- Email: [email protected]
Reply from Authors re: Martin Spahn, Alan Dal Pra, Daniel Aebersold, Bertrand Tombal. Radiation Therapy Versus Radical Prostatectomy: A Never-ending Discussion. Eur Urol 2016;70:31–2
EUROPEAN UROLOGY 70 (2016) 31–34
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Platinum Priority Reply from Authors re: Martin Spahn, Alan Dal Pra, Daniel Aebersold, Bertrand Tombal. Radiation Therapy Versus Radical Prostatectomy: A Never-ending Discussion. Eur Urol 2016;70:31–2 Prostate Cancer Treatment: Take Out the Emotion, Please Christopher J.D. Wallis a,b,c, Robert K. Nam a,b,c,* a Division of Urology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, Canada; b Division of Urology, Department of Surgery, University of Toronto, Toronto, Canada; c Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
We thank the editors for the opportunity to respond to the editorial [1] and the letters [2–5] regarding our paper examining survival following radical prostatectomy and radiotherapy (RT) for patients with clinically localised prostate cancer (PCa) [6]. Among the responses, a common theme seems to have emerged that does not question our analytical methodology (described by Ost and Ghadjar [2] as ‘‘rigourous’’) but rather concerns the validity of the included studies as well as the use of the Newcastle-Ottawa Scale (NOS) for risk-of-bias assessment. The editorial [1] succinctly summarises the limitations that we described in our report [6]. Spahn and colleagues seem to assert that, because there was variability in the type and extent of surgery, the methods of RT, and the provision of adjuvant and salvage treatments, the results of the analysis are invalid. We hold a different view: Despite different authors assessing different cohorts of patients treated with somewhat differing therapies over a period of time, we identified remarkable consistency in the relative effect estimate between RT and surgery [6]. This consistency is in keeping with criterion four of Hill’s criteria for causation [7]. Blanchard and colleagues [4] stated that the NOS was designed solely for case–control series. In reality, it was designed to assess the quality of nonrandomised studies including case–control and cohort studies [8]. Deeks et al undertook a systematic review of 182 tools designed to assess the methodological quality of nonrandomised studies and found the NOS to be one of two ‘‘most useful tools’’ [9]. Thus, the NOS is recommended by the Cochrane Handbook for Systematic Reviews of Interventions for evaluation of risk of bias for observational studies [10]. Ost and Ghadjar highlighted the issue of residual confounding in their assessment of the quality of evidence and cited the GRADE criteria to discount our meta-analysis [2]. However, using the GRADE criteria, other factors strengthen our DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2016.01.049, http://dx.doi.org/10.1016/j.eururo.2016.02.040, http://dx.doi.org/10.1016/j.eururo.2016.02.041, http://dx.doi.org/10.1016/j.eururo.2016.02.042, http://dx.doi.org/10.1016/j.eururo.2016.02.039, http://dx.doi.org/10.1016/j.eururo.2015.11.010. * Corresponding author. 2075 Bayview Avenue, Room MG-406, Toronto, Ontario M4N 3M5, Canada. Tel. +1 416 480 5075; Fax: +1 416 480 6934. E-mail address: [email protected] (R.K. Nam).
