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Position statement on ethics, equipoise and research on charged particle radiation therapy
  1. Mark Sheehan1,
  2. Claire Timlin2,
  3. Ken Peach2,
  4. Ariella Binik3,
  5. Wilson Puthenparampil4,
  6. Mark Lodge5,
  7. Sean Kehoe6,
  8. Michael Brada7,
  9. Neil Burnet8,
  10. Steve Clarke9,
  11. Adrian Crellin10,
  12. Michael Dunn1,
  13. Piero Fossati11,
  14. Steve Harris2,
  15. Michael Hocken12,
  16. Tony Hope1,
  17. Jonathan Ives13,
  18. Tadashi Kamada14,
  19. Alex John London15,
  20. Robert Miller16,
  21. Michael Parker1,
  22. Madelon Pijls-Johannesma17,
  23. Julian Savulescu18,
  24. Susan Short19,
  25. Loane Skene20,
  26. Hirohiko Tsujii14,
  27. Jeffrey Tuan11,
  28. Charles Weijer3
  1. 1The Ethox Centre, University of Oxford, Oxford, UK
  2. 2Particle Therapy Cancer Research Institute, University of Oxford, Oxford, UK
  3. 3Rotman Institute of Philosophy, University of Western Ontario, London, Canada
  4. 4Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK
  5. 5International Network for Cancer Treatment and Research UK, Oxford, UK
  6. 6School of Cancer Sciences, University of Birmingham, Birmingham, UK
  7. 7Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, London
  8. 8Department of Oncology, University of Cambridge, Cambridge, UK
  9. 9Centre for Applied Philosophy and Public Ethics, Charles Sturt University, Canberra, Australia
  10. 10St James' Institute of Oncology, St James's University Hospital, Leeds, UK
  11. 11National Center for Oncological Hadron Therapy (CNAO), Pavia and Dipartimento di Scienze della Salute, University of Milano, Italy, Italy
  12. 12Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK
  13. 13Centre for Biomedical Ethics, University of Birmingham, Birmingham, UK
  14. 14Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan
  15. 15Center for Ethics and Policy, Department of Philosophy, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
  16. 16Department of Radiation Oncology and Proton Beam Therapy Program, Mayo Clinic, Rochester, USA
  17. 17Maastricht Radiation Oncology (MAASTRO) Clinic, Maastricht, The Netherlands
  18. 18Oxford Uehiro Centre for Practical Ethics, Faculty of Philosophy, University of Oxford, Oxford, UK
  19. 19Leeds Institute of Molecular Medicine, St James University Hospital, Leeds, UK
  20. 20Melbourne Law School, University of Melbourne, Australia
  1. Correspondence to Dr Mark Sheehan, The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Rosemary Rue Building Headington, Oxford OX3 7LG, UK; mark.sheehan{at}ethox.ox.ac.uk

Abstract

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

  • Clinical Trials
  • Position Statements (of organizations/groups)
  • Radiology
  • Research Ethics
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Introduction

Charged-particle radiation therapy (CPRT), a form of radiotherapy using protons or light ions (eg, carbon), is increasing rapidly, with the number of centres using such therapy doubling every eight years. Research is required to enable these centres to develop new procedures, providing for improved patient outcomes, and to realise the full potential of CPRT. There is debate about the research required before this technique can become the treatment of choice in many forms of cancer. Some express doubts as to whether the more targeted radiation dose distributions obtainable with CPRT are sufficient to alter clinical outcomes in many applications and so randomised trial comparisons with other forms of treatment are ethically justified. Others insist that these dose distributions are so advantageous that it would be unethical not to offer CPRT to patients if it is available.

The debate about the ethical acceptability of randomised trials comparing CPRT with other forms of treatment centres on the concept of equipoise: the broad idea that a trial between two treatments is ethically justified when there is uncertainty about the relative therapeutic merits of those treatments.1 ,2 Those who insist on trials claim that equipoise exists in this context.3–6 Those who think that it would be unethical not to offer CPRT to patients in the context of such trials hold that equipoise does not exist.7 ,8

The aim of the workshop was to reach a consensus about the ethical issues involved in research on CPRT through better understanding of the concept of equipoise, its relative weight for different outcomes and its role in guiding CPRT research (http://www.ptcri.ox.ac.uk/CPTREthics). As such, the workshop took as its starting point the claim that a properly articulated concept of equipoise has a central role in the ethical justification of research. The workshop included sessions examining (1) the concept of equipoise and its application to research on CPRT, (2) the nature and quality of the available evidence, including areas of uncertainty, (3) current clinical practice and potential developments and (4) the prospects for data-sharing and the role of patient and public involvement in these decisions.

