1 What Is Evidence-Based Medicine?

It is difficult to begin to describe evidence-based medicine (EBM) without first mentioning Dr. David Sackett. A Chicago-born and bred internal medical physician who quickly switched his career path to clinical epidemiology, Dr. Sackett went on to make enormous contributions to clinical community. By placing importance on the understanding and measurement of patient adherence to prescribed treatments, the methodology of randomized control trials (RCTs), Dr. Sackett’s influence has led to the improvements in patient care across indications beyond his own specialty field [1]. Fundamentally, his work led to a mind-set shift in the way clinicians and academic authorities thought about the role of evidence in clinical care. In doing so, he laid the foundation for EBM, which is defined as the process of systematically reviewing, appraising, and using clinical research findings to aid the delivery of optimum clinical care to patients [1]. Dr. Sackett himself describes this practice as the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients [2]. Since its early definitions in clinical epidemiology, the concept of EBM has been recognized by hundreds of thousands of clinicians across the globe and across various medical disciplines [3]. In light of the importance of grading clinical evidence in everyday practice and care, this chapter highlights EBM in the context of endometrial cancer. This chapter describes how good gyne-oncologists use both clinical expertise and the best available external evidence to guide treatment choices for their patients with endometrial cancer.

2 Defining Level 1 Evidence

Evidence-based care requires critical review of published resources for evidence to help direct and guide care for the specific clinical question. These resources are commonly obtained from searches in databases such as PubMed, EBSCO, Cochrane Consumer Network (CCN) , field-specific association resources , government sites, and other electric resources. The clinician or practitioner must be able to systematically evaluate the evidence obtained for its relevance and validity as related to the specific clinical question.

There are a number of different hierarchies of evidence available which can be used to rank the strength and validity of the evidence from expert opinion to systematic reviews and meta-analyses (see Tables 8.1 and 8.2, Fig. 8.1). Efficacy is defined as the capacity or power to produce a clinical effect . This can be assessed based on meta-analyses and systematic reviews (Level 1 according to CCN). Evidence guidelines , randomized clinical trials , observational studies , cohort, case control, case series, and case reports address effectiveness—the quality or amount of the effect in practice, outside the laboratory or other controlled environment (Level 2 evidence). Evidence from expert committees, opinions, or clinical experience is considered the lowest grade of evidence due to the higher probability for bias (Level 3).

Table 8.1 Example of grading of evidence
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Table 8.2 Grades of evidence as per the Oxford Centre for Evidence-Based Medicine (OCEBM)
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Fig. 8.1
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Grades of evidence as per the Cochrane Consumer Network (CCN)

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The clinician or practitioner can incorporate the published evidence, the individual patient’s case and their own clinical expertise to develop an appropriate plan of care. Additionally, clinical guidelines or algorithms may be available to assist in care planning. These guidelines are generally developed by a multidisciplinary team with support from professional organizations, institutions, or governmental agencies that publish the guidelines (i.e. ESMO, ASCO, NIH/NCI, EMA etc.).

3 Why Are Randomized Clinical Trials Needed?

The National Cancer Institute classifies RCTs as a study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. RCTs have been ubiquitous in Phase III settings over the past half century [4]. RCTs serve as the basic clinical research tool for evaluating new interventions or existing methods previously not tested [4]. The methodology for the design, conduct and analysis of clinical trials has evolved greatly but the need has not changed. RCTs today still stand as the most effective way to discriminate the effects of treatments for a given patient population.

Given the variation in clinical trial design, not all RCTs can be defined as equal in terms of their objectivity. Chalmers et al. [5] were among the first to suggest the importance of evaluating the design, implementation, and analysis of RCT. The qualification of RCTs was suggested to be based on four factors: (1) basic descriptive material, (2) the study protocol, (3) the analysis of the data, and (4) data useful for potential combining of several RCT results [5]. By considering these factors in clinical evidence, a clinician is equipped with tools to determine whether new findings in an indication should be considered in the treatment plan of patient population. Table 8.3 offers an overview of intervention RCTs currently conducted in endometrial cancer, which are either complete, actively recruiting or not yet recruiting (search conducted on www.clinicaltrials.gov, accessed 9th October 2017). The outcomes of these studies will guide the future standard of care options for patients with endometrial cancer.

Table 8.3 Currently active or complete RCTs in endometrial cancer
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4 Primary End-Points in Clinical Trials Matter

There is no single ideal clinical trial end-point for all situations, but there are many new ways to define end-points beyond the classical terms. Given that most cases of endometrial cancer are diagnosed in women who are past menopause and aged in their mid-60s, the primary endpoints which are selected in new RCTs should be carefully matched to the needs of this patient population. In the European context, there has been recent scrutiny over the lack of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency (EMA) since 2009 by a retrospective cohort study [6]. This suggests that more than ever before must clinicians carefully design their trials to incorporate the most favorable outcomes for patients especially in intervention studies. Below is a list of classical primary end-points used as well as some new options that are becoming increasingly more popular in new clinical trial designs.