analysis, including the lack of heterogeneity in both primary and subgroup analyses, the precision of the results, and the lack of publication bias. The interpretation of the quality of these studies, a subjective task at all times, appears to depend in large part on the clinical specialty of the reader. Each of the authors raised concerns regarding the validity of the included studies and the potential for residual confounding. Parker stated that observational studies, even when well conducted, cannot account for unmeasured confounders in the manner of randomisation [5]. We clearly and explicitly acknowledged this limitation in our discussion [6]. Other correspondence indicated the need for randomised studies and advised not conducting observational studies such as ours. We agree that randomised studies may provide the answer we are looking for, and we wish them to be of a pragmatic nature so that not many patients in routine clinical practice meet the exclusion criteria. In the meantime, we feel it continues to be important to examine the survival benefits of current treatment options for clinically localised PCa. Lazar and colleagues [3] raised the example of the study by Cooperberg et al [11]. They stated that because the surgery and RT groups had differing ages at baseline, the study must be heavily biased in favour of surgery. Such differences in baseline characteristics are precisely the reason we chose to include only studies that reported multivariate adjusted hazard ratios (aHRs) that accounted for demographic and clinical oncologic variables in addition to comorbidities [6]. Notably, Cooperberg et al [11] conducted a very elegant sensitivity analysis of their findings: They artificially increased the Kattan scores of patients undergoing prostatectomy until the results were nullified to quantify the degree of unmeasured confounding that would be required to account for the observed results. They found that residual confounding would have to be 20 Kattan points for radical prostatectomy and RT to be equivalently effective. Even with residual confounding equivalent to 35 Kattan points, RT was not superior to surgery. They concluded that it is implausible for such a large unmeasured confounder to exist [11]. Consequently, although a quantitative change in our effect measure is plausible, a qualitative difference in our conclusions is unlikely. Lazar and colleagues also expressed concern regarding the presentation of relative treatment effects [3]. Although we did not pool the absolute risk estimates from each study, as we wished to use risk-adjusted estimates for the reasons presented above, we presented the absolute risks from each study in our Table 2 [6]. The risk of both overall and PCaspecific mortality is, numerically, consistently higher among those patients treated with RT, in keeping with our analysis of relative treatment effects. Parker noted that even among patients with low-risk disease, patients treated with RT had worse outcomes than those treated with surgery [5]. Although we lack the data to fully explore this finding, a number of observations seem
34
EUROPEAN UROLOGY 70 (2016) 31–34
relevant. First, many patients in the included cohorts were treated in the late 1980s and early 1990s; because of the well-described Will Rogers phenomenon, these patients would likely be considered intermediate risk if diagnosed today [12]. Second, as Parker suggested, residual confounder or selection bias may be at play [5]. When both overall and cancer-specific mortality data are available, a selection bias is considered likely when the observed effect is greater in overall mortality than cancer-specific mortality. In our analysis, we observed that a greater difference was observed for PCa-specific mortality (aHR: 1.70) than for overall mortality (aHR: 1.47) [6]. Finally, there was correspondence about the upcoming randomised controlled trials in this field (PROTECT and SPCG-15), a point that we acknowledged [6]. Although the oncology community awaits the results of these trials, the synthesised evidence in this review and meta-analysis of observational studies remains the most robust evidence to date regarding survival outcomes following PCa treatment. To dismiss the available evidence because of its faults and assume equipoise when this clearly has not been proven does a disservice to patients, clinicians, and the urologic community. Indeed, current treatment guidelines do not acknowledge the selection biases and potential confounding and instead recommend either surgery or radiation equally to all patients. We believe that treatment guidelines and patient counselling should reflect this evidence while acknowledging its limitations. Conflicts of interest: The authors have nothing to disclose.
prostate cancer: a systematic review and meta-analysis. Eur Urol 2016;70:21–30. Eur Urol 2016;70:e11–2. [3] Lazar AA, Lizarraga TLC, Roach III M.Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery versus radiotherapy for clinically-localized prostate cancer: a systematic review and meta-analysis. Eur Urol 2016;70:21–30. Eur Urol 2016;70:e13–4. [4] Blanchard P, Briganti A, Bossi A. Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery versus radiotherapy for clinically-localized prostate cancer: a systematic review and metaanalysis. Eur Urol. 2016;70:21–30. Eur Urol 2016;70:e15–6. [5] Parker C. Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery versus radiotherapy for clinically-localized prostate cancer: a systematic review and meta-analysis. Eur Urol 2016;70:21–30. Eur Urol 2016;70:e17. [6] Wallis CJ, Saskin R, Choo R, et al. Surgery versus radiotherapy for clinically-localized prostate cancer: a systematic review and metaanalysis. Eur Urol 2016;70:21–30. [7] Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295–300. [8] Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in metaanalyses. The Ottawa Hospital Web site. http://www.ohri.ca/ programs/clinical_epidemiology/oxford.asp. Accessed September 14, 2014. [9] Deeks JJ, Dinnes J, D’Amico R, et al. Evaluating non-randomised intervention studies. Health Technol Assess 2003;7:iii–x, 1–173. [10] Reeves BC, Deeks JJ, Higgins JP, Wells GA. Tools for assessing methodological quality of risk of bias in non-randomized studies. In: Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions, version 5. 1. 0 [updated March 2011]. London, UK: Cochrane Collaboration; 2011. [11] Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative risk-adjusted mortality outcomes after primary surgery, radiother-
References [1] Spahn M, Dal Pra A, Aebersold D, Tombal B. Radiation therapy versus radical prostatectomy: a never-ending discussion. Eur Urol
apy, or androgen-deprivation therapy for localized prostate cancer. Cancer 2010;116:5226–34. [12] Albertsen PC, Hanley JA, Barrows GH, et al. Prostate cancer and the Will Rogers phenomenon. J Nat Cancer Inst 2005;97:1248–53.