This report represents a position statement, agreed by 30 of the 35 workshop participants, arrived at during the workshop and refined over the following months.

Ethical considerations

Society has an interest in ensuring that medical treatment decisions rest on high quality evidence. This claim is fundamental to the considerations below. Within the broader context of clinical research, equipoise is an ethical concept that reconciles broader social interests with the obligations of physicians and the rights of patients. Perhaps the most persuasive interpretation of equipoise, clinical equipoise, is an evidentiary standard that guides research ethics committees’ decisions about the permissibility of a trial. Clinical equipoise requires that at the start of a clinical study there be a state of reasonable, professional disagreement among members of the relevant expert community about the relative merits of treatments.9 ,10

Clinical equipoise is (1) consistent with a strong treatment preference on the part of individual clinicians and (2) not an impediment to the conduct of high quality clinical research on the safety, effectiveness and cost-effectiveness of CPRT. Clinical equipoise functions as a way of providing a social permission for the conduct of clinical research: society (through, eg, regulation, oversight and funding) is implicated in the research process.

The articulation of what ought to count as ‘reasonable disagreement’ and the process by which it is determined that such disagreement exists, present challenges. In the first instance, this meeting was an example of the kind of process that is taken to operationalise this issue and so provides an illustration of the requirements of reasonable disagreement. More generally, the purpose of such a process is to formulate recommendations in the face of reasonable disagreement. Depending on the generality of the research question, different levels of process may be required: international and national level processes ought to play a role in establishing general research programmes, whereas local research ethics committees should consider specific research questions. At each level, a legitimate process includes the following characteristics:

  • A comprehensive range of stakeholders

  • An appropriate range of disciplines

  • Proponents of the differing views on the question being asked

  • A thorough review of current practice

  • A thorough review of the available evidence, including the quality of that evidence

Moreover, participants in such processes need to accept that the decisions need to be made and that there is a range of reasonable positions that can be taken. Recommendations produced by the process should include justification for conclusions reached and should be made public.

Consistent with this requirement, decisions about priorities in research and the connection between research and clinical practice should be made with input from the public and take due account of patient experiences. Individual members of the public can provide an important, disinterested perspective on these issues and should be encouraged to do so. Decisions about which clinical needs should receive attention can often be helpfully guided by systematic accounts of patient concerns and experiences.

Finally, because of society's interest in medical treatment resting on high quality evidence, lack of evidence can be grounds for reasonable disagreement.

Even though clinical equipoise provides a sanction for clinical research it does not provide an overriding obligation for individual clinicians to enrol their patients. Clinical equipoise gives clinicians a reason to offer enrolment—namely that this trial is permitted by society—but it does not give an overriding reason. Clinicians’ decisions concerning the enrolment of particular patients in a trial should also be guided by clinical judgment.9

Clinical and scientific considerations

CPRT offers significant advantages over conventional radiotherapy using X-rays in terms of the distribution of radiation dose because it is possible to ‘paint’ the tumour with a clinically effective dose by varying the energy and position of the particle beam, while depositing a significantly smaller dose in the surrounding normal tissues. This means that CPRT can reduce the total radiation deposited within the body by a factor of up to 10, which can potentially reduce side effects and so enhance the quality of life in cured patients compared with those treated by X-rays. This is particularly important in paediatric cancers where there is greater susceptibility for radiation to produce side effects, and a significant risk of developing second cancers due to unnecessary irradiation of organs. There are also clinical contexts where an escalation of the dose to the tumour is possible with CPRT, but not with X-rays. This can lead to higher local tumour control/cure rates.

While reducing unnecessary dose to normal tissues is clearly advantageous, especially in the cases where it is possible to completely avoid irradiating some organs at risk with CPRT (which would be difficult with X-rays in many practical situations), dose distribution is only a surrogate end point for more pertinent clinical outcomes. In many clinical situations, the physical dose distributions undoubtedly suggest a potential benefit of CPRT over X-ray in terms of higher tumour control rates, lower normal tissue effects or both. However, it may be that this does not result in the overall anticipated clinical benefit because of:

  • Intrinsic uncertainties in delivering the physical dose due to uncertainties in particle range, daily positioning and changes in body shape during treatment.

  • Uncertainties concerning how physical dose translates to clinical effect.