Overall Survival (OS)—high impact for patients but its relevance can be hampered in elderly patients due to death by other causes and does not include QoL.

Disease-specific survival (DSS) —perhaps a better measure but essentially it does not matter to the patient what the cause of death is.

Progression-Free Survival (PFS) —“the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse”.

Functional Decline (FD) —a new endpoint which considers if there are new loss of independence in self-care capabilities associated with deterioration in mobility and in the performance of activities of daily living such as dressing, toileting, and bathing. This end-point can be incorporated into elderly patient trials [7].

Overall Treatment Utility (OTU) —at set intervals: was the treatment worthwhile for the patient? Decided by the patient and the clinician.

Good OTU score: satisfied patient, clinician and low toxicity.

Classical endpoints are frequently not suitable for elderly patient populations. Thus, co-primary endpoints are recommended and statisticians often prefer a composite endpoint which can take into account multiple dimensions. A hallmark example of a composite endpoint (overall treatment utility) is illustrated by FOCUS2, a UK phase II randomized trial in which older and frail patients with inoperable colorectal cancer were randomized to receive treatment with infusional fluorouracil/levofolinic acid or capecitabine or either fluoropyrimiide schedule with the addition of oxaliplatin [8]. These drugs were administered at 80% of the standard doses. The composite endpoint included measures of response, toxicity, as well as clinician and patient perception of treatment efficacy. This trial is an exceptional example of how clinical trials can address the needs of the patient population at hand with well-designed and rational clinical end-points.

5 Clinical Trials in the New Era of Personalized Medicine

Several terms, including precision medicine , stratified medicine , targeted medicine , and pharmacogenomics , are sometimes used interchangeably to describe personalized medicine [9]. The European Union describes personalized medicine as “providing the right treatment to the right patient, at the right dose at the right time.” The National Cancer Institute extends upon this definition by stating that personalized medicine is “a form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease” [9]. In order to fulfill this health delivery ethos, future clinical trial designs must be able to accessibly integrate molecular analysis such as next-generation sequencing in order to profile patient prior to entry into intervention studies. Furthermore, a number of parallel translational research activities must be performed in order to tailor personalized medicine for future patient populations. Endometrial cancer is no exception to the diseases which can be approached with this transformative healthcare approach. Below are some key definitions of relevant clinical trial designs.

Comparative Trials : also known as controlled, clinical trials involve one group of patients who receive the new drug and a control group who receives a placebo or gold standard treatment. Comparative studies are typically conducted as double-blind trials, where neither the physician nor the patient knows which group is receiving the new drug. Double-blind trials help to eliminate any biased results [10].

Open Label Trials : do not attempt to disguise the new drug or treatment, meaning that no standard treatment or placebo is utilized. This leans towards bias, as both the patient and the physician are aware of which groups are receiving what type of treatment [10].

Basket Trials : test the effect of one drug on a single mutation in a variety of tumor types, at the same time. These studies also have the potential to greatly increase the number of patients who are eligible to receive certain drugs relative to other trial designs [11].

Umbrella Trials : have many different treatment arms within one trial and one indication. People are assigned to a particular treatment arm of the trial based on their type of cancer and the specific molecular makeup of their cancer [11].

The phases of clinical trials are described as I, II, and III below [11].

Phase I Clinical Trials : An experimental drug or treatment, which has proven to be safe for use in animals, is tested in a small group of people (15–30) for the first time. Data are collected on the dose, timing, and safety of the treatment. The purpose is to evaluate its safety and identify side effects.

Phase II Clinical Trial : An experimental drug or treatment is tested in a larger group (100 or less) to provide more detailed information about the safety of the treatment, in addition to evaluating how well it works for a broader range of people. Phase II trials usually take about 2 years to complete.

Phase III Clinical Trials : Before an experimental drug or treatment is approved by the FDA and made available to the public, Phase III trials are conducted on a large group of people (from 100 to several thousand). At least two (and often more than two treatment options, including standard of care) are compared to find out whether the new treatment is better, and possibly has fewer side effects, than the current standard treatment. Phase III clinical trials are usually randomized, meaning that patients receive either the investigational drug or treatment or another drug or treatment in a non-ordered way.

Phase IV Clinical Trial : After a drug is approved by the FDA and made available to the public, researchers track its safety, seeking more information about a drug or treatment’s risks, benefits, and optimal use. Several hundred to several thousand people participate in Phase IV trials.

Future clinical trial design for endometrial cancer patients must progress with the innovations achieved across other cancer forms such as the inclusion of a translational research aspects across all phases of trials, pre-stratification of patients via next-generation sequencing (NGS), and or immuno-profiling . Evidence-based medicine is an approach to clinical problem-solving which will continue to drive better treatment options for patients with endometrial cancer.