2016;71:31–2. [2] Ost P, Ghadjar P. Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery versus radiotherapy for clinically-localized
http://dx.doi.org/10.1016/j.eururo.2016.02.038
33
Platinum Priority Reply from Authors re: Martin Spahn, Alan Dal Pra, Daniel Aebersold, Bertrand Tombal. Radiation Therapy Versus Radical Prostatectomy: A Never-ending Discussion. Eur Urol 2016;70:31–2 Prostate Cancer Treatment: Take Out the Emotion, Please Christopher J.D. Wallis a,b,c, Robert K. Nam a,b,c,* a Division of Urology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, Canada; b Division of Urology, Department of Surgery, University of Toronto, Toronto, Canada; c Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
We thank the editors for the opportunity to respond to the editorial [1] and the letters [2–5] regarding our paper examining survival following radical prostatectomy and radiotherapy (RT) for patients with clinically localised prostate cancer (PCa) [6]. Among the responses, a common theme seems to have emerged that does not question our analytical methodology (described by Ost and Ghadjar [2] as ‘‘rigourous’’) but rather concerns the validity of the included studies as well as the use of the Newcastle-Ottawa Scale (NOS) for risk-of-bias assessment. The editorial [1] succinctly summarises the limitations that we described in our report [6]. Spahn and colleagues seem to assert that, because there was variability in the type and extent of surgery, the methods of RT, and the provision of adjuvant and salvage treatments, the results of the analysis are invalid. We hold a different view: Despite different authors assessing different cohorts of patients treated with somewhat differing therapies over a period of time, we identified remarkable consistency in the relative effect estimate between RT and surgery [6]. This consistency is in keeping with criterion four of Hill’s criteria for causation [7]. Blanchard and colleagues [4] stated that the NOS was designed solely for case–control series. In reality, it was designed to assess the quality of nonrandomised studies including case–control and cohort studies [8]. Deeks et al undertook a systematic review of 182 tools designed to assess the methodological quality of nonrandomised studies and found the NOS to be one of two ‘‘most useful tools’’ [9]. Thus, the NOS is recommended by the Cochrane Handbook for Systematic Reviews of Interventions for evaluation of risk of bias for observational studies [10]. Ost and Ghadjar highlighted the issue of residual confounding in their assessment of the quality of evidence and cited the GRADE criteria to discount our meta-analysis [2]. However, using the GRADE criteria, other factors strengthen our DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2016.01.049, http://dx.doi.org/10.1016/j.eururo.2016.02.040, http://dx.doi.org/10.1016/j.eururo.2016.02.041, http://dx.doi.org/10.1016/j.eururo.2016.02.042, http://dx.doi.org/10.1016/j.eururo.2016.02.039, http://dx.doi.org/10.1016/j.eururo.2015.11.010. * Corresponding author. 2075 Bayview Avenue, Room MG-406, Toronto, Ontario M4N 3M5, Canada. Tel. +1 416 480 5075; Fax: +1 416 480 6934. E-mail address: [email protected] (R.K. Nam).