Some important scientific questions remain to be answered within CPRT which affect the confidence with which the potential advantages can be proclaimed, and which therefore present ethical challenges. These include uncertainties in the relative biological effectivenessi which is known to vary along the path of a charged particle beam, dose uncertaintiesii, the pattern of the dose distribution, total dose and the dose per fractioniii, all of which can influence clinical outcomes. These need to be addressed through further basic and clinical research, efficiently and as soon as possible, especially to provide data on critical tissues/organs in several anatomical locations (eg, brain, lung, heart, kidney, etc). These goals can be achieved by further experimental studies in vivo, and in humans within formal phase II trials of CPRT, by randomisation of patients with respect to normal tissue dose constraints, dose fractionation and dose distribution pattern (eg, the desirability or not of dose homogeneity in target tissues, or the use of different beam delivery systems). A better understanding of these radiobiological effects is likely to lead through better optimised treatment planning to safer and more effective CPRT treatment, and to a better identification of the likely benefits of different management strategies using CPRT.

Published clinical series suggest some clinical benefit from CPRT in a number of conditions when compared with current conventional X-ray techniques.11 Despite the fact that the existing evidence is not at the highest level (2011 Oxford CEBM Levels of Evidence (Introductory Document), Oxford Centre for Evidence-Based Medicine: http://www.cebm.net/index.aspx?o=5653), the available clinical results have important implications in that they may influence the judgment of individual clinicians and could disturb clinical equipoise, while also possibly influencing patients’ views.

CPRT is rarely given in isolation from other treatments including surgery, systemic therapy and conventional radiotherapy. This implies integration of CPRT within major cancer centres able to offer a wide infrastructure of clinical services as well as the ability to conduct clinical and in some cases more basic research. Such integration would provide a platform for wider research that looks at the place of CPRT within the optimum treatment pathway.

Methodological and evidential considerations

A recent (July 2011) systematic review of the clinical effectiveness and cost effectiveness of proton and light ion beam therapies in cancer reports that although high local control rates with proton and ion beam therapies in ocular cancers and in head and neck cancers have been identified, the case for the wider adoption of either modality is not as strong as it might be.12–14 There has been very little new clinical evidence published in the last 5 years. Most of the extant data remains retrospective and largely based on earlier techniques used in clinical facilities located in physics laboratories, which cannot be compared easily with recent refinements in X-ray based radiotherapy. The available evidence is also based on rare, usually slow-growing, forms of cancer. The evidence of cost-effectiveness was even scarcer.

Overall, there is a decided need for research on CPRT. In designing the next generation of studies a number of factors need to be considered and are given below. While these issues are not unique to CPRT, the particular features of the interplay between physical dose distributions and therapeutic outcomes require specific ethical consideration in the design of clinical trials and the interpretation of clinical evidence.

Where (1) the dose distribution with CPRT is substantially improved and suggests substantial superiority to conventional or other X-ray treatments and (2) existing clinical results suggest significant superiority, a randomised controlled trial (RCT) would be neither necessary nor appropriate. In each case, the superiority must be sufficiently large to overcome the well-documented biases in non-randomised studies.15 However, where predicted differences are small, such as if the same target dose is used and where sparing of normal tissue is unlikely to confer a useful clinical benefit, a RCT may be clinically unrewarding and a poor use of resources. In rare tumour entities, low patient numbers may limit the practicalities of RCTs. The intermediate position would provide the appropriate set of opportunities for trials. As such, it would allow RCTs to play a role in fully defining the societal benefits of CPRT and in facilitating the use of CPRT for other tumour sites.

In some cases, there is a need for more definitive phase I/II studies in order to determine optimum dose (ie, considering effects on tumour and normal tissues) and to assess the expected range of benefits/harms. In other cases, there is compelling evidence from phase II trials and there is an important need for further research progression into definitive phase III studies in order to demonstrate unbiased and real therapeutic outcomes. Where the results of phase II studies are inconclusive, there are clear indications for definitive phase III trials (as eg, in early stage peripheral lung cancer). These goals can be achieved by further experimental studies within formal phase II trials of CPRT, by randomisation of patients with respect to normal tissue dose constraints, dose fractionation and dose distribution. The same considerations also apply to evaluation of more conventional X-ray treatment technologies.16

The following six steps should be undertaken in the development of research questions to address the above needs:

  1. Synthesis of existing evidence at all levels (from basic science to the clinic), systematic review, etc

  2. Identification of gaps in evidence, methodological challenges

  3. Social or clinical importance of bridging the gap in evidence and the existence of equipoise

  4. Formulation of research question, including input from patients

  5. Development of appropriate research design: (in phase III) CPRT should be compared against the most clinically and scientifically appropriate alternative intervention

  6. Formation of a clear picture of the efficacy and side-effect profile to be formulated before conducting cost effectiveness analysis of novel treatment modalities

