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Advanced topics in evidence-based urologic oncology: Surrogate endpoints
Urologic Oncology: Seminars and Original Investigations 29 (2011) 447– 453
Seminar article
Advanced topics in evidence-based urologic oncology: Surrogate endpoints Luke T. Lavallée, M.D.a, Victor M. Montori, M.D.b, Stephen E. Canfield, M.D.c, Rodney H. Breau, M.D., F.R.C.S.C.a,d,* a
Division of Urology, University of Ottawa, Ottawa, ON, Canada Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55901, USA c Department of Surgery, Division of Urology, University of Texas Medical School, Houston, TX 77030, USA d Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55901, USA b
Received 25 March 2010; received in revised form 15 June 2010; accepted 15 June 2010
Abstract Clinical trials often report surrogate endpoint data. A surrogate endpoint is a biological marker or clinical sign that can be substituted for a patient-important outcome. Using surrogate endpoints correctly may facilitate and expedite clinical trials and may improve medical decisions. However, rigorous criteria must be met for an endpoint to be considered a valid surrogate. The purpose of this article is to review the topic of surrogate endpoints in the context of a urologic encounter. © 2011 Elsevier Inc. All rights reserved. Keywords: Evidence-based medicine; Surrogate endpoints; Data Interpretation; Biological Markers
1. Introduction Urologists should rely on methodologically strong clinical trials when making patient management decisions. Trials directly examining the impact of an intervention on patient-important outcomes. such as quality of life, serious morbidity, disease-specific survival, and overall survival, provide the best evidence. Such trials are uncommon because of logistical obstacles, including the requirement for large sample size, long follow-up, and monetary support. Using a surrogate endpoint in place of a patient-important outcome may decrease sample size and trial duration [1]. Ultimately, these advantages result in more rapid evaluation and implementation of interventions that may improve patient care. In urology, biological markers are frequently used for clinical decision-making and prognostication. Common
prostate cancer biological markers include Gleason grade, prostate-specific antigen (PSA), and tumor stage [2]. Biological markers, however, are infrequently valid surrogate endpoints. Unless a marker has been validated as a surrogate endpoint, the impact of an intervention on that marker may not consistently and predictably reflect the impact of the intervention on the patient-important outcome. Alternatively stated, using invalid surrogates may misrepresent the true consequences of an intervention [1]. The identification of valid surrogate endpoints in urologic oncology would be of tremendous benefit. The purpose of this article is to review the basic principles of surrogate endpoints. Using a clinical scenario and examples from the available literature, we detail advantages and limitations of surrogate endpoints and provide a framework for reviewing studies that report surrogate data (Table 1). 2. Clinical scenario
Ray et al. validated distant metastasis at 3 years as a surrogate endpoint for PCSS. For simplicity, we refer to distant metastasis rather than distant metastasis at 3 years throughout this article. * Corresponding author. Tel.: ⫹613-761-4500; fax: ⫹613-761-5305. E-mail address: [email protected] (R.H. Breau). 1078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2010.06.010
A 64-year-old patient with a PSA of 20 ng/ml was diagnosed with clinical T3aN0M0, Gleason sum (4⫹4) prostate adenocarcinoma. He elected to receive primary external beam radiotherapy and androgen deprivation therapy (ADT). Despite the recommendation to continue ADT
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Table 1 Objectives
4. Definitions
● Provide definitions of key terms pertaining to surrogate endpoints. ● Explain the rationale for using surrogate endpoints and the limitations inherent in doing so. ● Review methods of validating surrogate endpoints. ● Provide a framework from which to critically appraise articles that report surrogate endpoint data.
4.1. Patient-important outcomes
after completion of radiation, he would like to discontinue this treatment because of bothersome hot flashes, fatigue, and decreased libido. He asks if pursuing adjuvant ADT will decrease his probability of dying from prostate cancer. You recall large studies that revealed significant benefit to patients receiving adjuvant ADT. While there were large reductions in several outcomes, you are unsure if any of the reported outcomes were good surrogates (i.e., could serve as substitutes) for prostate cancer-specific survival (PCSS). You decide to review the literature to address your patient’s question.
3. Literature search Using the PICOS pneumonic, you formulate a clinical question to guide your literature search [3]: Patient Population ⫽ locally advanced prostate cancer Intervention ⫽ adjuvant ADT following external beam radiotherapy Comparison ⫽ no adjuvant ADT Outcomes ⫽ PCSS and surrogate endpoints Study type ⫽ randomized controlled trial You find an article by Hanks et al. titled “Phase III Trial of Long-Term Adjuvant Androgen Deprivation After Neoadjuvant Hormonal Cytoreduction and Radiotherapy in Locally Advanced Carcinoma of the Prostate: The Radiation Therapy Oncology Group Protocol 92– 02 (RTOG 92– 02),” which addresses your question [4]. In this study, over 1,500 men received 4 months of ADT, 2 months prior to radiotherapy, and 2 months during radiotherapy. Men were then randomized to two groups. Group 1 (experimental arm) received 24 additional months of ADT. Group 2 (control arm) received no further ADT. The study reports a significant reduction in distant metastasis in the experimental (5.2%) compared with the control arm (10.7%) at 3 years [5]. This intuitively supports the notion that your patient may benefit from continuing adjuvant ADT, however, a more important outcome for the patient is PCSS. You search the literature further and find a recent article by Ray et al. that evaluated if distant metastasis was a valid surrogate endpoint for PCSS in the patients enrolled in the RTOG 92– 02 trial [5]. Using the clinical scenario and data from the above articles, we review the topic of surrogate endpoints.
