related events during follow-up. Hence, localised prostate cancer, stratified survival PCBaSe is a truly population-based dataset OBSERVATIONAL DATA outcome based not only on treatment but and with near-complete data on almost all There is a large amount of such also on life expectancy. 9 It found that in variables of interest. observational data, but unfortunately men with an estimated life expectancy it is of variable quality. Much of the greater than 10 years, surgery was Methods data examines surrogate oncological associated with improved survival over We examined prostate cancer mortality as endpoints such as biochemical recurrence, radiotherapy for all localised disease our primary outcome, and compared an outcome with differing definitions stages. Interestingly, survival benefits subjects who had been managed with between treatment modalities and with a were not consistent for those with shorter radical prostatectomy as their initial variable progression to clinically significant life expectancies. treatment with those who had undergone oncological outcomes such as death. 4 primary radiotherapy. 11 A total of 34 515 Only few observational studies remain One problem with these US datasets is men made this study cohort, with a if we therefore consider survival as that they are not comprehensive, in that follow-up to 15 years (median 5.37 years). the outcome of primary interest when they capture only a proportion of the Subjects were classified by clinical risk (low, comparing treatments. prostate cancer population. For example, intermediate, high), age (<65, 65 or more) the SEER registry represents only 14% of and Charlson score (0, 1 or more). Data from an observational study of more the US population before 2000 and 26% than 404 000 men treated at over 1000 thereafter, and the Medicare insurance- To visualise cause-specific mortality, community hospitals in 44 states of the linked programme captures only those cumulative incidence curves were plotted USA found that surgery had superior aged over 65 years. Another problem is for the treatment groups, and differences prostate cancer and other-cause mortality that these datasets have a lot of missing in cancer-specific and other-cause outcomes for men aged under 80 with data in their captured variables, and mortality were investigated using low- and intermediate-risk disease. 5 This do not include many important covariates subdistribution hazard ratios corrected study used the Nationwide Inpatient that can influence outcome, such as for competing risks by Fine and Gray Sample of the United States as its dataset, comorbidities. proportional hazards regression. To deal and others have found similar benefits for with differences in baseline characteristics surgery over radiotherapy using other SWEDISH STUDY between the treatment groups, we US datasets, such as SEER (Surveillance, We therefore wanted to interrogate this produced both traditional multivariable Epidemiology and End Results)/Medicare, question of comparative oncological model-adjusted and propensity score- and CapSUrE (Cancer of the prostate effectiveness in our most common cancer, adjusted estimates of subdistribution Strategic Urologic research Endeavor). 6,7 using a higher-quality dataset. In Sweden, hazard ratios. Propensity scores were every person is assigned a national identity calculated using logistic regression, with Recently, the Prostate Cancer Outcomes number that tracks them throughout life, treatment group as the outcome variable Study, based on SEER data, reported and thus the National Prostate Cancer and all adjustment covariates as predictors. on 1655 men with localised prostate Registry (NPCR) of Sweden has been shown We also used propensity scores for cancer. 8 The majority of the subjects to cover 98% of all cases diagnosed since matching, which was carried out within were diagnosed in the PSA era as a 1998 (and with coverage from 1996 to 1997 each risk group. As well as all the above, result of screening and thus the cohort limited to certain geographical regions). we performed a sensitivity analysis to look was relatively contemporary. Another for residual confounding, analysis by year advantage of this study was the use of The NPCR has been linked to eight other of surgery to examine what effect, if any, different, robust statistical techniques, national registries, including the Swedish higher radiotherapy dosing with time including using propensity scores cancer register and the cause-of-death would have had, and an inverse probability as covariates in survival analyses, register, to compose the PCBaSe Sweden. 10 of treatment weights analysis. for stratification, for matched-pair PCBaSe has virtually complete data on year analyses, and in an inverse probability of of diagnosis, age, clinical (TNM) stage, Results treatment weights analysis. The authors tumour grade, serum PSA, planned primary At baseline, radiotherapy patients generally found consistent benefits for radical treatment within 6 months of diagnosis, had worse patient-tumour characteristics; prostatectomy over radiotherapy for county of residence, marital status, specifically, they had a higher proportion overall and prostate cancer mortality. educational level, socioeconomic status, of high clinical stage and grade disease,

