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Proposal for Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials: The STEEP System

Clifford A. Hudis, William E. Barlow, Joseph P. Costantino, Robert J. Gray, Kathleen I. Pritchard, Judith-Anne W. Chapman, Joseph A. Sparano, Sally Hunsberger, Rebecca A. Enos, Richard D. Gelber, Jo Anne Zujewski

From the Memorial Sloan-Kettering Cancer Center, New York; Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Cancer Research and Biostatistics, Seattle, WA; Biostatistical Center, National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; Dana-Farber Cancer Institute, Boston, MA; National Cancer Institute, Division of Cancer Treatment and Diagnosis, Biometrics Research Branch, Rockville, MD; EMMES Corporation (National Cancer Institute contractor), Rockville, MD; National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Rockville, MD; and the Sunnybrook Health Sciences Centre and University of Toronto; and the Queen's University, Kingston, Ontario, Canada

Address reprint requests to Clifford A. Hudis, MD, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 206, New York, NY 10021; e-mail: hudisc{at}mskcc.org

	ABSTRACT

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Purpose Standardized definitions of breast cancer clinical trial end points must be adopted to permit the consistent interpretation and analysis of breast cancer clinical trials and to facilitate cross-trial comparisons and meta-analyses. Standardizing terms will allow for uniformity in data collection across studies, which will optimize clinical trial utility and efficiency. A given end point term (eg, overall survival) used in a breast cancer trial should always encompass the same set of events (eg, death attributable to breast cancer, death attributable to cause other than breast cancer, death from unknown cause), and, in turn, each event within that end point should be commonly defined across end points and studies.

Methods A panel of experts in breast cancer clinical trials representing medical oncology, biostatistics, and correlative science convened to formulate standard definitions and address the confusion that nonstandard definitions of widely used end point terms for a breast cancer clinical trial can generate. We propose standard definitions for efficacy end points and events in early-stage adjuvant breast cancer clinical trials. In some cases, it is expected that the standard end points may not address a specific trial question, so that modified or customized end points would need to be prospectively defined and consistently used.

Conclusion The use of the proposed common end point definitions will facilitate interpretation of trial outcomes. This approach may be adopted to develop standard outcome definitions for use in trials involving other cancer sites.

	INTRODUCTION

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Randomized prospective clinical trials are conducted with a variety of specific aims. A common aim is to demonstrate that one treatment approach has a statistically superior advantage over another in terms of impact on some clinically or biologically important end point. Clinical trial end points can refer to efficacy, adverse events, or quality of life. This report specifically reviews efficacy end points and proposes standard definitions for efficacy end points for use in adjuvant breast cancer clinical trials. The goal of this effort is to increase the quality of breast cancer clinical trial conduct and reporting while reducing the chances for miscommunication and misunderstanding among investigators, clinicians, regulatory agencies, sponsors and funding agencies, clinicians, and patients on matters of interpretation of efficacy results from breast cancer clinical trials.

We propose a standard set of events for several efficacy end points and standard definitions for each event comprising these end points. Use of standard definitions for breast cancer clinical trial events and end points will help to reduce the inconsistencies that currently confound the analysis and interpretation of results across clinical trials. The confounding arises from the variable inclusion and exclusion of events in definitions of end points that bear the same name, and from the inconsistent definition of the events themselves. Such standardization will eliminate this problem and, in turn, will help to hasten delivery of new, improved therapies to breast cancer patients.

Background
There is a lack of consistency in the definitions of many efficacy end points used in clinical trials, and the need to have standardization can be illustrated using the end point disease-free survival (DFS) as an example. In this section, we provide some background information regarding the use of DFS as an end point in clinical trials culminating with an illustration of the extent of variation in the definition that exists across several recent adjuvant therapy trials assessing aromatase inhibitors.

Overall survival (OS) has been recognized as the least ambiguous and most clinically relevant clinical end point in clinical trials of cancer therapy. However, in evaluating postoperative treatment for stage I, II, and IIIA breast cancer where all identifiable tumor has been resected, DFS is frequently employed as a surrogate. Generally, DFS identifies the proportion of patients without recurrent disease. If recurrence predicts death over a longer period of time, DFS can serve as an early indicator of improved survival. The use of a surrogate is reasonable because the relatively long expected survival time for patients, even those with metastatic recurrence after treatment in adjuvant trials, can make it take decades before improvements in OS can reliably be confirmed. Combined with the heterogeneous and somewhat unpredictable natural history of breast cancer, it would not be practical to wait for OS to serve as the primary end point of many adjuvant trials. Sole use of OS could slow the development of improved therapies.

