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