A patient-important outcome, sometimes called a “clinical,” “hard,” or “final” outcome, is significant to patients [6]. It represents how patients feel, function, or survive. Examples of patient-important outcomes in prostate cancer include: quality of life, disease and treatment-induced morbidities (incontinence, erectile dysfunction, and pain), PCSS, and overall survival. Modifying these outcomes should be the objective of medical or surgical interventions. 4.2. Prognostic marker A prognostic marker is a measurable biological characteristic that is independently associated with disease outcome and provides mechanistic evaluation of a physiologic process. Physicians use prognostic markers to delineate subgroups of patients within a population who should be able to expect a different destiny. PSA is an example of a prognostic marker that is used to stratify patients diagnosed with prostate cancer into low, intermediate, and high risk groups [7]. Prognostic markers include molecules (i.e., protein concentration in blood) histologic appearance (i.e., tumor grade), and sub-clinical disease (i.e., asymptomatic metastasis) [1]. Prognostic markers may qualify as surrogate endpoints, however this is the exception rather then the rule. It can be said that all surrogate endpoints should be prognostic markers; however few prognostic markers are good surrogates (Fig. 1). 4.3. Surrogate endpoint The term surrogate literally means “substitute.” Biological markers in medicine that are used as surrogate endpoints include laboratory measurements, physical signs, and radiological findings [1]. Surrogate endpoints are used for diagnosis, staging, prognosis, and treatment response assessment [8]. A common biomarker considered as a surrogate is CD4 cell count for acquired immunodeficiency syndrome [1]. In prostate cancer, PSA and distant metastasis are examples of potential surrogate endpoints for PCSS. It is important to remember that a surrogate endpoint is validated for one specific patient-important outcome and may not be a surrogate for other patient-important outcomes (Fig. 1). For example, distant metastasis may be a surrogate endpoint for PCSS but may not be a surrogate for quality of life (Fig. 2). It is important to appreciate the difference between a prognostic marker and a surrogate endpoint as the two are frequently confused (Table 2). A valid prognostic marker, despite being highly associated with an outcome, is not necessarily a valid surrogate endpoint because an intervention may impact the patient-important outcome without impacting the prognostic marker, and vice versa. For a prognostic marker to qualify as a surrogate endpoint, a high
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Fig. 1. The relationship of prognostic markers and surrogate endpoints. All surrogate endpoints are prognostic markers; however few prognostic markers are valid surrogates. (Color version of figure is available online.)
association between an intervention’s effect on the marker and the intervention’s effect on the patient-important outcome must be established [1]. Otherwise stated, the effect of the intervention on that marker must predict the patientimportant outcome [1,8].
5. Why use surrogate endpoints? 5.1. Convenience and statistical power Surrogate endpoints may offer advantages over patientimportant outcomes for clinicians, researchers, and patients (Table 3). An ideal surrogate is convenient, safe (noninvasive), and inexpensive. Furthermore, candidate surrogates are often continuous variables (e.g., blood concentrations) that can be repeatedly measured and generally provide more statistical power compared with dichotomous outcomes, such as death.
5.2. Early detection A surrogate provides earlier detection of treatment effects, allowing investigators to expedite conclusions regarding an intervention, ultimately facilitating earlier implementation or discontinuation of an experimental therapy. This advantage is particularly useful for studying prostate cancer since the disease often has a protracted course. Trials of patient-important prostate cancer outcomes, such as PCSS and overall survival, must be large and of long duration [4,5,9]. 5.3. Establishing promise In general, surrogate endpoints are used as preliminary outcomes and are limited to early phase studies. These outcomes can serve a role in establishing, or shedding doubt, on the promise of an intervention. In addition, surrogate endpoints can occasionally be used as the primary
Fig. 2. A surrogate endpoint should capture the entire effect of all interventions on the patient-important outcome. Interventions may also affect patient-important outcomes that are not captured by the surrogate. (Color version of figure is available online.)
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Table 2 Definitions Patient-important outcome The outcome(s) that should guide medical decisions. Examples include significant morbidity, disease specific survival, and overall survival. Surrogate endpoint A variable that fully captures the effect of an intervention on the patient-important outcome of interest and can therefore be used as a substitute for it. Prognostic marker A variable that is highly associated with the patient-important outcome.
outcome of trials examining interventions of diseases that have no acceptable treatments. Such was the case in studies examining tyrosine kinase inhibitors for the treatment of metastatic renal cell carcinoma [10,11].