Any end point, including DFS, should be standard to facilitate both accurate communications and exploratory cross-study comparisons. DFS is the primary end point for many large adjuvant breast cancer trials whose results will likely have implications for changing clinical practice. Historically, the types and variety of events (eg, ductal carcinoma in situ [DCIS], second primary nonbreast cancers, death from other causes) included in or excluded from the definition of DFS have been inconsistent. In addition to distant disease recurrence (metastasis), DFS definitions across breast cancer trials have included a mixed bag of other events. Moreover, each individual event has been inconsistently defined, compounding the variability in end point definitions. Thus, in evaluating the breast cancer trial literature, readers are forced to confirm if the definition of DFS as used by a particular trial has included or excluded certain events. Then they must determine if the events that comprise the end point include or exclude certain criteria themselves (eg, if contralateral breast cancer includes invasive cancer only, or both invasive and in situ carcinomas).

In the adjuvant clinical trial setting for breast cancer, DFS has typically included the events of local, regional, and distant recurrence. As many patients die of causes that are unknowable to clinical trialists and that may or may not be related to breast cancer, death from any cause also has been an event most often included in DFS. Events that have been inconsistently included and defined within the definition of breast cancer DFS follow:

• Contralateral breast cancer includes only invasive lobular or invasive ductal cancer, such as DCIS or including both lobular carcinoma in situ (LCIS) and DCIS.
  
• In situ carcinomas includes DCIS only or both DCIS and LCIS.
  
• Second primary cancers include or exclude contralateral breast cancer, including or excluding nonbreast cancers or unknown cancers at nonbreast sites.
  
• Death from other causes are those known to be other than breast cancer.
  

The five randomized trials of aromatase inhibitors in the adjuvant setting recently reported illustrate the confusion that may arise from the use of heterogeneous definitions of DFS.^1-5 In general, each trial demonstrated a consistent but modest advantage for an aromatase inhibitor over tamoxifen or placebo. Attempts to compare benefits among the studies, however, have been fraught not only with the usual difficulties inherent to cross-study comparisons, but with confusion resulting from the varying definitions of DFS used by these trials (Table 1). (Please note the Arimidex, Nolvadex 95 Study [ARNO] designated the outcome as event-free survival, rather than DFS.) Historically, similarly variable definitions of DFS also have been used. The practice of defining DFS inconsistently across clinical trials raises the troubling possibility that a treatment may be declared as resulting in improved DFS as defined one way, but not when defined differently.

	METHODS

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	RESULTS

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The standard definitions proposed by the expert panel for use as clinical trial end points in the adjuvant setting for breast cancer are summarized in Table 2. The discussion that follows provides details regarding the rationale for the panel's determinations for key end points. It also identifies basic principles that should be employed as conventions for the naming of end points not included in Table 2, and it proposes steps to be taken to ensure the use of standard end points.

• Ipsilateral invasive breast tumor recurrence (IIBTR): invasive breast cancer involving the same breast parenchyma as the original primary.
  
• Regional invasive breast cancer recurrence: Invasive breast cancer in the axilla, regional lymph nodes, chest wall, and skin of the ipsilateral breast.
  
• Distant recurrence: Metastatic disease-breast cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer.
  
• Death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause.
  
• Contralateral invasive breast cancer.
  
• Second primary nonbreast invasive cancer.
  

This definition of IDFS is broad and includes the most commonly accepted DFS events used in published trials to date. IDFS specifically excludes all in situ cancer events (ipsilateral or contralateral DCIS, ipsilateral or contralateral LCIS and all in situ cancers of non-breast sites). We note that this definition is consistent with the some earlier DFS definitions. For example, it corresponds to the DFS definition used in Breast International Group 1-98 as shown in Table 1.

The inclusion of the event of second primary cancer in the IDFS definition was a subject of considerable discussion. In the published literature, some trials include contralateral breast cancer as a second primary cancer event, whereas other trials clearly distinguish between nonbreast second primary cancer and breast second primary cancer (ie, contralateral breast cancer). If the specific anatomic site of the second primary has not been reported for a patient, it may not be known if the second primary has occurred in the breast or in a non-breast site. Some trials exclude nonbreast second primaries from their definition of DFS, while others do not. It may be difficult, however, to distinguish a second primary cancer in a nonbreast site (which may or may not be related to the primary cancer) from a distant recurrence of the primary breast cancer. Inclusion of nonbreast second primary cancer in the IDFS definition has the disadvantage of including events not related to the cancer or the treatment under study, thereby potentially diluting any treatment effect. However, it has the advantage of including invasive cancer events that may be related to treatment (invasive uterine cancer with tamoxifen, bladder cancer with cyclophosphamide, leukemia and myelodysplasia with chemotherapy). It also avoids the problem of excluding distant recurrences of breast cancer that are misdiagnosed as a second primary cancer (metastatic breast cancer to the lung misdiagnosed as a second primary lung cancer). The panel was in favor of including invasive nonbreast cancer as events in IDFS as invasive nonbreast cancers are usually serious and linked to OS and might not be easily distinguishable from breast cancer or treatment-related events.

