Elsevier

The Lancet

Volume 363, Issue 9405, 24 January 2004, Pages 263-270
The Lancet

Articles
Comparison of outcomes in cancer patients treated within and outside clinical trials: conceptual framework and structured review

https://doi.org/10.1016/S0140-6736(03)15383-4Get rights and content

Summary

Background

Many oncologists believe that patients with cancer who enrol in clinical trials have better outcomes than those who do not enrol. We aimed to assess the empirical evidence that such a trial effect exists.

Methods

We developed a conceptual framework for comparison of trial and non-trial patients. We then did a comprehensive literature search to identify studies that compared outcomes between these groups. We critically evaluated these studies to assess whether they provide valid and generalisable support for a trial effect.

Findings

We identified 26 comparisons, from 24 published articles, of outcomes among cancer patients enrolled and not enrolled in clinical trials. 21 comparisons used retrospective cohort designs. 14 comparisons provided some evidence that patients enrolled in trials have improved outcomes. However, strategies to control for potential confounding factors were inconsistent and frequently inadequate. Only eight comparisons restricted non-trial patients to those meeting trial eligibility criteria. Of these, three noted better outcomes in trial patients than in non-trial patients. Children with cancer, patients with haematological malignant disease, and patients treated before 1986 were disproportionately represented in positive studies.

Interpretation

Despite widespread belief that enrolment in clinical trials leads to improved outcomes in patients with cancer, there are insufficient data to conclude that such a trial effect exists. Until such data are available, patients with cancer should be encouraged to enrol in clinical trials on the basis of trials' unquestioned role in improving treatment for future patients.

Introduction

The belief that clinical trials offer the best treatment for patients with cancer is widespread in the oncology community. This claim, motivated partly by aims to increase accrual1, 2, 3 and ensure third-party payment,4, 5 appears frequently in pronouncements by professional organisations and leaders. For example, the American Federation of Clinical Oncologic Societies maintains that “treatment in a clinical trial is often a cancer patient's best option”.6 Other people argue that “clinical trials are proven to offer children the best chance of survival”,7 and that trial access is one of the “basic requirements of quality cancer care.”5 Such claims suggest that trials are viewed not only as a way to improve future treatment, but also as the best treatment for current patients.

The view that trials lead to better outcomes, if correct, has important implications. First, that more than 95% of adults and perhaps 40% of children with cancer do not enrol in trials would constitute evidence of substandard care. Second, the suggestion that patients benefit directly by becoming research participants changes the traditional model of human experimentation. If so, clinicians arguably should advocate forcefully for enrolment on grounds of direct benefit, rather than presenting the risks and benefits for patients to weigh. In the conventional view, such advocacy might be criticised as misleading or coercive. Third, acceptance of this view might require substantial changes in trial financing and organisation, eligibility criteria, and patient selection. Anything that might constitute a barrier to participation (including considerations of scientific validity and integrity8) would be suspect. We must therefore be confident that trial participation improves outcomes before using the claim to inform practice or policy.

Ideally, the statement that trials are the best treatment option should rest on evidence that trial participants have better outcomes than similar patients treated off-protocol. Several studies9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 have shown such a trial effect, also sometimes known as an inclusion benefit.23 However, showing a causal relation between trial participation and improved outcome is difficult.

Here, we seek to develop a conceptual framework for assessing the trial effect; describe the methodological challenges in studying this effect and the hierarchy of evidence that could be used to support its existence; and use these insights to assess systematically the quality, validity, and generalisability of the published work.

Section snippets

Methods

We sought to identify articles that presented primary data comparing outcomes between trial and non-trial patients with cancer. As others note,24 there is no obvious set of terms to capture all relevant reports. We therefore searched MEDLINE using the terms trial effect, inclusion benefit, population outcomes, community outcomes, trial benefit, patient preference trial, and comprehensive cohort trial, cross-referenced with cancer, oncology, neoplasms, and clinical trials. We also scanned an

Inclusion criteria

We identified 24 published articles that met our inclusion criteria.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 29, 30, 31, 32, 33, 34, 35 Of these, seven were included in previous reviews.24, 49 Two articles22, 29 reported two comparisons each, thus, there was a total of 26 comparisons. Table 1 summarises these studies, arranged by population, study design, and dates of the primary data reported in the reports. Additional detail is available from the authors.

Study characteristics

table 2 presents

Discussion

In our review of the published work, we found little high-quality evidence to support the pervasive belief that cancer trial participation leads to improved outcomes. Although about half the studies provided some evidence for a trial effect, and none found trial participation to be harmful, methodological difficulties with most studies suggest the need for cautious interpretation.

There are four possible reasons that trial participants might be found to have improved outcomes when compared with

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