6. Assessing a candidate surrogate endpoint When evaluating a candidate surrogate endpoint, several criteria should be considered. The surrogate should be acceptable to both patient and physician; the surrogate should be a prognostic marker for the patient-important outcome; the effect of an intervention on the surrogate must translate into an effect on the patient-important outcome; and, other randomized controlled trials examining the effect of interventions within the same and different classes, should demonstrate a consistent relationship between the surrogate and patient-important outcome. 6.1. Is the candidate surrogate endpoint acceptable to patients and physicians? Before assessing the statistical validity of an outcome as a surrogate endpoint it must meet several basic requirements. A surrogate should be easily and reliably measured. It should have a good risk-benefit profile and ideally be cost-effective for the health care system. Distant metastases may be an acceptable surrogate for prostate cancer since metastases are often detected via cross-sectional images and radionucleotide scans that are well tolerated by patients. However, these investigations are not sensitive to micrometastatic disease and are expensive. Therefore, distant metastases should be considered a passable, but not ideal, surrogate endpoint. 6.2. Is the candidate surrogate endpoint a prognostic marker for the patient-important outcome? As detailed earlier, prognostic markers are independently associated with the patient-important outcome and are often used to predict the clinical course of a patient. While prognostic markers need not be causally linked to the patient-
important outcome, a surrogate endpoint must be within the chain of causality (Fig. 1). Therefore, to justify formal validation of a candidate surrogate, there should be a reasonable pathophysiologic mechanism to link the endpoint to the patient-important outcome. For our example, there is an intuitive connection between development of distant metastases and prostate cancer death. Thus, distant metastasis is justified in being considered for validation as a surrogate endpoint for PCSS. 6.3. Is there a consistent association between the candidate surrogate endpoint and the patient-important outcome? The effect of the intervention on the surrogate endpoint should consistently result in effect on the patient-important outcome. In addition, the entire effect of the intervention on the patient-important outcome should be captured by changes in the surrogate (Fig. 1). If the intervention is found to have beneficial or deleterious effects on the patientimportant outcome that are not captured by the surrogate, the surrogate is not valid. This point may be demonstrated in the context of our clinical scenario if we consider overall survival as the patient important outcome instead of PCSS (Fig. 3). The intervention may consistently improve PCSS but may decrease overall survival via an alternate mechanism not captured by the surrogate. Recent studies examining long-term outcomes of patients treated with ADT have reported an increase in the relative risk of cardiovascular mortality [12,13]. Cardiovascular disease may affect survival but is not captured by incidence of distant metastasis. Thus, distant metastasis may be a valid surrogate for PCSS but not for overall survival. 6.4. Do data from other trials demonstrate a consistent relationship between the candidate surrogate endpoint and patient-important outcome? When assessing a candidate surrogate endpoint, establish if similar studies and studies of other interventions have demonstrated the candidate surrogate is linked to the patient-important outcome. Returning to the clinical scenario of ADT following external beam radiotherapy, another trial randomized 401 men with locally advanced prostate cancer treated with either external beam radiotherapy plus immeTable 3 Advantages of surrogate endpoints for patients and physicians ● ● ● ● ●
Convenient Safe (noninvasive) Inexpensive Expedites results, allowing earlier implementation of therapy.* Establish (or negate) promise of new therapy. ⴱ
This is particularly important for diseases such as prostate cancer that have protracted courses and require long follow-up to obtain patientimportant outcome data.
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Fig. 3. The candidate surrogate endpoint is associated with cancer survival, a component of overall survival. The candidate surrogate may not be valid for overall survival since the intervention may also effect overall survival via an alternate pathway. (Color version of figure is available online.)
diate ADT for 3 years (experimental arm) or external beam radiotherapy alone (control arm) [9]. The proportion of surviving patients free of disease at 5 years (a composite outcome incorporating distant metastasis) was significantly greater in ADT patients (85%) compared with control patients (48%). Furthermore, overall survival at 5 years was 79% and 62%, respectively [9]. Thus, a similar trial of adjuvant ADT following external beam radiotherapy revealed consistent results. If the surrogate endpoint is valid, changes in the surrogate should reflect changes in the patient-important outcome, regardless of intervention. For example, radical prostatectomy is an alternative to external beam radiotherapy for patients with locally advanced prostate cancer (Fig. 2). A historic cohort study revealed time to development of metastasis was predictive of time until death (P ⬍ 0.02) [2]. In addition, a randomized controlled trial of pelvic radiation following radical prostatectomy revealed improvement in metastasis-free survival and in overall survival [14]. Combined these data support a consistent pathophysiologic relationship between distant metastasis and survival in prostate cancer patients.
7. Is PSA a valid surrogate endpoint in prostate cancer? PSA is an easily measured, convenient, and relatively inexpensive test that is a well-known prognostic factor in prostate cancer and therefore is an appealing surrogate for PCSS. However, numerous studies reveal PSA is an invalid surrogate for PCSS since there is an inconsistent relationship between PSA and prostate cancer death [15–18]. Many interventions decrease PSA concentration without modifying the clinical course of prostate cancer. Such is the case for mitoxantrone and prednisone in patients with castrate resistant prostate cancer, where a large PSA effect is observed with little or no effect on PCSS [19]. Collette et al. performed and reported an in-depth review of PSA as a candidate surrogate. They concluded that PSA is unlikely to be a surrogate endpoint for patient important
outcomes in prostate cancer [15]. Thus, PSA should not be considered a valid endpoint for phase III trials of a prostate cancer intervention. Even though PSA currently appears to be an inadequate surrogate endpoint for PCSS, it may still be useful in certain clinical contexts as it is unlikely that an intervention will impact PCSS if there is no decrease in the patients’ serum PSA concentration. Thus, PSA may be useful as an early stop signal in prostate cancer clinical trials [15–18,20,21]. 8. Statistical validation of surrogate endpoints Most of the criteria described above can be represented and tested using mathematical models. Several methods of statistically validating a surrogate have been proposed and these statistical criteria should be satisfied before a biomarker is considered a surrogate endpoint. Detailed explanation of statistical validation is beyond the scope of this article (Table 4). In our example, Ray et al. retrospectively examined the data of the RTOG 92– 02 trial by applying the Prentice Criteria (Table 4) and conclude that improved PCSS in the experimental arm compared with the control arm is due to the lower rate of distant metastasis at 3 years [5]. Specifically, they revealed: Table 4 Statistical validation of surrogate endpoints Prentice Criteria [3,4,17] 1. The intervention must have a statistically significant impact on the patient-important outcome. 2. The intervention must have a statistically significant impact on the surrogate endpoint. 3. The surrogate endpoint has a statistically significant impact on the patient-important outcome, and is independent of the treatment arm. 4. The full effect of the treatment on the patient-important outcome is captured by the surrogate endpoint. Meta-Analytical Method [2] ● Integrates data from multiple randomized controlled trials. ● Allows for estimation of the performance of the surrogate in representing the effect of the intervention on the patient-important outcome.