IDFS and DCIS End Point
It was recognized that in certain situations it would be appropriate to consider in situ breast cancer events as well as invasive cancer events as a primary end point in the clinical trial. Examples of this include situations where the target population is patients diagnosed with DCIS, or in trials where the treatment under study may have a potentially favorable risk-benefit ratio for both preventing a breast cancer recurrence as well as preventing a contralateral breast cancer. An example of this would include the testing of well-tolerated endocrine therapies in patients with a low risk of disease recurrence. The panel recommended that this term be distinguishable from IDFS by noting it as IDFS-DCIS. This end point would be a composite of all the events included in IDFS as well as both ipsilateral and contralateral DCIS. This end point is similar to what was used in the Arimidex, tamoxifen alone, or in combination (ATAC) trial, although non-breast second primaries were not included as outcomes in that trial. The panel did not recommend including the diagnosis of LCIS as an event in any efficacy end point in adjuvant treatment trials because it is not generally considered to be a true precursor lesion for invasive cancer.

Distant DFS
Of all the nondeath events listed above, it is generally accepted that distant recurrence (metastasis) trumps other events because it is a threat to patient survival. Indeed, it is the main predictor of death in all end point definitions. Our proposed definition for distant DFS (DDFS) preserves this focus. Therefore, it excludes ipsilateral breast tumor recurrence, regional invasive recurrences, contralateral breast cancer, and all in situ carcinomas, as these events are potentially nonlethal. The separation of distant as a specific end point is also very important for ancillary studies involving microarray analysis and for developing genetic panels for use in determining prognosis and/or response to treatment. In these situations, distant disease recurrence is often used as a marker for survival to increase statistical power because there is such a strong correlation between these end points and because there will be more distant events than deaths. Using a combined regional/distant end point would dilute the correlation with survival and weaken the discriminatory power of the analysis.

Other End Points
Other frequently encountered end points along with the authors' preferred definitions are included in Table 2. Recurrence-free interval signifies time from random assignment or registration until invasive recurrence in the ipsilateral breast or locoregionally, at a distant site, or death from breast cancer. Breast cancer–free interval includes these events plus either contralateral or ipsilateral breast DCIS. Distant recurrence-free interval is restricted to invasive recurrence at a distant site or death from breast cancer.

Disease-Free Interval
In some instances, investigators may wish to assess an end point that focuses only on recurrences and, as such, may wish to exclude deaths from the definition of the end point of interest. In such situations, we recommend that the term interval be used to differentiate from the definitions where death is included as an event. For example, recurrence-free interval would be the alternative definition to recurrence-free survival, and distant recurrence-free interval would be the alternative definition to distant relapse-free survival. In addition, if one wishes to focus on all breast cancer events including contralateral disease, then the term breast cancer–free interval would identify that death is not included as an event and would differentiate this end point from that of recurrence-free interval.

Custom End Points
We recognize that investigators may have entirely appropriate trial-specific reasons for modifying a standard end point. We have done so ourselves in formulating the term IDFS-DCIS. When modification of a standard end point is necessary, however, the name of the modified end point should likewise be modified to reflect the change. Therefore, if an end point is used that adds to the standard list of events for that end point or that modifies the standard definition of any component event, then this modification should be explained to those involved in the conduct of the trial (eg, included in the protocol and communicated clearly to the clinical research staff collecting data for the study) and to those reading its results (ie, in publications resulting from the trial). The name of the end point should be hyphenated to add a reference to the specific change, and a common data element (CDE) should be developed for the new end point so that future investigators wishing to use the same end point will use the same term. In this way, events can be added to or subtracted from a standard end point definition, or a component event can be substituted for another while still preserving the standard meaning of the original end point. Of utmost importance is that the two end points defined in any way differently do not share the same name. As an example, the term event-free survival should not be used. Instead, the end point name should clearly indicate the end point being measured (eg, IDFS plus a specific event of interest). We also stress that the term survival should include all deaths as events. This guarantees the inclusion of the sequelae of treatment, such as cardiac effects, and avoids the problems associated with inaccurately classifying the cause of death.⁶