analysis, including the lack of heterogeneity in both primary and subgroup analyses, the precision of the results, and the lack of publication bias. The interpretation of the quality of these studies, a subjective task at all times, appears to depend in large part on the clinical specialty of the reader. Each of the authors raised concerns regarding the validity of the included studies and the potential for residual confounding. Parker stated that observational studies, even when well conducted, cannot account for unmeasured confounders in the manner of randomisation [5]. We clearly and explicitly acknowledged this limitation in our discussion [6]. Other correspondence indicated the need for randomised studies and advised not conducting observational studies such as ours. We agree that randomised studies may provide the answer we are looking for, and we wish them to be of a pragmatic nature so that not many patients in routine clinical practice meet the exclusion criteria. In the meantime, we feel it continues to be important to examine the survival benefits of current treatment options for clinically localised PCa. Lazar and colleagues [3] raised the example of the study by Cooperberg et al [11]. They stated that because the surgery and RT groups had differing ages at baseline, the study must be heavily biased in favour of surgery. Such differences in baseline characteristics are precisely the reason we chose to include only studies that reported multivariate adjusted hazard ratios (aHRs) that accounted for demographic and clinical oncologic variables in addition to comorbidities [6]. Notably, Cooperberg et al [11] conducted a very elegant sensitivity analysis of their findings: They artificially increased the Kattan scores of patients undergoing prostatectomy until the results were nullified to quantify the degree of unmeasured confounding that would be required to account for the observed results. They found that residual confounding would have to be 20 Kattan points for radical prostatectomy and RT to be equivalently effective. Even with residual confounding equivalent to 35 Kattan points, RT was not superior to surgery. They concluded that it is implausible for such a large unmeasured confounder to exist [11]. Consequently, although a quantitative change in our effect measure is plausible, a qualitative difference in our conclusions is unlikely. Lazar and colleagues also expressed concern regarding the presentation of relative treatment effects [3]. Although we did not pool the absolute risk estimates from each study, as we wished to use risk-adjusted estimates for the reasons presented above, we presented the absolute risks from each study in our Table 2 [6]. The risk of both overall and PCaspecific mortality is, numerically, consistently higher among those patients treated with RT, in keeping with our analysis of relative treatment effects. Parker noted that even among patients with low-risk disease, patients treated with RT had worse outcomes than those treated with surgery [5]. Although we lack the data to fully explore this finding, a number of observations seem
34
EUROPEAN UROLOGY 70 (2016) 31–34
relevant. First, many patients in the included cohorts were treated in the late 1980s and early 1990s; because of the well-described Will Rogers phenomenon, these patients would likely be considered intermediate risk if diagnosed today [12]. Second, as Parker suggested, residual confounder or selection bias may be at play [5]. When both overall and cancer-specific mortality data are available, a selection bias is considered likely when the observed effect is greater in overall mortality than cancer-specific mortality. In our analysis, we observed that a greater difference was observed for PCa-specific mortality (aHR: 1.70) than for overall mortality (aHR: 1.47) [6]. Finally, there was correspondence about the upcoming randomised controlled trials in this field (PROTECT and SPCG-15), a point that we acknowledged [6]. Although the oncology community awaits the results of these trials, the synthesised evidence in this review and meta-analysis of observational studies remains the most robust evidence to date regarding survival outcomes following PCa treatment. To dismiss the available evidence because of its faults and assume equipoise when this clearly has not been proven does a disservice to patients, clinicians, and the urologic community. Indeed, current treatment guidelines do not acknowledge the selection biases and potential confounding and instead recommend either surgery or radiation equally to all patients. We believe that treatment guidelines and patient counselling should reflect this evidence while acknowledging its limitations. Conflicts of interest: The authors have nothing to disclose.
prostate cancer: a systematic review and meta-analysis. Eur Urol 2016;70:21–30. Eur Urol 2016;70:e11–2. [3] Lazar AA, Lizarraga TLC, Roach III M.
References [1] Spahn M, Dal Pra A, Aebersold D, Tombal B. Radiation therapy versus radical prostatectomy: a never-ending discussion. Eur Urol
apy, or androgen-deprivation therapy for localized prostate cancer. Cancer 2010;116:5226–34. [12] Albertsen PC, Hanley JA, Barrows GH, et al. Prostate cancer and the Will Rogers phenomenon. J Nat Cancer Inst 2005;97:1248–53.
2016;71:31–2. [2] Ost P, Ghadjar P. Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery versus radiotherapy for clinically-localized
http://dx.doi.org/10.1016/j.eururo.2016.02.038