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● Use of adjuvant ADT (intervention) significantly improved PCSS (patient-important outcome) ● Use of adjuvant ADT (intervention) significantly improved distant metastasis (candidate surrogate endpoint) ● Distant metastasis (candidate surrogate endpoint) had a significant impact on PCSS (patient-important outcome) ● The full effect of ADT (intervention) on PCSS (patient-important outcome) was captured by distant metastasis (candidate surrogate endpoint) [5,22]
9. Limitations of surrogate endpoints 9.1. Reliability Even when a surrogate is valid, surrogate endpoint data should not be considered equivalent to patient-important outcome data (Table 5). Conclusions and recommendations based on surrogate data should be considered preliminary, and can be modest at best [23]. It is expected that trials reporting surrogate data will follow-up by reporting patientimportant outcomes and safety data [15]. 9.2. Magnitude of association The magnitude of the association between the intervention and the surrogate may be different than the association between the intervention and patient-important outcome. Meta-analytical methods may improve the precision of effect size estimates, however, this limitation should be considered regardless of validation technique. 9.3. Patient-important outcomes not captured by the surrogate As described earlier, a surrogate endpoint should capture the full effect of an intervention on the patient-important outcome it is replacing. However, it may not capture an interventions effect (benefit or harm) on other patient-important outcomes (Fig. 2). Thus, even when surrogate endpoints are used, long and exhaustive follow-up of all patient-important outcomes relevant to the study population
Table 5 Limitations of surrogate endpoints ● Surrogate endpoint data is less reliable than patient-important outcome data. ● The magnitude of the association between the intervention and the surrogate may be different than the association between the intervention and patient-important outcome. ● The intervention may have consequences on patient-important outcomes not captured by the surrogate endpoint. ● Use of surrogate endpoint data can prompt amendments or early trial closure limiting assessment of patient-important outcomes.
should be performed to ensure appropriate clinical decision making [24]. 9.4. Early trial closure Relying on surrogate endpoints risks early trial closure or protocol amendments before the effect on the clinical endpoint can be established. For example, trials examining tyrosine kinase inhibitors as a treatment for metastatic renal cell carcinoma were amended by allowing patients to crossover based on promising early surrogate endpoint data showing a decreased risk of progression. The cross-over effect in these trials has limited our ability to determine if these medications delay death in patients with metastatic renal cell carcinoma [10,11,25].
10. Is distant metastasis a valid surrogate endpoint for PCSS in locally advanced prostate cancer? After reviewing the literature and considering the criteria required to establish a surrogate endpoint you draw the following conclusions: ● Screening for distant metastasis is acceptable to patients and physicians ● Distant metastasis is associated with, and is a prognostic marker for, PCSS ● Based on the RTOG 92– 02 trial, the effect of adjuvant ADT on distant metastasis translates into an effect on PCSS for men with locally advanced prostate cancer [4] ● Distant metastasis was statistically validated by Ray et al. using the Prentice Criteria as a surrogate marker for PCSS based on RTOG 92– 02 trial data [5] ● A randomized controlled trial demonstrates a consistent relationship between the surrogate and patient-important outcome within the same intervention class [9] ● Studies demonstrate a consistent relationship between the surrogate and patient-important outcome within another intervention class [14,16,17] You are satisfied that distant metastasis is a valid surrogate endpoint for PCSS. You understand the limitations inherent in using surrogate endpoints, especially one in which the validation is based on one randomized control trial as opposed to multiple trials.
11. Resolution of clinical scenario You have a new appreciation of the benefits and limitations of surrogate endpoints. You are surprised to learn the vigorous process required to validate a biomarker as a surrogate for a patient-important outcome. On review, you are satisfied that distant metastasis is a reasonable surrogate endpoint for PCSS. You discuss the benefits of ADT to your patient in the context of numerous side-effects and decrease
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in quality of life. With this information, your patient elects to continue ADT. You help the patient manage adverse effects of ADT and commit to reviewing the literature periodically for future trials that may reaffirm or shed doubt on his chosen therapy. In future trials, you will consider distant metastasis as a reasonable surrogate for hypothesis generation.
12. Conclusions A marker can be considered a surrogate of a patientimportant outcome when it is highly associated with the patient-important outcome, interventions that affect this marker translate into predictable changes in the patientimportant outcome, and this relationship is consistently demonstrated in studies evaluating the same and other intervention classes. The surrogate should be statistically validated, ideally using data from multiple, well performed randomized controlled trials. When this has been accomplished, researchers and clinicians may draw conclusions and base management decisions on surrogate data. Such decisions should be reserved for patients who are at high risk of the patient-important outcome, and for whom no alternative therapies have demonstrated improvement based on patient-important outcomes themselves. Finally, conclusions based on validated surrogate endpoint data have inherent limitations, necessitating ongoing follow-up of patient-important outcome data.
Acknowledgments In the original article used as an example (RTOG 92– 02), Hanks et al. report PCSS. For the purpose of this article PCSS data was ignored to allow review of the process of surrogate endpoint validation.