The ability to customize end points was deemed necessary because, at times, precise definitions of the site of recurrence may be appropriate depending on the trial question. An example of this is in a study designed to evaluate a new treatment modality for ipsilateral local control in patients who have been previously diagnosed with DCIS. In such a trial, the investigators may want to distinguish between ipsilateral invasive disease in the breast parenchyma and skin of the ipsilateral breast. Ipsilateral invasive breast cancer recurrence (IIBCR) could be used to indicate only invasive recurrence in the ipsilateral parenchyma. Another option is to use the end point IIBCR+DCIS as that which would include DCIS of the ipsilateral parenchyma. Also, one could alternatively define an end point invasive ipsilateral breast cancer and skin cancer recurrence (IIBCR-SCR) that would include ipsilateral skin, which could then be combined with DCIS as IIBSCR+DCIS to include ipsilateral skin and also DCIS. While the acronyms may grow long, this would be in compliance with the philosophy and nomenclature we are proposing. These end points were specifically developed to apply to adjuvant treatment trials; however, the ability to customize end points, particularly in relation to local control, makes them applicable to many surgical trials as well.

Need for Follow-Up Beyond the First Event and Other Comments
Although not the main purpose of this article, we wish to comment on the need to record sequential events beyond the first. In situations where IDFS or IDFS-DCIS is the primary end point, it may be of increasing interest to determine the DDFS. The common practice of only capturing a first event would preclude the ability to accurately ascertain DDFS if the first event was a contralateral breast cancer or local/regional recurrence. Our earlier discussion of studies of gene expression profiling highlights this need, as a profile predicting distant metastases for a particular invasive cancer might not predict a local recurrence. If data recording ends with the first event in a trial, then this patient's subsequent and informative natural history would be lost to the trialists. This approach also could limit the utility of surgical studies. In this situation, even censoring the DDFS survival time at first local recurrence would be inappropriate because the censoring is informative (ie, patients with local recurrence are more likely to have distant recurrence).⁷ Censoring would violate a principle of standard survival analysis that censoring be noninformative (ie, independent of the probability of failure in the future). Therefore, the panel recommended that patients who develop an ipsilateral breast tumor recurrence, a local regional recurrence, or a contralateral breast cancer should continue to be followed for other sites of recurrence, which must be reported if they occur. Patients who develop a second primary nonbreast invasive cancer should be followed for a breast cancer recurrence, which must be reported if it occurs. It also was noted that patients who develop a distant recurrence should ideally continue to be followed for survival, but that this requirement be individualized by study as appropriate and recognized throughout the study process (ie, from design to patient consent). It was recommended that the site of first distant recurrence be collected. However, in this case, other sites of recurrence (after the first site of distant recurrence) would not need to be collected or reported. Finally, we considered the issue of simultaneous or near-simultaneous events. Because the timing of testing could influence the determination of the first event, we consider events diagnosed within 2 months as simultaneous, and declaring the site of first event to be the worst site according to a hierarchy of prognosis from worst to best. For example, simultaneous (within 2 months) local and liver would have first site classified as distant. The date of the DFS event remains the date of the first evidence. The statistical analysis plan of the study should clearly describe the censoring procedure to the followed. The protocol document and informed consent for should also clearly state the expectation of long-term follow-up of subjects.

Implementation of Standardized End Points and Events in Clinical Trials
The panel proposed that the following steps should be taken to ensure the use of standard clinical trial end points and events in the design, conduct, and reporting of breast cancer clinical trials.

Before trial initiation. Primary and secondary end points are chosen a priori, and their definitions adhere to the standard definitions proposed previously. Use of Common Data Elements (CDEs) curated (http://ncicb.nci.nih.gov; http://cdebrowser.nci.nih.gov/CDEBrowser) for breast cancer trials should be used to ensure the selection of standard end points. If a custom end point is needed, the name and definition of that end point should clearly reflect the intended deviation from the standard end point on which it is based. A new CDE should be curated for any custom end point used in a phase III randomized clinical trial.

End point definitions both identify the component events that comprise an end point, as well as provide the definitions for each component event. Definitions are specified in the protocol and provided readily to data managers and clinical research associates involved in the conduct of the trial. The data collection tools (case report forms) contain separate fields for each component event collected by the trial.