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Recent evidence from a large Canadian KEY POINTS population-based study has shown that • Conventional treatments for localised prostate cancer include radical men who received radiotherapy had a prostatectomy and radiotherapy higher incidence of hospital admissions, rectal or anal procedures, open surgical • No randomised trial data that compare surgery and radiotherapy are procedures, and secondary cancers at currently available 5 years post-treatment than did those who • Low-risk prostate cancer, especially in older and/or unfit men, is highly underwent radical prostatectomy. 13 Hence, unlikely to result in death regardless of treatment choice radical prostatectomy may be superior over radiotherapy for localised prostate cancer, • There is a large body of high- and intermediate-quality observational data in terms of not only a survival advantage that suggest that radical prostatectomy is oncologically superior to but also decreased complications and radiotherapy for young and/or fit men with intermediate and high-risk improved functional outcomes. prostate cancer Declaration of interests Prasanna Sooriakumaran is part-funded by higher PSAs, were older, and had higher oncological benefit for surgery over the National Institute for Health Research Charlson scores. Also, radiotherapy radiotherapy (hazard ratio 0.57), and (NIHR) Oxford Biomedical Research Centre subjects had a greater proportion of low when stratified by year of treatment based at Oxford University Hospitals NHS educational level, low socioeconomic the treatment differences persisted, Trust and the University of Oxford. The status, and were more likely to be suggesting that lower radiotherapy views expressed are those of the author and unmarried. By the end of the study, dosing in the early study period was not not necessarily those of the NHS, the NIHR 339 prostate cancer deaths and 1064 responsible for the results. or the Department of Health. deaths from other causes occurred in the surgery arm, with 697 and 1127 SURGERY AS FIRST CHOICE REFERENCES respectively in the radiotherapy cohort. The current conventional wisdom 1. Siegel R, Naishadham D, Jemal A. Cancer is that there is no difference in statistics, 2013. CA Cancer J Clin 2013; The most striking finding of this study was oncological outcome between surgery 63:11–30. that all adjustments from all different and radiotherapy, and men with 2. Makarov DV, Trock BJ, Humphreys EB, statistical methodologies gave consistent prostate cancer should choose their et al . Updated nomogram to predict results; surgery was associated with treatment primarily based on adverse pathologic stage of prostate cancer lower prostate cancer mortality than event profiles. However, absence of given prostate- specific antigen level, radiotherapy, especially in those most evidence for a difference is not evidence clinical stage, and biopsy Gleason at risk of death from prostate cancer, for absence of a difference, and thus score (Partin tables) based on cases ie young, fit men with intermediate- or this conventional viewpoint is certainly from 2000 to 2005. Urology 2007; high-risk disease (Figure 1). Low-risk men, not evidence-based. 69:1095–101. especially if they were older, had a very low 3. Lane JA, Hamdy FC, Martin RM, et al . chance of dying from prostate cancer and Rather, taking the literature as a whole, Latest results from the UK trials evaluating thus treatment differences were negligible. radical prostatectomy appears superior in prostate cancer screening and treatment: oncological outcome over radiotherapy as the CAP and ProtecT studies. Eur J Cancer This mirrors the recent Prostate cancer primary treatment for men with clinically 2010;46:3095–101. Intervention Versus Observation Trial localised prostate cancer. Of course, 4. Sooriakumaran P, Spahn M, Wiklund P. (PIVOT), which randomised US men to some men do not require treatment with Apples and oranges: comparison of surgery versus surveillance, and found either, but for those who do, surgery is treatment methods for prostate oncological benefit for surgery in the likely to be superior. We will have to cancer using biochemical recurrence higher-risk group and younger men, similar await confirmation of this with the as an endpoint. BJU Int 2012;110:477–8. to our findings (albeit with a different randomised trials that are underway, 5. Abdollah F, Sun M, Thuret R, et al . A treatment modality used for comparison). 12 such as SPCG-15, but in the interim men competing-risks analysis of survival In our study, a sensitivity analysis showed with prostate cancer offered radical after alternative treatment modalities that residual confounding was highly treatment should consider surgery as for prostate cancer patients: 1988–2006. unlikely to account for the entirety of the their first-choice treatment. Eur Urol 2011;59:88–95.

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6. Abdollah F, Schmitges J, Sun M, et al . 9. Sun M, Sammon JD, Becker A, et al . 12. Wilt TJ, Brawer MK, Barry MJ, et al . The Comparison of mortality outcomes after radical Radical prostatectomy vs radiotherapy vs Prostate cancer Intervention Versus prostatectomy versus radiotherapy in patients observation among older patients with Observation Trial:VA/NCI/AHRQ Cooperative with localized prostate cancer: a population- clinically localized prostate cancer: a Studies Program #407 (PIVOT): design and based analysis. Int J Urol 2012;19:836–45. comparative effectiveness evaluation. baseline results of a randomized controlled 7. Cooperberg MR, Vickers AJ, Broering JM, BJU Int 2014;113:200–8. trial comparing radical prostatectomy to et al . Comparative risk-adjusted mortality 10. Van Hemelrijck M, Wigertz A, Sandin F, et al . watchful waiting for men with clinically outcomes after primary surgery, Cohort profile: the National Prostate Cancer localized prostate cancer. Contemp Clin radiotherapy, or androgen-deprivation Register of Sweden and Prostate Cancer Trials 2009;30:81–7. therapy for localized prostate cancer. data Base Sweden 2.0. Int J Epidemiol 13. Nam RK, Cheung P, Herschorn S, et al . Cancer 2010;116:5226–34. 2013;42:956–67. Incidence of complications other 8. Hoffman RM, Koyama T, Fan KH, et al . 11. Sooriakumaran P, Nyberg T, Akre O, et al . than or erectile Mortality after radical prostatectomy or Comparative effectiveness of radical dysfunction after radical prostatectomy external beam radiotherapy for localized prostatectomy and radiotherapy in prostate or radiotherapy for prostate cancer: a prostate cancer. J Natl Cancer Inst cancer: observational study of mortality population-based cohort study. Lancet 2013;105:711–18. outcome. BMJ 2014;348:g1502. Oncol 2014;15:223–31.

THE UROLOGY FOUNDATION RESEARCH SCHOLARSHIP PROGRAMME 2015/16 CALL FOR APPLICATIONS

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