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[6] Guyatt G, Montori V, Devereaux PJ, et al. Patients at the center: In our practice, and in our use of language. ACP J Club 2004;140:A11–2. [7] D’Amico AV, Moul J, Carroll PR, et al. Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol 2003;21:2163–72. [8] Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89 –95. [9] Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295–300. [10] Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584 –90. [11] Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27:3312– 8. [12] Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer 2009;115 2388 –99. [13] Tsai HK, D’Amico AV, Sadetsky N, et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007;99:1516 –24. [14] Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009;181:956 – 62. [15] Collette L, Burzykowski T, Schroder FH. Prostate-specific antigen (PSA) alone is not an appropriate surrogate marker of long-term therapeutic benefit in prostate cancer trials. Eur J Cancer 2006;42:1344 –50. [16] Moul JW, Wu H, Sun L, et al. Early vs. delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 2004;171:1141–7. [17] D’Amico AV, Moul JW, Carroll PR, et al. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 2003;95:1376 – 83. [18] Vicini FA, Vargas C, Abner A, et al. Limitations in the use of serum prostate specific antigen levels to monitor patients after treatment for prostate cancer. J Urol 2005;173:1456 – 62. [19] Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;14:1756 – 64. [20] Buyse M, Molenberghs G, Burzykowski T, et al. The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostatistics 2000;1:49 – 67. [21] Collette L, Burzykowski T, Carroll KJ, et al. Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organization for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals. J Clin Oncol 2005;23:6139 – 48. [22] Prentice RL. Surrogate endpoints in clinical trials: Definition and operational criteria. Stat Med 1989;8:431– 40. [23] Swiglo BA, Murad MH, Schunemann HJ, et al. A case for clarity, consistency, and helpfulness: State-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab 2008;93:666 –73. [24] Efstathiou JA, Bae K, Shipley WU, et al. Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: Analysis of RTOG 92– 02. Eur Urol 2008;54:816 –23. [25] Breau RH, Leibovich BC. Therapy for metastatic RCC— questions remain. Nat Rev Urol 2009;6:580 –1.
Seminar article
Advanced topics in evidence-based urologic oncology: Surrogate endpoints Luke T. Lavallée, M.D.a, Victor M. Montori, M.D.b, Stephen E. Canfield, M.D.c, Rodney H. Breau, M.D., F.R.C.S.C.a,d,* a
Division of Urology, University of Ottawa, Ottawa, ON, Canada Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55901, USA c Department of Surgery, Division of Urology, University of Texas Medical School, Houston, TX 77030, USA d Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55901, USA b
Received 25 March 2010; received in revised form 15 June 2010; accepted 15 June 2010
Abstract Clinical trials often report surrogate endpoint data. A surrogate endpoint is a biological marker or clinical sign that can be substituted for a patient-important outcome. Using surrogate endpoints correctly may facilitate and expedite clinical trials and may improve medical decisions. However, rigorous criteria must be met for an endpoint to be considered a valid surrogate. The purpose of this article is to review the topic of surrogate endpoints in the context of a urologic encounter. © 2011 Elsevier Inc. All rights reserved. Keywords: Evidence-based medicine; Surrogate endpoints; Data Interpretation; Biological Markers
1. Introduction Urologists should rely on methodologically strong clinical trials when making patient management decisions. Trials directly examining the impact of an intervention on patient-important outcomes. such as quality of life, serious morbidity, disease-specific survival, and overall survival, provide the best evidence. Such trials are uncommon because of logistical obstacles, including the requirement for large sample size, long follow-up, and monetary support. Using a surrogate endpoint in place of a patient-important outcome may decrease sample size and trial duration [1]. Ultimately, these advantages result in more rapid evaluation and implementation of interventions that may improve patient care. In urology, biological markers are frequently used for clinical decision-making and prognostication. Common
prostate cancer biological markers include Gleason grade, prostate-specific antigen (PSA), and tumor stage [2]. Biological markers, however, are infrequently valid surrogate endpoints. Unless a marker has been validated as a surrogate endpoint, the impact of an intervention on that marker may not consistently and predictably reflect the impact of the intervention on the patient-important outcome. Alternatively stated, using invalid surrogates may misrepresent the true consequences of an intervention [1]. The identification of valid surrogate endpoints in urologic oncology would be of tremendous benefit. The purpose of this article is to review the basic principles of surrogate endpoints. Using a clinical scenario and examples from the available literature, we detail advantages and limitations of surrogate endpoints and provide a framework for reviewing studies that report surrogate data (Table 1). 2. Clinical scenario
Ray et al. validated distant metastasis at 3 years as a surrogate endpoint for PCSS. For simplicity, we refer to distant metastasis rather than distant metastasis at 3 years throughout this article. * Corresponding author. Tel.: ⫹613-761-4500; fax: ⫹613-761-5305. E-mail address: [email protected] (R.H. Breau). 1078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2010.06.010
A 64-year-old patient with a PSA of 20 ng/ml was diagnosed with clinical T3aN0M0, Gleason sum (4⫹4) prostate adenocarcinoma. He elected to receive primary external beam radiotherapy and androgen deprivation therapy (ADT). Despite the recommendation to continue ADT
448
L.T. Lavallée et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 447– 453
Table 1 Objectives
4. Definitions
● Provide definitions of key terms pertaining to surrogate endpoints. ● Explain the rationale for using surrogate endpoints and the limitations inherent in doing so. ● Review methods of validating surrogate endpoints. ● Provide a framework from which to critically appraise articles that report surrogate endpoint data.
4.1. Patient-important outcomes
after completion of radiation, he would like to discontinue this treatment because of bothersome hot flashes, fatigue, and decreased libido. He asks if pursuing adjuvant ADT will decrease his probability of dying from prostate cancer. You recall large studies that revealed significant benefit to patients receiving adjuvant ADT. While there were large reductions in several outcomes, you are unsure if any of the reported outcomes were good surrogates (i.e., could serve as substitutes) for prostate cancer-specific survival (PCSS). You decide to review the literature to address your patient’s question.