These treatment modalities are complex interventions and this must be adequately reflected in the design and conduct of research studies. Such studies require:

  1. The anonymisation of patient data

  2. The registration of all studies

  3. The standardisation of trial protocols, and including quality assurance

  4. The standardisation of data collection

  5. Collection and inclusion of data on adverse events and more sophisticated quality of life measures that reflect patient experience

  6. Collection and inclusion of data on long-term follow-up, especially when care is fragmented across multiple care centres

It is crucially important that all clinical outcomes, including adverse outcomes and negative research results, are made available for clinicians and researchers. ‘Bad experiences’ and data about what does not seem to be effective should be included in the total data available. There is a need to share the experience that has been gained from the thousands of patients that have already been treated using CPRT, so registry of these data should be obligatory.

Progress in this area would be enhanced if the centres involved in the use of CPRT were to engage in the production and sharing of data, perhaps through the development of high-quality shared infrastructure, preferably in an international or global collaboration. To accomplish this, there should be a meeting of relevant stakeholders with the goal of identifying and establishing concrete agreements, structures and mechanisms necessary for clinicians and researchers to carry out the above objectives.

Key Recommendations

Ethical considerations

  1. Clinical equipoise requires that at the start of a clinical study there be a state of reasonable, professional disagreement among members of the relevant expert community about the relative merits of treatments.

  2. Clinical equipoise gives clinicians a reason to offer enrolment but it does not give an over-riding obligation.

  3. ‘Reasonable disagreement’ occurs when participants accept that the decisions need to be made and that there is a range of reasonable positions that can be taken. Paucity of evidence can be grounds for reasonable disagreement.

  4. There should be a fair and legitimate process by which it is determined that such disagreement exists. Recommendations that are produced by the process should include justification for conclusions reached and should be made public.

  5. Decisions about priorities in research and the connection between research and clinical practice should be made with input from the public and take due account of patient experiences.

Clinical and scientific considerations

  1. CPRT offers significant advantages in physical dose distributions.

  2. However, it may be that the better physical dose distribution does not result in the overall anticipated clinical benefit.

  3. The available clinical results have important implications that may influence the judgment of individual clinicians and could disturb clinical equipoise.

  4. There are important clinical and scientific uncertainties associated with how physical dose translates into clinical effect, for different tissues/organs.

Methodological and evidential considerations

  1. Overall, there is a decided need for more basic scientific and clinical research on CPRT.

  2. Where the dose distribution with CPRT is substantially improved and suggests substantial superiority to other treatments and existing clinical results suggest significant superiority, a RCT would be neither necessary nor appropriate.

  3. In some cases, there is a need for more definitive phase I/II studies. In other cases, where there is more compelling evidence from phase II trials, there is an important need for further research progression into definitive phase III studies in order to demonstrate therapeutic outcomes.

  4. These treatment modalities are complex interventions, which must be adequately reflected in the design and conduct of research studies.

Acknowledgments

MS is supported by the Oxford NIHR Biomedical Research Centre. CT and KP are supported by the Oxford Martin School. NB is supported by the Cambridge NIHR Biomedical Research Centre.

References

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Footnotes

  • Correction notice This paper has been corrected since it was published Online First. One of the authors' surnames was incorrect. ‘Neil Burnett’ should be ‘Neil Burnet’.

  • Contributors The drafting was led by MS, CT and KP. All authors were delegates at the workshop and were involved in the initial drafting of the document at the workshop. All authors were involved in subsequent editing decisions and all agreed to the final version of this document.

  • Funding Oxford Martin School, Wellcome Trust (WT097468MA), the Gray Institute for Radiation Oncology and Biology and the Oxford NIHR Biomedical Research Centre.

  • Competing interests ML has been compensated for a consultancy role on these issues with the European Investment Bank. PF has received honoraria from the Fondazione CNAO. SS has an uncompensated advisory role with The Cyclotron Trust.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • i Relative biological effectiveness is the ratio of dose of a reference radiation type (typically γ-rays from Cobalt-60 or X-rays of 250 keV energy) to dose of a test radiation (in this case charged-particle radiation), that produce equal effect.

  • ii Greater dose uncertainties may occur with CPRT than with X-rays, due to small variations in tissue density or patient positioning, which affect charged particle range, but which have very little effect on X-ray beams.

  • iii Using X-rays, the size of the dose per fraction can alter the biological effect differently in different tissues, including tumour and any normal tissue which is irradiated. The phenomenon is thought to occur with CPRT, but different tissues may differ in their response compared with X-rays. Effects may also be different for different charged particles (eg, protons versus carbon ions).

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