During the trial. Individual events included in each end point of interest are collected. Patients who develop an ipsilateral breast tumor recurrence, a local regional recurrence, a contralateral breast cancer, or a new noninvasive breast cancer should continue to be followed for distant recurrence. All patients must continue to be followed for survival. The site of first recurrence should be collected.

At analysis. The end points calculated in the data analysis are based on standard definitions. Each end point using a given name should include the same set of events associated with that end point term by its standard definition (eg, IDFS always uses the same set of events as standard for IDFS). In these analyses, patients who do not have the end point of interest are censored at the date of last evaluation. If healthy patients are not followed clinically, then they may be excluded from the analysis after their last clinic visit. This may not be differential by random assignment, but the absolute estimates of survival may be downwardly biased if all patients are not followed.

At publication. Publications resulting from the clinical trial should identify the list of the events included in each end point that is reported. Ideally, a table would be included that provides a breakdown of the type of event by study arm.

	CONCLUSION

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Clinical trials, like other areas of experimental science, rely on clear and reproducible measures of the impact of interventions. The use of nonstandard end point terms in breast cancer clinical trials diminishes the stability and interpretability of breast cancer clinical trial results. Standardization of events and end points across breast cancer clinical trails should help to hasten the delivery of new and improved therapies for patients with breast cancer. Furthermore, the use of standard definitions should also bring more consistency to clinical trial operations, thereby reducing resource consumption.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Clifford A. Hudis, William E. Barlow, Joseph P. Costantino, Robert J. Gray, Kathleen I. Pritchard, Judith-Anne W. Chapman, Joseph A. Sparano, Sally Hunsberger, Rebecca A. Enos, Richard D. Gelber, Jo Anne Zujewski

Administrative support: Clifford A. Hudis, William E. Barlow, Joseph P. Costantino, Robert J. Gray, Kathleen I. Pritchard, Judith-Anne W. Chapman, Joseph A. Sparano, Sally Hunsberger, Rebecca A. Enos, Richard D. Gelber, Jo Anne Zujewski

Provision of study materials or patients: Clifford A. Hudis, William E. Barlow, Joseph P. Costantino, Robert J. Gray, Kathleen I. Pritchard, Judith-Anne W. Chapman, Joseph A. Sparano, Sally Hunsberger, Rebecca A. Enos, Richard D. Gelber, Jo Anne Zujewski

Collection and assembly of data: Clifford A. Hudis, William E. Barlow, Joseph P. Costantino, Robert J. Gray, Kathleen I. Pritchard, Judith-Anne W. Chapman, Joseph A. Sparano, Sally Hunsberger, Rebecca A. Enos, Richard D. Gelber, Jo Anne Zujewski

Data analysis and interpretation: Clifford A. Hudis, William E. Barlow, Joseph P. Costantino, Robert J. Gray, Kathleen I. Pritchard, Judith-Anne W. Chapman, Joseph A. Sparano, Sally Hunsberger, Rebecca A. Enos, Richard D. Gelber, Jo Anne Zujewski

Manuscript writing: Clifford A. Hudis, William E. Barlow, Joseph P. Costantino, Robert J. Gray, Kathleen I. Pritchard, Judith-Anne W. Chapman, Joseph A. Sparano, Sally Hunsberger, Rebecca A. Enos, Richard D. Gelber, Jo Anne Zujewski

Final approval of manuscript: Clifford A. Hudis, William E. Barlow, Joseph P. Costantino, Robert J. Gray, Kathleen I. Pritchard, Judith-Anne W. Chapman, Joseph A. Sparano, Sally Hunsberger, Rebecca A. Enos, Richard D. Gelber, Jo Anne Zujewski

	ACKNOWLEDGMENTS

 
We thank Charles Geyer, MD, FACP, and Boris Freidlin, PhD, for their critical review of the manuscript.

	NOTES

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

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS CONCLUSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
1. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349: 1793-1802, 2003[Abstract/Free Full Text]

2. Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359: 2131-2139, 2002[CrossRef][Medline]

3. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350: 1081-1092, 2004[Abstract/Free Full Text]

4. Thurlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353: 2747-2757, 2005[Abstract/Free Full Text]

5. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366: 455-462, 2005[CrossRef][Medline]

6. Green S, Benedetti J, Crowley J: Clinical Trials in Oncology (ed 2). Boca Raton, FL, Chapman and Hall, 2003, pp 44-45

7. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data (ed 2). Hoboken, New Jersey: John Wiley & Sons, 2002, pp 195-196

Submitted December 15, 2006; accepted February 20, 2007.

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