3. Literature search Using the PICOS pneumonic, you formulate a clinical question to guide your literature search [3]: Patient Population ⫽ locally advanced prostate cancer Intervention ⫽ adjuvant ADT following external beam radiotherapy Comparison ⫽ no adjuvant ADT Outcomes ⫽ PCSS and surrogate endpoints Study type ⫽ randomized controlled trial You find an article by Hanks et al. titled “Phase III Trial of Long-Term Adjuvant Androgen Deprivation After Neoadjuvant Hormonal Cytoreduction and Radiotherapy in Locally Advanced Carcinoma of the Prostate: The Radiation Therapy Oncology Group Protocol 92– 02 (RTOG 92– 02),” which addresses your question [4]. In this study, over 1,500 men received 4 months of ADT, 2 months prior to radiotherapy, and 2 months during radiotherapy. Men were then randomized to two groups. Group 1 (experimental arm) received 24 additional months of ADT. Group 2 (control arm) received no further ADT. The study reports a significant reduction in distant metastasis in the experimental (5.2%) compared with the control arm (10.7%) at 3 years [5]. This intuitively supports the notion that your patient may benefit from continuing adjuvant ADT, however, a more important outcome for the patient is PCSS. You search the literature further and find a recent article by Ray et al. that evaluated if distant metastasis was a valid surrogate endpoint for PCSS in the patients enrolled in the RTOG 92– 02 trial [5]. Using the clinical scenario and data from the above articles, we review the topic of surrogate endpoints.
A patient-important outcome, sometimes called a “clinical,” “hard,” or “final” outcome, is significant to patients [6]. It represents how patients feel, function, or survive. Examples of patient-important outcomes in prostate cancer include: quality of life, disease and treatment-induced morbidities (incontinence, erectile dysfunction, and pain), PCSS, and overall survival. Modifying these outcomes should be the objective of medical or surgical interventions. 4.2. Prognostic marker A prognostic marker is a measurable biological characteristic that is independently associated with disease outcome and provides mechanistic evaluation of a physiologic process. Physicians use prognostic markers to delineate subgroups of patients within a population who should be able to expect a different destiny. PSA is an example of a prognostic marker that is used to stratify patients diagnosed with prostate cancer into low, intermediate, and high risk groups [7]. Prognostic markers include molecules (i.e., protein concentration in blood) histologic appearance (i.e., tumor grade), and sub-clinical disease (i.e., asymptomatic metastasis) [1]. Prognostic markers may qualify as surrogate endpoints, however this is the exception rather then the rule. It can be said that all surrogate endpoints should be prognostic markers; however few prognostic markers are good surrogates (Fig. 1). 4.3. Surrogate endpoint The term surrogate literally means “substitute.” Biological markers in medicine that are used as surrogate endpoints include laboratory measurements, physical signs, and radiological findings [1]. Surrogate endpoints are used for diagnosis, staging, prognosis, and treatment response assessment [8]. A common biomarker considered as a surrogate is CD4 cell count for acquired immunodeficiency syndrome [1]. In prostate cancer, PSA and distant metastasis are examples of potential surrogate endpoints for PCSS. It is important to remember that a surrogate endpoint is validated for one specific patient-important outcome and may not be a surrogate for other patient-important outcomes (Fig. 1). For example, distant metastasis may be a surrogate endpoint for PCSS but may not be a surrogate for quality of life (Fig. 2). It is important to appreciate the difference between a prognostic marker and a surrogate endpoint as the two are frequently confused (Table 2). A valid prognostic marker, despite being highly associated with an outcome, is not necessarily a valid surrogate endpoint because an intervention may impact the patient-important outcome without impacting the prognostic marker, and vice versa. For a prognostic marker to qualify as a surrogate endpoint, a high
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Fig. 1. The relationship of prognostic markers and surrogate endpoints. All surrogate endpoints are prognostic markers; however few prognostic markers are valid surrogates. (Color version of figure is available online.)
association between an intervention’s effect on the marker and the intervention’s effect on the patient-important outcome must be established [1]. Otherwise stated, the effect of the intervention on that marker must predict the patientimportant outcome [1,8].
5. Why use surrogate endpoints? 5.1. Convenience and statistical power Surrogate endpoints may offer advantages over patientimportant outcomes for clinicians, researchers, and patients (Table 3). An ideal surrogate is convenient, safe (noninvasive), and inexpensive. Furthermore, candidate surrogates are often continuous variables (e.g., blood concentrations) that can be repeatedly measured and generally provide more statistical power compared with dichotomous outcomes, such as death.
5.2. Early detection A surrogate provides earlier detection of treatment effects, allowing investigators to expedite conclusions regarding an intervention, ultimately facilitating earlier implementation or discontinuation of an experimental therapy. This advantage is particularly useful for studying prostate cancer since the disease often has a protracted course. Trials of patient-important prostate cancer outcomes, such as PCSS and overall survival, must be large and of long duration [4,5,9]. 5.3. Establishing promise In general, surrogate endpoints are used as preliminary outcomes and are limited to early phase studies. These outcomes can serve a role in establishing, or shedding doubt, on the promise of an intervention. In addition, surrogate endpoints can occasionally be used as the primary
Fig. 2. A surrogate endpoint should capture the entire effect of all interventions on the patient-important outcome. Interventions may also affect patient-important outcomes that are not captured by the surrogate. (Color version of figure is available online.)
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Table 2 Definitions Patient-important outcome The outcome(s) that should guide medical decisions. Examples include significant morbidity, disease specific survival, and overall survival. Surrogate endpoint A variable that fully captures the effect of an intervention on the patient-important outcome of interest and can therefore be used as a substitute for it. Prognostic marker A variable that is highly associated with the patient-important outcome.
outcome of trials examining interventions of diseases that have no acceptable treatments. Such was the case in studies examining tyrosine kinase inhibitors for the treatment of metastatic renal cell carcinoma [10,11].
6. Assessing a candidate surrogate endpoint When evaluating a candidate surrogate endpoint, several criteria should be considered. The surrogate should be acceptable to both patient and physician; the surrogate should be a prognostic marker for the patient-important outcome; the effect of an intervention on the surrogate must translate into an effect on the patient-important outcome; and, other randomized controlled trials examining the effect of interventions within the same and different classes, should demonstrate a consistent relationship between the surrogate and patient-important outcome. 6.1. Is the candidate surrogate endpoint acceptable to patients and physicians? Before assessing the statistical validity of an outcome as a surrogate endpoint it must meet several basic requirements. A surrogate should be easily and reliably measured. It should have a good risk-benefit profile and ideally be cost-effective for the health care system. Distant metastases may be an acceptable surrogate for prostate cancer since metastases are often detected via cross-sectional images and radionucleotide scans that are well tolerated by patients. However, these investigations are not sensitive to micrometastatic disease and are expensive. Therefore, distant metastases should be considered a passable, but not ideal, surrogate endpoint. 6.2. Is the candidate surrogate endpoint a prognostic marker for the patient-important outcome? As detailed earlier, prognostic markers are independently associated with the patient-important outcome and are often used to predict the clinical course of a patient. While prognostic markers need not be causally linked to the patient-
important outcome, a surrogate endpoint must be within the chain of causality (Fig. 1). Therefore, to justify formal validation of a candidate surrogate, there should be a reasonable pathophysiologic mechanism to link the endpoint to the patient-important outcome. For our example, there is an intuitive connection between development of distant metastases and prostate cancer death. Thus, distant metastasis is justified in being considered for validation as a surrogate endpoint for PCSS. 6.3. Is there a consistent association between the candidate surrogate endpoint and the patient-important outcome? The effect of the intervention on the surrogate endpoint should consistently result in effect on the patient-important outcome. In addition, the entire effect of the intervention on the patient-important outcome should be captured by changes in the surrogate (Fig. 1). If the intervention is found to have beneficial or deleterious effects on the patientimportant outcome that are not captured by the surrogate, the surrogate is not valid. This point may be demonstrated in the context of our clinical scenario if we consider overall survival as the patient important outcome instead of PCSS (Fig. 3). The intervention may consistently improve PCSS but may decrease overall survival via an alternate mechanism not captured by the surrogate. Recent studies examining long-term outcomes of patients treated with ADT have reported an increase in the relative risk of cardiovascular mortality [12,13]. Cardiovascular disease may affect survival but is not captured by incidence of distant metastasis. Thus, distant metastasis may be a valid surrogate for PCSS but not for overall survival. 6.4. Do data from other trials demonstrate a consistent relationship between the candidate surrogate endpoint and patient-important outcome? When assessing a candidate surrogate endpoint, establish if similar studies and studies of other interventions have demonstrated the candidate surrogate is linked to the patient-important outcome. Returning to the clinical scenario of ADT following external beam radiotherapy, another trial randomized 401 men with locally advanced prostate cancer treated with either external beam radiotherapy plus immeTable 3 Advantages of surrogate endpoints for patients and physicians ● ● ● ● ●
Convenient Safe (noninvasive) Inexpensive Expedites results, allowing earlier implementation of therapy.* Establish (or negate) promise of new therapy. ⴱ
This is particularly important for diseases such as prostate cancer that have protracted courses and require long follow-up to obtain patientimportant outcome data.
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Fig. 3. The candidate surrogate endpoint is associated with cancer survival, a component of overall survival. The candidate surrogate may not be valid for overall survival since the intervention may also effect overall survival via an alternate pathway. (Color version of figure is available online.)
diate ADT for 3 years (experimental arm) or external beam radiotherapy alone (control arm) [9]. The proportion of surviving patients free of disease at 5 years (a composite outcome incorporating distant metastasis) was significantly greater in ADT patients (85%) compared with control patients (48%). Furthermore, overall survival at 5 years was 79% and 62%, respectively [9]. Thus, a similar trial of adjuvant ADT following external beam radiotherapy revealed consistent results. If the surrogate endpoint is valid, changes in the surrogate should reflect changes in the patient-important outcome, regardless of intervention. For example, radical prostatectomy is an alternative to external beam radiotherapy for patients with locally advanced prostate cancer (Fig. 2). A historic cohort study revealed time to development of metastasis was predictive of time until death (P ⬍ 0.02) [2]. In addition, a randomized controlled trial of pelvic radiation following radical prostatectomy revealed improvement in metastasis-free survival and in overall survival [14]. Combined these data support a consistent pathophysiologic relationship between distant metastasis and survival in prostate cancer patients.
7. Is PSA a valid surrogate endpoint in prostate cancer? PSA is an easily measured, convenient, and relatively inexpensive test that is a well-known prognostic factor in prostate cancer and therefore is an appealing surrogate for PCSS. However, numerous studies reveal PSA is an invalid surrogate for PCSS since there is an inconsistent relationship between PSA and prostate cancer death [15–18]. Many interventions decrease PSA concentration without modifying the clinical course of prostate cancer. Such is the case for mitoxantrone and prednisone in patients with castrate resistant prostate cancer, where a large PSA effect is observed with little or no effect on PCSS [19]. Collette et al. performed and reported an in-depth review of PSA as a candidate surrogate. They concluded that PSA is unlikely to be a surrogate endpoint for patient important
outcomes in prostate cancer [15]. Thus, PSA should not be considered a valid endpoint for phase III trials of a prostate cancer intervention. Even though PSA currently appears to be an inadequate surrogate endpoint for PCSS, it may still be useful in certain clinical contexts as it is unlikely that an intervention will impact PCSS if there is no decrease in the patients’ serum PSA concentration. Thus, PSA may be useful as an early stop signal in prostate cancer clinical trials [15–18,20,21]. 8. Statistical validation of surrogate endpoints Most of the criteria described above can be represented and tested using mathematical models. Several methods of statistically validating a surrogate have been proposed and these statistical criteria should be satisfied before a biomarker is considered a surrogate endpoint. Detailed explanation of statistical validation is beyond the scope of this article (Table 4). In our example, Ray et al. retrospectively examined the data of the RTOG 92– 02 trial by applying the Prentice Criteria (Table 4) and conclude that improved PCSS in the experimental arm compared with the control arm is due to the lower rate of distant metastasis at 3 years [5]. Specifically, they revealed: Table 4 Statistical validation of surrogate endpoints Prentice Criteria [3,4,17] 1. The intervention must have a statistically significant impact on the patient-important outcome. 2. The intervention must have a statistically significant impact on the surrogate endpoint. 3. The surrogate endpoint has a statistically significant impact on the patient-important outcome, and is independent of the treatment arm. 4. The full effect of the treatment on the patient-important outcome is captured by the surrogate endpoint. Meta-Analytical Method [2] ● Integrates data from multiple randomized controlled trials. ● Allows for estimation of the performance of the surrogate in representing the effect of the intervention on the patient-important outcome.
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● Use of adjuvant ADT (intervention) significantly improved PCSS (patient-important outcome) ● Use of adjuvant ADT (intervention) significantly improved distant metastasis (candidate surrogate endpoint) ● Distant metastasis (candidate surrogate endpoint) had a significant impact on PCSS (patient-important outcome) ● The full effect of ADT (intervention) on PCSS (patient-important outcome) was captured by distant metastasis (candidate surrogate endpoint) [5,22]
9. Limitations of surrogate endpoints 9.1. Reliability Even when a surrogate is valid, surrogate endpoint data should not be considered equivalent to patient-important outcome data (Table 5). Conclusions and recommendations based on surrogate data should be considered preliminary, and can be modest at best [23]. It is expected that trials reporting surrogate data will follow-up by reporting patientimportant outcomes and safety data [15]. 9.2. Magnitude of association The magnitude of the association between the intervention and the surrogate may be different than the association between the intervention and patient-important outcome. Meta-analytical methods may improve the precision of effect size estimates, however, this limitation should be considered regardless of validation technique. 9.3. Patient-important outcomes not captured by the surrogate As described earlier, a surrogate endpoint should capture the full effect of an intervention on the patient-important outcome it is replacing. However, it may not capture an interventions effect (benefit or harm) on other patient-important outcomes (Fig. 2). Thus, even when surrogate endpoints are used, long and exhaustive follow-up of all patient-important outcomes relevant to the study population
Table 5 Limitations of surrogate endpoints ● Surrogate endpoint data is less reliable than patient-important outcome data. ● The magnitude of the association between the intervention and the surrogate may be different than the association between the intervention and patient-important outcome. ● The intervention may have consequences on patient-important outcomes not captured by the surrogate endpoint. ● Use of surrogate endpoint data can prompt amendments or early trial closure limiting assessment of patient-important outcomes.
should be performed to ensure appropriate clinical decision making [24]. 9.4. Early trial closure Relying on surrogate endpoints risks early trial closure or protocol amendments before the effect on the clinical endpoint can be established. For example, trials examining tyrosine kinase inhibitors as a treatment for metastatic renal cell carcinoma were amended by allowing patients to crossover based on promising early surrogate endpoint data showing a decreased risk of progression. The cross-over effect in these trials has limited our ability to determine if these medications delay death in patients with metastatic renal cell carcinoma [10,11,25].
10. Is distant metastasis a valid surrogate endpoint for PCSS in locally advanced prostate cancer? After reviewing the literature and considering the criteria required to establish a surrogate endpoint you draw the following conclusions: ● Screening for distant metastasis is acceptable to patients and physicians ● Distant metastasis is associated with, and is a prognostic marker for, PCSS ● Based on the RTOG 92– 02 trial, the effect of adjuvant ADT on distant metastasis translates into an effect on PCSS for men with locally advanced prostate cancer [4] ● Distant metastasis was statistically validated by Ray et al. using the Prentice Criteria as a surrogate marker for PCSS based on RTOG 92– 02 trial data [5] ● A randomized controlled trial demonstrates a consistent relationship between the surrogate and patient-important outcome within the same intervention class [9] ● Studies demonstrate a consistent relationship between the surrogate and patient-important outcome within another intervention class [14,16,17] You are satisfied that distant metastasis is a valid surrogate endpoint for PCSS. You understand the limitations inherent in using surrogate endpoints, especially one in which the validation is based on one randomized control trial as opposed to multiple trials.
11. Resolution of clinical scenario You have a new appreciation of the benefits and limitations of surrogate endpoints. You are surprised to learn the vigorous process required to validate a biomarker as a surrogate for a patient-important outcome. On review, you are satisfied that distant metastasis is a reasonable surrogate endpoint for PCSS. You discuss the benefits of ADT to your patient in the context of numerous side-effects and decrease
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in quality of life. With this information, your patient elects to continue ADT. You help the patient manage adverse effects of ADT and commit to reviewing the literature periodically for future trials that may reaffirm or shed doubt on his chosen therapy. In future trials, you will consider distant metastasis as a reasonable surrogate for hypothesis generation.
12. Conclusions A marker can be considered a surrogate of a patientimportant outcome when it is highly associated with the patient-important outcome, interventions that affect this marker translate into predictable changes in the patientimportant outcome, and this relationship is consistently demonstrated in studies evaluating the same and other intervention classes. The surrogate should be statistically validated, ideally using data from multiple, well performed randomized controlled trials. When this has been accomplished, researchers and clinicians may draw conclusions and base management decisions on surrogate data. Such decisions should be reserved for patients who are at high risk of the patient-important outcome, and for whom no alternative therapies have demonstrated improvement based on patient-important outcomes themselves. Finally, conclusions based on validated surrogate endpoint data have inherent limitations, necessitating ongoing follow-up of patient-important outcome data.
Acknowledgments In the original article used as an example (RTOG 92– 02), Hanks et al. report PCSS. For the purpose of this article PCSS data was ignored to allow review of the process of surrogate endpoint validation.
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